Synthesis of Conformationally-Locked cis- and trans-Bicyclo[4.4.0] Mono-, Di-, and Trioxadecane Modifications of Galacto- and Glucopyranose; Experimental Limiting 3JH,H Coupling Constants for the Estimation of Carbohydrate Side Chain Populations and beyond

Article abstract of DOI:10.1021/acs.joc.7b02891

Hexopyranose side chains populate three staggered conformations, whose proportions can be determined from the three sets of ideal limiting ³J_H5,H6R and ³J_H5,H6S coupling constants in combination with the time-averaged experimental coupling constants. Literature values for the limiting coupling constants, obtained by the study of model compounds, the use of the Haasnoot-Altona and related equations, or quantum mechanical computations, can result in computed negative populations of one of the three ideal conformations. Such values arise from errors in the limiting coupling constants and/or from the population of nonideal conformers. We describe the synthesis and analysis of a series of cis- and trans-fused mono-, di-, and trioxabicyclo[4.4.0]octane-like compounds. Correction factors for the application of data from internal models (-CH(OR)-CH(OR)-) to terminal systems (-CH(OR)-CH₂(OR)) are deduced from comparison of further models, and applied where necessary. Limiting coupling constants so-derived are applied to the side chain conformations of three model hexopyranosides, resulting in calculated conformer populations without negative values. Although, developed primarily for hexopyranose side chains, the limiting coupling constants are suitable, with the correction factors presented, for application to the side chains of higher carbon sugars and to conformation analysis of acyclic diols and their derivatives in a more general sense.

Full text of DOI:10.1021/acs.joc.7b02891

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Article
Synthesis of Conformationally-Locked cis- and trans-Bicyclo[4.4.0]
Mono-, Di- and Trioxadecane Modifications of Galacto- and
Glucopyranose. Experimental Limiting 3JH,H Coupling Constants for
the Estimation of Carbohydrate Side Chain Populations and Beyond.
Harsha Amarasekara, Suresh Dharuman, Takayuki Kato, and David Crich
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02891 • Publication Date (Web): 14 Dec 2017
Downloaded from http://pubs.acs.org on December 15, 2017
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Synthesis of Conformationally-Locked cis- and trans-
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Bicyclo[4.4.0] Mono-, Di- and Trioxadecane Modifications of
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Galacto- and Glucopyranose. Experimental Limiting J
H,H
Coupling Constants for the Estimation of Carbohydrate Side
Chain Populations and Beyond.
†
†
Harsha Amarasekara, Suresh Dharuman, Takayuki Kato, and David Crich*
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
dcrich@chem.wayne.edu
ABSTRACT: Hexopyranose side chains populate three staggered conformations, whose proportions can be
3
3
determined from the three sets of ideal limiting J
and J
coupling constants in combination with the
H5,H6S
H5,H6R
time-averaged experimental coupling constants. Literature values for the limiting coupling constants, obtained
by the study of model compounds, the use of the Haasnoot-Altona and related equations, or quantum
mechanical computations, can result in computed negative populations of one of the three ideal conformations.
Such values arise from errors in the limiting coupling constants and/or from the population of non-ideal
conformers.
We describe the synthesis and analysis of cis- and trans-fused mono-, di-, and tri-
oxabicyclo[4.4.0]octane-like compounds. Correction factors for the application of data from internal models (-
CH(OR)-CH(OR)-) to terminal systems (-CH(OR)-CH2(OR)) are deduced from comparison of further models,
†
These authors contributed equally.
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and applied where necessary. Limiting coupling constants so-derived are applied to the side chain conformations
of three model hexopyranosides, resulting in calculated conformer populations without negative values.
Although, developed primarily for hexopyranose side chains, the limiting coupling constants are suitable, with
the correction factors presented, for application to the side chains of higher carbon sugars and to conformation
analysis of acyclic diols and their derivatives in a more general sense.
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Introduction.
The growing need for the synthesis of complex oligosaccharides with which to address and
exploit the varied roles in biology of glycosides and their conjugates provides the impetus for the
1ꢀ3
development of improved glycosylation methodology.
For this to take place in a rational
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ꢀ14
manner, increased understanding of the mechanism(s) of glycosylation
and of the factors that
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influence the reactivity and selectivity of glycosyl donors and acceptors is required.
The
conformational dynamics of donors, whether of the furanoside or pyranoside rings themselves or
simply of their side chains, is one factor that has a profound influence on reactivity and
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4ꢀ38
selectivity.
With regard to the side chain, in freely rotating systems the conformation is
usually considered as an equilibrium mixture of three staggered conformers (Fig. 1), which are
described as gaucheꢀgauche (gg), gaucheꢀtrans, and transꢀgauche (tg) where the first and second
6
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descriptors refer to the spatial relationship of O with the pyranoside ring oxygen (O ) and C ,
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respectively.
The mole fractions (f , f and f ) of these conformers at equilibrium can be
gg gt tg
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determined in the usual way from the experimental JH5,H6R and J
coupling constants
H5,H6S
provided that accurate limiting values of these coupling constants are available for each of the
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2ꢀ43
three ideal staggered conformations.
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Figure 1. Staggered Conformations of the Hexopyranose Side Chain Illustrated for Methyl αꢀDꢀ
Glucopyranoside, and the Associated Limiting Coupling Constants.
Knowledge of the six limiting coupling constants, whose values vary according to the
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electronegativity and orientation of the substituents attached to the coupled system,
is
therefore critical for determining side chain conformational distributions and ultimately for
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relating them to reactivity. The parameterization of the Karplus, and HaasnootꢀAltona
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equations, to take account of substituent effects has resulted in a number of suggested values
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for J – J whose reliability depends on the underlying models, as summarized by Bock and
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S,tg
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Duus in 1994, and subsequently revisited by various authors.
The situation is further
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complicated by the possible dependence of J
– J on the orientation of substituents not
R,gg
S,tg
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1ꢀ53
directly attached to the coupled system.
An alternative approach to deriving limiting coupling constants makes use of experimental
measurements on model compounds. This approach was followed by Bock and Duus, who
employed the C1ꢀC2 bonds of the 1,5ꢀanhydroalditol 1 as models of the gg conformer, and of 2
5
6R
6S
and 3 as models of the tg conformer, as depicted in Figure 2 where H , H and H are the side
39
chain hydrogens modeled. In 2 and 3 the relationship of the C1ꢀC2 bond to the C5ꢀC6 bond in
the Dꢀsugars is formally a pseudoenantiomeric one, but the modelled diastereotopic hydrogens
6
R
6S
are labelled H and H for ease of comparison. Subsequently, Serianni and coꢀworkers,
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following the earlier work of Ohrui et al with related benzylidene acetals, employed the
galactoꢀconfigured pyruvate acetal 4, the transꢀ2,5ꢀ(bishydroxymethyl)ꢀ1,4ꢀdioxane 5 and the
glucoꢀconfigured pyruvate acetal 6 as models for the gt, gg and tg conformations, respectively,
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and determined the relevant coupling constants in D O (Fig 2). Clearly, there are significant
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differences in the limiting coupling constants for the gg and tg conformers predicted by the two
sets of compounds (Fig 2); only one set of data is available for the gt conformer. Earlier models
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for the gg and gt conformers, 7 and 8, respectively, are of limited value because of ambiguities
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in the degree to which they model the conformations in question.
Figure 2. 1,5ꢀAnhydroalditols and Other Models for the gg, gt ,and tg Conformers (Numbers in
3
9,49,55
bold colors refer to the hydrogens modeled in the hexopyranose side chain).
Ongoing projects in our laboratory requiring the determination of pyranoside side chain
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conformational populations, focused our attention on the discrepancies in the data from the
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different sets of existing models. We considered that accurate values of the necessary limiting
coupling constants would be best accessed by the synthesis and analysis of a series of
conformationally rigid oxabicyclo[4.4.0]decane derivatives 9ꢀ20 designed to model the full set of
staggered conformations in the gluco and galacto series.
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Figure 3. Oxaꢀ, Dioxaꢀ, and Trioxadecalins for the Determination of Limiting JH,H Coupling
Constants About the C5ꢀC6 bond in Galactoꢀ and Glucopyranosides (Numbers in bold colors
refer to the hydrogens modeled in the hexopyranose side chain).
Potential problems with the legitimacy of individual members of this set of model compounds
including i) the conformational purity in particular of the cisꢀfused systems, and of systems with
1
,3ꢀdiaxial interactions; ii) the measurement of coupling constants in tetrasubstituted systems at
as opposed to the trisubstituted ones of the hexose side chains; and iii) the combination of both
of these factors led us to prepare a further series of compounds 21ꢀ26 (Fig 4) for comparison
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purposes. Models 21 and 24 additionally enable verification of the literature data obtained with
compounds 1 and 2, and in doing so probe the influence of etherꢀtype protecting groups on the
relevant coupling constants. As with models 2 and 3, the relationship of the C1ꢀC2 bond in
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compounds 21ꢀ23 with the side chain of the Dꢀsugars is pseudoenantiomeric, and the labels H
6S
and H are retained for ease of comparison.
Figure 4. Further Bicyclic Model Systems for Comparison of Coupling Constants Between Triꢀ
and Tetrasubstituted Systems (Numbers in bold colors refer to the hydrogens modeled in the
hexopyranose side chain).
We report here on the synthesis of the twelve compounds 9ꢀ20 (Fig 3) and of the further models
2
1ꢀ26 (Fig 4), and on the measurement of the relevant coupling constants in perdeuteriobenzene,
chloroform, and methanol. On the basis of careful comparative analysis of the spectral data for
9ꢀ26, and the literature comparators 1ꢀ6, an optimal set of model compounds and the associated
limiting coupling constants are defined.
While the primary focus of this Article is on the side chain conformations of the common
hexopyranoses, the limiting coupling constants derived from models carrying an additional CC
bond at the 6ꢀposition are also directly applicable to the side chains of the octulosonic and
34,57
nonulosonic acids
and to those of other higher carbon sugars such as are frequently found in
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bacterial oligosaccharides.
Finally, the limiting coupling constants presented should also be
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applicable to the conformational analysis of other organic constructs based on the vicinal
dihydroxy or dialkoxyalkane structural motif, whether triꢀ or tetrasubstituted, as well as to the
development of improved computational models.
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Results and Discussion
Synthesis
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27
27
25
25
63
64ꢀ67
Compounds 10, 11, 14, 16, 18, 20 and 21ꢀ26
were either prepared as previously
reported or as described in the experimental section. Compounds 9, 12, 17, and 19 were
prepared as outlined in Scheme 1. Thus, reduction of methyl 2,3ꢀOꢀmethyl,4,6ꢀOꢀpꢀ
6
8
methoxybenzylideneꢀαꢀDꢀglucopyranoside 27 with sodium cyanoborohydride in the presence
69ꢀ70
of HCl
gave 71% of the 6ꢀOꢀpꢀmethoxybenzyl ether 28, whose unique hydroxyl group was
71
subjected to the DessꢀMartin protocol to give ketone 29 in 85% yield. Reaction with
o
allylmagnesium chloride in THF at 0 C then gave the 4ꢀCꢀallyl galactoꢀ and glucopyranosides
30 and 31 in 54 and 19% yield, respectively. The individual isomers were treated with sodium
hydride and methyl iodide to give the corresponding ethers 32 and 33, from which the PMB
groups were cleaved with CAN giving the primary alcohols 34 and 35. Dess Martin oxidation of
the galactoꢀisomer 34 gave an aldehyde 36 that on treatment with vinylmagnesium bromide in
o
THF at ꢀ78 C gave an 81% overall yield of an inseparable 1.5:1 mixture of the allylic alcohols
3
8 and 39, whose relative configurations were assigned retrospectively. Adapting earlier work
3
6,72
on the synthesis of bicyclic pyranose derivatives,
the mixture of 38 and 39 was subjected to
7
3
ringꢀclosing metathesis with the second generation Grubbs catalyst to give 40 and 41 at which
stage separation was achieved. This was followed by saturation of the double bond giving 42
and 43 and finally methylation with sodium hydride and methyl iodide to give 12 and 9,
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respectively, at which stage H NMR spectral analysis allowed unambiguous assignment of
relative configuration. In an analogous manner oxidation of 35 with the Dess Martin periodinane
gave an aldehyde 37, whose treatment with vinylmagnesium bromide afforded the
diastereomeric allylic alcohols 44 and 45 in 12 and 48% yield, respectively. The diastereomers
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4 and 45 were then processed individually through the sequence of ring closing metathesis to
give 46 and 47, respectively, hydrogenation to 48, and 49, and finally methylation to give 17 and
1
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9 whose H NMR spectra allowed unambiguous assignment of relative configuration.
Scheme 1. Synthesis of the Bicyclic Pyranosides 9, 12, 17, and 19.
Compounds 13 and 15 were obtained (Scheme 2) by Dess Martin oxidation of methyl 6ꢀOꢀ
7
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benzylꢀ2,3ꢀdiꢀOꢀmethylꢀαꢀ
D
ꢀglucopyranoside 50 to the corresponding ketone 51 followed by
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treatment with allylmagnesium chloride in THF at 0 C when the 4ꢀCꢀallyl galacto and 4ꢀCꢀallylꢀ
glucopyranosides 52 and 53 were obtained in 60 and 22% yield, respectively. Etherification with
sodium hydride and methyl iodide then gave the ethers 54 and 55, which were subjected to
ozonolysis with reductive work up to give the 4ꢀCꢀ(2ꢀhydroxyethyl) derivatives 56 and 57 in
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25,27
good yield. Adapting a protocol previously employed for the synthesis of 11, 14, 16, and 18,
reaction of the galactoꢀisomer 56 with toluenesulfonyl chloride in pyridine afforded the tosylate
5
8 in 66% isolated yield, which on hydrogenolysis and subsequent treatment with sodium
hydride gave the transꢀfused bicyclic system 13 in 80% yield. The glucoꢀisomer 57 was
similarly processed through the mesylate to the cisꢀfused bicyclic product 15. Attempted
tosylation of 57, in direct analogy to the protocol applied to 56, and under a variety of different
conditions afforded an unstable tosylate 60 that decomposed on standing and on attempted silica
gel chromatography to give the cisꢀfused dioxabicycloꢀ[4.3.0]ꢀnonane 61 in varying yields. This
compound, which was also a byproduct from the mesylationꢀhydrogenationꢀring closing
sequence, was obtained as a single diastereomer whose structure was assigned on the basis of
multiple HMBC correlations and nOe measurements as described in the Supporting Information.
Scheme 2. Synthesis of the Bicyclic Pyranosides 13 and 15 and the Dioxahydrindane Derivative
6
1.
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X
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OBn
O
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O
O
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O
AllylMgCl,
THF, 0 oC
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O
Y
+
MeO
MeO
MeO
MeO
OMe
MeO
MeO
OMe
OMe
(52:53 = 2.8:1)
50: X = H, Y = OH
1: X = Y = O
52: X = H, 60%
54: X = Me, 93%
53: X = H, 22 %
55: X = Me, 86%
NaH,
MeI
NaH,
MeI
DMP
5
i) O3
ii) NaBH4
i) O3
ii) NaBH4
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
MeO OBn
O
MeO
MeO OBn
O
MeO
MeO
OMe
HO
OBn
O
TsCl, py,
DMAP
TsO
HO
MeO
MeO
MeO
OMe
MeO
OMe
5
8, 66%
56, 71%
57, 85%
MsCl, py,
0 o
i) H2, Pd(OH)2/C
ii) NaH
C
O
OMe
H , Pd(OH) /C MsO
OBn
O
2
2
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
OMe
OMe
OMe
1
3, 80%
15, 21%
59
OBn
TsO
MeO
OBn
O
O
MeO
O
MeO
MeO
MeO
OMe
OMe
61
60
51% from 57 via tosylation
3% from 57 via mesylation
2
Determination of Coupling Constants and Influence of Solvent and Protecting Groups
1
H NMR spectra of the bicyclic models 9ꢀ21 were recorded in C D , CDCl , and CD OD. All
6
6
3
3
first order couplings were analyzed directly on the spectra. For second order spectra,
complicated by the presence of virtual couplings, first order coupling constants were extracted
with the help of spectral simulation using the DAISY simulation tool in the Bruker Topspin 3.5
suite of programs. As the spectra of 9ꢀ21, revealed only minimal differences across the three
3
solvents, spectra for the models 22ꢀ26 were only obtained in CDCl . The J
coupling
3
H1,H2
constants obtained in CDCl with the benzylidene protected
Dꢀ1,5ꢀOꢀglucitol and mannitol
3
derivatives 21 and 24 carrying benzyl ethers at the 2ꢀ and 3ꢀpositions do not differ in any
significant way from those reported by Bock and Duus for the parents, 1,5ꢀanhydroglucitol 2 and
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mannitol 1, in water, indicating that neither inclusion in a bicyclic system, nor the ether
protecting groups, nor solvents have a substantial influence on these coupling constants.
3
The complete set of JH,H coupling constants for 9ꢀ20 and 21ꢀ26 and are tabulated in the
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
3
Supporting Information (Tables S1 and S2) for ease of comparison. The J
and J
H5,H6S
H5,H6R
coupling constants for 9ꢀ21 and 24, and the literature models 1ꢀ8 are presented in Tables 1ꢀ3. To
facilitate comparison and subsequent discussion Tables 1ꢀ3 are each broken down into two
3
3
subsets of data: a first for the J
coupling constants followed by a second for the J
H5,H6S
H5,H6R
coupling constants. Further, in each subset, coupling constants modelled for the galacto
configuration precede those for the gluco isomer.
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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
3
3
Table 1. J
and J
Coupling constants for gg conformers
H5,H6S
H5,H6R
Experimental and (corrected)
Cmpd
Ring
C6
Correction
3
c
Entry
Config
J
H5,H6 values (Hz)
Comment
a
b
(
bond)
fusion
Subst
(Hz)
C D
6
CDCl3
CD OD
6
3
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
5
6R
H ,H
1
2
3
4
5
6
10
galacto
gluco
ꢀ
cis
cis
ꢀ
CH2
CH2
CH2
CH2
CH2
CH2
na
na
na
na
na
na
1.9
1.7
nd
1.8
1.7
1.1
1.7
1.7
nd
exclude
exclude
include
include
exclude
exclude
15
24 (C1,C2)
d
1 (C1,C2)
ꢀ
ꢀ
0.9
d
4
7
galacto
gluco
cis
ꢀ
1.8
5.4
5
6S
H ,H
7
8
9
9
galacto
galacto
gluco
gluco
ꢀ
trans
cis
trans
cis
ꢀ
CH
ꢀ0.5
na
3.2 (2.7)
1.6
3.0 (2.5)
1.8
3.2 (2.7)
1.6
exclude
exclude
include
exclude
include
include
exclude
exclude
10
CH2
CH
16
ꢀ0.5
na
2.6 (2.1)
1.6
2.6 (2.1)
1.6
2.6 (2.1)
1.6
1
1
1
1
1
0
1
2
3
4
15
CH2
CH2
CH2
CH2
CH2
24
na
nd
2.2
nd
d
1 (C1,C2)
ꢀ
ꢀ
na
2.2
d
4
7
ꢀ
cis
ꢀ
na
1.8
gluco
na
1.2
a) Unless otherwise stated the C5ꢀC6 bond is considered. b) Correction factor for the presence of the
additional CC bond per Table 5 and text. c) Compounds are either excluded or included from further
consideration as valid models as discussed in the text. d) Measured in D O
2
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Table 2. J
and J
Coupling constants for gt conformers
H5,H6S
H5,H6R
Experimental and (corrected)
Ring
C6
Cmpd
(bond)
Correction
(Hz)
3
c
Entry
a
Config.
b
J
H5,H6 values (Hz)
Comment
fusion
Subst
C D
6
CDCl3
CD OD
3
6
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
5
6R
H ,H
1
2
3
4
12
galacto
gluco
ꢀ
trans
CH
+2.0
+2.0
na
9.2 (11.2) 9.2 (11.2) 9.2 (11.2)
9.2 (11.2) 9.0 (11.0) 9.2 (11.2)
include
include
include
exclude
18
trans
CH
d
5 (C1,C2)
ꢀ
ꢀ
CH2
CH2
10.7
8
gluco
9.5
5
6S
H ,H
5
6
7
8
11
galacto
gluco
ꢀ
cis
cis
ꢀ
CH
ꢀ0.5
ꢀ0.5
na
3.2 (2.7)
3.0 (2.5)
3.2 (2.7)
3.1 (2.6)
3.1 (2.6)
3.1 (2.6)
include
include
include
exclude
17
CH
d
5 (C1,C2)
CH2
CH2
2.5
8
gluco
na
1.5
a) Unless otherwise stated the C5ꢀC6 bond is considered. b) Correction factor for the presence of the
additional CC bond per Table 5 and text. c) Compounds are either excluded or included from further
consideration as valid models as discussed in the text. d) Measured in D O
2
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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
3
3
Table 3. J
and J
Coupling constants for tg conformers
H5,H6R
H5,H6S
Experimental and (corrected)
Ring
fusion
C6
Cmpd
bond)
Config
Correction
(Hz)
3
c
Entry
a
b
J
H5,H6 values (Hz)
Comment
(
.
Subst
C D
6
CDCl3
CD OD
6
3
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
5
6R
H ,H
1
2
3
4
5
6
7
8
9
13
14
19
20
galacto trans
galacto cis
CH2
CH
na
0
4.8
3.0
2.8
4.9
5.7
4.4
3.1
2.8
4.7
5.7
4.7
3.1
2.7
4.7
5.6
include
exclude
exclude
include
exclude
exclude
exclude
include
include
gluco
cis
CH
0
gluco
trans
trans
ꢀ
CH2
CH2
CH2
CH2
CH2
CH2
na
na
na
na
na
na
21 (C1,C2)
ꢀ
d
2
3
6
ꢀ
5.5
d
ꢀ
ꢀ
5.6
d
gluco
trans
trans
5.0
21 (C5,C6) gluco
5.0
5.0
5.0
5
6S
H ,H
1
1
1
1
1
1
1
0
1
2
3
4
5
6
13
galacto trans
CH2
CH2
CH2
CH2
CH2
CH2
CH2
na
na
na
na
na
na
na
10.5
10.3
10.6
10.8
10.1
10.1
10.5
10.3
10.2
10.5
include
include
exclude
exclude
exclude
include
include
20
gluco
trans
trans
ꢀ
21 (C1,C2)
ꢀ
d
2
3
6
ꢀ
d
ꢀ
ꢀ
~10
d
gluco
trans
trans
~10.3
10.2
21 (C5,C6) gluco
10.2
10.2
a) Unless otherwise stated the C5-C6 bond is considered. b) Correction factor for the presence of the
additional CC bond per Table 5 and text. c) Compounds are either excluded or included from
further consideration as valid models as discussed in the text. d) Measured in D O
2
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9
Analysis of Bicyclic Systems 9ꢀ20.
The viability of the bicyclic derivatives 9ꢀ20 as accurate models of the staggered conformations
of pyranoside side chains depends critically on the adoption of the pure chairꢀchair
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
conformations depicted in Figure 3. Six of the models are transꢀdecalin analogs and, with one
3
exception, present little reason for concern. Indeed, analysis of the complete set of J
H,H
coupling constants for compounds 12, 13, 16, 18, and 20 (Table S1) provide no evidence of
significant deviation from the chairꢀchair conformation. For the benzylidene acetal 20 this is
further supported by the examination of literature Xꢀray crystal structures of cognate structures
o
(eg, CCDC: HEGREQ) that show >2 deviation in torsion angles from the ideal tg conformation
75
1
about the C5ꢀC6 bond.
Comparison of the complete set of HꢀNMR spectral data of the
remaining transꢀdecalinoid structure 9 with that of its diastereomer 12 (Table S1) reveals a
significant difference in the axial,equatorial (a,e) coupling constants between H7 and H8, and H8
and H9 suggesting that the unfavorable steric and dipolar interactions between the two axial
methoxy groups in 9, despite the small size of a methoxy group (steric A values range from 0.55ꢀ
ꢀ1 43
0
.75 kcal.mol ) is relieved by distortion of the carbocyclic ring. This distortion is minor as the
pattern of nOe interactions around the carbocyclic ring of 9 (Figure 5) are indicative of a chairꢀ
like conformation, nevertheless they are sufficient for us to exclude 9 as a model for the ideal gg
conformation of the galactopyranose side chain. The unfavorable interaction between the two
methoxy groups of 9 in a synꢀpentane conformation is directly comparable to the interaction
between O4 and O6 that is responsible for the low population of the ggꢀconformer of
galactopyranose. Indeed, the conformational distortion that this interaction imposes on the
bicyclic system 9 strongly suggests that the ideal gg conformer of 4,6ꢀdiꢀOꢀmethyl ethers of
galactopyranose and its derivatives can have no appreciable population.
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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
H8ax
H8ax
MeO
MeO
H7ax
H9ax
MeO
H2
O
O
H7
ax
O
MeO
MeO
Me
H9ax
H5
O
MeO
H3
OMe
Me
OMe
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
9
19
3
3
7ax 8ax
3J(H7ax,H8ax) = 13.5-13.9 Hz
3J(H8ax,H9ax) = 13.1-13.3 Hz
J(H ,H ) = 13.5-14.1 Hz
8ax 9ax
J(H ,H ) = 13.3-13.5 Hz
Figure 5. Selected nOe Interactions and Coupling Constants (Mean values across the three
solvents employed) Diagnostic of ChairꢀChairꢀlike Conformations for 9 and 19.
Compounds 10, 11, 14, 15, 17, and 19 on the other hand, because of the inherently more
conformationally mobile nature of the cisꢀdecalin framework, are of concern even though
analysis of the complete set of coupling constants (Table S1) indicates only minor distortions
7
6
from the ideal chairꢀchair conformation. Inspection of a previous crystallographic analysis of
o
o
two 4,6ꢀOꢀbenzylideneꢀprotected galactopyranosides reveals torsion angles of 67 and 68 for
o
o
O5ꢀC5ꢀC6ꢀO6 and of 52 and 52 for C4ꢀC5ꢀC6ꢀO6 indicating that the benzylidene acetal 10,
and indeed the acetal 4 employed by Serianni, are likely not good models of the ideal gg
3
3
conformation. As compound 15 displays J
and J
coupling constants that are
H5,H6R
H5,H6S
identical to those in 10 (Table 2), we are forced to conclude that it, too, is not a good model of
3
the ideal staggered gg conformation. Comparison of the complete set of JH,H coupling constants
around the carbocyclic rings of compounds 17 and 19, which differ only in configuration at C6
3
also reveals, minor differences in conformation (Table S1). As the J
coupling constant for
H5,H6R
1
9 is markedly different to those of the transꢀfused systems 13 and 20, even after correction for
the addition CC bond as discussed below, we conclude that 19 is also not a suitable model for the
present purposes even though nOe considerations indicate that any deviation from a chairꢀchair
3
conformation is minor (Figure 5). Compound 14 displays a J
coupling constant
16
H5,H6R
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comparable to that of 19 and substantially smaller than those of 13 and 20, leading to the
3
conclusion that it also is not a suitable model. The gt models 11 and 17 have very similar J
H5,H6S
coupling constants, which also differ only marginally from that determined on the monocylic
model 5 by Serianni, suggesting that of all the cisꢀfused compounds prepared these two may be
the most reliable. Overall, of the six cisꢀfused models prepared we exclude 10, 14, 15, and 19
from further consideration.
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
Inspection of the complete data set for 9ꢀ20 (Table S1) reveals an interesting difference in the
3
magnitude of the J
coupling constant in the pyranoside ring between the six gluco and six
H2,H3
3
galacto configured compounds. Thus, in the galactoꢀseries (9ꢀ14) J
is 10.0±0.1 Hz,
H2,H3
whereas in the glucoꢀseries (15ꢀ20) it is 9.4±0.2 Hz, independent of the cisꢀ or transꢀfused nature
of the ring junction. We attribute this difference to the βꢀeffect noted by Altona and Haasnoot for
a pair of coupled antiperiplanar hydrogens when one of the two is also antiplanar to an electronꢀ
withdrawing CꢀX bond in the βꢀposition, as in the H2, H3 and O4 relationship in the galactoꢀ
5
1
series, resulting in a mean coupling constant increase of 0.5 Hz.
Comparison of the 4,6ꢀOꢀAcetals and the 1,5ꢀAnhydrohexitols as Models for the tg
Conformation.
Comparison of the spectral data for the literature 1,5ꢀanhydrohexitols tg models 2 and 3 and the
3
3
4
,6ꢀOꢀalkylidene derivative 6, reveals significant differences in the JH5,H6R and J
coupling
H5,H6S
constants. These differences are reflected in the internal comparison of the H1,H2 and H5,H6
coupling constants in the 4,6ꢀOꢀbenzylidene protected 1,5ꢀanhydrohexitol 21 (Figure 6), begging
the question as to which of the two is the most suitable model for the tg conformation. We select
the H5,H6R,H6S spin system in the 4,6ꢀOꢀacetals 6, 20, 21 and 24 and in the bicyclic model 13
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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
model over the H1R,H1S,H2 spin system in the 1,5ꢀanhydrohexitols 2, 3 and 21, and exclude the
latter from further consideration. This choice is grounded in the closer homology of the selected
3
models to the tg conformation, and is supported by the similarity between the J
coupling
H5,H6
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 in the acetals and in the bicyclic model 13. This latter indicates that the presence of the
acetal function has negligible influence on the coupling constants in the adjacent spin system.
The freezing of rotation about the C6ꢀO6 bond in the selected bicyclic models is not expected to
4
9
exert a significant influence on the measured coupling constants.
3
Figure 6. Comparison of JH,H Coupling Constants in the 4,6ꢀOꢀBenzylidene Protected 1,5ꢀ
Anhydrohexitol 21.
Derivation of Correction Factors for the Use of Tetrasubstituted Stereodiads as Models for
the Trisubstituted Side Chain of the Hexopyranosides.
The exocyclic C5ꢀC6 bond of the hexopyranoses is trisubstituted whereas the corresponding
bond in eight of the bicyclic models (9, 11, 12, 14, 16ꢀ19) is tetrasubstituted, leading to concerns
about the influence of the extra CꢀC bond on coupling constants Altona and Haasnoot addressed
this issue in their study of substituent effects on coupling constants in pyranose rings and
suggested that no corrections were required to (a,e), and (e,e) couplings for systems carrying the
additional CC bond. However, for (aa) couplings the same authors suggested that one of two
5
1
alternative interpretations of their data necessitated a + 0.4 Hz correction for (a,a) couplings.
The considerable differences in some of the experimental coupling constants between triꢀ and
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tetrasubstituted models of the same side chain conformation in 9ꢀ20 prompted closer
investigation of this issue.
For each configuration, erythro or threo, of a given stereodiad there are three staggered
conformations that can be represented by a total set of six Newman projections, of which two, II
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
77
and III, are pseudoꢀenantiomeric (Figure 7).
Figure 7. The Staggered Conformations of the C5ꢀC6 Bonds in the Bicyclic Models 9ꢀ20 and
other 4,6ꢀOꢀAcetals, the C2ꢀC1 Bonds in the 1,5ꢀAnhydrohexitols, and the C1ꢀC2 Bonds in the
1
,4ꢀDioxanes 5, 62 and 63. In the Tetrasubstituted Stereodiads R′ is an Alkyl Group, whereas in
the Trisubstituted Systems it is a Hydrogen Atom.
The three staggered conformations about the tetrasubstituted C5ꢀC6 bond of models 9, 11, 12,
1
4, and 16ꢀ19 can each be assigned to one of the six Newman projections IꢀVI as described in
detail in Table S5 and summarized in Table 4. When R′ is hydrogen, the staggered
conformations of the C5ꢀC6 bond in systems 10, 13, 15, and 20, and of the C2ꢀC1 bonds in 1ꢀ3,
2
1 and 24 may be similarly assigned. For these trisubstituted systems, containing only a single
stereogenic center, projections I and IV are formally identical as are projections II and V, and III
and VI. To complete the analysis two further model compounds are required for comparison
with the Serianni dioxane 5. The literature compounds, cisꢀ2,3ꢀdimethylꢀ1,4ꢀdioxane 62 and
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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
transꢀ2,3ꢀdimethylꢀ1,4ꢀdioxane 63 (Figure 8), whose coupling constants were extracted by study
1
3
78ꢀ79
of the C side bands at low temperature, were selected for this purpose.
The Newman
projections of the C1ꢀC2 bonds in these compounds were analyzed according to the system of
Figure 6 (Table 4).
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
Figure 8. cisꢀ and transꢀ2,3ꢀDimethylꢀ1,4ꢀdioxanes 62 and 63.
Table 4. Assignment of Compounds According to Newman Projections IꢀVI.
Entry cmpd
bond config
projection
1
2
3
4
5
6
7
8
6, 13, 20, 21, 24
entꢀ2, entꢀ3, entꢀ21
5ꢀ6
2ꢀ1
2ꢀ1
5ꢀ6
5ꢀ6
2ꢀ1
2ꢀ1
1ꢀ2
6ꢀ5
5ꢀ6
1ꢀ2
5ꢀ6
2ꢀ1
2ꢀ1
5ꢀ6
1ꢀ2
ꢀ
ꢀ
I (and IV)
I (and IV)
I
II (and V)
II
II (and V)
II
entꢀ22
4, 10, 15
9, 16
1, 24
26
erythro
ꢀ
erythro
ꢀ
erythro
ꢀ
erythro
erythro
erythro
threo
threo
threo
threo
threo
5
III (and VI)
9
entꢀ9, entꢀ16
11, 17
62
14, 19
entꢀ23
25
III
III
III
IV
IV
V
10
11
12
13
14
15
16
12, 18
63
VI
VI
It follows from Table 4 that comparison of the (a,a)ꢀcoupling constants about the C2ꢀC1 bond of
entries 2 and 3 yields a correction factor for triꢀ and tetrasubstituted systems belonging to
projection I. Similarly, comparisons of Table 4, entry 6 with 7, entry 8 with 11, entry 1 with 13,
entry 6 with 14, and entry 8 with 16 lead to correction factors in the remaining five projections
IIꢀVI as summarized in Table 5. We note that for the derivation of each correction factor the triꢀ
and tetrasubstituted compounds employed (Table 5) belong to the same class of compounds,
such that minimization of systematic errors can be expected.
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Table 5. Derivation of Correction Factors for Use with Tetrasubstituted Models
Config
Project Type
Correction Derivation
Correction
(Hz)
Relevant
Models
a
Trisubs
cmpd,
J (Hz)
21, 10.5
24, 2.2
5, 2.5
Tetrasubs
cmpd,
J (Hz)
22, 9.6
26, 1.5
62, 3.2
23, 5.8
25, 1.1
63, 8.5
erythro
erythro
erythro
threo
threo
threo
I
(a,a)
(e,e)
(a,e)
(a,e)
(a,e)
(a,a)
+1.0
+0.5
ꢀ0.5
0
0
+2.0
ꢀ
ꢀ
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
II
III
IV
V
9, 11, 16, 17
14, 19
ꢀ
21, 5.7
24, 1.1
5, 10.7
VI
12, 18
a) Corrections are rounded to the nearest 0.5 Hz.
The derived correction factors cover a considerable range from ꢀ0.5 Hz, through zero, to as much
as +2.0 Hz, with the two largest corrections involving two coupled antiperiplanar spins. While
51
quantitatively different this pattern parallels the suggestion of Altona and Haasnoot that only
(a,a) coupling constant need correction in this manner. The large magnitude of the (a,a)
correction factor is corroborated by inspection of the complete set of literature coupling
78
constants for compound 63. Thus, Gatti and coworkers reported a coupling constant of 11.5 Hz
8
0
for the (a,a) coupling in the disubstituted OꢀCH CH ꢀO system of 63, which is 3.0 Hz more
2
2
than the 8.5 Hz found for the tetrasubstituted portion OꢀCHMeCHMeꢀO system of the same
molecule. Assuming a linear relationship, the (a,a) coupling constant in a related trisubstituted
system OꢀCHMeCH ꢀO would be 3.0/2 = 1.5 Hz in reasonable agreement with the 2.0 Hz
2
derived in Table 5. Application of the correction factors leads to a set of revised limiting
coupling constants for data derived from tetrasubstituted systems as indicated in Tables 1ꢀ3.
Limiting Coupling Constants for the gg, gt, and tgꢀConformations
gg-Conformation. On the basis of the above discussion literature compound 4 and the bicyclic
systems 9, 10, and 15 are considered to be inadequate models and are consequently excluded
from further consideration. The bicyclic disiloxane 7 is not considered an appropriate model
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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
3
because of the significant deviation of its J
coupling from all others in Table 1. After
H5,H6R
application of the appropriate correction factor for the presence of the extra CC bond (Table 5)
3
there is good consistency in the J
coupling constants from the glucoꢀconfigured transꢀ
H5,H6S
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
fused model 16, the literature monocyclic model 1, and its benzylidene analog 24, and we
consider these three systems to be good models of the ggꢀconformation. Accordingly, limiting
3
3
coupling constants of 1.0 and 2.2 Hz are recommended for the J
and J
spin systems,
H5,H6R
H5,H6S
respectively (Table 6, entry 1).
gt-Conformation. After application of the necessary correction factors (Table 5) there is
reasonable conformity of the transꢀfused models 12 and 18 with the literature monocyclic model
3
5 for the limiting J
coupling constant in the gtꢀconformation. Taking an average, we arrive
H5H6R
at a coupling constant of 11.0 Hz for this spin system (Table 6, entry 1). Again after application
of the appropriate correction, there is good agreement between the cisꢀfused bicyclic models 11
and 17, and the monocyclic model 5 for a value of 2.5 Hz for the limiting coupling constant of
3
the J
spin system in the gtꢀconformation (Table 6, entry 1). The bicyclic disiloxane 8 does
H5,H6S
3
not constitute an appropriate model as its J
coupling constant is markedly lower than all
H5,H6S
others in Table 2.
tg-Conformation. Following the above analyses, bicyclic models 14 and 19 are deemed to be
inadequate as are the C1ꢀC2 bonds in compounds 2, 3 and 21. Models 13, 20, the literature
model 6, and the C5ꢀC6 bond of 21, on the other hand, are considered viable systems leading us
3
3
to adopt 4.8 and 10.2 Hz as limiting coupling constants for the J
and J
spin systems,
H5,H6R
H5,H6S
respectively, in the tgꢀconformation (Table 6, entry 1).
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9
Comparison with Literature Values. In addition to the limiting coupling constant derived here,
4
7
literature values obtained with the HaasnootꢀAltona equation, experimentally with the models
3
9
49
54
1ꢀ3 and 4ꢀ6 and a related set of peracteylated benzylidene acetals, and computationally for
4
9
3
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 are presented in Table 6. With regard to the J
limiting coupling constants the new set
H5,H6R
of gg, gt, and tg (Table 6, entry 1) values most closely resemble those obtained on the basis of
3
the HaasnootꢀAltona equation (Table 6, entry 2). The largest individual discrepancies in JH5,H6R
are with the experimental value for the gg conformation derived experimentally from model 4
and computed for the gt on the basis of model 5 (Table 6, entries 4 and 5, respectively). For the
3
JH5,H6S limiting coupling constants the data obtained with 1ꢀ3 (Table 6, entry 3) are in closest
agreement with the values obtained in this study.
Table 6. Recommended and Literature Limiting Coupling Constants.
3
3
JH5,H6R
JH5,H6S
gt
2.5
Entry
Source
gg
1.0
0.9
gt
11.0
10.7
tg
4.8
5.0
gg
2.2
2.8
tg
10.2
10.7
1
2
This work
Haasnoot–
3.1
47
Altona
39
3
4
BockꢀDuus
0.9
1.8
10.7
10.7
5.5
5.0
2.2
1.8
2.5
2.5
10.7
10.3
Serianni
49
(
expt)
5
6
Serianni
0.8
1.7
9.9
4.5
4.1
1.3
2.2
1.5
2.4
10.8
11.1
49
(
calc)
54
Nishida
10.8
Application of the Recommended Values to the Side Chain Conformations of Glucoꢀ and
Galactopyranosides
To calculate the side chain populations of representative hexopyranosides we employed a set of
3
39
literature experimental J
and JH5,H6S coupling constants measured by Bock and Duus for
H5,H6R
methyl αꢀ
D
ꢀglucopyranoside (5.5 and 2.4 Hz), methyl βꢀ
D
ꢀglucopyranoside (6.1 and 2.5 Hz), and
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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
methyl βꢀ
D
ꢀgalactopyranoside (7.5 and 4.8 Hz) and the limiting coupling constants from Table 6
to solve equations 1ꢀ3.
3
3
3
3
3
3
JH5,H6R =
J
f + J f + J f (1)
R,gg gg R,gt gt R,tg tg
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
JH5,H6S =
J
f + J f + J f (2)
S,gg gg S,gt gt S,tg tg
1
= f + f + f (3)
gg
gt
tg
The populations of all three test substrates calculated in this manner using the new limiting
coupling constants (Table 7, entry 1) compare favorably with those calculated using the various
literature coupling constants (Table 7, entries 2ꢀ6). The absence of negative population values is
noteworthy and marks a clear difference between use of the limiting coupling constants derived
from the present series of bicyclic models, and those determined based on the HaasnootꢀAltona
equation. Such negative populations are usually interpreted as either i) inaccurate limiting
3
9
48ꢀ50
coupling constants, or ii) the population of nonꢀideal conformers.
The absence of negative
populations with the new data set suggests that the equilibration between the three ideal
staggered conformation of the side chain is an adequate model.
Table 7. Calculated Side Chain Populations.
a
a
a
Me αꢀDꢀGlc
Me βꢀDꢀGlc
Me βꢀDꢀGal
Entry
Source
gg
54
57
gt
45
50
tg
1
ꢀ7
gg
48
50
gt
50
56
tg
2
ꢀ6
gg
16
19
gt
53
58
tg
31
23
1
2
This work
Haasnoot–
4
7
Altona
3
9
3
4
BockꢀDuus
Serianni
53
56
47
40
1
4
46
49
52
47
2
4
17
16
54
53
29
31
4
9
(
expt)
5
6
Serianni
42
57
47
41
11
1
35
50
54
48
12
2
5
59
56
36
28
4
9
(
calc)
5
4
Nishida
16
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a) Populations calculated using the experimental coupling constants of Bock and Duus: Me αꢀDꢀGlc, J
= 5.5
= 4.8
H5,H6R
= 7.5 Hz, J
H5,H6R H5,H6S
3
3
3
3
3
Hz, J
= 2.4 Hz; Me βꢀDꢀGlc, J
= 6.1 Hz, J
= 2.5 Hz; Me βꢀDꢀGal, J
H5,H6S
H5,H6R
H5,H6S
Hz.
Application to Higher Carbon Sugars and NonꢀCarbohydrate Diols
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
While the limiting coupling constants presented in Table 6, entry 1 were derived with the
solution of hexopyranoside side chain populations in mind, they should also be applicable to any
terminal vicinal diols (ie, with the HOꢀCH ꢀCHOHꢀR motif) and related ethers. Limiting
2
coupling constants derived from models 11, 12, 16, 17, and 18 (Tables 1 and 2) should be valid,
without the application of the correction factors, for direct use in studies of the conformations of
internal vicinal diols (ie, with the RꢀCHOHꢀCHOHꢀR’ motif) and related ethers. Such systems
5
8ꢀ
include the side chains of the higher carbon sugars as found in the bacterial heptopyranosides,
6
1
octulosonic and nonulosonic acids including the KDO glycosides and the sialic acid
3
4,57
81ꢀ82
glycosides,
as well as a host of acyclic polyols.
Limiting coupling constants obtained
with the trisubstituted systems 13 and 20 (Table 3) should also be suitable for internal vicinal
diols following application of the appropriate correction factors from Table 5.
Conclusions.
Twelve cisꢀ or transꢀfused bicycloꢀ[4.4.0]ꢀoctaneꢀlike systems have been synthesized as models
of the ideal gg, gt, and tg staggered conformations of the hexopyranoside side chain.
Consideration of the complete set of NMR spectral data leads to the exclusion of some
compounds from the data set, mainly in the cisꢀfused series, on the grounds of deviation from the
ideal chairꢀchair conformations. Consideration of a further series of model compounds permits
the derivation of correction factors enabling the use of data from tetrasubstituted systems as
models for the trisubstituted side chains. Ultimately, a series of limiting coupling constants for
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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
3
the J
and JH5,H6S coupling constants of the hexopyranose side have been derived and
H5,H6R
compared to literature values obtained from either other model systems, on the basis of the
HaasnootꢀAltona equation, or computationally. In conjunction with literature experimental
coupling constants, the limiting coupling constants obtained from the rigid bicyclic models lead
to calculated populations of the glucoꢀ and galactopyranoside side chains that are essentially
devoid of the negative values found with other systems and, in doing so, remove the need for
consideration of nonꢀideal conformations. While the data were derived expressly for use in the
hexopyranosides it is expected that, with suitable application of the necessary correction factors,
they will also prove useful in the analysis of the side chain conformations of the higher carbon
sugars and even acyclic vicinal diols. Finally, the new limiting coupling constants should serve
to inform the development of improved computational models for the prediction of saccharide
side chain conformations.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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Experimental Part.
General Experimental.
All extracts were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced
pressure at ~ 35 °C. Flash column chromatographic purifications were carried out over silica gel
unless otherwise stated. Commercially available anhydrous solvents were used for moisture
sensitive reactions unless otherwise stated. NMR spectra were recorded in CDCl with 400 or
3
6
00 MHz instruments unless otherwise stated. NMR spectra of final compounds were recorded
in CD OD, CDCl , and C D at 600 MHz unless otherwise stated. The DAISY 1DꢀNMR spectra
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simulation tool in the TopSpin 3.5 pl 7 software package was used to simulate HꢀNMR spectra.
Specific rotations were recorded in dichloromethane unless otherwise stated. ESIꢀHRMS were
recorded using a Waters LCT Premier Xe time of flight mass spectrometer.
Methyl 4,6ꢀOꢀBenzylideneꢀ2,3ꢀdiꢀOꢀmethylꢀαꢀ
D
ꢀgalactopyranoside (10). Compound 10 was
6
2
1
synthesized following literature protocol. In CHCl : H NMR (600 MHz, CDCl ) δ 7.52 – 750
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(
m, 2H), 7.37 – 7.29 (m, 3H), 5.54 (s, 1H), 4.98 (d, J = 3.5 Hz, 1H), 4.34 (dd, J = 3.5, 1.3 Hz,
1H), 4.26 (dd, J = 12.5, 1.8 Hz, 1H), 4.07 (dd, J = 12.5, 1.8 Hz, 1H), 3.78 (dd, J = 10.1, 3.5 Hz,
1
H), 3.67 (dd, J = 10.1, 3.5 Hz, 1H), 3.63 (td, J = 1.8, 1.3 Hz, 1H), 3.52 (s, 3H), 3.50 (s, 3H),
3
.44 (s, 3H).
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
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2
3
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4
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4
4
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5
5
5
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0
1
2
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0
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0
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0
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0
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1
In C D : H NMR (600 MHz, C D ) δ 7.71 – 7.70 (m, 2H), 7.15 – 7.03 (m, 3H), 5.27 (s, 1H),
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6
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4.75 (d, J = 3.5 Hz, 1H), 4.06 (dd, J = 12.2, 1.6 Hz, 1H), 3.80 (dd, J = 10.1, 3.5 Hz, 1H), 3.77
dd, J = 3.6, 1.1 Hz, 1H), 3.62 (dd, J = 10.1, 3.6 Hz, 1H), 3.44 (dd, J = 12.2, 1.9 Hz, 1H), 3.28 (s,
(
3
H), 3.18 (s, 3H), 3.10 (s, 3H), 3.05 (ddd, J = 1.9, 1.6, 1.1 Hz, 1H).
1
In CD OD: H NMR (600 MHz, CD OD) δ 7.49 – 7.47 (m, 2H), 7.36 – 7.30 (m, 3H), 5.59 (s,
3
3
1
H), 4.95 (d, J = 2.4 Hz, 1H), 4.45 (dd, J = 2.2, 1.1 Hz, 1H), 4.15 (dd, J = 12.5, 1.6 Hz, 1H), 4.12
dd, J = 12.5, 1.7 Hz, 1H), 3.66 – 3.65 (m, 2H), 3.64 (ddd, J = 1.7, 1.6, 1.1 Hz, 1H), 3.46 (s, 3H),
.44 (s, 3H), 3.41 (s, 3H).
(
3
Methyl 4,8‐Anhydro‐7‐deoxy‐2,3,6‐tri‐O‐methyl‐α‐
D‐glycero‐
D‐galacto‐octopyranoside (11).
2
7
1
Compound 11 was synthesized following literature protocol. In CHCl : H NMR (600 MHz,
3
CDCl ) δ 4.95 (d, J = 3.7 Hz, 1H), 4.13 (ddd, J = 11.9, 4.8, 1.7 Hz, 1H), 4.00 (dd, J = 3.2, 0.8
3
Hz, 1H), 3.68 (dd, J = 10.0, 3.7 Hz, 1H), 3.68 (dd, J = 3.2, 0.8, 1H), 3.55 (dd, J = 10.0, 3.2 Hz,
1H), 3.52 (s, 3H), 3.49 (s, 3H), 3.47 (s, 3H), 3.41(s, 3H), 3.40 (ddd, J = 12.6, 11.7, 2.2, 1H), 3.34
(ddd, J = 11.9, 4.5, 3.2 Hz, 1H), 1.98 (dddd, J = 12.6, 12.4, 11.9, 4.8 Hz, 1H), 1.74 (dddd, J =
1
2.4, 4.5, 2.2, 1.7 Hz, 1H).
1
In C D : H NMR (600 MHz, C D ) δ 4.81 (d, J = 3.7 Hz, 1H), 3.88 (dd, J = 10.0, 3.7 Hz, 1H),
6
6
6
6
3.80 (ddd, J = 11.6, 4.8, 1.8 Hz, 1H), 3.71 (d, J = 3.2 Hz, 1H), 3.57 (dd, J = 10.0, 3.2 Hz, 1H),
.29 (s, 3H), 3.27 (s, 3H), 3.22 (dd, J = 3.2, 0.8 Hz, 1H), 3.22 (s, 3H), 3.10 (s, 3H), 2.92 (ddd, J
12.7, 11.6, 2.2 Hz, 1H), 2.80 (ddd, J = 11.8, 4.5, 3.2 Hz, 1H), 2.10 (dddd, J = 12.7, 12.5, 11.8,
3
=
4.8 Hz, 1H), 1.31 (dddd, J = 12.5, 4.5, 2.2, 1.8 Hz, 1H).
1
In CD OD: H NMR (600 MHz, CD OD) δ 4.90 (d, J = 3.7 Hz, 1H), 4.01 (dd, J = 3.1, 0.7 Hz,
3
3
1
H), 4.00 (ddd, J = 11.7, 4.9, 1.7 Hz, 1H), 3.77 (dd, J = 3.2, 0.7 Hz, 1H), 3.58 (dd, J = 10.1, 3.7
Hz, 1H), 3.52 (dd, J = 10.1, 3.2 Hz, 1H), 3.45 (ddd, J = 12.0, 4.6, 3.1 Hz, 1H), 3.44 (s, 3H) 3.42
,
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(
ddd, J = 12.5, 11.7, 2.0 Hz, 1H), 3.41 (s. 6H), 3.39 (s, 3H), 1.86 (dddd, J = 12.5, 12.4, 12.0, 4.9
Hz, 1H), 1.71 (dddd, J = 12.4, 4.6, 2.0, 1.7 Hz, 1H).
Methyl 4,8ꢀAnhydroꢀ7ꢀdeoxyꢀ2,3,6ꢀtriꢀOꢀmethylꢀβꢀ
L
ꢀglyceroꢀ
D
ꢀgalactoꢀoctopyranoside (14).
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Compound 14 was prepared using literature protocol. In CHCl : H NMR (600 MHz, CDCl )
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0
1
2
3
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0
1
2
3
4
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6
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0
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δ 4.86 (d, J = 3.6 Hz, 1H), 4.00 (dd, J = 3.4, 1.1 Hz, 1H), 3.84 (ddd, J = 11.4, 5.3, 1.3 Hz, 1H),
3.71 (ddd, J = 13.1, 11.4, 2.6 Hz, 1H), 3.67 (dd, J = 10.1, 3.6 Hz, 1H), 3.61 (dd, J = 3.1, 1.1 Hz,
1
H), 3.52 (dd, J = 10.1, 3.4 Hz, 1H), 3.52 (s, 3H), 3.49 – 3.46 (m, 4H), 3.42 (s, 3H), 3.39 (s, 3H),
.97 (dddd, J = 14.3, 13.1, 5.2, 2.8 Hz, 1H), 1.65 (dddd, J = 14.3, 3.7, 2.6, 1.3 Hz, 1H).
1
1
In C D : H NMR (600 MHz, C D ) δ 4.84 (d, J = 3.6 Hz, 1H), 4.15 (dd, J = 3.4, 1.1 Hz, 1H),
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6
6
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4
.00 (dd, J = 10.1, 3.6 Hz, 1H), 3.76 – 3.69 (m, 3H), 3.40 (ddd, J = 3.0, 2.9, 2.8 Hz, 1H), 3.37 (s,
H), 3.27 (s, 3H), 3.19 (s, 3H), 3.00 (s, 3H), 2.05 (dddd, J = 14.1, 13.0, 7.6, 2.8 Hz, 1H), 1.36
3
(dddd, J = 14.1, 2.9, 2.8, 1.1 Hz, 1H).
1
In CD OD: H NMR (600 MHz, CD OD) δ 4.89 (d, J = 3.6 Hz, 1H), 4.01 (dd, J = 3.4, 1.1 Hz,
3
3
1
3
3
H), 3.73 (ddd, J = 11.3, 5.4, 1.2 Hz, 1H), 3.68 (ddd, J = 13.2, 11.4, 2.1 Hz, 1H), 3.62 (dd, J =
.1, 1.1 Hz, 1H), 3.60 (dd, J = 10.1, 3.6 Hz, 1H), 3.50 (dd, J = 10.1, 3.4 Hz, 1H), 3.47 (ddd, J =
.1, 3.0, 2.9 Hz, 1H), 3.46 (s, 3H), 3.41 (s, 3H), 3.40 (s, 3H), 3.40 (s, 3H), 1.95 (dddd, J = 14.3,
13.0, 5.4, 2.9 Hz, 1H), 1.67 (dddd, J = 14.3, 3.0, 2.8, 1.2 Hz, 1H).
Methyl 4,8ꢀAnhydroꢀ7ꢀdeoxyꢀ2,3,6ꢀtriꢀOꢀmethylꢀαꢀ
D
ꢀglyceroꢀ
D
ꢀglucoꢀoctopyranoside (16).
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Compound 16 was synthesized using the literature protocol. In CHCl : H NMR (600 MHz,
3
CDCl ) δ 4.89 (d, J = 3.6 Hz, 1H), 3.75 (ddd, J = 11.6, 5.5, 1.5 Hz, 1H). 3.72 (ddd, J = 3.6, 2.6,
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2
3
3
.2 Hz, 1H), 3.69 (ddd, J = 12.7, 11.6, 2.2 Hz, 1H), 3.60 (s, 3H), 3.56 (dd, 10.1, 8.9 Hz, 1H),
.54 (dd, 10.1, 2.6 Hz, 1H), 3.50 (s, 3H), 3.46 (dd, J = 9.4, 8.9 Hz, 1H), 3.43 (s, 3H), 3.42 (s,
H), 3.28 (dd, J = 9.4, 3.6 Hz, 1H), 1.98 (dddd, J = 14.5, 3.6, 2.2, 1.5 Hz, 1H), 1.71 (dddd, J =
14.5, 12.7, 5.5, 2.2 Hz, 1H).
In C D : H NMR (600 MHz, C D ) δ 4.71 (d, J = 3.6 Hz, 1H), 3.96 (dd, J = 10.1, 9.2 Hz, 1H),
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6
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6
3
.83 (dd, J = 9.4, 9.2 Hz, 1H), 3.73 (ddd, J = 12.7, 11.4, 2.5 Hz, 1H), 3.68 (s, 3H), 3.63 (dd, J =
0.1, 2.6 Hz, 1H), 3.55 (ddd, J = 11.4, 5.4, 1.5 Hz, 1H), 3.40 (ddd, J = 3.6, 2.6, 2.5 Hz, 1H), 3.27
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(
s, 3H), 3.26 (s, 3H), 3.24 (dd, J = 9.4, 3.6 Hz, 1H), 3.16 (s, 3H), 1.45 (dddd, J = 14.1, 3.6, 2.5,
1.5 Hz, 1H), 1.38 (dddd, J = 14.1, 12.7, 5.4, 2.5 Hz, 1H).
1
In CD OD: H NMR (600 MHz, CD OD) δ 4.88 (d, J = 3.7 Hz, 1H), 3.70 (ddd, J = 11.5, 5.6,
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3
1
.5 Hz, 1H), 3.70 (ddd, J = 3.6, 2.6, 2.4 Hz, 1H), 3.64 (ddd, J = 12.8, 11.5, 2.2 Hz, 1H), 3.53 (s,
H), 3.52 (dd, J = 10.1, 2.6 Hz, 1H), 3.48 (dd, J = 10.1, 9.0 Hz, 1H), 3.47 (s, 3H), 3.43 (s, 3H),
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3.40 (s, 3H), 3.36 (dd, J = 9.5, 9.0 Hz, 1H), 3.19 (dd, J = 9.5, 3.7 Hz, 1H), 1.95 (dddd, J = 14.5,
.6, 2.2, 1.5 Hz, 1H), 1.74 (dddd, J = 14.5, 12.8, 5.6, 2.4 Hz,1H).
3
Methyl 4,8ꢀAnhydroꢀ7ꢀdeoxyꢀ2,3,6ꢀtriꢀOꢀmethylꢀβꢀ
L
ꢀglyceroꢀ
D
ꢀglucoꢀoctopyranoside (18).
2
5
1
Compound 18 was synthesized following literature protocol. In CHCl : H NMR (600 MHz,
3
CDCl ) δ 4.87 (d, J = 3.7 Hz, 1H), 4.00 (ddd, J = 11.9, 5.3, 1.5 Hz, 1H), 3.61 (s, 3H), 3.52 (s,
3
3
H), 3.50 (t, J = 9.3 Hz, 1H), 3.47 (s, 3H), 3.45 (s, 3H), 3.42 (dd, J = 9.6, 9.0 Hz, 1H), 3.42 (ddd,
J = 12.9, 11.9, 2.3 Hz, 1H), 3.30 (ddd, J = 11.0, 9.0, 5.1 Hz, 1H), 3.24 (dd, J = 9.3, 3.7 Hz, 1H),
2.98 (dd, J = 9.3, 9.6 Hz, 1H), 2.04 (dddd, J = 13.2, 5.1, 2.3, 1.5 Hz, 1H), 1.55 (dddd, J = 13.2,
1
2.9, 11.0, 5.3 Hz, 1H).
1
In C D : H NMR (600 MHz, C D ) δ 4.65 (d, J = 3.7 Hz, 1H), 3.74 (t, J = 9.2 Hz, 1H), 3.62 –
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6
6
6
3
.60 (ddd, J = 11.8, 5.2, 1.6 Hz, 1H), 3.59 (s, 3H), 3.57 (dd, J = 9.7, 9.4 Hz, 1H), 3.27 (s, 3H),
3.22 (s, 3H), 3.19 (s, 3H), 3.17 (dd, J = 9.2, 3.7 Hz, 1H), 2.99 (dd, J = 9.7, 9.2 Hz, 1H), 2.99
ddd, J = 11.0, 9.0, 5.1 Hz, 1H), 2.98 (ddd, J = 12.7, 11.8, 2.4 Hz, 1H), 1.51 (dddd, J = 13.1, 5.1,
(
2
.4, 1.6 Hz, 1H), 1.40 (dddd, J = 13.1, 12.7, 11.0, 5.2 Hz, 1H).
1
In CD OD: H NMR (600 MHz, CD OD) δ 4.85 (d, J = 3.8 Hz, 1H), 3.94 (ddd, J = 11.8, 5.2,
3
3
1
.6 Hz, 1H), 3.51 (s, 6H), 3.45 (s, 3H), 3.42 (ddd, J = 12.8, 11.9, 2.3 Hz, 1H), 3.39 (s, 3H), 3.37
(
dd, J = 9.4, 9.3 Hz, 1H), 3.33 (ddd, J = 10.8, 9.2, 4.8 Hz, 1H), 3.31 (t, J = 9.2 Hz, 1H), 3.20
dd, J = 9.4, 3.8 Hz, 1H), 2.96 (dd, J = 9.4, 9.3 Hz, 1H), 2.06 (dddd, J = 13.2, 4.8, 2.3, 1.6 Hz,
(
1H), 1.48 (dddd, J = 13.2, 12.8, 10.8, 5.2, 1H).
Methyl 4,6ꢀOꢀBenzylideneꢀ2,3ꢀdiꢀOꢀmethylꢀαꢀ
D
ꢀglucopyranoside (20). Compound 20 was
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1
synthesized by following the literature protocol. In CHCl : H NMR (600 MHz, CDCl ) δ
3
3
7
.51 – 7.48 (m, 2H), 7.39 – 7.33 (m, 3H), 5.54 (s, 1H), 4.86 (d, J = 3.7 Hz, 1H), 4.28 (dd, J =
10.2, 4.7 Hz, 1H), 3.81 (ddd, J = 10.1, 9.6, 4.7 Hz, 1H), 3.73 (dd, J = 10.2, 10.1 Hz, 1H), 3.69
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