Synthesis of Thiacrown and
Azacrown Ethers Based on the
Spiroacetal Framework
By
Marica Nikac
A Thesis submitted in partial fulfillment
of the requirements for the degree
of Doctor of Philosophy.
University of Western Sydney
February 2005.
To my family
and friends
Acknowledgements
I would like to express my enormous gratitude to my supervisors Dr. Robyn
Crumbie, Prof. Margaret Brimble and Dr. Trevor Bailey for all their advice, support and
encouragement throughout this project. I would also like to thank Assoc. Prof. Paul
Woodgate and Dr. Vittorio “Cappy” Caprio for their suggestions.
I would also like to thank the members of the Brimble group particularly Rosliana
Halim, Michelle Lai, Christina Funnell, Jae Hyun Park and Kit Sophie Tsang for their
encouragement and especially their friendship. I would not have made it without them. I
would also like to thank Daniel Furkert and Adrian Blaser for their assistance and
friendship.
I would like to express my gratitude to Dr. Narsimha Reddy and Mike Walker for
their help with everything to do with NMR. I also wish to thank the technical staff at the
Universities of Auckland and Western Sydney particularly, Noel Renner, Chris
Myclecharane and Gloria Tree.
I would like to thank my family (especially my sister Milka) and friends for their
support, encouragement and love throughout all these years.
Finally I wish to thank all the students and staff at the Universities of Auckland
and Western Sydney.
Statement of Authentication
The work presented in this thesis is, to the best of my knowledge and
belief, original except as acknowledged in the text. I hereby declare that I have
not submitted this material, either in whole or in part, for a degree at this or any
other institution.
………………………………………….
Table of Contents
Page
Table of Contents
i
List of Tables
v
List of Figures
vi
Abbreviations
vii
Abstract
ix
Chapter 1: Crown Ethers
1.0
Discovery of Crown Ethers
1
1.1
Crown Ethers Containing Carbohydrate Scaffolds
4
1.1.1
Crown Ethers Containing Pyranose Units
6
1.1.2
Lactose Trehalose and Other Di- and Trisaccharides
10
1.1.3
Furanoside Derivatives
12
1.2
Crown Ethers Containing the Spiroacetal Framework
1.2.1
Starands
1.2.2
Incorporation of the 1,4,7,10-Tetraoxaspiro[5.5]undecane
13
13
Ring System
14
1.2.3
Polyspiroacetal Ligands
15
1.2.4
Incorporation of 1,7-Dioxaspiro[5.5]undecane
Ring System
15
Chapter 2: Synthetic Strategies for the Preparation of Crown Ethers
2.0
General Synthetic Principles for the Preparation of Crown Ethers
20
2.0.1
The Effect of the Chain Length
20
2.0.2
Nature of the Atoms
21
2.0.3
Type Of Cyclisation
21
2.0.4
Ring Closure Methods
22
2.1
Selectivity of Crown Ethers for Metal Ions
23
2.2
Nitrogen Macrocycles (Azacrown Ethers)
26
i
2.3
2.2.1
Templated Syntheses
27
2.2.2
The Sulfonamide Method
29
2.2.3
Azacrown Ethers via Amide Formation
31
2.2.4
Peptide Chemistry
34
2.2.5
Crab-like Cyclisation
34
Sulfur Macrocycles (Thiacrown Ethers)
2.3.1
Synthesis of Thiacrown Compounds Using Cs2CO3
38
2.3.2
The Cesium Effect
38
2.3.3
Templated Syntheses
39
Chapter 3: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
3.0
Synthetic Targets
42
3.1
Synthesis of Spiroacetal Diol (50)
43
3.1.1
Synthesis of (±)-1,7-Dioxaspiro[5.5]undec-4-ene
43
3.1.2
Epoxidation of Olefin (114)
45
3.1.3
Base-Induced Ring opening of Epoxide (115) and Epoxidation
3.1.4
3.2
46
Reduction of syn-Epoxy Alcohol (119)
48
Synthesis of the Spiroacetal Thiacrown Ethers via Path A
3.2.1
3.2.2
3.2.3
3.4
of Allylic Alcohol (117)
Synthesis of the β-Chloroethyl Sulfides (104), (127) and (128) 49
Reaction Between Spiroacetal Diol (50) and β-Chloroethyl
Sulfide (104)
51
Attempted Synthesis of Thiacrown Ether (134) via Olefin
52
Metathesis of Diene (132) with Spiroacetal Diene (133)
52
3.2.3.1
Synthesis of Spiroacetal Bisallyl Ether (133)
53
3.2.3.2
Olefin Metathesis
54
Synthesis of the Spiroacetal thiacrown Ethers via Path B
61
3.4.1
Synthesis of Spiroacetal Diol (145)
62
3.4.2
Ditosylation of Spiroacetal Diol (145)
64
3.4.3
Synthesis of Spiroacetal Thiacrown Ethers (55), (56)
and (57)
3.5
49
65
Synthesis of Spiroacetal Azacrown Ethers
3.5.1
68
Attempted Synthesis of Spiroacetal Azacrown Ethers (58), (59)
And (60) via Imine Formation from Aldehyde (150)
ii
69
3.5.2
3.6
The Sulfonamide Method
Summary
70
74
Chapter 4: Spiroacetal Thiacrown Ethers As Primary and Secondary
Ligands
4.0
4.1
Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
75
4.0.1
Crown Ethers As Primary Ligands
75
4.0.2
Second-Sphere Coordination
76
Binding Studies
78
4.1.1 Determination of Association Constants Using Picrate Salts
78
4.1.2
Interaction of Thiacrown Ethers (55), (56) and (57) with Neutral
and Ionic Complexes (Second-Sphere Coordination)
4.1.2.1
4.1.2.2
4.2
82
Interaction With [Co(NH3)NO2](BPh4)2 (165) and
[Co(en)3](BPh4)3 (166)
83
Interaction With [Al(acac)3] (164)
84
Summary
86
Chapter 5: Kinetic Resolution of the Spiroacetal Moiety
5.0
Kinetic Resolutions
87
5.1
Base-Induced Rearrangement Of Epoxides
88
5.1.1 Ring Opening of α-Epoxide (115) Using Chiral Non-Racemic
Lithium Amide Bases
5.2
Hydrolytic Kinetic Resolution
91
5.2.1
91
5.2.2
5.3
5.4
89
Jacobsen Hydrolytic Resolution Reaction
Hydrolytic Kinetic Resolution of α-Epoxide (115)
92
Sharpless Epoxidation
94
5.3.1
96
Sharpless Epoxidation of Allylic Alcohol (117)
Summary
98
iii
Chapter 6: Conclusion
Conclusion
100
Chapter 7: Experimental
7.0
General Details
105
(50)
106
bis(ethyl p-toluenesulfonate) (146)
Preparation of β-Chloroethyl Sulfides (104) and (127) and Dithiols
115
(122) and (123)
120
7.4
Synthesis of Spiroacetal Thiacrown Ethers (55), (56) and (57)
125
7.5
Synthesis of Spiroacetal Azacrown Ether (58)
128
7.6
Olefin Metathesis of Spiroacetal Bisallyl Ether (142)
132
7.7
Kinetic Resolution Reactions
134
7.8
Second-Sphere Complexation
142
7.1
Preparation of [3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diol
7.2 Synthesis of [3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl
7.3
Chapter 8: References
References
143
iv
List of Tables
Page
1
Table 1: Selected H Chemical Shifts and Coupling For Dimers (142a), (142b)
and (142c)
60
Table 2: Reaction Conditions Used in the Synthesis of Diester (149)
62
Table 3: Reaction Conditions Used in the Synthesis of Protected
Azacrown (159)
72
Table 4: Association Constants For Spiroacetal Thiacrown Ethers
(55), (56) and (57)
79
Lithium Amide Bases
90
Table 5: Base-Induced Rearrangement of α-Epoxide (115) Using Chiral
v
List of Figures
Page
Figure 1: Association Constants of the Axial Crown Ethers
16
Figure 2: Association Constants of the Equatorial Crown Ethers
17
Figure 3: Resolution of Spiroacetal Diol (50)
19
Figure 4: Common Approaches to Synthesising Macrocycles
20
Figure 5: Sandwich Effect
24
Figure 6: Common Structure of Complexed Azacrown Ethers
25
Figure 7: Effect of the Longer Carbon-Sulfur Bond on the Cavity
of Thiacrown Compounds
26
Figure 8: Cesium Effect
39
Figure 9: Hydrogen Bonding in the Epoxidation of Allylic Alcohol (117) using
meta -chloroperoxybenzoic acid
48
Figure 10: Proton Driven Transport of Metal Ions Through Membranes
76
Figure 11: Second-Sphere Coordination
77
Figure 12: Second-Sphere Coordination of Carboplatin
77
Figure 13: Association Constants of the Thiacrown Ethers (55), (56) and (57)
80
Figure 14: Expanded Region
80
Figure 15: Holodirected and Hemidirected Geometry of Pb(II)
82
Figure 16: Electrostatic Potential Map of [Al(acac)3]
85
Figure 17: Electrostatic Potential Map of Thiacrown (55)
85
Figure 18: Differentiation Between Two syn β-Protons in Cyclohexene Oxide
88
Figure 19: Mechanism of the Sharpless Epoxidation
95
Figure 20: Kinetic Resolution of Stereochemically Rigid Compounds
Using Sharpless Epoxidation
96
Figure 21: Determination of the Appropriate Tartrate in the Epoxidation of
Allylic Alocohol (117)
97
vi
Abbreviations
2D.
two dimensional
18-Crown-6
1,4,7,10,13,16-hexaoxacyclooctadecane
18-S-6
1,4.7,10,13,16-hexathiacyclooctadecane
9-S-3
1,4,7-trithiacyclononane
Ar.
Aryl
aq.
aqueous
ax.
axial
n-Bu, Bun.
n-butyl
t-Bu, But.
tert-butyl
CI.
chemical ionisation (mass spectroscopy)
cm3.
cubic centimetres
conc.
concentration
COSY.
correlation spectroscopy
D.
deuterium
deg.
degrees
DEPT.
distortionless enhancement by polarisation transfer
dil.
dilute
DMDO.
dimethyldioxirane
DMAP.
4-dimethylaminopyridine
DMF.
N,N-dimethylformamide
DMSO.
dimethylsulfoxide
ee.
enantiomeric excess
EI.
electron impact ionisation (mass spectroscopy)
eq.
equatorial
equiv.
equivalent
Et.
ethyl
h.
hour
HMQC.
Heteronuclear Multiple Quantum Correlation
HMBC.
Heteronuclear Multiple Bond Correlation
HSQC.
Heteronuclear Single Quantum Correlation
vii
IR.
infrared spectroscopy
J.
NMR coupling constant
Ka.
association constant
L.
ligand
m-CPBA.
meta-chloroperoxybenzoicacid
Me.
methyl
min.
minute
mmol.
millimoles
mol.
moles
mp.
melting point
NMR.
nuclear magnetic resonance
Ns.
nosyl, o-nitrobenzenesulfonyl
Oxone®
potassium peroxymonosulfate
I
Pr.
isopropyl
PPTS.
pyridinium p-toluenesulfonate
THF.
tetrahydrofuran
TMS.
trimethylsilyl
Ts.
tosyl, p-toluenesulfonyl
viii
Abstract
This thesis describes the synthesis of novel thiacrown and azacrown ethers based
on the 1,7-dioxaspiro[5.5]undecane ring system.
Chapter one presents an overview of the discovery and development of crown
ethers. The incorporation of naturally occurring compounds into the crown ether
framework such as carbohydrates and more recently the spiroacetal functionality is also
described.
Chapter two describes the synthetic strategies available for the synthesis of crown
ethers, azacrown ethers and thiacrown ethers. The ability of crown ethers to bind metal
ions is also discussed especially in terms of cavity size (and shape) and donor
heteroatom.
Chapter three describes the synthesis of the thiacrown ethers (55), (56) and (57)
and azacrown ether (58) incorporating the spiroacetal 3,5-diol (50). The synthesis of the
spiroacetal moiety was carried out starting from δ-valerolactone (110) and trimethylsilyl
protected alcohol (111) to form spiroacetal alkene (114). Subsequent treatment of alkene
(114) with DMDO yielded the β-epoxide (116) and desired α-epoxide (115). The base-
induced ring opening of α-epoxide (115) afforded allylic alcohol (117) and homoallylic
alcohol (118). Epoxidation of allylic alcohol (117) using m-CPBA, followed by reduction
of the desired syn-epoxy alcohol (119) afforded the 3,5-diol (50) and the 4,5-diol (121).
Three methods to synthesise spiroacetal thiacrown ethers (55), (56) and (57) are
then discussed, (a) the reaction between spiroacetal diol (50) and β-chloroethyl sulfide
(104), (b) the cross olefin metathesis reaction between diene (132) and spiroacetal
bisallyl ether (133) and (c) the reaction of the spiroacetal ditosylate (146) and the
appropriate dithiol (99), (122) or (123).
Chapter three also describes two synthetic routes for the analogous spiroacetal
azacrown ethers (58), (59) and (60). The first of these involved the reaction of spiroacetal
dialdehyde (150) and triamine (151) and the second involved the reaction of the
spiroacetal ditosylate (146) with Ts or Ns-protected triamines (157) and (158).
Chapter four describes the complexing ability of thiacrown ether compounds (55),
(56), (57) and (100) as primary receptors and as ligands in second-sphere coordination.
The binding affinity of thiacrown ethers (55), (56), (57) and (100) for alkali metal ions,
transition metal ions and heavy metals was determined using the ultraviolet spectroscopic
method. The spiroacetal thiacrown ethers (55), (56) and (57) showed a large preference
for the heavy metal ions, particularly silver. The large difference in the complexing
ix
behaviour of the thiacrown ethers (55), (56) and (57) indicates their selective extraction
ability.
The interaction between crown compounds (55), (56), (57), (64) and (100) with
neutral [Al(acac)3] (164) and ionic [Co(NH3)5NO2](BPh4)2 (165) and [Co(en)3](BPh4)3
(166) was investigated via 1H NMR spectroscopy. It was found that spiroacetal thiacrown
ethers (56) and (57) showed interaction with the aluminium complex (164).
Chapter five describes the attempted kinetic resolution of the spiroacetal moiety,
to provide enantiopure starting material for the synthesis of non-racemic spiroacetal
crown ethers. Three different approaches were investigated (a) base-induced
rearrangement of the spiroacetal α-epoxide (115) using chiral non-racemic bases, (b) the
hydrolytic kinetic resolution of the α-epoxide (115) using a cobalt-acetate complex (177)
and (c) Sharpless epoxidation of the allylic alcohol (117). The enantiomeric excesses
were determined by 1H NMR spectroscopic analysis of the Mosher’s ester of the
appropriate alcohol.
Chapter six summarises the results achieved and discusses possible strategies
emanating from these results.
x
INTRODUCTION : Crown Ethers
1.0
The Discovery of Crown Ethers
In 1987, Charles Pedersen, Donald Cram and Jean-Marie Lehn were awarded the
Nobel Prize in chemistry for their work with crown ethers and cryptands (bimacrocyclic
nitrogen derivatives of crown ethers). Their pioneering work led to the development of a
new area of chemistry known as macrocyclic or supramolecular chemistry.1,2
Macrocyclic chemistry deals with the interactions between the atoms of the macrocycle
and various metal ions.2 Since the discovery of crown ethers by Charles J. Pedersen in
1967,3 numerous macrocycles have been synthesised and their ability to complex ions
has been investigated.
A few examples of macrocycles were already known in literature before
Pedersen’s synthesis, however he is credited with their discovery because he was the first
to recognise the complexation ability of these compounds and describe the specific
characteristics of the complexation. Some of the early work carried out in macrocyclic
chemistry was by Lüttringhaus4 who was interested in preparing large ring molecules.
His idea was to prepare structures that would possess unusual properties. Using
resorcinol (1,3-dihydroxybenzene) as a nucleophile, he carried out reactions with a
variety of substituted diol derivatives, resulting in the isolation of several macrocyclic
polyethers of general structure (1). Unfortunately for Lüttringhaus, the compounds did
not possess sufficient donor groups to exhibit cation binding abilities.
O
O
O
O
1
The condensation of furan (2) and acetone (3) in the presence of a protic or Lewis
acid catalyst lead to the furan-acetone tetramer (4) (Scheme 1). Brown et al5 named these
initial compounds anhydrotetramers because the analytical data corresponded to the furan
and ketone starting materials with the loss of four water molecules.
1
INTRODUCTION : Crown Ethers
O
O
+
2
O
O
O
O
Lewis Acid
3
4
Scheme 1
In 1957, Stewart, Wadden and Borrows6 patented a process for the cyclooligomerisation of ethylene oxide. They treated an oxirane with alkyl aluminium, zinc
and magnesium to produce dioxane and a variety of other cyclic compounds, one of
which was the cyclic tetramer of ethylene oxide (5). In the same year Wilkinson et al7
reported the synthesis of a cyclic tetramer from propylene oxide. The workers recognised
the interesting properties of the cyclic compounds but did not appreciate their potential.
O
O
O
O
5
Then in 1967 Pedersen synthesised dibenzo-18-crown-6 as a by-product in the
preparation of biphenol (8).3 Mono-protected catechol (6) was reacted with 2,2’dichlorodiethyl ether (7) using sodium hydroxide in n-butanol to give the phenolic
derivative (8) after deprotection. A small amount of unprotected catechol was also
present in the initial reaction mixture and it was this unprotected compound that gave rise
to the crown ether (9) (Scheme 2). Pedersen was the first to recognise the complexing
ability of this type of compound. He found that dibenzo-18-crown-6 (9) had an increased
solubility in methanol in the presence of sodium hydroxide. This was attributed to the
complexation between the crown ether and the sodium ion. Pedersen also showed that
several other species could be coordinated to the electron rich compounds and that sulfur
and nitrogen could be substituted in place of oxygen. Cram et al8 elaborated further on
these discoveries and introduced the term host-guest complexation to describe the
relationship between the crown ether (host) and the metal ion (guest).
2
INTRODUCTION : Crown Ethers
OR
O
O
O
OH
OH
R = THP, H
HO
6
8
i
+
O
O
Cl
O
O
O
O
Cl
7
O
9
Reagents and Conditions: (i) NaOH, n-BuOH, reflux
Scheme 2
In the ensuing years, since the synthesis of dibenzo-18-crown-6, a large number
of macrocycles have been synthesised and their impact on the understanding of hostguest interactions and separation science has been significant.9 This has also allowed for
a greater understanding of the properties and behaviour of biologically important crown
ethers and ionophores. Nonactin (10), a macrotetralide antibiotic, is a naturally occurring
ionophore whose cation binding and transport abilities are now better understood in
terms of the principles discovered through crown ether research.
O
O
O
O
O
O
O
O
O
O
O
O
10
The introduction of biological systems into the crown ether structure has provided
scientists with an even greater insight into biological ionophores, such as cyclic
peptides10 and macrolide antibiotics.11 Alternatively, macrocycles have been synthesised
on the basis of their resemblance to biological systems. This has provided molecules
3
INTRODUCTION : Crown Ethers
potentially capable of mimicking various aspects of macromolecular biological
systems.12
Macrocycles that incorporate rings identical or closely related to various ring
systems found in nature are known as classical macrocycles.13 The carbohydrate structure
is commonly incorporated into the crown ether framework because they introduce
chirality to a macrocycle and have multiple interaction sites making them attractive as
chiral receptors.14 The spiroacetal ring system has also been investigated more recently.
The description of the structure of monensin (11) in 196715 and the discovery of its cation
binding properties instigated extensive interest in spiroacetal ionophores. Monensin is an
acyclic ionophore, which has been used in the synthesis of its cyclised lactone
derivative.16
HO
O
O
O
H
H
O
H
O
H
H
O
O
HO
HO
HO
11
1.1
Crown Ethers Containing Carbohydrate Scaffolds
Interest in crown ethers containing the carbohydrate moiety was initiated with the
isolation of cyclic oligosaccharides, which are more commonly known as cyclodextrins.
Cyclodextrins are produced by the action of Bacillus macerans amylase on starch.17 The
most studied representitives of this class of compounds are the α-, β- and γ-cyclodextrins
and are composed of six (12), seven and eight α-1,4-linked D-glucopyranose units,
resectively. The α-D-glucopyranose units exist as 4C1 chair conformations and are joined
to each other by glycosidic linkages involving axial C-1-O and equatorial C-4-O bonds.
Ogawa and Takahashi18 reported the first total synthesis of two cyclic oligosaccharides.
Starting from maltose they synthesised both (12) and the 8-membered compound in 21
steps. These syntheses represented pioneering investigations and have led to the synthesis
4
INTRODUCTION : Crown Ethers
of many cyclodextrins including the bicyclic 3,6-anhydro analogues of type (13) that
exist as the 1C4 chair conformations.19
OH
HO
O
O
4
O
O
HO
HO
OH
HO
HO
O
O
OH
HO
OH
O
OH
O
O O
HO
OH
OH
O
HO
O
O
O
O
O
O O
O
OH
HO
O
OH
HO
O
1
4
1
O
HO
O
OH
O
OH
O
O
OH
O
HO
12
O
O
O
13
The carbohydrate structure can provide relatively inexpensive chiral starting
materials for the synthesis of optically active macrocycles.20 This is important in terms of
chiral recognition, as it is a fundamental property of biological molecules. Chiral
recognition deals with the ability of a macrocycle to complex only one of the two
enantiomers in a racemic mixture. Chiral barriers are required in the molecule for chiral
discrimination to occur. Chiral crown ether compounds have been used as catalysts in
enantioselective syntheses,21 chromatographic separations,22,23 1H NMR spectroscopy24
and differentiating between protonated enantiomers of amines, amino acids, amino
alcohols and other derivatives.25
Cram and co-workers26 pioneered this area of research by incorporating 1,1’binaphthyl chiral units into crown ether structure (14). Stoddart et al27 expanded on this
work by synthesising a number of compounds derived from D-mannitol (15). Both sets of
compounds showed a good degree of enantiomeric differentiation of amine salts based on
1
H NMR spectroscopic data. Stoddart and co-workers28 were also interested in
macrocycles having two different chiral centres. They synthesised 18-crown-6 possessing
both the binaphthyl and D-mannitol derived units. These compounds also showed their
capability of acting as chiral hosts.
5
INTRODUCTION : Crown Ethers
O
O
O
O
O
O
14
O
Me
H
Me
O
O
Me
H
Me
O
O
O
O
O
O
H
O
O
H
O
O
O
Me
Me
Me
Me
15
1.1.1 Crown Ethers Containing Glucose, Mannose, Galactose and Other
Pyranose Units
The majority of compounds synthesised, which possess the carbohydrate
structure, are composed of D-hexopyranoside units. The most commonly used Dhexopyranosides are D-glucoside, D-mannoside and D-galactoside. Stoddart et al20a,29
synthesised a series of 18-crown-6 α- and β- analogues containing the glycosides. They
also investigated α-D-altroside. They found that α-D-mannoside (16) and D-galactoside
(17) compounds showed a greater binding ability to the ammonium thiocyanate salt than
the α-D-glucoside crown ether (18). They also found that the α-D-altroside compound
(19) formed very weak complexes. This was due to the introduction of one anti C–C
bond into the 18-crown-6 structure which removed the opportunity for all six oxygens to
act co-operatively in the binding. This work has been reviewed by Stoddart.20a
OMe
H
H
O
O
O
H
OH
O
OMe
H
O
H
O
O
O
OH
O
O
Ph
H
O
O
O
O
O
O
Ph
16
17
6
INTRODUCTION : Crown Ethers
OMe
H
H
O
OMe
H
O
O
O
H
OH
O
H
O
O
OH
O
O
Ph
O
H
O
O
O
O
O
O
Ph
18
19
Joly and co-workers23b built upon the work by Stoddart20a and synthesised a
number of carbohydrate crown ethers based on the 18-crown-6 structure (20-22). They
evaluated the extraction ability of these compounds toward racemic phenylglycine and
found that no enantiomeric differentiation was exhibited. The naphthalene analogue of
(22a), synthesised by Pietraszkiewicz et al,30 showed a marked increase in
enantioselectivity. This observation suggested that the increased aromatic content
favoured chiral recognition. The α-D-mannoside derivative31 (23) also showed good
enantioselectivity. It was suggested that the α-D-mannoside moiety contributed to the
enantioselectivity by providing extra binding strength through the hydrogen bonding of
the hydroxyl groups. Part of this work has been reviewed by Bradshaw et al.20b
Ph
OMe
O
O
O
OMe
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
20
OMe
OR
OR'
21
OMe
O
O
O
O
O
O
O
OH
OH
O
O
O
O
O
O
23
22
(a) R = R' = OH
(b) R = OH, R' = OMe
(c) R = OH, R' = O(n-C12H25)
(d) R = OH, R' = O(CH2CH2O) 3Me
7
O
O
OMe
Ph
Ph
O
O
INTRODUCTION : Crown Ethers
Tõke and co-workers32 synthesised a number of glucose derived 18-crown-6
compounds having the structure of (24) to act as catalysts in asymmetric Michael
addition. The reaction of methyl phenylacetate (25) and methyl acrylate (26) in the
presence of (24) as a complex with potassium tert-butoxide lead to the formation of the
new C–C bond in compound (27) (Scheme 3). The enantiomeric excesses were
determined by 1H NMR spectroscopy and found to be relatively high for some of the
reactions (76 – 85%).
O
OMe
O
O
O
O
O
OR OR'
O
+
OR' OR
O
O
O
O
O
O
OMe
24
O
O
*
25
26
O
* R or S
27
Scheme 3
Wenzel et al24c were interested in synthesis of crown ether (28) containing a β-Dgalactoside moiety. The crown ether was investigated as a chiral shift reagent in 1H NMR
spectroscopy. With the addition of an achiral lanthanide species crown ether (28) proved
to be effective in determining the ee of an L- enriched DL-alanine salt.
Ph
O O
O
O
O
O
O
O
O
28
8
OMe
INTRODUCTION : Crown Ethers
Much of the research into carbohydrate-based crown ethers discussed thus far has
dealt with the incorporation of the carbohydrate moiety through the 2,3-hydroxyl
positions onto an 18-crown-6 framework. In 1994, Mani and co-workers33 synthesised
novel chiral macrocycles, which incorporated the glycoside unit bound to the 1,4hydroxyl groups. Miethchen et al34 synthesised similar compounds via a slightly different
synthetic pathway. The macrocycles (29) and (30) were based on the D-glucose unit.
Mani et al33a reported the binding ability of the crown hosts for lithium, sodium,
potassium, cesium and the ammonium ion. They found that the results were comparable
to those published in the literature for monosaccharide crown ethers.
OBn
OR
O
O
RO
OR
O
O
O
O
BnO
O
OBn
O
O
O
O
O
O
29
O
OBn
BnO
O
O
OBn
30
Incorporation of macromolecular polyether derivatives into lipids has been shown
to result in cation transport rates comparable to those ion channels formed by natural and
synthetic oligopeptides or antifungal macrolides.35 Martin et al35 were interested in
synthesising a polyether based ion channel incorporating a D-glucose unit (31) and
investigating whether it could mimic the essential functional features of natural transport
processes. They postulated that the inner macroring would embed in the membrane and
the two carbohydrate units would be near the bilayer surfaces.
They found that
compounds with a length greater than 26 Å were active in the lipid bilayer.
OBn
BnO
OBn
BnO
BnO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
31
9
O
O
O
O
O
O
O
O
OBn
INTRODUCTION : Crown Ethers
Calixarene chemistry has been well documented and has had applications in
analytical and separation chemistry,36 however limited literature exists relating to chiral
calixcrowns. Recently, Bitter and co-workers37 described the synthesis and binding
ability of novel chromogenic monosaccharide-appended calixcrowns. Compound (32)
was synthesised as part of their investigations into the development of optical sensors.
The authors established that (32) exhibited noticeable optical recognition towards (R)and (S)-α-methylbenzylamine enantiomers.
HO
O
HO
OH
OMe
O
O
O
O
O
O
HO
R1
R1
32
1.1.2 Lactose, Trehalose and Other Di- and Trisaccharides
Penadés and co-workers21c,d,38 introduced both lactose and trehalose units into the
crown ether framework. They synthesised a number of macrocycles with different cavity
shapes and sizes from the disaccharides. The idea behind the disaccharides was to
increase the rigidity of the macrocycles and thereby the stability of the complexes formed
in order to achieve chiral recognition. The lactose derivatives including (33) and (34)
were evaluated for their binding ability and used as catalysts in asymmetric Michael
addition. The results were comparable to those of the monosaccharides. Investigation of
the trehalose derivatives, for example (35), was based on molecular energy calculations.
10
INTRODUCTION : Crown Ethers
OR
OR
O
O
O
O
O
OR'
O
O
O
O
O
OR
O
O
O
O
O
O
O
O
O
OR
OR
O
OR'
OR
33
34
R'O
OR'
R'O
O
O
OR'
O
O
O
OR
OR
O
O
O
O
O
O
OR
O
OR
O
O
R'O
O
O
OR'
R'O
OR'
35
Joly et al39 synthesised a series of 18-crown-6 crown ethers possessing di- and
trisaccharide units to investigate whether these crown compounds would be recognised
by lectins (a carbohydrate-binding protein). The authors tested the compounds including
(36) and (37) against the galactose-specific lectin Kluyveromyces bulgaricus.
OR
OR
R'
R'
RO
O
O
O
RO
O
RO
OR
O
OMe
O
OR
RO
O
RO
O
O
OR
O
Me
O
O
OR
36
O
O
O
37
O
O
O
O
11
O
INTRODUCTION : Crown Ethers
1.1.3 Furanoside Derivatives
Unlike the pyranoside analogues, there are only limited examples of crown ethers
containing the furanoside units. Some of the early work carried out in relation to crown
ethers containing a five-membered carbohydrate was by Gross and co-workers.40 They
synthesised a number of 18-crown-6 macrocycles incorporating various carbohydrate
structures, one of which was glucofuranoside. Compound (38) was then investigated for
its complexing behaviour towards primary alkylammonium and α-amino acid ester salts.
It was found that (38) was not very successful as a complexing or discriminating agent.
O
O
O
OMe
O
O
O
O
O
O
38
Miethchen et al41 also utilised the glucofuranoside, as well as the
galactofuranoside moieties in their syntheses of 12-crown-4 derivatives. They were able
to synthesise
(39) from glucofuranosyl fluoride as part of their investigations into
organofluorine compounds and fluorinating agents.
MeO
O
O
O
O
O
O
MeO
OMe
OMe
MeO
OMe
39
In recent years, Sharma and co-workers42 have investigated D-xylose as a chiral
source in the 18-crown-6 structure. Their interest primarily lay in the synthesis of four
isomeric macrocycles. Using a substitution reaction they synthesised all four compounds
including (40) and (41) in 40 – 60% yields.
12
INTRODUCTION : Crown Ethers
O
O
OMe
MeO
O
O
O
O
O
O
MeO
OMe
O
40
1.2
O
O
O
MeO
O
O
O
O
OMe
MeO
OMe
41
Crown Ethers Containing the Spiroacetal Framework
The increasing pharmacological importance of compounds containing the
spiroacetal structure/s has increased interest in both their synthesis and reactivity.43 The
spiroacetal ring system enjoys widespread occurrence in insects, plants, microbes, fungi
and marine organisms. The vast majority of chemistry in this area is focused on the three
common
spiroacetal
structures:
1,7-dioxaspiro[5.5]undecane
(42),
1,6-
dioxaspiro[5.4]decane (43) and 1,6-dioxaspiro[4.4]nonane (44). The conformation of the
spiroacetal ring system is influenced by three factors: steric effects, anomeric effects44
and intramolecular hydrogen bonding or other chelation effects. The anomeric effect
deals with the preference of C-O bond of the rings to be in an axial orientation with
respect to each other.
8
9
7
O
4
5
6
10
11
42
7
3
O
1
2
6
6
4
O
3
7
9
10
3
5
5
8
4
O
O
43
1
2
8
9
O
2
1
44
Much of the early research into ionophores containing the spiroacetal moiety has
dealt with naturally occurring compounds. In recent years however, the spiroacetal
system has been incorporated into crown ethers not biologically derived.
1.2.1 Starands
In 1993, Lee and co-workers45 synthesised a macrocycle containing a
polyspiroacetal framework. At the time they were investigating a new branch of
13
INTRODUCTION : Crown Ethers
orthocyclophane chemistry. The initial idea was to synthesise a polyoxa compound (45)
via a series of oxidations. However, the isolated product proved to be the polyacetal
compound (46) and not the desired polyoxa compound. Since the oxidation was carried
out under acidic conditions it was proposed that an acid catalysed cyclisation occurred
after the final oxidation (Scheme 3). They synthesised a series of compounds, which they
named starands because of their star-shaped structure.
O O
O
H
O
O
O O
O O
HO
O
O O
O
O O
HO
O O
O
O
O
O
45
O
46
Scheme 4
1.2.2 Incorporation of the 1,4,7,10-Tetraoxaspiro[5.5]undecane Ring System
Garcia and co-workers46 synthesised a number of enantiopure spiroacetal crown
ethers of the type (47). They were also able to obtain a small amount of the dimeric
products (48) as a result of the 2+2 condensation. They investigated the binding ability of
the crown ether compounds (47) towards group IA and IIA cations. In the smaller ring
systems (n = 1, 2) they found that the distortions of the spiran functionality adversely
affected the spatial distribution of the donor oxygen atoms and thus the binding ability of
the macrocycle.
O
O
n
O
n
O
X
O
O
XO
OO
OO
OX
O
O
O
n = 1, 2, 3
O
O
X = O, NR
O
n
47
n = 1, 2
X = O, NR
48
14
INTRODUCTION : Crown Ethers
1.2.3 Polyspiroacetal Ligands
McGarvey et al47 synthesised a number of polyspiroacetal ligands, including (49),
that offer a 1,3,5-triaxial orientation of the ring system in their search for nonmacrocyclic
alternatives to the crown ethers. That axial orientation of the donor groups creates the
coordination cavity. They found that the compounds with the hydroxy or methoxy
substituents were poor ligands. However, when the substituent was benzylamine the
binding was considerably greater.
O
O M O
X
O
M
O
X
O
X = OH, OMe, NHBn
49
1.2.4 Incorporation of the 1,7-Dioxaspiro[5.5]undecane Ring System
Brimble et al48 were the first to deliberately incorporate the 1,7dioxaspiro[5.5]undecane spiroacetal ring system into the crown ether structure. They
synthesised a number of spiroacetal crown ethers starting from spiroacetal (50) and
evaluated their potential to act as pH dependent ionophores. The initial spiroacetal
structure has the hydroxyl groups at C-3 and C-5 in an axial orientation. Upon treatment
with acid the structure can undergo a ring opening followed by reclosure to form the
diequatorial isomer (51) with the two hydroxyl substituents adopting the more
thermodynamically stable equatorial position (Scheme 5).
O
O
H
O
5
3
OH
O
HO
5
OH
3
51
OH
50
Scheme 5
The diaxial (53a-c) and diequatorial (54a-c) crown ethers were synthesised by
reacting the dianion of spiroacetal diol (50) or (51) with ethylene glycol ditosylate (52)
(Schemes 6 and 7). The crown ethers were formed in moderate yields. The association
15
INTRODUCTION : Crown Ethers
constants of the crown ethers were evaluated for cesium, lithium, sodium, potassium and
the ammonium ion. The results of the binding studies are represented in Figures 1 and 2.
O
O
O
O
+
OTs
OH
OH
50
i, ii
n
O
OTs
n = 1, 2, 3
O
O
52
O
O
O
n
53a, n = 1 (16-Crown-5)
53b, n = 2 (19-Crown-6)
53c, n = 3 (22-Crown-7)
Reagents and Conditions: (i) KH, THF, reflux, 30 min; (ii) 52 in
THF over 3 h, reflux 24 h; 53a (48%), 53b (42%), 53c (32%)
Scheme 6
Associations Constants (Axial Crown Ethers)
25000
Ka x 10 3
20000
15000
10000
5000
0
Li
Na
K
NH4
Cs
Picrate Salts
16-Crown-5 (53a)
19-Crown-6 (53b)
22-Crown-7 (53c)
Figure 1: Association Constants of the Spiroacetal Axial Crown Ethers
16
INTRODUCTION : Crown Ethers
O
O
O
HO
O
OH
+
i, ii
n
OTs
O
O
OTs
O
n = 1, 2, 3
51
52
O
O
O
n
54a, n = 1 (16-Crown-5)
54b, n = 2 (19-Crown-6)
54c, n = 3 (22-Crown-7)
Reagents and Conditions: (i) KH, THF, reflux, 30 min; (ii) 52 in
THF over 3 h, reflux 24 h; 54a (34%), 54b (28%), 54c (42%)
Scheme 7
Association Constants (Equatorial Crown Ethers)
100
90
80
Ka x 103
70
60
50
40
30
20
10
0
Li
Na
K
NH4
Cs
Picrate Salts
16-Crown-5 (54a)
19-Crown-6 (54b)
22-Crown-7 (54c)
Figure 2: Association Constants of the Spiroacetal Equatorial Crown Ethers
The results showed that the diaxial crown ethers had a much greater binding
ability than the diequatorial crown ethers. For example, in the case of potassium the
binding of the axial crown ethers was on average 300 times greater than that of the
diequatorial analogues. This was explained by the fact that the two oxygen atoms at C-3
and C-5 in the equatorial crown ethers were further away for binding to take place
(Scheme 8). Therefore, it was theoretically possible for the diaxial crown ethers to
complex metals, which would then be released upon exposure to acid when the diaxial
crown ethers underwent ring opening and reclosure to the equatorial crown ethers. These
17
INTRODUCTION : Crown Ethers
results were also compared to 18-crown-6. The axial spiroacetal crown ethers proved to
have a stronger complexing ability than 18-crown-6 itself, in some cases.
O
O
H
O
O
O
M
+
O
O
O
O
O
M
O
O
O
n
O
n = 1, 2, 3
n
n = 1, 2, 3
Scheme 8
This unique ability of spiroacetal crown ethers to selectively bind metal ions is
desirable in terms of separation science as they offer the potential to act as pH dependent
ionophores. It was proposed that the spiroacetal thiacrown and azacrown ethers would
behave in a similar fashion but would have affinities for different metal ions, such as the
transition and heavy metals. This would provide compounds with interesting possibilities
for environmental and medicinal chemistry. The aim of the present work was to
synthesise the sulfur (55, 56, 57) and nitrogen (58, 59, 60) analogues and evaluate their
binding ability. A review of the synthetic methods available to construct azacrown and
thiacrown compounds is given in the sections 2.0, 2.2 and 2.3. A further course for
investigation was directed towards the synthesis of enantiopure spiroacetal crown ethers
via the kinetic resolution of the spiroacetal functionality (Figure 3) because of the
increased interest in enantiopure crown compounds.
O
O
O
O
O
O
O
S
S
O
O
O
S
O
S
S
S
O
S
S
S
55
S
56
18
S
S
57
INTRODUCTION : Crown Ethers
O
O
O
O
NH
O
O
O
H
N
O
HN
NH
NH
O
O
O
NH
HN
NH
HN
58
HN
N
H 60
59
O
O
O
OH
O
O
OH
OH
Figure 3
19
OH
NH
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
2.0
General Synthetic Principles for the Preparation of Crown Ethers
The synthesis of macrocyclic systems can be achieved starting from a chain or a
linear group of segments in which the final step is the joining of the two ends of the chain
to form the desired macrocycle.49 This chain can be the result of an in situ assembly of
bifunctional units or it can be directly from the starting material. There are three common
approaches for synthesising macrocycles: (a) simple cyclisation, (b) cyclisation in
conjunction with another molecule, known as capping and (c) condensation of two or
four identical or non-identical units (Figure 4).
(a)
(b)
(c) 1 + 1
(c) 2 + 2
Figure 4
In the synthesis of crown ethers, the desired cyclisation reaction must compete
with the polycondensation reaction.49 Cyclisation involves the terminal chain ends
reacting with each other in an intramolecular fashion while polycondensation involves
the terminal ends reacting with another molecule, i.e. an intermolecular reaction.
Cyclisation is influenced by four main factors: (1) chain length, (2) nature of the atoms,
(3) type of cyclisation and (4) ring closure methods.
2.0.1 The Effect of Chain Length
The ease of ring formation is dependent on the chain length.50 In the cyclisation
process, the interaction of the atoms and the ensuing entropy change leads to different
degrees of ring strain and this particularly affects the yield.49 Ring strain can be
expressed in terms of heat of combustion, with a maximum for small rings (n = 3, 4) and
as a result of angular strain with a minimum for six membered rings. The ring strain
increases for medium sized rings and then decreases for the larger rings (n > 14),
becoming almost zero.
20
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
The concept effective molarity (EM)51 is another influence relating to the chain
length. Effective molarity is the concentration needed in order for the intramolecular
reaction to take place at the same rate as the intermolecular reaction.49 At this
concentration, equal amounts of both the cyclic and open chain product are formed;
therefore a dilute solution will give predominantly the desired macrocycle while a
concentrated solution will give predominantly polymers. The greater the effective
molarity, as seen with four, five and six membered rings, the more prevalent the
cyclisation reaction.50
2.0.2 Nature of the Atoms
The presence of oxygen, nitrogen or sulfur in a chain favours the formation of
rings.52 Replacement of a methylene group with the less bulky heteroatoms leads to a
decrease in transannular interactions.49 This is especially true in the synthesis of smaller
and medium ring systems. In larger rings, however, the effect of the heteroatoms is not as
pronounced since even in their absence the transannular interactions are weak or nonexistent.53
The effect of incorporating rigid groups (aromatic, double and triple bonds) into
chains increases the probability of cyclisation.54 As the chain length and internal entropy
increase, the probability of an intramolecular reaction between the two ends decreases.
This is due to the greater flexibility of the chains and the increased number of possible
conformations. Because rigidity in a molecule decreases the flexibility and therefore the
number of conformations, the probability of an intramolecular reaction are increased.
2.0.3 Type of Cyclisation
As mentioned previously, there are three common approaches to synthesising
macrocycles. However, the desired cyclisation type (one component, two component,
etc) is influenced by various factors.49 For example, in the synthesis of dibenzo-18crown-6 (9), catechol (6) and dichlorodiethyl ether (7) can react in a one, two or three
component fashion to form the monomer (61), the dimer (62) or the trimer (63)
respectively.1 By varying the reaction conditions, such as the type of nucleophile, base,
leaving groups, solvent and concentration, the synthesis of different sized macrocycles
may be targeted.
21
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
O
O
O
O
O
O
O
O
O
O
61
O
O
O
O
62
O
O
O
O
63
The type of base (weak or strong) used in a reaction will depend on the particular
nucleophile being generated. Oxygen nucleophiles can be generated as alkoxide or
phenoxide ions.1 The phenoxide ion is much easier to generate so weaker bases such as
sodium and potassium hydroxide can be used. Deprotonation of alkoxides by hydroxide
is less efficient so stronger bases such as potassium tert-butoxide or sodium or potassium
hydride are used. Amines can act as nucleophiles based on their basicity or they can be
converted to sulfonamides and deprotonated using metal carbonates or sodium or
potassium hydride (Section 2.2). Sulfur nucleophiles are commonly formed using cesium
carbonate.55 The use of cesium carbonate creates what is termed as the ‘cesium effect’
(Section 2.3).56
Specific bases sometimes require certain solvents but it is the nucleophile that
more often dictates the solvent. In most cases, the choice of solvent is dependent on its
ability to solubilise the anion formed. Polar aprotic solvents such as tetrahydrofuran and
dimethylformamide are most commonly used for this purpose.1 The amount of solvent
used can be critical to the size of the ring formed. A concentrated solution favours more
intermolecular reactions and thus larger rings (or polymers).
The question of leaving groups in macrocyclic reactions is based on economy,
efficiency and reactivity. The most common choices are the halides, mesylates and
tosylates. The tosylate group is the most reactive followed by mesylate, iodine, bromine
and finally the chloride ion.
2.0.4 Ring Closure Methods
The reaction between the two ends of a chain to form the cyclic compound
depends greatly on chain end proximity, i.e. the closer the two chain ends are to each
other the greater the chance for an intramolecular reaction.49 The template effect deals
22
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
directly with this issue. It involves the use of a cation to act as a temporary or permanent
coordination site allowing the negative heteroatoms of the chain to assemble themselves
around the positive ion in a circle or semicircle, thus bringing the two reacting ends
closer together.1 An example is shown in Scheme 9.
TsO
OTs
O
O
O
O
M
O
O
O
O
O
O
O
O
O
M
O
OTs
O
O
O
O
Scheme 9
Another commonly employed method used to promote cyclisation is the high
dilution technique. It follows that the intramolecular reaction is first order and its rate is
proportional to concentration, while the intermolecular reaction is second order and its
rate is proportional to the square of the concentration. Dilution should therefore favour
the intramolecular reaction.49 In principle, the high dilution technique can be carried out
under homogeneous or heterogeneous conditions. It requires the use of a large amount of
solvent with a small amount of reactants, so that once the linear chain has formed the
remaining reactants are so dilute that the intermolecular collisions are decreased and the
two functional ends of the chain react with each other.57 In practice, the conditions
involve the use of a reduced amount of solvent with the reactants added over a period of
time. If the reaction rate is greater than the addition rate, the reactant concentration is
kept low and the dilution is high.1
2.1
Selectivity of Crown Ethers for Metal Ions
One of the properties of crown ethers is their ability to complex metal ions. A
complexed macrocycle can be defined by the spatial arrangement of its components, its
superstructure and the nature of the intermolecular bonds that hold the components
together.2 There are many factors that influence the selectivity of the macrocycle for
different ions; they include the cavity size and shape, substituent effects, conformational
flexibility/rigidity and the type of heteroatom.
23
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
The formation of the most stable complex between a metal and macrocycle, in
respect to cavity size, is explained in terms of the size match selectivity hypothesis.58
This is when the ionic radius of the metal and the cavity size of the macrocycle are the
closest. This rule applies very well to the complex of 18-crown-6 and the potassium ion.
Models show that the potassium ion fits in the cavity best and that potassium forms the
most stable complex compared with the other cations. This rule however, does not
always apply. Macrocycles of the rigid type (smaller macro ring) tend to discriminate
between cations that are either smaller or larger than the one that exactly fits in to the
cavity.59 This is known as peak selectivity. In some cases the macrocycle creates a
sandwich effect, that is, two macrocycles form a complex with the one cation. This type
of interaction is seen between 12-crown-4 (cavity size, 1.5 Å) and the sodium ion (ionic
radius, 2 Å) (Figure 5).60 The incorporation of groups such as benzene, cyclohexane,
pyridine rings or other constituents into the crown ether framework can lead to more
rigid macrocycles which can alter the strength and selectivity of the crown ether.
Macrocycles of the flexible type (larger macro ring) prefer the smaller cations. This is
known as plateau selectivity.59 A flexible crown ether can accommodate a wider range of
metals than the rigid crown ethers as such factors like ligand conformations and the
cation solvation enthalpy become important.58
O
O
O
O
Na+
O
O
O
O
Figure 5
Crown ethers fall into three different categories with respect to metal binding
affinities. The first group contains the small macrocycles and usually coordinate to metal
ions outside the cavity as in the case of 12-crown-4. The second group contains only 18crown-6. When 18-crown-6 is complexed to certain metal ions it exhibits the idealised
D3d geometry (64).61 In the uncomplexed compound (65)62 the methylene groups occupy
the central area, however they can rotate outward to create a cavity. The third group
incorporates the larger macrocycles. Due to their flexibility they can wrap around the
24
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
cation. This phenomenon is seen in nature with valinomycin, which envelops the
potassium ion and transports it in vivo.49 In this way it protects the potassium from the
lipid environment.
O
O
O
O
O
H
O
O
O
H
H
H
O
O
O
O
64
65
The substitution of nitrogen or sulfur leads to crown compounds capable of
targeting different cations. Oxygen donor groups have an affinity for alkali, alkaline earth
and lanthanide ions.57 Nitrogen and sulfur donor groups are considered soft bases and
therefore prefer the transition metal ions (eg, nickel, copper, iron) and heavy metal ions
(eg, silver, lead, mercury), which are classified as soft acids.63 It has been shown through
X-ray crystal analysis64 that complexed azacrown ethers tend to adopt the structure
shown in Figure 6.63 It shows the metal at the centre coordinated by the surrounding
nitrogen groups on almost the same plane and the anions are located on the axis normal
to the plane. Many reviews are available on the different complexes formed by azacrown
compounds64 and thiacrown compounds.65
Y
N
N
M
N
N
X
Figure 6
The macrocyclic effect is based on the ability of the crown ether to complex a
metal ion more strongly than its open-chain analogue. The macrocyclic effect is observed
quite strongly in the oxa and aza macrocycles but is much less pronounced in thiacrown
25
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
ethers.66 This is related to the tendency of the sulfide linkages (-SCH2CH2S-) to assemble
themselves outside (exodentate) the cavity.67 This is because of the longer carbon-sulfur
bond and the 1,4-interactions in gauche C-C-E-C and E-C-C-E units (E = O, S) (Figure
7).68 In the oxa analogues this orientation gives anti C-O and gauche C-C bonds while in
thiacrowns the opposite effect is observed, therefore the sulfur lone pairs point out. It
follows that a considerable amount of reordering is necessary for metal binding to take
place, which is energetically not favoured. Due to this phenomenon, some thiacrown
ethers tend to bridge metal ions rather than chelate to them.69 It has been observed that
the binding ability of some thiacrown compounds is only slightly greater than the open
chain ligand.66a There are, however, exceptions with (96) and (100) (Section 2.3) having
the endodentate orientation of their sulfur atoms.
O
O
C
S
C
S
C
C
destabilising
weakly
stabilising
gauche C-C bonds
2.4 Å
C
H
C
1.8 Å
H
H
H
C
C
C
1.4 Å
O
gauche is
destabilised
C
1.8 Å
S
gauche is not
disfavoured
gauche C-X bonds
Figure 7
2.2
Nitrogen Macrocycles (Azacrown Ethers)
Macrocycles containing nitrogen have been known for over 100 years. Examples
include a number of biologically important compounds such as the green pigment of
chorophyll and the haem of haemoglobin. They were recognised as tetrapyrrole
porphyrin macrocycles (68) and were later synthesised by a series of condensations
between pyrrole (66) and formaldehyde (67) (Scheme 10). During this early period in
azacrown chemistry, Baeyer70 synthesied tetraazaquaterene, a compound resembling the
porphyrins, via an acid catalysed condensation between pyrrole (66) and acetone (3) in
an analogous fashion to the furan-acetone reaction (Section 1.0). The reaction is believed
26
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
to take place under a hydrogen bonding network.57 Since these early discoveries and
syntheses there have been many synthetic approaches to the assembly of macrocycles
containing nitrogen.
H
N
N
HN
O
+
H
66
H
NH
N
67
68
Scheme 10
A second wave of interest in nitrogen macrocycles occurred in the 1930s. The
early part of that decade saw significant interest in complexed azacrowns because of their
industrial importance as pigments and dyeing agents. It is also interesting to note that in
1937, the same year that Lüttringhaus synthesised the first cyclic polyether (1), Alphen
obtained the first saturated macrocyclic polyamine, cyclam (69).71
NH HN
NH HN
69
2.2.1
Templated Syntheses
The first observed templated synthesis of a macrocyclic ligand was by Braun and
Tcheriac72 in 1907 when they obtained metal derivatives of phthalocyanines from the
reaction of pyrrole and o-diaminobenzene or o-cyanobenzamide or their related
compounds with metals. In 1928, a dark by-product was isolated during the synthesis of
phthalimide in an iron reaction vessel and proved to be the ferrous iron complex of
phthalocyine.57 This area of research became the province of the pigments/dyestuffs
industry. The term ‘template effect’ was not applied to the synthesis of macrocycles until
the 1960s when Busch et al73 and Hurley et al74 recognised the role of the ferrous ion.
27
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
Busch73 noted that the coordination sphere of the metal ion could hold the reactive
groups in the correct orientation for cyclisation to occur.
In 1960, Curtis et al75 used Ni(II) and Cu(II) to promote the cyclo condensation
of ethylenediamine with acetone to afford a bisimine. Acetone (3) was added to the
complexed diamine (70) to form the complexed tetraazadienes (71) in both the cis and
trans forms (Scheme 11). The complexes were precipitated as the perchlorate salts. In
order to explain the mechanism of formation of the macrocycles the compounds and their
intermediates were decomposed. The authors found that ethylenediamine, mesityl oxide
and/or acetone were generated depending on the conditions used for decomposition.
They proposed that the acetone reacted with an N-isopropylidene imine to form either a
mesityl oxide imine, which would then undergo a Michael type reaction with the adjacent
amine group. Alternatively, a β-amino ketone would react with the adjacent amino group
to form an imine.
2+
H2
N
H2
N
M
II
+
N
H2
N
H2
O
4
H3C
N
CH3
i
3
+
M
HN
NH
NH
M
NH
N
N
N
70
71
Reagents and Conditions: (i) room temp. 1 week, 80%
Scheme 11
In many cases the use of a metal template is needed for cyclisation to occur.
Examples of non-template cyclised macrocyclic-Schiff bases76 are known, however a
requirement of these reactions is that the starting materials contain rigid groups, such as
benzene and pyridine rings.
Jackels et al77 reported that the reaction of 1,3-
diaminopropane monohydrochloride (72) and biacetyl (73) to form (74) was only
possible in the presence of cobalt acetate tetrahydrate (Scheme 12). The use of metal ions
in reactions has also led to an increase in the yield of the macrocycle being formed.57
28
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
O
H3C
O
+
NH2
NH3Cl
72
H3C
N
i
CH3
Co
H3C
N
CH3
N
CH3
II
N
73
74
Reagents and Conditions: (i) CH3OH, KOH, 15 min 2 °C,
Co(OAc)2•4H2O, CH3OH, room temp. 12 h, 30%
Scheme 12
The macrocyclic imine ligands can be reduced to form the cyclic amines using
hydrogen and a catalyst, sodium borohydride, nickel-aluminium alloy or cathodic
reduction.57 Subsequent demetallation can be effected by the addition of acid, a ligand
exchange process whereby cyanide, sulfide or EDTA are added, or by the reduction of
the metal if it has a suitable redox couple.78 Removal of the metal proved to be difficult
in some cases.77
2.2.2 The Sulfonamide Method
The so-called Richman-Atkins reaction does not utilise a metal template but
rather relies on the conformational constraints of its reactants to promote cyclisation. In
1974, Richman and Atkins79 reported the generality of the sulfonamide reaction to
synthesise polyazacrowns. Conversion of primary amines to sulfonamides increases the
acidity, which makes deprotonation of the nitrogen easier and allows it to react in an SN2
fashion. In the initial reaction, the disodium salt of a polysulfonamide (75) was reacted
with a ditosylate or dimesylate (76) in dimethylformamide to yield the polytosylated
cyclen (77) (Scheme 13). Detosylation with sulfuric acid afforded the polyamine
macrocycle in 80% yield. The use of a tosylate or mesylate ester leaving group was
found to give greater yields.80 Stetter et al81 and Koyama et al82 previously prepared
similar macrocycles by reacting polysulfonamides with dihalides. The yields obtained
were poor. This result was in contrast to the dihalide derivatives of the polyoxygen
systems.3 The sulfonamide method can be used to synthesise small and large ring
macrocycles including azacrowns possessing other heteroatoms.
29
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
Ts
Ts
X
N Na
Ts
+
N
N Na
Ts
75
N
N
i
Ts
Ts
N
N
Ts
N
X
Ts
X = OTs, OMs
77
76
Reagents and Conditions: (i) DMF, 100 °C, 76 was added over 1-2 hr, 80%
Scheme 13
Richman and Atkins used preformed sulfonamide salts in their reaction, however
the sulfonamide nucleophiles can be generated in situ by using a base. Metal carbonates
are commonly used to form the nucleophile. Changing the metal carbonate can affect the
cyclisation yield of the protected azacrown. Chavez and Sherry83 found using potassium
and cesium carbonate in dimethylformamide gave the best results while the use of
lithium and sodium carbonate yielded no product. Sodium and potassium hydride are
often used when bases stronger than the carbonates are needed to deprotonate the
sulfonamide.
The diminished template effect in certain polytosylated azacrowns has been
attributed to the effects of restricted rotational freedom of the starting material due to the
bulky tosyl groups.83,84 It was postulated that the resulting small change in entropy
allowed cyclisation to occur without a need for preorganisation of the starting materials
or intermediates. These same reasons are used to explain why high dilution was not
needed in some cases. It is interesting to note that replacement of the sodium ion for the
tetramethylammonium ion in a Richman-Atkins reaction resulted in a decrease in yield of
the macrocycle formed. This was explained as a slight template effect by the sodium
ion.85
The tosylation of the nitrogen not only increases the acidity but it also protects the
nitrogen from further reaction. For example, the reaction between 2-aminophenol (78)
and tetraethylene glycol dichloride (79) can yield two monoaza compounds. Lockhart
and co-workers86 formed a 12-membered ring (80) and a 15-membered ring (81)
(Scheme 14). In this case the authors found that by changing the solvent they could
obtain the desired crown ether. However, in many cases it is not that straightforward.
30
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
O
NH2
+
Cl
O
3
NH
O
+
Cl
N
OH
78
O
O
O
O
O
79
OH
80
81
Scheme 14
There are three main methods for the removal of the tosyl group: (1) acid
hydrolysis with concentrated sulfuric acid, (2) reductive cleavage using a mixture of
hydrobromic and acetic acid and (3) reduction using lithium aluminium hydride. The
choice of method for removing the protecting group is based on the sensitivity of the
macrocycle and its substituents for the particular conditions. More recently, Fukuyama et
al87 showed that removal of a p- or o-nitrobenzenesulfonyl group could be achieved with
relative ease using thiophenol and potassium carbonate in dimethylformamide. However,
it was found that some thiolate addition occurred at the nitro group when it was in the
para position, forming the phenylthioether. This effect was not observed using the ortho
derivative.88
The sulfonamide method has been prominent in the synthesis of azacrown ethers,
however there are other protecting groups that can be used. The diethoxyphosphoryl
group has been shown to be an excellent activator of primary amines and can be removed
using gaseous hydrochloric acid in tetrahydrofuran.89 The trifluroacetyl group has also
been used.90 It can be easily prepared and readily removed after the reaction. The
disadvantage of this group is the poor cyclisation yields due to the electronegativity of
the trifluoroacetyl moiety, which reduces the nucleophilicity of the nitrogen. When
activation is not a consideration, the benzyl protecting group can be used and easily
removed by hydrogenolysis.
2.2.3 Azacrown Ethers via Amide Formation
Macrocycles with the amide (lactam) functional group are commonly used
intermediates in the synthesis of various azacrowns. The ring-closure reaction can be
effected by nitrogen addition to a diester or diacid chloride, or by Michael addition to an
α,β-unsaturated ester. Addition of nitrogen to a diester has led to the synthesis of many
cyclic bislactams. The cyclisation process, often referred to as the Tabushi method, does
not require high dilution in many cases. An example of this is the reaction between 1,331
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
bis(2’-aminoethylpropane) (82) and diethyl malonate (83) which afforded the bisamide
(84). Reduction of the amide groups using borane/tetrahydrofuran yielded cyclam (69)
(Scheme 15). 91 Lithium aluminium hydride has also be used to reduce the amides.57
O
O
NH HN
+
EtO
OEt
N
H2
82
NH HN
NH HN
i
ii
NH HN
NH HN
N
H2
83
O
O
84
69
Reagents and Conditions: (i) EtOH, reflux 3 days,
(ii) B2H6/THF, reflux 24 h, HCl, KOH/CH3OH, 80%.
Scheme 15
In alcoholic solvents esters react with primary amines but not with secondary
amines, therefore avoiding the need for nitrogen protection.91 This is in contrast to the
use of diacid chlorides, which require nitrogen protection. Stetter and Marx92 were the
first to utilise the reaction between a diamine and diacid chloride in the synthesis of
tetraaza macrocycles.
The cyclisation proceeded cleanly and no by-products were
observed. Dietrich et al53,93 first used this method to synthesise the diazacrown
compounds, which are precursors to the cryptands. Later Dietrich and co-workers94
showed that macrocycles containing large numbers of nitrogen atoms could also be
synthesised via this method. The bisamide (87) was formed by the reaction of a protected
diamine (85) and a diacid chloride (86). The protected azacrown (88) was obtained after
reduction (Scheme 16).
32
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
O
O
Ts
NH2
Cl
N
N
N
N
NH2
N
N
H
Ts
N
i
+
Ts
Ts
Ts
Cl
85
O
Ts
N
N
H
N
Ts
ii
Ts
Ts
N
86
H
N
N
Ts
Ts
N
87 O
H
N
N
Ts
88
Reagents and Conditions: (i) NEt3, CH2Cl2/toluene (3:2),
room temp. 7 h (ii) B2H6/THF, reflux 20 h, 85%.
Scheme 16
Reaction of an α,β-unsaturated ester (89) with a diamine (90) has lead to the
synthesis of cyclic compounds containing one amide group (91) (Scheme 17). The
reaction proceeds via Michael addition of one amine to the β-unsaturated carbon
followed by amide formation by the reaction of the other amine and the ester functional
group. Kimura and co-workers95 have used this method to synthesise triamines,
tetraamines and pentaamines. The lactam functional group was reduced to yield the
desired azacrown. The yields obtained, however, were generally low.
O
H2
N
O
OEt
H2
N
NH HN
i
+
NH HN
NH HN
90
91
89
Reagents and Conditions: (i) CH3OH, room temp. 12 h→reflux 24 h, 50%.
Scheme 17
33
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
2.2.4 Peptide Chemistry
Peptide chemistry has also proved to be useful in azacrown synthesis. A bisamide
can be formed in the reaction between a dicarboxylic acid and a diamine. In these cases
the carboxylic acid functionality has to be activated. The use of dicyclohexylcarbodimide
(DCC), diphenylphosphoryl azide (DPPA) and many other activating reagents has led to
the synthesis of azacrown ethers in good yields. Qian and co-workers96 reacted (85) and
the carboxylic acid derivative of (86) to form (87) (Scheme 16) using DPPA in
dimethylformamide.
Other
work
has
included
the
use
of
DCC
with
1-
hydroxybenzotriazole (HOBT) to form azacrowns in 50-55% yields.97 An example of the
activating properties of DCC is shown in Scheme 18.
O
O
HN
R
OH
RI
N C
R
O
NH2
N
N
(DCC)
O
R
O
I
R
NHR
RI
HN
O
N
N
H
Scheme 18
2.2.5 Crab-Like Cyclisation
The reaction between a bis-α-chloramide (92) and a diamine (93) is another
method that has been used to form cyclic bisamides (94) (Scheme 19).98 Subsequent
reduction of the amide functionalities using borane/tetrahydrofuran yielded the
substituted azacrown (95). The cyclisation is different from other reactions to form
bislactams in that the amide functional groups are not formed in the ring closure step.
The advantages of using this method are: (1) nitrogen protection can be avoided because
the secondary amide functionality on the starting material is unreactive as a nucleophile;
34
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
(2) the reaction is short and the overall yields are good; and (3) the chloride is activated
by the amide group but the molecule does not possess the blistering properties of the βchloroamines.57 The ‘crab-like’ bis-α-chloramide starting material (92) can be
synthesised from simple primary and secondary diamines and oligooxadiamines but not
from polyamines with terminal secondary and internal tertiary amine groups. One
problem is that the starting material is susceptible to strong acids and bases as the
chloroacetamide group can be cleaved. This method has been used to prepare azacrowns
of different sizes with various nitrogen substituents.
O R
R O
N
N
R O
O R
Cl
R = CH3
ii
RI
NH
N RI
N
N
+
RI
NH
N
N
i
92
R
R
N
N
Cl
R
RI
N
II
94
RII
RI
N RI
N
N
RII
95
RI= CH2CH3, RII= (CH2)2O(CH2)2OH
93
Reagents and Conditions: (i) Na2CO3 CH3CN, reflux 24 h, (ii) B2H6/THF, reflux, 60%
Scheme 19
2.3
Sulfur Macrocycles (Thiacrown Ethers)
Much of the early research into cyclic sulfur compounds was in relation to
understanding ring formation and theories of ring strain.99 The reaction between a
dihalide and a dithiol yielded high polymers and small amounts of the cyclic sulfur
compounds. Ray et al100 was the first to report the synthesis of a trithia macrocyclic
compound from ethanedithiol, in 1920. In the ensuing years subsequent research proved
that the isolated compound was not 1,4,7-trithiacyclononane (9-S-3) (96) but rather pdithiane (97).101,102 The first reported synthesis of (96) was by Ochrymowycz et al102 in
1977. This will be discussed later.
35
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
S
S
S
S
S
96
97
In 1934, Meadow and Reid103 synthesised a number of cyclic sulfur compounds
containing two, four and six sulfur atoms. The reaction between various dithiols and
dibromides lead to the formation of polymers and small amounts of the cyclic
compounds. One of the macrocycles formed was a hexathia compound (18-S-6) (100) via
a tetra-component cyclisation. Ethylene bromide (98) was added to 3-thiapentane-1,5dithiol (99) in absolute ethanol containing an equivalent amount of base to afford the
thiacrown, albeit in 1.7% yield (Scheme 20).
S
Br
Br
+
S
S
S
S
i
HS
S
SH
99
98
S
100
Reagents and Conditions: (i) NaOEt, EtOH, room temp., 1.7%
Scheme 20
Thirty-five years later, Black and McLean104 managed to improve the yield
significantly to 31%. In this case, the reaction was carried out under high dilution
conditions. They also managed to synthesise cyclic sulfur compounds containing oxygen
and/or nitrogen groups using these same reaction conditions. In the same year, Rosen and
Busch105 synthesised a number of cyclic tetrathia compounds (101), (102) and (103) in
7.5%, 4% and 16% respectively.
S
S
S
S
S
S
S
S
S
S
S
S
101
102
36
103
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
As interest in crown ethers increased so did the interest in macrocyclic
compounds containing sulfur atoms. Following on from the work by Pedersen3,
Bradshaw et al106 were interested in the synthesis of crown ethers containing both oxygen
and sulfur atoms. Bradshaw and co-workers106 found that the reaction between an
ethylene glycol dichloride and a dithiol or sodium sulfide in basic ethanol afforded the
desired oxathiacrown ethers. At the same time Ochrymowycz and co-workers107 were
investigating the synthesis of several polythiacrown compounds. Their initial attempt at
the synthesis of (100) proved to be less successful than previously reported. They were
only able to obtain the desired product in 8% yield following the procedure by Black and
McLean104 however by adopting a two-component approach they were able to improve
the yield to 33%. They reacted a β-chlorothioether (104) with (99) in n-butanol using
sodium (Scheme 21). The disadvantage of this procedure is the use of the βchlorothioethers, which are powerful vesicants as they are analogues of mustard gas
(blister-causing agent).
S
Cl
n
S
n=3
Cl
+
S
S
S
S
i
HS
S
SH
99
S
104
100
Reagents and Conditions: (i) NaOnBu, room temp. 2 days, 33%
Scheme 21
Using these conditions, Ochrymowycz and co-workers107 synthesised a number of
thiacrown compounds and investigated their metal-binding properties as a function of
ring size and the number of donor atoms. To further understand the relationship,
Ochrymowycz et al102 became interested in the synthesis of the smaller nine-membered
ring (96). The synthesis of the thia analogue proved difficult even though the oxa, aza or
mixed oxa-aza-thia nine membered ligands had been synthesised in good yields. The
product was obtained in only 0.04% yield. The reaction was initially carried out in nbutanol but the desired product was not observed. The nine membered ring only formed
when ethanol was used. This was explained by the solvating effect of ethanol at a
particular stage in the cyclisation process.
37
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
2.3.1 Synthesis of Thiacrown Compounds Using Cs2CO3
Much of the early research into sulfur macrocycles was hampered by the lack of a
good yielding general procedure. In 1980, Kellogg and co-workers108 revolutionised the
synthesis of thiacrown compounds using cesium carbonate in dimethylformamide. In
general, the procedure required that the dithiol (105) and the dibromide (106) be added
over a period of time to a stirred suspension of cesium carbonate in dimethylformamide
at 50-60 °C to form (107) (Scheme 22). Using this procedure they were able to form a
number of macrocycles containing sulfur and oxygen in yields of 65% and higher. They
later applied this method to the synthesis of polythia compounds by reacting a dithiol and
a β-chlorothioether.
O
HS
O
n
SH
+
n=3
S
O
O
O
i
Br
O
Br
106
S
105
107
Reagents and Conditions: (i) CsCO3, DMF, 50 °C, 105
and 106 were added over 12-15 hr.
Scheme 22
2.3.2 The Cesium Effect
Substitution of cesium carbonate with rubidium, potassium, sodium and lithium
carbonates gave reduced yields or no product at all.108 This advantageous function of the
cesium ion is known as the cesium effect. Based on the ω-halo carboxylate cyclisations,
Kellogg et al109 initially postulated that the tight ion pairs formed by the carboxylate
anion and the cesium cation promoted the intramolecular cyclisation. It was believed that
the cesium ion assisted in the transition state by attaching to the carboxylate while
providing electrophilic assistance to the leaving group (Figure 8). In essence the
cyclisation occurred on the ‘surface’ of the cesium ion. This theory was the basis for
other reactions involving thiols, phenols, sulfonamides and 1,3-dicarbonyl compounds
with Cs2CO3.
38
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
(CH2)n
C
I
R
R
O
O
X
Cs
Figure 8
Subsequent research by Kellogg110 and Galli111 and their co-workers showed that
this was not the case. Using
133
Cs NMR studies110 and kinetic studies111 both groups
determined that the cesium salts exist as free ions or solvent separated ion pairs in dipolar
aprotic solvents such as DMSO and DMF. In relation to thiolate chemistry, the effect of
the cesium in promoting the cyclisation is believed to occur after the intermediate ω-
halo-α-thiolate has been formed.65a The large cesium cations form weak ion pairs with
the thiolate anions, producing ‘naked anions’ which are very soluble and highly reactive.
Under high dilution conditions, the enhanced reactivity would therefore favour the
intramolecular over the intermolecular reaction.
2.3.3 Templated Syntheses
Unlike the strong template effect exhibited by the oxo and azacrown ethers, low
sulfur-active metal ion coordination renders template effects of little consequence in the
synthesis of thiacrown ethers. Attempts to use transition metals as templates have not
been very successful, although there have been exceptions. Sellman and Zapf112 reported
the synthesis of (96) in 60% yield via a templated synthesis. Dithiol (99) was coordinated
to a molybdenum(0) carbonyl complex to form (108), which was then reacted with
ethylene bromide (98) to form the complexed thiacrown (109). The complexed
macrocycle was liberated from the metal under regeneration of the starting complex to
form (96) (Scheme 23). Edema et al113 reported more recently that boric acid and a
boron/aluminium isopropoxide cocktail were effective in the synthesis of a number of
thiacrown ethers.
39
INTRODUCTION : Synthetic Strategies for the Preparation of Crown Ethers
S
OC
S
Mo
CO
S
CO
[N(CH3)4]2 +
S
i
Br
Br
OC
98
S
Mo
CO
S
ii
S
S
CO
S
96
108
109
Reagents and Conditions: (i) CH3CN, room temp. 15 min, (ii)
(NCH3)4(SC2H4SC2H4S), DMSO, room temp. 2 days, 60%.
Scheme 23
40
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
3.0
Synthetic Targets
As discussed in Chapter 1 the aim of the present work was to synthesise the sulfur
(55, 56, 57) and nitrogen (58, 59, 60) analogues of the axial spiroacetal crown ethers
(53a-c) in order to evaluate their binding affinities towards specific metal ions and their
interactions with metal complexes (second sphere coordination).
O
O
O
O
O
O
O
O
S
S
S
S
S
O
O
O
S
S
S
56
NH
57
O
O
O
O
H
N
O
NH
S
S
O
O
O
S
S
55
O
O
O
O
NH
HN
NH
O
HN
NH
HN
58
HN
59
N
H 60
NH
According to the retrosynthesis outlined (Scheme 24) it was envisaged that the
synthesis of the thiacrown and azacrown ethers could be carried out via two possible
pathways. The first approach (Path A) involves the reaction between the spiroacetal diol
and the respective β-chloroethyl sulfide or amine. It was envisaged that the cyclisation
would be effected in a similar fashion to the method used by Brimble et al48 to synthesise
spiroacetal crown ethers (53a-c) and (54a-c).
The second approach (Path B) involves the reaction between a dithiol or diamine
with an electrophilic group attached to the spiroacetal moiety. The electrophilic group
could be a leaving group such as a tosylate or mesylate for reaction with a dithiol or a
protected diamine. Alternatively, the electrophilic group could be a carbonyl group such
as an ester or aldehyde, which could undergo nucleophilic addition with an amine. This
42
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
latter method is more amenable for the construction of the azacrown ethers than the
thiacrown ethers. The spiroacetal containing the electrophilic side chain can be
synthesised from the parent spiroacetal diol (50), which had previously been prepared by
Brimble et al.114 The synthesis of the spiroacetal diol (50) is described in the next section.
O
O
A
O
B
X
O
A
B
X
X
n
Path A
Path B
O
O
+
O
Cl
X
n
+
O
Cl
HX
n
XH
X = S, NH, NR
X = S, NH
OH
X
O
OH
O
R
R
R = CH2OMs, CH2OTs
or R = CHO
or R = C Y
O
(Y = leaving group)
Scheme 24
3.1
Synthesis of Spiroacetal Diol (50)
3.1.1 Synthesis of (±)-1,7-Dioxaspiro[5.5]undec-4-ene (114)
The synthesis of spiroacetal diol (50) has previously been reported by Brimble et
al
114
starting from alkene (114) (Scheme 25). Alkene (114) was treated with
dimethyldioxirane to form the α-epoxide (115), which in turn was treated with lithium
diethyl amide to form the allylic alcohol (117). Epoxidation of the allylic alcohol (117)
using meta-chloroperoxybenzoic acid, followed by reduction of the epoxy alcohol (119)
formed the spiroacetal diol (50). The incorporation of the hydroxyl groups after
cyclisation was necessary so as to avoid the formation of the thermodynamically more
stable equatorial isomer.
43
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
O
O
O
O
O
114
O
O
115
O
O
OH
117
O
OH
O
119
O
OH
OH
50
Scheme 25
Alkene (114) was prepared following Scheme 26 starting from δ-valerolactone
(110) and trimethylsilyl protected 3-butyn-1-ol (111). The protected alcohol (111) was
treated with n-butyllithium in THF at –78 °C. δ-Valerolactone (110) was then added to
the acetylide. The coupled product was isolated and treated with acidic methanol or
ethanol to yield the methoxyacetal (112) or ethoxyacetal (113) respectively (Scheme 26).
Initially, this reaction proved to be problematic with only low yields (20 - 36%) obtained
for the methoxyacetal. Changing the acid source did not increase the yield to the reported
70%. It was hoped that changing the alkoxy group would increase the stability and yield
of the product. Indeed using ethanol as the solvent afforded ethoxyacetal in an improved
88% yield.
The low resolution mass spectrum of the product showed a molecular ion at
m/z 153 which corresponded to the molecular formula of C9H13O2 indicating the loss of
the ethoxy group. The infrared spectrum exhibited a broad absorbance at 3419 cm-1
supporting the presence of the alcohol group. Another absorbance at 2249 cm-1 showed
the presence of the acetylene. The 1H NMR spectrum was assigned on the basis of 2D
COSY and HSQC experiments. The OH group resonated at δH 2.54 as a triplet with
JOH,4’ 6.2 Hz. A triplet (J3’,4’ 6.5 Hz) at δH 2.51 was assigned to 3’-CH2. The ethoxy CH3
group resonated as a triplet at δH 1.24 with JCH3,OCH2 7.1 Hz. The 13C NMR spectrum was
assigned with the aid of HSQC and HMBC experiments. The quaternary carbons at
δC 80.2 and δC 81.7 were characteristic of the acetylenic carbons C-1’ and C-2’ and a
quaternary carbon at δC 94.4 was assigned to the acetal carbon.
With the ethoxyacetal in hand, the next step involved the semi-hydrogenation of
the acetylene over Lindlar catalyst in pentane/ether (4:1) followed by acid catalysed
cyclisation using pyridinium p-toluenesulfonate to afford the spiroacetal olefin in 80%
yield. The 1H and
13
C NMR spectra were in agreement with the literature NMR data
reported for spiroacetal (114).115 Notably the spiroacetal carbon C-6 was observed at
δC 92.8 and the vinylic protons 5-H and 4-H resonated at δH 5.62 and δH 5.91-5.97
respectively in the 1H NMR spectra.
44
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
OH
O
O
+
MeO
i, MeOH,
Amberlite resin
OSiMe3
O
111
110
112
OH
i, EtOH,
PPTS
ii, iii
3'
4'
2'
EtO
2
1'
10
ii, iii
O1
3
8
9
O
7
6
1
4
6
5
4
5
2
O
11
3
114
113
Reagents and Conditions: (i) n-BuLi, -78 °C, THF, 45 min, then 110, 45 min; (ii) H2,
Lindlar catalyst, pentane/ether (4:1); (iii) CH2Cl2, PPTS, room temp., 30 min, 78%.
Scheme 26
3.1.2 Epoxidation of Olefin (114)
Having successfully synthesised the spiroacetal olefin (114) the next step
involved epoxidation using dimethyldioxirane to form both the desired α-epoxide (115)
together with the minor β-epoxide (116) (Scheme 27). The dimethyldioxirane/acetone
solution was added to the spiroacetal olefin and the reaction was monitored by TLC until
completion. The α-epoxide (115) was obtained in 71% yield and the β-epoxide (116) in
11% yield after purification by flash chromatography. The 1H and 13C NMR spectra for
both epoxides were in agreement with the literature.114
O
O
O
i or ii
O
114
O
O
115
+
O O
116
Reagents and Conditions: (i) Dimethyldioxirane, acetone, room
temp., 18 h, 115 (71%), 116 (11%) (ii) NaHCO3, acetone, Oxone®
(1.2 equiv), H2O, 0 °C→room temp., 18 h, 115 (41%), 116 (36%)
Scheme 27
45
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
Dimethyldioxirane is a three membered cyclic peroxide that can be prepared
under buffered conditions from Oxone® (potassium peroxymonosulfate) and acetone and
subsequently isolated by distillation116 or it can be generated in situ.117 When the 0.1 M
solution of dimethyldioxirane was used in the epoxidation reaction the desired α-epoxide
formed preferentially, however in situ formation of dimethyldioxirane led to the
synthesis of the α- and β-epoxides in a 1:1 ratio. A possible explanation for this
observation is that Oxone®, which itself is used as an oxidising agent, competes with
dimethyldioxirane in the epoxidation of olefin (114). Since Oxone® is a less sterically
sensitive oxidant than dimethyldioxirane it does not discriminate between the α- or
β-faces. Dimethyldioxirane, on the other hand, delivers the oxygen primarily to the less
sterically hindered α-face, which is reflected by the α:β product ratio.
There are two proposed transition states for the epoxidation of olefins using
dimethyldioxirane. Transition state A shows the direct delivery of the oxygen atom to the
double bond proceeding via formation of a three membered ring, whereas, transition state
B shows the addition of the oxygen atom via a ring opened diradical (Scheme 28).118 The
authors suggest that oxidation by the diradical is the most likely mechanism however
further study needs to be carried out to conclusively determine the mechanism of
epoxidation.
O O
O O
O
O
R1 O R3
O
R1
R2
A
R3
R1
R4
R2
O
+
O
R2
R3
R4
Me
Me
R4
B
Scheme 28
3.1.3 Base-Induced Ring Opening of Epoxide (115) and Epoxidation of Allylic
Alcohol (117)
With the α-epoxide (115) successfully in hand, attention turned to its baseinduced ring opening to allylic alcohol (117). The mechanism involves the removal of a
β-proton syn to the epoxide oxygen and is thought to proceed via a cyclic six-membered
transition state.119 This mechanism can be applied to the reaction of the α-epoxide with
lithium diethyl amide (Scheme 29). The base coordinates to a lone pair of electrons on
46
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
the epoxide oxygen and promotes syn β-proton removal rather than anti β-proton
removal. In this case the β-epoxide cannot react because it does not possess a syn
β-proton. The base-induced ring opening of α-epoxide (115) yielded the allylic alcohol
(117) in 76% yield and the homoallylic alcohol (118) in 3% yield (Scheme 30). Baseinduced ring opening has also been performed using chiral lithium amide bases and this
will be discussed in more detail in Chapter 5.
O
O
O
O
O
H
Li
O
O
N
Et
O
H
Li
N Et
Et
OH
Et
Scheme 29
O
O
O
i
O
O
O
+
OH
117
115
O
OH
118
Reagents and Conditions: (i) Lithium diethylamide (1.1 equiv),
hexane, -35 °C→room temp., 20 h, 117 (76%), 118 (3%)
Scheme 30
Allylic alcohol (117) was next treated with meta-chloroperoxybenzoic acid
buffered with sodium acetate in dichloromethane affording the syn-epoxy alcohol (119)
and anti-epoxy alcohol (120) in 88% and 9% yields respectively (Scheme 31). Metachloroperoxybenzoic acid is capable of hydrogen bonding with hydroxyl groups and
other oxygen substituents in the substrate. It is envisaged that adoption of the stabilised
transition state depicted in Figure 9 together with the fact that the lower α-face is less
sterically hindered allows for the fact that syn-epoxy alcohol (119) is the major product.
The 1H and 13C NMR spectra recorded for the syn-epoxy alcohol (119) was in agreement
with those reported in literature.114
47
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
O
O
O
i
O
O
O
OH
OH
117
119
+
O
O
OH
120
Reagents and Conditions: (i) m-CPBA (2.0 equiv),
NaOAc, CH2Cl2, 0 °C→room temp., 119 (88%), 120 (9%)
Scheme 31
O
O
O
O
H
O
O
R
Figure 9
3.1.4 Reduction of syn-Epoxy Alcohol (119)
Finally, the reduction of the syn-epoxy alcohol (119) with lithium aluminium
hydride in tetrahydrofuran afforded the desired 3,5-diaxial diol (50) in 81% yield
together with the 4,5-diol (121) in 10% yield (Scheme 32). In order to establish that the
1,3-diaxial relationship of the hydroxyl groups was obtained, the coupling constants
observed for the resonances assigned to the methine protons 3-H and 5-H were
examined. 5-H resonated as a triplet at δH 3.45 with J5,4 3.0 Hz. This observation
established that 5-H adopted an equatorial position because the coupling constant was
within the range for typical equatorial-equatorial or axial-equatorial coupling.120 3-H
resonated as a multiplet hence an indirect assignment of the stereochemistry at C-3 was
obtained from the coupling patterns of 4ax-H and 4eq-H. The magnitude of the coupling
constants J4ax,3 3.0 Hz and J4eq,3 3.0 Hz established that 3-H adopted the equatorial
position.
48
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
50
O7
O
i
O
6
O
Heq
OH
O
+
2
O
Heq
5
OH
Hax
O
Heq
3
OH
OH
OH
121
J4ax,3 = 3.0 Hz
J4eq,3 = 3.0 Hz
J5,4 = 3.0 Hz
119
Reagents and Conditions: (i) LiAlH4, THF, room temp., 12 H, 50 (81%), 121 (10%)
Scheme 32
3.2
Synthesis of the Spiroacetal Thiacrown Ethers via Path A
With the successful synthesis of spiroacetal diol (50) in hand, attention next
focused on the synthesis of the spiroacetal thiacrown ethers (55), (56) and (57). Adopting
the retrosynthetic strategy depicted for Path A in Scheme 33 it was envisaged that the
reaction between the spiroacetal diol (50) and the β-chloroethyl sulfides (104), (127) and
(128) would afford the thiacrown ethers (55), (56) and (57).
O
Path A
O
O
+
O
O
OH
O
OH
50
S
Cl
S
n
Cl
104, n = 3
127, n = 4
128, n = 5
S
S
n
55, n = 3
56, n = 4
57, n = 5
Scheme 33
3.2.1 Synthesis of the β-Chloroethyl Sulfides (104), (127) and (128)
β-Chloroethyl sulfides (104) and (127) were synthesised starting from
commercially available 2-mercaptoethyl sulfide (99) and 3,6-dithia-1,8-octanediol by
well-established methods reported in the literature (Scheme 34).68,121 The general
procedure involved the reaction between the dithiols (99) and (122) with 2-chloroethanol
49
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
to form diols (124) and (125) which were then treated with thionyl chloride to yield the
desired β-chloroethyl sulfides (104) and (127) (Scheme 34). The 1H NMR spectra were
in agreement with the literature.68,121a
HS
S
n
i
SH
HO
n
S
ii
OH
Cl
S
124, n = 3
125, n = 4
126, n = 5
99, n = 1
122, n = 2
123, n = 3
n
Cl
104, n = 3
127, n = 4
128, n = 5
Reagents and Conditions: (i) Absolute EtOH, Na(s), 2-chloroethanol (2.0
equiv), reflux, 18 h, 124 (80%), 125 (77%); (ii) thionyl chloride (3.0 equiv),
CH2Cl2, 18 h, 104 (90%), 127 (85%).
Scheme 34
Dithiols (122) and (123) required for the synthesis of β-chloroethyl sulfides (127)
and (128) were prepared by reduction of the corresponding thioacetates (130) and (131)
using lithium aluminium hydride (Scheme 35). Thioacetate (130) was prepared from
β-chloroethyl sulfide (129), which in turn was synthesised from commercially available
3,6-dithia-1,8-octanediol. Thioacetate (131) was prepared from β-chloroethyl sulfide
(104) by reaction with cesium thioacetate. The direct synthesis of dithiols (122) and
(123) from the respective β-chloroethyl sulfides (129) and (104) using acid and thiourea
was found to give a mixture of products that were difficult to separate. It was found that
synthesis via the thioacetate species was much more effective. Edema et al122 did not
purify the intermediate thioacetates (130) and (131), however it was found that
purification led to an increased yield of the respective dithiols.
O
2
i
Cl
S
n
S
129, n = 1
104, n = 2
Cl
H3C
3
O
5
S
S
1
4
ii
n
S
S
CH3
HS
130, n = 1
131, n = 2
Reagents and Conditions: (i) cesium thioacetate, DMF, 16 h, 130
(86%), 131 (79%); (ii) LiAlH4, ether, 122 (89%), 123 (68%).
Scheme 35
50
S
n
122, n = 2
123, n = 3
SH
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
The high resolution mass spectrum for thioacetate (130) exhibited a molecular ion
at m/z 298.01821 corresponding to the molecular formula C10H18O2S4. The infrared
spectrum exhibited an absorbance at 1685 cm-1 supporting the presence of a carbonyl
group of the thioacetate moiety. The 1H NMR spectrum was assigned with the aid of 2D
COSY and HMQC experiments. A singlet at δH 2.34 was assigned to the methyl group.
5-CH2 and 6-CH2 also resonated as a singlet at δH 2.83. The
13
C NMR spectrum
exhibited resonances at δC 30.6 and δC 195.3 assigned to the methyl groups and the
carbonyl carbons respectively.
Thioacetate (131) analysed correctly for C12H22O2S5 with a molecular ion at
m/z 158.02229 in the high resolution spectrum. A molecular ion m/z at 360.01736 was
also observed supporting the molecular formula C12H22O2S434S. The infrared spectrum
exhibited a carbonyl group absorbance at 1691 cm-1. The 1H NMR spectrum exhibited a
singlet at δH 2.33 representing the methyl groups. An eight-proton singlet at δH 2.80 was
assigned to the CH2S groups. The
δC 195.3.
13
C NMR spectrum showed the carbonyl group at
Treatment of thioacetate (130) with lithium aluminium hydride in diethyl ether
afforded dithiol (122) after work-up and purification by flash chromatography. The
1
H NMR spectrum was in agreement with the literature.68 Using a similar procedure
dithiol (123) was prepared in 68% yield. The high resolution mass spectrum for dithiol
(123) exhibited a molecular ion at m/z 274.00046 corresponding to the molecular formula
C8H18S5. The 1H NMR spectrum exhibited a multiplet at δH 1.68-1.77 assigned to the SH
groups. A sixteen proton multiplet at δH 2.67-2.81 was assigned to the CH2S protons.
3.2.2 Reaction Between Spiroacetal Diol (50) and β-Chloroethyl Sulfide (104)
Having successfully synthesised both the spiroacetal diol (50) and the
β-chloroethyl sulfide (104), the synthesis of spiroacetal thiacrown ether (55) was next
attempted. It was envisaged that the high dilution technique could be employed in the
synthesis of the thiacrown ethers. Methods used successfully by Kellogg108 and
Brimble48 and their co-workers were investigated. The method by Kellogg et al108
involved the addition of the spiroacetal diol (50) and the β-chloroethyl sulfide (104) to a
suspension of Cs2CO3 in DMF at 60 °C for 3 h. Subsequent work-up afforded the
recovered diol (50) and diene (132) (Scheme 36). Alternatively diol (50) was treated with
sodium hydride under reflux for 30 min then the dichloride (104) was added over 3 h
following a similar method previously reported by Brimble et al.48 Once again, the
51
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
reaction yielded diene (132) and the recovered diol (50). Clearly the dianion generated
from diol (50) acted as a base rather than a nucleophile.
HA
O
1
O
OH
+
OH
Cl
S
n
2
4
5
i or ii
Cl
HB
S
S
6
3
104, n = 3
S
132
50
Reagents and Conditions: (i) Cs2CO3, DMF, 60°C, 50 and 104 in
DMF added over 3 h, 132 (85%); (ii) KH (1.2 equiv), THF,
reflux, 30 min, then 104 in THF over 3 h, reflux, 24 h, 132 (90%)
Scheme 36
The high resolution mass spectrum recorded for (132) showed a protonated
molecular ion at m/z 207.03352 which corresponded to the molecular formula C8H15S3.
The 1H NMR spectrum was assigned on the basis of 2D COSY and HSQC experiments.
The vinylic proton at C-2 resonated as a double doublet at δH 6.33 with JCH,CHB 16.7 and
JCH,CHA 10.1 Hz. The terminal vinylic protons resonated at δH 5.17 and δH 5.26 as
doublets with JCHB,CH 16.7 and JCHA,CH 10.1 Hz respectively, consistent with the trans and
cis relationship between the terminal vinylic protons and the CHS proton. The 13C NMR
spectrum exhibited resonances at δC 112.1 and δC 131.3 that were assigned to the two
sets of vinylic carbons (CH2 and CH respectively).
3.2.3 Attempted Synthesis of Thiacrown Ether (134) via Olefin Cross
Metathesis of Diene (132) with Spiroacetal Diene (133)
The synthesis of diene (132) prompted an investigation into the possibility of
synthesising the spiroacetal thiacrown ethers via an olefin cross metathesis reaction. This
would provide crown ethers with additional double bonds that could either be
functionalised further or reduced to give the saturated thiacrown ethers. It was envisaged
that a reaction between diene (132) and bisallyl ether (133) would result in the formation
of the unsaturated crown ether (134) (Scheme 37).
52
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
O
S
S
O
+
S
O
132
O
O
O
O
133
O
S
S
S
134
Scheme 37
3.2.3.1 Synthesis of the Spiroacetal Bisallyl Ether (133)
In order to investigate the cross metathesis of diene (132) with spiroacetal diene
(133) a synthesis of the bisallyl ether (133) was required. Thus, treatment of a solution of
3,5-diaxial diol (50) in THF with NaH followed by the addition of allyl bromide (135)
yielded the desired bisallyl ether (133) in 84% yield (Scheme 38).
O
O7
O
OH
+
OH
6
i
Br
1
2
O
5
135
3
O
O
1'
1'
50
HA
2'
3'
2'
3'
HB
133
Reagents and Conditions: (i) NaH, THF, reflux, 30
min, then 135 (2.0 equiv), 18 h, 133 (84%)
Scheme 38
The high resolution mass spectrum for bisallyl ether (133) exhibited a protonated
molecular ion at m/z 269.17533 in the high resolution mass spectrum, supporting the
molecular formula of C15H25O4. The infrared spectrum exhibited an absorbance at
1646 cm-1 due to the unsaturated double bonds and the absence of an OH absorbance was
noted. In the 1H NMR spectrum 5-H resonated as a triplet at δH 3.16 with J5,4 4.7 Hz
suggesting that 5-H is in an equatorial orientation. 3-H resonated as a double double
double doublet at δH 3.45 with J3,2ax 4.1, J3,2eq 4.1, J3,4ax 4.1 and J3,4eq 4.1 Hz, confirming
53
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
that 3-H is also in an equatorial position. 1’-HA resonated as a double double triplet at
δH 4.13 with Jgem 12.9, J1’A,2’ 5.4 and J1’A,3’ 1.5 Hz. The double double doublet at δH 5.25
with J3’A,2’ 17.2, J3’A,1’A 1.5 and J3’A,1’B 1.5 Hz was assigned to 3’-HA, suggesting that it is
trans to 2’-H while 3’-HB resonated as a doublet at δH 5.13 with J3’B,2’ 10.3 Hz consistent
with a cis relationship with 2’-H. The 13C NMR spectrum exhibited methine resonances
δC 70.7 and δC 76.0, assigned to C-3 and C-5 respectively. The characteristic quaternary
spirocarbon C-6 resonated at δC 97.4.
The vinylic C-2’ carbons were observed at
δC 116.54 and 116.55 while the resonances at δC 135.27 and 135.29 were assigned to the
terminal vinylic carbons C-3’.
3.2.3.2 Olefin Metathesis
Olefin metathesis has become a powerful tool for carbon-carbon double bond
formation with the development of well-defined new catalysts, such as Shrock’s
molybdenum catalyst (136)123 and Grubbs’ ruthenium catalysts (137)124 and (138).125 The
use of molybdenum catalyst (136) in olefin metathesis reactions was first reported by
Grubbs,126 Wagener,127 Forbes128 and their co-workers. A limitation of (136) is that it is
extremely sensitive to oxygen, water and acid functionalities, including, alcohols and
carboxylic acids.129 In contrast, Grubbs’ first generation ruthenium catalyst (137) has
displayed a much greater tolerance for a wider range of functional groups and solvents.
However, the range of substrates susceptible to olefin metathesis has been limited
because of the lower reactivity exhibited by (137) compared to that of the molybdenum
catalyst (136). The more recent introduction of N-heterocyclic carbene-coordinated
catalysts, such as (138), has considerably improved the reactivity of the ruthenium based
catalysts while retaining the functional group tolerance of (137).130
R
N
Cl
Mo
F3C
O
CF3 O
Ph
Cl
PCy3
Ph
Ru
F3C
PCy3
137
CF3
136
54
H
N
Cl
Cl
N
R
Ph
Ru
PCy3
138
H
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
Olefin metathesis forms part of three closely related reactions: ring-opening
metathesis polymerisation (ROMP), acyclic cross metathesis and ring-closing metathesis
(RCM).131 The general mechanism involves a series of alternating [2+2] cycloadditions
and cycloreversions between the metal alkylidene and the metallacyclobutane species.129
This mechanism was first postulated by Chauvin132 for polymerisation reactions and is
now generally accepted for olefin metatheses. Using RCM as an example, the first step
involves the cycloaddition between the metal catalyst and an alkene to form the
metallacyclobutane species. This then undergoes a cycloreversion to form the metal
alkylidene with the elimination of ethene. Another cycloaddition followed by a
cycloreversion regenerates the activated catalyst and forms the new carbon-carbon
double bond as either the E isomer or Z isomer or a mixture of the two. The
stereochemical outcome of the reaction is governed by the conformation of the substrate
and the stability of the possible products. The mechanism is illustrated in Scheme 39
which also shows the overall reactions.129,131 The mechanism is in reverse in the case of
ROMP.
Overall Reaction
Ring-Closing Metathesis
Polymerisation
RI
+ R
Overall Reaction
Acyclic Cross Metathesis
II
n
RI
R
II
Overall Reaction
Ring-Closing Metathesis
LnM
LnM
CHR
LnM
CHR
CHR
LnM
LnM
H2C
CHR
Scheme 39
Cyclic Cross Metathesis Reaction
In cross metatheses three unique products can be formed: one desired
heterodimeric product and two homodimeric products, each as a mixture of olefin
isomers.133 Our aim was to determine whether the cyclic cross metathesis reaction of
55
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
diene (132) that contains three sulfur atoms, with spiroacetal diene (133) would proceed
to give the cross metathesis product (134) as depicted in Scheme 40.
O
S
S
S
132
O
O
+
O
O
O
O
133
O
S
S
S
134
Scheme 40
Much of the literature suggests that compounds containing sulfur atoms are not
very susceptible to olefin metathesis reactions because the sulfur atoms and the metal
centres of the catalysts interact favourably.134 The sulfur atoms can coordinate to the
metal and deplete the active catalyst and thereby terminate the catalysis. Despite this
observation several authors have shown that olefin metathesis has been successful in
compounds containing one or two sulfur atoms. 135
In 1995 Basset et al135a were the first to report the formation of a cyclic sulfur
compound via RCM using a tungsten alkylidene catalyst (139) (Scheme 41).
Armstrong,135b Lee135c and their co-workers have since reported the application of olefin
metathesis to a range of sulfide and disulfide compounds.
139
W
O
OEt2
ArO Cl
S
S
(Ar = 2,6-diphenyl-C6H3)
Scheme 41
Initially the cross metathesis between diene (132) and the bisallyl ether (133) was
attempted using Grubbs’ catalyst (137) (5 mol%) in dichloromethane. It was observed
that the colour of the reaction mixture changed almost immediately from a deep
purple/red to a yellow/black as soon as the reactants were added to the catalyst. This was
a probable indication that the catalyst had been poisoned.129 It has been reported that
Shrock’s molybdenum catalyst (136) is much more stable towards sulfide groups. This is
because the sulfur atoms do not coordinate as well to the molybdenum as they do to the
56
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
ruthenium metal. Using Shrock’s catalyst (136) in benzene also proved to be
disappointing with no change in either starting materials being detected after 5 h at room
temperature or reflux. The catalyst eventually deteriorated and only the spiroacetal
bisallyl ether (133) starting material was recovered.
In order to conclusively determine the effect of each of the substrates on the
catalysts, a ring-closing metathesis reaction was attempted using each of the individual
reactants (132) and (133). The nine-membered cyclic sulfide (140) and spiroacetal olefin
(141) were the envisaged products (Scheme 42) from the ring-closing metathesis of (132)
and (133) respectively.
O
O
S
S
S
S
132
S
O
O
S
140
O
O
133
O
O
141
Scheme 42
Attempted ring-closing metathesis of diene (132) using Grubbs’ catalyst (137)
was not successful and was again indicated by a colour change of the reaction mixture.
The use of Shrock’s catalyst (136) also proved to be ineffective. On the other hand, the
RCM reaction of the bisallyl ether (133) led to the formation of an interesting set of
spiroacetal compounds with a general structure represented by compound (142) (Scheme
43). The initial reaction was performed using Grubbs’ catalyst (137) (5 mol%) in
dichloromethane for 6 h at reflux and yielded three relatively polar compounds after
purification by flash chromatography. These same products were obtained using Shrock’s
catalyst (136) in similar yields.
57
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
8
9
O7
10
6
1
5
4
3
O
O
O
1'
4'
i or ii
O
O
2
O
11
3'
2'
2'
3'
1'
O
4'
O
O
3
5
O
1
142a
142b
142c
6
7
O
Reagents and Conditions: (i) Grubbs’ catalyst (137), CH2Cl2, reflux, 6 h,
142a (15%), 142b (40%), 142c (10%); (ii) Shrock’s catalyst (136), benzene,
room temp., 5 h, 142a (18%), 142b (45%), 142c (9%)
Scheme 43
Initial examination of the 1H and
13
C NMR spectra of the three compounds
suggested they were structurally very similar. The spectra also resembled that of the
bisallyl ether with the exception that the terminal carbons of the alkene were absent. This
initial analysis suggested the formation of three RCM products as a mixture of isomers.
However, further analysis by high resolution mass spectroscopy indicated that the
compounds obtained were not the desired RCM product (141) since the mass spectra
exhibited molecular ions with twice the mass expected for the desired RCM compound
(141). This was consistent with the formation of spiroacetal dimers (142a-c) arising from
a cross metathesis reaction. Only one set of signals was observed in the 1H and 13C NMR
spectra, which suggested that all three compounds were symmetrical. This also implied
each dimeric compound had the same stereochemistry on each of its two double bonds.
Detailed assignment of the exact stereochemistry for the three isomers of the dimers
(142a-c) obtained proved to be elusive. However, the three isomeric products, dimer
(142a), (142b) and (142c) were readily separated and purified by flash chromatography
and exhibited unique 1H and 13C NMR spectra.
Dimer (142a) was obtained as fine white needes in 15% yield. A molecular ion at
m/z 480.27238 in the high resolution mass spectrum established the molecular formula
C26H40O8. The 1H NMR spectrum was assigned with the aid of 2D COSY and HSQC
experiments. 5-H resonated as a triplet at δH 3.05 with J5,4 3.4 Hz. Two broad singlets
58
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
were observed for 3-H at δH 3.32 and the vinylic protons resonated at δH 5.89. 4-Hax
resonated as a double double doublet at δH1.85 with J4ax,4eq 15.0, J4ax,3 3.4 and
J4ax,5 3.4 Hz confirming that both 5-H and 3-H were in an equatorial orientation. The
C NMR spectrum exhibited resonances at δC 71.3 and δC 76.2, which are characteristic
13
of C-3 and C-5 respectively. The quaternary spirocarbon C-6 resonated at δC 96.3. The
vinylic carbons were observed at δC 129.0 and δC 129.2. Attempted crystallisation of
dimer (142a) using several solvent systems did not afford crystals suitable for X-ray
crystallographic analysis.
Dimer (142b) was obtained as a viscous oil in 40% yield with a molecular ion at
m/z 480.27275 which supported the molecular formula C26H40O8. 5-H resonated as a
triplet at δH 3.07 with J5,4 3.4 Hz suggesting that 5-H was in an equatorial orientation.
4-Hax resonated as a double double doublet at δH 1.86 with J4ax,4eq 14.9, J4ax,3 3.4 and
J4ax,5 3.4 Hz confirming that 5-H adopts an equatorial position. The vinylic protons 2’-H
and 3’-H resonated as a triplet at δH 5.89 with JCH,OCH2 2.8 Hz. The 13C NMR spectrum
exhibited resonances at δC 71.0 and δC 76.4 assigned to C-3 and C-5 respectively and the
vinylic carbons resonated at δC 129.1 and δC 129.2.
Dimer (142c) was synthesised in 10% yield as a viscous oil and the high
resolution mass spectrum exhibited a molecular ion at m/z 480.27248 establishing the
molecular formula C26H40O8. In the 1H NMR spectrum 4-Hax resonated slightly further
downfield at δH 1.95 with J4ax,4eq 14.6, J4ax,3 3.7 and J4ax,5 3.7 Hz compared to the
analogous protons in dimers (142a) and (142b). 4-Heq was observed as multiplet at
δH 2.05 and 3-H resonated as a multiplet at δH 2.05. 5-H was observed as a triplet at
δH 3.09 with J5,4 3.7 Hz. The vinylic protons resonated as triplets at δH 5.89 and δH 5.91
with JCH,OCH2 2.6 Hz. The 13C NMR spectrum exhibited resonances at δC 70.7 and δC 76.1
representing C-3 and C-5 respectively and the quaternary spirocarbon C-6 resonated at
δC 96.9. The vinylic carbons resonated at δC 128.9 and δC 128.4. A summary of the
1
H NMR data is presented in Table 1.
59
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
O
O
5
O
O
3'
O
4'
Dimer
142a
3-H
3.32, br s
2'
O
6
4
7
O1
O
3
142a
142b
142c
1'
4-Hax
5-H
OCH2CH=CH
1.85, ddd, J4ax,4eq 15.0, 3.05, t, J5,4 3.4 3.86-4.06, m
CH=CH
5.89, br s
J4ax,5 3.4, J4ax,3 3.4
142b
3.31, br s
1.86, ddd, J4ax,4eq 14.9, 3.07, t, J5,4 3.4 3.84-4.07, m
5.89, t, J 2.8
J4ax,5 3.4, J4ax,3 3.4
142c
3.35, m
1.95, ddd, J4ax,4eq 14.6, 3.09, t, J5,4 3.7 3.84-4.10, m
5.89, t, J 2.5
J4ax,5 3.7, J4ax,3 3.7
5.91, t, J 2.5
Table 1: Selected 1H NMR Chemical Shifts and Coupling Constants for Dimers (142a),
(142b) and (142c).
As mentioned previously, the NMR data indicates that all three dimers are symmetrical.
It is proposed there are two possible forms of symmetry inherent in dimers (142a),
(142b) and (142c). Structure (143) shows a Ci centre of symmetry while structure (144)
shows a C2 axis of symmetry. Each symmetrical conformation is also capable of having
both unsaturated bonds in either E or Z orientations.
O
O
O
O
O
O
O
O
C2 Axis of Symmetry
Ci Centre of Symmetry
O
O
O
O
O
O
O
O
143
144
60
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
3.4
Synthesis of the Spiroacetal Thiacrown Ethers via Path B
Disappointed by the inability to effect reaction of the spiroacetal diol (50) with
β-chloroethyl sulfide (104) via Path A, our attention next focused on the alternative
disconnection summarised by Path B in Scheme 44.
O
O
Path B
O
O
+
n
HS
O
O
O
S
O
OR
S
S
S
SH
99, n = 3
122, n = 4
123, n = 5
RO
146, R = Ts
147, R = Ms
n
55, n = 3
56, n = 4
57, n = 5
Scheme 44
Adoption of Path B in the retrosynthetic analysis involved the use of dithiols (99),
(122) and (123) as nucleophiles in the displacement of two leaving groups attached to the
present on the C-3 and C-5 on the spiroacetal ring system. The thiols (99), (122) and
(123) had previously been prepared using the method by Edema et al122 (Scheme 35). It
was envisaged that spiroacetal diol (145) could be synthesised from spiroacetal diol (50)
and in turn the hydroxyl groups of (145) could be tosylated or mesylated to yield (146) or
(147) respectively (Scheme 45).
O
O
OH
O
O
O
O
OH
O
O
O
O
O
O
O
RO
S
O
50
OH
OR
HO
146, R = Ts
147, R = Ms
145
S
S
n
55, n = 3
56, n = 4
57, n = 5
Scheme 45
61
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
3.4.1 Synthesis of Spiroacetal Diol (145)
In order to pursue the synthetic strategy outlined in Scheme 45, initial synthesis
of the spiroacetal diol (145) was required starting from the previous diol (50). In the
synthesis of diol (145) two different approaches were investigated. It was envisaged that
reduction of a diester (149) (Scheme 46) or ozonolysis of the bisallyl ether (133)
(Scheme 47) would provide effective methods for the synthesis of diol (145). Several
procedures were evaluated for the synthesis of the diester (Table 2). Treatment of the
spiroacetal diol (50) with sodium hydride for 30 min in THF at 0 °C followed by the
addition of tert-butyl bromoacetate (148) gave the desired diester in 52% yield after
work-up and purification by flash chromatography.
O
O
OH
+
6
i
Br
O
O7
O
1
O
O
O
5
OH
3
O
O
O
O
O
O
148
50
O
OH
O
HO
145
149
Reagents and Conditions: (i) NaH, THF, 0 °C, 30 min, then 18-Crown-6
and 148 (2.0 equiv), 0 °C→room temp, 18 h, 149 (52%)
Scheme 46
Entry
Base
Temperature
Reagent
Product
(°C)
1
NaH
Reflux
BrCH2CO2Et
Complex mixture
2
n-BuLi
-78
BrCH2CO2Et
Recovered starting material
3
NaH
0
BrCH2CO2Et
Recovered starting material
4
NaH
0
BrCH2CO2tBu
Diester (149) 52% yield
Table 2: Reactions Conditions Used in the Synthesis of Diester (149)
The spiroacetal diester (146) analysed correctly for C21H36O8 with a molecular ion
at m/z 416.24092 being observed in the high resolution mass spectrum. The 1H NMR
spectrum exhibited an eighteen-proton singlet δH 1.46 assigned to the methyl groups of
the tert-butyl group. 5-H resonated as a triplet at δH 3.29 with J5,4 4.6 Hz. 3-H resonated
62
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
as a double double double doublet at δH 3.53 with J3,2ax 3.5, J3,2eq 3.5, J3,4ax 3.5 and
J3,4eq 3.5 Hz. The
13
C NMR spectrum exhibited resonances at δC 71.9 and δC 76.8
assigned to C-3 and C-5. The quaternary spirocentre C-6 resonated at δC 97.4. The two
carbonyl carbons resonated very close to each other at δC 170.001 and δC 170.011.
Due to the moderate yield of the diester (149) obtained, the alternative ozonolysis
method was investigated to provide diol (145). Ozone was bubbled through a solution of
the bisallyl ether (133) in methanol until a pale blue colour persisted (ca 10-15 min)
indicating that an excess of ozone was present (Scheme 47). The intermediate ozonide
was reduced using sodium borohydride. Subsequent work-up and purification by flash
chromatography afforded diol (145) in 75% yield.
O7
O
6
i
O
1
O
5
O
3
O
O
O
1'
1'
2'
2'
OH
133
HO
145
Reagents and Conditions: (i) ozone, MeOH, -78 °C, 15 min
then NaBH4, room temp, 18 h, 145 (75%).
Scheme 47
A molecular ion m/z at 276.15725 in the high resolution mass spectrum supported
the molecular formula C13H24O6. The infrared spectrum exhibited a broad absorbance at
3628-3290 cm-1 supporting the formation of a diol group. A double double doublet at
δH 1.98 with J4ax,4eq 15.1, J4ax,3 3.6 and J4ax,5 3.6 Hz was assigned to the axial proton at
C-4. The equatorial proton at C-4 also resonated as a multiplet at δH 2.11-2.29 together
with 11-Heq. 5-H resonated as a triplet at δH 3.11 with J5,4 3.6 Hz. The equatorial 3-H
resonated as a multiplet at δH 3.37-3.41. The 13C NMR spectrum exhibited resonances at
δC 26.0 assigned to C-4, δC 72.2 assigned to C-3 and δC 77.2 assigned to C-5. The
methine carbons bearing the OH groups resonated at δC 70.9 and 71.3 and the quaternary
spirocarbon C-6 resonated at δC 96.1.
63
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
3.4.2 Ditosylation of Spiroacetal Diol (145)
The synthesis of the ditosylate (146) was next attempted. The tosylate group was
chosen over the mesylate because of its greater stability. The synthesis was achieved by
the addition of n-butyllithium to a solution of diol (145) in THF at –78 °C followed by
the addition of p-toluenesulfonyl chloride after 30 min. The reaction mixture was then
warmed to room temperature and the solution left to stir for 16 h (Scheme 48).
Subsequent work-up and purification by flash chromatography yielded the ditosylate
(146) in 90% yield.
O7
O
6
i
O
1
O
5
O
3
O
O
O
1'
1'
2'
OH
2'
OTs TsO
HO
145
146
Reagents and Conditions: (i) n-BuLi, THF, -78 °C, 30 min,
then TsCl, 30 min, room temp, 16 h, 143 (90%)
Scheme 48
Spiroacetal ditosylate (146) analysed correctly for C27H36O10S2 with a molecular
ion m/z at 585.18336 being observed in the high resolution mass spectrum. The 1H NMR
spectrum exhibited a six-proton singlet δH 2.44 assigned to the methyl groups of the tosyl
moiety. The proton at C-5 resonated as a triplet at δH 2.44 with J5,4 3.9 Hz and the
equatorial proton at C-3 resonated as a double double double doublet at δH 3.34 with
J3,2ax 3.2, J3,2eq 3.2, J3,4ax 3.2 and J3,4eq 3.2 Hz confirming, that 3-H and 5-H were both
equatorial. The aromatic protons were observed as a multiplet at δH 7.31-7.79. The
13
C
NMR spectrum exhibited resonances at δC 69.5 and δC 69.6 assigned to C-1’. C-3 and
C-5 resonated at δC 72.2 and δC 77.2 respectively. A quaternary resonance at δC 96.5
confirmed the presence of the spiroacetal carbon.
64
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
3.4.3 Synthesis of Spiroacetal Thiacrown Ethers (55), (56) and (57)
Thiacrown ether (55)
Having successfully prepared ditosylate (146) and the thiols (99), (122), and
(123), the synthesis of the thiacrown ethers was next undertaken. It was decided to use
the method reported by Kellogg et al108,136 for related systems. Thus, ditosylate (146) and
2-mercaptoethyl sulfide (99) were added simultaneously from separate addition funnels
to a suspension of Cs2CO3 in DMF over 2-3 h at 60 °C (Scheme 49). The reaction was
allowed to proceed for 18 h at 60 °C after the final addition. Subsequent work-up and
purification by flash chromatography afforded the first thiacrown ether (55) in 86% yield.
6'
5'
O
O 1'
4'
O
O
+
O
HS
S
n
2' 18
i
17
SH
1
n=1
16
O
3'
2
19
15
O 14
O
3
99
13
12
4
OTs TsO
5
146
S
S 11
S
6
8
7
Reagents and Conditions: (i) Cs2CO3, DMF, 60 °C,
10
9
55
99 and 146 in DMF added over 2.5 h, 55 (86%)
Scheme 49
A molecular ion at m/z 394.13104 in the high resolution mass spectrum supported
the molecular formula C17H30O4S3. The 1H NMR spectrum was assigned with the aid of
2D COSY and HMQC experiments. Characteristically, 3’-Heq resonated as a double
double doublet at δH 1.26 with J3’ax,3’eq 13.6, J3’ax,4’ax 13.6 and J3’ax,4’eq 4.4 Hz. 1-H
resonated as a triplet at δH 3.09 with J1,19 3.4 Hz suggesting that 1-H is equatorial. 15-H
was observed as a multiplet at δH 3.37 however the double double doublet at δH 1.91 with
J19ax,19eq 15.2, J19ax,1 3.4 and J19ax,15 3.4 Hz assigned to 19-Hax established that 15-H is
also equatorial. 3-HA resonated as a double double doublet at δH 3.41 with Jgem 6.8,
J3A,4A 9.0 and J3A,4B 9.0 Hz. It is unusual for geminal coupling to be smaller than vicinal
coupling however it was reasoned that the coupling constants of the same magnitude
(9.0 Hz) are representative of protons on the same carbon. The
65
13
C NMR spectrum
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
exhibited resonances at δC 31.4, 31.8, 32.3, 32.4, 33.2 and 33.5 assigned to the six CH2S
carbons. C-3 showed a resonance at δC 70.3, whilst C-15 and C-1 resonated at δC 72.0
and δC 77.2 respectively. The characteristic resonance at δC 96.6 was assigned to the
spirocentre.
Thiacrown Ether (56)
The synthesis of the larger 19-thiacrown-6 (56) analogue was next undertaken
using similar methodology to that described for the synthesis of thiacrown (55).
Spiroacetal thiacrown ether (56) was prepared in 68% yield by the reaction of ditosylate
(146) with dithiol (122) in the presence of cesium carbonate in DMF at 60 °C for 18 h
(Scheme 50). Thiacrown ether (56) was isolated as a colourless oil after purification by
flash chromatography.
6'
5'
O
O1'
4'
O
O
+
O
HS
n
S
2' 21'
i
SH
1
n=2
3
122
20
19
O
3'
22
18
2
17
O
O
16
4
15
5
OTs TsO
S 14
S
6
146
13
7
8
S
S 11
9
Reagents and Conditions: (i) Cs2CO3, DMF, 60 °C,
12
10
56
122 and 146 in DMF added over 2.5 h, 56 (68%)
Scheme 50
A molecular ion at m/z 454.13397 in the high resolution mass spectrum supported
the molecular formula C19H34O4S4. In the 1H NMR spectrum 1-H resonated as a triplet at
δH 3.09 with J1,22 3.7 Hz. 18-H resonated as a double double double doublet at δH 3.37
with J18eq,22ax 3.7, J18eq,22eq 3.7, J18eq,19ax 3.7 and J18eq,19eq 3.7 Hz, suggesting that 1-H and
18-H were in equatorial orientations. A double double doublet at δH 1.97 with
J22ax,22eq 14.8, J22ax,18 3.7 and J22ax,1 3.7 Hz was assigned to the axial proton 22-Hax.
22-Heq resonated as a double double double doublet at δH 2.07 with J22eq,22ax 14.8,
J22eq,1 3.7, J22eq,18 3.7 and J22eq,19eq 1.9 Hz. The 13C NMR spectrum exhibited resonances
66
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
for C-1 and C-18 at δC 77.2 and δC 71.9 respectively whilst the characteristic resonance at
δC 96.5 indicated the presence of the spirocentre.
Thiacrown Ether (57)
Finally, the synthesis of the 22-thiacrown-7 (57) was carried out using a similar
procedure to that used for the preparation of thiacrown ethers (55) and (56) (Scheme 51).
Thiacrown ether (57) was obtained by treatment of ditosylate (146) with dithiol (123) in
the presence of cesium carbonate in DMF at 60 °C. 22-Thiacrown-7 (57) was isolated as
a pale yellow oil in 64% yield after purification by flash chromatography.
6'
5'
O
O 1'
4'
O
+
HS
S
n
SH
2' 24
i
23
25
1
21
n=3
O
O
2
123
OTs TsO
5
146
22
O
3'
O 20
O
3
19
4
18
S
S 17
6
16
7
8
15
S
10
9
S
13
11
Reagents and Conditions: (i) Cs2CO3, DMF, 60 °C,
S 14
12
57
123 and 146 in DMF added over 2.5 h, 57 (64%)
Scheme 51
Spiroacetal thiacrown ether (57) analysed correctly for C21H38O4S5 with a
molecular ion m/z 514.13764 in the high resolution mass spectrum supporting this
molecular formula. In the 1H NMR spectrum 1-H resonated as a triplet at δH 3.08 with
J1,25 3.8 Hz . 25-Hax resonated as a double double doublet at δH 1.95 with J25ax,25eq 14.8,
J25ax,1 3.8 and J25ax,21 3.8 Hz, confirming that 1-H and 21-H adopt equatorial positions. A
twenty proton multiplet at δH 2.69-2.84 was assigned to the CH2S protons. The 13C NMR
spectrum exhibited resonances at δC 71.9 and δC 77.1 assigned to C-21 and C-1
respectively and the quaternary spirocentre resonated at δC 96.5.
67
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
3.5
Synthesis of the Spiroacetal Azacrown Ethers
The synthesis of azacrown ethers (58), (59) and (60) proved to be much more
difficult than anticipated. The choice of method was dependent on the sensitivity of the
spiroacetal functionality to the corresponding reaction conditions. Having established
previously that the synthesis of the thiacrown ethers via Path A was not successful it was
envisaged that the synthesis of azacrown ethers could be carried out following the
retrosynthetic outline for Path B (Scheme 24). The reaction between the appropriate
spiroacetal compound and diamine was predicted to yield the desired azacrown ethers
(58), (59) and (60).
O
O
NH
O
O
O
O
O
O
H
N
O
NH
O
O
NH
HN
NH
O
HN
NH
HN
58
HN
59
N
H 60
NH
It has been reported that the addition of unprotected triamine (151) to a
dialdehyde without the use of a template formed the desired azacrown ether after
reduction of the intermediate diimine.137 It was believed that this method would yield the
unsaturated azacrown ethers (152), (153) and (154) which would then be reduced to give
(58), (59) and (60) respectively (Scheme 52). The spiroacetal dialdehyde (150) required
for this reaction was prepared from bisallyl ether (133) via an ozonolysis reaction.
The sulfonamide method is one of the most commonly used synthetic
methodologies in the synthesis of azacrown ethers. The reaction between the spiroacetal
ditosylate (146) and the protected polyamines, such as (155) and (156), was envisaged to
afford the spiroacetal azacrown ethers (58), (59) and (60) after deprotection (Scheme 53).
68
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
O
O
O
O
H
H
N
O
+
H2N
O
O
O
O
+
RHN
n
N
R
O
NR
OTs TsO
N
H
N
154, n = 1
155, n = 2
156, n = 3
152, n = 2
153, n = 3
O
O
n
n
N
NH2
H 151, n = 1
O
146
O
O
O
O
O
150
NR
R
N
n
NHR
159, n = 1
160, n = 2
161, n = 3
157, R = Ts
158, R = Ns
Scheme 52
Scheme 53
3.5.1 Attempted Synthesis of Spiroacetal Azacrown Ethers (58), (59) and (60)
via formation of Imines from Aldehyde (150)
Starting with the bisallyl ether (133) it was envisaged that a reductive ozonolysis
using dimethyl sulfide would furnish spiroacetal dialdehyde (150) required for the
subsequent reaction with the diamines. In a protic solvent, such as methanol, ozonolysis
yields the aldehyde and a hydroperoxide by-product. Dimethyl sulfide readily reduces the
hydroperoxide at low temperatures but not the aldehyde to form dimethyl sulfoxide,
which is easily removed by purification.138 Thus, treatment of the bisallyl ether (133) in
methanol with ozone at –78 °C followed by the addition of dimethyl sulfide afforded the
dialdehyde (150) in 86% yield as an oil (Scheme 54).
8
9
O
10
6
i
O
1
O
11
5
O
O7
4
O
O
O
133
3
O
H
H
O
150
Reagents and Conditions: (i) ozone, MeOH, -78 °C,
15 min then (CH3)2S, room temp, 18 h, 150 (86%)
Scheme 54
Spiroacetal dialdehyde (150) analysed correctly for C13H20O6 with a molecular
ion m/z at 272.12576 in the high resolution mass spectrum. The infrared spectrum
69
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
exhibited a strong absorbance at 1733 cm-1 supporting the formation of the dialdehyde.
The aldehyde protons resonated as a multiplet at δH 9.68-9.74. The characteristic axial
proton 11-Hax resonated as a double double doublet at δH 1.43 with J11ax,11eq 13.5,
J11ax,10ax 13.5 and J11ax,10eq 4.8. 5-H resonated as a triplet at δH 3.21 with J5,4 3.8 Hz,
confirming that 5-H is in the equatorial orientation. 3-H resonated as a multiplet at
δH 3.44-3.46 and 4-CH2 also resonated as a multiplet with 11-Heq at δH 2.04-2.22. The
C NMR spectrum exhibited characteristic resonances at δC 72.7 and δC 76.8 assigned to
13
C-3 and C-5 respectively. The quaternary spirocarbon resonated at δC 96.6 and the two
aldehyde carbonyl groups resonated at δC 201.1 and 201.3.
Having successfully synthesised dialdehyde (150), its subsequent condensation
reaction with diamine (151) was investigated (Scheme 55). Dialdehyde (150) and
commercially available diethylenetriamine (151) were added to a solution of refluxing
benzene. The reaction was heated for 18 h with removal of the water by azeotropic
distillation. Disappointingly, this procedure did not afford the desired unsaturated crown
ether (154) and only polymeric material was obtained.
O
O
O
O
+
O
O
H
H
i
H2N
N
H
O
NH2
O
151
N
O
150
O
H
N
N
154
Reagents and Conditions: (i) benzene, reflux
Scheme 55
3.5.2 The Sulfonamide Method
The sulfonamide method was considered to be a more effective route for the
synthesis of the spiroacetal azacrown ethers (58), (59) and (60). The first consideration
was the protection of the nitrogen atoms in the triamine compound. The choice of
protecting group was primarily based on the conditions required for the subsequent
removal of the protecting groups because of the sensitivity of the spiroacetal
functionality. Initially the tosyl protected triamine (157) was used in the reaction with
70
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
spiroacetal ditosylate (Table 3, entries 1 and 2). However, due to the unsuccessful
attempt to effect cyclisation and the usually harsh conditions required to remove the tosyl
group (namely, use of strong acids) other protecting groups were investigated. It was
thought that the o-nosylate group utilised by Fukuyama et al87 would be more successful.
Thus,
triamine
(151)
was
treated
with
2-nitrobenzenesulfonyl
chloride
in
dichloromethane at 0 °C. The reaction was allowed to proceed for 18 h at room
temperature. Subsequent work-up and purification afforded the desired o-nosyl protected
triamine (158) in 80% yield.
O
1
O2N
O
2
3
S
O
NO2
NH
N
O
S
HN
O
S
O
NO2
158
A protonated molecular ion at m/z 659.05478 in the high resolution mass
spectrum supported the molecular formula C22H23N6O12S3. In the 1H NMR spectrum the
NH resonated as a triplet at δH 5.72 with JNH,CH2 6.1 Hz. The CH2NH group resonated as
a multiplet at δH 3.30-3.37. The CH2N group resonated as triplet at δH 3.54 with
JCH2N,CH2NH 6.1 Hz. The 13C NMR spectrum exhibited resonances at δC 42.3 and δC 49.0,
which were assigned to CH2NH and CH2N respectively.
The reaction between the Ns-protected triamine (158) and the spiroacetal
ditosylate (146) was next attempted. The ideal conditions for sulfonamide reactions
include using cesium or potassium carbonate in dimethylformamide at 20-50 °C. The
reaction of ditosylate (146) with trinosylate (158) was attempted using reaction
conditions successfully utilised by several other groups (Table 3). The slow (ca 2 h)
addition of the spiroacetal ditosylate (146) to a suspension of (158) and NaH in THF
eventually afforded the Ns-protected azacrown ether (159), albeit in 27% yield (Scheme
56).
71
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
6'
5'
O
O 1'
4'
O
O
HN
Ns
N
Ns
n
NH
Ns
2' 18
i
O
19
1
2
n=1
17
16
O
3'
15
O 14
O
3
158
O
Ns =
13
12
4
OTs TsO
S
5 NNs
146
O
6
7
NO2
11
NNs
8
N
Ns
9
10
159
Reagents and Conditions: (i) NaH, reflux,
30 min then 146 over 3 h, 18 h, 159 (27%)
Scheme 56
Entry
Base
Temperature
Solvent
Product
(°C)
1
NaHa
Reflux
THF
Complex Mixture
2
K2CO3a
60
DMF
Complex Mixture
3
Cs2CO3
RT
DMF
Recovered Starting Material
4
Cs2CO3
60
DMF
Complex Mixture
5
Cs2CO3
40
DMF
Starting Material and Mixture
6
NaH
45
DMF
Complex Mixture
7
Cs2CO3
60
CH3CN
Starting Material
8
NaH
Reflux
THF
Protected Azacrown (159) 27% yield
Table 3: Reaction Conditions Used in the Synthesis of Protected Azacrown (159)
The high resolution mass spectrum for the protected spiroacetal azacrown ether
(159) exhibited a protonated molecular ion at m/z 899.18910 consistent with the
molecular formula C35H43N6O16S3. The 1H NMR spectrum was assigned with the aid of
2D COSY and HMQC experiments. 1-H resonated as triplet at δH 3.03 with J1,19 3.0 Hz,
affirming that 1-H adopted an equatorial position. 15-H resonated as a broad singlet at
δH 3.24. 19-CH2 resonated as a multiplet at δH 2.03. The equatorial 3’-H resonated as a
double double doublet at δH 1.96 with J3’eq,3’ax 13.5, J3’eq,4’ax 2.1 and J3’eq,4’eq 2.1 Hz. The
C NMR spectrum exhibited resonances at δC 48.4-51.0 assigned to the CH2N carbons.
13
a
Reaction carried out with Ts-protected triamine (157)
72
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
The spirocarbon resonated characteristically at δC 96.1 whilst C-15 and C-1 resonated at
δC 72.0 and δC 77.5 respectively.
The deprotection of (159) was carried out using thiophenol and potassium
carbonate in DMF at room temperature for 18 h to afford the spiroacetal azacrown ether
(58) in 84% yield (Scheme 57). It is believed that the removal of the 2-nitrosulfonyl
groups using potassium carbonate and thiophenol is achieved via the formation of the
Meisenheimer complex (162).87
6'
5'
O
O
2' 18
i
O
O 1'
4'
O
19
1
O
O
O
2
O
17
16
O
3'
15
O 14
O
13
3
12
4
NNs
NNs
N
Ns
NNs
NNs
5
6
N
O
PhS
159
S
NH
7
O
H
N
8
11
9
NH
10
58
NO2
162
Reagents and Conditions: (i) K2CO3, PhSH, DMF, 58 (84%)
Scheme 57
A protonated molecular ion at m/z 344.25423 in the high resolution mass
spectrum supported the molecular formula C17H34N3O4. The 1H NMR spectrum was
assigned with the aid of 2D COSY experiment. 1-H resonated as triplet at δH 3.04 with
J1,19 3.2 Hz whilst 15-H resonated as a broad singlet at δH 3.29. The CH2N protons
resonated as a multiplet at δH 2.63-2.89. A 13C NMR spectrum for this compound could
not be obtained as there was insufficient material to give a satisfactory signal to noise
ratio.
Disappointingly, subsequent attempts to synthesise the protected spiroacetal
azacrown ether (159) proved difficult to repeat. Attempts to vary the conditions, the
concentration of the reactants, addition time and nature of the bases used, did not lead to
any improvement in the reaction. In light of the difficulties to synthesise azacrown ether
(58) efficiently, subsequent attempts to prepare the homologues azacrown ethers (59) and
(60) were not undertaken.
73
DISCUSSION: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers
3.6
Summary
In summary, the synthesis of the target spiroacetal thiacrown ethers (55), (56),
and (57) was successfully achieved following the retrosynthetic outline in Scheme 24 via
Path B. Reaction between the requisite dithiols (99), (122) and (123) and the spiroacetal
ditosylate (146) afforded the desired thiacrown ethers in good yields. The diol (145)
precursor to the ditosylate (146) was obtained via a reductive ozonolysis of the bisallyl
ether (133), which in turn was synthesised from the (±)-1,7-dioxaspiro[5.5]undec-4-ene
(114). During attempts to synthesise thiacrown ethers (55), (56) and (57) a novel set of
spiroacetal dimers (142a), (142b) and (142c) were synthesised by a cross metathesis
reaction of the bisallyl ether (133).
Disappointingly, the synthesis of the desired spiroacetal azacrown ethers (58),
(59) and (60) was achieved with limited success. The synthesis of (58) was carried out by
the reaction of the protected diamine (158) and the spiroacetal ditosylate (146) to afford
the Ns-protected azacrown ether (159). Subsequent removal of the protecting groups
afforded the azacrown ether (58).
74
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
4.0
Spiroacetal Thiacrown Ethers As Primary and Secondary
Ligands
Having successfully synthesised thiacrown ethers (55), (56) and (57) attention
then turned to their binding ability. Crown compounds can serve not only as primary
receptors for simple organic and inorganic cations, anions and neutral molecules but also
as second-sphere ligands for metal complexes.139 These different types of interactions
can be investigated using various spectroscopic methods such as UV-Visible
spectrometry and NMR spectroscopy.
O
O
O
O
O
O
O
S
O
S
S
O
O
O
S
S
S
O
S
S
S
55
S
56
S
S
57
4.0.1 Crown Ethers As Primary Ligands
The complex between a crown compound and an inorganic salt is formed by iondipole interactions between the cation and the donor atoms in the polyether ring.63 The
complexation ability of crown compounds and the stability of the resulting complex is
dependent on several factors, including the type of heteroatom in the ring and the cavity
size and shape. This is particularly true for the oxa- and azacrown compounds, which
have been shown to coordinate the cation within the crown ether cavity. In these cases,
the lone pairs of electrons are directed toward the inside (endodentate) of the cavity and
the donor atoms are located at an equal distance from the cation. Conversely, thiacrown
compounds tend to bridge metal ions rather than chelate to them because the sulfur atoms
have been shown to exist outside (exodentate) the cavity in many cases (Section 2.1).68,69
The design of biomimetic macromolecules has led to synthesis of many crown
compounds capable of transporting ions through cell membranes.140 Crown ethers play a
pivotal role in modifying the properties and behaviour of the metal compounds with
which they complex. For example, ions do not easily diffuse through the lipid bilayers
that surround cells, yet the transport of cations across cellular membranes is crucial in
75
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
such physiological processes as nerve impulse transmission, the control of muscular
function and protein biosynthesis.141 One way to achieve permeability is through the use
of ion carriers, such as crown ethers. Membrane cation transport has also been applied in
the selective separation of metal ions.142 Figure 10 illustrates the proton-driven transport
of metal ions through a membrane impregnated with water-immiscible solvent containing
the crown ether ligand.142b
HO
M
O
O
O
O
C12H25
NO2
M
O
H
H
O
O
M
O
Aqueous Source Phase
O
C12H25
Membrane Phase
NO2
Aqueous Receiving Phase
Figure 10
4.0.2 Second-Sphere Coordination
The idea of second-sphere coordination was first postulated by Alfred Werner143
in 1912 to explain a number of phenomena he observed through research with metal
complexes. In the ensuing years, advances in optical, spectroscopic and crystallographic
techniques have revealed a much wider range of phenomena that can only be explained
in terms of second-sphere coordination.144 Second-sphere coordination can generally be
described as the “non-covalent bonding of chemical entities to the first coordination
sphere of a transition metal complex.”145 The non-covalent interactions responsible
include electrostatic interactions, hydrogen bonding, charge transfer and hydrophobic
interactions.144,146
Second-sphere coordination can significantly affect the electronic state of the
metal centre and result in a modification of the properties of the metal complexes and
macrocycles
in
terms
of
photochemical,
magnetic
and
electrochemical
characteristics.144,146 For example, the photochemical properties of the second-sphere
adduct shown in Figure 11 are altered from those of the free compounds.147 Dibenzo-30crown-10 and [Pt(bpy)(NH3)2](PF6)2 interact through π-π stacking of the pyridine rings
and the aromatic units in the crown ether and hydrogen bonding of the amine groups to
the crown ether oxygen atoms. The absorption spectrum of the adduct showed a strong
76
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
charge transfer band as a result of the π-π stacking interaction. In addition, the
luminescence properties were altered, showing a new, broad, low-intensity emission
band.
N
N
O Pt2
O NH3
+
O
O
O
O
O
N H
H H
O
O
O
Figure 11
The adducts formed through second-sphere interactions have found applications
in a variety of areas including the possible treatment of cancer. For example, the
increased solubility of the neutral anti-cancer platinum complex, carboplatin (163), in
aqueous solutions of α-cyclodextrin (12) has lead to its possible application in cancer
chemotherapy.145 It has been shown that the cyclobutane ring of carboplatin (163) is
directed inside the ring while the amine ligands are positioned over one of the
glucopyranosyl residues. This allows for the formation of two hydrogen bonds with the
secondary hydroxyl groups of the glucopyranosyl residues (Figure 12).
O
OR
O
NH3
O
Pt
O
O
HO
HO
NH3
n = 6, R = H
163
12
NH3
H3N
Pt
OH
L
OH
Figure 12
77
OR
O
n
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
4.1
Binding Studies
4.1.1 Determination of Association Constants Using Picrate Salts
Conditional stability constants for thiacrown ethers (55), (56), (57) and 18-S-6
(100) were determined using the ultraviolet spectroscopic method devised by Cram et
al.148 This method relies on the fact that most crown ethers are insoluble in water and
most metal salts are insoluble in organic solvents. The procedure involves the
partitioning of the crown ether (host) and the metal picrate (guest) between chloroform
and water. The molar ratio (R) of host to guest in the chloroform layer is measured by
ultraviolet spectroscopy. The association constant (Ka) for the equilibrium (Equation 1)
and the free energy of complexation (∆G) (Equation 2) can then be determined from this
ratio.
Host org
+
Guest aq
Ka
Host.Guest Complex organic
Equation 1
CDCl3
∆G = -RT ln(Ka)
Equation 2
The affinity of thiacrowns (55), (56) and (57) for Li+, Na+, K+, Cs+, Co2+, Cd2+,
Ag+ and Pb2+ cations was determined using this method. The alkali metals are considered
‘hard’ ions, silver and cadmium are classified as ‘soft’ ions while lead and cobalt are
classed as ‘intermediate’ ions based on Pearson’s classification of hard-soft acid-base
theory (HSAB).149 The results are summarised in Table 4. Graphical representations are
depicted in Figures 14 and 15.
78
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
Host
Cation
Ka (M-1 x 103)
∆G° (kJ mol-1)
1,4,7,10,13,16Hexathiacyclooctadecane
(18-Thiacrown-6)
Li+
Na+
K+
Cs+
Co2+
Cd2+
Ag+
Pb2+
0.05
0.21
0.40
8.95
0.05
8.25
3801.27a
1.33
-9.37
-13.08
-14.71
-22.32
-9.82
-22.12
-37.16
-17.64
Li+
Na+
K+
Cs+
Co2+
Cd2+
Ag+
Pb2+
0.11
0.41
0.32
0.51
0.84
1.19
3683.06
35.71
-11.52
-14.78
-14.16
-15.27
-16.51
-17.39
-37.08
-25.71
Li+
Na+
K+
Cs+
Co2+
Cd2+
Ag+
Pb2+
0.24
1.83
0.45
0.66
1.10
1.15
1576.61
8.93
-13.49
-18.43
-15.00
-15.93
-17.18
-17.28
-35.00
-22.31
Li+
Na+
K+
Cs+
Co2+
Cd2+
Ag+
Pb2+
0.09
0.62
0.70
0.83
0.38
1.30
922.85
67.71
-11.08
-15.78
-16.05
-16.49
-14.60
-17.59
-33.69
-27.28
[1S*,15R*,18S*]Spiro[2,14,17-trioxa5,8,11-trithiabicyclo
[13.3.1]nonadecane18,2’-tetrahydropyran]
[1S*,18R*,21S*]Spiro[2,17,20-trioxa5,8,11,14-trithiabicyclo
[16.3.1]docosane-21,2’tetrahydropyran]
[1S*,21R*,24S*]Spiro[2,20,23-trioxa5,8,11,14,17pentathiabicyclo
[19.3.1]pentacosane24,2’-tetrahydropyran]
Table 4: Association Constants for Spiroacetal Thiacrown Ethers (55), (56) and (57)
a
3 x 10-3 M solution of silver picrate and 0.075 M solution of 18-S-6 (100) were used in the experiment because at
higher concentrations of silver picrate a precipitate formed.
79
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
Association Constants for Spiroacetal
Thiacrown Ethers (55), (56) and (57)
4000
3500
Ka x 103
3000
2500
2000
1500
1000
500
0
Li
Na
K
Cs
Co
Picrate Salts
19-Crown-6 (56)
16-Crown-5 (55)
Cd
Ag
22-Crown-7 (57)
Pb
18-S-6
Figure 14: Association Constants
Association Constants for Spiroacetal
Thiacrown Ethers (55), (56) and (57)
80
70
Ka x 103
60
50
40
30
20
10
0
Li
Na
16-Crown-5 (55)
K
Cs
Picrate Salts
19-Crown-6 (56)
Co
Cd
22-Crown-7 (57)
Pb
18-S-6
Figure 15: Association Constants (Expanded Region)
An initial comparison between the association constants of the spiroacetal crown
ethers (53a-c) and the spiroacetal thiacrown ethers (55), (56), (57) revealed that the
replacement of oxygen for sulfur donor atoms significantly decreased the ability of the
crown ethers to complex alkali metals. This is in accordance with the HSAB theory. The
spiroacetal crown ethers (55), (56), (57) do show a slightly greater ability to bind the
alkali metals compared to the 18-S-6 (100). A possible explanation for this is the fact that
80
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
the spiroacetal thiacrown ethers possess two oxygen atoms, which have an affinity for
alkali metals.
The thiacrown ethers exhibited an expected affinity for the heavy metals,
particularly silver. It is believed that electrostatic interactions do not predominate in the
complexation of silver by thiacrown macrocycles.150 The interaction is thought to be
largely covalent based on the Ag-S bond length.49,151 Spiroacetal thiacrown ethers (55),
(56) and (57) showed a lower binding affinity for silver than 18-S-6 (100). The difference
in the binding of silver by thiacrown (55) and 18-S-6 (100) is only small. Interestingly,
the difference in binding between thiacrown (56) and 18-S-6 (100) is much larger even
though (56) can be regarded as having a similar cavity size to 18-S-6 (100). The most
likely explanations for the reduced binding of silver are the conformation of thiacrown
(56) and the presence of the two oxygen atoms.
The spiroacetal thiacrown ethers (55), (56), (57) also showed an affinity toward
lead, however the stability of complexation was much lower than that for the silver. The
complexing ability was reduced by a factor of approximately 150. The association
constants for cadmium and cobalt were low indicating a weak interaction.
The large difference in the complexing behaviour of thiacrown ethers (55), (56),
(57) with silver compared to that of the alkali metals, cobalt and cadmium can be
explained in terms of the HSAB theory. Sulfur donor atoms are considered soft bases and
therefore prefer soft acids. Cadmium is classified as a soft acid however it has a low
value of softness.152
The large difference in the complexation of silver over lead cannot be completely
explained using the HSAB theory. Lead is considered a borderline acid and this may
partly explain the lower association constant. However, lead and silver are both thiophilic
metals, that is, they have an affinity for sulfur donor groups.153 One possible explanation
is the difference in the oxidation states. Generally, metal ions with lower oxidation states
exert less electrostatic attraction, however thiacrown ethers are known to stabilise lower
oxidation states of metals due to their π-acidity.154 This results in stronger binding of
metals with lower oxidation states (eg. Ag+) than those with higher oxidation states (eg.
Pb2+) and in this case could indicate that there may be some covalent (polar covalent)
bonding taking place.
Another possible reason for the difference in complexing stability of silver over
lead is that the conformation and arrangement of the donor atoms in the macrocycles may
favour the coordination geometry of the silver ion. Silver(I) has been found to favour a
linear or tetrahedral coordination geometry155 while lead(II) has been found to adopt
many different coordination geometries because of its ability to coordinate in a
81
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
holodirected or hemidirected geometry (Figure 13).156 In a holodirected geometry, the
bonds are directed throughout the surface of the metal, while in a hemidirected geometry
the bonds are only directed throughout a part of the metal.156b The void created is
assumed to be occupied by the Pb2+ lone pair of electrons. In hemidirected complexes,
the resulting bonds are believed to be weaker because there is less transfer of electrons
from the ligands to the bonding orbitals of the metal which may explain the lower
stability constant for lead(II). Lead(IV) was found to only exhibit the holodirected
coodination geometry for all coodination numbers.
Pb
Pb
Holodirected
Hemidirected
Figure 13
The size-match selectivity theory was also considered as a basis for the
discrimination of the silver ion over lead. However in this case it was not judged
fundamentally important because silver(I) and lead(II) have ionic radii of similar size.
4.1.2 Interaction Of Thiacrown Ethers (55), (56) and (57) with Neutral and
Ionic Complexes (Second-Sphere Coordination)
The aim of these experiments was to determine if any interactions could be
observed between metal complexes [Al(acac)3] (164), [Co(NH3)5NO2](BPh4)2 (165) and
[Co(en)3](BPh4)3 (166) and the crown compounds (55), (56), (57), 18-crown-6 (64) and
18-S-6 (100). This would provide a greater understanding of the nature of these
thiacrown compounds. The interaction was monitored by 1H NMR spectroscopy at 25 °C
in either chloroform or dimethylsulfoxide. The choice of solvent was dependent
primarily on its ability to solubilise the complexes. Proton NMR spectroscopy can be
used to measure the kinetic aspects of complexation and dissociation because of the small
chemical shift or linewidth differences between the complexed and uncomplexed species.
It can be used to detect differences in either the ligand or the cation. The direct
82
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
observation of the metal ions, such as 7Li,
23
Na,
39
K and
59
Co, has enhanced the
versatility of this method.
O
O
Al
(BPh4)2
NO2
O
O
O
H3N
H3N
O
164
Co
NH3
NH3
NH3
165
(BPh4)3
NH2
H2N
H2N
Co
NH2
N
H2
NH2
166
The interaction of (55), (56), (57), (64) and (100) with readily available
[Al(acac)3] (164), [Co(NH3)5NO2](BPh4)2 (165) and [Co(en)3](BPh4)3 (166) complexes
were thus examined. It was envisaged that the thiacrown ethers would behave differently
towards the neutral [Al(acac)3] (164) than with [Co(NH3)5NO2](BPh4)2 (165) and
[Co(en)3](BPh4)3 (166) species.
4.1.3 Interaction with [Co(NH3)5NO2](BPh4)2 (165) and [Co(en)3](BPh4)3 (166)
The interaction of the crown compounds with metal complexes was first
investigated using the cobalt complexes (165) and (166). The advantage of using the
cobalt complexes was that they had the potential to provide addition information through
the direct observation of the metal ion using 59Co NMR spectroscopy. Thus, a mixture of
the crown compounds was shaken for 5 minutes with one equivalent of the metal
complex in dimethylsulfoxide and monitored by 1H NMR for 1 h. Disappointingly, the
1
H NMR spectra were identical to those of the parent thiacrown ethers (55), (56), (57)
and 18-S-6 (100). It was particularly surprising that 18-crown-6 (64) also did not show
any interaction with [Co(NH3)5NO2](BPh4)2 (165), since it was envisaged that an
interaction based on hydrogen bonding would be observed between the amine groups and
the oxygen donor atoms.
There are several reasons for the lack of interaction between the cobalt complexes
and the thiacrown ethers. Firstly, the electrostatic interactions between these crown
compounds and the cobalt complexes may have been weak and difficult to detect. Direct
coordination of the crown compounds with the metal centre is not expected. It is possible
for ligand substitution to occur, however in these cases it was unlikely. Secondly, the
anion may have an effect on the possible interactions, however further investigations are
needed to conclusively determine any anionic effect. Finally, solvation may affect the
83
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
ability of the two species to interact as ion pairs. The concept of ion pairing deals with
two ions that are in close proximity to each other for a short time before their thermal
motions tear them apart.157 There are several proposed models for representing the
possible ion associations that exist in solution.157,158 The three types of ion pairs that exist
are solvated ions, solvent separated ion pairs and contact ion pairs. The extent of ionic
association is qualitatively related to the dielectric constant of the solvent,157 and it has
been found that the extent of ionic association increases as the dielectric constant of a
solvent decreases.159 DMSO has a high dielectric constant so it is not unreasonable to
assume that the ionic species in these experiments may have existed as solvated ions or
solvent separated ion pairs in DMSO.
4.1.4 Interaction with [Al(acac)3] (164)
The experiments carried out with the neutral [Al(acac)3] (164) complex did show
second sphere interaction with thiacrown crown compounds (56) and (57). The crown
compounds (55), (56), (57), (64) and (100) were again treated with one equivalent of the
metal complex and shaken in chloroform for 5 minutes and monitored by 1H NMR for
1 h. Thiacrown ethers (55) and (100) and 18-crown-6 (64) did not show any chemical
shift or line width differences in the 1H NMR spectrum. However, thiacrowns (56) and
(57) did show a change in their 1H NMR spectra.
In the uncomplexed form, thiacrown (56) exhibits a sixteen-proton multiplet at δH
2.72-2.82 assigned to the protons next to the sulfur atoms (CH2S). However, when
[Al(acac)3] (164) is added to the solution, the 1H NMR spectrum shows a broadening of
the signal to give a broad singlet at δH 2.77. Since no other signals were affected, this
suggested an interaction between the components of the polythioether segment and the
aluminium complex. Thiacrown (57) exhibited a similar type of interaction. A twentyproton multiplet was observed at δH 2.69-2.84, which was assigned to the CH2S groups in
the free crown compound. Once again, the addition of [Al(acac)3] (164) lead to a
broadening of the signal to produce a broad singlet at δH 2.78. Changes in line
broadening (and chemical shift) provide information on the nuclear environment of the
nucleus of interest.160 The line broadening observed in an NMR spectrum is related to the
rate of exchange and/or relaxation time of the particular nuclei. In this case, the increase
in line broadening was believed to be due to a restriction (decrease) in the rate of
exchange of the CH2S groups.
The charge distributions of both sets of compounds were determined using
electrostatic potential maps to better understand the type of interaction between the
84
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
thiacrown ethers and the aluminium complex. Electrostatic potential maps are used to
calculate the electron rich (red) and electron poor (blue) areas in a molecule. The
electrostatic potential map for [Al(acac)3] (164) showed that the area surrounding the
Al3+ metal is electron rich and is depicted by a red-yellow-green colour while the blue
hydrocarbon area was electron poor (Figure 16). Using thiacrown (55) as an example, the
electrostatic potential map (focusing on the thioether groups) indicated that the sulfur
atoms are partially negative (green) while the ethylene chain is partially positive (blue)
(Figure 17). Based on the electrostatic potential maps of charge distribution it was
considered that the most likely interaction observed in the 1H NMR spectrum was an
electrostatic interaction between the partially negative (δ-) sulfur atoms of the
macrocycle and the partially positive (δ+) hydrocarbon area of the aluminium complex.
[Space filling diagram of [Al(acac)3] (164)]
[Diagram with mesh surface (to view atoms)]
Figure 16
[Space filling diagram of thiacrown (55)]
[Diagram with mesh surface (to view atoms)]
Figure 17
85
DISCUSSION: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands
This interaction also provided information about the flexibility of the spiroacetal
thiacrown ethers (55), (56) and (57). It suggested that thiacrown ethers (56) and (57) are
much more flexible than the smaller thiacrown (55). This greater flexibility enables the
thiacrown ethers to adopt a conformation which maximises favourable interactions and
minimises unfavourable interactions. It is likely that this also includes the conformation
of the spiroacetal ring system. The greater flexibility of thiacrown ethers (56) and (57)
allows the spiroacetal moiety to arrange itself in the most thermodynamically stable
conformation while positioning itself away from the metal complex. The size of the
cavity is thought to permit extra flexibility and is consistent with the results.
4.2
Summary
The present work constitutes a detailed analysis of the binding abilities of the
three thiacrown ethers (55), (56) and (57). The association constants were determined for
lithium, potassium, sodium, cesium, cobalt, silver, cadmium and lead. The superior
complexing ability observed for (55), (56) and (57) with silver is encouraging in terms of
selective extraction.
The interaction between thiacrown ethers (55), (56) and (57) and [Al(acac)3]
(164), [Co(NH3)5NO2](BPh4)2 (165) and [Co(en)3](BPh4)3 (166) yielded some interesting
results. Because of the promising results achieved with the aluminium complex, future
work in this area will include investigating other aluminium complexes. Further work
will also involve the use of other deuterated solvents to monitor any interactions with the
cobalt complexes and the thiacrown ethers.
86
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
5.0
Kinetic Resolutions of the Spiroacetal Moiety
The synthesis of enantiopure crown ethers has led to compounds capable of
selectively binding enantiomeric species; this is known as chiral recognition. The first
reported syntheses of chiral macrocycles was carried out by Wudl et al161 in 1972 starting
from enantiopure materials. It was envisaged that the synthesis of optically active
spiroacetal crown ethers could be achieved via the kinetic resolution of the initial racemic
spiroacetal α-epoxide (115) or allylic alcohol (117) (Scheme 58). Kinetic resolution
requires the use of a chiral reagent to promote the selective reaction of one enantiomer
over the other to give both the starting material and product in enantiomerically enriched
form.162 Kinetic resolution reactions are carried out at approximately 50% conversion of
the starting material to the product. In this way, the reaction of the faster reacting
enantiomer is promoted while the reaction of the slower reacting enantiomer is retarded.
Three different approaches were investigated in the present study: (a) the base induced
rearrangement of α-epoxide (115) using chiral lithium amide bases,163 (b) the hydrolytic
kinetic resolution164 (HKR) of the α-epoxide (115) using a cobalt catalyst and (c) the
Sharpless asymmetric epoxidation165 of allylic alcohol (117).
O
R
O
O
R
O
S
O
O
O
O
O
S
O
O
S
O
115
O
OH
O
S
O
S
OH
O
S
n
O
O
O
OH
O
R
OH
117
S
S
O
O
R
O
O
OH
Scheme 58
87
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
5.1
Base-Induced Rearrangement of Epoxides
The rearrangement of an epoxide to an allylic alcohol using lithium amide bases
is thought to proceed via a cyclic six-membered transition state involving the
coordination of an oxygen lone pair with the electron deficient lithium centre (Scheme
59).119a The proposed mechanism involves the removal of a proton syn to the epoxide
oxygen (β-elimination).
R
R
R
N Li
H
R
N
H
+
O
OLi
Scheme 59
When the epoxide reacted is prochiral, the use of chiral lithium amide bases
results in enantioselective rearrangement to afford optically active products.163a Whitesell
and Felman166 were the first to recognise the possibility of using chiral lithium amide
bases to differentiate between two syn β-protons in cyclohexene oxide (167). Later,
Asami167 used an S-proline-derived (169) base that resulted in a considerable
improvement in the level of asymmetric induction reported by Whitesell and Felman.166
Deprotonation of the pseudoaxial proton was suggested to occur preferentially through
the complex where the steric interactions between the cyclohexane ring and the amide
were minimised (Figure 18).
H
R
O
H
167
HO
167
H
H
N
N
H
N Li
H
N Li
H
H
O
Favoured
S
H
H
H
OH
H
O
H
H
H
H
O
Disfavoured
Figure 18
In addition to providing enantiopure products from prochiral epoxides, chiral
lithium amide bases have been used to generate enantiopure materials from racemic
88
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
epoxides via a kinetic resolution process. The aim is to convert the faster reacting
enantiomer present in the mixture to the allylic alcohol while the slower reacting
enantiomer remains as unreacted epoxide. Asami et al168 were able to achieve high
selectivity in the reaction of cis-disubstituted epoxides such as (168) by using less than
the stoichiometric quantity of the S-2-(pyrrolidine-1-yl)methylpyrrolidide base (169)
(Scheme 60).
169
H
O
N
Li
H
N
H
O
OH
H
+
Ph
168
Me
Ph
Epoxide : Base
4 : 3
3 : 1
Me
Yield (%) ee (%)
95
31
30
67
Ph
H
Yield (%) ee (%)
33
60
72
21
Scheme 60
Chiral lithium amide bases possessing a second nitrogen or a lithium alkoxide
have proved to be the most successful chiral bases in epoxide rearrangement
reactions.163d Examples of the bases that have been used, both in stoichiometric and
catalytic amounts, in the rearrangement of epoxides are shown below. Some of the bases
such as (169), (170), (171) and (172) are commercially available while others including
(173)169, (174)170 and (175)171 require lengthy syntheses.
Ph
Me
N
H
Me
H
Ph
Me
170
NH
H
N
N
H
173
171
NH2
Ph
Me
172
NH
N
N
Ph
H
HO
N
174
NH
175
5.1.1 Ring Opening of α-Epoxide (115) Using Chiral Non-Racemic Lithium
Amide Bases
It was thought that using readily available chiral non-racemic bases, such as, [R(R*,R*)]-(+)-bis(α-methylbenzyl)amine (170), (-)-sparteine (171) and (1S,2R)-(+)norephedrine (172) would provide access to allylic alcohol (117) in enantioenriched
form. The allylic alcohol could then be converted to enantiopure spiroacetal crown ethers
(55), (56) and (57). Racemic α-epoxide (115) was therefore treated with several chiral
89
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
lithium amide bases (Table 5) in an effort to afford allylic alcohol (117)
enantioselectively (Scheme 61). The reaction was monitored by TLC and quenched at
approximately 50% conversion. The determination of the enantiomeric excess of the
allylic alcohol thus produced was carried out by NMR analysis of the α-methoxy-α(trifluoromethyl)phenylacetate ester (Mosher ester) of the allylic alcohol (117). The
synthesis of ester (176) was monitored by TLC to ensure complete consumption of the
starting material so as to avoid any possibility that kinetic resolution could occur in this
step. Unfortunately, the use of the chiral lithium amide bases derived from amines (170),
(171) and (172) only afforded racemic allylic alcohol (117).
O7
O
O
i or ii
O
iii
O
7
6
1
1
O
5
O
+
3
5
3
4
O
115
OH 117
O
6
4
O
O
O
O
OMe
F3C
Ph
F 3C
176
Ph
OMe
Reagents and Conditions: (i) n-BuLi, 0 °C, THF, (172), 30 min, then (115), 3 h,
room temp., 18 h; (ii) n-BuLi, 50-55 °C, hexane, (170) or (171),30 min, then (115),
3 h, room temp., 18 h; (iii) DMAP, triethylamine, (S)-MTPA-Cl, CH2Cl2, 18 h, 88%
Scheme 61
Entry
Base/n-BuLi
Temperature
Solvent
(°C)
Ph
1
Me
Ph
N
Me
2
a
b
-55
Hexane
0
THF
Ratio
(%)a
R:S
59
(43% conversion)b
1:1
H
48
N
N
H
3
Hexane
170
H
H
-50
Yield
H
HO
NH2
Ph
Me
171
172
(55% conversion)
21
(35% conversion)
Table 5: Base-Induced Rearrangement of α-Epoxide (115)
Yield based on conversion after flash chromatography
Conversion calculated from the recovery of α-epoxide (115) by flash chromatography
90
1:1
1:1
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
The title compound (176) analysed correctly for C19H21F3O5 with a protonated
molecular ion m/z at 387.14255 in the high resolution spectrum. The 1H NMR spectrum
exhibited two sets of signals representing the two diastereomers. The quartets at δH 3.49
with JOMe,CF3 1.1 Hz and δH 3.55 with JOMe,CF3 1.1 Hz were assigned to the two methoxy
groups of the individual diastereomers. The methoxy groups showed long range coupling
to fluorine. Integration of these two peaks established the ratio of the diastereomers to be
1:1. The resonances at δH 6.05 with J3,4 10.2 and J3,2 2.6 Hz and 6.12 with J3,4 10.2 and
J3,2 2.6 Hz were assigned to vinylic protons 3-H. The
13
C NMR spectrum showed
quartets at δC 55.4 and δC 55.5 representing the methoxy carbons. Another set of quartets
at δC 127.3 and δC 127.6 were assigned to the CF3 carbons. The
19
F NMR spectrum
showed two resonances at δF -72.9 and δF -72.7 which were assigned to the CF3 groups
and resonated as quartets. Integration of the two peaks also confirmed the diastereomers
were present as a 1:1 mixture in each case.
5.2
Hydrolytic Kinetic Resolution
5.2.1 Jacobsen Hydrolytic Kinetic Resolution Reaction
The Jacobsen hydrolytic kinetic resolution of racemic epoxides catalysed by
chiral (salen)Co(III) complexes was first reported in 1997164 and has emerged as a
general and effective method for the preparation of highly enantioenriched epoxides and
1,2-diols. The acetate complex [R,R-(177) and S,S-(178)], prepared by aerobic oxidation
of (salen)Co(II) in the presence of acetic acid, has been the most commonly used
catalyst. Using water as the nucleophile, the (R,R)-catalyst (177) selectively reacts with
the S-epoxide to afford the S-1,2-diol while the (S,S)-catalyst (178) yields the R-1,2-diol
and S-epoxide (Scheme 62).
H
H
H
N
H
N
N
t-Bu
O
O
t-Bu t-Bu
O
O
OAc
OAc
t-Bu
N
Co
Co
t-Bu
t-Bu
177
t-Bu
178
91
t-Bu
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
OH
O
R-epoxide
+
OH
(R,R)-Catalyst
H2O
O
(S,S)-Catalyst
H2O
Racemic Mixture
S-1,2-diol
O
S-epoxide
OH
+
OH
R-1,2-diol
Scheme 62
Jacobsen et al172 have postulated that the mechanism follows a second-order
dependence on the concentration of the catalyst. Based on this, the authors suggest a
cooperative, bimetallic mechanism whereby two separate catalyst molecules cooperate to
activate both the electrophile (epoxide) and the nucleophile (water). The proposed
mechanism is shown in Scheme 63.
O
X
Co
R
H2O
X
X
X
Co
Co
Co
O
O
R
OH
Co
OH
H2O
R
OH
R
OH
OH
Co
Co
OH
L
L
Co
L
Scheme 63
5.2.2 Hydrolytic Kinetic Resolution of α-Epoxide (115)
The hydrolytic kinetic resolution of α-epoxide (115) relies on the different rates
of hydrolysis of the two enantiomers in the presence of the chiral cobalt catalyst. It was
envisaged that the reaction would afford the 1,2-diol and the starting α-epoxide in
enantiopure form. The synthesis of enantiopure crown compounds would then be
possible starting from the enantiopure α-epoxide (Scheme 58).
The first step in the hydrolytic kinetic resolution was the aerobic oxidation of the
commercially available (R,R)-(salen)Co(II) complex using acetic acid to form (177) as a
brown solid. The α-epoxide was stirred in THF in the presence of the catalyst (177)
(0.5 mol%) and water (0.55 equiv) to afford the recovered starting material (115) and the
92
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
diol (179b) in 55% yielda based on 53% conversionb (Scheme 64). Diol (179b) had
identical spectroscopic properties to those previously published.173 From previous
studies, it has been shown through X-ray crystallographic data that the diol adopts the
diequatorial conformer depicted by structure (179b).173 Trans-diaxial opening of the
epoxide initially forms diaxial diol (179a), however due to the unfavourable 1,3-diaxial
interactions between the 4-OH and the C-O bond of the neighbouring tetrahydropyran,
the substituted cyclohexane ring (179b) flips to form the less sterically hindered chair
conformation with both OH groups adopting equatorial positions. In diol (179a),
stabilisation from two anomeric effects is possible, while in diol (179b) only one
anomeric stabilisation is possible. In this case, the decrease in the number of favourable
anomeric effects is compensated for by the fact that the hydroxyl groups occupy the more
sterically favoured equatorial positions.
O
O
O
i
O
O
+
O
OH
O
4
O 115
O 115
OH 179a
ring
flip
HO
O
179b
OH
Reagents and Conditions: (i) (177), H2O, THF, 55% (based on 53% conversion)
Scheme 64
To determine the enantiomeric excess, the recovered starting material was first
converted to the allylic alcohol (117) via base-induced rearrangement of the epoxide
(115) using lithium diethylamide. The α-methoxy-α-(trifluoromethyl)phenylacetate ester
(Mosher ester) (176) was then synthesised from the allylic alcohol (117) as described
earlier (Scheme 61). The spectroscopic data was identical to that previously
discussed (vide supra). The
1
H and
19
F NMR spectrum of the α-methoxy-α-
(trifluoromethyl)phenylacetate derivative once again showed that the diastereomers were
present as a 1:1 mixture establishing that the hydrolytic kinetic resolution of the racemic
α-epoxide (115) had not taken place.
a
b
Yield based on conversion after flash chromatography
Conversion calculated from the recovery of α-epoxide (115) by flash chromatography
93
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
5.3
Sharpless Epoxidation
In 2001, K. Barry Sharpless was awarded the Nobel Prize in chemistry for his
contribution to asymmetric syntheses. The Sharpless asymmetric epoxidation relies on an
in situ formation of a complex of titanium tetraisopropoxide, dialkyl tartrate, tert-butyl
hydroperoxide and the allylic alcohol.165a The formation of epoxy alcohols proceeds with
high enantiomeric purity and the enantioface selection is determined by the chirality of
the dialkyl tartrate used (Scheme 65). When the allylic alcohol is arranged with the
hydroxymethyl group at the bottom right, oxygen is delivered from the bottom side using
(R,R)-(+)-dialkyl tartrate and from the top side using (S,S)-(-)-dialkyl tartrate. This
empirical rule applies to all reactions of achiral alcohols174, however epoxidation of some
chiral allylic alcohols has shown unusual face selectivity.175
(S,S)-(-)-dialkyl tartrate
O
R
R1
O
1
R3
Ti(OiPr)4
R2
OH
t
R2
BuOOH, CH2Cl2
OH
R1
O
R2
R3
R3
OH
O
(R,R)-(+)-dialkyl tartrate
Scheme 65
The mechanism has been proposed to occur via the dimeric transition state
represented by complex (180).176 In the conformation of substrate (180) shown the
olefinic moiety, having a small dihedral angle (O-C-C=C, ca 30°), is arranged in an
appropriate space for epoxidation to occur. The coordination of the distal oxygen (O2) to
the titanium activates the peroxide bond and promotes the nucleophilic attack by the
double bond (Figure 19).177 The olefin approaches the proximal (O1) oxygen in an SN2type reaction. The electrophilic centre (O1) and the leaving group (O2) are chiral in the
transition state.
The conformation and therefore the enantioselectivity can be affected by the size
of the substituents on the alkene R2 and R3 (181).165b The R2 substituent is in the vicinity
of the tartrate ligand while the R3 group is directed toward the ligand. When the allylic R4
94
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
is a substituent other than hydrogen, the epoxidation is strongly retarded due to steric
hindrance, which is attributed to the poor reactivity of tertiary allylic alcohols.
R
OR
RO
Ti
O
O
E
O
E
O
Ti
O2
O
O
R4
R
O
E
E = CO2R
R2 O
O
R1
R1
O
CO2R
t-Bu
t-Bu
RO
R4
R3
O
2
1R3
O
R5
CO2R
5
180
(The View Down O1-Ti Bond Axis)
181
O
MLn
O2
O1
R
Figure 19
The kinetic resolution of racemic secondary allylic alcohols using the titaniumtartrate complex deals with the rates of epoxidation of the two enantiomers.178 When the
(R,R)-(+)-tartrate is used as the chiral source, the (S)-enantiomer of the allylic alcohol
reacts faster to form the anti-epoxy alcohol, while the (R)-enantiomer reacts faster when
the (S,S)-(-)-tartrate is used as the chiral source (Scheme 66). For example, the reaction
of (E)-1-trimethylsilyl-1-octen-3-ol with (R,R)-(+)-diisopropyl tartrate at 50% conversion
affords both the anti-epoxy alcohol and the unreacted alcohol in enantiomerically
enriched forms.179 The relative rates (krel) of epoxidation can be improved as the
bulkiness of the ester alkyl group increases, for example, diisopropyl tartrate is better
than diethyl tartrate which is better than dimethyl tartrate.
Me3Si
C5H11
(R,R)-(+)-diisopropyl tartrate
Me3Si
OH
C5H11
OH
Racemic Mixture
Recovered Substrate
>99% ee, 42%
Scheme 66
95
+
Me3Si
O
C5H11
OH
Epoxide
>99% ee, 42%
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
Kinetic resolution is not restricted to allylic alcohols in which chirality exists at
the carbinol carbon. Sharpless et al175 have shown the kinetic resolution of a variety of
compounds with chiral centres present at carbons other than the carbinol carbon. The
authors were able to selectively react one enantiomer to obtain highly enantioenriched
epoxide and starting material. In stereochemically rigid cases, the faster reacting
enantiomer is predicted to be the one in which the reacting olefin face is also the lesshindered olefin face. Hamon and Tuck180 have been able to kinetically resolve the allylic
alcohol (182) depicted in Figure 20 using diisopropyl L-tartrate. The tartrate enantiofacial
selection rule dictates that diisopropyl L-tartrate attacks one enantiomer from the top and
the other from the bottom. In this case, the faster reacting enantiomer is found to be
(182a) because attack at the less sterically hindered convex side is favoured.
H
H
L-(+)-DIPT
(attack fast to
unhindered convex side)
182b
HO
OH
182a
L-(+)-DIPT
(attack slow to
hindered concave side)
Figure 20
5.3.1 Sharpless Epoxidation of Allylic Alcohol (117)
The Sharpless epoxidation of allylic alcohol (117) was expected to provide
enantiopure syn-epoxy alcohol (119) by relying on the different rates of epoxidation of
the two enantiomers with the respective tartrate ligands. This would lead to the synthesis
of enantiopure thiacrown ethers (55), (56) and (57).
The choice of tartrate ligand was dependent on the model developed by Sharpless
(Scheme 65). When the spiroacetal allylic alcohol (117) is positioned correctly on the
template, a complex containing (-)-diisopropyl D-tartrate delivers the oxygen to the top
face while the (+)-diisopropyl L-tartrate delivers the oxygen to the bottom face (Figure
21). When (-)-diisopropyl D-tartrate is used the (S)-enantiomer is expected to react faster
to form the syn-epoxy alcohol (119) while the (R)-enantiomer should yield the antiepoxy alcohol (120). Alternatively, using (+)-diisopropyl L-tartrate the (R)-enantiomer is
predicted to react faster to form the syn-epoxy alcohol (119) while the slower reacting
(S)-enantiomer should produce the anti-epoxy alcohol (120) (Scheme 67). At 50%
96
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
conversion of the allylic alcohol (117) the slower reacting enantiomer is recovered as the
starting allylic alcohol (117). The presence of steric barriers in a molecule contribute to
the stereochemical outcome. In this case, the presence of the axial tetrahydropyran ring is
expected to hinder formation of the anti-epoxy alcohol using either tartrate ligand.
(S,S)-(-)-dialkyl tartrate
O
O
S
R
O
O
OH
OH
(R,R)-(+)-dialkyl tartrate
Figure 21
Thus, treatment of allylic alcohol (117) with titanium tetraisopropoxide,
diisopropyl D-tartrate and anhydrous tert-butyl hydroperoxide in dichloromethane at
-20 °C afforded the syn-epoxy alcohol in 77% yielda based on 40% conversion.b The
formation of the anti-epoxy alcohol (120) was not observed. The determination of the
enantiomeric excess was carried out by the 1H and 19F NMR analysis of the α-methoxy-
α-(trifluoromethyl)phenylacetate (Mosher ester) derivative (183) of the syn-epoxy
alcohol (119) and found to be a 1:1 mixture of the diasteromers.
O
O
O
i
O7
6
ii
O
O
+
3
5
3
4
117
OH
O
4
O
O
O
119
6
1
O
5
OH
O
7
1
O
O
O
OMe
F 3C
Ph
F 3C
183
Ph
OMe
Reagents and Conditions: (i) Ti(OiPr)4, diisopropyl D-tartrate, 4Å molecular
sieves, tBuCOOH, -20 °C, CH2Cl2, 18 h; 77%a (based on 40% conversion)b
(ii) DMAP, triethylamine, (S)-MTPA-Cl, CH2Cl2, 18 h, 93%
Scheme 67
a
b
Yield based on conversion after flash chromatography
Conversion calculated from the recovery of allylic alcohol (114) by flash chromatography
97
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
The Mosher ester derivative (183) analysed correctly for C19H22F3O6 with a
protonated molecular ion m/z at 403.13675 in the high resolution spectrum. The 1H NMR
spectrum exhibited two sets of signals representing the two diastereomers. The quartets at
δH 3.51 with JOMe,CF3 1.0 Hz and δH 3.64 with JOMe,CF3 1.0 Hz were assigned to the
methoxy groups. Integration of these two peaks showed a 1:1 mixture of the two
diasteromers. 3-H resonated as a double double doublet at δH 3.24 with J3,4 4.0, J3,2ax 1.2
and J3,2eq 1.2 Hz, and δH 3.29 with J3,4 4.0, J3,2ax 1.2 and J3,2eq 1.2 Hz. 5-H resonated as a
doublet at δH 4.71 with J5,4 4.8 Hz and at δH 4.73 with J5,4 4.8 Hz. This suggested that
both 3-H and 5-H adopted equatorial positions. The
13
C NMR spectrum exhibited
quartets at δC 55.5 and δC 55.7 representing the methoxy carbons. Another set of quartets
at δC 127.5 and δC 127.9 were assigned to the CF3 carbons. The
19
F NMR spectrum
showed two quartets at δF –73.4 and δF -72.9, which were assigned to the CF3 groups.
Integration of these two signals confirmed the two diastereomers of the Mosher ester
were present in a 1:1 ratio. Disappointingly, attempts to effect the kinetic resolution of
the allylic alcohol via Sharpless epoxidation were not successful.
5.4
Summary
The three different attempts used to promote the kinetic resolution of the
α-epoxide (115) and the allylic alcohol (117) proved to be unsuccessful (Scheme 68).
The based-induced rearrangement of the α-epoxide (115) using lithium amide bases
derived from [R-(R*,R*)]-(+)-bis(α-methylbenzyl)amine (170), (-)-sparteine (171) and
(1S,2R)-(+)-norephedrine (172) yielded the desired allylic alcohol (117) and recovered
starting material (115). Analysis of the Mosher ester derivative (176) of the allylic
alcohol by
1
H and 19F NMR established that the allylic alcohol was a 1:1 mixture of the
two diasteromers.
The Jacobsen hydrolytic kinetic resolution of the α-epoxide (115) using a chiral
cobalt catalyst (177) afforded the 1,2-diol (179a) and recovered starting material (115).
The recovered α-epoxide (115) was converted to the allylic alcohol (117) which, in turn,
was converted to the Mosher ester derivative (176). Analysis of the Mosher ester
derivative (176) by 1H and
19
F NMR established that the allylic alcohol was a 1:1
mixture of the two diasteromers. This supported the unsuccessful kinetic resolution of the
α-epoxide (115).
98
DISCUSSION: Kinetic Resolution of the Spiroacetal Moiety
The Sharpless epoxidation of allylic alcohol (117) was carried out using
(-)-diisopropyl D-tartrate as the chiral source. The epoxidation was expected to occur
faster with the (S)-enantiomer to form the syn-epoxy alcohol (119) while the (R)-
enantiomer remained as unreacted α-epoxide (115). Conversion of the syn-epoxy alcohol
(119) to the Mosher ester (183) and its subsequent analysis by NMR spectroscopy
established that the diastereomers were present in a 1:1 ratio.
O
Base-Induced
Epoxide Rearrangement
O
No Kinetic
Resolution
O
O
115
O
OH
O
Jacobsen Hydrolytic
Kinetic Resolution
O
No Kinetic
Resolution
O
O
114
O
HO
179b
115
OH
Sharpless Epoxidation
O
O
No Kinetic
Resolution
O
O
OH
OH 117
Scheme 68
99
O
119
DISCUSSION: Conclusion
6.0
Conclusion
In conclusion, the synthesis of the target spiroacetal thiacrown ethers (55), (56)
and (57) was successfully achieved. The reaction between the spiroacetal ditosylate (146)
and the appropriate dithiol (99), (122) or (123) in dimethylformamide containing cesium
carbonate yielded thiacrown ethers (55), (56) and (57) in 86%, 68% and 64%
respectively (Scheme 69). The spiroacetal ditosylate (146) was prepared from the diol
(145) precursor, which in turn was obtained by the reductive ozonolysis of the bisallyl
ether
(133).
The
bisallyl
ether
was
synthesised
starting
from
(±)-1,7-
dioxaspiro[5.5]undec-4-ene (114).
O
O
O
O
+
O
OTs TsO
HS
S
n
O
SH
O
99, n = 1
122, n = 2
123, n = 3
O
S
146
S
S
n
55, n = 1
56, n = 2
57, n = 3
Scheme 69
The binding ability of thiacrown ethers (55), (56) and (57) with lithium, sodium,
potassium, cesium, cobalt, cadmium, silver and lead showed an affinity for the heavy
metals. This can largely be explained in terms of the HSAB theory, the large difference
in the complexing behaviour of the thiacrown ethers with silver compared to that of lead
being the exception. Both silver and lead are considered to be thiophilic. One possible
explanation for their different complexing abilities is the difference in oxidation states.
Thiacrown ethers can thermodynamically stabilise lower oxidation by binding more
strongly to them than those with higher oxidation states. Another explanation is that the
conformation and arrangement of the donor atoms favours the coordination geometry of
the silver ion. The size-match selectivity was also considered, however silver and lead
have radii of similar size.
The ability of thiacrown compounds (55), (56) and (57) to act as second-sphere
ligands with [Al(acac)3] (164), [Co(NH3)5NO2](BPh4)2 (165) and [Co(en)3](BPh4)3 (166)
revealed some interesting results. Thiacrown ether (55) did not show any interaction with
100
DISCUSSION: Conclusion
the three complexes while thiacrown ethers (56) and (57) did show interaction with the
aluminium complex. This interaction was observed using 1H NMR spectroscopy and was
represented by the appearance of a broad singlet of the CH2S multiplet at δH 2.77 and
δH 2.78 for (56) and (57) respectively. The electrostatic potential map for [Al(acac)3]
(164) and spiroacetal thiacrown (55) suggested an electrostatic interaction between the
hydrocarbon area (δ+) of the metal complex and the sulfur atoms (δ-) of the thiacrown
ether.
O
NH3
NH3
O
Al
O
(BPh4)2
NO2
O
H3N
H3N
O
O
Co
H2N
H2N
NH3
164
(BPh4)3
NH2
NH2
Co
N
H2
NH2
165
166
The synthesis of the target spiroacetal azacrown ethers (58), (59) and (60) was
only achieved with limited success. Initially, the reaction between diethylenetriamine
(151) and spiroacetal dialdehyde (150) was carried out in an attempt to avoid nitrogen
protection, with azeotropic removal of water, however, the unsaturated crown ether (154)
was not obtained. The spiroacetal dialdehyde (150) was prepared via ozonolysis of the
bisallyl ether (133). Reduction of the intermediate ozonide with dimethyl sulfoxide
afforded the desired spiroacetal dialdehyde (150).
The successful synthesis of azacrown (58) was achieved after removal of the
protecting groups of azacrown ether (159). The slow addition of spiroacetal ditosylate
(146) to a solution of Ns-protected triamine (158) in tetrahydrofuran containing sodium
hydride afforded the protected azacrown ether (159) in 27% yield. Subsequent
deprotection yielded azacrown (58) in 84% yield (Scheme 70). Attempts to apply a
similar methodology in the synthesis of (59) and (60) were not successful.
O
O
+
O
O
HN
Ns
158
146
O
NH
Ns
n=1
O
OTs TsO
n
N
Ns
O
O
O
O
O
O
O
Ns =
S
NNs
O
NNs
N
Ns
NO2
159
Scheme 70
101
NH
H
N
58
NH
DISCUSSION: Conclusion
Kinetic resolution reactions of the spiroacetal moiety were also carried out to
provide enantiopure starting materials for the synthesis of the spiroacetal crown ethers
(Scheme 71). Theoretically enantiopure compounds can be obtained by relying on the
different rates of reaction of the two enantiomers. The base-induced rearrangement of the
α-epoxide (115) afforded the allylic alcohol (117) and recovered starting epoxide (115).
The 1H and 13F NMR analysis of the Mosher ester derivative (176) of the allylic alcohol
(117) revealed a 1:1 ratio of the diastereomers. Jacobsen’s hydrolytic kinetic resolution
of α-epoxide (115) using a cobalt catalyst (177) and water as the nucleophile afforded
diol (179b) and the starting α-epoxide (115). Analysis of the Mosher ester derivative
(176) showed a racemic mixture. The Sharpless epoxidation of allylic alcohol (117) was
performed using titanium tetraisopropoxide, diisopropyl D-tartrate and anhydrous
tert-butyl hydroperoxide. The 1H and
19
F NMR analysis of the syn-epoxy alcohol (183)
obtained showed a 1:1 mixture of the two diastereomers.
O
Base-Induced
Epoxide Rearrangement
O
No Kinetic
Resolution
O
O
115
O
OH
O
Jacobsen Hydrolytic
Kinetic Resolution
O
No Kinetic
Resolution
O
O
114
O
HO
179b
115
OH
Sharpless Epoxidation
O
O
No Kinetic
Resolution
O
O
OH
OH 117
119
O
Scheme 71
A novel set of spiroacetal dimers (142a), (142b) and (142c) were synthesised
during attempts to synthesise crown compounds via a cross metathesis reaction.
Treatment of bisallyl ether (133) with Grubbs’ ruthenium catalyst (137) or Shrock’s
molybdenum catalyst (136) afforded the three isomeric compounds represented by the
general structure (142). Detailed assignment of the stereochemistry for the three dimers
proved to be elusive, however each compound exhibited unique 1H and
spectra.
102
13
C NMR
DISCUSSION: Conclusion
O
O
O
O
O
O
142a
142b
142c
O
O
6.1
Future Work
Future work in this area will involve a further investigation into the synthesis of
the spiroacetal azacrown ethers (58), (59) and (60) using other methodologies. One
option is using the method developed by Tabushi et al,91 which involves the addition of a
diamine to a diester. Synthesis of the spiroacetal diamine could be achieved via the
reaction of the spiroacetal ditosylate (146) and sodium azide followed by reduction of the
diazide. The spiroacetal diamine could then be reacted with the appropriate diester to
yield the macrocyclic diamide. Reduction of the amide group would afford the
spiroacetal crown ethers. The advantage of this method is that the need for nitrogen
protection is avoided.
The use of peptide chemistry is another option in the synthesis of azacrown ethers
(58), (59) and (60). The reaction of the spiroacetal diamine with the appropriate
dicarboxylic acid using an activating agent could be used to yield the protected diamide.
Reduction of the amide group would afford the spiroacetal crown ethers.
Crown ethers can be designed to target specific metal ions by changing the
number, type and location of the macrocycle donor groups. The synthesis of spiroacetal
crown ethers having a mixture of oxygen, nitrogen and sulfur atoms may also be
undertaken based on this idea. Similar synthetic methods to those already used could be
applied in these cases.
The successful synthesis of the spiroacetal azacrown ethers and mixed donor
crown ethers would then allow an analysis of their binding abilities as primary and
second-sphere ligands. A greater investigation will also be undertaken in the ability of
103
DISCUSSION: Conclusion
the spiroacetal crown compounds to bind a variety of other metals. Thiacrown ligands are
noted for their significant affinity for copper, platinum, gold and mercury and have a
wide application in medicine and the environment. The ability of the spiroacetal crown
compounds to act as pH dependent ionophores may allow them to be used to carry metal
ions across a membrane, which upon interaction with acid would release the ion. The
addition of fatty acid substituents to the spiroacetal moiety may provide ion channels.
The promising results obtained using thiacrown ethers (56) and (57) as secondsphere ligands with [Al(acac)3] (164) suggests that this work should be extended to
include a larger range of complexes and include a larger number of metals. The
interaction of spiroacetal crown ethers with platinum complexes is of particular interest
because of their anti-cancer abilities.
Another area of interest is the synthesis of optically active spiroacetal crown
ethers. The asymmetric epoxidation of spiroacetal alkene (114) to afford α-epoxide (115)
may be achieved by using a fructose-derived ketone in the presence of Oxone®.181 This
method may be applied to the kinetic resolution of spiroacetal alkene (114) whereby one
enantiomer reacts faster than the other yielding the recovered starting material and
desired epoxide.
104
EXPERIMENTAL
7.0
General Details
Melting points were determined using a Gallenkamp Melting Point Apparatus and
are uncorrected. Ultraviolet measurements were determined on a Varian CARY 1E ultraviolet spectrophotometer at 380 nm in a 1 cm cell at the concentrations specified. All
measurements were performed at 22 °C. Infrared spectra were recorded with a
Shimadzu FTIR-8300 spectrometer or Perkin Elmer Spectrum One Fourier
Transform IR spectrometer as thin films between sodium chloride plates. Absorption
maxima are expressed in wavenumbers (cm-1).
Thin layer chromatography (TLC) was performed using 0.2 mm thick precoated
silica gel plates (Merck Kieselgel 60 F254 or Riedel-de Haen Kieselgel S F254).
Compounds were visualised by ultraviolet fluorescence or by staining with vanillin in
methanolic sulfuric acid. Flash chromatography was performed using Merck Kieselgel 60
(230-400 mesh) with the indicated solvents.
1
H nuclear magnetic resonance spectra were recorded on a Bruker Advance 300
(300 MHz), Bruker DRX 400 (400 MHz), Varian Unity Plus 300 (300 MHz) or Varian
Mercury 400 (400 MHz) spectrometer at 25 °C. Data is expressed in parts per million
using tetramethylsilane or the solvent peak as the internal reference and reported as
position (δH), relative integral, multiplicity (s = singlet, br s = broad singlet, d = doublet,
dd = double doublet, ddd = double double doublet, dddd = double double double doublet,
t = triplet, dt = doublet of triplets, ddt = double double triplet, q = quartet or m =
multiplet), coupling constant and assignment (aided by COSY, HMBC and HSQC (or
HMQC)).
13
C nuclear magnetic resonance spectra were recorded on a Bruker Advance 300
(75 MHz), Bruker DRX 400 (100 MHz), Varian Unity Plus 300 (75 MHz) or Varian
Mercury 400 (100 MHz) spectrometer at 25 °C. Data is expressed in parts per million
using tetramethylsilane or the solvent peak as the internal reference and reported as
position (δC), multiplicity and assignment.
Mass spectra were recorded using a VG70-SE spectrometer operating at a
nominal voltage of 70eV. Chemical ionisation (CI) mass spectra were obtained with the
indicated reagent gas and fast atom bombardment (FAB) mass spectra were obtained
using 3-nitrobenzyl alcohol as the matrix.
All reactions were performed in dry glassware under an inert atmosphere unless
otherwise stated. 3-Butyn-1-ol, δ-valerolactone, diethylenetriamine, [R-(R*,R*)]-(+)-
bis(α-methylbenzyl)amine, (-)-sparteine (1S,2R)-(+)-norephedrine, (R,R)-N,N’-bis(3,5di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II),
105
benzylidene
EXPERIMENTAL
bis(tricyclohexylphosphine)-dichlororuthenium, diisopropyl D-tartrate, 2-mercaptoethyl
sulfide and 3,6-dithia-1,8-octanediol were purchased from Aldrich Chemical Company
and purified as necessary. 2,6-Diisopropylphenylimidoneophylidenemolybdenum(VI)
bis(hexafluoro-t-butoxide)
was
purchased
from
Strem
Chemicals.
[Al(acac)3]
[Co(NH3)5NO2](BPh4)2 and [Co(en)3](BPh4)3 were provided by Dr. Trevor Bailey.
Solvents were purified and dried according to the procedures outlined by Leonard, Lygo
and Procter.182
Molecular modelling was executed using Spartan ’02 (Wavefunction Inc, Irvine,
CA.) operating on a Macintosh G5 (operating system 10.3). The electrostatic potential
maps
for
[1S∗,
compounds
15R∗,
18S∗]-Spiro[2,14,17-trioxa-5,8,11-
trithiabicyclo[13.3.1]-nonadecane-18,2’-tetrahydropyran] (55) and [Al(acac)3] (164) were
calculated from semi-empirical PM3 calculations.
7.1 Preparation of [3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan3,5-diol (50)
1-Trimethylsilyloxy-3-butyne (111)
Chlorotrimethylsilane (7.75 g, 71.3 mmol) was added to a mixture of 3-butyn-1ol (5.0g, 71.3 mmol) and triethylamine (14.44 g, 142.7 mmol) in tetrahydrofuran
(150 cm3) using the procedure reported by Brimble et al.115 Removal of the solvent
yielded a pale yellow oil that was purified by flash chromatography using pentanediethyl ether (4:1) as eluent to give the trimethylsilyl ether as a colourless oil (9.01 g,
89%). The 1H and
13
C NMR spectra were in agreement with that reported in the
literature.115
HC
OSi(CH3)3
111
106
EXPERIMENTAL
2-Methoxy-1-(Tetrahydropyran-2-yl)-1-butyn-4-ol (112) and 2Ethoxy-1-(Tetrahydropyran-2-yl)-1-butyn-4-ol (113)
A solution of n-butyllithium (13.2 cm3 of a 1.6 mol dm-3 solution in hexane,
21.1 mmol) was added to a solution of 1-trimethylsiloxy-3-butyne (2.50 g, 17.8 mmol) in
tetrahydrofuran (250 cm3) at –78 °C. The mixture was stirred for 30 min at which time
δ-valerolactone (110) (2.28 g, 22.8 mmol) in tetrahydrofuran (7 cm3) was added. The
reaction mixture was left to stir for a further 30 min. It was quenched with a saturated
aqueous ammonium chloride (15 cm3) and allowed to warm to room temperature. After
extraction with ethyl acetate (5 x 50 cm3) the combined extracts were washed with water
and dried over magnesium sulfate. Removal of the solvent in vacuo yielded an orange oil
which was dissolved in methanol or ethanol (20 cm3) and stirred for 16 h with catalytic
acid. Triethylamine (5 drops) was added and the solvent removed under reduced pressure
to give an oil which was purified by flash chromatography using hexane-ethyl acetate
(4:1) as eluent to yield the desired alkoxy acetals.
(i) 2-Methoxy-1-(tetrahydropyran-2-yl)-1-butyn-4-ol (112). Prepared following the
procedure reported by Brimble et al.115 Using methanol and Amberlite resin yielded a
pale yellow oil (1.17 g, 36%). The 1H and 13C NMR spectra were in agreement with that
reported in literature.115
OH
H 3C
O
O
112
(ii) 2-Ethoxy-1-(tetrahydropyran-2-yl)-1-butyn-4-ol (113). Prepared using ethanol and
pyridinium p-toluenesulfonate to yield a pale yellow oil (3.06 g, 88%); νmax(film)/cm-1
3419 (br,
OH), 2249 (w, C≡C); δH (300 MHz; CDCl3; Me4Si) 1.24 (3 H, t,
JCH3,OCH2 7.1 Hz, CH3), 1.45-1.70 (3 H, m, 5-CH2 and 4-HA), 1.77-1.89 (3 H, m, 3-CH2
and 4-HB), 2.51 (2 H, t, J3’,4’ 6.5 Hz, C-9), 2.54 (1 H, t, JOH,4’ 6.2 Hz, OH), 3.60-3.82
(6 H, m, 3 x OCH2); δC (75 MHz; CDCl3; Me4Si) 15.7 (CH3, CH2CH3), 19.1 (CH2, C-4),
22.8 (CH2, C-3’), 24.6 (CH2, C-5), 36.8 (CH2, C-3), 58.6 (CH2, OCH2CH3), 60.8 (CH2,
107
EXPERIMENTAL
C-4’), 62.1 (CH2, C-6), 80.2, 81.7, 94.4 (quat, C-1’, C-2’, C-2); m/z (EI) 153
(M+-OCH2CH3, 28%), 129 (89), 101 (100), 97 (54), 83 (36), 67 (29), 55 (68).
OH
3'
4'
2'
H3C
O
1'
2
O1
3
4
6
5
113
(±)-1,7-Dioxaspiro[5.5]undec-4-ene (114)
Potassium carbonate (0.20 g) and Lindlar catalyst [5 wt. % Palladium on calcium
carbonate, poisoned with lead (0.02 g)] were added to a solution of the 2-ethoxy-1(tetrahydropyran-2-yl)-1-butyn-4-ol (113) (3.25 g, 16.4 mmol) in 4:1 pentane-diethyl
ether (50 cm3) and left to stir for 16 h under a balloon of hydrogen following the
procedure reported by Brimble et al.115 The reaction mixture was then filtered through a
short pad of Celite and the solvent removed under reduced pressure to afford a colourless
oil. The oil was dissolved in dichloromethane (20 cm3), pyridinium p-toluenesulfonate
(0.01 g) was added and the mixture was left to stand at room temperature for 1 h. The
solvent was removed under reduced pressure and the residue purified by flash
chromatography using pentane-diethyl ether (9:1) as eluent, to afford the desired
spiroacetal as a colourless oil (1.97 g, 78%); δH (300 MHz; CDCl3; Me4Si) 1.42-1.94
(7H, m, 3 x CH2 and 3-HA), 2.12-2.38 (1H, m, 3-HB), 3.51-3.99 (4H, m, 2 x OCH2), 5.62
(1H, ddd, J5,4 10.3, J5,3ax 2.9 and J5,3eq 1.5 Hz, 5-H), 5.91-5.96 (1H, m, 4-H); δC (75 MHz;
CDCl3; Me4Si) 18.6, 24.7, 25.0 (C-9, C-10 and C-11), 34.8 (C-3), 57.7 (C-2), 60.8 (C-8),
92.8 (C-6), 127.7 (C-5), 130.6 (C-4). The 1H and
13
C NMR spectra were in agreement
with that reported in literature.115
8
9
10
O7
1
6
2
O
11
5
3
4
114
108
EXPERIMENTAL
[4S∗, 5S∗, 6S∗] and [4R∗, 5R∗, 6S∗]-4,5-Epoxy-1,7dioxaspiro[5.5]undecane (115) and (116)
(a) Preparation of Dimethyldioxirane
Oxone® (120 g, 195.2 mmol) was added to a cooled mixture of water (254 cm3),
acetone (192 cm3) and sodium hydrogen carbonate (58 g) in five portions following the
procedure described by Adam et al.116 The dimethyldioxirane/acetone solution was
distilled and collected in a cooled (-78 °C) receiving flask as a pale yellow liquid
(150 cm3, ca 0.1 mol dm-3).
(b) Epoxidation Using Dimethyldioxirane
Dimethyldioxirane (135 cm3, 0.1 mol dm-3 solution in acetone) was added to a solution
of (±)-1,7-dioxaspiro[5.5]undec-4-ene (114) (1.90 g, 12.3 mmol) in acetone (10 cm3) and
the mixture was left to stir for 18 h. Removal of the solvent under reduced pressure
afforded a colourless oil which was dissolved in dichloromethane and dried over sodium
sulfate. The solvent was removed and the oil purified by flash chromatography using
hexane-ethyl acetate (4:1) to afford:
(i) [4S∗, 5S∗, 6S∗]-4,5-Epoxy-1,7-dioxaspiro[5.5]undecane (115) (1.49 g, 71%) as
colourless needles mp 47-49 °C (lit.,114 48-49 °C); δH (400 MHz; CDCl3; Me4Si) 1.471.78 (7H, m, 9-CH2, 10-CH2, 11-CH2 and 3-Heq), 1.97-2.06 (1H, m, 3-Hax), 2.76 (1H,
dd, J5,4 4.0 and J5,3eq 0.9 Hz, 5-H), 3.29 (1H, dd, J4,5 4.0 and J4,3ax 4.5 Hz, 4-H), 3.39 (1H,
ddd, J2eq,2ax 11.0, J2eq,3ax 7.0 andJ2eq,3eq 0.9 Hz, 2-Heq), 3.59-373 (3H, m, 8-CH2 and
2-Hax); δC (100 MHz; CDCl3; Me4Si) 17.6, 22.7, 25.0, 31.9 (CH2, C-3, C-9, C-10 and
C-11), 50.5 (CH, C-4), 52.9 (CH, C-5), 54.9 (CH2, C-2), 60.9 (CH2, C-8), 93.7 (quat,
C-6). The 1H and 13C NMR spectra were in agreement with that reported in literature.114
8
9
10
O7
1
6
2
O
11
5
4
O
115
109
3
EXPERIMENTAL
(ii) [4R∗, 5R∗, 6S∗]-4,5-Epoxy-1,7-dioxaspiro[5.5]undecane (116) (0.23 g, 11%) as a
colourless oil. δH (400 MHz; CDCl3; Me4Si) 1.45-1.78 (6H, m, 9-CH2, 10-CH2 and
11-CH2), 1.84-1.92 (2H, m, 3-CH2), 3.01 (1H, d, J5,4 4.0 Hz, 5-H), 3.26-3.29 (1H, m,
4-H), 3.36-3.41 (1H, m, 2-Heq), 3.57-369 (2H, m, 2-Hax and 8-Heq), 3.74 (1H,
ddd, J8ax,8eq 11.3, J8ax,9ax 11.3 and J8ax,9eq 2.7 Hz, 8-Hax); δC (100 MHz; CDCl3; Me4Si)
18.1, 24.8, 25.0, 34.5 (CH2, C-3, C-9, C-10 and C-11), 50.2 (CH, C-4), 54.9 (CH2, C-2),
55.3 (CH, C-5), 60.9 (CH2, C-8), 92.8 (quat, C-6). The 1H and 13C NMR spectra were in
agreement with that reported in literature.114
8
9
10
O7
1
6
11
5
2
O O
4
3
116
(c) Generation of Dimethyldioxirane in situ
A solution of Oxone® (0.49 g, 0.78 mmol) in water (cm3) was added to a stirred
solution of (±)-1,7-dioxaspiro[5.5]undec-4-ene (114) (0.10 g, 0.65 mmol), NaHCO3 (0.11
g, 1.36 mmol) and acetone (5 cm3) at 0 °C using the procedure by Ferraz et al.183 The
resulting slurry was then stirred at room temperature for 18 h. The acetone was removed
under reduced pressure and the residue extracted with ethyl acetate (3 x 10 cm3). The
combined extracts were washed with brine and died over magnesium sulfate. Purification
by flash chromatography afforded the α-epoxide (115) (45 mg, 41%) and the β-epoxide
(116) (40 mg, 36%). The 1H and 13C NMR spectra were in agreement with that reported
in literature.114
[5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undec-3-en-5-ol (117) and [5S∗, 6S∗]1,7-Dioxaspiro[5.5]undec-2-en-5-ol (118)
n-Butyllithium (2.0 cm3 of a 1.6 mol dm-3 solution in hexane, 3.23 mmol) was
added dropwise to a solution of diethylamine (0.36 cm3, 3.55 mmol) in hexane (25 cm3)
at –35 °C and the suspension was left to stir for 30 min. [4S∗, 5S∗, 6S∗]-4,5-Epoxy-1,7110
EXPERIMENTAL
dioxaspiro[5.5]undecane (115) (0.5 g, 2.93 mmol) as a solution in hexane (5 cm3) was
added to the mixture. The solution was allowed to warm slowly (ca 3 h) to room
temperature and then left to stir for a further 18 h. The reaction mixture was then
quenched with sodium dihydrogen phosphate solution (5 cm3, 10% w/v) and extracted
with ethyl acetate (5 x 25 cm3). The combined extracts were washed with water (10 cm3)
and dried over sodium sulfate. Removal of the solvent under reduced pressure yielded an
orange oil that was purified by flash chromatography using hexane-ethyl acetate (3:2) as
eluent to afford:
(i) [5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undec-3-en-5-ol (117) (0.38 g, 76%) as colourless
needles mp 54-56 °C (from pentane) (lit.,114 54-56 °C ); δH (300 MHz; CDCl3; Me4Si)
1.49-1.60 (3H, m, 9-CH2 and 11-Hax), 1.65-1.82 (2H, m, 10-CH2), 2.03-2.07 (3H, m,
11-Heq and OH), 3.59 (1H, s, 5-H), 3.71 (1H, ddd, J8ax,8eq 11.3, J8ax,9ax 11.3 and
J8ax,9eq 3.3 Hz, 8-Hax), 3.75-3.80 (1H, m, 8-Heq), 4.13 (1H, d, J2eq,2ax 16.4 Hz, 2-Heq),
4.17 (1H, dd, J2ax,2eq 16.4 and J2ax,3 1.8 Hz, 2-Hax), 5.96-5.97 (2H, m, 3-H and 4-H);
δC (100 MHz; CDCl3; Me4Si) 18.3, 24.9, 30.3, (CH2, C-9, C-10 and C-11), 60.2 (CH2,
C-2), 62.9 (CH2, C-8), 66.9 (CH, C-5), 96.9 (quat, C-6), 124.6, 128.7 (CH, C-3 and C-4).
The spectroscopic data were in agreement with those reported in literature.114
8
9
10
O7
6
1
2
O
11
5
4
3
OH
117
(ii) [5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undec-2-en-5-ol (118) (17 mg, 3%) as a pale yellow
oil; δH (400 MHz; CDCl3; Me4Si) 1.44 (1H, ddd, J11ax,11eq 13.5, J11ax,10ax 13.5 and
J11ax,10eq 4.7 Hz, 11-Hax), 1.50-1.81 (4H, m, 9-CH2 and 10-CH2), 1.91 (1H, dddd,
J4eq,4ax 17.4, J4eq,5 4.0, J4eq,3 4.0 and J4eq,2 1.0 Hz, 4-Heq), 2.01-2.05 (2H, m, 11eq and
OH), 2.42 (1H, dddd, J4ax,4eq 17.4, J4ax,5 4.5, J4ax,3 2.5 and J4ax,2 2.5 Hz, 4-Hax), 3.58 (1H,
ddd, J5,OH 8.5, J5,4ax 4.5 and J5,4eq 4.0 Hz, 5-H), 3.66 (1H, dt, J8eq,8ax 11.6 and J8eq,9 1.9 Hz,
8-Heq), 3.79 (1H, ddd, J8ax,8eq 11.6, J8ax,9ax 11.6 and J8ax,9eq 3.2 Hz, 8-Hax), 4.65-4.69
(1H, m, 3-H), 6.26 (1H, d, J2,3 6.2 Hz, 2-H); δC (100 MHz; CDCl3; Me4Si) 17.9, 24.9
(CH2, C-9 and C-10), 25.8 (CH2, C-4), 29.4 (CH2, C-11), 61.8 (CH2, C-8), 68.5 (CH,
111
EXPERIMENTAL
C-5), 96.7 (quat, C-6), 98.6 (CH, C-3), 139.9 (CH, C-2). The spectroscopic data was in
agreement with that reported in literature.114
8
9
10
O7
6
1
2
O
11
5
4
3
OH
118
[3S∗, 4S∗, 5S∗, 6S∗]-3,4-Epoxy-1,7-dioxaspiro[5.5]undecan-5-ol (119)
and [3R∗, 4R∗, 5S∗, 6S∗]-3,4-Epoxy-1,7-dioxaspiro[5.5]undecan-5-ol
(120)
A solution of [5S∗, 6S∗]-1,7-dioxaspiro[5.5]undec-3-en-5-ol (117) (0.20 g,
1.18 mmol) in dichloromethane (20 cm3) was cooled to 0 °C in an ice/water bath.
Sodium acetate (0.35 g, 4.23 mmol) was added, followed by meta-chloroperoxybenzoic
acid (0.58 g, 70% w/w, 2.35 mmol) in five portions over 1 min. The reaction was
allowed to warm to room temperature and stirred for 72 h. The suspension was then
filtered through a short pad of Celite. The solution was washed with sodium sulfite
(10 cm3, 10% w/v), saturated aqueous sodium hydrogen carbonate (2 x 5 cm3), water
(5 cm3) and dried over sodium sulfate. The solvent was removed under reduced pressure
to yield a pale yellow oil that was purified by flash chromatography using hexane-ethyl
acetate (3:2) to afford:
(i) [3S∗, 4S∗, 5S∗, 6S∗]-3,4-Epoxy-1,7-dioxaspiro[5.5]undecan-5-ol (119) (0.19 g, 88%)
as colourless prisms mp 130-133 °C (lit.,114 130-132 °C); (200 MHz; CDCl3; Me4Si) 1.40
(1H, ddd, J11ax,11eq 13.7, J11ax,10ax 13.7 and J11ax,10eq 5.2 Hz, 11-Hax), 1.48-1.67 (4H, m,
9-CH2 and 10-CH2), 1.90 (1H, dt, J11eq,11ax 13.7 and J11eq,10 2.8 Hz, 11-Heq), 2.32 (1H, d,
JOH,5 11.6 Hz, OH), 3.36 (1H, d, J3,4 3.0 Hz, 3-H), 3.46-3.67 (4H, m, 4-H, 5-H and
8-CH2), 3.84 (1H, d, J2eq,2ax 13.4 Hz, 2-Heq), 3.96 (1H, d, J2ax,2eq 13.4 Hz, 2-Hax);
δC (100 MHz; CDCl3; Me4Si) 18.1, 24.8, (CH2, C-9 and C-10), 29.9 (CH2, C-11), 51.2
(CH, C-4), 51.9 (CH,
C-3), 57.3 (CH2, C-2), 61.8 (CH2, C-8), 65.7 (CH, C-5), 95.2
(quat, C-6). The spectroscopic data were in agreement with those reported in literature.114
112
EXPERIMENTAL
8
9
10
O7
6
1
2
O
11
5
3
4
O
OH
119
(ii) [3R∗, 4R∗, 5S∗, 6S∗]-3,4-Epoxy-1,7-dioxaspiro[5.5]undecan-5-ol (120) (0.02 g, 9%)
as a colourless oil; (400 MHz; CDCl3; Me4Si) 1.48-1.83 (6H, m, 9-CH2, 10-CH2 and
11-CH2), 2.35 (1H, d, JOH,5 6.8 Hz, OH), 3.22 (1H, dd, J3,2eq 3.0 and J3,4 4.0 Hz, 3-H),
3.25 (1H, d, J4,3 4.0 Hz, 4-H), 3.66 (1H, d, J5,OH 6.8 Hz, 5-H), 3.70-3.77 (2H, m, 8-CH2),
3.92 (1H, dd, J2eq,2ax 13.7 and J2eq,3 3.0 Hz, 2-Heq), 4.07 (1H, d, J2ax,2eq 13.7 Hz, 2-Hax);
δC (100 MHz; CDCl3; Me4Si) 17.9, 24.7, 26.3 (CH2, C-9, C-10 and C-11), 49.3 (CH,
C-3), 53.2 (CH, C-4), 60.2 (CH2, C-2), 61.9 (CH2, C-8), 68.9 (CH, C-5), 97.1 (quat, C-6).
The spectroscopic data were in agreement with those reported in literature.114
8
9
10
O7
6
1
O
O
11
5
4
2
3
OH
120
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diol (50) and [4S∗,
5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-4,5-diol (121)
Lithium aluminium hydride (0.13 g, 3.38 mmol) was added in 3 portions over 1
min to a solution of [3S∗, 4S∗, 5S∗, 6S∗]-3,4-epoxy-1,7-dioxaspiro[5.5]undecan-5-ol
(119) (0.14 g, 0.77 mmol) in tetrahydrofuran (15 cm3) at 0 °C. The reaction was stirred
at 0 °C for 1 h then at room temperature for 16h. The reaction was quenched with sodium
dihydrogen phosphate (5 cm3, 10% w/v) and half the tetrahydofuran removed under
reduced pressure. The residue was then extracted with ethyl acetate (5 x 20 cm3) and the
combined extracts washed with water (15 cm3) and dried over sodium sulfate. The
113
EXPERIMENTAL
solvent was removed in vacuo to give a pale yellow oil that was purified by flash
chromatography using hexane-ethyl acetate (2:1) as eluent to yield:
(i) [3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diol (50) (120 mg, 81%) as a
colourless oil; (300 MHz; CDCl3; Me4Si) 1.39 (1H, ddd, J11ax,11eq 13.2, J11ax,10ax 13.2 and
J11ax,10eq 4.7 Hz, 11-Hax), 1.50-1.79 (4H, m, 9-CH2 and 10-CH2), 1.96 (1H, dddd,
J4eq,4ax 14.5, J4eq,5 3.0, J4eq,3 3.0 and J4eq,2eq 3.0 Hz, 4-Heq), 2.09 (1H, dt, J11eq,11ax 13.2 and
J11eq,10 3.2 Hz, 11-Heq), 2.15 (1H, ddd, J4ax,4eq 14.5, J4ax,5 3.0 and J4ax,3 3.0 Hz, 4-Hax),
3.46 (1H, t, J5,4 2.9 Hz, 5-H), 3.65-3.72 (4H, m, 8-CH2, 3-H and 2-Heq), 3.82 (1H, dd,
J2ax,2eq 12.1 and J2ax,3 1.4 Hz, 2-Hax), 3.88-3.90 (2H, m, 3-OH and 5-OH); δC (75 MHz;
CDCl3; Me4Si) 18.1, 24.9 (CH2, C-9 and C-10), 30.8 (CH2, C-4), 31.1 (CH2, C-11), 60.9
(CH2, C-8), 64.8 (CH2, C-2), 65.3 (CH, C-3), 70.3 (CH, C-5), 96.6 (quat, C-6). The 1H
and 13C NMR spectra were in agreement with that reported in literature.114
8
9
10
O7
6
1
2
O
11
5
4
3
OH
OH
50
(ii) [4S∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-4,5-diol (121) (15 mg, 10%) as a
colourless oil; (300 MHz; CDCl3; Me4Si) 1.35-2.01 (6 H, m, 4 x CH2), 2.51 (1 H, d,
JOH,5 6.2 Hz, OH), 2.58 (1 H, d, JOH,4 5.6 Hz, OH), 3.49-3.54 (1 H, m, 5-Heq), 3.58-3.70
(4 H, m, 2 x OCH2), 4.01-4.11 (1 H, m, 4-Hax); δC (75 MHz; CDCl3; Me4Si) 18.1 (CH2,
C-10), 24.9 (CH2, C-9), 28.4 (CH2, C-3), 31.5 (CH2, C-11), 58.2, 60.4 (CH2, C-2 and
C-8), 65.7 (CH, C-4), 72.8 (CH, C-5), 97.9 (quat, C-6). The 1H and
were in agreement with that reported in literature.114
8
9
10
O7
6
1
2
O
11
5
3
4
OH
OH
121
114
13
C NMR spectra
EXPERIMENTAL
7.2 Preparation of [3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan3,5-diyl bis(ethyl p-toluenesulfonate) (146)
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl bis-tertbutylacetate (149)
Sodium hydride (4 mg, 0.16 mmol) was added to a solution of [3R∗, 5S∗, 6S∗]-1,7-
dioxaspiro[5.5]undecan-3,5-diol (50) (14 mg, 0.07 mmol) in THF (15 cm3) at 0 °C. The
reaction mixture was stirred for 30 min at 0 °C then 18-crown-6 was added followed by
tert-butyl bromoacetate (148) (29 mg, 0.15 mmol). The reaction mixture was stirred at
0 °C for 1 h then at room temperature for 16 h. After filtration through a short Celite pad
the solvent was removed at reduced pressure to yield a pale yellow oil which was
purified by flash chromatography using hexane-ethyl acetate (2:1) to afford the title
compound (149) (16 mg, 52%) as a colourless oil [Found: M+ (EI) 416.24092. C21H36O8
requires: M+, 416.24102]; νmax(film)/cm-1 1740 (s, C=O) δH (300 MHz; CDCl3; Me4Si)
1.46 (18 H, s, 6 x CH3), 1.53-1.64 (4 H, m, 9-CH2, 10-HA or 10-HB and 11-Hax),
1.67-1.80 (1 H, m, 10-HA or 10-HB) 2.09-2.19 (3 H, m, 4-CH2 and 11-Heq), 3.29 (1 H, t,
J5,4 4.6 Hz, 5-H), 3.53 (1 H, dddd, J3,2ax 3.5, J3,2eq 3.5, J3,4ax 3.5 and J3,4eq 3.5 Hz, 3-H),
3.62-3.82 (4 H, m, 2-CH2 and 8-CH2), 3.99-4.19 (4 H, m, 2 x OCH2CO); δC (75 MHz;
CDCl3; Me4Si) 17.9 (CH2, C-10), 25.2 (CH2, C-9), 27.0 (CH2, C-4), 28.12, 28.14 (CH3,
Me), 28.4 (CH2, C-11), 61.3 (CH2, C-8), 62.4 (CH2, C-2), 66.5, 67.3 (CH2,
2 x OCH2CO), 71.9 (CH, C-3), 76.8 (CH, C-5), 81.3, 81.4 (quat, 2 x OCMe3), 97.4 (quat,
C-6), 170.00, 170.01 (quat, 2 x C=O); m/z (EI) 416 (M+, 0.2%), 101 (86), 69 (28), 57
(100), 41 (34).
8
9
10
O7
6
5
O
1
2
O
11
4
3
O
O
O
O
149
115
O
EXPERIMENTAL
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl bisallyl ether
(133)
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diol (50) (0.22 g, 1.17 mmol) as
a solution in tetrahydrofuran (5 cm3) was added to a suspension of sodium hydride
(0.08 g, 3.51 mmol) in tetrahydrofuran (10 cm3). The reaction mixture was heated under
reflux for 0.5 h, allyl bromide (135) (0.22 cm3, 2.51 mmol) was then added dropwise and
the reaction heated under reflux for a further 18 h. After cooling, the reaction was
quenched with sodium dihydrogen phosphate (7 cm3, 10% w/v) and extracted with ethyl
acetate (5 x 20 cm3). The combined extracts were washed with water (15 cm3) and dried
over sodium sulfate. Removal of the solvent under reduced pressure gave a yellow oil
that was purified by flash chromatography using ethyl-acetate (4:1) as eluent to afford the
title compound (133) as a pale yellow oil (0.26 g, 84%); [Found: M+H (CI, NH3)
269.17533. C15H25O4 requires: M+H, 269.17528]; νmax(film)/cm-1 1646 (w, C=C);
δH (300 MHz; CDCl3; Me4Si) 1.41 (1 H, ddd, J11ax,11eq 13.6, J11ax,10ax 13.6 and
J11ax,10eq 4.3 Hz, 11-Hax), 1.48-1.82 (4 H, m, 9-CH2 and 10-CH2), 1.91-2.02 (2 H, m,
4-CH2), 2.14 (1 H, dt, J11eq,11ax 13.6 and J11eq,10 2.5 Hz, 11-Heq), 3.16 (1H, t, J5,4 4.7 Hz,
5-H), 3.45 (1 H, dddd, J3,2ax 4.1, J3,2eq 4.1, J3,4ax 4.1 and J3,4eq 4.1 Hz, 3-H), 3.60-3.81
(3 H, m, OCH2), 4.13 (1 H, ddt, Jgem 12.9, J1’A,2’ 5.4 and J1’A,3’ 1.5 Hz, 1’-HA), 5.13 (2 H,
d, J3’B,2’ 10.3 Hz, 2 x 3’-HB), 5.25 (2 H, ddd, J3’A,2’ 17.2, J3’A,1’A 1.5 and J3’A,1’B 1.5 Hz,
2 x 3’-HA), 5.85-5.97 (2 H, m, 2 x 2’-H); δC (75 MHz; CDCl3; Me4Si) 17.9 (CH2, C-10),
25.2 (CH2, C-9), 27.1 (CH2, C-4), 28.5 (CH2, C-11), 61.1 (CH2, C-8), 62.8 (CH2, C-2),
69.7, 70.6 (CH2, 2 x OCH2), 70.7 (CH, C-3), 76.0 (CH, C-5), 97.4 (quat C-6), 116.54,
116.55 (CH2, 2 x C-3’), 135.27, 135.29 (CH, 2 x C-2’); m/z (CI, NH3) 269 (M+H, 17%),
211 (100), 127 (38), 101 (78), 84 (42), 71 (47).
8
9
O7
10
6
1
2
O
11
4
5
O
3
O
1'
1'
2'
2'
3'
3'
133
116
EXPERIMENTAL
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl bis(2hydroxyethyl) ether (145)
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl bisallyl ether (133) (75 mg,
0.28 mmol) was dissolved in methanol (8 cm3) and the solution cooled to -78°C. Ozone
was bubbled through the solution until a pale blue colour persisted (10 – 15 min). Excess
ozone was removed by passing oxygen through the solution. The reaction was taken out
of the cooling bath and sodium borohydride (42 mg, 1.12 mmol) was added. The reaction
was allowed to warm to room temperature and left to stir for 16 h. The solution was
diluted with brine (5 cm3) and the methanol removed. The aqueous solution was
extracted with dichloromethane (5 x 15 cm3). The combined extracts were dried over
sodium sulfate and the dichloromethane removed under reduced pressure. The pale
yellow oil was purified by flash chromatography using 8% MeOH in CH2Cl2 to afford
the title compound (145) (120 mg, 75%) as colourless needles mp 62-65 °C. [Found: M+
(EI) 276.15725. C13H24O6 requires: M+, 276.15729]; νmax(film)/cm-1 3628-3290 (br s,
OH); δH (400 MHz; CDCl3) 1.31 (1 H, ddd, J11ax,11eq 13.6, J11ax,10ax 13.6 and
J11ax,10eq 4.5 Hz, 11-Hax), 1.49-1.62 (3 H, m, 9-CH2, 10-HA or 10-HB), 1.73-1.82 (1 H, m,
10-HA or 10-HB), 1.98 (1 H, ddd, J4ax,4eq 15.1, J4ax,5 3.6 and J4ax,3 3.6 Hz, 4-Hax), 2.112.29 (2 H, m, 4-Heq and 11-Heq), 3.11 (1 H, t, J5,4 3.6 Hz, 5-H), 3.37-3.41 (1 H, m, 3-H),
3.47-3.84 (12 H, m, 2-CH2, 8-CH2, 2 x 1’-CH2 and 2 x CH2OH); δC (75 MHz; CDCl3)
18.1 (CH2, C-10), 25.1 (CH2, C-9), 26.0 (CH2, C-4), 31.1 (CH2, C-11), 60.9 (CH2, C-8),
61.0 (CH2, C-2), 61.5, 61.6 (CH2, 2 x C-1’), 70.9, 71.3 (CH2, 2 x CH2OH), 72.2 (CH,
C-3), 77.2 (CH, C-5), 96.1 (quat, C-6); m/z (EI) 276 (M+, 0.4%), 158 (10), 101 (41), 88
(95) 73 (42), 69 (23), 45 (100).
8
9
10
O7
6
1
2
O
11
4
5
3
O
O
1'
1'
2'
2'
OH
HO
145
117
EXPERIMENTAL
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl diacetaldehyde
(150)
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl bisallyl ether (133) (0.19 g,
0.71 mmol) was dissolved in methanol (10 cm3) and the solution cooled to -78°C. Ozone
was bubbled through the solution until a pale blue colour persisted (10 – 15 min). Excess
ozone was discharged by passing oxygen and nitrogen through the flask. The reaction
was taken out of the cooling bath and dimethyl sulfide (0.16 cm3, 2.1 mmol) was added.
The reaction was allowed to warm to room temperature and left to stir for 16 h. The
volatiles were removed in vacuo to yield an oil that was purified by flash
chromatography using 8% methanol in dichloromethane to yield the title compound (150)
as a colourless viscous oil (0.165 g, 86%). [Found: M+ (EI) 272.12576. C13H20O6
requires: M+, 272.12599]; νmax(film)/cm-1 1733 (s, C=O); δH (400 MHz; CDCl3) 1.43
(1 H, ddd, J11ax,11eq 13.5, J11ax,10ax 13.5 and J11ax,10eq 4.8 Hz, 11-Hax), 1.51-1.64 (3 H, m,
9-CH2, 10-HA or 10-HB), 1.69-1.83 (1 H, m, 10-HA or 10-HB), 2.04-2.22 (3 H, m, 4-CH2
and 11-Heq), 3.21 (1 H, t, J5,4 3.8 Hz, 5-H), 3.44-3.46 (1 H, m, 3-H), 3.64-3.79 (4 H, m,
2-CH2 and 8-CH2), 3.96-4.28 (4 H, m, 2 x OCH2CHO), 9.68-9.74 (2 H, m, 2 x HC=O);
δC (75 MHz; CDCl3) 17.9 (CH2, C-10), 25.0 (CH2, C-9), 26.5 (CH2, C-4), 29.8 (CH2,
C-11), 61.2 (CH2, C-8), 61.8 (CH2, C-2), 74.5, 75.4 (CH2, 2 x OCH2CHO), 72.7 (CH,
C-3), 76.8 (CH, C-5), 96.6 (quat, C-6), 201.1, 201.3 (quat, 2 x C=O); m/z (EI) 272 (M+,
1%), 172 (10), 101 (100), 69 (81), 43 (27).
8
9
10
O7
6
1
5
O
2
O
11
4
3
O
O
H
H
150
118
O
EXPERIMENTAL
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl bis(2-ptoluenesulfonyl) ethyl ether (146)
A solution of n-butyllithium (0.41 cm3 of a 1.6 mol dm-1 solution in hexane, 0.66 mmol)
was added to a solution of [3R∗, 5S∗, 6S∗]-1,7-dioxaspiro[5.5]undecan-3,5-diyl bis(2hydroxyethyl) ether (145) in tetrahydrofuran (8 cm3) at -78 °C. The mixture was stirred
for 0.5 h. A solution of tosyl chloride (0.15 g, 0.79 mmol) in tetrahydrofuran (5 cm3) was
added and the mixture stirred for a further 0.5 h at –78 °C. The reaction was then taken
out of the cooling bath, allowed to warm to room temperature and left to stir for 16 h.
The reaction was quenched with sodium dihydrogen phosphate solution (5 cm3, 10%
w/v) and extracted with ethyl acetate (5 x 20 cm3). The combined organic layers were
dried over magnesium sulfate and the solvent removed in vacuo to yield a pale yellow
oil. Purification by flash chromatography using hexane-ethyl acetate (3:2) as eluent
yielded the title compound (146) as a colourless oil (0.17 g, 90%) [Found: M+H (FAB)
585.18336. C27H37O10S2 requires: M+H, 585.18282]; δH (300 MHz; CDCl3; Me4Si) 1.25
(1 H, ddd, J11ax,11eq 14.3, J11ax,10ax 14.3 and J11ax,10eq 4.3 Hz, 11-Hax), 1.45-1.56 (3 H, m,
9-CH2 and 10-HA or 10-HB), 1.65-1.76 (1 H, m, 10-HA or 10-HB), 1.83-2.02 (3 H, m,
4-CH2 and 11-Heq), 2.44 (6 H, s, 2 x ArCH3), 3.07 (1 H, t, J5,4 3.9 Hz, 5-H), 3.34 (1 H,
dddd, J3,2ax 3.2, J3,2eq 3.2, J3,4ax 3.2 and J3,4eq 3.2 Hz, 3-H), 3.56-3.79 (8 H, m, 2-CH2,
8-CH2 and 2 x C-1’), 4.08-4.14 (4 H, m, 2 x CH2OTs), 7.31-7.79 (8 H, m, Ar-H);
δC (75 MHz; CDCl3; Me4Si) 17.9 (CH2, C-10), 21.6 (CH3, Ar-CH3), 25.1 (CH2, C-9),
26.0 (CH2, C-4), 29.6 (CH2, C-11), 61.1 (CH2, C-8), 62.3 (CH2, C-2), 66.5, 67.5 (CH2,
2 x C-1’), 69.5, 69.6 (CH2, 2 x CH2OTs) 72.2 (CH, C-3), 77.6 (CH, C-5), 96.5 (quat,
C-6), 127.9, 127.9, 129.83, 129.84 (CH, 4 x Ar) 133.0, 133.0, 144.75, 144.81 (quat, 2 x
Ar-CH3 and 2 x ArSO2); m/z (FAB) 585 (M+H, 6%), 369 (45), 199 (27), 154 (100), 136
(72), 91 (33).
119
EXPERIMENTAL
8
9
10
O7
6
1
2
O
11
5
4
O
3
O
1'
1'
2'
2'
O
O
S
O
O
O
CH3
S
O
CH3
146
7.3
Preparation of β-Chloroethyl sulfides (104) and (127) and
Dithiols (122) and (123)
3,6,9-Trithiaundecane-1,11-diol (124) and 3,6,9,12Tetrathiadodecane-1,14-diol (125)
General Procedure. The appropriate dithiol (6.5 mmol) was added to a solution of
sodium ethoxide (13.0 mmol) in refluxing ethanol (20 cm3). 2-Chloroethanol
(13.0 mmol) was added dropwise and the mixture heated under reflux for 18 h following
the procedure reported by Wolf et al.121a The solvent was removed in vacuo and the
product recrystallised from acetone to yield the appropriate diol:
(i) 3,6,9-Trithiaundecane-1,11-diol (124). Prepared from 2-mercaptoethyl sulfide
(Aldrich) (1.0 g, 6.5 mmol) (99) and 2-chloroethanol (1.1 g, 13.0 mmol) as a white solid
(1.25 g, 80%) mp 96-98 °C (from acetone) [Found: M+ (EI) 242.04645 C10H22O2S4,
requires: M+, 242.04690]; δH [200 MHz; CDCl3] 2.16 (2 H, br s, OH), 2.74-2.80 (12 H,
m, 6 x CH2S), 3.76 (4 H, t, JCH2,OH 5.8 Hz, 2 x CH2OH); m/z (EI) 242 (M+, 0.5%), 164
(21), 138 (23), 105 (100), 61 (76), 45 (43). The 1H NMR was in agreement with the
published data.121a
120
EXPERIMENTAL
4
2
1
HO
5
7
10
8
S
S
S
3
6
9
11
OH
124
(ii) 3,6,9,12-Tetrathiadodecane-1,14-diol (125). Prepared from 3,6-dithiaoctane-1,8dithiol (1.4 g, 6.5 mmol) (122) and 2-chloroethanol (1.1 g, 13.0 mmol) as a white solid
(1.51 g, 77%) mp 115-117 °C (from acetone) [Found: M+ (EI) 302.04914. C10H22O2S4,
requires: M+, 302.05027]; δH [300 MHz; (CD3)2SO] 2.30 (2 H, b s, OH) 2.74-2.80 (16 H,
m, 8 x CH2S), 3.75 (4 H, t, JCH2,OH 6.0 Hz, 2 x CH2OH); m/z (EI) 302 (M+, 0.2%), 224
(10), 198 (22), 164 (31), 105 (100), 61 (52). The 1H NMR was in agreement with the
published data.121a
1
4
2
HO
5
7
10
8
S
S
S
3
6
9
13
11
S
12
14
OH
125
1,8-Dichloro-3,6-dithiaoctane (129), 1,11-Dichloro-3,6,9trithiaundecane (104) and 1,14-Dichloro-3,6,9,12tetrathiadodecane (127)
General Procedure. Thionyl chloride (13.6 mmol) was added to the appropriate diol
(4.1 mmol) in dichloromethane (10 cm3) at room temperature using well established
literature procedures.68,121 The reaction mixture was stirred for 18 h then treated with
methanol (2 cm3) to quench the excess thionyl chloride. The resulting solution was
evaporated to dryness. The residue was taken up in dichloromethane (10 cm3) and
washed with sodium hydrogen carbonate (10 cm3). The organic layer was then dried with
sodium sulfate and the solvent removed in vacuo to yield the appropriate dichloride:
(i) 1,8-Dichloro-3,6-dithiaoctane (129). Prepared from 3,6-dithia-1,8-octanediol
(Aldrich) (0.75 g, 4.1 mmol) as a white solid (0.77 g, 85%) mp 55-57 °C [Found: M+ (EI)
219.97258. C6H12Cl2S2, requires: M+, 219.97280]; δH (200 MHz; CDCl3) 2.80 (4 H, s, 2
x CH2S), 2.90 (4 H, t, JSCH2,CH2Cl 7.7 Hz, 2 x CH2S), 3.61-3.69 (4 H, m, 2 x CH2Cl). The
1
H NMR was in agreement with that reported in literature.68
121
EXPERIMENTAL
1
2
Cl
4
5
S
7
8
S
3
Cl
6
129
(ii) 1,11-Dichloro-3,6,9-trithiaundecane (104). Prepared from 3,6,9-trithiaundecane1,11-diol (1.0 g, 4.1 mmol) (124) as a white solid (1.04 g, 90%) [Found: M+ (EI)
279.97616. C8H16Cl2S3, requires: M+, 279.97617]; δH (200 MHz; CDCl3) 2.79 (8 H, s,
4 x CH2S), 2.91 (4 H, t, JSCH2,CH2Cl 7.7 Hz, 2 x CH2S), 3.61-3.69 (4 H, m, 2 x CH2Cl). The
1
H NMR spectrum was in agreement with that reported in literature.68
2
1
Cl
4
5
7
10
8
S
S
S
3
6
9
11
Cl
104
(iii) 1,14-Dichloro-3,6,9,12-tetrathiatetradecane (127). Prepared from 3,6,9,12tetrathiadodecane-1,14-diol (1.24 g, 4.1 mmol) (125) as a white solid (1.18 g, 85%)
[Found: M+ (EI) 339.97882. C10H20Cl2S4, requires: M+, 339.97954]; δH (200 MHz;
CDCl3) 2.78 (12 H, s, 6 x CH2S), 2.91 (4 H, t, JSCH2,CH2Cl 7.7 Hz, 2 x CH2S), 3.61-3.69
(4 H, m, 2 x CH2Cl). The 1H NMR was in agreement with that reported in literature.68
1
Cl
4
2
5
7
10
8
13
11
S
S
S
S
3
6
9
12
14
Cl
127
4,7-Dithiaoctane-1,10-dithiyldiacetate (130) and 4,7,10Trithiaundecane-1,13-dithiyldiacetate (131)
General Procedure. Cesium carbonate (0.33 g, 1.0 mmol) was added in small portions
to a solution of thiolacetic acid (0.15 g, 2.0 mmol) in methanol (5 cm3). The mixture was
stirred for 30 min and then evaporated to dryness. The white solid obtained was then
122
EXPERIMENTAL
dissolved in dimethylformamide (5 cm3) and the requisite dichloride (1.0 mmol) in
dimethylformamide (1 cm3) was added. The mixture was stirred for 16 h at room
temperature. The solvent was removed under reduced pressure and the residue was
extracted with diethyl ether (3 x 20 cm3). The combined extracts were washed with brine
(15 cm3) and dried over sodium sulfate. The solvent was removed in vacuo to yield the
appropriate thioester:
(i) 4,7-Dithiaoctane-1,10-dithiyldiacetate (130). Prepared from 1,8-dichloro-3,6-
dithiaoctane (0.22 g, 1.0 mmol) (129) as a pale orange solid (0.26 g, 86%) mp 58-60 °C
[Found: M+ (EI) 298.01821. C10H18O2S4 requires: M+, 298.01897]; νmax(film)/cm-1 1685
(s, C=O); δH (400 MHz; CDCl3) 2.33 (6 H, s, 2 x CH3C=O), 2.68-2.72 (4 H, m, 2 x
CH2S), 2.81 (4 H, s, 2 x CH2S), 3.04-3.08 (4 H, m, 2 x CH2SC=O); δC (100 MHz;
CDCl3) 29.3 (CH2, 2 x CH2SC=O), 30.6 (2 x CH3C=O), 31.8, 32.0 (CH2, 4 x CH2S),
195.3 (2 x C=O); m/z (EI) 298 (M+, 2%), 222 (20), 103 (25), 43 (100).
O
2
3
5
6
1
H3C
O
9
8
10
S
S
S
4
7
S
CH3
130
(ii) 4,7,10-Trithiaundecane-1,13-dithiyldiacetate (131) was prepared from 1,11dichloro-3,6,9-trithiaundecane (0.28 g, 1.0 mmol) (104) as a pale orange solid (0.28 g,
79%) mp 80-83 °C [Found: M+ (EI) 358.02229. C12H22O2S5 requires: M+, 358.02234];
νmax(film)/cm-1 1691 (s, C=O); δH (400 MHz; CDCl3) 2.32 (6 H, s, 2 x CH3C=O), 2.682.71 (4 H, m, 2 x CH2S), 2.80 (8 H, s, 4 x CH2S), 3.03-3.07 (4 H, m, 2 x CH2SC=O);
δC (100 MHz; CDCl3) 29.3 (CH2, 2 x CH2SC=O), 30.7 (2 x CH3C=O), 31.8, 32.1, 32.2
(CH2, 6 x CH2S), 195.3 (2 x C=O); m/z (EI) 358 (M+, 1.5%), 222 (6.5), 162 (22), 103
(38), 43 (100).
O
H3C
2
1
S
3
5
6
8
11
9
O
12
13
S
S
S
4
7
10
131
123
S
CH3
EXPERIMENTAL
3,6-Dithiaoctane-1,8-dithiol (122) and 3,6,9-Trithiaundecane-1,11dithiol (123)
General Procedure. Lithium aluminium hydride (0.17 g, 4.5 mmol) was added to a
solution of the appropriate thiolate (1.8 mmol) in diethyl ether using the procedure
described by Edema et al.122 Excess lithium aluminium hydride was quenched with
saturated ammonium chloride (10 cm3). The reaction mixture was extracted with ethyl
acetate (3 x 20 cm3), washed with water (15 cm3) and dried over sodium sulfate. The
solvent was removed under reduced pressure and the product purified by flash
chromatography using dichloromethane as eluent to yield the appropriate dithiol:
(i)
3,6-Dithiaoctane-1,8-dithiol
(122).
Prepared
from
4,7-dithiaoctane-1,10-
dithiyldiacetate (0.5 g, 1.8 mmol) (130) as a white solid (0.34 g, 89%) [Found: M+ (EI)
21399764. C12H22O2S5 requires: M+, 213.99784]; δH (200 MHz; CDCl3) 1.69-1.77 (2 H,
m, SH), 2.71-2.80 (12 H, m, CH2S). The 1H NMR spectrum was in agreement with that
reported in literature.68
1
4
2
HS
5
S
7
8
S
3
SH
6
122
(ii) 3,6,9-Trithiaundecane-1,11-dithiol (123). Prepared from 4,7,10-Trithiaundecane1,13-dithiyldiacetate (0.64 g, 1.8 mmol) (131) as a white solid (0.34 g, 68%) [Found: M+
(EI) 274.00046. C8H18S5 requires: M+, 274.00121]; δH (200 MHz; CDCl3) 1.68-1.77 (2
H, m, SH), 2.67-2.81 (16 H, m, CH2S); m/z (EI) 274 (M+, 0.7%), 120 (39), 61 (100).
1
HS
4
2
S
3
5
7
S
6
123
124
10
8
S
9
11
SH
EXPERIMENTAL
3,6,9-Trithiaundeca-1,10-diene (132)
Potassium hydride (0.18 g, 30% dispersion in mineral oil, 1.34 mmol) was added
to a solution of [3R*,5S*,6S*]-1,7-dioxaspiro[5.5]undecane-3,5-diol (50) (0.12 g, 0.64
mmol) in tetrahydrofuran (40 cm3) and the resulting solution was heated under reflux for
30 min. A solution of 1,11-dichloro-3,6,9-trithiaundecane (104) (0.21 g, 0.77 mmol) in
tetrahydrofuran (10 cm3) was added dropwise over 3 h and the reaction mixture heated
under reflux for a further 20 h. The solution was then cooled and filtered through a short
pad of Celite. The solvent was removed under reduced pressure and the residue purified
by flash chromatography using hexane-ethyl acetate (4:1) as eluent to afford the title
compound (132) (0.12 g, 90%) as a pale yellow oil [Found: M+H (CI, NH3) 207.03352.
C8H15S3 requires: M+H, 207.03359]; δH (300 MHz; CDCl3; Me4Si) 2.79-2.94 (8 H, m, 4
x CH2S), 5.17 (2 H, d, JCHB,CH 16.7 Hz, HCHB=CH), 5.26 (2 H, d, JCHA,CH 10.1 Hz,
HCHA=CH), 6.33 (2 H, dd, JCHB,CH 16.7, JCHA,CH 10.1 Hz, CH2=CH); δC (75 MHz;
CDCl3; Me4Si) 31.60, 31.64 (CH2, CH2S), 112.1 (CH2, 2 x CH2=CH), 131.3 (CH, 2 x
CH2=CH).
HA
1
HB
4
2
S
3
5
7
S
6
10
8
11
S
9
132
7.4
The Synthesis of Spiroacetal Thiacrown Ethers
[1S∗, 15R∗, 18S∗]-Spiro[2,14,17-trioxa-5,8,11trithiabicyclo[13.3.1]nonadecane-18,2’-tetrahydropyran] (55)
A solution of the spiroacetal ditosylate (146) (100 mg, 0.17 mmol) in
dimethylformamide (5 cm3) and a solution of the 2-mercaptoethyl sulfide (99) (220 mg,
0.17 mmol) in dimethylformamide (5 cm3) were added from separate addition funnels
over 2.5 h to a vigorously stirred suspension of cesium carbonate (170 mg, 0.51 mmol) in
dimethylformamide (20 cm3) at 60 °C. The mixture was left to stir for 16 h. The reaction
mixture was then filtered through a short pad of Celite and the filter cake washed with
125
EXPERIMENTAL
dichloromethane (3 x 15 cm3). The solvent was removed under reduced pressure to yield
a yellow oil that was purified by flash chromatography using hexane-ethyl acetate (4:1)
as eluent to afford the title compound (55) (58 mg, 86%) as a pale yellow oil [Found: M+
(EI) 394.13104. C17H30O4S3 requires: M+, 394.13063]; δH (400 MHz; CDCl3) 1.26 (1 H,
ddd, J3’ax,3’eq 13.6, J3’ax,4’ax 13.6 and J3’ax,4’eq 4.4 Hz, 3’-Hax), 1.51-1.57 (3 H, m, 5’-CH2
and 4’-Ha or 4’-HB), 1.73-1.81 (1 H, m, 4’-HA or 4’-HB), 1.91 (1 H, ddd, J19ax,19eq 15.2,
J19ax,15 3.4 and J19ax,1 3.4, Hz, 19-Hax), 2.15-2.25 (2 H, m, 19-Heq and
3’-Heq), 2.72-
2.82 (12 H, m, 6 x CH2S), 3.09 (1 H, t, J1,19 3.4 Hz, 1-H), 3.37 (1 H, m, 15-H), 3.41
(1 H, ddd, JA,B 6.8, J3A,4A 9.0 and J3A,4B 9.0 Hz, 3-HA), 3.55-3.68 (4 H, m, 16-CH2 and
13-CH2), 3.72-3.82 (3 H, m, 3-HB and 6’-CH2); δC (100 MHz; CDCl3) 18.0 (CH2, C-4’),
24.3 (CH2, C-19), 25.2 (CH2, C-5’), 31.2 (CH2, C-3’), 31.4, 31.8, 32.3, 32.4, 33.2, 33.5
(CH2, 6 x CH2S), 60.9 (CH2, C-6’), 62.2 (CH2, C-16), 70.1 (CH2, C-13), 70.3 (CH2, C-3),
72.0 (CH, C-15), 77.2 (CH, C-1), 96.6 (quat, C-18); m/z (EI) 394 (M+, 23%), 120 (54),
103 (57), 87 (100), 61 (76), 41 (46).
6'
5'
O 1'
4'
2' 18
17
16
O
3'
1
2
19
15
O 14
O
3
13
12
4
5
S
S 11
S
6
7
8
10
9
55
[1S∗, 18R∗, 21S∗]-Spiro[2,17,20-trioxa-5,8,11,14tetrathiabicyclo[16.3.1]docosane-21,2’-tetrahydropyran] (56)
The title compound (56) was prepared from the spiroacetal ditosylate (146)
(140 mg, 0.24 mmol), 3,6-dithiaoctane-1,8-dithiol (122) (50 mg, 0.24 mmol) and cesium
carbonate (230 mg, 0.72 mmol) using a similar procedure to that described above for
crown ether (55). The crude product was purified by flash chromatography using hexaneethyl acetate (4:1) as eluent to afford the title compound (56) (75 mg, 68%) as a
colourless oil [Found: M+ (EI) 454.13397. C19H34O4S4 requires: M+, 454.13400]; δH (400
MHz; CDCl3) 1.32 (1 H, ddd, J3’ax,3’eq 13.6, J3’ax,4’ax 13.6 and J3’ax,4’eq 4.4 Hz, 3’-Hax),
126
EXPERIMENTAL
1.49-1.60 (3 H, m, 5’-CH2 and 4’-HA or 4’-HB), 1.71-1.79 (1 H, m, 4’-HA or 4’-HB), 1.97
(1 H, ddd, J22ax,22eq 14.8, J22ax,18 3.7 and J22ax,1 3.7 Hz, 22-Hax), 2.07 (1 H, dddd,
J22eq,22ax 14.8, J22eq,1 3.7, J22eq,18 3.7 and J22eq,19eq 1.9 Hz, 22-Heq), 2.12 (1 H, dt,
J3’eq,3’ax 13.6 and J3’eq,4’ 2.8 Hz, 3’-Heq), 2.72-2.82 (16 H, m, 8 x CH2S), 3.09 (1 H, t,
J1,22 3.7 Hz, 1-H), 3.37 (1 H, dddd, J18eq,22ax 3.7, J18eq,22eq 3.7, J18eq,19ax 3.7 and
J18eq,19eq 3.7 Hz, 18-H), 3.55-3.78 (8 H, m, 6’-CH2, 19-CH2, 16-CH2 and 3-CH2);
δC (100 MHz; CDCl3) 17.9 (CH2, C-4’), 25.2 (CH2, C-5’), 26.4 (CH2, C-22), 30.2 (CH2,
C-3’), 32.01, 32.04, 32.41, 32.46, 32.49, 32.52, 33.15, 33.18 (CH2, 8 x CH2S), 61.0 (CH2,
C-6’), 62.1 (CH2, C-19), 69.2 (CH2, C-16), 70.5 (CH2, C-3), 71.9 (CH, C-18), 77.2 (CH,
C-1), 96.5 (quat, C-21); m/z (EI) 454 (M+, 19%), 131 (42), 120 (71), 87 (100), 61 (74),
41 (35).
6'
5'
O1'
4'
2' 21
22
1
3
20
19
O
3'
18
17
2
O
O
16
15
4
5
S 14
S
13
6
7
S
S 11
8
9
12
10
56
[1S∗, 21R∗, 24S∗]-Spiro[2,20,23-trioxa-5,8,11,14,17pentathiabicyclo[19.3.1]pentacosane-24,2’-tetrahydropyran] (57)
The title compound (57) was prepared from the spiroacetal ditosylate (146) (0.27
g, 0.46 mmol), 3,6,9-Trithiaundecane-1,11-dithiol (123) (0.13 g, 0.46 mmol) and cesium
carbonate (0.45 g, 1.4 mmol) using a similar procedure to that described above for crown
ether (55). The crude product was purified by flash chromatography using hexane-ethyl
acetate (4:1) as eluent to afford the title compound (57) (0.15 g, 64 %) as a pale yellow
oil [Found: M+ (EI) 514.13764. C21H38O4S5 requires: M+, 514.13737]; δH (400 MHz;
CDCl3) 1.32 (1 H, ddd, J3’ax,3’eq 13.3, J3’ax,4’ax 13.3 and J3’ax,4’eq 4.3 Hz, 3’-Hax), 1.461.60 (3 H, m, 5’-CH2 and 4’-HA or 4’-HB), 1.66-1.82 (1 H, m, 4’-HA or
4’-HB), 1.95
(1 H, ddd, J25ax,25eq 14.8, J25ax,21 3.8 and J25ax,1 3.8 Hz, 25-Hax), 2.05-2.14 (2 H, m,
127
EXPERIMENTAL
3’-Heq and 25-Heq), 2.69-2.84 (20 H, m, 10 x CH2S), 3.08 (1 H, t, J1,25 3.8 Hz, 1-H),
3.53 (1 H, br s, 21-H), 3.55-3.79 (8 H, m, 6’-CH2, 22-CH2, 3-CH2 and 19-CH2);
δC (100 MHz; CDCl3) 17.9 (CH2, C-4’), 25.2 (CH2, C-5’), 26.1 (CH2, C-25), 30.3 (CH2,
C-3’), 31.9, 32.1, 32.30, 32.32, 32.4, 32.5, 32.6, 32.7, 32.9, 33.0 (CH2, 10 x CH2S), 61.0
(CH2, C-6’), 62.0 (CH2, C-22), 69.2 (CH2, C-19), 70.1 (CH2, C-3), 71.9 (CH, C-21), 77.1
(CH, C-1), 96.5 (quat, C-24); m/z (EI) 514 (M+, 13%), 120 (72), 105 (54), 87 (100), 61
(72), 41 (32).
6'
5'
O 1'
4'
2' 24
1
2
5
23
22
O
3'
25
21
O 20
O
3
19
4
18
S
S 17
6
16
7
8
15
S
10
9
S 14
12
S
11
13
57
7.5
The Synthesis of Spiroacetal Azacrown Ethers
N1,N3,N5-Tris(p-tosylsulfonyl)diethylenetriamine (157)
A solution of p-toluenesulfonyl chloride (2.77 g, 14.5 mmol) in ether (12 cm3)
was added dropwise to a vigorously stirred solution of diethylenetriamine (151) (0.50 g,
4.8 mmol) and NaOH (0.58 g, 14.5 mmol) in water (5 cm3). The mixture was then stirred
for 1 h at room temperature then heated at 65 °C for 3 h. The precipitate, collected by
filtration, was then suspended in EtOH and refluxed for 4 h to afford a white crystalline
solid (2.21 g, 80%) [Found: M+H (EI) 566.14504. C25H31N3O6S3 requires: M+H,
566.14533]; δH (300 MHz; CDCl3; Me4Si) 2.50 (9 H, s, 3 x CH3), 2.91 (4 H, m, 2 x
CH2NH), 3.12 (4 H, t, JCH2N,CH2NH 6.7 Hz, 2 x CH2N), 7.46-7.80 (12 H, m, Ar);
m/z (FAB) 566 (M+H, 21%), 154 (100), 136 (72). The 1H NMR was in agreement with
that reported in the literature.184
128
EXPERIMENTAL
O
1
2
4
5
O
HN
S
3
H3C
S
NH
O
N
O
S
O
CH3
O
CH3
157
N1,N3,N5-Tris(2-nitrobenzenesulfonyl)-1,5-diamino-3-azapentane
(158)
A solution of diethylenetriamine (151) (0.25 g, 2.4 mmol) and triethylamine (0.5
3
cm , 3.9 mmol) was added to a stirred solution of 2-nitrobenzenesulfonyl chloride
(1.61 g, 7.7 mmol) in dichloromethane (20 cm3) at 0 °C. The reaction mixture was stirred
for 20 h. The solvent was removed in vacuo and the residue dissolved in H2O-CHCl3.
The organic layer was separated and the aqueous layer extracted with CHCl3 (3 x 10
cm3), washed with saturated NaHCO3 (15 cm3) and dried over Na2SO4. Removal of the
solvent and purification by flash chromatography using hexane-ethyl acetate (3:2)
afforded the title compound (158) (1.27 g, 80%) as a yellow solid mp 70-74 °C [Found:
M+H (FAB) 659.05478. C22H23N6O12S3 requires: M+H, 659.05361]; νmax(film)/cm-1 3323
(w, NH); δH (400 MHz; CDCl3) 3.33 (4 H, m, 2 x CH2NH), 3.54 (4 H, t, JCH2N,CH2NH 6.1
Hz, 2 x CH2N), 5.72 (2 H, t, JNH,CH2 6.1 Hz, NH); δC (100 MHz; CDCl3) 42.3 (C-1), 49.0
(C-2), 124.5, 124.7, 125.6, 131.0, 131.4, 132.1, 132.6, 133.0, 133.9, 134.5, 135.9 (18 x
Ar); m/z (FAB) 659 (M+H, 10%), 154 (100), 136 (73).
O
1
2
5
4
O2N
O
3
S
O
NH
N
O
S
NO2
HN
O
O
NO2
158
129
S
EXPERIMENTAL
[1S∗, 15R∗, 18S∗]-Spiro[2,14,17-trioxa-5,8,11-tris(2-nitrobenzenesulfonyl)-5,8,11-triazabicyclo[13.3.1]nonadecane-18,2’tetrahydropyran] (159)
To a solution of the Ns-protected triamine (158) (46 mg, 0.07 mmol) in
tetrahydrofuran (20 cm3) was added sodium hydride (5 mg, 0.17 mmol) and the resulting
mixture heated under reflux for 30 min. A solution of [3R∗, 5S∗, 6S∗]-1,7-
dioxaspiro[5.5]undecan-3,5-diyl bis(2-p-toluenesulfonyl) ethyl ether (146) (41 mg,
0.07 mmol) in tetrahydrofuran (5 cm3) was added over 3 h and the reaction mixture was
heated under reflux for a further 20 h. The solvent was removed under reduced pressure
to yield a tan oil which was purified by flash chromatography using ethyl acetate-hexane
(4:1) as eluent to afford the title compound (159) (17 mg, 27%) as a colourless oil
[Found: M+H (FAB)
899.18910. C35H43N6O16S3
requires:
M+H,
899.18977];
δH (300 MHz; CDCl3; Me4Si) 1.30-1.34 (1 H, m, 3’-Hax), 1.51-1.59 (4 H, m, 4’-CH2 and
5’-CH2), 1.96 (1 H, dt, J11eq,11ax 13.5 and J11eq,10 2.1 Hz, 3’-Heq), 2.03-2.07 (2 H, m,
19-CH2), 3.03 (1 H, t, J1,19 3.0 Hz, 1-H), 3.24 (1 H, br s, 15-H), 3.38-3.88 (20 H, m,
6’-CH2, 16-CH2, 3-CH2, 13-CH2 and 6 x CH2N), 7.61-8.11 (12 H, m, Ar); δC (75 MHz;
CDCl3; Me4Si) 18.2 (CH2, C-4’), 25.1 (CH2, C-5’), 27.5 (CH2, C-19), 31.6 (CH2, C-3’),
48.4, 48.6, 49.8, 49.9, 50.9, 51.0 (CH2, 6 x CH2N), 60.5 (CH2, C-6’), 60.9 (CH2, C-16),
71.1 (CH2, C-13), 71.9 (CH2, C-3), 72.0 (CH, C-15), 77.2 (CH, C-1), 96.1 (quat, C-18),
124.2, 124.4, 131.2, 131.5, 132.0, 132.0, 132.1, 132.2, 132.4, 133.6, 133.7, 133.8 (18 x
Ar); m/z (EI) 899 (M+H, 0.6%), 368 (11), 194 (57), 181 (60), 167 (91), 101 (85), 71
(100).
6'
5'
O 1'
4'
2' 18
17
16
O
3'
19
1
2
15
O2N
O 14
O
3
O
13
4
N5
S
O
NO2
O
12
11
8
6
7
N
9
O
S
O
N S
O
10
NO2
159
130
EXPERIMENTAL
[1S∗, 15R∗, 18S∗]-Spiro[2,14,17-trioxa-5,8,11triazabicyclo[13.3.1]nonadecane-18,2’-tetrahydropyran] (58)
Thiophenol (5 mg, 0.05 mmol) was added to a stirred mixture of the
[1S∗,
15R∗,
18S∗]-spiro[2,14,17-trioxa-5,8,11-tris(2-nitro-benzenesulfonyl)-5,8,11-
triazabicyclo[13.3.1]nonadecane-18,2’-tetrahydropyran] (159) (10 mg, 0.01 mmol) and
K2CO3 (21 mg, 0.15 mmol) in DMF (5 cm3). The resulting solution was stirred at room
temperature for 18 h. The solvent was removed under reduced pressure to yield a tan
residue that was redissolved in H2O-CHCl3 (3:5). The organic phase was separated and
the aqueous layer extracted with CHCl3 (5 x 5 cm3). The combined organic layers were
washed with brine (5 cm3), dried over Na2SO4 and the solvent concentrated. The residue
was purified by flash chromatography using CH2Cl2:MeOH (20:1), then CH2Cl2:MeOH30% NH4OH (20:1) as eluent to afford the title compound (58) (3.2 mg, 84%) as a
viscous tan oil [Found: M+H (FAB) 344.25423. C17H34N3O4 requires: M+H, 344.25493];
δH (300 MHz; CDCl3; Me4Si) 1.32-1.36 (1 H, m, 3’-Hax), 1.55-1.70 (4 H, m, 4’-CH2 and
5’-CH2), 1.96 (1 H, m, 3’-Heq), 2.17 (2 H, m, 19-CH2), 3.04 (1 H, m, 1-H), 3.29 (1 H,
br s, 15-H), 3.55-3.84 (8 H, m, 3-CH2, 6’-CH2, 13-CH2 and 16-CH2); m/z (EI) 344 (M+H,
2%), 299 (52), 287 (73), 226 (61), 153 (58), 99 (68), 56 (100), 44 (75). 13C NMR data
was not acquired for this compound as there was insufficient material to give a
satisfactory signal to noise ratio.
6'
5'
O 1'
4'
2' 18
17
16
O
3'
1
2
19
15
O 14
O
3
13
12
4
5 NH
NH
11
8
6
7
N
H
58
131
10
9
EXPERIMENTAL
7.6
Olefin Metathesis of the Spiroacetal Bisallyl Ether (133)
Bis[1,7-dioxaspiro[5.5]undec-3,5-diyl 2-buten-1,4-diyl] ether (142)
(a) Using Grubbs’ First Generation Ruthenium Catalyst
[3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl bisallyl ether (133) (89 mg,
0.33mmol) in dichloromethane (10 cm3) was slowly added via syringe or cannula to a
solution of benzylidene-bis(tricyclohexylphosphine)- dichlororuthenium (137) (Aldrich)
(14 mg, 5 mol%) in dichloromethane (20 cm3) over 2 h at reflux. The reaction mixture
was heated under reflux for 6 h. The solvent was then removed in vacuo and the brown
residue was purified by flash chromatography using hexane-ethyl acetate (3:2) as eluent
to afford three diastereomers of bis[1,7-dioxaspiro[5.5]undec-3,5-diyl 2-buten-1,4-diyl]
ether (142) for which the stereochemistry was not defined:
8
9
O7
10
1
6
2
O
11
4
5
3
O
O
1'
4'
3'
2'
2'
3'
142a
142b
142c
4'
1'
O
O
3
2
5
4
O
1
11
6
O
7
8
10
9
(i) Dimer (142a) (12 mg, 15%) as fine needles mp 164-168 °C [Found: M+ (EI)
480.27238. C26H40O8 requires: M+, 480.27232]; δH (300 MHz; CDCl3; Me4Si) 1.28 (2 H,
ddd, J11ax,11eq 13.4, J11ax,10ax 13.4 and J11ax,10eq 4.3 Hz, 11-Hax), 1.51-1.64 (8 H, m, 9-CH2
and 10-CH2), 1.85 (2 H, ddd, J4ax,4eq 15.0, J4ax,5 3.4 and J4ax,3 3.4 Hz, 4-Hax), 2.18-2.24 (4
H, m, 11-Heq and 4-Heq), 3.05 (2 H, t, J5,4 3.4 Hz, 5-H), 3.32 (2 H, br s, 3-H), 3.60-3.81
(8 H, m, 2-CH2 and 8-CH2), 3.86-4.06 (8 H, m, 4 x CH2CH=CH), 5.89 (4 H, br s, 4 x
132
EXPERIMENTAL
CHCH2O); δC (75 MHz; CDCl3; Me4Si) 18.1 (CH2, C-10), 24.7 (CH2, C-4), 25.3 (CH2,
C-9), 31.0 (CH2, C-11), 60.8 (CH2, C-8), 62.3 (CH2, C-2), 69.1, 70.1 (CH2, 4 x
CH2CH=CH), 71.3 (CH, C-3), 76.2 (CH, C-5), 96.3 (quat, C-6), 129.0, 129.2 (CH, 4 x
CHCH2O); m/z (EI) 480 (M+, 2.6%), 171 (33), 153 (41), 111 (43), 101 (100), 69 (64), 54
(58), 41 (63).
(ii) Dimer (142b) (32 mg, 40%) as a viscous oil [Found: M+ (EI) 480.27275. C26H40O8
requires: M+, 480.27232]; δH (300 MHz; CDCl3; Me4Si) 1.25-1.33 (2H, m, 11-Hax),
1.49-1.59 (8 H, m, 9-CH2 and 10-CH2), 1.86 (2 H, dt, J4ax,4eq 14.9, J4ax,3 3.4 and J4ax,5 3.4
Hz, 4-Hax), 2.17-2.24 (4 H, m, 4-Heq and 11-Heq), 3.07 (2 H, t, 3.4 Hz, 5-H), 3.31 (2 H,
br s, 3-H), 3.60-3.83 (8 H, m, 2-CH2 and 8-CH2), 3.84-4.07 (8 H, m, 4 x CH2CH=CH),
5.89 (4 H, t, JCH,OCH2 2.8 Hz, 4 x CHCH2O); δC (75 MHz; CDCl3; Me4Si) 18.1 (CH2,
C-10), 24.7 (CH2, C-4), 25.3 (CH2, C-9), 31.0 (CH2, C-11), 60.8 (CH2, C-8), 62.4 (CH2,
C-2), 68.9, 70.3 (CH2, 4 x CH2CH=CH), 71.0 (CH, C-3), 76.4 (CH, C-5), 96.4 (quat,
C-6), 129.1, 129.2 (CH, 4 x CHCH2O); m/z (EI) 480 (M+, 2%), 171 (34), 153 (52), 111
(48), 101 (100), 85 (40), 69 (83), 54 (75), 41 (99).
(iii) Dimer (142c) (8 mg, 10%) as a viscous oil [Found: M+ (EI) 480.27248. C26H40O8
requires: M+, 480.27232]; δH (300 MHz; CDCl3; Me4Si) 1.20-1.39 (2 H, m, 11-Hax),
1.47-1.63 (8 H, m, 9-CH2 and 10-CH2), 1.95 (2 H, ddd, J4ax,4eq 14.6, J4ax,5 3.7 and
J4ax,3 3.7 Hz, 4-Hax), 2.05-2.20 (2 H, m, 4-Heq and 11-Heq), 3.09 (2 H, t, J5,4 3.7 Hz,
5-H), 3.35 (2 H, m, 3-H), 3.61-3.78 (8 H, m, 2-CH2 and 8-CH2), 3.84-4.10 (8 H, m, 4 x
CH2CH=CH), 5.89 (2 H, t, JCH,OCH2 2.5 Hz, CHCH2O) 5.91 (2 H, t, JCH,OCH2 2.5 Hz,
CHCH2O); δC (75 MHz; CDCl3; Me4Si) 18.1 (CH2, C-10), 25.3 (CH2, C-4), 26.6 (CH2,
C-9), 30.0 (CH2, C-11), 60.9 (CH2, C-8), 61.8 (CH2, C-2), 68.4, 69.9 (CH2, 4 x
CH2CH=CH), 70.7 (CH, C-3), 76.1 (CH, C-5), 96.9 (quat, C-6), 128.4, 128.9 (CH, 4 x
CHCH2O); m/z (EI) 480 (M+, 2%), 171 (31), 153 (51), 101 (96), 69 (83), 55 (73), 41
(100).
(b) Using Shrock’s Molybdenum Catalyst
A
solution
of
2,6-diisopropylphenylimidoneophylidenemolybdenum(VI)
bis(hexafluoro-t-butoxide) (136) (Strem Chemicals) (17 mg, 25 mol%) in benzene (5
cm3) was added to a solution of [3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl
133
EXPERIMENTAL
bisallyl ether (133) (25 mg, 0.09 mmol) in benzene (5 cm3) at room temperature. The
reaction mixture was left to stir for 6 h. The solvent was then removed in vacuo and the
brown residue was purified by flash chromatography using hexane-ethyl acetate (3:2) as
eluent to afford dimer (142a) (4 mg, 18%), dimer (142b) (10 mg, 45%) and dimer (142c)
(2 mg, 9%) for which the spectroscopic data was in agreement with that reported above.
7.7
Kinetic Resolution of Spiroacetal α-Epoxide (155) and
Spiroacetal Allylic Alcohol (117)
7.7.1 Base-Induced Rearrangement of α-Epoxide (155)
[5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undec-3-en-5-ol (117)
General Procedure. n-Butyllithium (0.21 cm3 of a 1.6 mol dm-3 solution in hexane,
0.36 mmol) was added dropwise to a solution of the appropriate chiral non-racemic base
(0.36 mmol) in hexane (8 cm3) at –55 °C or in tetrahydrofuran at 0 °C (8 cm3) and the
suspension
was
left
to
stir
for
30
min.
[4S∗,
5S∗,
6S∗]-4,5-Epoxy-1,7-
dioxaspiro[5.5]undecane (115) (56 mg, 0.33 mmol) was added to the mixture as a
solution in hexane (5 cm3). The solution was allowed to warm slowly (ca 3 h) to room
temperature and then left to stir for a further 18 h. The reaction mixture was then
quenched with sodium dihydrogen phosphate solution (5 cm3, 10% w/v) and extracted
with ethyl acetate (3 x 10 cm3). The combined extracts were washed with water (10 cm3)
and dried over sodium sulfate. Removal of the solvent under reduced pressure yielded an
orange oil that was purified by flash chromatography using hexane-ethyl acetate (3:2) as
eluent to afford [5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undec-3-en-5-ol (117). The 1H NMR
spectrum was in agreement with that previously reported.114
(a) [R-(R*,R*)]-(+)-bis(α-methylbenzyl)amine (170) (81 mg, 0.36 mmol) in hexane (10
cm-3) at –50 °C to yield (117) as colourless needles (14 mg, 59%, based on recovered
starting material, 32 mg).
(b) (-)-sparteine (171) (84 mg, 0.36 mmol) in hexane (8 cm-3) at –55 °C to yield (117) as
colourless needles (15 mg, 48%, based on recovered starting material, 25 mg).
134
EXPERIMENTAL
(c) (1S,2R)-(+)-norephedrine (172) (54 mg, 0.36 mmol), n-butyllithium (0.43 cm3 of a
1.6 mol dm-3 solution in hexane, 0.69 mmol) in tetrahydrofuran (8 cm3) at 0 °C as
colourless needles (4 mg, 21%, based on recovered starting material, 36 mg).
[5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undec-3-en-5-yl (R)-α-methoxy-α(trifluoromethyl)phenylacetate (176)
Triethylamine
(0.015
cm3,
0.11
mmol)
and
(S)-α-methoxy-α-
(trifluoromethyl)phenylacetyl chloride (0.015 cm3, 0.084 mmol) were added to a solution
of [5S∗, 6S∗]-1,7-dioxaspiro[5.5]undec-3-en-5-ol (117) (12 mg, 0.07 mmol) and
4-(dimethylamino)pyridine (34 mg, 0.28 mmol) in dichloromethane (1 cm3). The reaction
mixture was left to stir for 16 h at room temperature. Removal of the solvent under
reduced pressure gave a brown oil that was purified by flash chromatography using ethylacetate (4:1) as eluent to afford a tan oil (24 mg, 88%) as a 1:1 mixture of diastereomers
[Found: M+H
(CI,
NH3)
387.14255.
C19H21F3O5
requires:
M+,
387.14193];
νmax(film)/cm-1 1790 (C=O); δH (400 MHz; CDCl3) 1.18 (0.5 H, ddd, J11ax,11eq 13.1 and
J11ax,10ax 13.1, J11ax,10eq 4.1 Hz, 11-Hax), 1.40 (0.5 H, ddd, J11ax,11eq 13.1, J11ax,10ax 13.1 and
J11ax,10eq 4.7 Hz, 11-Hax), 1.43-1.91 (6 H, m, 9-CH2, 10-CH2, and 11-CH2), 3.49
(1.5 H, q, JOMe,CF3 1.1 Hz, OMe), 3.55 (1.5 H, q, JOMe,CF3 1.1 Hz, OMe), 3.60-3.80 (2 H,
m, 8-CH2), 4.10-4.16 (2 H, m, 2-CH2), 4.94-4.99 (1 H, m, 5-H), 5.87-5.99 (1 H, m, 4-H),
6.05 (0.5 H, dt, J3,4 10.2 and J3,2 2.6 Hz, 3-H), 6.12 (0.5 H, dt, J3,4 10.2 and J3,2 2.6 Hz,
3-H), 7.35-7.39 (3 H, m, Ar), 7.48-7.54 (2 H, m, Ar); δC (75 MHz; CDCl3) 18.1, 18.2
(CH2, C-10), 24.7, 24.8 (CH2, C-9), 30.3, 30.5 (CH2, C-11), 55.4, 55.5 (CH3, OMe), 60.1,
60.2 (CH2, C-2), 62.8, 62.8 (CH2, C-8), 70.3, 70.6 (CH, C-5), 95.1, 95.2 (quat, C-6),
119.2, 119.3 (CH, Ar), 121.3,121.4 (quat, C-CF3) 127.3, 127.6 (CF3), 128.3, 128.4 (CH,
Ar), 129.5, 129.6 (CH, Ar), 132.0, 132.3 (quat, Ar), 165.9, 166.1 (quat, C=O);
δF (300 MHz; CDCl3) -72.9 (CF3), -72.7 (CF3); m/z (CI, NH3) 387 (M+H, 4%), 189 (31),
153 (100).
135
EXPERIMENTAL
8
9
O7
10
1
6
2
O
11
5
3
4
O
O
F3C
OMe
Ph
176
7.7.2 Jacobsen Hydrolytic Kinetic Resolution of α-Epoxide (115)
(a) Preparation of the Activated Catalyst
A
mixture
of
(R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane-
diaminocobalt(II) (Aldrich) (50 mg, 0.08 mmol) and acetic acid (10 mg, 0.16 mmol) in
toluene (1 cm3) was stirred open to the atmosphere at room temperature for 1 h using the
procedure by Jacobsen et al.185 Removal of the solvent under reduced pressure yielded
(R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(III)
acetate
(177) as a brown solid (50 mg, 91%) that was used without further purification.
(b) Reaction using the Activated Catalyst (177)
(R,R)-N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(III) acetate
(177) (2 mg, 3.0 µmol, 0.5 mol%) was added to a mixture of α-epoxide (115) (100 mg,
0.60 mmol) and water (5.0 mg, 0.30 mmol) in tetrahydrofuran (0.5 cm3) at room
temperature. The mixture was allowed to stir for 18 h. The solvent was removed at
reduced pressure and the residue purified by flash chromatography using hexane-ethyl
acetate (4:1) as eluent to afford [4R∗, 5R∗, 6S∗]-1,7-dioxaspiro[5.5]undecan-4,5-diol
(179b) (32 mg, 55%, based on recovered starting material, 47 mg) as colourless needles
mp 134-136 °C (lit.,173 mp 135-137 °C); δH (300 MHz; CDCl3; Me4Si) 1.47 (1 H, ddd,
J11ax,11eq 13.5, J11ax,10ax 13.5 and J11ax,10eq 4.4 Hz, 11-Hax), 1.53-1.85 (5 H, m, 9-CH2,
10-CH2 and 3-Hax), 1.91 (1 H, dt, J11eq,11ax 13.5 and J11eq, 10 2.7 Hz, 11-Heq), 2.05-2.14
(1 H, m, 3-Heq), 3.41 (1 H, dd, J5,4 7.4 and J5,OH 3.7 Hz, 5-H), 3.62 (1 H, ddd,
J2eq,2ax 12.0, J2eq,3ax 5.5 and J2eq,3eq 2.3 Hz, 2-Heq), 3.71-4.00 (6 H, m, 8-CH2, 4-H, 2-Hax,
136
EXPERIMENTAL
4-OH, 5-OH); δC (75 MHz; CDCl3; Me4Si) 17.6, 24.8, 27.6, 30.6 (CH2, C-3, C-9, C-10
and C-11), 55.6, 61.3 (CH2, C-2 and C-8), 68.6 (CH, C-4), 71.1 (CH, C-5), 98.4 (quat,
C-6). The 1H and 13C NMR were in agreement with published data.173 The enantiomeric
excess was determined to be 1:1 mixture of the two diastereomers by conversion of the
recovered starting material (115) to the allylic alcohol (117) and its subsequent
conversion to the Mosher ester (176). The 1H,
13
C and
19
F NMR spectra of the Mosher
derivative (176) were in agreement with that previously discussed.
8
9
O7
10
6
O1
11
HO
5
2
4
3
OH
179b
7.7.3 Sharpless Epoxidation of Allylic Alcohol (117)
Titanium tetraisopropoxide (28 mg, 0.10 mmol) was added to a solution of
diisopropyl D-tartrate (34 mg, 0.15 mmol), allylic alcohol (117) (166mg, 0.98 mmol) and
powdered 4Å molecular sieves (25 mg) in dichloromethane (15 cm3) at –20 °C and the
mixture stirred for 30 min following the procedure by Sharpless et al.165a Anhydrous tertbutyl hydroperoxide solution in dichloromethane (2.4 M, 0.28 cm3, 0.68 mmol) was then
added and the reaction stirred at –20 °C for 5 h. The reaction mixture was allowed to
stand for a further 18 h in the freezer at –20 °C. The cold reaction mixture was quenched
with 10% NaOH solution in brine (1 cm3). Ether (5 cm3) was added to the mixture and
the solution was allowed to warm to room temperature, whereupon MgSO4 (1.5 g) and
Celite (0.14 g) were added. The mixture was stirred for 15 min, diluted with
dichloromethane and filtered through a short pad of Celite. Removal of the solvent under
reduced pressure and purification by flash chromatography using hexane-ethyl acetate
(3:2) as eluent afforded the syn-epoxy alcohol (119) (55 mg, 77%, based on recovered
starting material, 101 mg) as colourless prisms. The 1H NMR was in agreement with
published data.114
137
EXPERIMENTAL
[3S∗, 4S∗, 5S∗, 6S∗]-3,4-Epoxy-1,7-dioxaspiro[5.5]undecan-5-yl (R)α-methoxy-α-(trifluoromethyl)phenylacetate (183)
Triethylamine
(0.03
cm3,
0.2mmol)
and
(S)-(+)-α-methoxy-α-
(trifluromethyl)phenylacetyl chloride (0.07 cm3, 0.29 mmol) were added to a solution of
[3S∗, 4S∗, 5S∗, 6S∗]-3,4-epoxy-1,7-dioxaspiro[5.5]undecan-5-ol (119) (25 mg, 0.13
mmol) and 4-(dimethylamino)pyridine (66 mg, 0.54 mmol) in dichloromethane (1 cm3).
The reaction mixture was left to stir for 16 h at room temperature. Removal of the solvent
under reduced pressure gave a brown oil that was purified by flash chromatography using
ethyl-acetate (4:1) as eluent to afford a tan oil (50 mg, 93%) as a 1:1 mixture of
diastereomers [Found: M+ (EI) 403.13675. C19H22F3O6 requires: M+, 403.13685];
νmax(film)/cm-1 1790 (C=O); δH (400 MHz; CDCl3) 1.03 (0.5 H, ddd, J11ax,11eq 14.0,
J11ax,10ax 14.0 and J11ax,10eq 4.4 Hz, 11-Hax), 1.31 (0.5 H, ddd, J11ax,11eq 13.2, J11ax,10ax 13.2
and J11ax,10eq 4.8 Hz, 11-Hax), 1.46-1.74 (4.5 H, m, 2 x 9-CH2, 2 x 10-CH2, and 11-Heq),
1.84 (0.5 H, dt, J11eq,11ax 14.0 and J11eq,10 2.8 Hz, 11-Heq), 3.24 (0.5 H, dt, J3,4 4.0 and
J3,2 1.2 Hz, 3-H), 3.29 (0.5 H, dt, J3,4 4.0 and J3,2 1.2 Hz, 3-H), 3.51 (1.5 H, q, JOMe,CF3 1.0
Hz, OMe), 3.53-3.60 (1 H, m, 8-CH2), 3.64 (1.5 H, q, JOMe,CF3 1.0 Hz, OMe), 3.68-3.74
(2 H, m, 2 x 4-H and 8-CH2), 3.83 (1 H, ddd, J2eq,2ax 13.2, J2eq,3 1.2 and J2eq,4 1.2 Hz, 2 x
2-Heq), 3.97 (0.5 H, d, J2ax,2eq 13.2 Hz, 2-Hax), 4.00 (0.5 H, d, J2ax,2eq 13.2 Hz, 2-Hax),
4.71 (0.5 H, d, J5,4 4.8 Hz, 5-H), 4.73 (0.5 H, d, J5,4 4.8 Hz, 5-H), 7.36-7.41 (2 H, m, Ar),
7.57-7.65 (4 H, m, Ar); δC (75 MHz; CDCl3) 17.9, 18.0 (CH2, C-10), 24.5, 24.6 (CH2,
C-9), 29.6, 30.0 (CH2, C-11), 47.9, 48.0 (CH, C-4), 50.0, 50.1 (CH, C-3), 55.5, 55.7
(CH3, OMe), 57.0, 57.1 (CH2, C-2), 61.7, 61.8 (CH2, C-8), 71.2, 71.3 (CH, C-5), 93.7,
93.6 (quat, C-6), 127.5, 127.9 (CF3), 128.3, 128.4 (CH, Ar), 129.6, 129.7 (CH, Ar),
131.6, 132.1 (quat, Ar), 166.1, 166.3 (quat, C=O); δF (300 MHz; CDCl3) -73.4 (CF3),
-72.9 (CF3); m/z (CI, NH3) 403 (M+, 20%), 189 (100), 169 (60), 114 (47).
8
9
O7
10
6
1
2
O
11
5
3
4
O
O
O
OMe
F3C
Ph
183
138
EXPERIMENTAL
6.8
Determination of the Association Constants
Lithium, potassium, sodium, cesium, lead, cobalt and cadmium picrates were
prepared from picric acid and the appropriate carbonate in distilled water following the
procedure by Silberrad et al.186 Silver picrate was prepared from picric acid and silver
oxide in distilled water using the procedure described by Silberrad et al.186 The picrate
salts were recrystallised twice from distilled water and dried in vacuo at room
temperature.
Association constants were determined using the ultraviolet spectroscopic method
developed by Cram et al.148 Solutions of the picrate salts were prepared in distilled water
at a concentration of 0.015 mol dm-3. Solutions of the hosts were prepared in 2.0 cm3
volumetric flasks as 0.075 mol dm-3 solutions in chloroform.
General procedure. A solution of the host (0.2 cm3) was added to a solution of
the guest (0.5 cm3) in a 2 cm3 centrifuge tube. The tubes were stoppered, shaken for 2
minutes and centrifuged for 2 minutes. An aliquot of the chloroform layer (0.15 cm3) was
transferred to a 50 cm3 volumetric flask and diluted to the mark with acetonitrile. An
appropriate blank was also prepared. Ultraviolet measurements were carried out at 380
nm at 22 °C. Calculations were based on the Beer’s law relationship, a = εbc, where a is
the absorbance, ε is the extinction coefficient, b is the path length of the cell and c is the
concentration of the measured species. The total number of millimoles of picrate salt
extracted into the chloroform layer could be determined from Beer’s law. The millimoles
of the host was calculated from the initial host concentration and the aliquot volume. The
guest to host molar ration (R) was given by the millimoles of picrate salt divided by the
millimoles of host. The extraction constant (Ke) could be calculated from Equation 3
using the experimentally determined values for R.
Ke =
R
(1-R){[Guest]i - R[Host]i (Vorganic/Vaq)}2
Equation 3
R = molar ratio of guest to host in the chloroform layer determined by UV.
[Guest]i = initial concentration of the guest in the aqueous layer.
[Host]i = initial concentration of the host in the chloroform layer.
Vorganic and Vaq are the volumes of the organic and aqueous phases respectively.
139
EXPERIMENTAL
The association constant (Ka) is defined by Equation 1 and the distribution constant (Kd)
by Equation 4.
Host org
+
Guest aq
Ka
Host.Guest Complex organic
Equation 1
CDCl3
Guest aq
Kd
Guest organic
Equation 4
Ka is then related to Ke and Kd by Equation 5
Ka = Ke/Kd
Equation 5
The Kd values were determined using the procedure described by Cram.148 Picrate
solutions (20 cm3, 0.015 M) were shaken in a separatory funnel with chloroform (30
cm3). The layers were allowed to separate and clarify. The lower chloroform layer was
carefully transferred to a flask and the solvent was removed in vacuo. The residue was
quantitatively transferred with acetonitrile to a volumetric flask (10 cm3) and diluted to
the mark with acetonitrile. The amount of picrate salt extracted was calculated using the
UV techniques discussed above.
The Gibbs free energy could then be calculated using Equation 2.
∆G = -RT ln(Ka)
Equation 2
140
EXPERIMENTAL
A sample calculation for spiroacetal thiacrown (55) and silver picrate is illustrated below.
[Guest]i = 0.015 mol L-1
[Host]i = 0.075 mol L-1
ε (silver picrate) = 16111 cm-1 mol-1 L
Sample absorbance at 380 nm = 1.64
Sample volume = 50 mL
Aliquot volume = 0.15 mL
Vorganic = 0.5 mL
Vaqueous = 0.2 mL
Kd (Ag+.picrate) = 0.108 M-1
mmols of Ag+.picrate in host.guest complex =
Sample absorbance x sample volume (mL) x Vorganic (mL)
ε (silver picrate) (cm-1 mol-1 L) x aliquot volume (mL)
=
1.64 x 50 x 0.2
16111 x 0.15
= 6.786 x 10-3
mmol of host (55) in the organic phase = 0.075 mmol mL-1 x 0.2 mL
= 0.015 mmol
R = 6.786 x 10-3
0.015
=
0.4524
From Equation 3:
Ke =
0.4524
(1 – 0.4524){0.015 – (0.452 x 0.075 x 0.2/0.5)}2
=
397.77 x 103
141
EXPERIMENTAL
From Equation 5:
Ka = Ke/Kd
=
397770
0.108
= 3683.06 x 103
From Equation 2:
∆G = -RT ln(Ka)
= -8.3145 x 295 x ln 3683.06 x 103
= -37.08 kJ mol-1
6.9
Second-Sphere Complexation
General procedure. [Al(acac)3] (164), [Co(NH3)5NO2](BPh4)2 (165) or
[Co(en)3](BPh4)3 (166) (0.011 mmol ) were added to a solution of deuterated chloroform
or dimethylsulfoxide (0.8 cm3) containing crown compounds (55), (56), (57), (64) or
(100) (0.011 mmol). The solution was shaken for 5 minutes and the 1H NMR spectrum
was measured at 25 °C. The 1H NMR spectrum was monitored for 1 h.
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