CALIFORNIA STATE UNIVERSITY, NORTHRIDGE
TOTAL SYNTHESIS OF THE ANTITUMOR NATURAL PRODUCT
POLYCARCIN V
A thesis submitted in partial fulfillment of the requirements
For the degree of Master of Science in Chemistry
By
Xiao Cai
May 2014
The thesis of Xiao Cai is approved:
Dr. Yann Schrodi
Date
Dr. Simon J. Garrett
Date
Dr. Thomas G. Minehan, Chair
Date
California State University, Northridge
ii
ACKNOWLEDGEMENT
I would like to express the deepest appreciation to my research advisor, Dr. Thomas
G. Minehan, who has the attitude and the substance of a genius: he continually and
convincingly conveyed a spirit of an adventure in regard to science. Without his
guidance and persistent help this thesis would not have been possible.
I would like to thank my other committee members, Dr. Yann Schrodi and Dr. Simon
J. Garrett, who have provided valuable suggestions on this thesis.
In addition, a thank you to my parents for all the support and understanding they have
given to me. Without them, none of these accomplishments would have become true.
iii
DEDICATION
I would like to dedicate my thesis to my fiancée Judy R. Salandanan.
iv
Table of Contents
Signature Page
ii
Acknowledgement
iii
Dedication
iv
List of Schemes
viii
List of Figures
ix
Abstract
xi
Chapter 1: Introduction
1
1.1 Background
1
1.2 Methods for the Synthesis of C-aryl Glycosides
5
1.2.1 Activation of the Anomeric Carbon Followed by the Addition of an
Aromatic Nucleophile
5
1.2.2 C-Glycosylation Through O!C-Glycosides Rearrangement
7
1.2.3 Addition of an Anomeric Carbanion to an Electrophilic Aromatic
Equivalent
8
1.2.4 Transition Metal Mediated C-glycosylation
Chapter 2: Progress towards Total Synthesis of Polycarcin V
9
10
2.1 Retrosynthetic Analysis of Polycarcin V
10
2.2 Synthesis of L-Rhamnosyl Diacetate
12
2.2.1 Overview
12 2.2.2 Regioselective Acetonide Protection of the Syn C.2 and C.3 Hydroxyl
Groups
14
v
2.2.3 Regioselective Benzylation on C.3 Hydroxide
15
2.3 C-glycosylation of Naphthalene 8
17
2.4 Preparation of C-glycoside 9 to Naphthol 14
19
2.4.1 Overview
19
2.4.2 Two Different Pathways toward Formation of 5-(benzyloxy)-4methoxynaphthalen-1-ol
22
2.4.3 Unfruitful Temporary Silyl Protection Reaction
24
2.4.4 Proposed Mechanism of the Formation of Aldehyde 10
26
2.4.5 proposed Mechanism of the Formation of Naphthol 11
27
2.5 Preparation of Iodoarenecarboxylic Acid 22
2.5.1 Overview
28
28
2.5.2 Proposed Mechanism of Palladium-catalyzed Cross Coupling with
Allyltributyltin
30
2.5.3 Proposed Mechanism of Osmium-catalyzed Formation of Diol
Intermediate
31 2.5.4 Proposed Mechanism of the Formation of Aldehyde Intermediate with
KIO4
32
2.5.5 The Likely Mechanism of Forming Undesired Benzoic Aldehyde from
KIO4 Reaction
33
2.6 Completion of the Synthesis of Polycarcin V
34
2.6.1 Overview
34
2.6.2 Mechanism of Intra-molecular Heck Reaction
36
2.6.3 Model Study on Grieco’s Elimination
38
2.6.4 Grieco Elimination towards the Formation of Tetraacetate Polycarcin V
39
vi
Chapter 3: DNA Study and Conclusion
40
Chapter 4: Experimental Procedures
42
References
77
Appendix 1H and 13C NMR Spectra
80
vii
List of Schemes
Scheme 1 Synthesis of Rhamnosyl Diacetate 7
13
Scheme 2 C-glycosylation of Naphthalene 8
18
Scheme 3 Preparation of Naphthol 14
21
Scheme 4(a) Formation of 5-(benzyloxy)-4-methoxynaphthalen-1-ol from Juglone
22 Scheme
4(b)
Formation
of
5-(benzyloxy)-4-methoxynaphthalen-1-ol
from
Dibenzylnaphthalene
23
Scheme 5 Unfruitful Trials Using TIPSCl on the Diol System
25
Scheme 6 Preparation of Iodoarenecarboxylic Acid 22
29
Scheme 7 Completion of the Synthesis Polycarcin V
35
viii
List of Figures
Figure 1.1.1 Structures of Gilvocarcins V (2), M (3), and E (4)
2
Figure 1.1.2 Light-activated Interaction between Gilvocarcin V and Thymine Residue
from DNA with Exclusive Sterochemistry
3
Figure 1.1.3 Structure of Polycarcin V
4
Figure 1.2.1 Glycosylation through Electrophilic Glycosyl Donors
6
Figure 1.2.2 O!C Glycoside Rearrangement
7
Figure 1.2.3 Addition of an Anomeric Carbonion to an Electrophilic Aromatic
Equivalent
8
Figure 1.2.4 Formation of C-aryl Glycal through Cross-coupling
9
Figure 2.1 Retrosynthetic Analysis of Polycarcin V
11
Figure 2.2.1 Regioselective Acetonide Protection on the Syn C.2 and C.3 Hydroxyl
Groups
14
Figure 2.2.2 Regioselective Benzylation of the C.3 Hydroxyl Group
16
Figure 2.4.1 Resonance Contribution from C.1 Benzyloxy Ether and C.2 Hydroxyl
Group
20
Figure 2.4.2 Proposed Mechanism of the Formation of Aldehyde 10
26
Figure 2.4.3 Proposed Mechanism of the Formation of Naphthol 11
27
Figure 2.5.1 Mechanism of Palladium-catalyzed Cross-coupling with Allyltributyltin
30
Figure 2.5.2 Osmium-catalyzed Oxidation of Alkene 17.
31
Figure 2.5.3 Proposed Mechanism of the Formation of Aldehyde Intermediate with
KIO4
32
Figure 2.5.4 Proposed Mechanism of the Observed Undesired Side Product from
KIO4 Reaction
33
ix
Figure 2.6.1 Mechanism of Intramolecular Heck Arylation
37
Figure 2.6.2 Test Study on Grieco’s Elimination Reaction
38
Figure 2.6.3 Formation of Tetraacetate Polycarcin V
39
Figure 3.1 Phenol Derivative of Polycarcin
41
x
ABSTRACT
TOTAL SYNTHESIS OF THE ANTITUMOR NATURAL PRODUCT
POLYCARCIN V
By
Xiao Cai
Master of Science in Chemistry
Polycarcin V is a member of the gilvocarcin family that is naturally produced from
Streptomyces polyformus. It has shown to have selective cytotoxicity to non-smallcell lung cancer, breast cancer, and melanoma cells. In order to analyze the interaction
of this natural substance and its other family members with sequential specificity to
duplex DNA, we undertook the convergent total synthesis of Polycarcin V in 4.6%
overall yield from three major fragments of suitably protected rhamnosyl diacetate,
aromatic naphthol and regioselectively iodinated carboxylic acid; the synthesis also
demonstrates a stereoselective α-C-glycosylation reaction for the assembly of the
structurally unique rhamnose sugar and the selectively methylated aromatic naphthol.
xi
Chapter 1: Introduction
1.1 Background
The gilvocarcin family is a series of C-aryl glycoside natural products (Figure 1.1.1)1
that has been shown to exhibit high antitumor biological activity with low overall
toxicity. Gilvocarcin V, the most studied of the gilvocarcin family, involves
intercalation of the aromatic chromophore into the DNA double helix. This
intercalation is known to occur through a UV-induced covalent linkage between the
vinyl moiety on the natural product and a thymine residue on duplex DNA via a
[2+2]-cycloaddition reaction (Figure 1.1.2).3 Light-activated Gilvocarcin V is also
able to selectively crosslink DNA and the phosphorylated form of histone H3 and
GRP78, a heat shock protein.4 Intriguingly, gilvocarcin M and E, which bear different
aliphatic moieties instead of a vinyl substituent at C.8 on the chromophore, do not
present cytotoxicity.5
1
OH
O
O
8 R1
O
HO
HO
OMe
OH
OMe
gilvocarcin V (2) R1=CHCH2
gilvocarcin M (3) R1=CH3
gilvocarcin E (4) R1=CH2CH3
Figure 1.1.1 Structures of gilvocarcins V (2), M (3), and E (4).
Both Waring6 and McGee7 have previously studied that a carbohydrate attached to an
intercalating chromophore contributes strongly and positively when binding with
DNA double helix. Their studies on the interaction of C-aryl glycoside natural
products with DNA also have shown that the carbohydrate moieties typically reside in
the minor grooves in the bound structure. This is a known place where non-covalent
interactions between functional groups on the carbohydrate and residues in the minor
groove are presented.8 It has been hypothesized that these carbohydrate-DNA noncovalent contacts may be responsible for the binding-site sequence selectivity of the
C-aryl glycosides.9 Furthermore, cell-type specificity, potency, transport and
pharmacokinetics may also be relevant to the type of the sugar substituent of C-aryl
glycosides.10
2
H
O
Me
HO
HO
O
Thymine
Me
O
O
N
NH
H
O
OH
O
OH
O
Figure 1.1.2 Light-activated interaction between Gilvocarcin V and thymine residue
from DNA with exclusive sterochemistry.
Polycarcin V (Figure 1.1.3) is a recently discovered gilvocarcin-type natural product
isolated from a culture extract of Streptomyces polyformus sp. nov. (YIM 33176).11
This substance is co-produced with Gilvocarcin V. However, instead of a β−Dfucofuranose moiety, it exhibits a α−L-rhamonopyranose substituent. Rhamnose is
one of a few rare sugars that naturally occur in an “L” form. Furthermore, most
natural C-aryl glycosides favor a β form of C-aryl linkage while Polycarcin V stands
as a α-C-aryl glycoside. The rare “α” C-aryl linkage, together with the rare “L” sugar,
has been one of the interests on natural product synthesis in our research group.
More importantly, Polycarcin V also shows significant selective cytotoxicity to a nonsmall-cell lung cancer (LXF 1211 L and LXFL 529 L, IC70 < 0.3 ng/mL and 0.3
3
ng/mL), breast cancer (MCF7, MDAMB231, MDAMB 468, IC70 from < 0.3 ng/mL
to 4 ng/mL), and melanoma cells (MEXF 462NL, MEXF 514L, MEXF 520L, IC70
from < 0.3 ng/mL to 0.4 ng/mL). With the goal to compare biological activity of
Polycarcin V, such as DNA binding affinity and sequence specificity, with other
known gilvocarcins, we determined to carry out the total synthesis of this natural
product.
HO
OH
HO
O
H3C
O
O
OMe
OH
OMe
polycarcin V (1)
Figure 1.1.3 Structure of Polycarcin V.
4
1.2 Methods for the Synthesis of C-aryl Glycosides
For the past few decades, coupling of different natural sugars and a variety of
structurally specific aromatic chromophores has been a major issue in assembly of
various natural C-aryl glycosides. Overall, there are two essential parameters: the
control of the stereochemistry at the anomeric carbon (C.1 on the sugar) and the
control of the allocation of the sugar to the aromatic system, the combination of which
gives rise to the fundamental challenge of the synthesis of C-aryl glycosides. Most of
the syntheses of C-aryl glycosides involve a direct usage of inexpensive natural
sugars, which can directly facilitate the incorporation of chiral centers into target
molecules. In this thesis, some modern methods of the direct use of natural
carbohydrates have been reviewed.
1.2.1 Activation of the Anomeric Carbon Followed by the Addition of an Aromatic
Nucleophile
The presence of a suitable Lewis acid is a key to generate an electrophilic anomeric
carbon on a glycosyl donor that may be readily coupled with electron rich aromatic
nucleophiles.12,13 Multiple types of electrophilic glycosyl donors in the presence of a
variety of Lewis acids have been used in the preparation of different C-glycosides.14,15
For instance (Figure 1.2.1), commonly, a C.1 ester is equipped before the Lewis acidmediated activation on the sugar partner. Due to the sensitivity of Lewis acid to
moisture, most of the coupling reactions are performed under dry conditions. The use
of an acetate group at the C.2 position ensures the aromatic coupling substrate attacks
5
only in the β-position.14 The equatorial C.2 acetate group coordinates to the
oxocarbenium ion in the axial position, blocking the addition of the nucleophile in the
α-position, which results in an exclusively stereoselective β-glycosylation.
O
Ar
n(RO)
M
O
n(RO)
Ar
Glycosyl Acceptor
Glycosyl Donor
Retrosynthetic Cut
BnO
BnO
BnO
O
BnO
BnO
O
R
Entry
Lewis Acid
+
O
O
R
BnO
OBn
OBn
2:1 CH2Cl2: THF
0 oC
O
O
BnO
BnO
O
OBn
O
OBn
R
Lewis Acid (equiv.)
R
% Yield
1
TMSOTf (10)
(CH3)3C
55
2
TESOTf (10)
(CH3)3C
50
3
BF3. OEt2 (10)
(CH3)3C
<5
4
TMSOTf (5)
(CH3)2CH
65
5
SnCl4 (5)
(CH3)2CH
45
InCl3 (5)
(CH3)2CH
<5
Et2AlCl (5)
(CH3)2CH
<5
6
7
Figure 1.2.1 Glycosylation through electrophilic glycosyl donors.
6
1.2.2 C-Glycosylation Through O!C-Glycosides Rearrangement
This type of method usually involves a C-O temporary connection followed by an
O!C rearrangement.16,17,18,19 Suzuki et al. developed a route for the regio- and
stereoselective synthesis of ortho-substituted α/β-C-aryl glycosides. In this method,
the Lewis acid mediated the formation of an aryl O-glycoside followed by its in situ
conversion to a C-glycoside. The α/β selectivity was controlled during rearrangement
and was highly dependent on the temperature and the use of Lewis acid. For instance,
the Lewis acid Cp2HfCl2-AgClO4 promoted the formation of the kinetically favored
α-O-glycoside at low temperature but the thermodynamically stable β-C-glycoside
anomer at higher temperature.
OH
Step 1
Promoter
O
+
n(RO)
R
O
n(RO)
O
-78 oC- 0 oC
F
R
O
Step 2
O
n(RO)
R
n(RO)
O-C
Rearrangement
OH
+
OH
R
α
Figure 1.2.2 O!C Glycoside rearrangement.
7
β
1.2.3 Addition of an Anomeric Carbanion to an Electrophilic Aromatic Equivalent
As opposed to the method discussed in 1.2.1, in this study the glycoside attacks the
electrophilic aromatic chromophore as a nucleophile. This is usually carried out by
the addition of a nucleophilic glycal to an electrophilic aromatic quinone ketal.12,13
For instance, Parker et al. developed a method for the synthesis of C-aryl glycals as
potential intermediates for the synthesis of C-aryl glycosides. The lithiated glycal
gave rise to the addition to an electrophilic aromatic species followed by Lewis acid
mediated reductive aromatization.
O
OTBS
OTBS
OTBS
O
O
Reverse
Polarity
+
ZnCl2
Rearrangement
HO
HO
O
Li
OTBS
OTBS
H3CO
OCH3
OTBS
OCH3
OCH3
OCH3
OTBS
OH
O
OH
OTBS
Hydroboration
Oxidation
1,2-Trans
Glycosidic Linkage
α-D-manno
OCH3
Figure 1.2.3 Addition of an anomeric carbonion to an electrophilic aromatic
equivalent.
8
1.2.4 Transition Metal Mediated C-glycosylation
Transition metal catalyzed C-C bond formation has been well established over the
decades. Using different types of metals catalysts, such as palladium, to carry out the
coupling between a glycal and an aromatic species has been successful in a crosscoupling fashion. In this study, depending on the places of substitution of the metal
and halogen, both glycal and aromatic chromophore can play a role of either
electrophile or nucleophile in coupling. Figure 1.2.4 shows that the glycal is adding as
a nucleophile to the aromatic ring. Next, the resulting C-aryl glycal can be further
adjusted to produce 2-Deoxy C-aryl glycoside or C-aryl glycoside via hydrogenation
or hydroboration,20 respectively.
RO
RO
M
O
RO
RO
O
Pd Catalyst RO
+
RO
I
R
R=TIPS
R=TIPS
ArM
C-Aryl Glycal
Entry
1
Solvent/Temp/Time
R
PhB(OH)2
R
%Yield
THF, Na2CO3 / 75oC / 1.5 h
81
2
4-CNC6H4B(OMe)2
THF, Na2CO3 / 70oC / 15 h
90
3
4-MeOC6H4B(OH)2
THF, Na2CO3 / 75oC / 40 min
81
4
1-NaphthylB(OH)2
THF, Na2CO3 / 75oC / 1.5 h
75
5
4-MeOC6H4BZnCl
THF / rt / 15 min
73
Figure 1.2.4 Formation of C-aryl glycal through cross-coupling.
9
Chapter 2: Progress towards Total Synthesis of Polycarcin V
2.1 Retrosynthetic Analysis of Polycarcin V (Figure 2.1)
As mentioned, Suzuki type O!C rearrangement21 glycosidation favors formation of
β-C-aryl glycoside, thermodynamically, while α-C-aryl glycoside mainly occurs at
low temperature. Our research group discovered that the direct C-C bond with
α linkage between the aromatic chromophore and rhamnose sugar of Polycarcin V
could be furnished by a Lewis acid-mediated Friedel Crafts-type glycosylation22
between 1,8-dibenzyloxynaphthalene and a suitably protected rhamnosyl diacetate at
room temperature. Standard formylation and oxidation on the ortho-directing
glycoside followed by sequential oxidation-reduction through a quinone aromatic
system would give rise to corresponding diol glycosylated chromophore.
Furthermore, selective hydroxyl group protection would then provide a naphthol
glycoside that is capable of undergoing carbodiimide-mediated coupling with a
correlatively protected iodoarene carboxylic acid. The iodoarene carboxylic acid
fragment can be prepared from a commercially available compound, 3,5dihydroxybenzoic acid. By following the precedent of Suzuki23 palladium-catalyzed
intramolecular arylation, Lewis acid-catalyzed deprotection of ethyl acetal protecting
group and selenide-transitioned elimination would then lead to the natural product.
10
HO
HO
H 3C
AcO
OH
AcO
H 3C
O
O
OAc
OH
O
O
O
O
OMe
OH
OMe
OMe
OAc OMe
polycarcin V (1)
BnO
BnO
BnO
H 3C
BnO
H 3C
OAc
O
O
OH
I
OAc
O
O
O
O
O
OBn OMe
OBn OMe
OEt
OBn
O
BnO
+
OBn
OMe
OMe
HO
+
BnO
H 3C
I
OAc
HO
2
O 1
OH
OH
OAc
Figure 2.1 Retrosynthetic analysis of Polycarcin V.
11
OEt
2.2 Synthesis of L-rhamnosyl Diacetate
2.2.1 Overview
For the preparation of acetate 7 (Scheme 1), L-rhamnose was first treated with allyl
alcohol under acidic condition (cat. H2SO4, 85°C, 3h)24 to provide the corresponding
allyl sugar, which then underwent regioselective acetonide protection of the syn C.2
and C.3 hydroxyl groups (DMP, cat. pTsOH, DMF) to furnish 5 with 90% overall
yield. Benzylation of the C.4 hydroxyl group and acetonide deprotection utilizing
BiCl3 in CH3N and water25 then gave rise to 16 in 95% yield. Diol 16 was then
regioselectively benzylated according to Hanessian’s method.26 Standard acylation of
the C.2 hydroxyl and acetolysis of the allyl rhamnose under acidic conditions were
performed to provide corresponding diacetate 7 (70% yield from 6), the carbohydrate
substrate for glycosylation.
12
H3C
O
HO
OH
OH
1. allyl alcohol
cat. H2SO4,
85oC,#3h
2. CH3C(OCH3)2CH3
cat. TsOH, DMF
90%
H3C
O
HO
O
5
OH
O
95%
H3C
O
BnO
O
OAc
OAc
1. Bu2SnO, toluene
reflux, 2h; BnBr
TBAI, 65oC,#16h
2. Ac2O, pyr, DMAP
3. AcOH, Ac2O,
cat. H2SO4
H3C
1. NaH, BnBr, TBAI
DMF
2. cat. BiCl3, CH3CN
H2O
O
BnO
O
OH
OBn
OH
7
6
Scheme 1 Synthesis of rhamnosyl diacetate 7.
13
2.2.2 Regioselective Acetonide Protection of the Syn C.2 and C.3 Hydroxyl Groups
Our research group tested that the syn C.2 and C.3 hydroxyl groups could provide a
regioselective acetonide protection in high yield. In both ring conformations, the
protection on the trans C.3 and C.4 hydroxyl groups would not occur due to the long
distance and the ring restriction between the two trans hydroxyl groups (Figure 2.2.1).
Furthermore, the protection of C.2 and C.3 hydroxyl groups would also assist to lock
the preferred chair conformation of the sugar, which prevented the optimal sugar ring
from flipping.
Too Far
Crowded
OH
CH3 OH
OH
HO
Ring Flip
HO
O
O
O
O
DMP
cat TsOH, DMF
Favored
O
O
HO
O
O
OH
Not
Favored
DMP
cat TsOH
DMF
DMP
cat TsOH
DMF
OH
O
No Rxn
O
O
O
Figure 2.2.1 Regioselective acetonide protection on the syn C.2 and C.3 hydroxyl
groups.
14
2.2.3 Regioselective Benzylation on C.3 Hydroxide
The regioselective benzylation of the C.3 hydroxyl group was accomplished utilizing
the dibutyltin oxide method,26 in which Hanessian demonstrated that regioselective
alkylation always occurs on the more nucleophilic hydroxyl group. After the tin acetal
intermediate was formed (Figure 2.2.2), the addition of t-butyl ammonium iodide
(TBAI) gave rise to a pentavalent iodo tin acetal intermediate. The high energy of tin
oxygen bond along with its pentavalent coordination resulted in the Sn-O bond
breakage, which was open with an alkoxide ready to attack benzyl bromide. The fact
that the equatorial C.3 hydroxyl group bore less steric hindrance than axial C.2
hydroxyl group gave rise to the greater nucleophilicity of C.3 hydroxide.
15
nBu
nBu
I
nBu
Sn O
Sn O
O
O
BnO
H3C
OH
HO
BnO
H3C
nBu
Sn O
Bu2SnO, toluene
reflux, 2h
O
O
nBu
O
BnO
H3C
nBu
I
BnO
H3C
O
O
O
O
BnBr,
TBAI
65oC,#16h
O
O
nBu
nBu
I
nBu
Sn O
I
nBu
Sn O
O
O
BnO
H3C
BnO
H3C
O
O
O
O
I
nBu
OH
BnO
BnO
H3C
aq. NaHCO3
O
O
BnO
BnO
H3C
nBu
Sn O
O
Figure 2.2.2 Regioselective benzylation of the C.3 hydroxyl group.
16
O
2.3 C-glycosylation of Naphthalene 8
Benzylation protection of the commercially available 1,8-dihydroxy-naphthalene was
accomplished under standard basic conditions (K2CO3, acetone, BnBr, 65oC) to
provide the aromatic coupling partner 8.27a,b The treatment of compounds 7 and 8 in
CH2Cl2 (0.5 M) with 1.5 equivalents of TMSOTf at room temperature for 30 minutes
furnished coupled C-glycoside 9 cleanly in 65% yield with >95:5 α:β
stereoselectivity. No β stereoisomer was observed on the NMR spectrum. (see NMR
spectroscopy of 9 on page 93).22 It was first experimentally determined that the
presence of C.2 acetate was necessary to enable the cleavage of the carbohydrate C.1
acetate upon addition of Lewis acid (Scheme 1). Moreover, anchimeric participation
by the C.2 acetate group may also explain the accessibility of this α-type Cglycosylation. The axial C.2 acetate likely prohibits the incoming aromatic
nucleophile from approaching the C.1 equatorial (β) position by donating its electron
pair on the carbonyl oxygen atom to the anomeric carbon cation.27c
17
OH
K2CO3
BnBr
OBn
8
OBn
1.5 equiv
TMSOTf
rt
65%
7
BnO
O
BnO
H3C
O
O
O
OBn
9
CH3
CH3
BnO
O
BnO
H3C
O
OBn
7, CH2Cl2
acetone
91%
OH
BnO
OAc
BnO
H3C
O
α
CH3
O
9
X
8
OTMS
Scheme 2 C-glycosylation of naphthalene 8.
18
2.4 Preparation of C-glycoside 9 to Naphthol 14
2.4.1 Overview
The synthesis of C-aryl glycoside 9 toward Polycarcin V commenced with
formylation on the naphthalene ring under Vilsmeier conditions.28 After some
experimentation, it was found that stirring 9 with 10 equivalents of POCl3 and DMF
in toluene under refluxing condition for 6 hours gave aldehyde 10 in 70% yield.
Baeyer-Villiger oxidation of 10 under acidic conditions (H2O2, cat. H2SO4, THF,
MeOH)29 then provided phenol 11 quantitatively. Exposing 11 to ceric ammonium
nitrate and sodium dithionite in a two-step oxidation-reduction sequence then
provided diol 12 in 86% yield. At this point, attempts to selectively methylate the less
hindered C.2 hydroxyl group utilizing standard methylating methods produced
inseparable mixtures of mono- and dimethylated products. The decomposition of 12
when in contact with base led us to perform the deprotonation of the phenolic
hydroxyl groups at low temperature with a suitable base (NaHMDS) in the presence
of the electrophilic methylating agent (NaHMDS, Me2SO4, THF, -78 °C - 0 °C).
Intriguingly, analysis of 1H NMR data indicated that the major monomethylated
product possessed the methyl group on the C.5 hydroxyl, which bore greater steric
hindrance. This result, together with model studies on naphthyl systems without the
carbohydrate moiety, revealed that the more sterically hindered hydroxyl at C.5 is in
fact more reactive toward methylation under basic conditions than the less hindered
C.2 phenolic hydroxyl group, likely due to the resonance contributions from the C.1
benzyloxy ether (Figure 2.4.1), which resulted a more nucleophilic phenolic
hydroxide site regardless of the presence of the sugar moiety.30 It was ultimately
19
experimentally determined that temporary protection of the more sterically hindered
C.5 hydroxyl with the slightly bulkier chloromethyl ethyl ether (NaHMDS, THF, 78°C) provided the corresponding C.5 acetal 13 in 90% yield (see more supporting
model test experimentation in next two sections). Subsequent methylation (Me2SO4,
THF, NaHMDS, -78°C) of the C.2 hydroxyl and deprotection of the C.5 acetal
(catalytic HCl in methanol) provided the desired naphthol coupling substrate 14 in
73% overall yield from 12.
OBn
OBn
BnO
BnO
O
O
AcO
OH
AcO
OH
5
1
2
OBn
OH
OBn
12
OH
Resonance Contribution from C.1
Benzyloxy Ether
OBn
OBn
BnO
BnO
O
O
AcO
OH
AcO
OH
5
1
2
OBn
OH
OBn
12
OH
Resonance Contribution from C.2
Hydroxyl Group
Figure 2.4.1 Resonance contribution from C.1 benzyloxy ether and C.2 hydroxyl
group.
20
BnO
OAc
BnO
H3C
O
BnO
OAc
BnO
H 3C
O
OBn
POCl3, DMF
toluene, reflux
H2O2, THF
MeOH, H2SO4
6h
92%
OBn
9
OBn CHO
70%
OBn OH
10
11
BnO
OAc
BnO
H3C
O
1. CAN, CH3CN,
H2O
2. Na2S2O4, H2O
1
85%
OH
5
2
OBn OH
BnO
BnO
H 3C
O
11
OAc
OMe
NaHMDS,
MeOTf
THF,
-78°C-0°C
~40-50%
OBn OR
R=H +
R=Me
12
BnO
BnO
H 3C
O
BnO
OAc
BnO
H3C
O
NaHMDS,
Me2SO4, THF
-78°C
OAc EtO
O
O
Cl
NaHMDS, THF
OR
12
-78°C
90%
OBn OMe
OBn OH
13
cat. HCl,
MeOH
Scheme 3 Preparation of naphthol 14.
21
14a R=CH2OEt
14b R=H
91% from 13
2.4.2
Two
Different
Pathways
toward
Formation
of
5-(benzyloxy)-4-
methoxynaphthalen-1-ol
We examined the procedure towards target naphthol 14 (without the sugar moiety)
from dibenzylnaphthalene system using juglone as a different starting material and
both led us to the same corresponding naphthol product. On this test system, an
uncommon NMR spectrum of the diol intermediate presented only one phenolic
hydroxyl proton signal when using chloroform-D as the solvent but two respective
ones when using acetone-D, likely due to solubility issue. This supported our
conclusion discussed earlier on the real system and provided the ability to exclusively
distinguish the EOM protection and methylation on the two corresponding phenolic
hydroxyl groups on the diol intermediate.
O
O
Ag2O, BnBr
aq. Na2S2O4
1:3
DCM: Diethyl Ether
CH2Cl2
OH
O
OBn
O
OTIPS
Juglone
OH
OBn
OTIPS
K2CO3
MeI
Acetone
reflux
TIPSCl
Imidazole
DCM
OBn
OH
OH
TBAF
THF
OH
OBn
O
OBn
O
Scheme 4(a) Formation of 5-(benzyloxy)-4-methoxynaphthalen-1-ol from juglone.
22
OBn
OBn
OBn
POCl3
DMF
OBn
aq. CAN
MeCN
OBn
O
OBn
H2O2
THF, MeOH
cat. H2SO4
OBn
H
O
OH
OH
Matched
O
OBn
O
Scheme 4(b) Formation of 5-(benzyloxy)-4-methoxynaphthalen-1-ol from
dibenzylnaphthalene.
23
2.4.3 Unfruitful Temporary Silyl Protection Reaction
Regioselective silylation on the diol system using a standard method (TIPSCl,
Imidazole, DCM) was not accomplished in scheme 5. We hypothesized that the
neighboring sugar gave significant steric hindrance, which inhibited the addition of
the silyl group and successively resulted in decomposition of the diol compound
before silylation occurred.
The silyl protecting group was regioselectively equipped on the more hindered side
when using NaHMDS with TIPSCl in THF at -78oC. Nevertheless, the next
methylation on the less hindered hydroxyl group was unfruitful. The dimethyl
compound was found, likely due to the self-cleavage of the silyl ether under basic
condition followed by methylation in the presence of excess Me2SO4. This study
indicated that the stability of the temporary protecting group under basic condition
was crucial, from which we concluded that the usage of the EOM, an ethyl acetal and
base friendly protecting group, would assist us to achieve target naphthol.
24
BnO
OAc
BnO
H3C
O
OH
TIPSCl
Imidazole
DCM
Overnight
OBn
BnO BnO
H3C
No Reaction!
OH
BnO BnO
H3C
OAc
O
BnO BnO
H3C
OAc
O
O
NaHMDS
THF
Me2SO4
-78oC-r.t
NaHMDS
THF, -78oC
TIPSCl
OH
O
TIPS
OH
OBn
OAc
OBn
OBn
OH
O
Silyl Group Fell Off!
Scheme 5 Unfruitful trials using TIPSCl on the diol system.
25
2.4.4 Proposed Mechanism of the Formation of Aldehyde 10
Formylation of the ortho position on the aromatic ring of C-aryl glycoside 9 did not
occur due to the steric hindrance by the neighboring benzyl protecting group, which
also prohibited the second formylation after the first aldehyde group was installed.
The inaccessibility of the second formylation on the naphthalene core could also be
reasoned from the deactivation of the nucleophilicity-decreased ring system after the
addition of an aldehyde electron-withdrawing group.
O
P
Cl
O
O
Cl
Cl
P
P
Cl
O
Cl
H
Cl
Cl
H
Cl
N
Cl
N
N
N
Cl
O
O
Cl
H
N
H
OBn
H
-H+
N
O
H
-ClH2O
OBn
H
OBn
H
N
O
H
O
OBn
-H+
-Me2NH
OBn
OBn
Figure 2.4.2 Proposed mechanism of the formation of aldehyde 10.
26
2.4.5 proposed Mechanism of the Formation of Naphthol 11
Utilizing the Baeyer-Villiger oxidation method afforded the corresponding formate
intermediate, which was sequentially hydrolyzed to form naphtol 11 and formic acid
as a byproduct.
OBn
OBn
OBn
OBn
-H2O
-H+
H
O
H
H-O-O-H
O
H+
O
H
H
O
H
O
O
H
H
H
O
H
O
H
O
Formate Intermediate
OBn
OBn
OBn
-HCOOH
H
-H+
H
O
O
H
H
H
O
H+
O
O
H
OH
Naphthol 11
O
H
Figure 2.4.3 Proposed mechanism of the formation of naphthol 11.
27
2.5 Preparation of Iodoarenecarboxylic Acid 22
2.5.1 Overview
The iodoarene carboxylic acid coupling substrate was prepared from 3,5dihydroxybenzoic acid 15. With control of the reagent, methylation of 15 with
dimethyl sulfate (2.2 equiv) and excess K2CO3 in DMF afforded a methyl ester 16 in
75% yield.31 Next, triflation on a single phenolic hydroxyl group (Tf2O, Pyr),
followed by palladium-catalyzed cross coupling with allyltributyltin provided alkene
17 in 60% overall yield. Oxidative cleavage of the olefin was then performed in two
steps (OsO4, acetone, t-BuOH, NMO; KIO4, acetone, pH 6.5 buffer) to furnish an
intermediate aldehyde, which was immediately reduced by NaBH4 in methanol to
give rise to the primary alcohol 18 in 62% yield. Standard protection of the alcohol
with chloromethyl ethyl ether then afforded the acetal 19 in 90% yield.
In order to perform the introduction of the iodine atom by directed ortho metallation32
(nBuLi, ether, 0oC), the reduction of the methyl ester to the primary alcohol was
required. The reduction of the methyl ester was fashioned by exposing 19 to LiAlH4
in ether at room temperature to obtain 20 in 95% yield. Intermediate 20, bearing a
primary alcohol, was believed to direct lithiation at ortho position. Followed by
standard lithium-halogen exchange, the aromatic system was converted to target
iodoarene. Fusion of 20 with 4 equivalents of n-BuLi in ether for 3 hours at room
temperature, followed by quenching with I2 in THF furnished a 65% yield of iodide
21. Finally, standard sequential two-step oxidation of 21 with PCC (PCC, DCM,
28
KOAc) and NaClO2 (NaClO2, NaH2PO4, H2O, t-BuOH) gave rise to the target
carboxylic acid 22 in 80% yield.
O
O
OH
HO
3 eq K2CO3
OH
H3CO
2.2 eq Me2SO4
DMF
OH
OCH3
75%
15
16
1. Tf2O, Pyr.
2. Bu3SnCH2CHCH2
PdCl2(dppf), DMF, Δ
60%
O
O
OR
H3CO
OCH3
EtOCH2Cl,
DIEA, CH2Cl2
90%
18 R=H
19 R=CH2OEt
1. OsO4, acetone
NMO, H2O
H3CO
2. KIO4, acetone,
pH=6.5
3. NaBH4,MeOH
62%
OCH3
17
LiAlH4, ether
95%
OCH2OEt
OCH2OEt
1. n-BuLi, ether
HO
OCH3
20
HO
I
2. I2, THF
OCH3
65%
21
1. PCC, CH2Cl2, KOAc
2. NaClO2, NaH2PO4
t-BuOH, H2O
80%
OCH2OEt
O
HO
I
OCH3
22
Scheme 6 Preparation of iodoarenecarboxylic acid 22.
29
2.5.2
Proposed
Mechanism
of
Palladium-catalyzed
Cross-coupling
with
Allyltributyltin
The introduction of allyl group on the triflate aromatic ring involved a palladiumcatalyzed cross coupling mechanism. The triflate group, a pseudo-halide, is a greater
leaving group than most halides.
O
O
OTf
Pd(PPh3)2Cl2
+
2 Allytributyltin
O
O
Heat
O
O
Oxidative
Addition
Pd0(PPh3)2
Reductive
Elimination
O
L
O
II
Pd
O
II
L
Pd
O
L
L
O
O
OTf
nBu
nBu
Sn
nBu
trans-cis
isomerization
Transmetaltion
L
O
II
Pd
O
nBu
L
nBu
Sn
nBu
OTf
O
Figure 2.5.1 Mechanism of palladium-catalyzed cross coupling with allyltributyltin.
30
2.5.3 Proposed Mechanism of Osmium-catalyzed Formation of Diol Intermediate
Treatment of 17 with OsO4 water solution in acetone and t-butyl alcohol provided a
diol intermediate. The catalytic OsO4 was regenerated in a cycle with a quantitative
amount of N-Methylmorpholine N-oxide.
O
O
O
O
OH
O
O
O
O
O
O
Os O
VI
OH
H2O
O
O
17
Diol
Intermediate
O
O
O
Os
O
VIII
VI Os
O
O
O
O
Me
N
O
Me
N
O
Figure 2.5.2 Osmium-catalyzed oxidation of alkene 17.
31
2.5.4 Proposed Mechanism of the Formation of Aldehyde Intermediate with KIO4
Followed by oxidation with KIO4 in an acetone and pH 6.5 buffer solution, the diol
intermediate was converted to the desired aldehyde intermediate successfully.
OH
R
IO4-
OH
O
HO
R
Diol
Intermediate
I
O
OH
O
O
-H2O
H
O
+
O
R
+
H
IO3-
H
Aldehyde
Intermediate
Figure 2.5.3 Proposed mechanism of the formation of aldehyde intermediate with
KIO4.
32
2.5.5 The Likely Mechanism of Forming Undesired Benzoic Aldehyde from KIO4
Reaction
Complete removal of residual OsO4 in the previous step was required through silica
gel chromatography as undesired benzoic aldehyde product was obtained from the
enolated form of the aldehyde intermediate (Figure 2.5.4).
H
H
acid or base catalyzed
H
OH
O
R
R
OsO4
NMO
HO
O
H
H
KIO4
HO
R
OH
R
Undesired
Benzoic Aldehyde
Figure 2.5.4 Proposed mechanism of the observed undesired side product from KIO4
reaction.
33
2.6 Completion of the Synthesis of Polycarcin V
2.6.1 Overview
A DCM solution of naphthol 14 and carboxylic acid 22 was stirred overnight with the
treatment of EDC, a carbodiimide species, to produce corresponding ester 23 in 71%
yield. Next subsequent intramolecular Heck arylation in the presence of PPh3PdCl2
and KOAc in DMA gave rise to cyclized lactone 24a in 58% overall yield. Cleavage
of the benzyl ether protecting groups was smoothly accomplished by exposing 24a to
catalytic quantities of Pearlman’s catalyst in THF/MeOH under hydrogen atmosphere;
standard acylation (Ac2O, pyr, DMAP) then provided the tetraacetate 24b. Cleavage
of the EOM ether protecting group under Lewis acidic conditions (TMSBr, CH2Cl2, 78°C!-10°C)23 provided the corresponding primary alcohol 25; dehydration was
then accomplished under Grieco’s conditions (2-NO2C6H4SeCN, PBu3, THF; H2O2)33
to afford alkene 26. It was found that 26 is identical in its NMR spectroscopic
properties to a sample of Polycarcin V tetraacetate prepared by acylation (Ac2O, Pyr)
of the isolated natural product (see NMR spectroscopy for comparison of spectra on
P. 88-89). Ultimately, Polycarcin V tetraacetate was deacylated (cat. KCN, MeOH) to
provide natural product Polycarcin V 1 as a yellow amorphous powder, which was
also shown to be labile with exposure to light and high concentration; dimerization
likely happened due to the existence of the vinyl moiety.
34
BnO
EDC, CH2Cl2
DMAP
OAc
BnO
H 3C
OCH2OEt
O
O
O
I
14 + 22
71%
OCH3
OBn OMe
23
RO
cat. Pd(PPh 3)2Cl2
DMA, KOAc
23
OAc
OR'
O
RO
H 3C
O
O
120°C
58%
OCH3
OR
1. H 2, cat. Pd(OH) 2
2. Ac2O, Pyr, DMAP
24a R=Bn, R'=CH 2OEt
3. TMSBr, CH2Cl2
25 R=Ac, R'=OH, 91%
RO
PBu 3, THF, rt,
2-NO2-PhSeCN;
H 2O2
OMe
RO
H 3C
24b R=Ac, R'=CH 2OEt, 66%
OAc
O
O
O
25
81%
OCH3
OR
NaCN,
MeOH
OMe
26 R=Ac
1 R=H, 78%
Scheme 7 Completion of the synthesis Polycarcin V.
35
2.6.2 Mechanism of Intra-molecular Heck Reaction
The intra-molecular arylation was carried out according to Suzuki’s method utilizing
PPh3PdCl2 and KOAc in DMA. At a high temperature, a palladium(II) catalyst was
first reduced to palladium(0) by removing chlorine gas, which was then added to the
reacting iodine aromatic starting material in oxidative addition fashion. Electron
resonance triggered by the benzyl ether protecting group gave rise to the new C-Pd
bond formation followed by the cleavage of iodide from the palladium catalyst, which
then underwent re-aromatization in the presence of potassium acetate. Final reductive
elimination provided the target cyclized molecule and regenerated palladium catalyst
in a reactive oxidation state.
36
O
O
O
O
I
Product
Starting Material
PdII(PPh3)2Cl2
Reductive Elimination
Oxidative
Addition
Heat
Cl2
Pd0(PPh3)2
O
O
O
O
II
II
Pd Ln
Pd Ln
I
-HOAc
O
-I
O
II
Pd Ln
H
OAc
Figure 2.6.1 Mechanism of intramolecular Heck arylation.
37
2.6.3 Model Study on Grieco’s Elimination
Grieco’s elimination was first tested on the aromatic primary alcohol model shown in
Figure 2.6.3. The reaction was successful providing a nearly quantitative yield of
alkene product in a sequential two-step fashion.
Reaction
O
O
OH
O
o-nitrophenylselenocyanate
H
Se
O
H2O2
tributylphosphine
THF
NO2
O
O
O
O
H
O
O
Se
O
Retro-Hetero-Ene
Elimination
NO2
O
O
95% Yield
Proposed Mechanism of Formation of Selenide
Bu
CN
Bu
Se
No2
Bu
P
NO2
CN
P
Bu
Bu
P
Bu
Se
Bu
Bu
R
H
Bu
Se
Bu
Ar
Brown Salt
R
O
R
Se
+
CN
O2N
OH
Bu
P
Bu
+ HCN
Figure 2.6.2 Test study on Grieco’s elimination reaction.
38
O
2.6.4 Grieco Elimination towards the Formation of Tetraacetate Polycarcin V
With the experience from the previous model study, the elimination towards the
formation of tetraacetate Polycarcin V was partially fruitful. Within the first step
towards the production of selenide intermediate, complete removal of the brown
cyanide salts was performed via vacuum filtration. It was found that the stability of
the compound was significantly impacted upon the introduction of a vinyl residue.
Compound intended to dimerize either under light or concentrated to dryness. It was
found that the NMR spectrum of tetraacetate Polycarcin V matched with acylated
sample prepared from the naturally isolated product obtained by Dr. Ishida and Dr.
Hertweck (original group who isolated natural product Polycarcin V).
NC
AcO
OAc
AcO
Se
O
O
OAc
AcO
AcO
H3C
O
H3C
OH
O
O
Se
O
O2N
Bu
OMe
OAc
O2N
Bu
P
OMe
Bu
OMe
OAc
OMe
H2O2
AcO
OAc
AcO
O
AcO
H3C
OAc
AcO
O
H
O
H3C
O
O
O
Se
O
O2N
OMe
OAc
OMe
OMe
OAc
OMe
Figure 2.6.3 Formation of tetraacetate Polycarcin V.
39
Chapter 3: DNA Study and Conclusion
The binding of natural product Polycarcin V (1) to duplex DNA was studied using
fluorescence and UV spectroscopies. With increasing concentrations of calf thymus
(CT) DNA in the dark (avoid being constantly exposed to light), the excitation of 1
(0.5 mM in 10 mM Tris-EDTA buffer) at 380 nm demonstrated an enhancement of
the fluorescence emission intensity at 470 nm; the addition of CT DNA to 1 also
presented a blue shift in the fluorescence spectrum of 1. This observation is consistent
with previously reported results for both Gilvocarcin V and M.5,34 Analysis of the
fluorescence data by non-linear regression based on the crucial treatment of McGhee
and von Hippel35 demonstrated the association constant Ka=1.7 (±0.1) x106 M-1, a
value which is similar to those reported for Gilvocarcin V by Arce et al. (1.1 x 106 M1 5
) and Gasparro et al. (6.6 x 105 M-1).25 Furthermore, thermal denaturation studies
were performed to test binding affinity. The results of the studies demonstrated a
significant (+3 °C) shift in the TM (64 °C) of salmon testes DNA in the presence of 1,
even at low 1:DNA ratios (0.05).36 These data indicated that Polycarcin V associates
with DNA double helix via a strong non-covalent interaction in the dark and
confirmed that the mode of intercalation of 1 with duplex DNA is likely similar to
that of Gilvocarcin V. Future studies will be directed to focus on examining the DNA
sequence selectivity of Polycarcin V.
In conclusion, the total synthesis of the antitumor α-C-aryl glycoside natural product
Polycarcin V was accomplished in 4.6% overall yield from L-rhamnosyl diacetate
carbohydrate 7, naphthol 8, and iodoarene carboxylic acid 22. This synthetic pathway
can be easily altered to the synthesis of its other derivatives that bear similar
40
carbohydrate moieties and/or C.8 aryl substituents. Due to the light-sensitivity of 1,
future goal will shift towards the synthesis of the C.8 phenyl derivative of polycarcin
(Figure 3.1), which we hypothesize may extend its strong DNA binding ability
without the possibility of forming covalent adducts with DNA and proteins.
HO
OH
HO
O
H3C
O
O
OMe
OH
OMe
Figure 3.1 Phenol derivative of Polycarcin.
41
Chapter 4: Experimental Procedures
General Methods. Distilled water was used in all of the experiments. Organic
extracts were dried over Na2SO4, filtered, and concentrated using a rotary evaporator
at aspirator pressure (20-30mmHg). Chromatography refers to flash chromatography
and was carried out on SiO2 (silica gel 60, 230-400 mesh). 1H and 13C NMR spectra
were measured in CDCl3 at 400 MHz or 600MHz and 100 MHz or 150MHz,
respectively, using Me4Si as internal standard. Chemical shifts are reported in ppm
downfield (d) from Me4Si.
42
H 3C
O
O
HO
O
O
5
A solution of L-rhamnose (8 g, 48.7 mmol) and allyl alcohol (88 mL, 0.55 M) was
treated with 5 drops of sulfuric acid and stirred at 85°C for 3 hrs. The reaction was
then neutralized with 12 M NH4OH and diluted in toluene. The solution was
concentrated in vacuo. The crude allyl glycoside was dissolved in 2,2dimethoxypropane (29.8 mL, 244 mmol, 5 eq). To this solution p-TsOH (14 mg, 3.9
mmol, 0.08 eq) was added and the reaction was stirred for 10 min at room
temperature. The mixture was diluted with CH2Cl2 and quenched with saturated
sodium bicarbonate solution (10 mL). The organic layer was washed with brine (10
mL) and dried over anhydrous Na2SO4. After filtration the solvent was concentrated
in vacuo to furnish a crude oil. Purification by silica gel chromatography (10:1 ! 4:1
hexanes: ethyl acetate) afforded acetal 5 (10.7 g, 44 mmol, 90% yield).
43
See spectra on page 81
1
H NMR: (400 MHz, CDCl3)
5.97-5.87 (m, 1H); 5.32 (d, J=16.0 Hz, 1H); 5.23 (d, J=16.1 Hz, 1H);
5.04 (s, 1H); 4.24-4.17 (m, 2H); 4.11 (t, J=12.2 Hz, 1H); 4.05-3.99
(ddd, J=1.3, 8.8, 14.8 Hz, 1H); 3.74-3.66 (m, 1H); 3.45-3.44 (m, 1H);
2.50 (br s, 1H); 1.54 (s, 3H); 1.37 (s, 3H), 1.31 (d, J= 8.2 Hz, 3H)
13
C NMR: (100 MHz, CDCl3)
133.6; 117.8; 109.5; 96.3; 78.4; 77.3; 77.0; 76.7; 75.8; 74.5; 68.0;
66.0; 28.0; 26.1; 17.5.
HRMS (ESI): calculated for C12H20NaO5: 267.1208; found (M+Na)+: 267.1260
44
H 3C
O
O
BnO
OH
OH
6
Compound 5 (5 g, 20.5 mmol) was dissolved in DMF (77.3 mL, 0.26 M) and NaH
(2.64 g, 66 mmol, 3.2 eq) and imidazole (150 mg, 2.2 mmol, 0.09 eq) were added at
0°C. The mixture was stirred for 15 min at room temperature. BnBr (3.5 mL, 29
mmol, 1.45 eq) and TBAI (0.8 g, 0.1 eq) were then added to the reaction mixture. The
reaction was stirred for 14 hours at room temperature. The reaction was placed in an
ice bath and quenched with saturated sodium bicarbonate solution (30 mL); then ethyl
acetate (30 mL) was added. The phases were separated and the organic phase was
washed with brine. The organic phase was dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The crude product was purified by silica gel
chromatography (99:1 ! 20:1 hexanes: ethyl acetate) to furnish a yellow oil. The
benzylated allyl glycoside (6.2 g, 18.5 mmol) was then dissolved in MeCN (18.5 mL,
~1M) and a spatula tip (20 mg) of BiCl3 was added, followed by 20 drops of water.
The reaction was stirred for 14 hours at room temperature. The mixture was quenched
with saturated sodium bicarbonate solution (10 mL) and EtOAc (10 mL) was added.
The phases were separated and the organic extracts were washed with brine and dried
over Na2SO4. The organic layer was filtered and concentrated in vacuo to provide a
crude oil. Diol 6 (4.8 g, 16.3 mmol, 80% yield) was obtained after purification by
silica gel chromatography (10:1 ! 3:1 hexanes: ethyl acetate).
45
See spectra on page 82
1
H NMR: (400 MHz, CDCl3)
7.43-7.42 (m, 5H); 5.96-5.86 (m, 1H); 5.32 (dd, J=2.0, 16.0 Hz, 1H);
5.21 (dd, J=2.8, 12.1 Hz, 1H); 4.91 (d, J=15.0 Hz, 1H); 4.84 (s, 1H);
4.69 (d, J=12.0 Hz, 1H); 4.22-4.15 (m, 2H); 4.05-3.95 (m, 3H); 3.843.78 (m, 2H); 3.47 (t, J=9.6 Hz, 1H); 1.39 (d, J=6.2 Hz, 3H)
13
C NMR: (100 MHz, CDCl3)
138.5; 133.9; 128.5; 128.0; 127.8; 117.3; 98.9; 81.6; 77.7; 77.4; 77.1;
75.0; 71.7; 71.3; 68.0; 67.5; 18.0.
HRMS (ESI): calculated for C16H22NaO5: 317.1365; found (M+Na)+: 317.1423
46
H 3C
O
BnO
OAc
OAc
OBn
7
Compound 6 (4.4 g, 15.1 mmol) was dissolved in toluene (15.1 mL, 1.0 M) and
treated with Bu2SnO (4.1 g, 16.4 mmol, 1.1eq). The mixture was refluxed at 110 °C
for 2 hrs. After the reaction was cooled to 65 °C, BnBr (2 mL, 16.8 mmol, 1.1eq.) and
TBAI (6.14 g, 16.6 mmol 1.1eq.) were added to the solution. The reaction mixture
was then stirred for 14 hrs at 65 °C. Saturated sodium bicarbonate solution (10 mL)
was added, and after the reaction was cooled in an ice bath, the solids were vacuum
filtered and washed with EtOAc (20 mL). The filtrate phases were separated and the
organic layer was washed with brine and dried over anhydrous Na2SO4. The organic
phase was filtered and concentrated in vacuo to afford a crude oil. The product was
purified by silica gel column chromatography (10:1 ! 6:1 hexanes: ethyl acetate) to
afford the 3,4-di-O-benzyl allyl glycoside (5.3 g, 13.8 mmol), which was dissolved in
acetic anhydride (5 mL) and pyridine (5 mL). After a catalytic amount of DMAP (20
mg) was added, the mixture was stirred at room temperature for five hours and
concentrated in vacuo.
The crude acetate ester was dissolved in acetic anhydride (42 mL), and acetic acid (14
mL) and 12M H2SO4 (0.1 mL) were added and the mixture was stirred for 1 hr. The
reaction mixture was diluted with diethyl ether (50 mL) and carefully quenched with
saturated sodium bicarbonate solution (10 mL). The organic layer was washed with
saturated sodium bicarbonate solution and brine and dried over anhydrous Na2SO4.
The organic layer was filtered and concentrated in vacuo to afford a crude oil.
47
Purification by silica gel chromatography (99:1 ! 10:1 hexanes: ethyl acetate)
afforded 7 (4.1g, 10.6 mmol 70% overall yield).
See spectra on page 83
1
H NMR: (400 MHz, CDCl3)
7.40-7.31 (m, 10H); 6.08 (d, J= 2.0 Hz, 1H); 5.43 (q, J=1.6 Hz, 1H);
4.91 (d, J=10.7 Hz, 1H); 4.79 (d, J=11.2 Hz, 1H); 4.68 (d, J=10.7 Hz,
1H); 4.61 (d, J=11.1 Hz, 1H); 3.99 (dd, J=3.3, 12.0 Hz, 1H); 3.91-3.84
(m, 1H); 3.55 (t, J= 9.5 Hz); 2.21 (s, 3H); 2.12 (s, 3H); 1.40 (d, J=6.2
Hz, 3H)
13
C NMR: (100 MHz, CDCl3)
170.0; 168.5; 138.3; 138.0; 128.5; 128.4; 128.1; 128.0; 127.9; 127.8;
91.2; 79.5; 77.7; 77.6; 77.3; 77.0; 75.6; 71.2; 70.1; 67.9; 20.9; 20.8;
18.1
HRMS (ESI): calculated for C24H28NaO7: 451.1733; found (M+Na)+: 451.1785
48
BnO
OAc
BnO
H 3C
O
OBn
OBn 9
Acetate sugar 7 (1 g, 2.3 mmol) was combined with 1,5-dibenzyloxynaphthalene 8
(2.4 g, 6.9 mmol, 3 eq) and the mixture was dissolved in anhydrous CH2Cl2 (33.7 mL,
0.07 M). The solution was stirred under argon for 2 hrs with 4.4 g of 4 Å molecular
sieves. To this solution TMSOTf (1.27 mL, 6.9 mmol, 3 eq) was added dropwise.
After 5 min of stirring, TLC indicated complete consumption of 7. The reaction was
then quenched with saturated sodium bicarbonate (10 mL). The solids were filtered
and the product was extracted with CH2Cl2 (2x50 mL), and the combined organic
layers were dried over Na2SO4. The solvent was filtered and concentrated in vacuo to
give a crude oil. Purification by flash chromatography (99:1 ! 8:1 hexanes: ethyl
acetate) afforded 9 (1.1 g, 1.62 mmol, 70% yield).
49
See spectra on page 84
1
H NMR: (400 MHz, CDCl3)
8.12 (d, J=9.3 Hz, 1H); 7.75 (d, J=8.3 Hz, 1H); 7.58-7.22 (m, 16H);
7.06 (d, J=7.1 Hz, 1H); 6.93 (d, J=8.4 Hz, 1H); 6.03 (s, 1H); 5.82 (d,
J=4.3 Hz, 1H); 5.32-5.16 (m, 4H); 4.93 (d, J=11.3 Hz, 1H); 4.65 (d,
J=11.3 Hz, 1H); 4.47(d, J=11.0 Hz, 1H); 4.03 (d, J=11.0 Hz, 1H);
3.50-3.41 (m, 2H); 2.99 (dd, J=3.4, 6.7 Hz, 1H); 1.85 (s, 3H); 1.47 (d,
J=5.6 Hz, 3H)
13
C NMR: (100 MHz, CDCl3)
170.0; 155.5; 153.7; 139.2; 138.4; 137.2; 136.3; 129.1; 129.0; 128.6;
128.4; 128.3; 128.0; 127.9; 127.9; 127.6; 127.5; 127.4; 127.4; 126.3;
125.5; 124.7; 123.5; 116.0; 107.8; 105.1; 81.7; 80.3; 77.4; 77.1; 76.7;
76.3; 75.5; 74.7; 71.1; 71.1; 70.3; 70.2; 20.8; 18.6
HRMS (ESI): calculated for C46H44NaO7: 731.2985; found (M+Na)+: 731.2937
[a]25D:
-75.6° (c 0.018, CH2Cl2)
50
BnO
OAc
BnO
H 3C
O
OBn
OBn CHO
10
C-glycoside 9 (6.8 g, 10.0 mmol) was dissolved in toluene (10.0 mL, 1M) and treated
with DMF (7.7 mL, 100 mmol, 10 eq). To this mixture POCl3 (9.3 mL, 100 mmol, 10
eq) was added dropwise at 0 °C. The reaction was refluxed at 110 °C under argon for
6 hrs. The reaction mixture was then cooled to 0 °C and diluted with CH2Cl2 (10 mL).
1M aqueous sodium hydroxide solution (300 mL, 1M) was slowly added until the
aqueous layer became basic. The organic layer was separated, dried over Na2SO4, and
concentrated in vacuo. Purification by silica gel chromatography (10:1 ! 4:1
hexanes: ethyl acetate) furnished 10 (4.9 g, 6.9 mmol, 69% yield).
51
See spectra on page 85
1
H NMR: (400 MHz, CDCl3)
10.89 (s, 1H); 7.86 (d, J=8.2 Hz, 1H); 7.81 (d, J=8.1 Hz, 1H); 7.557.21 (m, 17H); 5.97 (s, 1H); 5.74 (d, J=4.3 Hz, 1H); 5.30-5.18 (m,
4H); 4.89 (d, J=11.2 Hz, 1H); 4.61 (d, J=11.3 Hz, 1H); 4.40 (d, J=11.0
Hz, 1H); 4.03 (d, J=11.0 Hz, 1H); 3.43-3.40 (m, 2H); 2.90 (dd, J=3.4,
6.6 Hz, 1H); 1.83 (s, 3H); 1.42 (d, J=5.6 Hz, 3H)
13
C NMR: (100 MHz, CDCl3)
194.3; 169.9; 159.0; 154.4; 139.1; 138.2; 135.9; 135.2; 129.5; 129.3;
129.2; 129.1; 128.9; 128.8; 128.4; 128.3; 128.3; 127.8; 127.6; 127.5;
127.5; 126.6; 126.0; 125.3; 124.0; 108.2; 107.0; 81.5; 80.1; 77.3; 76.0;
75.6; 74.7; 71.5; 71.3; 71.1; 70.1; 20.7; 18.6
HRMS (ESI): calculated for C47H44NaO8: 759.2934; found (M+Na)+: 759.2967
[a]25D:
-76.5° (c 0.016, CH2Cl2)
52
BnO
OAc
BnO
H 3C
O
OBn
OBn OH
11
Aldehyde 10 (49.3 mg, 0.07 mmol) was dissolved in THF (1.3 mL) and MeOH (2.8
mL). The solution was treated with 30% aqueous H2O2 (0.57 mL) and 3 drops of
H2SO4. After the reaction was stirred for 1 hr Et2O (4.2 mL) was added to the
mixture. An aqueous solution of NaHSO3 (341 mg) in water (11.3 mL) was then
added to the reaction at 0 °C. The aqueous layer was extracted with Et2O (250 mL)
and the combined organic layers were dried over Na2SO4. The organic layer was
filtered and concentrated in vacuo to give a crude oil. Column chromatography (10:1
! 7:1 hexanes: ethyl acetate) purification afforded naphthol 11 (44.6 mg, 0.064
mmol, 92%).
53
See spectra on page 86
1
H NMR: (400 MHz, CDCl3)
9.58 (s, 1H); 7.60-7.26 (m, 15H); 7.00 (d, J=8.5 Hz, 1H); 6.96 (d,
J=8.5 Hz, 1H); 6.86 (d, J=8.4 Hz, 1H); 6.07 (s, 1H); 5.87 (d, J=3.2 Hz,
1H); 5.28 (s, 2H); 5.13 (s, 2H); 4.96 (d, J=11.1 Hz, 1H); 4.65 (d,
J=11.2 Hz, 1H); 4.50 (d, J=11.0 Hz, 1H); 4.06 (d, J=11.0 Hz, 1H); 3.63.4 (m, 2H); 2.99 (dd, J=3.4, 6.7 Hz, 1H); 1.91 (s, 3H); 1.50 (d, J=5.6
Hz, 3H)
13
C NMR: (100 MHz, CDCl3)
169.9; 154.7; 149.3; 148.5; 139.2; 138.4; 136.5; 135.2; 129.1; 128.9;
128.8; 128.7; 128.2; 128.1; 128.1; 127.9; 127.5; 127.4; 125.7; 125.1;
116.6; 109.9; 109.8; 105.70; 81.62; 80.2; 77.5; 77.2; 76.9; 76.1; 75.5;
74.6; 71.8; 71.7; 71.1; 70.3
HRMS (ESI): calculated for C46H44NaO8: 747.2934; found (M+Na)+: 747.2991
[a]25D:
-84.7° (c 0.006, CH2Cl2)
54
BnO
OAc
BnO
H 3C
O
OEt
O
OBn OH
13
Naphthol 11 (1 g, 1.3 mmol) was dissolved with CH3CN (4 mL, 0.3M). To this
mixture an aqueous solution of ceric ammonium nitrate (1.8 g, 3.9 mmol, 2.5 eq) in
water (1 mL) was added. The reaction mixture turned bright yellow, at which point
TLC indicated complete consumption of 11. The reaction was then quenched with
water (5 mL). The aqueous layer was extracted with CH2Cl2 (5 mL) and combined
organic layers were washed with saturated NaCl solution (5 mL). Concentration in
vacuo gave a crude intermediate quinone. Due to the light sensitivity of the
compound, the quinone was immediately dissolved with Et2O and DCM (26 mL,
0.05M, 3:1) and transferred to a separatory funnel; then a freshly prepared 20%
sodium dithionite solution (30 mL) was mixed with the organic solution and the
biphasic mixture was shaken vigorously for 15 min. As the bright yellow organic
layer turned dark brown, TLC showed complete consumption of the quinone. The
organic layer was then concentrated in vacuo to afford 12 (660.1 mg, 1.04 mmol, 80%
yield overall). The crude red oil was quickly filtered through a silica gel column
(CH2Cl2) and concentrated in vacuo.
To a solution of diol 12 (1 g, 1.57 mmol) in THF (1.57 mL, 1 M) at -78°C, NaHMDS
(1 M solution in THF, 1.6 mL, 3.2 mmol, 2 eq) was added. Then chloromethyl ethyl
ether (0.2 mL, 1.88 mmol, 1.2 eq) was added and the reaction was stirred at -78°C for
5 min. At this point TLC indicated consumption of the starting material. The reaction
was diluted with EtOAc (10 mL), quenched with sodium bicarbonate (10 mL), and
55
the organic layer was washed with brine (10 mL). The organic extract was dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a brown oil, which
was purified by silica gel chromatography (10:1 ! 7:1 hexanes: ethyl acetate) to
provide 13 (707 mg, 1.02 mmol, 65% yield).
See spectra on page 87
1
H NMR: (400 MHz, CDCl3)
9.66 (s, 1H); 7.86 (d, J= 8.5 Hz, 1H); 7.54-7.38 (m, 15H); 7.27 (d, J=
8.4Hz, 1H); 6.96 (d, J=8.5 Hz, 1H); 6.90 (d, J=8.5 Hz, 1H); 6.16 (d,
J=3.1 Hz, 1H); 6.04 (s, 1H); 5.33 (d, J=7.8 Hz, 1H); 5.26-5.16 (m,
4H); 4.98 (d, J=11.4 Hz, 1H); 4.85 (d, J=11.0 Hz, 1H); 4.74 (d, J=11.4
Hz, 1H); 4.08 (dd, J=3.1, 6.2 Hz, 1H); 3.84- 3.73 (m, 4H); 2.02 (s,
3H); 1.64 (d, J=5.6 Hz, 3H); 1.34 (t, J=7.0 Hz, 3H).
13
C NMR: (100 MHz, CDCl3)
170.1; 154.8; 150.0; 147.0; 138.7; 138.2; 135.2; 129.0; 128.9; 128.5;
128.5; 128.2; 128.2; 128.1; 127.9; 127.8; 127.7; 127.4; 126.9; 125.7;
125.5; 116.5; 113.1; 110.24; 105.53; 94.9; 82.1; 80.8; 77.7; 77.4; 77.1;
76.6; 76.1; 75.7; 71.8; 71.3; 70.5; 64.8; 20.8; 18.7; 15.3
HRMS (ESI): calculated for C42H44NaO9: 715.2883; found (M+Na)+: 715.2936
[a]25D:
-57.8°(c=0.0028 , CH2Cl2)
56
BnO
OAc
BnO
H 3C
O
O
OEt
OBn OMe
14a
Naphthol 13 (0.7 g, 1.02 mmol) was dissolved in THF (1.02 mL, 1 M) at -78°C and
treated with NaHMDS (1M in THF, 1.02 mL, 1.02 mmol, 1 eq) at -78 °C. To this
mixture Me2SO4 (0.09 mL, 1.12 mmol, 1.1 eq) was added at -78 °C. The reaction was
warmed to room temperature and stirred for 1 hr. Saturated sodium bicarbonate
solution (10 mL) was then added and the mixture was extracted with EtOAc (10 mL)
and washed with brine (10mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo to yield a brown oil. Silica gel column
chromatography (9:1 hexanes: ethyl acetate) furnished 14a (0.65 g, 0.9 mmol, 90%
yield).
57
See spectra on page 88
1
H NMR: (400 MHz, CDCl3)
7.85 (d, J= 8.4 Hz, 1H); 7.66-7.35 (m, 15H); 7.23 (d, J=8.4 Hz, 1H);
7.02 (d, J= 8.5 Hz, 1H); 6.84 (d, J=8.5 Hz, 1H); 6.06 (d, J=3.0 Hz,
1H); 5.99 (s, 1H); 5.34 (d, J=6.8 Hz, 1H); 5.23 (s, 2H); 5.17 (d, J= 6.8
Hz, 1H); 5.10 (d, J=10.7 Hz, 1H); 4.92 (d, J= 11.3 Hz, 1H); 4.79 (d,
J=11.4 Hz, 1H); 4.67 (d, J= 11.5 Hz, 1H); 4.00 (dd, J= 3.1, 6.3 Hz,
1H); 3.93 (s, 3H); 3.80-3.65 (m, 4H); 1.96 (s, 3H); 1.58 (d, J=5.6 Hz,
3H); 1.31 (t, J=7.0 Hz, 3H)
13
C NMR: (100 MHz, CDCl3)
170.0; 155.6; 152.6; 148.4; 138.6; 138.1; 137.6; 128.4; 128.4; 128.3;
128.3; 128.2; 128.1; 128.0; 127.9; 127.8; 127.7; 127.5; 127.1; 126.8;
126.5; 126.4; 126.3; 120.0; 110.7; 108.9; 107.0; 94.5; 82.0; 80.7; 77.4;
77.1; 76.7; 76.7; 75.9; 75.6; 71.8; 71.1; 70.3; 64.7; 57.2; 20.7; 18.6;
15.2
HRMS (ESI): calculated for C43H46NaO9: 729.3040; found (M+Na)+: 729.3003
[a]25D:
-43.6° (c, CH2Cl2)
58
O
H 3CO
OCH3
17
Phenol 16 was prepared from 15 according to a literature procedure.31 Phenol 16 (5.5
g, 30 mmol) was dissolved in pyridine (5 mL) and CH2Cl2 (32 mL, 0.1M). To this
mixture a solution of Tf2O (6.2 ml, 36 mmol, 1.2 eq) in CH2Cl2 (~13 mL) was added
at 0°C. The reaction mixture was stirred for 1 hr and quenched with saturated
NaHCO3 (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL). The
organic extracts were washed with brine (10 mL), dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The crude product was rapidly
filtered through a pad of silica gel (CH2Cl2) and concentrated in vacuo.
To the triflate (0.5 g, 1.6 mmol) in 12.5 mL DMF, anhydrous LiCl (0.3 g, 6.4 mmol, 4
eq) was added. To this mixture (Ph3P)2PdCl2 (112 mg, 0.16 mmol, 10 mol%) and
allytributyltin (1ml, 3.18 mmol, 2 eq) were added. The suspension was heated at
100°C for 3 hrs, at which point TLC indicated complete consumption of the starting
material. The reaction was cooled and stopped by adding water (10 mL) and ethyl
ether (10 mL). The aqueous phase was extracted with diethyl ether (50 mL). The
combined ether extracts were washed with brine (10 mL) and saturated NaHCO3 (10
mL) and dried over anhydrous sodium sulfate and concentrated in vacuo. Silica gel
column chromatography (10:1 ! 5:1 hexanes: ethyl acetate) afforded 17 (0.27 g, 1.3
mmol, 80%).
59
See spectra on page 89
1
H NMR: (400 MHz, CDCl3)
7.41 (s, 1H); 7.34 (s, 1H); 6.85 (s, 1H); 5.92-5.82 (m, 1H); 5.065.02(m, 2H); 3.82 (s, 3H); 3.74 (s, 3H); 3.31 (d, J= 7.8Hz, 2H)
13
C NMR: (100 MHz, CDCl3)
166.5; 159.6; 141.6; 136.5; 131.2; 122.0; 121.9; 119.4; 119.3; 116.1;
111.6; 55.0; 54.9; 51.7; 51.6; 39.7; 35.3; 33.2; 22.1; 13.7
HRMS (ESI): calculated for C12H14NaO3: 229.08; found (M+Na)+: 229.0822
60
O
OH
H 3CO
OCH3
18
Compound 17 (0.10 g, 0.5 mmol) was dissolved in acetone and t-BuOH (1:1, 1 mL,
0.5 M) and treated with OsO4 (20 µL, 4% solution in water) and Nmethylmorpholine-N-oxide (0.5 mL, 50% solution in H2O) and stirred for 5 hrs at
room temperature. EtOAc (10 mL) was added and the layers were separated; the
organic extracts were washed with saturated NaHCO3 (5 mL) and brine (5 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The diol intermediate was
dissolved in acetone and pH 6.5 phosphate buffer (1:3, 20 mL) and treated with KIO4
(0.200 g, 1.0 mmol, 2 eq). The reaction was stopped after 3 hrs. The layers were
separated and the organic phase was washed with brine (10 mL) and saturated sodium
bicarbonate (10 mL) and concentrated in vacuo. The crude intermediate aldehyde was
immediately dissolved in MeOH (~10 mL), treated with NaBH4 (37.8 mg, 1.0 mmol,
2eq) and stirred for 10 min. At this time saturated sodium bicarbonate solution (5 mL)
and EtOAc (10 mL) was added and the layers were separated. The organic phase was
dried over anhydrous Na2SO4 and concentrated in vacuo. The crude alcohol
compound was purified by silica gel chromatography (10:1 ! 2:1 hexanes: ethyl
acetate) to afford 18 (66.3 mg, 0.33 mmol, overall 65%) as a colorless oil.
61
See spectra on page 90
1
H NMR: (400 MHz, CDCl3)
7.37 (s, 1H); 7.25 (s, 1H); 6.85 (s, 1H); 3.75 (s, 3H); 3.71 (t, J=10.2
Hz, 2H); 3.66 (s, 3H); 3.34 (br, 1H); 2.73 (t, J= 6.4 Hz, 2H)
13
C NMR: (100 MHz, CDCl3)
167.0; 159.5; 140.7; 131.1; 122.4; 120.1; 111.7; 77.6; 77.3; 76.9; 62.9;
55.1; 51.9; 38.8
HRMS (ESI): calculated for C11H14NaO4: 223.0790; found (M+Na)+: 233.0842
62
OCH2OEt
HO
I
OCH3
21
To alcohol 18 (1 g, 4.8 mmol) in CH2Cl2 (9.5 mL, 0.5 M) was added DIEA (2.1 mL,
12.1 mmol, 2.5 eq) followed by chloromethyl ethyl ether (0.75 ml, 7.2 mmol, 1.5 eq)
at 0°C. The reaction was stirred for 5 hours at room temperature and then saturated
NaHCO3 (10 mL) and ether (50 mL) was added. The layers were separated and the
organic extracts were washed with brine (10 mL), dried over anhydrous sodium
sulfate and concentrated in vacuo. The crude product was dissolved and CH2Cl2
rapidly filtered through a pad of silica gel. To ester 19 (1 g, 3.7 mmol) in dry Et2O (37
mL, 0.1 M) was added LiAlH4 (292.4 mg, 8.4 mmol, 2.25 eq) in four small portions
with caution. The reaction mixture was stirred for 10 min and stopped by carefully
adding water (0.3 mL), 15% NaOH (0.2 mL) and water (0.9 mL) dropwise. After the
residual LiAlH4 was quenched, the resulting white solids were diluted with EtOAc
(20 mL) and the mixture was filtered through celite; the filtrate was then concentrated
in vacuo. The crude product was purified by silica gel chromatography (10:1 ! 2:1
hexanes: ethyl acetate) to afford 20 (876.0 mg, 3.6 mmol, 98% yield).
To a suspension of 20 (3 g, 12.5 mmol) in anhydrous diethyl ether (125 mL, 0.1M)
was slowly added n-BuLi (37.5 mL, 37.5 mmol, 3eq, 1M solution in hexanes) at 0°C
and the solution turned light brown. This reaction was stirred for 1 hour at room
temperature. The mixture was then cooled in an ice bath and an additional portion of
n-BuLi (12.5 mL, 12.5 mmol, 1eq, 1M solution in hexanes) was added to the reaction,
which was then stirred for an additional 3 hours. To the dark red reaction solution, I2
(16 g, 62.5 mmol, 5eq) in THF (5 mL) was added at 0°C. In the titration process, the
63
reaction was first turned to colorless and then dark brown (due to the excess of
iodine). The titrated solution was then stirred for an additional hour. The residual
iodine was scavenged by addition of saturated sodium thiosulfate solution (10 mL)
and the product was extracted with EtOAc (20 mL). The organic layer was washed
with saturated NaHCO3 (10 mL) and brine (10 mL) and concentrated in vacuo. The
crude product was purified by silica gel chromatography (10:1 ! 4:1 hexanes: ethyl
acetate) to give 21 (2.98 g, 8.1 mmol, 65% yield) as a light yellow oil. Starting
material 20 (~0.3 g, 1.3 mmol, ~10%) was also recovered.
See spectra on page 91
1
H NMR: (400 MHz, CDCl3)
6.99 (s, 1H); 6.65 (s, 1H); 4.67-4.64 (m, 4H); 3.89 (s, 3H); 3.78 (t,
J=6.8 Hz, 2H); 3.53 (q, J= 7.2 Hz, 2H); 2.89 (t, J=6.8 Hz, 2H); 2.59
(br, 1H); 1.18 (t, J=8.0 Hz, 3H)
13
C NMR: (100 MHz, CDCl3)
157.8; 144.3; 140.8; 121.3; 110.8; 95.0; 86.4; 77.4; 77.0; 76.7; 69.4;
68.1; 63.3; 56.5; 36.1; 15.1
HRMS (ESI): calculated for C13H19INaO4: 389.0226; found (M+Na)+: 389.0222
64
O
OCH2OEt
HO
I
OCH3
22
Iodo alcohol 21 (2 g, 5.46 mmol) was dissolved in CH2Cl2 (10 mL, 0.5M) and PCC
(2.35 g, 10.9 mmol, 2eq) and KOAc (1.07 g, 10.9 mmol, 2eq) was added. After 2
hours, the reaction was diluted with EtOAc (20 mL) and filtered through a celite cake.
The combined eluates were concentrated in vacuo to give a dark brown oil. The crude
aldehyde was dissolved in CH2Cl2 (10 mL) and rapidly flushed through a pad of silica
gel and concentrated in vacuo. The aldehyde was dissolved in t-BuOH (~55 mL,
~0.1M). To this mixture, a solution of NaClO2 (~800 mg, 8.2 mmol, ~1.5eq) and
NaH2PO4 (~980 mg, 8.2 mmol, ~1.5eq) in water (8 mL) was added and the reaction
was stirred for 1 hr. The reaction was stopped by the addition of water (5 mL) and
CH2Cl2 (20 mL), the layers were separated and the organic phase was washed with
brine (10 mL). The CH2Cl2 extracts were dried over anhydrous sodium sulfate and
concentrated in vacuo. The crude carboxylic acid was diluted in diethyl ether (20
mL). To this solution, saturated aqueous NaHCO3 (10 mL) was added and the layers
were separated; the aqueous layer was acidified with 1M HCl (12 mL) and extracted
with DCM (20 mL). The combined extracts were collected and concentrated under
reduced pressure to give carboxylic acid 22 (1.6 g, 4.4 mmol, overall 80%).
65
See spectra on page 92
1
H NMR: (400 MHz, CDCl3)
10.60 (br, 1H); 7.22 (s, 1H); 6.78 (s, 1H); 4.61 (s, 2H); 3.78- 3.74 (m,
5H); 3.44 (q, J=7.2 Hz, 2H); 2.88 (t, J=6.8 Hz, 2H); 1.08 (t, J=8 Hz,
3H)
13
C NMR: (100 MHz, CDCl3)
171.7; 158.7; 141.0; 137.4; 123.7; 114.6; 94.9; 84.3; 77.4; 77.1; 76.8;
67.8; 63.4; 56.9; 35.9; 15.1;
HRMS (ESI): calculated for C13H17INaO5: 403.0018; found (M+Na)+: 403.0095
66
BnO
BnO
H 3C
OAc
O
OCH2OEt
O
O
I
OCH3
OBn OMe
23
Intermediate 14a (0.65 g, 0.9 mmol) was dissolved in CH2Cl2 (9 mL, 0.1M). To the
mixture a freshly prepared 10% HCl (1 mL, 0.1 eq) solution in methanol was added.
The reaction was stirred at room temperature for 8 hrs and stopped by adding
saturated sodium bicarbonate (10 mL) solution. The aqueous solution was extracted
with CH2Cl2 (2x10 mL). The combined CH2Cl2 extracts were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to give crude naphthol. The crude
oil was then flushed through a silica gel column (CH2Cl2) to give compound 14b
(0.55 g, 0.86 mmol, 95%). 14b was found to be unstable when exposed to light and
air. 14b (0.55 g, 0.86 mmol, 95%) and 22 (0.52 g, 1.29 mmol, 1.5 eq) were
immediately mixed and dissolved in CH2Cl2 (15 mL, 0.1M). To this solution, DMAP
(15.8 mg, 0.13 mmol, 0.1eq) was added and the reaction mixture was stirred for 15
hrs. The reaction was stopped by the addition of saturated NaHCO3 (10 mL). The
resulting aqueous solution was extracted with CH2Cl2 (20 mL). The combined organic
solution was washed with brine (10 mL), concentrated under reduced pressure and
purified through silica gel column (10:1 ~ 4:1 hexanes: ethyl acetate) to obtain ester
23 (0.84 g, 0.8 mmol, 90%).
67
See spectra on page 93
1
H NMR: (400 MHz, CDCl3)
7.79 (d, J=8.4Hz, 1H); 7.60-6.93 (m, 2H); 7.50- 7.20 (m, 16H); 6.97
(d, 8.4Hz, 1H); 6.93 (d, 8.3Hz, 1H); 6.81 (s, 1H); 5.85 (d, J=3.5Hz,
1H); 5.36 (s, 1H); 5.21 (s, 2H); 4.80 (d, J=11.8Hz, 1H); 4.63-4.51 (m,
5H); 3.97 (s, 3H); 3.75-3.72 (m, 5H); 3.51 (q, J=7.2 Hz, 2H); 3.443.40 (m, 2H); 2.85 (t, J=6.7Hz, 2H); 2.73 (d, J=, 3.3, 6.7Hz, 1H); 1.76
(s, 3H); 1.27 (d, J=5.5Hz, 3H); 1.18 (t, J=7.0Hz, 3H)
13
C NMR: (100 MHz, CDCl3)
169.6; 166.8; 158.9; 156.2; 156.1; 142.3; 139.4; 139.1; 139.1; 138.4;
137.4; 128.4; 128.3; 128.2; 128.2; 128.2; 128.2; 128.1; 128.0; 128.0;
127.9; 127.8; 127.8; 127.6; 127.6; 127.5; 127.4; 127.1; 127.0; 126.8;
124.6; 122.9; 121.2; 119.8; 114.5; 108.6; 105.5; 95.0; 83.7; 82.7; 79.9;
77.4; 77.2; 77.0; 76.7; 75.9; 75.8; 75.7; 74.6; 71.7; 71.6; 69.68; 67.4;
63.3; 56.6; 56.6; 35.9; 20.6; 18.5; 15.2
HRMS (ESI): calculated for C53H55INaO12: 1033.2636; found (M+Na)+: 1033.2626
[a]25D:
-32.5° (c=0.0004, CH2Cl2)
68
BnO
BnO
H 3C
OAc
OCH2OEt
O
O
O
OCH3
OBn OMe
24a
To ester 23 (145 mg, 0.2 mmol) in DMA (16 mL, 0.01M), (Ph3P)2PdCl2 (16 mg, 0.05
mmol, 27 mol%) and KOAc (87 mg, 0.6 mmol, 3eq) were added and the mixture was
heated to 120°C for 5 hrs. After the reaction was cooled, the resulting dark brown
solution was diluted with Et2O (20 mL). The mixture was successively washed with
saturated sodium bicarbonate (10 mL) and brine (10 mL). The combined ether
extracts were concentrated under in vacuo and the crude product was purified by
silica gel chromatography. The resulting product was re-purified by silica gel
chromatography (10:1 ! 2:1 hexanes: ethyl acetate) to furnish 24a as light yellow oil
(81.0 mg, 0.09 mmol, 47%).
69
See spectra on page 94
1
H NMR: (400 MHz, CDCl3)
8.55 (s, 1H); 8.01 (s, 1H); 7.94 (d, J=8.4Hz, 1H); 7.62 (d, J=8.5Hz,
1H); 7.46-7.26 (m, 15H); 7.08 (d, J= 8.4Hz, 1H); 6.33 (d, J=3.4Hz,
1H); 6.14 (s, 1H); 5.24 (s, 2H); 5.03 (d, J=11.5 Hz, 1H); 4.83 (d, J=
11.4Hz, 1H); 4.75-4.69 (m, 4H); 4.57 (dd, J=3.4, 6.7Hz, 1H); 4.12 (s,
3H); 4.01 (s, 3H); 3.90 (t, J=6.6Hz, 2H); 3.62-3.54 (m, 4H); 3.07 (t,
J=6.4Hz, 2H); 1.92 (s, 3H); 1.50 (d, J=5.6Hz, 3H); 1.20 (t, J=7.0Hz,
3H)
13
C NMR: (150 MHz, CDCl3)
170.2; 160.3; 157.4; 155.1; 153.3; 141.5; 141.3; 138.9; 138.5; 137.3;
132.0; 132.0; 128.4; 128.3; 127.8; 127.4; 127.0; 127.0; 126.9; 124.0;
122.9; 122.370; 122.125; 120.861; 119.0; 118.2; 114.7; 109.7; 105.1;
95.1; 95.0; 81.9; 80.5; 80.4; 77.2; 77.0; 76.8; 76.6; 75.9; 75.2; 75.0;
71.6; 71.5; 70.5; 70.4; 67.7; 67.6; 67.5; 63.3; 63.2; 56.8; 56.7; 56.4;
36.5; 36.2; 24.6; 20.9; 18.6; 15.1
HRMS (ESI): calculated for C53H54NaO12: 905.3513; found (M+Na)+: 905.3458
[a]25D:
-40.0° (c=0.0008, CH2Cl2)
70
AcO
AcO
H 3C
OAc
OH
O
O
O
OCH3
OAc OMe
25
In the presence of Pearlman’s catalyst Pd(OH)2(20% on C, 5 mg), a solution of
compound 24a (15mg, 16.6 µmol) in MeOH (4 mL) and THF (1mL) was stirred
under H2 at room temperature for 8 hrs. The mixture was filtered through a celite cake
and washed with EtOAc (20 mL). The solvent was concentrated in vacuo to give a
crude tetraol as bright yellow oil. This compound was dissolved in pyridine (5 mL,
0.003 M), to which was added Ac2O (0.75 mL) and a catalytic amount of DMAP (5
mg). After the mixture was stirred for 3hrs at room temperature, the reaction was
stopped by the addition of a small amount of MeOH (2 mL). The mixture was diluted
with Et2O (5 mL) and washed successively with saturated sodium bicarbonate (5 mL)
and Cu2SO4 solution (5 mL), dried (over Na2SO4), and concentrated in vacuo. The
residue was purified by silica gel chromatography (2:1 ! 1:4 hexanes: ethyl acetate)
to give pure tetraacetate 24b (8 mg, 11.0 mmol, 65.7%) as bright yellow foam. To a
solution of tetraacetate ether 24b (45 mg, 61 µmol) in CH2Cl2 (4.5 mL, 0.01M) was
added a solution of TMSBr (51.3 mg, 0.335 mmol, 5 eq) in CH2Cl2 (0.5 mL) at -78°C.
The reaction mixture was gradually warmed to -10 °C over 3 hrs, and the stirring was
continued for 30 min at this temperature. The reaction was stopped by the addition of
saturated aqueous NaHCO3 (10 mL) and the mixture was extracted with EtOAc (10
mL). The combined organic extracts were washed with brine (10 mL), dried over
sodium sulfate and concentrated under reduced pressure. The resulting yellow oil was
purified by silica gel column chromatography (1:1 ! 1:5 hexanes: ethyl acetate) to
give primary alcohol 25 (7mg, 10.28 µmol, 62.0% overall).
71
See spectra on page 95
1
H NMR: (400 MHz, CDCl3)
8.52 (s, 1H); 8.03 (s, 1H); 8.01 (d, J=8.4Hz, 1H); 7.26 (d, J=8.2Hz,
1H); 7.18 (d, J=8.2Hz, 1H); 6.40 (s, 1H); 6.00 (d, J=3.4Hz, 1H); 5.73
(dd, J= 3.4, 6.7 Hz, 1H); 5.25 (t, J= 16.1Hz, 1H); 5.15 (s, 1H); 4.033.80 (m, 8H); 3.50 (q, J=7.8Hz, 1H); 3.00 (t, J=7.0Hz, 2H); 2.40 (s,
3H); 2.13 (s, 3H); 1.97 (s, 3H); 1.88 (s, 3H); 1.39 (d, J=6.4Hz, 3H)
13
C NMR: (150 MHz, CDCl3)
173.0; 172.5; 172.5; 172.4; 162.5; 160.0; 153.9; 148.7; 143.9; 143.9;
134.2; 131.6; 130.3; 125.9; 125.2; 125.1; 125.1; 123.0; 122.7; 121.1;
117.5; 110.0; 107.5; 79.8; 79.6; 79.4; 77.3; 75.1; 74.6; 73.9; 65.6;
59.0; 58.9; 41.6; 34.2; 32.3; 25.3; 23.6; 23.3; 23.1; 23.1; 20.6; 17.9;
16.7
HRMS (ESI): calculated for C35H36NaO14: 703.2003; found (M+Na)+: 703.1940
[a]25D:
-96.8° (c=0.007, CH2Cl2)
72
AcO
AcO
H 3C
OAc
O
O
O
OCH3
OAc OMe
26
To a solution of alcohol 25 (7.7 mg, 0.01 mmol) in THF (0.1 mL, 0.1M) was added onitrophenyl selenocyanate (26 mg, 0.11 mmol, 10 eq) and n-Bu3P (21 mg, 0.11 mmol,
10 eq) at room temperature. After the mixture was stirred for 10 min, a 30% aqueous
hydrogen peroxide solution was added (0.089 mL) at 0°C, and after being stirred for
30 min at room temperature, the reaction mixture was concentrated under reduced
pressure and diluted with MeOH (5 mL). The resulting bright yellow solids were
filtered and the residual methanol solution was concentrated in vacuo to give crude
Polycarcin V tetraacetate 26. The product was purified by silica gel column
chromatography (2:1 ! 1:2 hexanes: ethyl acetate) to give 26 (4.3 mg, 6.1 µmol,
57%).
73
See spectra on page 96-97 (also for comparison)
1
H NMR: (400 MHz, CDCl3)
8.55 (s, 1H); 8.23 (s, 1H); 8.01 (d, J=8.4Hz, 1H); 7.39 (d, J=8.5Hz,
1H); 7.19 (d, J=8.4Hz, 1H); 6.82 (dd, J=8.7, 17.3Hz, 1H); 6.41 (s, 1H);
6.00 (s, 1H); 5.97 (d, J=14.8Hz, 1H); 5.74 (dd, J=3.4, 6.7Hz, 1H); 5.47
(d, J=10.8Hz, 1H); 5.24 (t, J=7.2Hz, 1H); 4.13 (s, 3H); 4.01 (s, 3H);
3.94 (q, J=6.1Hz, 1H); 2.40 (s, 3H); 2.12 (s, 3H); 1.97 (s, 3H); 1.88 (s,
3H); 1.39 (d, J= 6.1Hz, 3H)
13
C NMR: (150 MHz, CDCl3)
169.4; 168.9; 168.8; 168.7; 158.8; 156.6; 150.3; 145.0; 140.5; 138.0;
134.2; 130.7; 127.7; 122.7; 122.6; 122.3; 121.7; 119.6; 119.5; 119.2;
115.6; 113.8; 113.5; 104.8; 73.7; 71.4; 70.9; 70.2; 55.4; 55.0; 21.6;
20.0; 19.9; 18.7.
HRMS (ESI): calculated for C35H34NaO13: 685.19; found (M+Na)+: 685.1924
[a]25D:
-61° (c=0.0007, CCl4)
74
HO
HO
H 3C
OH
O
O
O
OCH3
OH
OMe
1
Tetraacetate 26 (3.4 mg, 5.1 µmol) was dissolved with MeOH (1.2mL, 0.01M). To
the solution was treated with NaCN (1 mg). The mixture was stirred for 20 hrs at
room temperature and was then diluted with 9:1 CHCl3:MeOH (10mL). The mixture
was concentrated in vacuo and then loaded onto a silica gel column. Elution with 9:1
CHCl3:MeOH gave synthetic 1 (~2.0 mg, 4 µmol, 78%)
75
See spectra on page 98
1
H NMR: (600 MHz, CDCl3)
9.71 (s, 1H); 8.44 (s, 1H); 7.96 (s, 1H); 7.80 (d, J=7.8 Hz, 1H); 7.71 (s,
1H); 6.95 (m, 2H); 6.13 (d, J=17.4 Hz, 1H); 5.82 (s, 1H); 5.49 (d,
J=10.8 Hz, 1H); 4.80 (m, 1H); 4.45 (m, 1H); 4.14 (s, 3H); 4.09 (s, 3H);
4.05 (m, 1H); 4.01 (m, 1H); 3.78 (m, 1H); 3.22 (s, 1H); 2.49 (s, 3H);
1.27 (d, J= 6.7 Hz, 3H).
13
C NMR: (150 MHz, CDCl3)
159.8; 157.9; 153.2; 152.5; 142.2; 139.3; 135.6; 130.4; 128.6; 128.0;
122.9; 122.3; 119.6; 117.7; 115.2; 112.5; 101.9; 77.9; 77.0; 75.1; 73.2;
72.0; 70.1; 57.2; 56.7; 55.7; 22.5; 18.9.
HRMS (ESI): calculated for C35H34NaO13: 517.1475; found 517.1528 (M+Na)+:
[a]25D:
-84.2° (c=0.0007, CH3OH)
76
References
[1] (a) Hua, D.H.; Saha, S. Recl. Trav. Chim. Pay-B. 1995, 114, 341. (b) Nakano, H.;
Matsuda, Y.; Ito, K.; Ohkubo, S.; Morimoto, M.; Tomita, F. J. Antibiot. 1981, 34,
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Antibiot. 1981, 34, 266.
[2] Wei, T.T.; Bryne, K.M.; Warnick-Pickle, D.; Greenstein, M. J. Antibiot. 1982, 35,
545.
[3] McGee, L.R.; Misra, R. J. Am. Chem. Soc. 1990, 112, 2386.
[4] Matsumoto, A.; Hanawalt, P.C. Cancer Res. 2000, 60, 3921.
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802.
[6] Bailly, C.; Colson, P.; Houssier, C.; Rodrigues-Periera, E.; Prudhomme, M.;
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Bicknell, W.; Craik, D. J.; Wickham, G. Biochemistry 1996, 35, 9314. (d) Hansen,
M.; Yun, S.; Hurley, L. Chem. Biol. 1995, 2, 229.
[9] (a) Cairns, M. J.; Murray, V. Biochem. Mol. Biol. Int. 1998, 46, 267. (b) Hardman,
L. C.; Murray, V. Biochem. Mol. Biol. Int. 1997, 42, 349. (c) Murray, V.; Moore, A.
G.; Matias, C.; Wickham, G. BBA-Gene Struct. Expr. 1995, 1261, 195. (d) Prakash,
A. S.; Moore, A. G.; Murray, V.; Matias, C.; McFadyen, W. D.; Wickham, G. Chem.Biol. Interact. 1995, 95, 17. (e) Kamei, N.; Sekiguchi, T.; Tsuboi, M.; Ishii, S.;
Ohtsubo, E.; Maeda, Y. Nucl. Acid. S. 1994, 31, 87. (f) Sun, D.; Hansen, M.; Hurley,
L. J. Am. Chem. Soc. 1995, 117, 2430.
[10] (a) Greenstein, M.; Monji, T.; Yeung, R.; Maiese, W.M.; White, R.J. Antimicrob.
Agents Chemother. 1986, 29, 861. (b) Singh, K. J. Antibiot. 1984, 37, 71. (c) Narita,
T.; Matsumoto, M.; Mogi, K.;Kukita, K.; Kawahara, R.; Nakashima, T. J. Antibiot.
1989, 42, 347. (d) Misra, R.; Tritch III, H.R.; Pandey, R.C. J. Antibiot. 1985, 38,
1280.
[11] Li, Y.Q.; Huang, X.S.; Ishida, K.; Maier, A.; Kelter, G.; Jiang, Y.; Peschel, G.;
Menzel, K.D.; Li, M.G.; Wen, M.L.; Xu, L.H.; Grabley, S.; Fiebig, H.H.; Jiang, C.L.;
Hertweck, C.; Sattler, I. Org. Biomol. Chem. 2008, 6, 3601.
[12] Pulley, S. R.; Carey, J. P. J. Org. Chem. 1998, 63, 5275-5579.
[13] Linhardt, R. J.; Du, Y. Tetrahedron 1998, 54, 9913-9959
77
[14] Minehan, T. G.; Yepremyan, A.; Salehani, B. Org. Lett. 2010, 12, 1580-1583
[15] Williams, R. M.; Stewart, A. O. J. Am. Chem. Soc. 1985, 107, 4289-4296
[16] Suzuki, K.; Hosoya, T.; Tahashiro, E.; Matsumoto, T. J. Am. Chem. Soc. 1994,
116, 1004-1015
[17] Suzuki, K. Pure& Appl. Chem. 1994, 66, 2175-2178
[18] Suzuki, K.; Matsumoto, T.; Katsuki, M.; Jona, H. J. Am. Chem. Soc. 1991, 113,
6982-6992.
[19] Balasubramanian, K. K.; Boga, S. B.; Arkivoc 2004, viii, 87-102.
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[21] (a) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1988, 29, 6935. (b)
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78
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79
Appendix: 1H and 13C NMR Spectra
1
H and 13C NMR spectra were measured in CDCl3 at 400 MHz or 600MHz and 100
MHz or 150MHz, respectively, using Me4Si as internal standard. Chemical shifts are
reported in ppm downfield (d) from Me4Si.
80
1
H3C
O
HO
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
O
O
5
O
81
1
H3C
O
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
O
OH
BnO
OH
6
82
1
H3C
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
O
OAc
OAc
BnO
OBn
7
83
1
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
BnO
OAc
BnO
H 3C
O
OBn
OBn
9
84
1
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
BnO
OAc
BnO
H3C
O
OBn
OBn CHO
10
85
1
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
BnO
OAc
BnO
H 3C
O
OBn
OBn OH
11
86
1
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
BnO
OAc EtO
BnO
H 3C
O
O
OBn OH
13
87
1
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
88
1
H(400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
O
H3CO
OCH3
17
89
1
H(400 MHz) (upper) and 13C NMR (100 MHz) (lower)spectra
O
OH
H3CO
OCH3
18
90
1
H(400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
OCH2OEt
HO
I
OCH3
21
91
1
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
OCH2OEt
O
HO
I
OCH3
22
92
1
H (400 MHz) (upper) and 13C NMR (100 MHz) (lower) spectra
93
1
H (400 MHz) (upper) and 13C NMR (150 MHz) (lower) spectra
94
[rel]
6
8
10
1.4036
1.3883
2.1261
3.2335
1.9694
1.8860
2.4021
2.8681
3.5072
3.4897
3.3699
1.0686
1.4510
3.0367
3.0207
3.0049
2.9768
2.9039
4.0319
3.9907
C:\Bruker\TopSpin3.1\examdata
6.5495
2
6.0112
6.0036
5.7525
5.7440
5.7277
5.7192
2
8.0321
8.0287
8.0235
8.0027
8.5179
2
6.4050
deeomcheckcrystals
H (400 MHz) (upper) and 13C NMR (150 MHz) (lower) spectra
7.2679
7.1993
7.1788
1
8
6
4
2
95
2
3.3384
0
4
3.2241
3.5341
1.7620
1.3351
0.9088
1.2218
1.1613
1.1246
0.9641
1.3246
0.8475
0.9600
1.0000
[ppm]
0
5
10
8
6
4
KIshida
96
4
2
2
1.3840
1.3718
6
2.1038
1.9458
1.8608
8
2.3755
C:\Bruker\TOPSPIN
0.8217
3.1664
4.4690
1.3438
3.1781
3.8903
3.0627
2.6866
2.6951
2.5125
0.5810
0.9514
0.7220
0.9337
0.9421
1.2246
0.4467
0
2
4
6
1.4059
1.3906
1.9675
1.8825
2.1244
2.3984
4.1261
4.0082
3.9637
3.9483
3.9395
3.9242
3.8949
3.8728
3.8552
6.4106
6.0124
6.0050
5.9970
5.9532
5.7636
5.7551
5.7387
5.7303
5.4922
5.4649
5.3188
5.2694
5.2449
5.2204
5.1376
6.8656
6.8384
6.8217
6.7945
1.0744
1
[rel]
H(400 MHz) synthetic (upper); natural (lower)
1
0.9301
7.4032
7.3991
7.3812
7.1996
7.1791
8.2362
8.2322
8.0226
8.0021
8.5528
1
4.0822
3.9760
3.9394
3.9271
3.9201
3.9078
3.7100
3.7050
3.6330
1
1.9261
4.2472
1.3713
1.0840
0.8594
1.0000
vinytetraacetate-polycarcin
6.3857
5.9877
5.9812
5.9626
5.9276
5.7379
5.7311
5.7180
5.7113
5.4589
5.4372
5.2430
5.2234
5.2038
1
7.3621
7.3595
7.1729
7.1566
6.8231
6.8013
6.7880
6.7662
5NKI176
8.2013
8.1984
7.9960
7.9797
8.5134
[rel]
15
1
C:\Bruker\TopSpin3.1\examdata
[ppm]
[ppm]
Comparison: 26 13C NMR (150 MHz) synthetic (upper); natural (lower)
0
2
4
6
160
140
120
104.8467
100
80
60
ppm
40
140
120
100
80
97
60
20.9258
20.6837
20.4899
18.0157
56.3925
56.3170
KIshida
74.6952
72.4697
71.9875
71.2758
C:\Bruker\TOPSPIN
146.0426
1
151.2992
2
170.3858
169.8934
169.8128
169.7373
8
[rel]
5NKI176
160
141.5448
139.0324
180
159.8070
157.5985
135.2844
131.7026
127.7001
123.6708
123.3421
122.7406
120.5365
120.4892
120.1816
116.6554
114.8171
114.4978
40
20
[ppm]
1
H(600 MHz) (upper) and 13C (150 MHz) (lower) NMR (DMSO-d6)
HO
HO
H 3C
OH
O
O
O
OMe
OH
OMe
polycarcin V (1)
98