Interplay of Protecting Groups and Side Chain Conformation in Glycopyranosides. Modulation of the Influence of Remote Substituents on Glycosylation?

Article abstract of DOI:10.1021/acs.joc.8b01459

The synthesis and conformational analysis of a series of phenyl 2,3,6-tri-O-benzyl-β-d-thio galacto- and glucopyranosides and their 6S-deuterio isotopomers, with systematic variation of the protecting group at the 4-position, are described. For the galactopyranosides, replacement of a 4-O-benzyl ether by a 4-O-alkanoyl or aroyl ester results in a small but measurable shift in side chain population away from the trans,gauche conformation and in favor of the gauche,trans conformer. In the glucopyranoside series on the other hand, replacement of a 4-O-benzyl ether by a 4-O-alkanoyl or aroyl ester results in a small but measurable increase in the population of the trans,gauche conformer at the expense of the gauche,gauche conformer. The possible modulating effect of these conformational changes on the well-known changes in the anomeric reactivity of glycosyl donors as a function of protecting group is discussed, raising the possibility that larger changes may be observed at the transition state for glycosylation. A comparable study with a series of ethyl 2,3,4-tri-O-benzyl-β-d-thioglucopyranosides reveals that no significant influence in side chain population is observed on changing the O6 protecting group.

Full text of DOI:10.1021/acs.joc.8b01459

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Article
Interplay of Protecting Groups and Side Chain
Conformation in Glycopyranosides. Modulation of the
Influence of Remote Substituents on Glycosylation?
Suresh Dharuman, Harsha Amarasekara, and David Crich
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01459 • Publication Date (Web): 31 Jul 2018
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Interplay of Protecting Groups and Side Chain Conformation in Glycopyranosides.
Modulation of the Influence of Remote Substituents on Glycosylation?
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Suresh Dharuman, Harsha Amarasekara, and David Crich *
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA
dcrich@chem.wayne.edu
Abstract. The synthesis and conformational analysis of a series of phenyl 2,3,6ꢀtriꢀOꢀbenzylꢀβꢀ
Dꢀthio galacto and glucopyranosides and their 6Sꢀdeuterio isotopomers, with systematic
variation of the protecting group at the 4ꢀposition, is described. For the galactopyranosides
replacement of a 4ꢀOꢀbenzyl ether by a 4ꢀOꢀalkanoyl or aroyl ester results in a small but
measurable shift in side chain population away from the trans,gauche conformation and in favor
of the gauche,trans conformer. In the glucopyranoside series on the other hand replacement of a
4
ꢀOꢀbenzyl ether by a 4ꢀOꢀalkanoyl or aroyl ester results in a small but measurable increase in
the population of the trans,gauche conformer at the expense of the gauche,gauche conformer.
The possible modulating effect of these conformational changes on the wellꢀknown changes in
the anomeric reactivity of glycosyl donors as a function of protecting group is discussed raising
the possibility that larger changes may be observed at the transition state for glycosylation. A
comparable study with a series of ethyl 2,3,4ꢀtriꢀOꢀbenzylꢀβꢀDꢀthioglucopyranosides reveals that
no significant influence in side chain population is observed on changing the O6 protecting
group.
Introduction
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In carbohydrate chemistry it is widely understood that anomeric reactivity is strongly influenced
1
by the relative configuration of the complete set of stereogenic centers in the backbone. Thus,
for example, galactopyranosides undergo both acidꢀcatalyzed and spontaneous hydrolysis more
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rapidly than their gluco isomers (Figure 1); the same pattern of reactivity is found in
6
glycosylation reactions with a series of comparably protected thioglycosides. The influence of
protecting groups on the anomeric reactivity of glycosyl donors also is broadly appreciated, with
the more electronꢀwithdrawing (or disarming) esters retarding reaction rates compared to the less
7ꢀ11
electronꢀwithdrawing (or arming) ethers.
Figure 1. Relative Rates of Spontaneous Hydrolysis of Galacto and Glucopyranosides in Water
o
5
at 37 C
Ring conformation is another important factor in anomeric reactivity. Thus, for any given
configuration, ring conformations that maximize the number of axial (or pseudoaxial) CꢀO bonds
1
2ꢀ15
generally exhibit the greatest anomeric reactivity (Figure 2).
The influence of configuration
and ring conformation on anomeric reactivity are best explained by the ability of axial CꢀO
bonds to stabilize nascent positive charge at the anomeric center as compared to their equatorial
1
6ꢀ19
counterparts.
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Figure 2. Influence of Ring Conformation on the Hydrolysis of Axial Methyl Glucosides in 2M
o
4,15
HCl at 60 C
OH
OMe
O
O
HO
O
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HO
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OMe
OH OH
krel = 1
krel = 450
The conformation of the side chain, defined as gauche,gauche (gg), gauche,trans (gt) or
trans,gauche (tg) where the first and second terms refer to the position of O6 relative to O5 and
2
0ꢀ22
C4 respectively,
is also increasingly recognized as influencing anomeric reactivity. Thus, the
trans,gauche conformation exerts maximal retardation due to the strongly electronꢀwithdrawing
23ꢀ25
antiperiplanar relationship of the C6ꢀO6 and the C5ꢀO5 bonds (Figure 3).
The interplay
between the conformation of the side chain and the glycosidic bond is further apparent from the
work of Vasquez and coworkers in which it is demonstrated by CD and NMR methods that both
the anomeric configuration and the nature of the aglycone influence the population of the
2
6ꢀ30
different side chain conformers.
Figure 3. Influence of the gauche,gauche (gg), gauche,trans (gt) and trans,gauche (tg) Side
Chain Conformations on the Relative Rates of Spontaneous Hydrolysis of 2,4ꢀDinitrophenyl
o
23,24
Glycosides in Water at 37 C
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In this Article we begin to explore the possibility that protecting groups, in addition to their wellꢀ
1
,7ꢀ11
known influence on glycoside reactivity as a function of their electronꢀwithdrawing ability,
also exert an indirect influence on anomeric reactivity by modulating the conformation of the
side chain. To this end we describe the preparation of a series of galacto and gluco
thiopyranosides and, to facilitate spectral assignment, their 6Sꢀdeuterio isotopomers, and study
the conformation of the side chain as a function of protecting group at either the 4 or the 6ꢀ
positions. We show that the side chain population in a series of phenyl 2,3,6ꢀtriꢀOꢀbenzylꢀβꢀDꢀ
thiogalacto and glycopyranosides does indeed vary in a systematic manner on changing the
functionality at the 4ꢀposition from a hydroxyl group to an ether and to an ester, albeit in a
different manner in the two configurations. While these protecting groupꢀinduced changes in
conformation are small they open the possibility that larger changes might arise at the transition
state for glycosylation and so open alternative avenues for the explanation of remote protecting
group effects.
Results and Discussion
Experimental Design and Synthesis
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In this investigation we focus on the interplay between the protecting groups at O4 and O6 in the
gluco and galactopyranosides as the strongest candidates for observation of any changes in side
chain conformation due to these interactions. Judging that the interaction in question could be
probed through the variation of the O4 protecting group in the presence of a fixed O6 protecting
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31
group, or the inverse, we prepared phenyl 2,3,6ꢀtriꢀOꢀbenzylꢀβꢀDꢀthiogalactopyranoside 1,
3
2
phenyl 2,3,6ꢀtriꢀOꢀbenzylꢀβꢀDꢀthioglucopyranoside 2,
and ethyl 2,3,4ꢀtriꢀOꢀbenzylꢀβꢀDꢀ
3
3
thioglucopyranoside 3 by standard means. The use of the ethyl thioglycoside in 3 as opposed
to the phenyl thioglycosides 1 and 2 was a matter of experimental convenience and was not
expected to affect the analysis of side chain conformations as is borne by the subsequent results.
As the rigorous assignment of the diastereotopic proꢀR and proꢀS hydrogens at the 6ꢀposition of
20
1ꢀ3 and their derivatives is critical to the correct conformational analysis of their side chains,
we also prepared 6Sꢀdeuterio 1ꢀ3 as outlined in Schemes 1 and 2. Thus, preferring a longer but
unambiguous route based on exoꢀselective quenching of radicals at the 6ꢀposition of 1,6ꢀ
3
4ꢀ38
anhydropyranoses
over shorter routes involving asymmetric reduction of 6ꢀaldehydoꢀ
2,3,4ꢀtriꢀOꢀacetylꢀ1,6ꢀanhydroꢀDꢀgalactose 4 was subjected to white lightꢀmediated
bromination with Nꢀbromosuccinimide to give the exoꢀbromide 5 in good yield. This
3
9ꢀ41
sugars,
36
transformation follows the literature description with the exception that the original solvent,
tetrachloromethane, was replaced by the more environmentally friendly α,α,αꢀ
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trifluoromethylbenzene
as described previously for the gluco series.
Reductive
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debromination with tributyltin deuteride, prepared according to Neumann, then gave the 6Sꢀ
deuterio anhydrogalactose 6 in 77% yield. A series of standard transformations were then
applied to convert 6 via intermediates 7ꢀ10 to the desired 6S-D-1 uneventfully (Scheme 1). The
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Sꢀdeuterio analog of 2 was prepared by inversion of 6S-D-1 by triflate formation, displacement
with sodium benzoate, and saponification as reported in detail in the experimental part.
Scheme 1. Synthesis of Phenyl 2,3,6ꢀtriꢀOꢀbenzylꢀ6SꢀdeuterioꢀβꢀDꢀthiogalactopyranoside 6S-D-
1
.
3
4,35,43
The 6Sꢀdeuterioꢀ1,6ꢀanhydroglucose derivative 11
was the starting material for the
preparation of 6S-D-3. Thus, 11 was converted to the thioglycoside 12 by cleavage of the 1,6ꢀ
4
5
anhydro bridge with trimethylsilyl ethanethiol in the presence of zinc iodide followed by
acetylation (Scheme 2). A series of standard reactions were then employed to convert 12 to the
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tribenzyl ether 6S-D-3 as described previously for the nonꢀdeuteriated isotopomer (Scheme 2).
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Scheme 2. Synthesis of Ethyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6SꢀdeuterioꢀβꢀDꢀthioglucopyranoside 6S-D-3.
The thiogalactoside 1 and its 6Sꢀmonodeuterio isotopomer were converted to a series of esters
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3ꢀ20 at the 4ꢀposition as well as to the benzyl ether 21 by standard methods as described in the
experimental part. The 4ꢀOꢀ(2,2,2ꢀtrifluoroethyl) ether 22 and its 6Sꢀdeuterio analog 6S-D-22
were obtained from 2 and 6Sꢀdeuterio 2 by triflation followed by displacement with sodium
trifluoroethoxide in DMF (Scheme 3). The thioglucoside 2 and its 6Sꢀmonodeuterio isomer were
also converted to the derivatives 23ꢀ27 by standard means as described in the experimental part.
Similarly, the thioglucoside 3 and its 6Sꢀmonodeuterio isotopomer were converted to the 6ꢀOꢀ
esters 28ꢀ34, the 6ꢀOꢀcarbamate 35, and the 6ꢀOꢀbenzyl ether 36 by standard means as described
in the experimental part.
Scheme 3.
Synthesis of Phenyl 2,3,6ꢀtriꢀOꢀbenzylꢀ4ꢀOꢀ(2,2,2ꢀtrifluoroethyl)ꢀβꢀDꢀ
thiogalactopyranoside 22 and its 6SꢀDeuterio Analog 6S-D-22.
Measurement of NMR Spectra, Influence of Solvent, and Estimation of Errors in Coupling
Constants
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The HꢀNMR spectra of 1ꢀ3, and 13ꢀ36 were recorded in CDCl and deuteriobenzene and fully
3
assigned by the usual array of 1 and 2DꢀNMR methods, with the distinction between the 6ꢀproꢀR
6
R
6S
and proꢀS resonances, herein after H and H , made on the basis of comparison with the
selectively 6Sꢀdeuteriated analogs. All first order couplings were analyzed directly. For second
order spectra, including those complicated by the presence of virtual coupling, the spin
simulation tool in the MestReNova 9.0 suite of programs was used to extract first order coupling
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6R
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constants. The chemical shifts and soꢀobtained J coupling constants in the H5, H and H spin
systems are presented in Table 1 for the 4ꢀOꢀsubstituted galacto series of compounds, in Table 2
for the corresponding 4ꢀOꢀsubstituted gluco compounds, and in Table 3 for the 6ꢀOꢀsubstituted
gluco series of compounds. For ease of comparison, in each of Tables 1ꢀ3, the alcohols are listed
first, followed by the ethers, and then esters grouped according to patterns in the side chain
conformations.
Inspection of the coupling constant data in Tables 1ꢀ3 reveals no systematic difference in
couplings constants for any given system on changing from CDCl to C D consistent with an
3
6
6
4
6
earlier study with rigid bicyclic models of galacto and glucopyranosides, from which we
conclude that the side chain conformation is unaffected by the nature of the solvent (CDCl or
3
C D ). It follows that data acquired in one of the two solvents can be extrapolated to the other
6
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solvent in cases for which resolution was insufficient to enable the determination of coupling
constants in both solvents. Small nonꢀsystematic differences between solvents are found and
3
3
permit the estimation of errors in the J5,6R and J
coupling constants. For the eighteen
5,6S
1
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compounds (and hence thirtyꢀsix sets of coupling constants) in which both values could be
measured in both solvents, differences in a given coupling constant are 0.4 Hz or less consistent
with the digital resolution of 0.38 Hz, leading us to adopt 0.4 Hz as the error limit in these
3
3
measurements. The differences in the J5 and J coupling constants of the phenyl and ethyl
,6R
5,6S
glycosides of 2,3,4,6ꢀtetraꢀOꢀbenzylꢀβꢀDꢀthioglucopyranoside 27 and 36 (Tables 2 and 3,
respectively) are less than the error limit and so substantiate the use of the different aglycones in
the two series.
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Table 1. Pertinent H Chemical Shifts, J Coupling Constants and Side Chain Populations for 1
and 13ꢀ22 in CDCl and C D .
3
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6
a
3
a
a
4
ꢀOꢀSubs
Chem Shift, ppm
J , Hz
5,6
Population, %
gg
6
R
6S
H
H
J5,6R
J5,6S
gt
tg
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
2
1
1
H
3.78
3.72)
3.65
3.57)
3.69
3.55)
3.64
3.47)
3.81
5.8
5.7
25.6
31.8
42.6
(
(3.75)
3.67
(6.1)
nd
(5.8)
nd
(21.9)
nd
(34.4)
nd
(43.7)
nd
1
2
3
4
PhCH
2
(
(3.66)
3.74
(5.7)
5.5
(7.4)
7.7
(13.2)
12.8
(22.6)
19.1
(64.2)
68.0
CF
Ac
CH
2
3
(
(3.68)
3.55
(5.7)
6.0
(7.6)
6.7
(11.7)
15.8
(21.7)
29.0
(66.7)
55.2
(
(3.42)
3.49
(6.1)
6.1
(6.5)
6.7
(16.4)
14.8
(31.0)
30.1
(52.6)
55.1
Me
CCO
3.62
3
(3.49)
3.69
(3.42)
3.59
(6.0)
5.8
(6.8)
6.8
(15.0)
17.0
(28.6)
26.5
(56.4)
56.5
17
PhCO
(
3.53)
3.68
3.56)
3.69
3.57)
3.69
3.47)
3.67
3.39)
(3.49)
3.57
(6.1)
5.9
(6.6)
6.8
(15.6)
16.0
(30.5)
27.5
(53.9)
56.5
1
1
2
1
1
8
9
0
5
6
pꢀMeC
6
H
4
CO
(
(3.52)
3.59
(6.2)
6.1
(6.5)
6.5
(15.4)
16.4
(32.0)
31.0
(52.5)
52.6
pꢀMeOC
H
CO
6
4
(
(3.54)
3.56
(6.2)
5.7
(6.4)
7.2
(16.2)
14.8
(32.5)
23.6
(51.3)
61.6
pꢀO NC H
2 6 4
CO
(
(3.42)
3.49
(5.6)
5.6
(7.0)
8.3
(17.3)
7.1
(23.5)
17.3
(59.1)
75.6
CF CO
3
(
(3.36)
3.59
(5.7)
5.7
(8.1)
8.2
(7.7)
6.9
(19.2)
18.8
(73.0)
74.3
Cl
CCO
3.71
3
(3.43)
(3.46)
nd
nd
nd
nd
nd
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2
3
4
5
6
7
8
9
a) Chemical shift, coupling constants, and populations in CDCl (Chemical
3
shift, coupling constants, and populations in C D ).
6
6
1
3
Table 2. Pertinent H Chemical Shifts, J Coupling Constants, and Side Chain Populations for 2
and 23ꢀ27 in CDCl and C D .
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
6
6
a
3
a
a
4
ꢀOꢀSubs
Chem Shift, ppm
J , Hz
Population, %
gg
5
,6
6R
6S
H
H
J5,6R
5.3
J5,6S
4.1
gt
tg
2
2
H
3.76
3.60)
3.73
3.63)
3.80
43.1
34.5
(36.4)
40.0
(nd)
22.4
(17.4)
ꢀ5.3
(nd)
nd
(
(3.64)
3.80
(5.3)
4.8
(3.7)
1.9
(46.2)
65.2
7
PhCH
Ac
2
(
(3.63)
3.58
(nd)
nd
(nd)
nd
(nd)
23
25
3.58
nd
nd
(3.54)
3.65
(3.58)
3.65
(5.8)
nd
(3.2)
nd
(45.3)
nd
(43.9)
nd
(10.8)
nd
PhCO
(
3.58)
3.58
3.30)
3.51
3.69)
(3.62)
3.61
(6.0)
4.7
(2.9)
3.6
(45.7)
52.9
(47.3)
30.8
(27.2)
47.1
(44.6)
(7.0)
16.3
(15.2)
ꢀ3.0
(ꢀ4.2)
2
2
4
6
CF CO
3
(
(3.37)
3.71
(4.3)
5.6
(3.5)
2.1
(57.6)
55.9
PhSO
2
(
(3.81)
(5.3)
(2.0)
(59.6)
a) Chemical shift, coupling constants, and populations in CDCl (Chemical shift, coupling
3
constants, and populations in C D ).
6
6
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
Table 3. Pertinent H Chemical Shifts and J Coupling Constants for 3 and 28ꢀ36 in CDCl and
3
C D .
6
6
a
3
a
a
6
ꢀOꢀSubs
Chem Shift, ppm
J , Hz
5,6
population, %
6
R
6S
H
H
J5,6R
J5,6S
gg
gt
tg
4.9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
H
3.71
3.58)
3.69
3.61)
4.20
4.26)
4.12
4.23)
4.46
4.51)
4.40
4.68)
4.58
4.56)
4.44
4.40)
3.87
4.8
2.7
59.0
(nd)
63.3
(nd)
36.1
(nd)
42.0
(nd)
(
(3.69)
3.76
(nd)
5.0
(nd)
1.9
(nd)
ꢀ5.3
(nd)
6
PhCH
2
(
(3.61)
(nd)
(nd)
2
2
3
8
9
1
Ac
4.33
5.4
2.4
55.5
43.7
0.9
(
(4.43)
(5.4)
(2.2)
(57.0)
(44.6)
(ꢀ1.7)
Me
CCO
4.44
5.6
1.8
58.2
(54.9)
nd
48.6
(48.2)
nd
ꢀ6.8
3
(
(4.55)
4.65
(5.7)
nd
(2.1)
nd
(ꢀ3.0)
nd
PhCO
(
(4.65)
(5.6)
(2.3)
(54.3)
(46.2)
(ꢀ0.5)
3
3
2
3
pꢀMeC
6
H
4
CO
4.59
5.5
2.2
56.1
45.6
ꢀ1.7
(
(4.54)
4.41
(5.7)
5.5
(2.2)
2.3
(54.1)
55.3
(47.7)
45.2
(ꢀ1.8)
ꢀ0.4
pꢀMeOC
H
CO
6
4
(
(4.69)
(5.6)
(2.2)
(55.1)
(46.7)
(ꢀ1.7)
3
3
4
0
pꢀO
2
NC
6
H
4
CO
4.62
5.4
2.2
57.0
44.6
ꢀ1.7
(
(4.56)
(5.6)
(2.3)
(54.3)
(46.2)
(ꢀ0.5)
CF
CO
4.32
4.54
6.3
2.1
49.0
(48.2)
nd
54.2
(53.8)
nd
ꢀ3.3
(ꢀ2.0)
nd
3
(4.05)
4.37
(4.24)
4.40
(6.3)
nd
(2.2)
nd
35
PhNHCO
(4.46)
(4.43)
(4.6)
(2.5)
(62.5)
(35.1)
(2.4)
a) Chemical shift, coupling constants, and populations in CDCl (Chemical
3
shift, coupling constants, and populations in C D ).
6
6
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9
Calculation of Side Chain Populations and Estimation of Errors
3
3
With the aid of limiting J
ꢀ J coupling constants for the pure gg, gt, and tgꢀconformers
S,tg
R,gg
46
(Table 4), determined using a series of rigid bicyclic models, the side chain populations (f ꢀf )
gg tg
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
of all compounds were determined with the aid of equations 1ꢀ3 in the usual manner and reported
47ꢀ49
in Tables 1ꢀ3.
Further inspection of Tables 1ꢀ3 reveals that an error of 0.4 Hz in one of the
coupling constants results in a maximal change of 5% in the population of any given conformer.
Therefore, in the discussion that follows we adopt 5% as the error limit for any given conformer.
In two series of compounds (Tables 2 and 3) small negative populations of the tg conformer are
computed for some derivatives, which have no physical significance. In view of the 5% error,
these negative populations are either indistinguishable from zero or so close to it as not to
warrant further discussion.
3
3
3
3
3
3
J5,6R =
J5,6S =
J
f + J f + J f (1)
R,gg gg R,gt gt R,tg tg
3
3
J
f + J f + J f (2)
S,gt gt S,tg tg
S,gg gg
1
= f + f + f (3)
gg gt tg
Table 4. Limiting Coupling Constants for the Pure gg, gt, and tg Staggered Conformers
3
3
JH5,H6R
JH5,H6S
JR,gg
JR,gt
JR,tg
JS,gg
JS,gt
JS,tg
1
.0
11.0
4.8
2.2
2.5
10.2
Corrections for the Influence of Electronegative Groups on the Magnitude of Coupling
Constants
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4
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The derivation of side chain populations from experimental NMR vicinal coupling constants
requires that the magnitude of the coupling constants not be affected by differences in
electronegativity of the substituents across the series. It is well known that vicinal coupling
5
0ꢀ53
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
constants are reduced by the presence of electronegative substituents in the coupled system,
51,54,55
but more subtle differences on replacement of ether groups by esters are less appreciated.
3
Consideration of the J coupling constants in the series of gluco and galactopyranoside
3,4
derivatives in Figure 4 indicates that replacement of a single ether group in a vicinal diether by
an ester results in an increase of approximately 0.5 Hz in the coupling constant, whether the
coupled spins have a fixed trans or a gauche relationship irrespective of the solvent, CDCl or
3
C D . However, it is known that in freely rotating systems that more closely approximate the
6
6
C5ꢀC6 bond in the 6ꢀOꢀsubstituted series 3 and 28ꢀ36 the difference in coupling constants on
54
replacing an ether by an ester substituent is only 0.1 Hz. As this is within the error limit no
correction for the change in substituents is required for the coupling constants in Table 3.
The influence of replacing an ether substituent by an ester in the βꢀposition to the coupled spins
3
is expected to be smaller, as is borne out by the constant magnitude of the J2 coupling
,3
constants in the glucoꢀ and galactopyranosides of Figure 4 regardless of the substituent at the 4ꢀ
3
position. The J coupling constants in the galactopyranosides 1 and 13ꢀ22 (Table 1), and the
5
,6
glucopyranosides 2 and 23ꢀ27 (Table 2) therefore do not require correction for the nature of the
substituent at the 4ꢀposition.
3
Comparison of the J coupling constants in the galactopyranosides reveals them to be ~0.4 Hz
2
,3
larger than the corresponding coupling constants in the glucopyranosides (Figure 4) as we have
4
6
noted previously in a series of rigid bicyclic models. This is a manifestation of the Altona and
Haasnoot βꢀeffect wherein the vicinal coupling constant between a pair of coupled antiperiplanar
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spins is increased by approximately 0.5 Hz when one of the coupled spin is also antiperiplanar to
5
6
an electronꢀwithdrawing substituent at the βꢀposition.
A comparable relationship exists
between H6R, H5 and O4 in the gt conformer and between H6S, H5 and O4 in the tg conformer
of the galactopyranosides (Figure 5) but not in the glucopyranosides, albeit in a series of rigid
bicyclic models no significant difference was found in the H5ꢀH6 coupling constants between
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
6
the galacto and gluco configurations, suggesting that the effect does not extend to this spin
system. Moreover, as the magnitude of the βꢀeffect is not influenced by the switch from an ether
to an ester (Figure 4), any residual influence will be of a systematic nature and affect all
derivatives to a similar extent. The result of any small systematic βꢀeffect simply will be to
overestimate the population of the gt and tg conformers in the galactopyranoside series (Table 1),
and underestimate that of the gg conformer correspondingly, with respect to the
glucopyranosides (Table 2).
In the final analysis no corrections to the diagnostic coupling constants used for conformational
analysis of the side chain arising from changes in electronegativity of the substituents or the
Altona and Haasnoot βꢀeffect were deemed necessary.
Figure 4. Differing Influences of Ether and Ester Substituents on Vicinal coupling Constants
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 5. Vicinal Coupling Constants Subject to the AltonaꢀHaasnoot βꢀEffect
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Influence of Substituents at the Galactopyranose 4-Position
Comparison of alcohol 1 with ethers 21 and 22 in Table 1 reveals that while the two ethers have
the same population distribution for the side chain given the 5% error, converting the 4ꢀhydroxy
group to a benzyl or trifluoroethyl ether has a significant influence on side chain conformation.
Thus, the side chain population of the two ethers of 21 and 22 consists of ~13% of the gg
conformer, ~21% of the gt, and 66% of the tg conformer, whereas the alcohol 1 has a much
greater population of the gg conformer (~24%), and a greater population of the gt conformer
(
~33%), which are balanced by a significantly lower occupancy of the tg conformer (~43%).
These differences reflect either the destabilizing influence of steric bulk at the 4ꢀposition on the
gg conformer or the stabilization of the gg conformer in the alcohol 1 by a favorable
intramolecular hydrogen bond to O6. Because of the differences in conformation between the
alcohol 1 and the ethers 21 and 22, and because glycosyl donors typically do not have
unprotected hydroxy groups, we retain the benzyl ether 21 as the standard for further
comparisons.
Esterification of 1 gives a series of 4ꢀOꢀesters, alkanoyl 13 and 14, or aroyl 17ꢀ20, that all adopt
the same side chain population, but one that differs significantly from that of the benzyl ether 21.
With similar proportions of the gg conformer in the ether 21 and the esters 13, 14, 17ꢀ20 the
change in overall side chain population can be described as one of an approximately 10%
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9
decrease in the population of the tg conformer in favor of the gt conformer on going from the
ethers to the esters. Installation of the more electronꢀwithdrawing trifluoroacetyl and
trichloroacetyl groups affords a separate set of two esters 15 and 16, respectively, whose side
chain populations exhibit a pronounced shift away from the gg conformer toward the tg
conformer. This change in population is also accompanied by a reduction in the population of
the gt conformer with respect to the more standard alkanoyl and aroyl esters such that the tg
conformer dominates the equilibrium and accounts for ~74% of the population. Albeit the effect
is smaller, the pꢀnitrobenzoate 20 exhibits a shift in side chain population shift away from that of
the more electronꢀrich benzoates 17ꢀ19 in the same direction as that observed with the trifluoro
and trichloroacetates 15 and 16 suggesting that this change is a function of the electronꢀ
withdrawing nature of these esters.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Influence of Substituents at the Glucopyranose 4-Position
In the glucopyranose series there is also a significant change in the side chain conformation
when the alcohol 2 is converted to the benzyl ether 27. Specifically, benzylation results in a drop
in the population of the tg conformer that is compensated by an increase in the population of the
gg conformer and a smaller one in that of the gt conformer (Table 2). This effect parallels that
seen in the galactopyranose series, in that it is the conformer in which O4 and O6 have a synꢀ
pentane type relationship (gg in galactose and tg in glucose) whose population is reduced on
benzylation (Figure 6) suggesting that this change in conformation is caused by the loss of a
favorable hydrogen bond or increased steric interactions in both cases.
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1
1
1
1
1
1
1
1
1
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Figure 6. synꢀPentane Conformations of the Galacto and Glucopyranoses Destabilized on
Replacement of a Hydroxy Group (X = H) by an Ether (X = R).
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As in the galactopyranose series we adopt the benzyl ether as the standard for the subsequent
comparisons with the influence of alternative protecting groups at the 4ꢀposition. The 4ꢀOꢀ
acetate 23 and the benzoate 25 adopt very similar conformations in which the gg conformer is
populated to a noticeably lower extent than in the benzyl ether 27, while the population of the tg
conformer increases. With the more electronꢀwithdrawing trifluoroacetate 24 the population of
the tg conformer increases further, but is balanced by a reduction in the population of both the gg
and gt conformers when compared to the benzyl ether 27. The population of side chain
conformation of the benzenesulfonate 26 is anomalous in so far as, unlike the other esters the tg
conformation is not occupied, presumably for steric reasons arising from an increased synꢀ
pentane interaction. This minimal population of the tg conformation in 26 results in a higher
population of the gg conformer than in the acetal and benzoate esters 23 and 25.
Influence of Substituents at the Glucopyranose 6-Position
In contrast to the differences in side chain population brought about by changing protecting
groups at the 4ꢀposition in the galacto and glucopyranose series, changes in the protecting group
at the 6ꢀposition of the 2,3,4ꢀtriꢀOꢀbenzyl glucopyranosides has minimal influence on the side
chain conformation (Table 3). It is noteworthy, however, that only two derivatives the 6ꢀalcohol
3
and the 6ꢀcarbamate 35 have a small positive population of the tg conformation, with the synꢀ
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pentane conformation (Figure 6), suggesting that this conformer is stabilized by hydrogen
bonding. The only other noteworthy feature from this series of compounds is the increased
population of the gt conformer at the expense of the gg conformer on the installation of the
strongly electronꢀwithdrawing trifluoroacetyl group. In view of the relatively small changes in
side chain conformation observed in the glucopyranose series with variation in the O6 protecting
group, we did not undertake a parallel study in the galactopyranose series.
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Discussion
The observed changes in side chain conformation with protecting groups at the 4ꢀposition for
both the galacto and glucopyranose systems are summarized in Figure 7. These changes are
ꢀ1
small, worth <1 kcal.mol , and are difficult to compute accurately with electronic structure
5
7ꢀ60
calculations,
and insufficient to account alone for the changes in anomeric reactivity and
6
,61ꢀ66
selectivity seen with such comparable changes in protecting group.
As the effects are small
we make no attempt here to rationalize them in terms of stereoelectronic or other phenomena,
other than to note that they are certainly related among other things to the distinct conformational
6
7ꢀ69
preferences of esters and ethers.
Nevertheless, such changes can be considered to modulate
the larger effects on anomeric reactivity arising from replacing an arming with a disarming
protecting group.
Figure 7. Summary of Changes in Side Chain Conformation with Protecting Groups at the 4ꢀ
Position of a) Galactopyranosides, and b) Glucopyranosides
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In both the galacto and glucopyranosyl systems the replacement of an arming ether protecting
group at the 4ꢀposition by an ester group results in diminished anomeric reactivity, whether
6
under standard conditions for the activation of thioglycosides, or in S 2ꢀdisplacements of
N
9
anomeric bromides by chloride. This change in reactivity is usually understood in terms of the
increased electronꢀwithdrawing ability of the ester destabilizing nascent positive, or partial
1
,5,6,8,17,70
positive charge at the reaction center (Scheme 4).
The results presented in Table 1 and
summarized in Figure 7a indicate that this effect will be moderated by the change in side chain
conformation in the galactopyranoside series. Thus, the increase in the gt conformation with its
intermediate reactivity at the expense of the less reactive tg conformation on replacement of a
benzyl ether by an alkanoyl or aroyl ester will partially offset the added electronꢀwithdrawing
effect of the ester group. In the glucopyranosyl series on the other hand (Table 2 and Figure 7b)
the main effect of the replacement of a benzyl ether by an alkanoyl or aroyl ester is to reduce the
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population of the most reactive gg conformer in favor of population of the least reactive tg
conformer, thereby complementing the increased electronꢀwithdrawing effect of the ester.
In both the galactoꢀ and glucopyranosyl series (Tables 1 and 2, Figure 7a and b) the replacement
of a benzyl ether at the 4ꢀposition by the strongly electronꢀwithdrawing trifluoroacetyl group
1
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(
and for the trichloroacetyl group investigated in the galactose series, Table 1) the population of
the most strongly electronꢀwithdrawing tg conformer is increased. Thus, in both the galacto and
glucopyranosides, the change in side chain conformation on installation of a trifluoroacetyl
group will reinforce the diminution of anomeric reactivity occasioned by the increased electronꢀ
withdrawing effect.
Scheme 4. Abbreviated General Glycosylation Mechanism and Influence of Protecting groups
and Side Chain Conformation.
The sulfonyl protecting group, initially explored as a strongly electronꢀwithdrawing group at the
7
1ꢀ73
2
ꢀposition capable of stabilizing mannoꢀ and rhamnopyranosyl triflates and other sulfonates,
and subsequently employed with varying degrees of success at the 4ꢀposition of 2,6ꢀ
7
4
75,76
dideoxyglycopyranosyl donors, and at the 3ꢀ, 4ꢀ, and 6ꢀpositions of other pyranosyl donors,
does not change the population of the side chain when replacing a benzyl ether at the 4ꢀposition
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of a glucosyl donor (Table 2, Figure 7b). The influence of 4ꢀOꢀsulfonyl group on
glucopyranosylation can therefore be interpreted solely in terms of the change in electronꢀ
withdrawing ability.
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The small changes in side chain conformation in a series of 4ꢀOꢀalkanoyl and aroyl esters in both
the galacto and glucopyranosyl series do not provide strong support for a protecting groupꢀ
induced change in side chain population as the basis for the changes in anomeric selectivity
7
7
78
previously seen in the series of 17ꢀ20 and related systems, previously explained by the
61ꢀ66
controversial
concept stereodirecting participation by remote groups. Similarly, the
consistent side chain conformation observed with numerous protecting groups at the 6ꢀposition
in the 2,3,4ꢀtriꢀOꢀbenzyl glucopyranosides (Table 3) does not support a role of the side chain
conformation in the changes in anomeric reactivity and glycosylation selectivity reported in such
7
9ꢀ81
series of compounds.
Conclusion
Replacement of a benzyl ether at the 4ꢀposition of phenyl 2,3,6ꢀtriꢀOꢀbenzylꢀβꢀDꢀthioꢀ
galactopyranosides by either an alkanoyl or aroyl ester results in a small but consistent change in
the population of the three staggered conformers of the side chain in which the proportion of the
less reactive tg conformer is reduced in favor of the gt conformer. This suggests that the
reduction in anomeric reactivity occasioned by the benzyl etherꢀester switch seen with glycosyl
donors, and attributed to the increased electronꢀwithdrawing ability of the ester, is moderated by
a change in side chain conformation in the galactose series. In the corresponding glucopyranosyl
series, on the other hand, the same etherꢀester change results in an increased population of the
less reactive tg conformer indicating that the change in conformation reinforces the effect of the
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increased electronꢀwithdrawing ability of the ester group.
In both the galacto and
glucopyranosyl series the installation of a trifluoroacetyl group at the 4ꢀposition results in an
enhanced population of the less reactive tg conformer. While the variations in side chain
conformation with changes in protecting group recorded here are small, it must be understood
that they are for the unactivated glycosyl donor. In view of the partial positive charge on the ring
oxygen during glycosylation, it is likely that such changes are accentuated at the transition state
for glycosylation reactions.. This possibility is under active investigation in our laboratory.
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Experimental Section
General Experimental Section: Commercial reagents were used without further purification
unless otherwise stated. NMR spectra were recorded in CDCl solution unless otherwise stated at
3
1
3
4
00, 500, or 600 MHz. C NMR spectra were recorded in CDCl solution unless otherwise stated
3
at 100, 125, or 150 MHz. Mass spectra were recorded in the +ve ion mode using electrospray
ionization (ESIꢀTOF). ESIꢀHRMS were recorded with a Waters LCT Premier Xe timeꢀofꢀflight
mass spectrometer. Specific rotations were recorded in dichloromethane solution at room
temperature.
Phenyl 2,3,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside (1). Compound 1 was synthesized as
3
1 1
described in the literature. H NMR (600 MHz, CDCl ) δ 7.59 – 7.57 (m, 2H), 7.42 – 7.41 (m,
3
2H), 7.36 – 7.21 (m, 13H), 7.25 – 7.23 (m, 3H), 4.83 (d, J = 10.3 Hz, 1H), 4.75 (d, J = 10.3 Hz,
1
2
3
H), 4.73 (d, J = 11.6 Hz, 1H), 4.69 (d, J = 11.6 Hz, 1H), 4.64 (d, J = 9.9 Hz, 1H), 4.57 (br s,
H), 4.11 (d, J = 3.2 Hz, 1H), 3.81 (dd, J = 5.7, 10.0 Hz, 1H), 3.78 (dd, J = 5.8, 10.0 Hz, 1H),
1
.76 (t, J = 9.5 Hz, 1H), 3.61 – 3.60 (m, 1H), 3.58 (dd, J = 3.3, 9.5 Hz, 1H), 2.55 (s, 1H). H
NMR (600 MHz, C D ) δ 7.68 (dd, J = 8.2, 1.0 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H, 2H), 7.23 (d, J
6
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=
7.6 Hz, 1H, 2H), 7.17 – 6.96 (m, 13H), 6.91 (t, J = 7.4 Hz, 1H), 4.85 (d, J = 10.8 Hz, 1H), 4.67
d, J = 10.8 Hz, 1H), 4.57 (d, J = 9.8 Hz, 1H), 4.34 – 4.26 (m, 4H), 3.83 (t, J = 9.3 Hz, 1H), 3.79
(d, J = 2.7 Hz, 1H), 3.75 (dd, J = 9.8, 5.8 Hz, 1H), 3.72 (dd, J = 9.8, 6.1 Hz, 1H), 3.25 (t, J = 5.9
(
−
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0
Hz, 1H), 3.20 (dd, J = 8.9, 3.2 Hz, 1H), 2.39 (s, 1H). IR (neat) ν 3480 cm (OꢀH).
2
Phenyl (6S)ꢀ[6ꢀ H ]ꢀ2,3,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀ
β
ꢀDꢀgalactopyranoside (6S-D-1). Compound 6S-
1
1
D-1 (0.40 g, 72%) was synthesized from compound 10 analogously to 1. H NMR (600 MHz,
CDCl ) δ 7.59 – 7.57 (m, 2H), 7.42 – 7.40 (m, 2H), 7.36 – 7.21 (m, 13H), 7.25 – 7.23 (m, 3H),
3
4.83 (d, J = 10.3 Hz, 1H), 4.75 (d, J = 10.3 Hz, 1H), 4.73 (d, J = 11.6 Hz, 1H), 4.69 (d, J = 11.6
Hz, 1H), 4.64 (d, J = 9.9 Hz, 1H), 4.56 (br s, 2H), 4.10 (d, J = 3.1 Hz, 1H), 3.76 (d, J = 2.9 Hz,
1
1
H), 3.75 (t, J = 9.5 Hz, 1H), 3.60 – 3.59 (m, 1H), 3.58 (dd, J = 3.2, 9.3 Hz, 1H). H NMR (600
MHz, C D ) δ 7.69 – 7.68 (m, 2H), 7.41 – 7.40 (m, 2H), 7.23 – 6.89 (m, 16H), 4.84 (d, J = 10.8
6
6
Hz, 1H), 4.66 (d, J = 10.8 Hz, 1H), 4.57 (d, J = 9.8 Hz, 1H), 4.31 (d, J = 11.9 Hz, 1H), 4.29 –
4
.27 (m, 3H), 3.82 (t, J = 9.2 Hz, 1H), 3.78 (d, J = 3.1 Hz, 1H), 3.70 (d, J = 6.2 Hz, 1H), 3.23 –
.22 (m, 1H), 3.19 (dd, J = 8.9, 3.2 Hz, 1H). HRMS (ESI) m/z calcd for C H DO SNa
3
3
3
33
5
+
[M+Na] , 566.2087; found, 566.2079.
Phenyl 2,3,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (2). Compound 25 (0.01 g, 0.015 mmol)
was dissolved in anhydrous methanol (0.5 mL) and cooled to 0 °C before it was treated with Na
(
catalytic amount). The reaction mixture was stirred under an argon atmosphere at room
temperature overnight, quenched with Amberlystꢀ15 (pH ~ 4), filtered, and concentrated to
dryness. The crude residue was purified by silica gel column chromatography, eluting with
hexane/ethyl acetate (19:1 to 4:1) to afford compound 2 (0.005 g, 62%) with spectral data
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1
consistent with the literature.
m, 18H), 4.92 (d, J = 11.4 Hz, 1H), 4.92 (d, J = 10.2 Hz, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.75 (d,
J = 10.2 Hz, 1H,), 4.70 (d, J = 9.6 Hz, 1H), 4.60 (d, J = 11.9 Hz, 1H), 4.56 (d, J = 11.9 Hz, 1H),
H NMR (600 MHz, CDCl ) δ 7.58 – 7.55 (m, 2H), 7.43 – 7.24
3
(
1
1
1
1
1
1
1
1
1
1
2
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4
.80 (dd, J = 10.4, 4.1 Hz, 1H), 3.76 (dd, J = 10.4, 5.3 Hz, 1H), 3.66 (dd, J = 9.6, 8.9 Hz, 1H),
.54 (dd, J = 8.9, 8.8 Hz, 1H), 3.50 (ddd, J = 9.6, 5.3, 4.1 Hz, 1H), 3.49 (dd, J = 9.6, 8.8 Hz, 1H),
1
.54 (br s, 1H). H NMR (600 MHz, C D ) δ 7.69 – 7.65 (m, 2H), 7.45 – 7.42 (m, 2H), 7.31 –
6
6
.94 (m, 16H), 4.94 (d, J = 10.6 Hz, 1H), 4.87 (d, J = 11.7 Hz, 1H), 4.76 (d, J = 11.7 Hz, 1H),
.69 (d, J = 10.6 Hz, 1H), 4.64 (d, J = 9.7 Hz, 1H), 4.33 (d, J = 11.9 Hz, 1H), 4.30 (d, J = 11.9
Hz, 1H), 3.66 (dd, J = 9.8, 8.9 Hz, 1H), 3.64 (dd, J = 10.4, 3.7 Hz, 1H), 3.60 (dd, J = 10.4, 5.3
Hz, 1H), 3.51 (dd, J = 9.7, 8.7 Hz, 1H), 3.43 (dd, J = 8.9, 8.7 Hz, 1H), 3.22 (ddd, J = 9.8, 5.3, 3.7
−1
Hz, 1H), 2.23 (s, 1H). IR (neat) ν 3441 cm (OꢀH).
2
Phenyl (6S)ꢀ[6ꢀ H ]ꢀ2,3,6ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (6S-D-2). Compound 6S-D-
1
1
2
(0.011 g, 60%) was synthesized from 6S-D-25 (21.7 mg, 0.034 mmol) analogously to 2. H
NMR (600 MHz, CDCl ) δ 7.58 – 7.53 (m, 1H), 7.44 – 7.22 (m, 18H), 4.91 (d, J = 11.4 Hz, 1H),
3
4
.91 (d, J = 10.4 Hz, 1H), 4.78 (d, J = 11.4 Hz, 1H), 4.74 (d, J = 10.4 Hz, 1H), 4.69 (d, J = 9.6
Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 3.74 (d, J = 5.4 Hz, 1H), 3.66 (dd,
J = 9.6, 8.8 Hz, 1H), 3.54 (t, J = 8.8 Hz, 1H), 3.48 (dd, J = 9.6, 8.8 Hz, 1H), 3.48 (dd, J = 9.6, 5.4
1
Hz, 1H), 2.53 (br s, 1H). H NMR (600 MHz, C D ) δ 7.71 – 7.64 (m, 2H), 7.46 – 7.41 (m, 2H),
6
6
7.30 – 6.93 (m, 16H), 4.94 (d, J = 10.6 Hz, 1H), 4.87 (d, J = 11.7 Hz, 1H), 4.75 (d, J = 11.7 Hz,
1
H), 4.69 (d, J = 10.6 Hz, 1H), 4.64 (d, J = 9.7 Hz, 1H), 4.32 (d, J = 12.2 Hz, 1H), 4.30 (d, J =
2.2 Hz, 1H), 3.65 (ddd, J = 9.7, 8.8, 2.9 Hz, 1H), 3.57 (d, J = 5.3 Hz, 1H), 3.51 (dd, J = 9.7, 8.7
1
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Hz, 1H), 3.42 (t, J = 8.8 Hz, 1H), 3.22 (dd, J = 9.7, 5.3 Hz, 1H), 2.19 (d, J = 2.9 Hz, 1H).
+
HRMS (ESI) m/z calcd for C H DO SNa [M+Na] , 566.2087; found, 566.2083.
3
3
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5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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9
0
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8
9
0
Ethyl 2,3,4ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (3). Compound 3 was synthesized as
33
1
described in the literature.
1.0Hz, 1H), 4.92 (d, J = 10.2 Hz, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.86 (d, J = 10.9 Hz, 1H), 4.75
d, J = 10.2 Hz, 1H), 4.66 (d, J = 10.9 Hz, 1H), 4.51 (d, J = 9.9 Hz, 1H), 3.87 (dd, J = 12.2, 2.7
Hz, 1H), 3.71 (dd, J = 9.1, 8.8 Hz, 1H), 3.70 (dd, J = 12.2, 4.8 Hz, 1H), 3.58 (dd, J = 9.6, 9.1 Hz,
H NMR (600 MHz, CDCl ) δ 7.40 – 7.26 (m, 15H), 4.93 (d, J =
3
1
(
1
H), 3.41 (dd, J = 9.9, 8.8 Hz, 1H), 3.38 (ddd, J = 9.6, 4.8, 2.7 Hz, 1H), 2.81 – 2.70 (m, 2H),
1
1.82 (br s, 1H), 1.33 (t, J = 7.4 Hz, 3H). H NMR (600 MHz, C D ) δ 7.45 – 7.42 (m, 2H), 7.35
6
6
–
7.31 (m, 2H), 7.26 – 7.23 (m, 2H), 7.19 – 7.05 (m, 9H), 4.99 (d, J = 10.6 Hz, 1H), 4.93 (d, J =
1.2 Hz, 1H), 4.85 (d, J = 11.2 Hz, 1H), 4.83 (d, J = 11.2 Hz, 1H), 4.74 (d, J = 10.6 Hz, 1H),
1
4.61 (d, J = 11.2 Hz, 1H), 4.36 (d, J = 9.7 Hz, 1H), 3.77 – 3.71 (m, 1H), 3.66 – 3.56 (m, 3H),
3
.43 (dd, J = 9.7, 8.4 Hz, 1H), 3.13 – 3.09 (m, 1H), 1.60 (br s, 1H) 2.56 – 2.42 (m, 2H), 1.11 (t, J
−1
=
7.4 Hz, 3H). IR (neat) ν 3484 cm (OꢀH).
2
Ethyl (6S)ꢀ[6ꢀ H ]ꢀ2,3,4ꢀtriꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (6S-D-3). A solution of
1
compound 12 (0.105 g, 0.27 mmol) in anhydrous methanol (1.0 mL) was cooled to 0 °C and
treated with Na (cat) and stirred under an argon atmosphere at room temperature for 1.5 h. Then
the reaction was quenched with Amberlystꢀ15 resin (pH ~7) and filtered through cotton before it
was concentrated to dryness. The crude residue was dissolved in anhydrous pyridine (0.8 mL)
and treated with tritylchloride (84 µL, 0.32 mmol) at room temperature. The reaction mixture
was stirred in dark at room temperature for 3 days. The reaction was then quenched with
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methanol (~ 70 µL), stirred for 1 h, and concentrated to dryness. The crude residue was dissolved
in chloroform, washed with cold aqueous saturated NaHCO , and cold brine. The organic layer
3
was dried over anhydrous Na SO and concentrated to dryness. The crude residue was dissolved
2
4
1
1
1
1
1
1
1
1
1
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
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8
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0
1
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7
8
9
0
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3
4
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8
9
0
in anhydrous DMF (0.9 mL) and cooled to 0 °C before it was treated with 60% NaH in mineral
oil (48 mg, 1.2 mmol) followed by benzyl bromide (141 µL, 1.2 mmol). The reaction mixture
was stirred under an argon atmosphere at room temperature for 6 h. The reaction mixture was
cooled to 0 °C before it was quenched with water. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine, dried over anhydrous Na SO and
2
4
concentrated to dryness. The crude residue was passed through a short pad of silica, eluting with
hexane/ethyl acetate (7:3) and concentrated. The residue was dissolved in a mixture of glacial
acetic acid and water (4:1, 1.3 mL) and heated at 80 °C for 2.5 h. The reaction mixture was
concentrated to dryness and purified using silica gel column chromatography, eluting with
1
hexane/ethyl acetate (4:1 to 7:2), obtain compound 6S-D-3 (0.045 g, 35%). H NMR (400 MHz,
CDCl ) δ 7.40 – 7.25 (m, 15H), 4.94 (d, J = 10.9 Hz, 1H), 4.92 (d, J = 10.2 Hz, 1H), 4.87 (d, J =
3
1
0.9 Hz, 1H), 4.87 (d, J = 10.9 Hz, 1H), 4.75 (d, J = 10.2 Hz, 1H), 4.66 (d, J = 10.9 Hz, 1H),
.51 (d, J = 9.8 Hz, 1H), 3.72 (t, J = 9.0 Hz, 1H), 3.68 (d, J = 4.9 Hz, 1H), 3.58 (dd, J = 9.7, 9.0
4
Hz, 1H), 3.41 (dd, J = 9.8, 8.8 Hz, 1H), 3.38 (dd, J = 9.7, 4.9 Hz, 1H), 2.84 – 2.69 (m, 2H), 1.33
+
(
t, J = 7.4 Hz, 3H). HRMS (ESI) m/z calcd for C H DO SNa [M+Na] , 518.2087; found,
2
9
33
5
5
18.2066.
(6S)ꢀl,6ꢀAnhydroꢀ2,3,4ꢀtriꢀOꢀacetylꢀ6ꢀbromoꢀ
β
ꢀDꢀgalactopyranose (5).
A mixture of l,6ꢀ
8
3
anhydroꢀ2,3,4ꢀtriꢀOꢀacetylꢀβꢀDꢀgalactopyranose
4
(0.77 g, 2.67 mmol) and Nꢀ
bromosuccinimide (1.9 g, 10.6 mmol)) in trifluorotoluene (40 mL) was refluxed over a 300ꢀW
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heat lamp for 8 h. After 8h, the solvent was evaporated under reduced pressure and the crude
product dissolved in EtOAc (50 mL). The solution was successively washed with aqueous
saturated Na S O , aqueous saturated NaHCO , and dried over Na SO . Evaporation of the
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solvent under reduced pressure gave a crude product which was purified through silicaꢀgel
column chromatography (eluent: 20% EtOAc in hexane) to give 5 (0.73g, 75%) as a yellowish
2
2
1
oil. [α]D = −63.6 (c 1.50, CH Cl ); H NMR (400 MHz, CDCl ) δ 6.60 (s, 1H), 5.81 (s, 1H),
2
2
3
5
.29 – 5.20 (m, 2H), 4.74 (dd, J = 4.0, 1.3 Hz, 1H), 4.71 (br s, 1H), 2.14 (s, 3H), 2.13 (s, 3H),
1
3
2
.05 (s, 3H); C NMR (100 MHz, CDCl ) δ 169.2, 169.1, 168.9, 101.7, 82.6, 79.6, 69.3, 66.9,
3
7
9
+
64.4, 20.7 (2), 20.5; HRMS (ESI) m/z calcd for C H BrO Na [M+Na] , 388.9848; found,
12
15
8
81
+
3
88.9849; calcd for C H BrO Na [M+Na] , 390.9828; found, 390.9828.
12 15 8
2
(
6S)ꢀ[6ꢀ H ]ꢀl,6ꢀAnhydroꢀ2,3,4ꢀtriꢀOꢀacetylꢀ
β
ꢀDꢀgalactopyranose (6). To a solution of 5 (2.3 g,
1
6
.26 mmol) and azobisisobutyronitrile (0.1 g, 0.63 mmol) in toluene (170 mL) was added freshly
44
prepared triꢀnꢀbutyltin deuteride (5.5 g, 18.79 mmol) and the reaction mixture was refluxed for
.5 h. The cooled reaction mixture was evaporated in vacuo to give a crude product which was
purified on silicaꢀgel column chromatography (eluent: 40% EtOAc in hexane) to give 6 (1.4 g,
0
22
1
7
7%) as a colorless oil. [α]D = −10.0 (c 1.15, CH Cl ); H NMR (400 MHz, CDCl ) δ 5.42 (s,
2
2
3
1H), 5.29 – 5.20 (m, 2H), 4.75 (s, 1H), 4.45 (d, J = 2.7 Hz, 1H), 4.31 (s, 1H), 2.12 (s, 6H), 2.02
1
3
(
s, 3H); C NMR (100 MHz, CDCl ) δ 169.5, 169.3, 169.2, 98.9, 72.0, 71.0, 67.4, 64.2 (t, J =
3
+
2
3
3.5 Hz), 20.8, 20.7, 20.5; HRMS (ESI) m/z calcd for C H DO Na [M+Na] , 312.0806; found,
1
2
15
8
12.0818.
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(
6S)ꢀ[6ꢀ H ]ꢀ1,2,3,4,6ꢀPentaꢀOꢀacetylꢀαꢀDꢀgalactopyranose (7). To a solution of compound 6
1
(
1.4 g, 4.84 mmol) in MeOH (20 mL) was added Na (catalytic amount) slowly and the reaction
®
mixture was stirred for 7 h, then neutralized with Amberlite IR120, filtered, and concentrated
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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0
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2
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2
3
4
5
6
7
8
9
0
2
2
under reduced pressure to give (6S)ꢀ[6ꢀ H ]ꢀ1,6ꢀanhydrogalactose. A solution of (6S)ꢀ[6ꢀ H ]ꢀ
1
1
1
,6ꢀanhydrogalactose (0.73 g, 4.47 mmol) in Ac O (20 mL) was treated with conc.H SO (0.35
2 2 4
o
mL) at 0 C and stirred for 3 h. The reaction mixture was poured into a saturated aqueous
NaOAc solution (50 mL) and extracted with CHCl (3 × 20 mL), washed with brine (10 mL),
3
dried over Na SO , and concentrated under high vacuum to give the crude product. Column
2
4
chromatography (eluent: 30% EtOAc in hexane) on silicaꢀgel yielded 7 (1.5 g, 81% over 2 steps)
3
6
1
as a colorless syrup with spectral data consistent with the literature.
H NMR (400 MHz,
CDCl ) δ 6.29 (d, J = 2.2 Hz, 1H), 5.42 (s, 1H), 5.29 – 5.19 (m, 2H), 4.27 (d, J = 6.4 Hz, 1H),
3
3
.99 (d, J = 6.5 Hz, 1H), 2.09 (s, 3H), 2.08 (s, 3H), 1.96 (d, J = 2.5 Hz, 3H), 1.95 (d, J = 3.9 Hz,
3H), 1.93 (s, 3H).
2
Phenyl (6S)ꢀ[6ꢀ H ]ꢀ2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀ
β
ꢀDꢀgalactopyranoside (8). To a stirred
1
2
solution of (6S)ꢀ[6ꢀ H ]ꢀ1,2,3,4,6ꢀpentaꢀOꢀacetylꢀαꢀDꢀgalactopyranose 7 (1.5 g, 3.83 mmol) and
1
o
thiophenol (047 mL, 4.59 mmol) in CH Cl was added BF
3
·Et
2
O (1.9 mL, 7.66 mmol) at 0 C.
2
2
The reaction mixture was stirred at room temperature for 22 h, then quenched with aqueous
saturated NaHCO solution (50 mL) and extracted with CH Cl (3 × 25 mL), dried over Na SO
and concentrated under high vacuum. The crude product was purified on silicaꢀgel column
2
2
4
,
3
2
8
4
1
(eluent: 20% EtOAc in hexane) chromatography to give 8 (900 mg, 56%) as a colorless oil. H
NMR (400 MHz, CDCl ) δ 7.51 – 7.48 (m, 2H), 7.30 – 7.28 (m, 3H), 5.40 (d, J = 2.8 Hz, 1H),
3
5
.22 (t, J = 10.0 Hz, 1H), 5.03 (dd, J = 9.9, 3.3 Hz, 1H), 4.70 (d, J = 10.0 Hz, 1H), 4.17 (d, J =
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