Efficient Carbohydrate Synthesis by Intra- and
Supramolecular Control
Hai Dong
Doctoral Thesis
Stockholm 2008
Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm
framlägges till offentlig granskning för avläggande av teknologie doktorsexamen i
kemi, med inriktning mot organisk kemi, torsdagen den 5 Feb 2009, kl 10.00 i sal F3,
KTH, Lindstedtsvägen 26, Stockholm. Avhandlingen försvaras på engelska. Opponent
är Ulf Nilsson, Lunds Tekniska Högskola/Lunds Universitet.
ISBN 978-91-7415-207-4
ISSN 1654-1081
TRITA-CHE-Report 2009:2
© Hai Dong, 2008
Universitetsservice US AB, Stockholm
献给晓溪, 东东和爱玲.
Till Emilia, Dongdong och Ailing.
The road ahead is hard and long, but nothing will stop me as I go
searching up and down.
………
Qu Yuan (B.C. 340 - 278)
Translated by Hai
Hai Dong, 2008: “Efficient Carbohydrate Synthesis by Intra- and Supramolecular
Control” Organic Chemistry, KTH Chemistry, Royal Institute of Technology, S10044 Stockholm, Sweden.
Abstract
The Lattrell-Dax method of nitrite-mediated substitution of carbohydrate triflates is
an efficient method to generate structures of inverse configuration. In this study, the
effects of the neighboring group on the Lattrell-Dax inversion were explored. A new
carbohydrate/anion host-guest system was discovered and the ambident reactivity of
the nitrite anion was found to cause a complicated behavior of the reaction. It has
been demonstrated that a neighboring equatorial ester group plays a highly important
role in this carbohydrate epimerization reaction, restricting the nitrite N-attack, thus
resulting in O-attack only and inducing the formation of inversion compounds in
good yields. Based on this effect, efficient synthetic routes to a range of carbohydrate
structures, notably β-D-mannosides and β-D-talosides, were designed by use of
double parallel and double serial inversion. A supramolecularly activated, triggered
cascade reaction was also developed. This cascade reaction is triggered by a
deprotonation process that is activated by anions. It was found that the anions can
activate this reaction following their hydrogen bonding tendencies to the hydroxyl
group in aprotic solvents.
Keywords: Carbohydrate Chemistry, Carbohydrate Protection, Epimerization,
Inversion, Neighboring Group Participation, Supramolecular Control, Anion
Activation, Ambident Reactivity, Cascade Reaction, Hydrogen Bonding, Basicity.
Abbreviations
A
Ac
AcCl
Ac2O
aq
Bn
BnBr
Bz
BzCl
Bu
Bu2SnO
Conv
DCM
DMF
DMSO
eq./equiv.
Et
EDA
Gal
Glc
h
HSAB
IM
Man
Manp
Me
NGP
NMR
rt/r.t.
S
T
Tal
TBA
TEA
Tf2O
THF
P/PG
py.
PMO
Anion
Acetyl group
Acetyl chloride
Acetic anhydride
aqueous
Benzyl group
Benzyl bromide
Benzoyl group
Benzoyl chloride
Butyl
Dibutyltin oxide
Conversion
Dichloromethane
Dimethylformamide
Dimethylsulfoxide
equivalent
Ethyl
Ethylenediamine
Galactoside
Glucoside
hour
Hard-Soft Acid-Base theory
Imidazole
Mannoside
Mannopyranoside
Methyl
Neighboring group participation
Nuclear magnetic resonance
room temperature
Solvent
Temperature
Taloside
Tetrabutylammonium
Triethylamine
Trifluoromethylsulfonic anhydride
Tetrahydrofuran
Protecting group
Pyridine
Perturbation Molecular Orbital theory
List of publications
This thesis is based on the following papers, referred to in the text by
their Roman numerals.
I.
Reagent-Dependent Regioselective Control in Multiple
Carbohydrate Esterifications
Hai Dong, Zhichao Pei, Styrbjörn Byström and Olof
Ramström
J. Org. Chem. 2007, 72, 1499-1502.
II.
Stereospecific Ester Activation in Nitrite-Mediated
Carbohydrate Epimerization
Hai Dong, Zhichao Pei and Olof Ramström
J. Org. Chem. 2006, 71, 3306-3309.
III.
Supramolecular Control in Carbohydrate
Epimerization: Discovery of a New Anion Host-Guest
System
Hai Dong, Martin Rahm, Tore Brinck, and Olof Ramström
J. Am. Chem. Soc. 2008, 130, 15270-15271.
IV.
Control of the Ambident Reactivity of the Nitrite Ion in
Carbohydrate Epimerization
Hai Dong, Lingquan Deng, and Olof Ramström
Preliminary manuscript.
V.
Efficient Synthesis of β-D-Mannosides and β-DTalosides by Double Parallel or Double Serial Inversion
Hai Dong, Zhichao Pei, Marcus Angelin, Styrbjörn
Byström and Olof Ramström
J. Org. Chem. 2007, 72, 3694-3701.
VI.
Synthesis of Positional Thiol Analogs of β-DGalactopyranose
Zhichao Pei, Hai Dong, Rémi Caraballo and Olof
Ramström
Eur. J. Org. Chem. 2007, 29, 4927-4934.
VII.
Supramolecular Activation in Triggered Cascade
Inversion
Hai Dong, Zhichao Pei and Olof Ramström
Chem. Commun. 2008, 11, 1359-1361.
VIII. Enhanced Basicity by Supramolecular Anion Activation
Hai Dong and Olof Ramström
Preliminary manuscript.
Papers not included in the thesis.
IX.
Solvent Dependent, Kinetically Controlled
Stereoselective Synthesis of Thioglycosides
Zhichao Pei, Hai Dong and Olof Ramström
J. Org. Chem. 2005, 70, 6952-6955.
X.
Direct, Mild, and Selective Synthesis of Unprotected
Dialdo-Glycosides
Marcus Angelin, Magnus Hermansson, Hai Dong and Olof
Ramström
Eur. J. Org. Chem. 2006, 19, 4323-4326.
Table of Contents
ABSTRACT
ABBREVIATIONS
LIST OF PUBLICATIONS
1 Introduction ..............................................................................................1
1.1 Carbohydrates – A General Introduction ............................................1
1.2 Carbohydrates – Challenging Synthetic Targets.................................2
1.3 Regioselective Protection/Deprotection..............................................4
1.4 Epimerization ......................................................................................4
1.5 Neighboring Group Participation ........................................................6
1.6 Aim of Study .......................................................................................7
2 Regioselective Carbohydrate Protection................................................9
2.1 Common Protection Strategies............................................................9
2.1.1 Acylation ......................................................................................9
2.1.2 Alkylation.....................................................................................9
2.1.3 Organotin Protection ..................................................................10
2.1.4 Integrated Protection Strategies .................................................10
2.2 Organotin Mutiple Esterification ......................................................11
3 Lattrell-Dax Epimerization ...................................................................15
3.1 Effects of Protecting Groups .............................................................15
3.1.1 Effects of Protection Patterns.....................................................15
3.1.2 Effects of Neighboring Group Configurations...........................17
3.2 Neighboring and Remote Group Participation..................................18
3.2.1 Neighboring Group Participation Effects...................................18
3.2.2 Remote Group Participation.......................................................19
3.3 Supramolecular Control ....................................................................21
3.3.1 Unusual Solvent Effect...............................................................21
3.3.2 Carbohydrate-Anion Complex ...................................................22
3.3.3 Binding Model............................................................................24
3.4 Ambident Reactivity of Nitrite Anions .............................................25
3.4.1 An O/N Selectivity Case in Carbohydrate Epimerization..........26
3.4.2 Carbohydrate Epimerization with Non-Ambident Reagents .....27
3.4.3 Nitration Products ......................................................................27
3.4.4 Solvent Effect.............................................................................29
3.4.5 Neighboring Equatorial Ester Group Activation........................30
3.5 Conclusions .......................................................................................31
4 Applications of the Lattrell-Dax Epimerization.................................. 33
4.1 Application in Synthesis of β-D-Mannosides and Talosides ........... 33
4.1.1 Introduction ................................................................................ 33
4.1.2 Double Parallel Inversion........................................................... 33
4.1.3 Double Serial Inversion.............................................................. 35
4.2 Application in Synthesis of Thio-β-D-Galactosides ........................ 37
4.2.1 Introduction ................................................................................ 37
4.2.2 Synthesis of Methyl 3-Thio-β-D-Galactoside ........................... 37
4.2.3 Synthesis of Methyl 4-Thio-β-D-Galactoside............................ 38
4.3 Conclusions ....................................................................................... 39
5 Enhanced Basicity by Supramolecular Anion Activation .................. 41
5.1 Supramolecular Activation in Cascade Inversion ............................ 41
5.1.1 Triggered Cascade Inversion...................................................... 41
5.1.2 Anion Activation........................................................................ 42
5.2 Enhanced Basicity by Supramolecular Effects ................................. 44
5.2.1 Supramolecular Effects of Anions and Solvents........................ 44
5.2.2 Basicity Controlled Cascade Reaction ...................................... 46
5.2.3 Enhanced Basicity by Supramolecular effects ........................... 48
5.3 Conclusions ....................................................................................... 50
6 General Conclusions .............................................................................. 51
ACKNOWLEDGEMENTS
APPENDIX
REFERENCES
1 Introduction
1.1 Carbohydrates – A General Introduction
Carbohydrates are the most abundant natural products, including monosaccharides,
disaccharides, oligosaccharides, and polysaccharides (Figure 1). They also include
substances derived from monosaccharides, such as when the carbonyl group is reduced to
form an alditol, one or more terminal groups are oxidized to form carboxylic acids, or a
hydroxyl group is replaced by a hydrogen, amino-, or thiogroup. All members of the
carbohydrates consist of monosaccharides as the basic units. There are a large number of
monosaccharides, classified in several ways. For example, they are classified as furanoses
(five-membered rings) and pyranoses (six-membered rings), etc, by the size of the ring.
The stereocenter at C-1 is called the anomeric center, where the hydroxyl group connected
to C-1 can alternate between pointing up and down, referred to as β and α, respectively.
When this hydroxyl group is replaced with an aglycone moiety, the configuration is locked
into either α or β and the term glycoside is used to classify this class of carbohydrates.
Monosaccharides
HO
6
4
HO
3
OH
HO
HO
O
5 O
2
HO
HO
1
OH
α-D-galactopyranose
HO
β-D-fucose
Disaccharides
HO
HO
OH
HO
HO
OH
O
HO
OH
HO
O
O
HO
OH
Sucrose (cane sugar)
Oligosaccharides
OMe
NH2
methyl 2-amino-β-D-galactoside
OH
HO
OH O
HO HO
O
HO
OMe
methyl α-D-mannoside
O
HO
OH O
OH
HO
OH
O
OH
OH
Lactose
OH
OH
HO
O
O
HO
O
O
O
O
AcHN
OH
NH
O
O
HO OH
Blood group antigen H
glycoprotein (O-glycosidic)
Polysaccharides
OH
OH
OH
O
HO
O
HO
OH
NHAc
O
HO
O
OH
HO
O
NHAc
Cellulose
Chitin
Figure 1 Natural carbohydrates.
1
O
OH
with other large biomolecules such as lipids or proteins, playing essential roles in diverse
biological processes.[1] Polysaccharides constitute the major volume of carbohydrates,
biosynthesized by plants, algae, animals and microbes. For example, cellulose is found in
all plants as the major structural component of the cell walls, and chitin is the principal
structural component of the exoskeleton of invertebrates such as crustaceans and insects.
1.2 Carbohydrates – Challenging Synthetic Targets
Carbohydrates have attracted an increasing amount of attention up to today, on account of
their diverse biological function. For example, specific protein-carbohydrate interactions
are involved in cell differentiation, cell adhesion, immune response, trafficking and tumor
cell metastasis.[2-4] These important processes occur between carbohydrates (glycoproteins,
glycolipids, and polysaccharide entities at cell surfaces) and lectins, proteins with
carbohydrate-binding domains. Carbohydrates are also widely used in medicine, for
example as anticoagulants, antibiotics and vaccines.[5, 6]
Uncovering the contributions of carbohydrates in cell biology would greatly promote
advancements in the biological and medical areas. However, the functions of
carbohydrates in biology have not been extensively studied due to the high complexity of
oligosaccharides and to a lack of general methods for synthesizing and analyzing these
molecules. One important case is β-mannoside synthesis. The β-mannopyranosidic linkage
is a common structural element in a wide range of natural products.[7-10] This biologically
important and widespread class of structures contains β-D-Manp units as the relevant
component. For example, the β-D-Manp unit is present as a central component in the
ubiquitous N-glycan core structure of glycoproteins,[7] and makes part of a range of fungal
and bacterial entities (Figure 2).[11, 12]
HO
HO
HO
OH
OH
O
HO
HO
OH
O
HO
O
OH
O
O
OH
NHAc
HO
O
O
O
O
HO
OH
N-linked pentasaccharide core structure
HO
HO
HO
HO
HO
HO
OH
O
β-D-Manp
OR
OH
O
NHAc
OH OH
OR
O
OH O
HO
Fungal metabolite deacetyl-caloporoside
Figure 2 Natural entities containing β-mannopyranosidic linkages.[11, 12]
The chemical synthesis of this 1,2-cis-mannosidic linkage is, however, especially difficult.
The α-mannosidic linkage is strongly favored because of the concomitant occurrence of
both the anomeric effect and the repulsion between the axial C-2 substituent and the
2
approaching nucleophile (Figure 3). Moreover, neighboring group participation of a 2-acyl
substituent leads to α-mannosides only.[1]
R
ROCO
POH
OO O
O
O
OP
Partial
dipole moments
Favored by the
anomeric effect
α
1,2-tr ans
OP
OP
Favored by the
neighboring group participation
HO
O
β
O
O
OP
OH
easy
OP
easiest
HO
O
1,2-cis
O
OP
HO OP
hardest
harder
Figure 3 Anomeric effect and neighboring group participation.
Another important case is thiosaccharide synthesis. Thiosaccharides, where an exocyclic
oxygen is replaced by a sulfur atom, constitute an increasingly important group of
compounds in glycochemistry, possessing unique characteristics compared to their oxygen
analogs (Figure 4).
HO
HO
HO
O
SH
OH
1-thio-β-D-glucose
HO
OH
HO
OH
OH
S
HO
O
O
HO
HO
O
O
OH
O
S
HO
HO
HO
S
S
HO
HO
HO
O
HO
HO
HO
OH
S
OH
OH
OH
O
O
O
HO
HO
HO
O
partial structure of the cell
wall phosphomannan antigen
modified by a sulfur atom
cyclic thiooligosaccharides
Figure 4 Thiosaccharides.[13-15]
These compounds are often used as efficient glycoside donors and acceptors in
oligosaccharide and neoglycoconjugate synthesis,[16-22] because the thiolate is a potent
nucleophile and a weak base that reacts easily and selectively with soft electrophiles.
Furthermore, the resulting thioglycosides and S-linked conjugates possess increased
3
resistance to degradation by glycosidases potentiating their use as efficient building blocks
in drug design and therapeutics.[23] Generally, in order to obtain those carbohydrate targets,
economic and efficient synthetic strategies have to be designed.[14, 15, 24, 25] Two of the most
important strategies in carbohydrate synthesis are epimerization and regioselective
protection/deprotection.
1.3 Regioselective Protection/Deprotection
Regioselectivity is a prominent challenge in carbohydrate chemistry since carbohydrates
contain several hydroxyl groups of similar reactivity. Selective protecting groups and
efficient protecting group strategies are therefore of crucial importance to efficiently obtain
desired carbohydrate structures. The most common protecting groups for hydroxyl
functions are esters, ethers, and acetals. Carbohydrate hydroxyl groups differ somewhat in
reactivity depending on whether they are anomeric, primary or secondary, and also
depending on their configurations. For example, in order to obtain 3- or 4-thio-β-Dgalactosides (Scheme 1), reasonable epimerization and regioselective protection
/deprotection strategies have to be used.[26]
HO
OH
O
HO
OAc
AcO
protection/
OR epimerization
OR
OH
OBz
OH
O
OH
epimerization
/deprotection
OAc
OH
HO
HO
HO
O
regioselective HO
OR /protection
BzO
OR
OBz
O
HS
HS
O
epimerization
/deprotection
OH
OR
OH
OH
O
HO
OR
OH
Scheme 1 Synthesis of methyl 3- and 4-thio-β-D-galactopyranosides.
1.4 Epimerization
Epimerization of carbohydrate structures to the corresponding epi-hydroxy stereoisomers
is an efficient means to generate compounds with inverse configuration that may otherwise
be cumbersome to prepare. Several different synthetic methods have been developed,
including protocols based on the Mitsunobu reaction,[27] sequential oxidation/reduction
routes[28] as well as enzymatic methods,[29] all of which having their respective advantages
and shortcomings. A common route to stereocenter inversion in carbohydrate chemistry
involves the triflation of a given hydroxyl group, followed by substitution using a variety
of nucleophilic reagents (Scheme 2). This method was used by Dax and co-workers who
first reported that glycoside triflate displacement by nitrite ion,[30] a reaction first found by
Lattrell and Lohaus,[31] produced carbohydrates with inversed hydroxyl configuration
under very mild conditions. Despite its reported efficiency,[16, 32-34] the Lattrell-Dax method
has unfortunately not been extensively adopted, likely because of difficulties in predicting
the product outcome.
4
RO
OR
O
HO
OMe
OR
1. py, Tf2O,
CH2Cl2
2. KNO2,
DMF
OR
RO
O
OMe
OH
OR
Scheme 2 Lattrell-Dax epimerization.
Binkley[35] reported a simple technique for converting methyl 2,6-dideoxy-β-D-arabino/
galacto-hexopyranosides into the corresponding ribo- and lyxo-isomers through internal
triflate displacement by a neighboring benzoyl group and a direct inversion method
through triflate displacement by nitrite ion when neighboring participation could not take
place (Scheme 3). He further reported that the inversion reaction appeared to be related to
the configuration, but no explanation was given.
BzO
TfO
O
OMe
H2O
CHCl3
O
HO
OMe
neighboring group
participation
OMe
Fast
OMe
Slow
OBz
BzO
TfO
O
OMe
O
nitrite BzO
toluene
OH
BzO
BzO
O
TfO
OMe
O
nitrite
toluene
OH
Scheme 3 Effect of carbohydrate configuration on inversion reaction.[35]
More recently, von Itzstein and co-workers[19] needed to perform a 3-position glycoside
inversion reaction when they developed a new approach toward the synthesis of lactosebased S-linked sialylmimetics of α-(2,3)-linked sialosides. Their strategy however failed
when they chose a glycoside where one hydroxyl group in 3-position was free and the
other positions protected with benzyl groups (Scheme 4). Interestingly, they obtained a
satisfactory result when the 2-position benzyl group was replaced by a benzoyl group. It
clearly showed that the choice of protecting group was crucial for the inversion of the
configuration at the 3-position of the galactose moiety. In light of these studies, it seems
that the type and configuration of the neighboring protecting group is crucial for the
reactivity in the Lattrell-Dax inversion. An equatorial trans-configuration is favored for the
inversion. However, the trans-configuration is also favored for the neighboring group
participation. Thus, a question can be put forward: can the neighboring ester group activate
the nitrite inversion process via a neighboring group participation mechanism?
5
Ph
Ph
O
O
O
O
nitrite
O
OR
TfO
O
OR
DMF
OBz
OH
Ph
OBz
O
O
nitrite
O
OR
TfO
failed
DMF
OBn
Scheme 4 Effect of the neighboring groups on the inversion reaction.[19]
1.5 Neighboring Group Participation
The neighboring group participation (NGP) mechanism requires two conditions: a
neighboring ester group and trans-configuration.[26, 36] In the polar solvent DMF, the
neighboring group participation reaction takes place immediately. However, in the
nonpolar solvent toluene the neighboring group participation is restrained. This indicates
that neighboring group participation is favored in polar solvents. Further analysis showed
that the products of the neighboring group participation were always compounds where the
ester group is axial and the hydroxyl group equatorial. The explanation was given by
King[37] and Binkley[36] (a in Scheme 5) according to Deslongchamps´ stereoelectronic
theory[38, 39].
a)
HO
OR
O
TfO
O
O
R
O
R
H2O
O
O
O
R
major
O
O
O
O
R
H2O
HO
O OH
major
O
O
minor
b)
HO
TfO
O
O
R
O
O
nitrite
toluene
O
O
R
Scheme 5 Comparison of the products formed by NGP reaction and the nitrite inversion.
a): Mechanism of major product formation by neighboring group participation given by
Binkley.[36] b): Nitrite-mediated inversion.[35]
6
In addition, for the Lattrell-Dax nitrite-mediated inversion, it is clear that the ester group
always remains in the same position and the hydroxyl group is inversed on the carbon
atom directly connected to the triflate group (b in Scheme 5). This indicates that the effect
of the neighboring ester group on the Lattrell-Dax inversion is not via a neighboring group
participation process.
1.6 Aim of Study
The main aims of this thesis has been to investigate the effects of the protecting group
pattern on the Lattrell-Dax nitrite-mediated inversion reaction, and by making use of this
very important reaction to synthesize thio-β-D-galactoside derivatives and develop
efficient methods for the synthesis of β-D-mannosides and talosides. In order to investigate
the Lattrell-Dax reaction, a series of galacto- and gluco-type derivatives, where one
hydroxyl group in the 2, 3, or 4-position is free and the other positions are protected with
acetyl, benzoyl, or benzyl/benzylidene groups were chosen for further evaluation (Figure
5). These compounds would be tested in the Lattrell-Dax nitrite-mediated reaction.
Ph
O
O
BzO
Ph
O
OMe
1
OH
O
O
BnO
O
OH
OMe
2
Ph
O
AcO
OAc
BzO
O
HO
O
OMe
OAc
3
O
OMe
OBz
4
HO
OBz
HO
BzO
O
OBz
HO
HO
OBz
O
OBn
OBn
HO
O
O
OMe
OBz
6
OMe
OBz
7
BzO
OMe
5
OMe
OBn
8
BnO
OBn
HO
BnO
O
OBn
OMe
9
Figure 5 Galacto- and gluco-type derivatives with different protecting group patterns.
To further analyze and explore the effect of the neighboring ester group configuration on
the reactivity, other systems were designed. To avoid effects from the 2- and 6-positions
and to isolate the effects arising from ester groups in the 3- and 4-positions, the 2- and 6positions were protected with benzyl ether groups (Figure 6). Thus, a range of compounds
where one of the hydroxyl groups in the 3- or 4-position is protected with an acetyl group
had to be prepared and subsequently tested in the Lattrell-Dax epimerization reaction.
However, all compounds mentioned above first had to be synthesized. Therefore we had to
make use of or develop efficient regioselective protection methods before these
investigations.
AcO
HO
OBn
OBn
O
O
AcO
OMe
HO
OBn 10
OBn
OBn
OMe
11
HO
O
AcO
OBn
OH
OMe AcO
12
OBn
OBn
O
O
HO
OMe AcO
OBn
13
OBn
OBn
OMe
14
O
HO
OBn
OAc
OMe
15
Figure 6 Methyl glycoside derivatives where the 2- and 6-positions are protected with
benzyl ether groups.
7
8
2 Regioselective Carbohydrate Protection
2.1 Common Protection Strategies
In order to efficiently obtain the desired carbohydrate compounds 1-15, selective
protecting groups and efficient regioselective protection strategies are of crucial
importance. The most common protection strategies for carbohydrates are acylation and
alkylation. In some case, they can be directly used to protect certain specific hydroxyl
groups by making use of reactivity differences. Furthermore, organotin acylation and
alkylation are often used to increase the selectivity. However, in most cases, it requires the
integration of several protection strategies to efficiently synthesize the desired protected
carbohydrates.
2.1.1 Acylation
Acylation can be used to protect hydroxyl groups with an acyl group. The most common
acylating reagents include benzoyl chloride, acetyl chloride and acetate anhydride. Usually,
these reagents are used in pyridine at room temperature to protect all free hydroxyl groups.
However, at low temperature regioselectively acylated structures may also be obtained.
For example, methyl 2,3,6-tri-O-benzoyl galactoside 7 could be efficiently synthesized in
60% yield by a one-step esterification process at -40 oC, starting from galactoside 16
(Scheme 6).
HO
OH
HO
BzCl
O
HO
OH
OMe
16
py, CH2Cl2
-40 oC
OBz
O
BzO
OBz
OMe
7
Scheme 6 Synthesis of compound 7.
2.1.2 Alkylation
An often used alkylation method in carbohydrate chemistry is benzylation. Especially, the
4- and 6-positions of a pyranoside can be regioselectively protected by a benzylidene
group, which can be reductively opened from the 4- or 6-position to obtain a free hydroxyl
group and a benzyl group. The glycoside derivatives 5 and 9 could be synthesized by this
benzylation method. Starting from galactoside 16 and glucoside 17, the 4,6-O-benzylidene
18 and 19 respectively were synthesized first. Compounds 18 and 19 were then allowed to
react with benzyl bromide in the presence of sodium hydride, producing 4,6-Obenzylidene-2-O-benzyl galactoside 5 (in 30% total yield) and 4,6-O-benzylidene-2,3-diO-benzyl glucoside 20 (Scheme 7). After the benzylidene ring of 20 was opened by
reduction, the 2,3,6-tri-O-benzyl glucoside 9 was finally obtained in 72% overall yield.
9
Ph
Ph
O
HO
O
HO
OH
OH
O
HO
HO
OH
O
O
OH
O
O
PhCH(OMe)2
OMe DMF, H
16
HO
Ph
PhCH(OMe)2
OMe DMF, H
17
O
O
HO
OH
O
OH
OMe
18
O
BnBr, NaH
DMF
HO
Ph
BnBr, NaH
OMe
DMF
19
O
O
BnO
OBn
OMe
5
O
Et3SiH,
CF3CO2H
OMe CH Cl
2 2
OBn 20
OBn
HO
BnO
O
OBn
OMe
9
Scheme 7 Synthesis of compound 5 and 9.
2.1.3 Organotin Protection
For obtaining mono-substituted compounds in one or a few steps, the use of organotin
reagents such as tributyltin oxide or dibutyltin oxide[40], provide useful means to efficient
regioselective acylations[41-44], alkylations[41, 45-47], silylations[48], sulfonylations[41, 49, 50] and
glycosylations[51-53]. Stannylene acetals are easily prepared by treatment of carbohydrates
with organotin in methanol at reflux condition, and generally lead to intermediate
structures with predictable reactivities. In these reactions, stoichiometric amounts of
organotin reagent are normally used. 4,6-O-Benzylidene-3-O-benzoyl glucoside 1 and 4,6O-benzylidene-3-O-benzyl glucoside 2 can for example easily be obtained through
regioselective organotin-mediated protection (Scheme 8). Starting from the 4,6-Obenzylidene 19 with 1.1 equivalent of dibutyltin oxide in methanol at 70 oC, a stannylene
intermediate can be obtained after removing the methanol. When the stannylene
intermediate was treated with benzoyl chloride or benzyl bromide in toluene, glucoside 1
(in 55% yield) and 2 (50% yield) can be obtained respectively. The relatively low yield
was in these cases caused by the similar reactivity of the hydroxyl groups in the 2- and 3positions of 19.
Ph
O
O
BnO
O
OH
1.Bu2SnO,
MeOH
OMe 2.BnBr, TBAI
2
toluene
Ph
O
O
HO
O
OH
OMe
19
1.Bu2SnO, Ph
MeOH
2.BzCl,
toluene
O
O
BzO
O
OH
OMe
1
Scheme 8 Synthesis of compounds 1 and 2.
2.1.4 Integrated Protection Strategies
Most of the glycoside derivatives were synthesized using a combination of esterification,
benzylation and organotin protection strategies. Some required only a few steps, whereas
others were more cumbersome. The synthesis of methyl 2,4,6-tri-O-acetyl galactoside 3
and methyl 2,4,6-tri-O-benzoyl galactoside 4 was somewhat more complex than the
synthesis of compounds 1 and 2. The hydroxyl group in the 3-position of galactoside 16
was first protected with a benzyl group by regioselective tin oxide benzylation, and then
the obtained compound 21 was acylated in the presence of pyridine in methanol to form
compounds 22 and 23. Finally, after removing the benzyl group in the 3-position by
10
catalytic hydrogenation, both methyl galactosides 3 and 4 were acquired in more than 70%
total yield (Scheme 9).
HO
OH
O
HO
OH
HO
1.Bu2SnO
MeOH
OMe 2.BnBr, TBAI,
BnO
16 toluene, 90 oC
OH
AcO
O
OH
OMe
21
Ac2O, py
MeOH
OAc
O
BnO
OAc
BzCl, py
MeOH
BzO
OBz
BzO
O
HO
OMe
4
OBz
Pd,
H2
OBz
AcO
OAc
O
O
Pd, H2
BnO
OMe
22
OMe
23
OBz
HO
OAc
OMe
3
Scheme 9 Synthesis of compound 3 and 4.
Generally, several steps are required to synthesize glycoside derivatives where one of the
hydroxyl groups in the 3- or 4-position is protected with an acetyl group and the 2- and 6position are blocked with benzyl groups. However, the methyl 4-O-acetyl-2,6-di-O-benzyl
galactoside 10 could be relatively easily obtained in more than 70% total yield via a onepot reaction (Scheme 10).[54] Removal of the acetyl group in compound 10 resulted in 2,6di-O-benzyl galactoside 26, which could easily be converted into 2,3,6-tri-O-benzyl
galactoside 8 or 3-O-acetyl-2,6-di-O-benzyl galactoside 13 by organotin methods (Scheme
10). Furthermore, the 2,6-di-O-benzyl compounds 11, 12, 14 and 15 can be synthesized by
epimerization and migration starting from compounds 10 and 13.
HO
OH
EtO O
O
HO
OH
CH3(OEt)3
OMe
16
THF, H
EtO O
OH
O
O
OH
OMe
24
BnBr, NaH
THF
OBn
O
O
OBn
OMe
25
H
HO
OBn
O
AcO
OBn
OMe
13
1.Bu2SnO
MeOH
2.Ac2O
toluene
HO
OBn
AcO
O
HO
OBn
OMe
26
MeOH
MeONa
OBn
O
HO
OBn
OMe
10
1.Bu2SnO
MeOH
2.BnBr, TBAI
toluene
HO
OBn
O
BnO
OBn
OMe
8
Scheme 10 Synthesis of compounds 8, 10, and 13.
2.2 Organotin Multiple Esterification (Paper I)
Of particular interest in carbohydrate protection is the possibility of acquiring multiple
protections in single step processes. The organotin method provided a good method for
11
such multiple protection strategies.[55] The unprotected glycoside was first treated with
excess (2-3 equivalents) of dibutyltin oxide in methanol at reflux condition, producing a
stannylene intermediate that was not isolated. This intermediate was subsequently treated
with the acylation reagent to yield the protected products in a one-pot process. For
example, 2,3,6-tri-O-benzoyl galactoside (or glucoside) 7 (or 6) can easily be obtained by
treatment of the stannylene intermediates, formed by the reaction of unprotected
galactoside 16 (or glucoside 17) and 3.3 equivalents of dibutyltin oxide, with 3.3
equivalents of benzoyl chloride (Scheme 11).
HO
OH
O
HO
OH
OMe
16
OH
HO
HO
1. Bu2SnO
MeOH
O
OH
1. Bu2SnO
MeOH
2. BzCl, rt,
toluene
OMe
17
2. BzCl, rt
toluene
HO
OBz
O
BzO
OBz
OMe
7 85%
OBz
HO
BzO
O
OBz
OMe
6 85%
Scheme 11 Synthesis of compound 6 and 7 by organotin multiple benzoylation.
Further studies indicated that the multiple esterification processes were highly dependent
on the acylation reagents and the polarity of the solvents. Different protection patterns
could be acquired from the same starting material by control of temperature, acylation
reagents, reagent mole ratio, and solvent polarity. In the course of these studies, it was
found that the benzoyl group can migrate to 3- and 4-position from 2- and 3-position at
high temperature (Scheme 12). Thus, the temperature could be used for dynamic migration
control.
HO
OH
1. Bu2SnO
MeOH
O
HO
HO
OH
OMe
16
2. BzCl, rt,
toluene
OMe
16
1. Bu2SnO
MeOH
2. BzCl, 90 oC
toluene
OMe
16
1. Bu2SnO
MeOH
2. BzCl, 90 oC
toluene
OH
O
HO
HO
OH
OH
O
HO
OH
HO
OBz
O
BzO
BzO
OH
OMe
27 90%
OBz
O
HO
BzO
OH
OMe
28 85%
OBz
O
BzO
OH
OMe
29 90%
Scheme 12 Multiple benzoylation controlled by temperature and reagent mole ratio.
According to the proposed organotin acyl group migration mechanism (Figure 7),[50, 56-58]
the resulting tin alkoxide intermediate is able to attack the acyl carbonyl group. However,
it is reasonable to assume that acylation reagents in general are able to migrate under the
same conditions. And yet, different from benzoyl chloride, it was found that migration
could be observed with acetyl chloride at room temperature, whereas acetic anhydride
proved inefficient under these conditions (Scheme 13). On the other hand, product 33,
12
protected in the 3,6-positions, was obtained with acetic anhydride whereas product 34,
protected in the 2,6-positions, was obtained with benzoyl chloride at room temperature.
Since no migration resulted with either acetic anhydride or benzoyl chloride at room
temperature, it is apparent that, in this case, the results controlled by the acylation reagents
were not brought about by this organotin acyl group migration (Scheme 13). Good
selectivity was always obtained when the esterification reactions were done in a more
polar solvent. The reason is likely due to decreased reactivity of the esterification reagent
from solvent-induced destabilization of the stannylene intermediates.[59]
Bu Cl
Bu Sn
O
O
R
O
Bu
Bu
OP
O
R
OMe
OP
Cl
Sn
O
O
O
R
OP
O
O
OP
O
OMe
Bu
OMe
O
Bu Sn
OP
O
Bu
O
O
OP
Sn
Bu Cl O
OP
O
OMe
OP
Cl
Figure 7 Proposed organotin acyl group migration mechanism.
HO
OAc
O
AcO
OH
OMe
32
Bu2SnO, MeOH
Ac2O, DMF, rt
90%
AcO
OAc
Bu2SnO
MeOH
O
AcO
OH
OMe
31
OBz
HO
HO
O
OMe
OBz 34
AcCl, rt
toluene
57%
HO
OH
Bu2SnO
MeOH
O
HO
Bu2SnO
MeOH HO
BzCl, rt
HO
CH3Cl
51%
HO
AcO
OH
OMe
16
OH
Ac2O, rt
toluene
70%
Bu2SnO
MeOH
O
OMe
17
Ac2O, rt
OH
DMF
70%
Bu2SnO, MeOH
Ac2O, CH3CN, rt
85%
OAc
HO
OAc
O
AcO
OAc
OMe
30
OAc
HO
AcO
O
OH
OMe
33
O
OAc
OMe
35
Scheme 13 Multiple esterifications controlled by acylation reagents and solvents.
13
14
3 Lattrell-Dax Epimerization
3.1 Effects of Protecting Groups (Paper II)
All the glycoside derivatives, designed to explore the effect of the neighboring group on
the Lattrell-Dax epimerization, were synthesized via the use of esterification, benzylation
or organotin methods. It was hypothesized that, whenever the triflate group is in 2-, 3-, or
4-position of these pyranosides, good inversion yields would be obtained with neighboring
ester groups, whereas poor inversion yields or complex mixtures would be obtained with
neighboring benzyl groups. Furthermore, good inversion yields would be obtained with
only neighboring equatorial ester groups, whereas neighboring axial ester groups would be
inefficient. Our first approach was to investigate the effect of the protecting group pattern
on the inversion reaction.
3.1.1 Effects of Protection Patterns
Initially, glycoside derivatives carrying a triflate group in the 3-position were subjected to
the examination. In order to compare the effects of different ester groups, two types of
ester-protected galactopyranosides (3, 4) were synthesized.
OAc
AcO
O
HO
OAc
OMe
3
OBz
BzO
O
HO
OBz
OMe
4
Ph
O
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 6h
DMF, 50 oC
AcO
OAc
O
OH
BzO
OAc
OMe
36 73%
OBz
O
OH
OBz
OMe
37 77%
O
O
HO
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 3h
DMF, 50 oC
OMe
OBn
5
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 3h
DMF, 50 oC
Complex
mixture
Scheme 14 Epimerization of glycosides where the 3-OH is unprotected.
As can be seen (Scheme 14), good yields were in these cases obtained only on the
condition that esters were chosen as protecting groups, benzoyl groups being slightly less
activating than the acetyl counterparts. When the ester protecting groups were replaced by
benzyl/benzylidene groups, a mixture of different products was instead obtained.
Similar results were obtained from the epimerization of glycopyranosides where the
hydroxyl group in the 4-position was unprotected, and all other positions were protected
with either benzoyl or benzyl groups (Scheme 15). Only when an ester group was present
at the carbon adjacent to the carbon atom carrying the leaving triflate group did the
15
reaction proceed smoothly, the axially oriented triflate being less reactive than the
equatorial leaving group.
OBz
HO
BzO
HO
O
OBz
OMe
6
OBz
O
BzO
HO
OBz
OMe
7
OBn
O
BnO
OMe
OBn
8
OBn
HO
BnO
O
OMe
OBn
9
2. KNO2, 2h
DMF, 50 oC
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 5h
DMF, 50 oC
OBz
HO
1. py, Tf2O,
CH2Cl2, 2h
O
BzO
OBz
OMe
7 70%
OBz
O
HO
BzO
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2,0.5h
DMF, 50 oC
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 0.5h
DMF, 50 oC
OBz
OMe
6 75%
Complex
mixture
Complex
mixture
Scheme 15 Epimerization of glycosides where the 4-OH is unprotected.
In contrast to this effect, no efficient reaction occurred when benzyl groups were employed
where compound mixtures were instead rapidly obtained. These results suggest that a
neighboring ester group is able to induce or activate the inversion reaction, whereas an
ether derivative is unable to produce this effect. The results also showed that the inversion
reaction proceeded smoothly regardless of the triflate configuration.
Ph
Ph
O
O
BzO
O
O
BnO
O
OH
OMe
1
O
OH
OMe
2
1. py, Tf2O, Ph
CH2Cl2, 2h
2. KNO2, 6h
DMF, 50 oC
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 3h
DMF, 50 oC
O
O
BzO
OH
O
OMe
38 74%
Complex
mixture
Scheme 16 Epimerization of glycosides where the 2-OH is unprotected.
Further tests were performed for glucopyranosides where the hydroxyl groups in the 2position were free (Scheme 16). After observing the inversion behavior in the 3- and 4position of the hexopyranosides, the 2-position was probed. The ester-protected
glucopyranoside compound 1 afforded the inversion mannopyranoside product 38 in good
yields, whereas the ether-protected compound 2 proved inefficient. In this case, slightly
longer reaction times were however necessary due to the lower reactivity of the 2-OTf
derivative.
16
3.1.2 Effects of Neighboring Group Configurations
It was demonstrated that a neighboring ester group was essential for the reactivity of the
nitrite-mediated triflate inversion from the above experiments. To further analyze these
findings and explore the effects of the neighboring ester group configurations on the
reactivity, glycoside derivatives 10 to 15 were tested in the nitrite-mediated inversion
reactions. To avoid the effects from the 2- and 6-positions and to isolate the effects arising
from ester groups in the 3- and 4-positions, the 2- and 6-positions were protected with
benzyl ether groups. The experimental results presented in Table 1 clearly indicated that
the configuration of the neighboring ester group directed the reactivity of the epimerization
reaction. Good inversion yields depended mainly on the relative configurations of the two
groups, and only with the ester group in the equatorial position did the reaction proceed
smoothly, regardless of the configuration of the triflate, whereas a neighboring axial ester
group proved inefficient.
Table 1 Epimerization reactions studied.
Entry
AcO
1
Reactant
Time /h
Product
OBn
O
3
mixture
OMe
OBn 10
HO
2
3
OBn
O
AcO
HO
AcO
OMe
OBn 11
OMe
OBn 12
OH
5
6
OBn
O
OMe
OBn 13
AcO
HO
AcO
HO
4
AcO
HO
4
HO
AcO
HO
OBn
O
OMe
OBn 14
0.5
OAc
OBn
OMe
15
OMe
12
69
OMe
11
73
OMe
14
75
OMe
13
72
OBn
OBn
O
OBn
OBn
O
OBn
OBn
O
AcO
OBn
O
_
OBn
O
OH
OBn
O
HO
4
AcO
1.5
Yield /%
OBn
_
mixture
3
o
o
Reaction conditions: i: Tf2O , py, CH2Cl2, -20 C-10 C, 2h; ii: KNO2,
o
50 C, DMF, 0.5-4h. All starting materials were consumed.
Rapid internal triflate displacements by neighboring acetyl or benzoyl groups will occur if
the ester group and the leaving group have trans-diaxial relationships. This leads to
products where the configuration is retained, thus excluding these combinations from the
present investigation. This internal displacement is indicative of the fast formation of an
intermediate acyloxonium carbocation, stabilized by polar solvent. In our cases,
compounds 11 and 14 hold 3,4-trans configurations in diequatorial relationships, where
the internal triflate displacement by the neighboring ester group is considerably less
17
efficient. Contrary to this situation, compounds 12 and 13 hold 3,4-cis configurations
where the ester groups are in the equatorial positions. This structural situation largely
excluded the conventional neighboring group participation.[60, 61]
Further study indicated that the nitrite-mediated reaction produced the same results also in
acetonitrile, a mixture being produced without neighboring equatorial ester group. The
reaction rates in the less polar solvent acetonitrile were always lower than in the more
polar solvent DMF. Normally, Lattrell-Dax epimerization reactions are performed in polar
aprotic solvents such as acetonitrile or DMF,[16, 19, 30, 32, 34, 62, 63] and nonpolar solvents are
mainly chosen to avoid neighboring group participation.[16, 26, 64]
3.2 Neighboring and Remote Group Participation
3.2.1 Neighboring Group Participation Effects
The results obtained seem to point to the importance of a neighboring group
(acyloxonium) effect. Compounds 11 and 14 (3,4-trans) expressed higher reactivity
compared to compounds 12 and 13 (3,4-cis) as a result of the activation from the
neighboring ester group inducing the inversion reaction. This is reflected in the longer
reaction times for the 3,4-cis compounds, as displayed in Table 1. However, acyloxonium
formation is still unlikely to be the sole explanation of the results for two reasons: first,
starting compounds 12 and 13 both have a cis relationship between the ester and the
leaving group, which largely disqualifies acyloxonium formation;[60, 61] and second,
formation of a carbocation intermediate would result in a nucleophilic displacement from
the triflate face of the compound leading to retention (double inversion) of configuration
rather than single inversion (Figure 8).
AcO
HO
OBn
O
Tf2O/py
OMe
OBn 11
CH2Cl2
AcO
TfO
OBn
O
OBn
OMe
KNO2
DMF
OBn
O
AcO
OMe
OBn 12
OH
DMF
OBn
O
O
OBn
O
Tf2O/py
OMe
OBn 14
CH2Cl2
OAc
HO
OBn
O
TfO
AcO
OBn
O
HO
OBn
O
HO
AcO
H2O
OMe
OBn
OMe
KNO2
DMF
AcO
OBn
OMe
15
OBn
O
OMe
OBn
13
DMF
O
AcO
OBn
O
O
OBn
H 2O
OMe
HO
OBn
O
OMe
OBn 10
Figure 8 Comparison of nitrite-mediated inversion with neighboring group participation.
18
The importance of the acyloxonium formation in the trans-configuration cases was further
supported by studies with addition of water. Compounds 11 and 14, both with 3,4-transdiequatorial relationships, mainly yielded compounds 12 and 13 from reaction with
potassium nitrite in dry DMF (Table 2). If on the other hand wet DMF without nitrite was
used, compounds 15 and 10 were instead obtained as the main products. This suggests
acyloxonium formation to the five-membered-ring intermediate, which rapidly collapses in
the presence of water to produce the axial ester and the equatorial hydroxyl group. These
results are indicative of (partial) acyloxonium formation in the trans-configuration cases,
but that the nitrite ion is unable to open the five-membered ring from either the triflate face
or from attacking the carbonyl cation, as has been suggested for water.[35] More
importantly, the ester group is, therefore, likely to induce or stabilize the attacking nitrite
ion regardless of the trans- or cis-configurational relationships. The effects observed for
the ether-protected carbohydrates are likely a result of their lower degree of positive
charge destabilization than the corresponding ester groups, leading to side reactions such
as ring contraction and elimination.[65, 66]
Table 2 Water effects in studied nitrite-mediated inversion reactions.
Nucleophile
Reactant
AcO
HO
AcO
HO
HO
AcO
HO
AcO
OBn
O
OBn
OMe
OMe
KNO2
AcO
14
AcO
OMe
H2O
HO
14
o
OBn
OMe
69
12
OBn
O
OAc
HO
OMe
OBn
O
OBn
HO
H2O
Yield /%
OBn
O
OH
11
OBn
O
OBn
AcO
KNO2
11
OBn
O
OBn
Product
OBn
OMe
OBn
O
OBn
70
15
OMe
72
13
OBn
O
OBn
OMe
70
10
o
Reaction conditions: i: Tf2O , py, CH2Cl2, -20 C-10 C, 2h; ii: KNO2,
o
50 C, DMF, 0.5-1.5h, or H2O, r.t., DMF, 6h.
3.2.2 Remote Group Participation
When the inversion of the triflate intermediates of compounds 29 and 31 was performed
with nitrite in DMF, it was expected to acquire inversed compounds 39 and 41 in high
yields since both compounds 29 and 31 contain a neighboring equatorial ester group.
However, a mixture of two compounds was obtained in both cases. Further experiments in
acetonitrile showed the same results, in which compounds 40 and 42 were also formed
simultaneously besides the expected compounds 39 and 41. 1H-NMR experiments
indicated that the formation of methyl talosides 39 and 41, where the hydroxyl group in the
2-position is unprotected, were more favored in less polar solvent acetonitrile (50%, 80%)
and less favored in polar solvent DMF (45%, 40%), whereas the formation of methyl
talosides 40 and 42, where the hydroxyl group in 4-position is free, were more favored in
19
polar solvent DMF (55%, 60%) and less favored in less polar solvent acetonitrile (50%,
20%). As a comparison, starting from the triflate intermediate of methyl 3,4,6-tri-O-acetyl
galactoside 31, it was expected that the fully protected methyl taloside would be produced
via the use of five equivalents of tetrabutylammonium acetate. However, the same mixture
of methyl talosides 41 (52%) and 42 (48%) was produced (Scheme 17).
BzO
O
AcO
a or b
OMe
BzO
OH
OMe +
OBz
OBz
O
AcO
a, b or c
OMe
HO
OMe +
OAc
OAc
O
OMe
AcO
41
31
40(%)
80
20
b
40
60
41(%)
50
42(%)
a
b
c
45
52
55
48
40
OAc
OH
O
AcO
39(%)
a
OMe
BzO
39
29
O
OH
HO
BzO
OAc
AcO
OBz
OH
O
BzO
OBz
42
(a) i: Tf2O, py, CH2Cl2, ii: TBANO2, CH3CN, 50 oC, 30h.
(b) i: Tf2O, py, CH2Cl2, ii: TBANO2, DMF, 50 oC, 20h.
(c) i: Tf2O, py, CH2Cl2, ii: TBAOAc, CH3CN, 50 oC, 30h.
50
NMR-yields.
Scheme 17 Epimerization by neighboring and remote group participation.
All of these results support a remote group (4-position) participation mechanism, where a
six-membered ring is generated first, and then opened by trace water to produce either a
free 4-hydroxyl group or a free 2-hydroxyl group in a reaction that is favored by polar
solvents (Figure 9). The direct nitrite competition reaction resulted in that the 2-hydroxyl
group products (39, 41) were favored in less polar solvents. In combination with the steric
effects of the nucleophilic reagent, this also explains why a mixture of methyl talosides 41
and 42 were primarily obtained when tetrabutylammonium acetate was employed as a
nucleophilic reagent.
AcO
AcO
O
OAc
O
AcO
AcO
O
O
OMe
43
OTf
O
H2 O
OMe
AcO
OH
O
O
OMe
AcO
OTf
OAc
HO
AcO
OAc
O
OMe
42
AcO
+
AcO
OAc
OH
O
OMe
41
Figure 9 Remote group participation.
To further support this mechanism, the triflate of methyl taloside 31 was directly tested in
wet acetonitrile at 50 oC for 20 hours. As a result, a mixture including methyl talosides 41
and 42 was also obtained. However, addition of the nucleophilic reagents
tetrabutylammonium nitrite/acetate can increase the reactivity of the remote group
participation. The test for neighboring group participation also supported this result. It
20
seems that not only the neighboring ester group can activate the nitrite-mediated
epimerization but also the nitrite ion can activate the neighboring or remote group
participation.
3.3 Supramolecular Control (Paper III)
Supramolecular control is an important advancement in modern synthetic chemistry,[67-69]
enabling for example improved selectivities and enhanced reaction rates. Recognitionbased proximity effects of participating reactants are generally involved in these systems,
positioning the components by templating prior to the reaction sequence.
3.3.1 Unusual Solvent Effect
For the inversion of 3-OTf β-D-galactopyranoside derivatives, an unusual solvent effect
was found. For example, when the β-D-galactopyranoside derivatives 3 and 4 were tested
in the reaction, the reaction rates proved generally higher in more polar solvents (Table 3).
Thus, the rate increased in the order: CHCl3 < CH2Cl2 < CH3CN < DMF. However, the
results in toluene and benzene broke this trend. Although these two solvents have the
lowest polarity, the reactions proceeded at a faster rate. When other glycoside triflate
derivatives were tested in toluene or benzene, the reaction rates were always lower in less
polar solvents. For example, inversion of the triflate intermediates of methyl β-Dgalactopyranosides 29 and 31 was successful in DMF and acetonitrile (Scheme 17),
whereas it completely failed in toluene. Furthermore, in contrast to the rapid reaction times
for the inversion of the 3-position of β-D-galactopyranoside 3 in benzene or in toluene, no
reaction occurred for its α-anomer.
Table 3 Comparison of the reactivity of 3-position inversion of β-galactoside.
AcO
OAc
O
HO
BzO
OAc
OMe
3
OBz
O
OMe
OBz
4
HO
Solvent
a
b
DMF
1. py, Tf2O,
2. TBANO2,
50 oC
AcO
OAc
O
OAc
OH
1. py, Tf2O,
2. TBANO2,
50 oC
CH3CN
BzO
a
OMe
37
b
OBz
O
OBz
OH
CH2Cl2
OMe
36
CHCl3
Benzene
Toluene
Time/h
1
3
6
20
1
1
Conv/%
87
91
80
60
90
89
Time/h
2
5
12
9
2
2
Conv/%
92
89
80
35
91
91
21
3.3.2 Carbohydrate-Anion Complex
During 1H-NMR studies of these reactions, it was surprisingly found that certain signals
were dramatically shifted when nitrite anion was added. More detailed studies were
performed, and the 3-OTf intermediate 44 was analyzed in deuterated DMF, acetonitrile,
chloroform, and benzene, respectively. Interestingly, it was found that the relative shift
differences in absence and presence of nitrite were close to negligible in DMF, acetonitrile
and chloroform, whereas pronounced differences were recorded in benzene (Table 4). The
signals for the protons in the 1-, 3- and 5-positions were in this case shifted downfield by
0.82, 1.03 and 1.14 ppm, respectively, while the shifts of the 2-, 4-, and 6-protons
remained largely constant.
Table 4 Comparison of 1H-chemical shifts of intermediate 44 with and without nitrite
anion in various d-solvents.
BzO
OBz
O
TfO
OBz
OMe
44
w/o nitrite
d-solvent
benzene
H1
4.11
H2
6.16
H3
5.10
H4
6.07
H5
3.42
H6a
4.22
H6b
4.58
w nitrite
benzene
4.93
6.24
6.13
6.34
4.56
4.41
4.69
0.82
0.08
1.03
0.27
1.14
0.19
0.11
w/o nitrite
CDCl3
4.67
5.74
5.23
6.05
4.22
4.41
4.66
w nitrite
CDCl3
4.68
5.63
5.30
5.96
4.26
4.32
4.54
0.01
-0.09
0.07
-0.09
0.04
-0.09
-0.12
4.85
5.60
5.60
6.04
4.40
4.42
4.55
Δδ
Δδ
w/o nitrite
CD3CN
w nitrite
CD3CN
Δδ
w/o nitrite
DMF
w nitrite
DMF
Δδ
4.94
5.57
5.78
6.03
4.52
4.41
4.52
0.09
-0.03
0.18
-0.01
0.12
-0.01
-0.03
5.20
5.82
6.21
6.29
4.85
4.70
4.56
5.25
5.85
6.28
6.32
4.91
4.72
4.60
0.05
0.03
0.07
0.03
0.06
0.02
0.04
Similar effects were also recorded for the 2-OTf intermediate 45 (Table 5), where the 1-,
3-, and 5-protons were deshielded by 0.78, 0.44 and 0.88 ppm, respectively, in benzene,
and the relative shifts of the 2-, 4-, and 6-protons were close to zero. In DMF, no
deshielding could be seen. Similar results were obtained when the benzoyl group was
replaced with an acetyl group for intermediates 44 and 45.
22
Table 5 Comparison of 1H-chemical shifts of intermediate 45 before and after addition of
nitrite anion in DMF and benzene.
BzO
OBz
O
OMe
BzO
OTf
45
d-solvent
H1
H2
H3
H4
H5
H6a
H6b
w/o nitrite
benzene
3.96
5.42
5.53
6.07
3.47
4.14
4.58
w nitrite
benzene
4.74
5.46
5.97
6.20
4.35
4.26
4.67
0.78
0.04
0.44
0.13
0.88
0.12
0.09
Δδ
w/o nitrite
DMF
5.30
5.13
6.10
6.09
4.85
4.53
4.66
w nitrite
DMF
5.30
5.15
6.10
6.10
4.85
4.53
4.65
0.00
0.02
0.00
0.01
0.00
0.00
0.01
Δδ
Furthermore, in contrast to the results for the β-anomer, no effects were observed for the αform of the 3-OTf intermediates 46 and 47 (Table 6). All these results point to a
supramolecular control effect. The carbohydrate structures present polar binding regions in
their favored conformations, accentuated by electron-withdrawing protecting/leaving
groups. Negatively charged species can thus interact with these structures, forming
relatively strong molecular complexes. The nitrite ion can in this case be accommodated at
the center of the pyranoside B-face to produce a carbohydrate complex, apparently
reinforced by weak CH-O bonds, resulting in a 1-, 3-, 5-hydrogen deshielding effect. This
also explains why the effect was only found in non-polar solvents, since competition in
better solvating media hampers the binding effect.
Table 6 Comparison of 1H-chemical shifts of intermediates 46 and 47 with and without
nitrite anion in d-benzene.
AcO
OAc
BzO
O
TfO
Compound
46
O
TfO
AcO
46 OMe
BzO
47 OMe
d-solvent
H1
H2
H3
H4
H5
H6a
H6b
w/o nitrite
benzene
4.95
5.44
5.35
5.60
3.54
4.08
4.01
w nitrite
benzene
Δδ
47
OBz
w/o nitrite
benzene
w nitrite
benzene
Δδ
4.95
5.42
5.35
5.60
3.60
4.08
4.01
0.00
-0.02
0.00
0.00
0.06
0.00
0.00
5.27
5.85
5.70
6.03
3.84
4.55
4.17
5.27
5.85
5.71
6.04
3.86
4.55
4.18
0.00
0.00
0.01
0.01
0.02
0.00
0.01
23
This model is further corroborated by the experimental results obtained from the LattrellDax reaction. Especially for the inversion of the β-galacto-type 3-position in nonpolar
solvents, an improved formation of this anion-carbohydrate complex controls the overall
rate leading to accelerated reaction compared to more polar solvents (Figure 10). Although
the host-guest complex is also formed between nitrite and derivatives 43 and 45, the
outcome is unproductive since the inversion path of the reaction originates from the Aface.
RO
OR
O
RO
OMe
TfO
NO2-
O
OMe
OR
H5
H3
RO
OR
O
NO2OMe
RO
Activated
O
O-
H1
N
OR
O
OMe
OR
OH
OR
RO
OH
Deactivated
O
X
RO
OMe
OTf
Figure 10 Supramolecular control from carbohydrate-anion recognition.
3.3.3 Binding Model
In order to further support the host-guest model, a quantum chemical study was performed.
Compound 43 and tetramethylammonium nitrite were chosen as the model, and the
binding mode and the association constant of the host-guest system were calculated
(Figure 11). The binding constant could be in this case estimated to 1.0 x 102/M, and the
guest nitrite anion was found to be situated slightly closer to the 1- and 3-hydrogens than
to the 5-hydrogen at the carbohydrate B-face.
AcO
OAc
O
AcO
H OTf
H
H
ON
OMe
43
N
O
Figure 11 Quantum chemical model of the nitrite-compound 43 complex.
The calculation predictions were subsequently confirmed by 1H-NMR titration
experiments using compound 43 and tetrabutylammonium nitrite in d-toluene (Figure 12).
24
The association constant amounted to 7.4 x 102/M, and Job's analysis indicated a 1:1 ratio
of the binding partners. The 1-, and 3- hydrogens were notably more deshielded than the 5proton, suggesting that the nitrite anion is located closer to these in the complex. In
principle, these results are compliant with the well known carbohydrate-aromatic
interactions often found in carbohydrate-binding proteins,[70-74] where recent results
suggest a “three point landing surface” via a CH 1-, 3-, 5-π interaction.[73, 74] Consequently,
the anion recognition effect presented here may have unknown implications in biological
recognition. To explore whether this supramolecular effect between β-glycosides which
contain axial 1-, 3-, 5-hydrogen and anions in nonpolar solvents is general, these
glycosides have been tested with different anions such as acetate, chloride anions and so
on. For β-glycosides which have at least one unprotected hydroxyl group, it seems that a
similar supramolecular effect can be observed, however the hydrogen bonding effect
between the hydroxyl group and anions make the results more complicated. Experiments
with fully protected glycosides indicated that the interaction between anions and the 1-, 3-,
5-hydrogen “bowl” from the carbohydrate B-face is related to the electron-withdrawing
ability of the protecting groups.
OAc
δ = 4.298
O
OMe
AcO
H5 OTf
H3
H1
+ δ = 4.788
δ = 4.056
OAcO
AcO
OAc
δ = 4.773
O
OMe
H5 OTf
H3
H
1
Oδ = 4.804
δ = 5.281
AcO
Ka
Kd
N
N
O
O
5.6
0.20
H1
0.15
4.8
Δδ x
δ
5.2
H5
4.4
0.05
H3
4.0
0
1
0.10
2
3
4
0.00
0.0
5
-
[NO2 ]/[43]0
0.2
0.4
0.6
0.8
1.0
mole fraction x of 43
Figure 12 Job´s plot for compound 43 with tetrabutylammonium nitrite in benzene. K =
7.4 x 102/M, R2 = 0.9996.
3.4 Ambident Reactivity of Nitrite Anions (Paper IV)
The ambident reactivity of the nitrite ion has been debated for a very long time.[75-82] The
Hard-Soft Acid-Base theory (HSAB) or the Perturbation Molecular Orbital theory (PMO)
has been used to explain how the O-attack or the N-attack generates mainly nitrite or nitroproducts.[78, 79, 83] Recently, Mayr´s group suggested that nitrite anions are a third type of
ambident anions (besides SCN- and CN-) which do not fit any previous theories.[84]
25
According to their experiments, the effect of the leaving groups on the O/N selectivity is
small, and instead it seems that solvents and reagents play more important roles (Figure
13). It was also shown that when tetrabutylammonium nitrite was allowed to react with
methyl triflate in chloroform, a mixture of nitrite and nitro products was obtained.
Me-OSO 2Me
KNO 2/[18]crown-6
TBANO2
Me-OSO2CF3
Me-ONO
Me-ONO
+ Me-NO 2
+ Me-NO 2
Solvent
MeONO/MeNO 2
EtOH
MeCN
THF
30/70
C 6H 6
50/50
92/8
85/15
CHCl 3
59/41
Figure 13 O/N selectivities for methylations of nitrite ions.[84]
3.4.1 An O/N Selectivity Case in Carbohydrate Epimerization
The phenomenon of O-attack or N-attack of benzoylcarbamate was reported in
carbohydrate epimerization by Knapp´s group when using a benzoylcarbamate cyclization
method for the synthesis of amino glycoside from precursors bearing a hydroxyl group and
a nearby electrophilic carbon center (Figure 14).[85]
O
O
OH
Ph
O
O
N
H2N
N-attack
O
TfO
Ph
O
O-attack
O
O
TfO
O
O
HO
O
Ph
O
O
OH
O
O
O
O
O
NCOPh
NHCOPh
TfO
OMe
NHCOPh
O
O
O
PhCOHN
48
51
Ph
OMe
O
Ph
O
O
O
O
OMe
TfO
O
PhCOHN
49
O
O
Ph
O
O
O
OMe
TfO
O
O
PhCOHN
O
O
OMe
O
TfO
NHCOPh
52
50
Figure 14 O/N selectivities controlled by glycoside configuration.[85]
It can be seen that glycosides 48-50 undergo N-attack to produce amino products and that
glycosides 51 and 52 undergo O-attack to produce diol derivatives under the same
conditions. The key step in the reaction is the proton abstraction at nitrogen creating a
negative species that may undergo either N- or O-cyclization. However, it was difficult to
predict the outcome of the reaction by the HSAB theory, whereas steric reasons could
instead be used to explain the selectivity. The N-attack requires more free space than the
26
O-attack. For glycosides 48-50, the face which will be attacked by benzoylcarbamate anion
has enough space to accommodate the whole N-attacking group. However, for glycoside
51 and 52, the methoxy and benzylidene groups are both on the A-face/B-face, blocking
the attack of the more hindered side of the benzoylcarbamate anion (N-attack). As a result,
only O-attack can occur. The above results show that O- or N- attack can be controlled by
the glycoside configuration and protecting group pattern.
3.4.2 Carbohydrate Epimerization with Non-Ambident Reagents
Similar effects could be the cause leading to the complex mixture in the Lattrell-Dax
inversion. In this case, the nitrite ester would be transformed to a hydroxyl group whereas
the nitro products could lead to side reactions such as decomposition, elimination and ring
contraction. In contrast, if carbohydrate triflate intermediates react with non-ambident
nucleophilic reagents, a single product will mainly be formed, independent of any
neighboring group to the triflate group. The experiments shown in Scheme 18 supported
this point. Even though triflate intermediates of 2 and 10 lead to complex mixture with
nitrite in acetonitrile, single products 53 and 54 were obtained in near quantitative yields
with acetate. The experiments further support that it is the ambident reactivity of nitrite
that leads to a mixture of products in the Lattrell-Dax epimerization.
Ph
O
O
BnO
AcO
HO
O
OMe
OH
2
1. Tf2O, py,
CH2Cl2
2. TBAOAc, Ph
MeCN
1. Tf2O, py,
CH2Cl2
2. TBAOAc,
O
MeCN
OMe
OBn 10
OBn
O
O
BnO
AcO
OAc
O
OMe
53
OBn
O
AcO
OBn
OMe
54
Scheme 18 Carbohydrate epimerization with single reactivity reagents.
3.4.3 Nitration Products
To obtain nitro products, the triflate intermediates of compounds 2, 9, and 10 were chosen
to perform a nitrite-mediated epimerization in acetonitrile at room temperature. The
experiments were followed by 1H-NMR. Compound 2 led to a very complex mixture
(Scheme 19), but the nitro compound 56, where the nitro group is in equatorial position,
could be separated from this mixture by column chromatography, instead of the expected
nitro compound 55 where the nitro group is in the axial position. IR analysis of compound
56 indicated a strong absorption at 1550 cm-1, typical for nitro groups. Separation of
compound 57 by column chromatography, however, always resulted in a mixture of
compounds 57 and 58. Within 24 hours, compound 57 was totally converted into
compound 58, supporting the presence of compound 57 in Scheme 19.
27
Ph
O
O
BnO
O
OH
OMe
2
1. Tf2O, py
2. TBANO2,
MeCN
Ph
O
O
BnO
NO2
O
Ph
OMe
55
+
O
O
BnO
24h,
r.t.
Ph
Ph
O
O
BnO
O
O
BnO
O
OMe
ONO 59
+
1. Tf2O, py
2. TBANO2,
MeCN
OH
O
OMe
58
O
1. Tf2O, py
2. TBANO2,
MeCN
OMe
OBn
9
Ph
Ph
O
O
BnO
O
O
BnO
O2N
BnO
HO
O
OMe
OBn 63
OBn
O
BnO
OMe
OBn
8
Ph
O
OMe
56
NO2
O
OMe
NO2 56
Ph
+
OMe
OBn 60
O
O
BnO
O
O
BnO
OH
O
OMe
58
O
ONO
ONO
OBn
O
+
OMe
59
OBn
O
BnO
OBn
OMe
62
24h,
r.t.
24h,
r.t.
OBn
ONO
BnO
OMe
57
24h,
r.t.
OBn
HO
BnO
ONO
O
OBn
+
1. Tf2O, py
2. TBANO2,
MeCN
O2N
BnO
HO
OMe
OBn 61
BnO
O
OMe
OBn 61
OBn
OMe
8
OBn
OBn
O2N
BnO
OBn
O
O
+
ONO
BnO
O
OBn
OMe
63
Scheme 19. Carbohydrate nitro compounds forming from nitrite-mediate reactions.
Compound 9 also led to a complex mixture. Similar to the reaction with compound 2,
instead of the expected inversed nitro product 60, nitro product 61, where the nitro group
retains the same configuration as the triflate group, was separated from the mixture.
According to the 1H-NMR experiments, it can be seen that the expected nitro compound 60
and the nitrite compound 62 were formed immediately upon addition of nitrite to the
solution of compound 9. Then, the nitrite compound 62 was slowly cleaved to compound 8.
The nitro compound 60 also disappeared. To further explore this, the triflate intermediates
of compounds 58 and 8 were tested in the same way. The 1H-NMR spectra clearly
indicated that compound 58 lead to 41% of the expected nitro compound 56 and 59% of
nitrite compound 59, and that compound 8 led to 36% of the expected nitro compound 61
and 64% of nitrite compound 63. Both the nitrite compounds 59 and 63 were cleaved to
the related compounds 2 and 9 in 24 hours at room temperature. All these results indicated
that the compounds where the nitro group is in axial position are very unstable and
undergo a second attack by the nitrite anion to produce nitro products where the nitro
group is in the more stable equatorial position and nitrite products that are cleaved to the
starting material. That starting material 2 was also separated from the above reaction
mixture supports this conclusion. Further analyses indicated that the reaction mixture
28
produced with compound 2 includes compounds 2, 55-59 and an unknown compound
resulting from the elimination of the nitro group. A trace of nitrite compound 63 could also
be seen during the reaction of compound 9, which suggests that the nitro compound 60
should lead to nitro compound 61 and nitrite compound 63.
Further experiments were carried out to test the product distribution for the triflate
intermediate of compound 64, a side product when preparing compound 2, where the
triflate group is in the equatorial 3-position (Scheme 20). According to the 1H-NMR
analysis, 55% of nitrite compound 65, where the nitrite group is in axial position, and 45%
of nitro compound 66, where the nitro group is in equatorial position were formed. For the
triflate intermediate of compound 10, due to its low reactivity in acetonitrile at room
temperature, it proved difficult to find any nitrite- or nitro products from the 1H-NMR
spectra. However, compound 10 was also separated from this reaction suggesting a
neighboring group participation mechanism of nitro compound 67 (Scheme 20), where an
axial nitro group in 3-position was formed first, followed by a neighboring group
participation from the acetate group in 4-position.
Ph
O
O
HO
AcO
HO
1. Tf2O, py
2. TBANO2, Ph
MeCN
OMe
OBn 64
O
1. Tf2O, py
2. TBANO2,
MeCN
O
2d
OMe
OBn 10
OBn
O
OMe
65
OBn
ONO
AcO
Ph
O
O
O
O
O
O2 N
AcO
OMe
OBn
67
ONO
OBn
OBn
OMe
68
OBn
O
O
OMe
O
OMe
66
O
+
AcO
OBn
O
OBn
OBn
O
NO2
+
OBn
OBn
OMe
69
HO
Scheme 20 Nitrite-mediated epimerization with compounds 64 and 10.
3.4.4 Solvent Effect
When the triflate intermediate of compound 10 was tested in d-benzene (Scheme 21), due
to the supramolecular control effect increasing the reactivity, nitrite compound 68 could be
clearly seen before it decomposed. However, almost no nitro compounds could be
identified. This is likely due to the solvent effect mentioned above, decreasing the extent of
N-attack. This effect was also found in Binkley´s experiments.[35] As can be seen (Scheme
21), compounds 70 and 71 led to very good inversion yields in the nonpolar solvent
toluene in the nitrite-mediated epimerization reaction. These compounds should otherwise
lead to mixtures in polar solvents due to the absence of neighboring equatorial ester groups.
29
AcO
HO
1. Tf2O, py
2. TBANO2,
benzene
O
OMe
7h
OBn 10
OBn
BzO
O
HO
O
HO
BzO
1. Tf2O, py
2. TBANO2,
toluene
18h, r.t.
OMe
70
1. Tf2O, py
2. TBANO2,
toluene
2d, r.t.
OMe
71
OBn
AcO
AcO
24h, r.t.
O
O
OMe
OBn
68
ONO
OBn
OBn
OMe
69
HO
BzO
O
OMe
72 88%
HO
HO
O
OMe
73 96%
BzO
Scheme 21 Nonpolar solvents decreasing the extent of N-attack.
3.4.5 Neighboring Equatorial Ester Group Activation
During the nitrite-mediated epimerization of carbohydrates with a neighboring equatorial
ester group, neither nitro products nor nitrite products were observed when the same tests
were performed at room temperature. The inversed hydroxyl group products were always
formed in near quantitative yields. These results indicate that only O-attack occurred and
that the nitrite products were cleaved simultaneously due to the effect of the neighboring
ester group. Then the question is why the neighboring equatorial ester group can decrease
the extent of N-attack and promote the cleavage of the nitrite group.
δ
NO
ONO
ONO2
ONO2
O
O
N
O
O
ONO2
δ
H2O
OH
ONO2
ONO2
Scheme 22 A neighboring nitrate group activation mechanism.[86]
During the hydrolysis of nitrite esters, Thatcher and coworkers suggested an
intramolecular Lewis acid or charge transfer catalysis by the β-nitrate group, in which the
β-nitrate substituent assists the departure of the leaving group (Scheme 22).[86] Their
hypothesis was further supported by ab initio and semi-empirical molecular orbital
calculations, on the model compound O2NO[CH2]2O-. This model can be applied also in
the Lattrell-Dax reaction, where a neighboring equatorial ester group can play the same
role as the neighboring nitrate group, whereas a neighboring axial ester group cannot (a in
Scheme 23).
30
a)
ON δ+
O
ONO
O
O
OMe
O
R
H2O
OMe
O
R
O δ−
O
O
HO
OMe
O
R
O
b)
TfO
R
O
O
O
NO2 -
O
N
O
O
O
TfO
R
O
O
R
O
O
O
O
A
ONO
N
O
R
OTf
O
OMe
O
B
Scheme 23 A neighboring ester group assistant catalysis mechanism.
However, it is more difficult to explain how the neighboring equatorial ester group can
restrain the occurrence of N-attack. First of all, we tried to apply the HSAB theory to
understand the experimental results. With neighboring ester protecting groups, the carbon
atom carrying the triflate group becomes more positively charged and thus more hard.
With ether protecting group, this carbon atom becomes less positively charged and
behaves as more soft. The harder nitrite oxygen sites will thus be favored in attack at the
harder electrophile with ester protecting groups, and the softer nitrogen site will be favored
in attack at the softer electrophile with ether protecting groups. However, this model can
not explain why the neighboring axial ester group does not have this effect, for example, in
reactions with compound 10.
Another explanation is instead proposed in Scheme 23b. In this case, secondary
interactions between the incoming nitrite and the neighboring ester group guide the
reaction towards O-attack. A six-membered transition state is here formed and the O-attack
preference is explained due to the interaction of the nitrogen center with the ester group.
The axial ester group is in this case unable to form an efficient transition state. In principle,
the incoming nucleophile may adopt the opposite angle where the oxygen interacts with
the ester group rather than the nitrogen, and this may be more favorable following the
HSAB theory, but this pathway appears to be unproductive. Ongoing molecular orbital
calculations aim at delineating these effects. A model where the nitrite activates the
neighboring group participation, and the carbonyl oxygen acts as the nucleophile, can also
be envisaged. This model is justified from the sometimes observed rate acceleration of acyl
migration in presence of nitrite, but can be largely ruled out in this case. Contrary to acyl
migration, the reaction proceeds well with equatorial ester groups, independent of the
configuration of the triflate moiety.
3.5 Conclusions
In conclusion, it has been demonstrated that esters play highly important roles in the
Lattrell-Dax reaction, facilitating nitrite-mediated carbohydrate epimerizations. Despite the
31
higher reactivity of carbohydrate triflates protected with ether functionalities, these
compounds proved inefficient in these reactions, where mixtures of compounds caused by
the ambident reactivity of nitrite ion were rapidly obtained. Neighboring ester groups, on
the other hand, could induce the formation of inversion compounds in good yields by
restraining the occurrence of the N-attack. The reactions further demonstrated
stereospecificity, inasmuch as axially oriented neighboring ester groups were unproductive
and only equatorial ester groups induced the nitrite-mediated reaction. Equatorial esters
thus favored O-attack, restrained the occurrence of N-attack, and activated the leaving of
triflate group and the cleavage of the nitrite group. A supramolecular control effect was
also found in this Lattrell-Dax reaction. This effect also proved sensitive to the
carbohydrate structure, requiring a H1-, H3-, H5-cis pattern for efficient complexation.
These findings expand the utility of this highly useful reaction in carbohydrate synthesis as
well as for other compound classes.
32
4 Applications of the Lattrell-Dax Epimerization
4.1 Application in Synthesis of β-D-Μannosides and Talosides (Paper V)
4.1.1 Introduction
It has been demonstrated that a neighboring equatorial ester group plays a highly important
role in the Lattrell-Dax (nitrite-mediated) carbohydrate epimerization reaction, inducing
the formation of inversion compounds in good yields. These studies suggested that new,
efficient synthetic methods to complex glycosides would be feasible under the guidance of
this principle, where the activating ester groups should be able to control the inversion of
two neighboring positions simultaneously. Thus, we next attempted to meet the synthetic
challenges of β-D-mannoside synthesis.
In consequence to these synthetic challenges, several different synthetic methods have
been developed for β-mannoside synthesis. These include Koenigs-Knorr coupling
methods using insoluble silver salt promoters blocking the α-face of mannosyl halides,[8789]
sequential oxidation/reduction routes,[24, 90, 91] use of 2-oxo and 2-oximinoglycosyl
halides,[92, 93] use of intermolecular, [94-97] or intramolecular,[25, 98, 99] SN2 reactions and
intramolecular aglycone delivery method, [100-107] inversion of configuration of α-mannosyl
triflate donors,[108-110] epimerization of β-glucopyranosides to β-mannopyranosides through
SN2 reactions,[33, 51, 52, 111, 112] as well as enzymatic methods,[113-115] all of which with their
respective advantages and short-comings. The 1,2-cis-glycosidic linkage is present also in
β-D-talopyranosides. However interesting, recently evaluated for their intriguing Hbonding motifs, these structures have been less investigated in part due to their
cumbersome synthesis.[85, 116, 117] However, via the application of the Lattrell-Dax
epimerization, novel and efficient methods to synthesize β-D-mannoside and β-D-taloside
can be designed.
4.1.2 Double Parallel Inversion
The glycoside derivatives 27, 29 and 31-33, which were synthesized by the one-pot
organotin multiple esterification strategy, were chosen as starting materials (Figure 15).
HO
OBz
BzO
BzO
OH
OBz
AcO
OMe BzO
27
OH
OAc
HO
O
O
O
OMe AcO
29
OH
O
OMe AcO
31
OAc
OAc
OH
HO
OMe AcO
32
O
OH
OMe
33
Figure 15 Glycosides obtained by organotin multiple esterification.
The taloside derivatives can be acquired starting from 29 and 31 via the inversion of the 2position, or starting from 33 via the double parallel inversion of 2- and 4-positions, if the
equatorial ester group in the 3-position is able to activate the epimerization of the
neighboring 2- and 4-positions at the same time (Figure 16). On the other hand, the
33
mannoside derivatives can be acquired starting from 27 and 32 via the same double
parallel inversion strategy.
OPG
OPG
HO
O
OMe
O
R
OH
i) Tf2O, Py, CH2Cl2
HO
ii) KNO2, DMF
O
R
O
OH
O
OMe
O
Figure 16 Double parallel inversion.
In order to evaluate whether an equatorial ester group in the 3-position would be able to
activate the epimerization of the neighboring 2- and 4-positions at the same time, a series
of inversion reactions was probed (Scheme 24). Galacto- and gluco-type derivatives 27-33
where the 3- and 6-positions were protected with acetyl groups and the other two positions
left unprotected were subjected to conventional triflation by triflic anhydride followed by
treatment with tetrabutylammonium nitrite in acetonitrile or toluene at 50 oC. In
acetonitrile, when methyl 3,6-di-O-acetyl glucopyranoside 33 was used as reactant, methyl
3,6-di-O-acetyl talopyranoside 76 was obtained in 85% yield. In contrast, the double
inversion of methyl 3,6-di-O-acetyl galactopyranoside 32 was not successful and a very
complex mixture was produced. It was hypothesized that this effect is likely due to acetyl
group migration and neighboring group participation from the 3-O-acetyl group. If this
explanation would be valid, the products produced would constitute an inversed-type
mixture, that is to say, only the free methyl β-D-talopyranoside would be obtained if the
inversed mixture was not isolated but directly deprotected under basic conditions. The
experimental results showed that only one compound was obtained following deprotection
of the complex mixture, indicating that this hypothesis was indeed valid.
HO
1. py, Tf2O,
CH2Cl2, 2h
OBz
O
BzO
HO
OH
OMe
27
OAc
1. py, Tf2O,
CH2Cl2, 2h
O
AcO
OH
OMe
32
OAc
HO
AcO
HO
OMe
33
OAc
OH
HO
AcO
HO
OMe
32
OMe
74 70%
OAc
OH
O
OMe
75 76%
OAc
OH
O
OMe
76 85%
2. TBANO2,
AcO
CH3CN, 50 oC
5h
1. py, Tf2O,
CH2Cl2, 2h
O
AcO
2. TBANO2,
toluene, rt
5h
1. py, Tf2O,
CH2Cl2, 2h
O
OH
HO
2. TBANO2,
BzO
CH3CN, 50 oC
5h
OBz
OH
O
2. TBAOAc,
CH3CN, rt
5h
AcO
AcO
OAc
OAc
O
OMe
77 90%
Scheme 24 Double parallel inversion reagent and conditions.
34
It is however well known that benzoyl groups are less reactive than acetyl counterparts to
migration, as well as for neighboring group participation. In addition, neighboring group
participation is disfavored in non-polar solvents.[26, 118] Thus, in order to avoid these side
reactions, both these approaches were tested. On the one hand, reactions with methyl
glucoside 33 and methyl galactoside 32 were performed in the non-polar solvent toluene;
on the other hand, the inversion of methyl 3,6-di-O-benzoyl galactopyranoside 27 was
attempted in acetonitrile. For comparison, the triflate of methyl galactoside 32 reacting
with tetrabutylammonium acetate in acetonitrile was also tested. When methyl glucoside
33 was inversed at 50 oC in toluene, the reaction time had to be prolonged to twelve hours
to obtain product 76 in 85% yield. This result indicates, as expected, that the reactivity was
decreased in non-polar solvent. In addition, both these approaches proved successful for
the double inversion of the methyl galactosides, efficiently reducing the neighboring group
participation.
4.1.3 Double Serial Inversion
During this epimerization process, it was found that the reactivity in the 4-position was
much higher than in the 2-position. At room temperature, the epimerization reaction in the
4-position occurred instantaneously, completed within ten to twenty minutes, whereas in
the 2-position the epimerization reaction proceeded very slowly under these conditions.
This result incited us to make use of the reactivity difference between the different
positions to develop a new method, stepwise inversion of the hydroxyl groups amounting
to a double serial inversion protocol, by which carbohydrate structures where one position
is a hydroxyl group and the other positions were protected with ester groups could be
obtained (Figure 17).
HO
OPG
O
O
R
i) Tf2O, Py, CH2Cl2
ii)TBAOAc, CH3CN
OH
O
OPG
O
O
O
AcO
O
R
OMe
OTf
O
HO
R
O
AcO
O
R
OMe
OH
OMe
O
HO
OMe
O
OPG
i) Tf2O, Py, CH2Cl2
ii) TBAOAc, CH3CN
OPG
R
OH
O
O
i) Tf2O, Py, CH2Cl2
ii)TBANO2, CH3CN
OMe
OPG
i) Tf2O, Py, CH2Cl2
ii) TBANO2, CH3CN
OPG
OTf
O
OAc
O
HO
O
R
OMe
O
Figure 17 Double serial inversion.
Using the same initial step for the double serial inversion strategy, from methyl glucoside
33, the 2,4-triflate intermediates 78 could be produced via a triflation process (Scheme 25).
The 4-triflates of these intermediates were subsequently inversed to the corresponding 4O-acetyl intermediates 79 by substitution with tetrabutylammonium acetate, followed by
inversion of the 2-position by tetrabutylammonium nitrite, to yield a mixture of methyl
3,4,6-tri-O-acetyl taloside 81 and methyl 2,3,6-tri-O-acetyl taloside 82. Conversely, When
35
the 2,4-triflates of intermediates 78 were first inversed to the corresponding 4-hydroxyl
groups intermediates 80 via the use of tetrabutylammonium nitrite, directly followed by
inversion of the 2-position by tetrabutylammonium acetate, in this case, however, instead
of the formation of product 82, the compound 83 was formed in 90% yield, due to the
strong deprotonation effect of the acetate anion.
AcO
OAc
TBANO2,
CH3CN, 24h
AcO
OAc
AcO
OAc
HO
AcO
Tf2O, py,
CH2Cl2, 2h
O
OAc
TfO
AcO
OMe
OH
33
90%
O
OTf
78
OMe
90%
HO
OMe
90%
OTf
79
TBAOAc,
toluene
TBANO2,
CH3CN
OAc
AcO
TBAOAc,
CH3CN, 4h
OMe
OTf
80
OMe
45%
AcO
+
82
OMe
45%
OAc
O
90%
OAc
OAc
O
AcO
81
O
AcO
HO
OH
O
O
O
OMe
83
Scheme 25 Double serial inversion from 33.
Starting from methyl glucoside 32 the 2,4-triflate intermediate 84 could be produced as
well (Scheme 26). The 4-triflate of this intermediate was subsequently inversed to the
corresponding 4-O-acetyl intermediates 85 by substitution with tetrabutylammonium
acetate, followed by inversion of the 2-position by tetrabutylammonium nitrite, to yield
methyl 3,4,6-tri-O-acetyl mannoside 87. When the intermediates 84 were first inversed to
the corresponding 4-hydroxyl groups intermediates 86 via the use of tetrabutylammonium
nitrite, directly followed by inversion of the 2-position by two equivalents of
tetrabutylammonium acetate, methyl 2,3,6-tri-O-acetyl mannoside 88 was efficiently
produced.
OAc
AcO
AcO
HO
OAc
Tf2O, py,
CH2Cl2, 2h TfO
O
AcO
O
OMe
OH
32
OAc
AcO
O
TBANO2,
toluene, 6h
OMe
OTf
85
90%
AcO
AcO
AcO
OH
O
OMe
87
90% TBAOAc,
toluene
OMe
OTf
84
TBANO2,
90% CH3CN
OAc
HO
AcO
O
TBAOAc,
CH3CN, 6h
OMe
OTf
75%
AcO
HO
AcO
86
OAc
O
OMe
88
Scheme 26 Double serial inversion from 32.
In addition, due to the fact that methyl glucoside 17 was produced in a lower yield (70%)
than methyl galactoside 16 (90%), following the double serial inversion strategy, an
alternative, more high-yielding, synthetic route to methyl taloside could be devised starting
36
from methyl galactoside 16 instead of methyl glucoside 17. Thus, compound 32 acquired
from methyl galactoside 16 by the organotin method, could be inversed to the intermediate
78 via intermediate 84 (Scheme 27). As a result, the use of methyl glucoside 17 could be
avoided and the overall yield increased.
HO
OAc
O
AcO
OMe
OH
32
Tf2O, py,
CH2Cl2
TfO
1. TBANO2,
CH3CN, 1h
TfO
OMe
AcO
OTf
2. Tf2O, py,
84
CH2Cl2
OAc
O
AcO
OAc
O
OMe
OTf
78
Scheme 27 Alternative double serial inversion strategy to intermediate 78.
4.2 Application in Synthesis of Thio-β-D-Galactosides (Paper VI)
4.2.1 Introduction
For sulfur-containing carbohydrates, the benzyl ether group is less attractive because of
deprotection difficulties by common reduction protocols. Organic sulfur compounds are
very poisonous to metal hydrogenation catalysts, consequently hampering the
deprotection. Thus, the ester and benzylidene protecting groups remain the more
prevalently used for the synthesis of sulfur-containing carbohydrates. Selective protection
protocols can furthermore be used to generate a variety of structures by hydroxyl
epimerization strategies. The Lattrell-Dax inversion reaction is an efficient means to
generate compounds with inverse configuration, where neighboring ester groups are
important for the inversion reactivity. Consequently, the ester protecting strategy is
essential for the synthesis of sulfur-containing carbohydrates when Lattrell-Dax
epimerization protocols are employed. In addition, due to neighboring group participation
of ester functionalities in triflate-activated carbohydrates, where 5- or 6-membered
acyloxonium intermediates may form during thiolation, the solvent also plays important
roles.
4.2.2 Synthesis of Methyl 3-Thio-β-D-Galactoside
The methyl guloside derivative 36, where the hydroxyl group in the 3-position was
unprotected and the other positions were protected with acetyl groups, was essential for the
synthesis of the 3-thiogalactose derivative. Compound 36 was easily obtained by LattrellDax epimerization from the methyl galactoside derivative 3. However, treatment of 36
with triflic anhydride, and subsequent thiolation with KSAc in DMF instead afforded side
product 3, which was generated via the neighboring ester group participation followed by
hydrolysis. Our study indicated that the efficient stereoselective synthesis of 3thiogalactose derivative from the corresponding 3-OTf gulose derivatives, where ester
protecting groups were used, were highly dependent on the solvent and the nucleophile
concentration. It could be proposed that the choice of the solvent and the nucleophile
concentration controlled the product formation. Neighboring group participation could be
attenuated by performing the reactions at high nucleophile concentration in toluene.
37
Consequently, introduction of a triflate group at C-3 in 36 followed by the SN2 reaction
with 40 equiv. of TBASAc in toluene at room temperature provided the desired compound
89 (Scheme 28). With this strategy, the byproduct 3-thiogulose derivative 91 was
competitively formed in only 4 % yield. Final deprotection of compound 89 under
Zemplén conditions afforded the methyl 3-thio-β-D-galactoside 90.
AcO
OAc
py, Tf2O
CH2Cl2, 2h
O
OMe
HO
OAc
AcO
OAc
TfO
3
OAc
TBANO2, 3h AcO
50 oC, MeCN
O
OMe
O
OMe
80%
OAc
OH
OAc
36
py, Tf2O
CH2Cl2, 2h
AcO
OAc
AcO
OMe
SAc
OAc
OAc
O
O
+
AcS
91
OAc
TBASAc,
toluene, r.t.
OMe
78%
89
NaOMe,
86% MeOH,
r.t., 2h
HO
OH
OAc
AcO
O
OMe
OTf
OAc
X TBASAc,
DMF, r.t.
89
O
HS
OMe
OH
90
Scheme 28 Synthesis of methyl 3-thio-β-D-galactoside.
4.2.3 Synthesis of Methyl 4-Thio-β-D-Galactoside
In our preliminary study, the key intermediate methyl β-D-glucoside derivative 6, where
the hydroxyl group in the 4-position was unprotected and the other positions were
protected with benzoyl groups, was obtained in three steps from methyl β-D-glucoside 17
by ester group migration. A more convenient route to obtain this key intermediate was
based on an one-pot organotin-mediated multiprotection procedure starting from methyl βD-glucoside 17 (Scheme 29) or the Lattrell-Dax epimerization of methyl 4-OH galactoside
derivative 7 which can be obtained by direct benzoylation. Our initial strategy included the
introduction of a triflate at C-4 in compound 6, followed by inversion with potassium
thioacetate in DMF to yield the desired C-4 inverted compound 92. Unfortunately,
attempted thiolation of the triflate intermediate with potassium thioacetate in DMF
afforded a reaction mixture. It was assumed that the problem was also caused by
neighboring group participation from the 3- or 6-OBz group in the polar solvents. To
suppress that, thiolation of the triflate intermediate with tetrabutylammonium thioacetate in
toluene was instead used, in this case, affording the C-4 inverted compound 92.
Subsequent deprotection of galactoside 92 yielded compound 93 in good yield.
38
OH
OBz
Organotin
HO
OMe esterification BzO
OH
17
O
HO
HO
HO
O
OMe
OBz
6
OBz
Lattrell-Dax
epimerization
O
BzO
OBz
OMe
7
Tf2O, py,
CH2Cl2,
-20 - 0 oC
AcS
OBz
O
OMe
BzO
OBz
AcS
OBz
KSAc,
DMF, r.t.
92
x
TfO
BzO
OBz
TBASAc,
toluene, r.t.
O
OMe
76%
O
BzO
OBz
OBz
OMe
92
NaOMe,
MeOH, r.t.
86%
HS
OH
O
HO
OH
OMe
93
Scheme 29 Synthesis of methyl 4-thio-β-D-galactoside.
4.3 Conclusions
In conclusion, by the application of the Lattrell-Dax epimerization, novel and convenient
double parallel, and double serial inversion methods have been developed, by which
methyl β-D-mannoside, methyl β-D-taloside, have been efficiently synthesized in very high
yields at very mild conditions in few steps. By use of the reactivity difference of the
hydroxyl groups in 2- and 4-positions, a range of methyl β-D-mannoside and methyl β-Dtaloside derivatives could be easily synthesized. On the other hand, the methyl 3- and 4thio-β-D-galactosides were also conveniently synthesized by the choice of the appropriate
synthetic strategies, including the Lattrell-Dax epimerization.
39
40
5 Enhanced Basicity by Supramolecular Anion Activation
5.1 Supramolecular Activation in Cascade Inversion (Paper VII)
5.1.1 Triggered Cascade Inversion
During the double serial inversion, an unexpected behavior of the nucleophilic reagent was
found and prompted us to study these reactions further (Scheme 25). When the purified
intermediates 86 and 80 were subjected to five equivalents of tetrabutylammonium acetate
in toluene or acetonitrile, expecting to obtain methyl β-D-mannoside 88 or taloside 82,
methyl 2,3-anhydro-4,6-di-O-acetyl-β-D-mannopyranoside 94 and talopyranoside 83 were
however obtained in near quantitative yields instead (Scheme 30).
OAc
OAc
OH
O
O
OAc
HO
AcO
TBAOAc,
O
r.t. 2h
AcO
OMe toluene
OTf
86
OAc
O
H2O
OMe
O
O
OMe
94
H
OH
O
HO
OMe
OAc
AcO
95
OAc
H O
O
OAc
H2O
OMe
OH
O
AcO
OMe
96
OH
OAc
HO
AcO
OAc
TBAOAc,
O
r.t. 2h
OMe toluene
OTf
80
AcO
O
H
O
OMe
83
H O
O
OAc
AcO
AcO
OAc
OH
O
H2O
OMe
OMe
OH
97
Scheme 30 Carbohydrate cascade epimerization controlled by acetate.
With acid, the 2,3-anhydro mannoside 94 was hydrolyzed to a mixture of 3,6-di-O-acetylβ-D-altropyranoside 95 and 4,6-di-O-acetyl-β-D-altropyranoside 96, resulting from
neighboring group participation and direct hydrolysis, whereas 2,3-anhydro taloside 83
was hydrolyzed to near quantitative yield of 4,6-di-O-acetyl-β-D-idopyranoside 97
(Scheme 30). For mannoside 94, when the reaction was performed in the polar solvent
acetonitrile, the neighboring acetyl group can participate in the hydrolysis process, where
attack from the acetyl group in the 4-position on C-3 opened the epoxide ring and formed a
five-membered acetoxonium intermediate. This intermediate was subsequently opened by
water, yielding the acetyl group in the axial position as the main product. Thus a mixture
of 3,6-di-O-acetyl-β-D-altropyranoside 95 (75%) and 4,6-di-O-acetyl-β-D-altropyranoside
96 (25%) were obtained. When the reaction was performed in the non-polar solvent
toluene, direct hydrolysis and neighboring group participation occurred competitively, and
a mixture of altroside 95 (50%) and altroside 96 (50%) were obtained.
In order to evaluate how the intermediates 80 and 86 were transformed into 2,3-anhydro
taloside 83 and the 2,3-anhydro mannoside 94, 1H-NMR-analyses were carried out (a, b in
Figure 18), indicating that only starting materials and the final products co-exist in the
41
reaction mixture, and no build-up of intermediates could be recorded. These results suggest
a base-dependent cascade reaction (Scheme 31), where the acetate anion initially acts as a
base in deprotonating the 4-OH group. Then due to a dynamic acetyl group migration
between the 4- and 3-positions, the 3-position alkoxide was generated that instantly
attacked the 2-position. As results of this nucleophilic substitution, 2,3-anhydro taloside 93
and 2,3-anhydro mannoside 94 were produced. Base-promoted deprotonation being the
trigger for the reaction cascade, similar results would also be obtained if the acetate anion
is replaced with a different base. The NMR-analyses with ethylenediamine (EDA) further
proved the base-dependent mechanism (c, d, e in Figure 25), where besides the starting
materials and the final products, a large amount of intermediate accumulated.
Figure 18 Cascade reaction with 5 eq. of TBAOAc (a-b) or EDA (c-e). * and ¤ indicate
resonances from compounds 83 and 80, respectively.
HO
OAc
AcO
OMe
OTf
k-1
OAc
O
k1
O
O
OAc
AcO
k1
OMe
OTf
O
OAc
O
OMe
OTf
OTf
80
O
HO
O
O
OMe
O
k-2
AcO
Fast
O
98
k-1
Fast
k2
AcO
OAc
k3
O
O
OMe
OTf
OAc
O
O
OMe
83
Scheme 31 Proposed cascade reaction mechanism for methyl galactoside 80.
5.1.2 Anion Activation
In order to further explore why the large amount of intermediate accumulated with EDA,
more tests with compound 80 was performed (Table 7). With imidazole no reaction
occurred, but with triethylamine (TEA) the cascade reaction was also initiated. The
reaction proceeded however in this case very slowly and a lower amount of migration
intermediate 98 accumulated compare to EDA (1-4 in Table 7). However, although nitrite
42
anion alone was unable to induce the cascade reaction (entries 5 in Table 7), the
combination of nitrite or acetate with amine resulted in large rate accelerations (entries 610 in Table 7). For example, one equivalent of acetate and ten equivalents of
ethylenediamine yielded full conversion in one hour (entry 10 in Table 7). In contrast,
acetate or EDA alone resulted in only 50% conversion after eight and forty hours,
respectively (entries 4, 9 in Table 7).
Table 7 Cascade reaction of compound 80 with anionic reagents and/or amine base.
HO
OAc
AcO
O
AcO
Entry
OMe
OTf
Nu / base
Benzene, r.t.
OAc
O
O
80
Reagent (eq.)
OMe
83
Base (eq.)
Time /h
Yield /%
1
IM (50)
72
a
b
2
TEA (15)
96
a
b
3
EDA (30)
7
a
b
4
EDA (10)
40
c
5
TBANO2 (10)
120
6
TBANO2 (10)
EDA (30)
0.1
quant
EDA (10)
4
quant
7
TBANO2 (1)
8
TBAOAc (5)
2
quant
b
9
TBAOAc (1)
8
10
TBAOAc (1)
EDA (10)
1
quant
a
b
c
Intermediate 98 formed. 50% conversion. Inversion obtained.
Interestingly, the large amount of intermediate 98 that accumulated with amine alone,
rapidly disappeared when adding acetate or nitrite. This suggests that the anions are able to
activate the cascade reaction. In this case, the acetate anion acts not only as a base, but also
as an activator of the whole cascade reaction. The nitrite anion, on the other hand,
exclusively acts as a cascade activator. According to these results, it could also be
anticipated that amino acids should display strong activation abilities for the cascade
reaction, carrying both an amine and an acetate group. Indeed, this proposition proved to
be valid. Starting from compound 80, and adding only two equivalents of the TBA salt of
either α-L-alanine or β-alanine in benzene, the 2,3-anhydro product 83 was obtained in
quantitative yield within one hour (Scheme 32). Based on these results, improved triggered
cascade reactions directly starting from intermediates 78, 84 could be designed (Scheme
32), where the cascade sequence involved two inversions, migration and epoxidation. By
combination of tetrabutylammonium nitrite with EDA, the cascade reaction proceeded
smoothly and compounds 83 and 94 were produced directly in up to 90% yield. In these
cases, EDA could not attack the 4-position and only maintained a basic condition. The
nitrite ion not only triggered the entire cascade reactions by substitution and inversion of
the 4-position, but furthermore activated the cascade reaction.
43
O
O
O TBA
O TBA
H2N
NH2
A
HO
AcO
O
AcO
B
OAc
OMe
OTf
80
A or B
toluene, r.t.1h
OAc
TfO
AcO
TfO
AcO
O
TBANO2/EDA
OMe
OTf
OMe
83
OAc
O
O
OMe
toluene, r.t. 4h,
83
OAc
OAc
OMe
OTf
O
78
O
AcO
OAc
O
TBANO2/EDA
AcO
toluene, r.t. 4h,
O
O
OMe
94
84
Scheme 32 Carbohydrate cascade epimerization activated by anions.
Under mild acidic work-up conditions, compounds 83 and 94 could subsequently be
transformed to the corresponding β-D-altrosides,[119, 120] and β-D-idosides,[121, 122]
respectively, in near quantitative yields. This provides a very efficient route to these
unusual carbohydrate structures,[123, 124] accessible in high overall yields (up to 80%) in
very few steps from the parent unprotected glucosides/galactosides. The 2,3-anhydro
compounds are furthermore potentially useful building blocks for alternative carbohydrate
substitution patterns, using a variety of suitable reagents.[125-127]
5.2 Enhanced Basicity by Supramolecular Effects (VIII)
5.2.1 Supramolecular Effects of Anions and Solvents
To further explore how the anionic reagents activate the cascade reaction, a range of
anions and solvents were further explored. Thus, hydroxide, fluoride, benzoate, chloride,
bromide, nitrate, iodide, hydrogensulfate, thiocyanate as well as acetate and nitrite ions
were tested together with compound 80 in the aprotic solvents benzene, acetonitrile and
DMSO, respectively. 1H-NMR analyses indicated the formation of hydrogen bonds
between the anions or solvents and 4-OH of compound 80.
When the tests were performed in d-benzene (Figure 19), the chemical shifts of the 4-OH
proton changed from 1.8 ppm for compound 80 alone to up to 9.0 ppm for NO2-. With
AcO- and BzO-, the 4-OH resonances were indiscernible, but the downfield change in
chemical shift of the 4-H protons indicates formation of hydrogen bonds. The 4-H
resonances thus changed from 3.7 ppm (compound 80 alone) up to 4.8 ppm (NO2-, AcOand BzO-).
44
Figure 19 1H-NMR spectra of compound 80, H-bonding forms between hydroxyl group
and anions. a: with TBANO2; b: with TBACl; c: with TBABr; d: with TBASCN.
When the tests were performed in d-acetonitrile (Figure 20), it can be seen that the
chemical shifts of the 4-OH proton changed from 3.7 ppm for compound 80 alone to up to
3.8 ppm for TBAI, 4.1 ppm for TBASCN, 4.5 ppm for TBABr and 5.5 ppm for TBACl.
With NO3-, NO2- and BzO-, the 4-OH resonances were indiscernible. Similarly, the
downfield change in chemical shift of the 4-H protons also indicates formation of
hydrogen bonds. The 4-H resonances thus changed from 4.1 ppm (compound 80 alone) up
to 4.2 ppm (NO3- and NO2-) and 4.4 ppm (BzO-).
Figure 20 1H-NMR spectra of compound 80 with various anions in d-acetonitrile.
Similarly, when the tests were performed in d-DMSO (Figure 21), except for TBAOAc,
TBAF and TBAOH, all other reagents induced downfield chemical shifts of the 4-OH
proton, which changed from 5.6 ppm (compound 80 alone or with TBAI, TBASCN,
45
TBAHSO4, TBANO3 and TBABr separately) up to 5.7 ppm (with TBACl), 6.3 ppm (with
TBANO2) and 6.4 ppm (with TBAOBz).
Figure 21. 1H-NMR spectra of compound 80 with various anions in d-DMSO.
5.2.2 Basicity Controlled Cascade Reaction
Further tests were performed to explore the solvent effects of the reaction and the origin of
the anion activation for the cascade reaction. In order to analyze and compare the
reactions, compound 80 was used as starting material for the cascade reaction in dbenzene, d-acetonitrile and d-DMSO, respectively. 1H-NMR analysis was used to follow
the reaction over time. Three systems were tested in all cases: a) Anions alone were used
as base; b) Neutral amines alone were used as base; and c) Combinations of anions and
neutral amines were used as base. Using kinetic analysis, the reaction rates could be
compared, and the reaction half lives of each reaction determined.
It seems that a tentative conclusion can be obtained from Table 8; the cascade reaction was
controlled by the basicity of anions or neutral amines. It can be seen that, in all solvents,
the hydroxide, fluoride, and acetate anions showed strong basicity, and the cascade
reaction proceeded smoothly and no any migration intermediate was recorded in the entire
process (entries 1-3 in Table 8). With chloride, bromide, nitrate, hydrogensulfate,
thiocyanate and nitrite, showing low basicity, the cascade reaction could not be triggered
(entries 7-13 in Table 8). However, some unexpected results were also observed when
using EDA, TEA, acetate or benzoate alone. For example, when using EDA alone, it
seems that more polar solvents promote the cascade reaction (entry 6 in Table 8), which is
expected because more polar solvents possess stronger hydrogen bonding properties. Thus,
46
the reaction half life was 7.4 hours in benzene, 4.3 hours in acetonitrile and 1.7 hours in
DMSO, respectively. However, when using acetate, benzoate or TEA alone, although the
more polar acetonitrile promoted the cascade reaction much more than the nonpolar
benzene, the reactions were suppressed or did not occur at all in the most polar solvent
DMSO (entries 3-5 in Table 8).
Table 8 Cascade reaction half lives in the presence of anions or amines alone in various
aprotic solvents.
Entry
Reagent
(eq.)
pKa(AH+)
(DMSO)
1
TBAOH (5)
31.4
t½ (h)
(benzene)
t½ (h)
(acetonitrile)
t½ (h)
(DMSO)
< 0.1
< 0.1
< 0.1
2
TBAF (5)
15
< 0.1
< 0.1
< 0.1
3
TBAOAc (5)
12.6
22.3
0.5
0.2
1.0
4
TBAOBz (5)
11.1
20.7
5.9
3.7
-a
5
TEA (15)
9.0
18.5
78.6
39.0
-a
6
EDA (10)
-
18.46
7.4
4.3
1.7
-
7
b
TBANO2 (5)
7.5
-
-
8
b
TBACl (5)
1.8
-
-
-
9b
TBABr (5)
0.9
-
-
-
10b
TBAI (5)
-
-
-
11
TBANO3 (5)
-
-
-
12b
TBAHSO4 (5)
-
-
-
-
-
-
b
b
13
a
pKa(AH+)
(CH3CN)
TBASCN (5)
no or very slow reaction.
b
no or very slow inversion reaction.
When combining these anionic reagents with ten equivalents of ethylenediamine, the
cascade reactions were accelerated (entries 1-9 in Table 9), compared to the neutral amine
alone (entries 7 in Table 8). Furthermore, since these anions can activate the base-triggered
cascade reaction, according to the activation ability, either a very small amount of
migration intermediate or no any intermediate at all was accumulated. All the anions
showed activation abilities in relation to their hydrogen bonding tendencies, in the order F-,
OH- > OAc- > OBz-, Cl-, NO2- > Br- > NO3- > I-, SCN-. An exceptional case was the
hydrogensulfate anion. Although the hydrogensulfate anion possesses low hydrogen
bonding tendencies, it showed strong activation ability in the reaction (entry 3 in Table 9).
The reason is likely due to the formation of the non-soluble salt RNH3HSO4. Mixing
compound 80 with five equivalents of TBAHSO4 in d-acetonitrile or d-DMSO, and adding
ten equivalents of EDA, a white precipitate appeared immediately and the cascade reaction
was simultaneously completed. Unexpected results were also observed. For example, when
using combinations of anions and EDA, the anions showed the highest activation ability in
47
the nonpolar solvent benzene, which seems to indicate that polar solvents suppress the
activation ability of anions (Table 9). The anions thus showed lower activation ability in
acetonitrile and DMSO than in benzene. Although it is expected that the anions show
stronger activation ability in acetonitrile than in DMSO due to the lower polarity of
acetonitrile, the anions showed the lowest activation ability in acetonitrile. In particular,
some anions which have low hydrogen bonding tendencies, such as nitrate, iodide and
thiocyanate, totally lost their activation ability in DMSO (comparing entry 7-9 in Table 9
with entry 6 in Table 8). Although the benzoate anion displays much stronger hydrogen
bonding tendency than the nitrite anion, it only showed a comparable activation ability.
Similarly, when comparing the nitrite and the chloride anions, it can be seen (entry 4, 5 in
Table 9) that the chloride anion showed stronger activation ability in benzene and
acetonitrile, whereas it had a weaker activation ability in DMSO.
Table 9 Cascade reaction half lives in the presence of combinations of anions and EDA in
aprotic solvents.
Entry
Reagent
(eq.)
t½ (h)
(benzene)
t½ (h)
(acetonitrile)
t½ (h)
(DMSO)
1
TBAOAc (5)
< 0.1
< 0.1
0.4
2
TBAOBz (5)
0.5
1.5
0.7
3
TBAHSO4 (5)
-
< 0.1
< 0.1
4
TBANO2 (5)
0.5
1.8
0.7
5
TBACl (5)
0.4
1.3
1.2
6
TBABr (5)
1.0
3.1
1.5
7a
TBANO3 (5)
-
3.4
1.7
8a
TBAI (5)
-
3.9
1.7
TBASCN (5)
1.5
3.9
1.7
9
a
a
The migration intermediate 98 were recorded in these NMR spectra.
5.2.3 Enhanced Basicity by Supramolecular Effects
These results indicate anion-assisted deprotonation through hydrogen bonding as a
rationale for the activation effect.[128] Reactions with amine base alone led to accumulation
of the migration product intermediate 98, but when the anionic reagent is present from the
start, or added after build-up of the intermediate, this is rapidly consumed and the 2,3anhydro product formed. The kinetic analysis indicates that the cascade reaction is mainly
controlled by basicity and the rate of the deprotonation. Fast deprotonation and medium
basicity led to a large amount of intermediate and a medium reaction rate, such as EDA.
Slow deprotonation and medium basicity lead to trace amounts of intermediate and a slow
reaction rate, such as TEA. Strong basicity led to no accumulation of intermediate and a
fast reaction rate, such as acetate. Too slow deprotonation and weak basicity could not
48
trigger this cascade reaction, such as imidazole and nitrite. Thus, how the anions can
activate the cascade reaction is likely to be due to either increasing the rate of the
deprotonation or the enhancing the basicity.
OAc
O
R1
O
S
H
S
OMe
AcO
OTf
CA
S
OAc
A
R2 N H
R3
CB
OMe
AcO
b
R1
OTf
CS
A
H
A
H
S
A
R3
CC
R1
H
O
H
or
or
A or R1R2R3N
S
H
A
N R2
R3
c
a
O
R1
R2 N H
or
R2
O
OAc
e
O
OTf
CN
S
CD
d
R1
R2 N H
A: Anions; S: Solvent
A
R3
OMe
AcO
R1 N R3
R2 N H
S
or
R3
CB
Figure 22 Enhanced deprotonation through supramolecular interaction.
It is clear that a hydrogen bond complex CS is formed between compound 80 and the
solvents. With amines or anions alone, a new hydrogen bond complex CN is competitively
formed between compound 80 and the amines or anions (Figure 22). These two complexes
will be further attacked by solvents or amines (or anions), leading to the deprotonation of
compound 80 and two homoconjugate complexes CA and CC as well as a heteroconjugate
complex CB by approaches a, b, c and d (usually by approaches c and d).[129, 130] For EDA
and TEA, the heteroconjugate complex CB is relative stable due to the lower steric
congestion compared to the homoconjugate complex CC. Especially for EDA, a more
stable complex CB can be formed, due to three possible hydrogen bonds. If the complex
CC is enough stable, such as with fluoride, benzoate, or acetate (likely forming a
[RCOO….H….OOR]- complex), these anions can activate the deprotonation process.
Support for this conclusion was also seen when one equivalent of acetate was used in the
reaction, resulting in final 50% conversion. On the other hand, with nitrite and the other
anions alone, the hydrogen bond complex is weaker, and the possible [A….H….A]- complex
is equally weak. As a result, deprotonation is less efficient. Since the more polar solvents
lead to more stable complexes CB, the more polar solvents will promote the cascade
reaction. However, the more polar solvents also lead to more stable complexes CS, which
result in fewer complexes CN due to competition. Consequently, in the polar solvent
DMSO, only very low amounts of the complex CN will be formed, and the deprotonation
process will be hampered for pathways c and d. As a result, the reactions were much
suppressed or did not occur at all in DMSO.
Dramatic rate enhancements were furthermore recorded with combinations of anions and
amines. In analogy with the formation of [RCOO….H….OOR]-, this effect suggests possible
complex formation between the amine and the anion [RNH2….H….A], leading to more
efficient formation of product 83, and no accumulation of intermediate 98. In the nonpolar
49
solvent benzene, the hydrogen bond complex CN is the major species due to the very weak
interaction between compound 80 and benzene (Figure 22). After addition of EDA,
complex CN was deprotonated following pathway e to form complex CD. Thus, the
cascade reaction rates will mainly depend on the stability of complex CD. In acetonitrile
and DMSO, the lower degree of complex CN formed leads to a decrease in the
deprotonation rate, and the stable complexes CA and CB formed lead to enhanced
basicity. Overall, the reaction was usually more suppressed in acetonitrile than in DMSO.
However, when the anion is acetate, due to its very strong hydrogen bonding tendency, the
hydrogen bonding effect caused by acetonitrile can be omitted, and, thus, only DMSO
suppress the proton transfer process (entry 1 in Table 9). In spite of the fact that the
benzoate anion shows much stronger hydrogen bonding tendency than the nitrite anion, the
steric effect reduces the deprotonation rate compare to nitrite, and, as a result, benzoate
anion shows almost the same activation ability as nitrite in all the solvents (entry 2, 4 in
Table 9). Similarly, although the nitrite anion displays stronger hydrogen bonding
tendency than chloride anion, the steric effect also reduces its deprotonation rate compared
to chloride, and, as a result, the nitrite anion shows weaker activation ability than the
chloride anion in benzene and acetonitrile (entry 4, 5 in Table 9). In DMSO, for both the
nitrite and the chloride ions, the solvent from the CS complex cannot be displaced. If the
pathway b (Figure 22) is the main deprotonation process, there will be no steric effect from
nitrite anion, and the hydrogen bonding tendency of the anions will govern the reaction so
that nitrite anion shows stronger activation ability than the chloride anion in DMSO.
Especially, since the solvent DMSO shows almost the same hydrogen bonding effect as
iodide, thiocyanate and nitrate, comparing the lower amount of ions with the large quantity
of DMSO, five equivalents of these anions are inefficient in DMSO, and, as a result, they
do not show any activation ability.
5.3 Conclusions
In conclusion, a convenient and highly efficient method for multiple carbohydrate
epimerization through triggered cascade reactions has been introduced. It was found that
reactions that normally involve many steps could be completed in one step in quantitative
yields. An intriguing activation effect was furthermore discovered, where combinations of
anionic reagents and amines resulted in dramatic rate enhancements. The mechanism by
which the anionic reagents activate the cascade reaction was initially explored, suggesting
a supramolecular process emanating from the enhanced deprotonation due to plausible
amine-anion complexation. The solvents also show important effects on this reaction due
to the supramolecular interactions between the solvents and the solutes.
50
6 General Conclusions
The effects of the neighboring group in the Lattrell-Dax epimerization have been explored.
During this research, a new carbohydrate/anion host-guest system was discovered and the
ambident reactivity of nitrite anion was found to cause a complicated behavior of the
reaction. Based on this effect, efficient synthetic routes to β-D-mannosides, β-D-talosides,
β-D-altrosides, and β-D-idosides from the corresponding β-D-galactosides and β-Dglucosides, have been designed. The supramolecular effect in these reactions was also
explored.
•
•
•
•
•
It has been demonstrated that a neighboring ester group is essential for the
reactivity of the Lattrell-Dax nitrite-mediated triflate inversion. Furthermore, a
good inversion yield also depended on the relative configuration of the
neighboring ester group to the triflate. Only with the ester group in the equatorial
position, whatever the configuration of the triflate, did the reaction proceed
smoothly, whereas a neighboring axial ester group proved largely inefficient.
A new carbohydrate/anion host-guest system has been discovered in the LattrellDax epimerization. This host-guest system exerts pronounced effects in the
nitrite–mediated inversion. The interaction between pyranosides and nitrite thus
resulted in dramatic rate control in the inversion reaction, leading to either
activation or deactivation effects.
It has been demonstrated that the origin of the importance of the neighboring
equatorial ester group in the Lattrell-Dax epimerization is its restriction of the
nitrite N-attack, thus resulting in O-attack only.
Based on the efficient multiple carbohydrate esterifications and the Lattrell-Dax
carbohydrate epimerization, novel and convenient double parallel- and double
serial inversion methods have been developed, by which methyl β-D-mannosides
and methyl β-D-talosides have been efficiently synthesized in very high yields at
very mild conditions in few steps. The results also indicate that an ester group
can, either in parallel or serially, induce its two neighboring groups in the
epimerization reaction.
A supramolecularly activated, triggered cascade reaction was developed. This
cascade reaction is triggered by a deprotonation process that is activated by
anions. It was found that the anions can activate this reaction following their
hydrogen bonding tendencies to the hydroxyl group in aprotic solvents.
51
52
Acknowledgements
I would like to express my sincere gratitude to:
My supervisor Olof Ramström for accepting me as a PhD-student, for sharing your vast
knowledge in chemistry, for your inspiring guidance and for your patience whenever I
want to discuss with you.
Prof. Tobias Rein, Prof. Krister Zetterberg for taking time and efforts of proof-reading my
licentiate and doctor thesis. Prof. Torbjörn Norin, Prof. Mingdi Yan for constructive
discussion in my licentiate defense.
My co-authors: Prof. Tore Brinck, Dr. Zhichao Pei, Dr. Styrbjörn Byström, Martin,
Marcus, Remi and Lingquan “Vince”.
My colleagues/friends in the Ramström group: A special thanks to Zhichao and Rikard for
helping me during my early time at the department. Marcus, Pornrapee “Jom” Vongvilai,
Remi, Gunnar, Oscar, Morakot, Lingquan and Dr. Luis for constructive criticism and
comments on this thesis, for being good friends, for pleasant times in the lab and for
spreading a nice atmosphere throughout the group, and all past and present group-members.
Prof. Christina Moberg, Prof. Peter Somfai, Prof. Torbjörn Norin, Prof. Licheng Sun, Prof.
Anna-Karin Borg Karlson, Dr. Zoltan Szabo for interesting graduate courses.
Dr. Ulla Jacobsson and Dr. Zoltan Szabo for support with the NMR instruments.
Lena Skowron, Ilona Mozsi, Henry Challis, Ingvor Larsson, Ann Ekqvist for all kinds of
help.
Everyone at the chemistry deparment for a friendly and pleasant working atmosphere.
All former and present colleagues at KTH for your friendship.
The Aulin-Erdtman foundation, Knut och Alice Wallenbergs Stiftelse, and Ragnar och
Astrid Signeuls for conferences and traveling support.
The Swedish Research Council (VR), the Swedish Foundation for International
Cooperation in Research and Higher Education, the Carl Trygger Foundation, for financial
support.
My children Emilia, Dongdong and my wife Ailing for their love and support during all
these years.
My parents and sister for their endless support and encouragement.
53
Appendix
The following is a description of my contributions to papers I-VIII.
Paper I:
I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
Paper II:
I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
Paper III:
I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript, excluding the computational
chemistry section.
Paper IV:
I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
Paper V:
I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
Paper VI:
I contributed to the formulation of the research problems and performed
some of the experimental work.
Paper VII:
I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
Paper VIII: I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
54
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