Stereoselective C -glycoside formation with 2- O -benzyl-4,6- O -benzylidene protected 3-deoxy gluco- and mannopyranoside donors: Comparison with o -glycoside formation

Article abstract of DOI:10.1021/jo3011655

Unlike alcohols, the reaction of C-nucleophiles with 2-O-benzyl-4,6-O- benzylidene-protected 3-deoxy-gluco- and mannopyranosyl thioglycosides is highly stereoselective providing the α-C-glycosides in the gluco-series and the β-C-glycosides in the manno-series. Conformational analysis of nucleophilic attack of putative intermediate glycosyl oxocarbenium ions suggests that the observed selectivities for C-glycoside formation can be explained by preferential attack on the opposite face of the oxocarbenium to the C2-H2 bond and that eclipsing interactions with this bond are the main stereodetermining factor. It is argued that the steric interactions in the attack of alcohols (sp³-hybridized O) and of typical carbon-based nucleophiles (sp ² C) on oxocarbenium ions are very different, with the former being less severe, and thus that there is no a priori reason to expect O- and C-glycosylation to exhibit parallel stereoselectivities for attack on a given oxocarbenium ion.

Full text of DOI:10.1021/jo3011655

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Article
Stereoselective C-Glycoside Formation with 2-O-Benzyl-4,6-O-
benzylidene Protected 3-Deoxy Gluco- and Mannopyranoside
Donors: Comparison with O-Glycoside Formation
Myriame Moume-Pymbock, and David Crich
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 25 Sep 2012
Downloaded from http://pubs.acs.org on September 28, 2012
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Page 1 of 26
The Journal of Organic Chemistry
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Stereoselective CꢀGlycoside Formation with 2ꢀOꢀ
Benzylꢀ4,6ꢀOꢀbenzylidene Protected 3ꢀDeoxy Glucoꢀ
and Mannopyranoside Donors: Comparison with Oꢀ
Glycoside Formation
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Myriame Moumé-Pymbock and David Crich*
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, and
dcrich@chem.wayne.edu
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. Unlike alcohols, the reaction of Cꢀnucleophiles with 2ꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ
protected glucoꢀ and mannopyranosyl thioglycosides is highly stereoselective providing the αꢀCꢀ
glycosides in the glucoꢀseries and the βꢀCꢀglycosides in the mannoꢀseries. Conformational analysis of
nucleophilic attack of putative intermediate glycosyl oxocarbenium ions suggests that the observed
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selectivities for Cꢀglycoside formation can be explained by preferential attack on the opposite face of the
oxocarbenium to the C2ꢀH2 bond and that eclipsing interactions with this bond are the main
stereodetermining factor. It is argued that the steric interactions in the attack of alcohols (sp3ꢀhybridized
O) and of typical carbonꢀbased nucleophiles (sp2 C) on oxocarbenium ions are very different, with the
former being less severe, and thus that there is no a priori reason to expect Oꢀ and Cꢀglycosylation to
exhibit parallel stereoselectivities for attack on a given oxocarbenium ion.
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Introduction
CꢀGlycosides are important mimics of Oꢀglycosides and accordingly numerous avenues have been
developed for their formation among which, as with Oꢀglycoside formation, conceptually the easiest and
the most direct involve the Lewis acidꢀmediated attack of carbonꢀbased nucleophiles on putative
glycosyl cations or their equivalents.1 Several years ago prompted by computational results2 implicating
donorꢀacceptor hydrogen bonding in the 4,6ꢀOꢀbenzylideneꢀdirected βꢀmannosylation3 and αꢀ
glucsoylation3 reactions developed in our laboratories, we investigated the stereoselectivity of Cꢀ
glycosylation reactions of 4,6ꢀOꢀbenzylideneꢀprotected mannosyl and glucopyranosyl donors.4 We
found that for 2,3ꢀdiꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀprotected glucoꢀ and mannopyranosyl donors the
same stereochemical trends were observed for the formation of Oꢀ and Cꢀglycosides, namely the
preferential formation of the αꢀisomers in the glucoꢀ series and that of the βꢀisomers in the mannoꢀ
series.4 Moreover, the same reversal of stereoselectivity was observed in the mannoꢀ series on replacing
a 3ꢀOꢀbenzyl ether in the donor by a 3ꢀOꢀcarboxylate ester for both Oꢀ5 and Cꢀ6 glycoside formation.
We concluded that there was likely a commonality of mechanism between the formation of the Oꢀ and
Cꢀglycosides, at least for the examples studied, and that donorꢀacceptor hydrogen bonding is likely not a
major stereodirecting factor in the formation of the Oꢀglycosides.4,6 Continuing the parallel between Oꢀ
and Cꢀglycosylation stereoselectivity, more recently we found that the Nꢀacetylꢀ4ꢀO,5ꢀNꢀoxazolidinoneꢀ
protected sialyl donors exhibit a strong equatorial preference in the formation of Cꢀglycosides7 just as
they were earlier shown to do for the Oꢀglycosides.8 The presence of a 3ꢀOꢀbenzyl ether or related
group is critical to the successful stereochemical outcome of 4,6ꢀOꢀbenzylideneꢀdirected βꢀOꢀ
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The Journal of Organic Chemistry
mannosylations and αꢀOꢀglucosylations as the corresponding 3ꢀdeoxy donors are far less selective (Fig.
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1).9
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Figure 1. Influence of the 3ꢀOꢀbenzyl ether on glycoside formation in the glucoꢀ and mannoꢀ series.10
Accordingly, we anticipated a comparable loss of stereoselectivity when studying the formation of the
4,6ꢀOꢀbenzylideneꢀ3ꢀdeoxyꢀCꢀglycosides in both the glucoꢀ and mannoꢀ series and were therefore
surprised to find high selectivity in both instances. These unexpected observations, and the further
reflections on the analogies between Cꢀ and Oꢀglycoside formation that they prompt, form the basis of
this Article.
Results
The 2,3ꢀdiꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylidene protected glycosyl donors 111 and 212 were prepared by
known methods, as were the 3ꢀdeoxy analogs 3 and 4.9 Activation of 1 and 2 with the BSP and/or
DPSO reagents3a,13 and triflic anhydride in the presence of the hindered nonꢀnucleophilic base TTBP3a at
ꢀ65 oC in dichloromethane was followed by the addition of allyltrimethylsilane, allyltributylstannane, or
αꢀtrimethylsiloxystyrene leading to the formation of the anticipated Cꢀglycosides.
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The results of these initial experiments are presented in Table 1 and, with the exception of minor
differences in selectivity for entries 1 and 2,14 confirmed our previous observations on the selectivity of
Cꢀglycoside formation; namely that the βꢀCꢀglycosides are formed selectively in the mannose series and
the αꢀCꢀglycosides in the glucose series. One noteworthy observation in this series of experiments was
the formation of the double adduct 9 in the glucoꢀseries (Table 1, entry 6) to which we return later.
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Table 1. Stereoselective Cꢀglycoside formation in the glucoꢀ and mannoꢀ series.
Entry
1
Donor
Nucleophile
Product
Yield
57%
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60%
76%
56%
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58%
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The Journal of Organic Chemistry
Ph
O
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40%
40%
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O
BnO
BnO
O
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+
Ph
Ph
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BnO
SPh
Ph
BnO
O
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Ph
O
9
The same reaction conditions were then applied to the 3ꢀdeoxy donors 3 and 4, with the exception that
in the activation of the 3ꢀdeoxy mannosyl donor 3 the BSP reagent was replaced by diphenyl sulfoxide
as this combination was found to give cleaner activation in this series. The results of these addition
reactions in the 3ꢀdeoxy series are presented in Table 2. Again, a double adduct was formed as a
significant byproduct in the reaction of the gluco donor with the silyl enol ether (Table 2, entry 6).
Table 2. Stereoselective Cꢀglycoside formation in the 3ꢀdeoxy glucoꢀ and mannoꢀ series.
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Entry
1
Donor
Nucleophile
Product
Yield
35%
3
17%
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2
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58%
75%
60%
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63%
34%
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Ph
Ph
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+
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O
37%
SPh
Ph
BnO
O
Ph
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14
The parallels between Tables 1 and 2 are obvious and indicate that, unlike the situation for Oꢀ
glycosylation, the presence or absence of a benzyloxy group at the 3ꢀposition of the donor has little or no
effect on the stereoselectivity of Cꢀglycosylation with the three standard nucleophiles employed. With
the mannoꢀstereochemistry at C2, βꢀCꢀglycosides are formed whereas with the glucoꢀstereochemistry at
the same position αꢀCꢀglycosides are formed. Formulated another way the nucleophile enters
preferentially cisꢀ to the C2ꢀO2 bond in both stereochemical series.
Formation of Double Adducts
The formation of the double adducts 9 and 14 (Table 1 and 2, entries 6) as significant byproducts is
interesting as it implies that the silyl enol ether is an ambident nucleophile and that attack via oxygen to
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The Journal of Organic Chemistry
form the vinyl glycosides15 15 and 16 competes with attack via carbon to form the Cꢀglycosides 8 and
13, at least in the glucoꢀ and deoxy glucoꢀ series. Related vinyl glycosides derived from the ambident
nucleophilicity of pinacolone trimethylsilyl enol ether were isolated in our initial study of Cꢀglycoside
formation, when they were also more significant in the glucoꢀ than in the mannoꢀseries, and when they
persisted in the reaction mixture presumably due to the steric bulk of the tꢀbutyl group.4 Adducts 9 and
14 must be formed via the attack of a sulfenyl cation equivalent, a byproduct of the thioglycoside
activation process, on 15 and 16, respectively, followed by quenching of the soꢀformed oxocarbenium
ions 17 and 18, respectively, by a second equivalent of the silyl enol ether. Precedent for the reaction of
other Oꢀglycosyl oxocarbenium ions related to 17 and 18 with a variety of nucleophiles in preference to
the obvious decomposition pathway to give glycosyl cations and a carbonyl compound, in the present
case βꢀphenylthioacetophenone, is found on studies on the formation and coupling reactions of
phenylthiomethyl glycosides.16 We tentatively assign adducts 9 and 14, both of which are formed with
high selectivity (only one isomer was isolated in each case), the (R)ꢀstereochemistry indicated on the
grounds that of the two conformations of the vinyl glycosides possible, assuming the operation of the
exoꢀanomeric effect, one is strongly favoured by the minimization of steric interactions between the
aglycone and the anomeric hydrogen. Sulfenylation of this conformer will then afford the Eꢀ
oxocarbenium ion, whereas sulfenylation of the minor isomer would provide the Zꢀisomer. Assuming
the preference for an exoꢀanomeric effectꢀlike conformation about the glycosidic bond, which minimizes
steric interactions with the C2 benzyloxy group, attack on the exposed face of the Eꢀisomer affords the
assigned stereochemistry of 9 and 14 (Scheme 1). This model is consistent with that applied to
rationalize inter alia diastereoselective DielsꢀAlder reactions of 1ꢀglucopyanosyloxy dienes.17
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Ph
O
Ph
O
O
O
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2
3
4
O
O
Ph
X
X
BnO
BnO
O
O
Ph
5
6
15: X = OBn, 16: X = H
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"PhS+"
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OTMS
Ph
OTMS
Ph
O
O
SPh
Ph
Ph
BnO
BnO
O
O
PhS
Z-
E-
17: 3-OBn, 18: 3-H
Ph
O
Ph
O
O
O
O
O
X
X
SPh
Ph
BnO
PhS
BnO
O
Ph
Ph
O
Ph
(S)-
(R)-
O
O
9: X = OBn, 14: X = H
Scheme 1. Rationale for the stereoselective formation of 9 and 14.
We also note the formation of an inverted thioglycoside 3α from thioglycoside 3β in the 3ꢀdeoxy
mannoꢀ series (Table 2, entry 1). As this phenomenon was only observed to a significant extent in the
one example when the external nucleophile was the weakest among those employed in this study,18 we
assume it arises from competing nucleophilic attack by thiol released in the course of the activation
reaction on the glycosyl oxocarbenium intermediate. As the transition states for the formation of an Sꢀ
glycoside are necessarily considerably different to those for the formation of a Cꢀglycoside, being in
principle more like but still looser than those for Oꢀglycoside formation (vide infra); there is no reason, a
priori, for Cꢀ and Sꢀglycoside formation to exhibit the same face selectivity on a common oxocarbenium
ion intermediate.
Mechanisms of Oꢀ and CꢀGlycoside Formation
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The Journal of Organic Chemistry
The formation of Oꢀglycosides is usually interpreted in terms of a continuum of mechanisms spanning
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the two extremes of pure SN1 and SN2 reactions, with most reactions considered to involve more or less
tightly associated glycoyl oxocarbenium ion/counterion pairs depending on the protecting groups and
reaction conditions employed.19 Kinetic enzymologists refer to exploded transition states to describe
associative SN2ꢀlike transition states that nevertheless have considerable oxocarbenium ion character
and longer partially formed or cleaved bonds than in simple SN2 transition states;20 such exploded
transition states can be viewed as alternative representations of reactions occurring via nucleophilic
attack on tight or intimate ion pairs. Direct spectroscopic evidence for the existence of glycosyl
oxocarbenium ions as discrete intermediates in organic solution (or aqueous) media has yet to be
obtained,19f,21 but indirect evidence exists in the form of glycosylation reactions exhibiting unimolecular
kinetics in certain cases.19a,22 At the other end of the mechanistic continuum, a number of Oꢀ
glycosylation reactions exhibiting bimolecular kinetics have recently been demonstrated.22c,23
With regard to the 4,6ꢀOꢀbenzylideneꢀdirected Oꢀglycosylations relevant to the work presented here,
13C primary kinetic isotope effect (KIE) measurements supported by DFT calculations indicate that the
formation of the βꢀmanno, βꢀgluco, and αꢀglucosides take place via associative mechanisms involving
exploded transitions states in which the incoming alcohol displaces triflate from a glycosyl triflate of
opposite configuration.24 On the other hand the 13C KIE measurements indicate that 4,6ꢀOꢀbenzylidene
protected αꢀmannopyranosides are formed by a dissociative mechanism that approaches the
intermediacy of a glycosyl oxocarbenium ion.24
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With respect to the formation of the Cꢀglycosides, the reaction of Cꢀcentered nucleophiles with putative
glycosyl oxocarbenium ions was first identified as a viable entry into Cꢀglycosides in 1973 by Hanessian
and coworkers in the furanoside series.25 The method gained considerable momentum following the
work of Kishi and coꢀworkers who used allyltrimethylsilane as nucleophile in the pyranoside series and
who interpreted their results in terms of pseudoaxial attack on a halfꢀchair conformation of the
intermediate glycosyl oxocarbenium ion.26 In more recent years, the Woerpel laboratory has studied
extensively the reaction of a variety of glycosyl donors with allylsilanes, stannanes and silyl enol ethers,
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first in the deoxyfuranoside series,27 and subsequently in the pyranoside series,28 with the results
interpreted in terms of nucleophilic attack on oxocarbenium ion intermediates. From these studies a
series of conclusions emerged according to which i) glycosyl oxocarbenium ions adopt conformations
which place electronegative substituents (CꢀO bonds) at all but the 2ꢀposition pseudoaxial when they
afford the maximum throughꢀspace stabilization to the positively charged center – a conclusion that is
corroborated by the extensive work of the Bols group on the differential stabilization of piperidinium
cations by electronegative substituents in axial or equatorial bonds sites29 – and by important
contributions from numerous other groups30 ii) that stereoelectronic control prevails in the attack of
nucleophiles on glycosyl cations that adopt the halfꢀchair conformation and leads preferentially to
products in the chair conformation with the nucleophile in an axial position; iii) that in cases of steric
hindrance to pseudoaxial axial attack on the lowest energy conformer of the glycosyl cation Curtinꢀ
Hammett kinetics come into play and pseudoaxial attack on less populated conformers may dominate;
and iv) that as the reaction rate approaches the diffusion controlled limit in cases involving strong
nucleophiles stereoelectronic control is eroded.
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Regarding stereochemical parallels between Oꢀ and Cꢀglycoside formation, in their initial work using a
2,3,5ꢀtriꢀOꢀbenzoyl protected ribofuranosyl donor and alkenes as nucleophiles Hanessian and coꢀ
workers noted the formation of the 1,2ꢀtransꢀproduct (βꢀCꢀDꢀribofuranoside) consistent with the
stereochemical picture for Oꢀglycoside formation.25 Subsequently Giannis and Sandhoff, adapting
Kishi’s allylsilane method to perꢀOꢀacetyl βꢀDꢀgluco and galactopyranose, found 1:1 α:βꢀmixtures of the
Cꢀglycosides on reaction in dichloromethane but very high αꢀselectivity in acetonitrile; a result that is
clearly at odds with the stereochemical expectations for Oꢀglycoside formation from the same donor.31
In contrast, in a later paper BeMiller and coꢀworkers reported the reaction of perꢀOꢀacetylꢀβꢀDꢀ
galactopyranose with allyltrimethylsilane and BF3OEt2 in nitromethane to give the βꢀCꢀgalactoside.32
An unclear picture therefore emerges with respect to possible analogies between Oꢀ and Cꢀglycoside
formation, particularly with regard to what are typically considered participating protecting groups.
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The Journal of Organic Chemistry
Conformational Analysis of Nucleophilic Attack on 4,6ꢀOꢀBenzylideneꢀProtected Glycosyl
Oxocarbenium Ions
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8
The presence of the 4,6ꢀOꢀbenzylidene acetal group severely limits the range of conformations
available to glycosyl oxocarbenium ions; in particular it excludes the possibility of “inverted”
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conformations such as the H4 halfꢀchair.33 Computational work from the Whitfield laboratory2
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corroborated by more recent computations in support of our primary 13C kinetic isotope effect studies24
suggests that any 4,6ꢀOꢀbenzylideneꢀprotected mannopyranosyl oxocarbenium ion will adopt the B2,5
conformation. This conformation puts the C2ꢀO2 bond in the minimally hindered bowsprit position and
the C3ꢀO3 bond in a pseudoꢀaxial position from which it achieves maximum stabilization of the
oxocarbenium ion. In the Stoddard projection33a of the pseudorotational itinerary for pyranoside rings
O
1
the B2,5 conformation is flanked by the S2 and S5 conformers to which any B2,5 oxocarbenium ion
necessarily deforms following attack on its αꢀ and βꢀfaces, respectively. Therefore, adopting the
oxocarbenium ion model for the formation of Cꢀglycosides, the selective formation of the βꢀCꢀ
mannopyranosides is most reasonably explained by βꢀface attack on the B2,5 conformation of the
oxocarbenium ion, in spite of the developing 1,3ꢀdiaxial interaction with the C3ꢀO3 bond in the
1
necessarily early transition state,34 leading initially to S5 conformer of the product in which the newly
formed bond adopts a pseudoaxial position (Scheme 2). The alternative possibility of αꢀface attack,
O
placing the isomeric product initially in the S2 twist boat conformation with the newly formed bond
pseudoꢀequatorial, suffers from a severe torsional interaction between the incoming nucleophile and the
to the C2ꢀH2 bond in the early transition state for this exothermic addition. In the 3ꢀdeoxy series,
despite the absence of the throughꢀspace stabilization afforded to the cation by any C3ꢀO3 bond, the B2,5
conformation with the sterically undemanding bowsprit 2ꢀOꢀbenzyl ether remains the more stable
conformation of the oxocarbenium ion on which βꢀface attack is now all the more favoured because of
the absent of a C3ꢀsubstituent.
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Scheme 2. Nucleophilic attack on the B2,5 conformation of the 4,6ꢀOꢀbenzylideneꢀprotected
mannopyranosyl (X = OBn) and 3ꢀdeoxymannopyranosyl (X = H) oxocarbenium ions.
In the 4,6ꢀOꢀbenzylidene protected glucopyranosyl oxocarbenium ion, the B2,5 conformation is no
longer favoured owing to the highly unfavourable positioning of the C2ꢀO2 bond in a flagpole position.
4
The preference is instead for the H3 half chair that retains the pseudoequatorial C2ꢀO2 bond and upon
which attack from the αꢀface in a pseudoaxial direction leads directly to the αꢀproducts observed in the
4
4
preferred C1 chair conformation (Scheme 3). The alternative mode of attack on the βꢀface of the H3
1
cation leading to the βꢀproduct in a S3 twist boat conformation is disfavored by a torsional interaction
between the incoming nucleophile and the pseudoaxial C2ꢀH2 bond (Scheme 3). 1,3ꢀDiaxial
interactions between the incoming nucleophile and pseudoaxial CꢀH bonds exist for attack on either face
4
of the H3 cation (H3 or H4) and as such are not considered to play a major role in face selectivity. As
4
the C3 substituent is pseudoequatorial in the H3 half chair and does not hinder approach of the
nucleophile, its removal is not expected to have a major influence on the stereoselectivity of reactions
involving the 4,6ꢀOꢀbenzylidene protected glucopyranosyl cation.
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H
Ph
1
2
3
4
H
X
O
O
O
BnO
H
5
6
7
H
4H3
-face attack
-face attack
X
8
9
10
11
Nu
Ph
O
O
Ph
O
BnO
O
O
BnO X
O
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Nu
1S3
4C1
-product
X
Ph
O
BnO
Nu
O
O
-product
4
Scheme 3. Nucleophilic attack on the H3 conformation of the 4,6ꢀOꢀbenzylideneꢀprotected
glucopyranosyl (X = OBn) and 3ꢀdeoxyglucopyranosyl (X = H) oxocarbenium ions.
Overall, the stereoselectivity of Cꢀglycoside formation in the 4,6ꢀOꢀbenzylidene series is adequately
explained by nucleophilic attack on the preferred conformations of the intermediate glycosyl
4
oxocarbenium ions, B2,5 for mannose and H3 for glucose, in such a way as to avoid torsional
interactions between the incoming nucleophile and the C2ꢀH2 bond in the necessarily early transition
states. These torsional interactions, which are indicated in Figures 2 and 3, are directly comparable to
those advanced by Boons and by Ito to rationalize the βꢀselectivity of arabinofuranosylation with donors
carrying a 3,5ꢀOꢀdiꢀtꢀbutylsilylene acetal or 3,5ꢀOꢀ(tetraisopropyl)disiloxane group.35
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Figure 2. Newman projections about C1ꢀC2 showing alternative modes of attack on the 4,6ꢀOꢀ
benzyideneꢀprotected mannosyl and glucosyl oxocarbenium ions, indicating torsional interactions
present in the disfavored modes.
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8
Discussion
9
If the oxocarbenium mechanism for Cꢀglycoside formation is adopted along with the conformational
analyses of Schemes 2 and 3, it is necessary to explain why the 2,3ꢀdiꢀOꢀbenzylꢀ4,6ꢀOꢀbenzylidene
protected mannopyranosyl oxocarbenium ion is βꢀselective toward the Cꢀnucleophiles whereas it is
moderately αꢀselective24 toward alcohols. Toward an understanding of this change in selectivity we note
the difference in steric size between alkoxy and vinyl groups apparent in the steric A values, with the
vinyl group being a simple model for the allylꢀtype Cꢀnucleophiles employed in this study. The
methoxy group has A value between 0.55 and 0.75 depending on the source and the tꢀbutoxy group has
the A value 0.75; the vinyl group on the other hand is unambiguously bigger with an A value of between
1.49 and 1.68.36 For related transition states with a comparable degree of advancement, those for the
formation of Cꢀglycosides will therefore necessarily be subject to greater steric hindrance than those for
the formation of Oꢀglycosides. Moreover the transition state requirements for Cꢀglycoside formation
with attack by πꢀelectronꢀdensity and, we assume on the basis of standard models,37 antiperiplanar
approach of the alkene to the oxocarbenium ion C=O bond are more rigid than those for Oꢀglycoside
formation which involve the use of electron density from an sp3 hybrid orbital and in which the alkyl
moiety of the alkoxy group can orient itself away from the bulk of the oxocarbenium ion. Simply stated,
in general alcohols will be less discerning than πꢀtype Cꢀnucleophiles in their attack on oxocarbenium
ions and therefore predictably less selective. In particular, the different transition state requirements for
Oꢀ and Cꢀglycoside formation suggest that the eclipsing interactions with the C2ꢀH2 suggested to be
important in determining face selectivity in Cꢀglycoside formation will be less important in Oꢀglycoside
formation leading to lower and perhaps even inverted selectivity (Fig 3).
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Figure 3. Representations of the transition states for antiperiplanar attack by πꢀtype Cꢀnucleophiles,
and alcohols on the disfavored face of the glycosyl oxocarbenium ions (cf Figure 2, αꢀfor mannoꢀ and βꢀ
for gluco) highlighting the influence of the C2ꢀH2 bond. Of the two unhindered staggered
conformations available for Oꢀglycoside formation only the one taking account of any developing exoꢀ
anomeric effect is illustrated.
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We cannot completely exclude another possibility that invokes αꢀOꢀmannoside formation via the less
4
populated H3 conformer of the oxocarbenium ion on which pseudoaxial attack on the αꢀface leads
4
directly to the product in the C1 conformation (Scheme 4). The transition state for such a mode of
attack can be considered to benefit from the developing anomeric stabilization of the nascent CꢀO bond.
However, as the transition state for this exothermic reaction step is early and cationꢀlike the stabilization
gained from the anomeric effect can only be small, as persuasively argued recently by Cumpstey34 and
previously by Sinnott.38 Accordingly, we do not consider it necessary to invoke such a pathway for αꢀOꢀ
mannoside formation.
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Scheme 4. Alternative pathway for the formation of αꢀOꢀmannopyranosides
1
2
3
4
5
6
7
8
9
Regarding the 3ꢀdeoxy series and the loss of selectivity in Oꢀglycosylation but not in Cꢀglycosylation,
the models presented for Cꢀglycosylation in Schemes 1 and 2 are adequate and no further discussion is
required, but the same cannot be said for the Oꢀglycosides. Computational work indicates that the
selective formation of the βꢀOꢀmannopyranosides in the 4,6ꢀOꢀbenzylidene acetal protected series may
be assisted by hydrogen bonding between the incoming acceptor and O3 of the donor,2a,2d,24 although it
has most recently been suggested that such hydrogen bonds are an artifact of the computational
method.39 Clearly such hydrogen bonds are not possible in the 3ꢀdeoxy series and any energetic
contribution that they may have provided toward selectivity in the normal glucoꢀ and mannoꢀ series will
be lost leading to lower selectivity. A comparable argument cannot be advanced to explain the loss of αꢀ
selectivity in the 4,6ꢀOꢀbenzylidene protected glucopyranose series as the computations predict
hydrogen bonding between the incoming acceptor and O2 of the donor in the formation of the αꢀ
glucoside24 and selfꢀevidently this can persist in the 3ꢀdeoxy series. An alternative, perhaps more
plausible explanation, invokes a change in mechanism away from associative and toward dissociative
mechanisms for the complete set of Oꢀglycoside formations owing to the removal of the electronꢀ
withdrawing C3ꢀO3 bond and its destabilizing effect on the glycosyl oxocarbenium ion such as we have
discussed previously.3 In such a hypothesis the differences in selectivity between Oꢀ and Cꢀglycoside
formation will arise from the less stringent transition state requirements for attack by alcohols than by Cꢀ
nucleophiles as discussed above. The possibility that the 2ꢀOꢀbenzyl ether is less sterically bulky in the
3ꢀdeoxy series than in the fully substituted systems owing to a loss a buttressing interactions,40 is a valid
consideration but one that is unlikely to be the origin of the diminished selectivity of Oꢀglycoside
formation in the 3ꢀdeoxy series as smaller protecting groups at the 2ꢀposition have been previously
found to afford greater rather than lower βꢀselectivity in mannosylation.3 Finally, in an elegant study,
Beaver and Woerpel have demonstrated that the simple alcohol ethanol attacks both faces of the 3,4,6ꢀ
triꢀOꢀbenzyl glucopyranosyl oxocarbenium ion in an unselective manner and have provided evidence
that is the consequence of a reaction taking place near the diffusion controlled limit when the selectivity
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simply reflects the relative probability of encounter of the two faces.28b Owing to the presence of
usually two electronꢀwithdrawing βꢀCꢀO bonds and their far greater steric bulk the nucleophilicity of
typical carbohydrate alcohols is expected to be somewhat lower than that of ethanol and, thus, the
probability of such a diffusionꢀcontrolled model operating for the 3ꢀdeoxyꢀOꢀglycosides small.
Conclusion
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The study of Cꢀglycoside formation in the 3ꢀdeoxyꢀ4,6ꢀOꢀbenzylidene protected mannoꢀ and
glucopyranoside series reveals no change in selectivity from the prototypical 3ꢀOꢀbenzyl series, an
observation which is in contrast to Oꢀglycoside formation where selectivity depends critically on the
presence of a benzyloxyꢀtype protecting group at the 3ꢀposition. These results are best understood in
terms of subtle changes in mechanism between the formation of the Oꢀ and Cꢀglycosides related to the
different steric requirements for the attack of sp2 and sp3 hybridized nucleophiles on oxocarbenium ions.
Experimental Section
General. Glycosyl donors 1,11 2,12 3,9 and 4.9 were prepared by the literature methods. High resolution
mass spectrometric measurements were made using an electrospray source coupled to a time of flight
mass analyzer.
General Procedure for Glycosylation Using the BSP or DPSO/TTBP/Tf2O Systems. To a stirred
solution of 0.05 M solution of donor, BSP or DPSO (1.2 equiv), TTBP (1.5 equiv) and 4 Å molecular
sieves in dichloromethane was added at ꢀ65 ºC Tf2O (1.2 equiv). The resulting mixture was stirred for
0.75 h before a solution of the acceptor (5 equiv) in dichloromethane (0.20 M) was slowly added. The
resulting mixture was stirred at – 65 ºC for 3 to 12 h. The reaction was quenched at ꢀ 65 ºC by adding a
saturated solution of NaHCO3. The temperature was allowed to warm to room temperature. The mixture
was taken up in dichloromethane and filtered through Celite before phase separation. The organic phase
was washed with a saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated.
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Purification by column chromatography eluting with hexanes/ethyl acetate 15:1 unless otherwise stated
1
2
3
afforded the Cꢀglycosides.
4
5
6
7
2,3ꢀOꢀDiꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ1ꢀallylꢀ1ꢀdeoxyꢀβꢀD
ꢀmannopyranose (5).4 Compound (5) was
8
9
prepared from 1 (100 mg) by the general glycosylation procedure and was obtained (50ꢀ52 mg) in 57 to
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60
1
60% yield as a white solid: mp = 80.9 – 90.5 °C; [ α]RT ꢀ 26.0 (c = 1.0 M, CHCl3); H NMR (500
D
MHz, CDCl3)
δ 7.52 (dd, J = 1.5, 7.5 Hz, 2H), 7.42 – 7.29 (m, 13H), 5.72 – 5.63 (m, 2H), 5.10 ꢀ5.02
(m, 3H), 4.93 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 12.5 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.30 – 4.24 (m,
2H), 3.86 (t, J = 10.0 Hz, 1) 3.81 (d, J = 2.0 Hz, 1H), 3.74 (dd, J = 2.5, 9.5 Hz, 1H), 3.46 (t, J = 7.0 Hz,
1H), 3.39 (dt, J = 5.0, 10.0 Hz, 1H), 2.47 (dt, J = 6.5, 14.0 Hz, 1H), 2.26 (dt, J = 7.0, 14.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3)
δ 138.6, 138.4, 137.7, 134.3, 128.8, 128.5, 128.4, 128.3, 128.2, 127.7, 127.6,
127.5, 126.0, 117.5, 101.3, 80.7, 79.6, 79.5, 76.3, 75.0, 73.1, 72.0, 68.7, 35.5, 29.7; ESIHRMS calcd for
C30H32O5Na [M + Na]+ 495.2147, found 495.2142.
2,3ꢀDi-Oꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ1ꢀdeoxyꢀ1ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀβꢀ
D
ꢀmannopyranose
(6).4
Compound (6) was prepared from 1 (100 mg) by the general glycosylation procedure and obtained in
76% yield (77 mg) as a colorless oil: [ α]RTD – 10.4 (c = 0.75 M, CHCl3); 1H NMR (500 MHz, CDCl3)
δ
7.82 (d, J = 7.0 Hz, 2H), 7.59 – 7.51 (m, 3H), 7.46 ꢀ 7.34 (m, 8H), 7.32 – 7.25 (m, 4H), 7.17 – 7.09
(m, 3H), 5.65 (s, 1H), 5.02 (d, J = 11.5 Hz, 1H), 4.96 (d, J = 12.5 Hz, 1H), 4.81 (d, J = 12.5 Hz, 1H),
4.61 (d, J = 12.0 Hz, 1H), 4.26 (ddt, J = 1.5, 6.5, 9.5, 2H), 4.15 (t, J = 6.0 Hz, 1H), 4.05 (d, J = 1.5 Hz,
1H), 3.88 (dd, J = 3.0, 9.5 Hz, 1H), 3.83 (t, J = 10.0 Hz, 1H), 3.48 (dt, J = 5.0, 10.0 Hz, 1H), 3.24 (dd, J
= 5.5, 17.5 Hz, 1H), 3.13 (dd, J =7.5, 17.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 197.2, 138.5, 138.0,
137.7, 136.5, 133.3, 120.9, 128.8, 128.5, 128.4, 128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 126.1, 101.4,
80.4, 79.4, 75.9, 75.6, 75.0, 73.3, 71.8, 68.6, 39.6; ESIHRMS calcd for C35H34O6Na [M + Na]+
573.2252, found 573.2255.
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2,3ꢀOꢀDiꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ1ꢀallylꢀ1ꢀdeoxyꢀαꢀD
ꢀglucopyranose (7).4 Compound (7) was
1
2
prepared from 2 (100 mg) by the general glycosylation procedure and obtained in 56 to 58% yield (49ꢀ
3
4
5
6
1
51 mg) as a white solid: mp = 90.8 – 91.2 °C; [ α]RTD– 0.9 (c = 0.75 M, CHCl3); H NMR (500 MHz,
7
8
9
CDCl3)
δ 7.50 (dd, J = 1.5, 8.0 Hz, 2H), 7.41 – 7.27 (m, 13H), 5.81 – 5.73 (m, 1H), 5.13 (dd, J = 1.5,
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17.0 Hz, 1H), 5.09 (d, J = 10.0 Hz, 1H), 4.92 (d, J = 11.0 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.64 (d, J
= 11.5 Hz, 1H), 4.26 – 4.21 (m, 1H), 4.08 (dd, J = 5.5, 8.0 Hz, 1H), 3.90 – 3.86 (m, 1H), 3.76 (dd, J =
13
5.5, 8.5 Hz, 1H), 3.70 – 3.64 (m, 3H), 2.54 (t, J = 7.5 Hz, 2H); C NMR (125 MHz, CDCl3)
δ 138.6,
138.1, 137.4, 134.3, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6, 126.0, 117.2, 101.1, 82.7, 79.4,
78.7, 74.9, 74.8, 73.6, 69.4, 63.4, 30.7; ESIHRMS calcd for C30H32O5Na [M + Na]+ 495.2147, found
495.2138.
2,3ꢀDi-Oꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ1ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀαꢀDꢀglucopyranose (8) and [(1R)ꢀ2ꢀ
Oxoꢀ1,2ꢀdiphenylꢀ1ꢀ(phenylthiomethyl)ethyl] 2,3ꢀdi-Oꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀαꢀ
D
ꢀ
glucopyranoside (9). Compounds (8)4 and (9) were obtained from 2 (100 mg) by the general
glycosylation procedure. Purification by column chromatography eluting with hexanes/ethyl acetate 15:1
to 8:1 gave compounds 8 (40 mg) and 9 (40 mg) both in 40% yield.
Compound (8) was isolated as a colorless oil, [ α]RTD + 17.6 (c = 0.75 M, CHCl3); 1H NMR (500 MHz,
CDCl3)δ 7.90 (d, J = 7.5 Hz, 2H), 7.56 (dd, J = 7.0, 8.0 Hz, 1H), 7.51 – 7.43 (m, 4H), 7.40 – 7.35 (m,
5H), 7.34 – 7.26 (m, 8H), 5.57 (s, 1H), 4.96 – 4.93 (m, 2H), 4.82 (d, J = 12.0 Hz, 1H), 4.73 (d, J = 11.5
Hz, 1H), 4.63 (d, J = 17.6 Hz, 1H), 4.21 (dd, J = 3.0, 9.5 Hz, 1H), 3.91 – 3.83 (m, 2H), 3.72 – 3.64 (m,
13
3H), 3.50 – 3.46 (m, 1H), 3.29 (dd, J = 7.5, 16 Hz, 1H); C NMR (125 MHz, CDCl3)
δ 197.2, 138.5,
137.7, 137.3, 137.0, 133.2, 128.9, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 126.0,
101.2, 82.4, 78.8, 78.7, 74.8, 73.8, 72.0, 69.3, 64.7, 36.0; ESIHRMS calcd for C35H34O6Na [M + Na]+
573.2253, found 573.2251.
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Compound (9) was isolated as a colorless oil, [ α]RTD + 28.0 (c = 0.25 M, CHCl3); 1H NMR (500 MHz,
CDCl3) 7.87 (d, J = 7.0 Hz, 2H), 7.57 – 7.15 (m, 27H), 7.05 (t, J = 7.5 Hz, 1H), 5.46 (s, 1H), 5.08 (d, J
1
2
3
4
δ
5
6
7
8
= 3.5 Hz, 1H), 4.84 (d, J = 11.5, 1H), 4.74 (d, J = 11.0 Hz, 1H), 4.62 (d, J = 11.5 Hz, 1H), 4.50 (d, J =
12.0 Hz, 1H), 4.18 – 4.11 (m, 2H), 4.01 (d, J = 8.0 Hz, 1H), 3.98 (d, J = 12.0 Hz, 1H), 3.88 – 3.82 (m,
2H), 3.70 (d, J = 14.0 Hz, 1H), 3.50 – 3.43 (m, 2H), 3.67 (dd, J = 3.5, 9.5 Hz, 1H); 13C NMR (125 MHz,
9
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CDCl3)
δ 195.8, 141.3, 138.9, 138.2, 137.6, 137.5, 137.1, 133.0, 129.5, 128.9, 128.6, 128.3, 128.2,
128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 127.4, 127.2, 126.1, 126.0, 101.2, 93.9, 82.7, 82.5, 79.6, 78.4,
75.2, 73.8, 68.9, 63.2, 45.9, 43.1, 29.7; ESIHRMS calcd for C49H46O7SNa [M + Na]+ 801.2862, found
801.2852.
2ꢀOꢀBenzylꢀ4,6ꢀOꢀbenzylideneꢀ1ꢀallylꢀ1,3ꢀdideoxyꢀ βꢀDꢀmannopyranose (10). Compound (10) was
prepared from 3 (80 mg) by the general glycosylation procedure and obtained in 35% to 59% yield (19ꢀ
40 mg) as a colorless oil: [ α]RTD + 1.7 (c = 0.75 M, CHCl3); 1H NMR (500 MHz, CDCl3)
δ
7.49 (dd, J
= 2.0, 8.0 Hz, 2H), 7.40 ꢀ 7.28 (m, 8H), 5.76 – 5.67 (m, 1H), 5.57 (s, 1H), 5.05 (ddd, J = 1.5, 10.0, 17.0
Hz, 2H), 4.74 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.27 (dd, J = 5.0, 10.5 Hz, 1H), 3.98 (m,
1H), 3.81 (t, J = 10.5 Hz, 1H), 3.65 (d, J = 1.0 Hz, 1H), 3.53 (dt, J = 1.5, 7.0 Hz, 1H), 3.44 (dt, J = 5.0,
13
10.0 Hz, 1H), 2.54 – 2.45 (m, 2H), 2.35 (dt, J = 7.5, 14.5 Hz, 1H), 1.67 (dt, J = 3.0, 13.5 Hz, 1H); C
NMR (125 MHz, CDCl3)
δ 137.9, 137.6, 134.4, 129.0, 128.4, 128.3, 128.1, 127.8, 126.1,117.3, 101.9,
80.1, 74.5, 74.1, 73.8, 71.2, 69.2, 35.5, 32.0, 29.7; ESIHRMS calcd for C23H26O4Na [M + Na]+
389.1731, found 389.1733.
SꢀPhenyl 2ꢀOꢀBenzylꢀ4,6ꢀOꢀbenzylideneꢀ3ꢀdeoxyꢀαꢀDꢀthioꢀmannopyranoside (3α). A colorless oil,
was isolated from the standard glycosylation procedure (10 mg, 17%). [ α]RT – 34.1 (c = 1.0 M,
D
1
CHCl3), H NMR (500 MHz, CDCl3)
δ 7.41 (dd, J = 1.5, 8.0 Hz, 2H), 7.38 (dd, J = 1.5, 8.0 Hz, 2H),
7.32 ꢀ 7.20 (m, 11 H), 5.53 (s, 1H), 5.49 (s, 1H), 4.54 (dd, J = 12.0, 17.5 Hz, 2H), 4.26 (dt, J = 5.0, 10.0
Hz, 1H), 4.13 (dd, J = 5.0, 10.0 Hz, 1H), 4.07 – 4.02 (m, 1H), 3.93 (br s, 1H), 3.77 (t, J = 10.5 Hz, 1H),
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2.82 – 2.38 (m, 1H), 1.96 (dt, J = 2.0, 13.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 137.6, 137.2, 134.1,
1
2
3
4
5
131.5, 129.1, 128.5, 128.3, 128.0, 127.7, 127.5, 126.2, 102.3, 86.2, 76.5, 74.3, 71.2, 69.0, 69.1, 30.7;
ESIHRMS calcd for C26H26O4SNa [M + Na]+ 457.1450, found 457.1433.
6
7
8
9
2ꢀOꢀBenzylꢀ4,6ꢀOꢀbenzylideneꢀ1,3ꢀdideoxyꢀ1ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀ βꢀ
D
ꢀmannopyranose
(11).
10
11
12
13
14
15
16
17
18
19
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23
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60
Compound (11) was prepared from 3 (80 mg) by the general glycosylation procedure and obtained in
75% yield (62 mg) as a α/β > 1:20 mixture. The β anomer was isolated as a colorless oil: [ α]RTD ꢀ 21.7
(c = 0.75 M, CHCl3) ;1H NMR (500 MHz, CDCl3)
δ 7.90 (dd, J 1.5, 8.5 Hz, 2H), 7.58 (t, J = 7.0 Hz,
1H), 7.50 (dd, J = 2.0, 8.0 Hz, 2H), 7.39 – 7.34 (m, 4H), 7.26 – 7.24 (m, 1H), 7.22 – 7.18 (m, 3H), 5.59
(s, 1H), 4.72 (d, J = 12.0 Hz, 1H), 4.35 (d, J = 12.0 Hz, 1H), 4.26 (dd, J = 3.0, 4.5 Hz, 2H), 3.98 (ddd, J
= 4.5, 9.5, 13.5 Hz, 1H), 3.85 (t, J = 3.0 Hz, 1H), 3.78 (t, J = 10.5 Hz, 1H), 3.53 (ddd, J =5.0, 9.0, 10.5
13
Hz, 1H), 3.30 (d, J = 7.0 Hz, 2H), 2.53 (dt, J = 3.5, 14.0 Hz, 1H), 1.84 – 1.78 (m, 1H); C NMR (125
MHz, CDCl3)
δ 197.6, 137.6, 136.8, 133.3, 129.0, 128.8, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0,
127.9, 127.7, 126.1, 102,0, 76.2, 74.4, 74.0, 73.7, 71.2, 69.1, 39.6, 31.8, 29.7; ESIHRMS calcd for
C28H28O5Na [M + Na]+ 467.1834, found 467.1830.
2ꢀOꢀBenzylꢀ4,6ꢀOꢀbenzylideneꢀ1ꢀallylꢀ1,3ꢀdideoxyꢀαꢀDꢀglucopyranose (12). Compound (12) was
prepared from 4 (80 mg) by the general glycosylation procedure and obtained in 60 to 63% yield (40ꢀ43
mg) as a white solid: mp = 101.2 – 101.8 °C; [ α]RTD + 30.2 (c = 0.75 M, CHCl3); 1H NMR (500 MHz,
CDCl3)
δ 7.49 (dd, J = 2.0, 8.0 Hz, 2H), 7.40 – 7.30 (m, 8H), 5.89 ꢀ5.81 (m, 1H), 5.52 (s, 1H), 5.17 (dd,
J = 9.0, 10.0 Hz, 2H), 4.58 (q, J = 12.0 Hz, 2H), 4.22 (dd, J = 4.3, 9.9 Hz, 1H), 4.12 (ddd, J = 3.8, 5.5,
7.3 Hz, 1H), 3.85 (ddd, J = 4.7, 5.5, 11.6 Hz, 1H), 3.63 (dd, J = 9.5, 10.5 Hz, 1H), 3.58 – 3.49 (m, 2H),
2.71 – 2.64 (m, 1H), 2.47 – 2.43 (m, 1H), 2.37 (dt, J = 4.3, 11.7 Hz, 1H), 1.85 (q, J = 1.6 Hz, 1H); 13C
NMR (125 MHz, CDCl3)δ 138.0, 137.4, 134.5, 129.1, 128.5, 128.4, 127.8, 127.5, 126.1, 117.2, 101.7,
74.6, 74.0, 71.0, 69.7, 64.9, 30.8, 29.7, 28.9; ESIHRMS calcd for C23H26O4Na [M + Na]+ 389.1729,
found 389.1725.
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2ꢀOꢀBenzylꢀ4,6ꢀOꢀbenzylideneꢀ3ꢀdeoxyꢀ1ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)ꢀαꢀDꢀglucopyranose (13) and [(1R)ꢀ
1
2
2ꢀOxoꢀ1,2ꢀdiphenylꢀ1ꢀ(phenylthiomethyl)ethyl]
2-Oꢀbenzylꢀ4,6ꢀOꢀbenzylideneꢀ3ꢀdeoxyꢀαꢀDꢀ
3
4
5
6
7
8
glucopyranoside (14). Compounds (13) and (14) were obtained from 4 (80 mg) by the general
glycosylation procedure. Purification by column chromatography eluting with hexanes/ethyl acetate 15:1
to 10:1 gave compounds 13 (28 mg) and 14 (30 mg) in 34 and 37% yield, respectively.
9
10
11
12
13
14
15
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60
Compound (13) was isolated as a white solid, mp = 90.8 – 91.2 °C; [ α]RTD + 32.4 (c = 0.5 M, CHCl3);
1H NMR (500 MHz, CDCl3)
δ 7.96 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.48 – 7.45 (m, 4), 7.39
– 7.27 (m, 8H), 5.50 (s, 1H), 4.98 – 4.94 (m, 1H), 4.55 (s, 2H), 4.17 (, 1H), 3.89 (dt, J = 5.0, J = 12.5
Hz, 1H), 3.63 – 3.50 (m, 3H), 4.70 (d, J = 4.5 Hz, 1H), 3.37 (dd, J = 8.0, 16.5, 1H), 2.41 (dt, J = 4.0,
13
12.0, 1H), 1.85 (q, J = 12.0, 1H); C NMR (125 MHz, CDCl3)
δ 197.6, 137.7, 137.3, 137.2, 133.1,
129.1, 128.6, 128.5, 128.4, 128.2, 127.8, 127.6, 126.1, 101.7, 73.3, 71.6, 71.2, 69.7, 66.2, 34.5, 31.4,
29.7; ESIHRMS calcd for C28H28O5Na [M + Na]+ 467.1834, found 467,1831.
Compound (14) was isolated as a colorless oil, [ α]RTD + 57.6 (c = 0.5 M, CHCl3); 1H NMR (500 MHz,
CDCl3)
δ 7.86 (d, J = 7.5 Hz, 2H), 7.58 – 7.53 (m, 3H), 7.48 (dd, J = 2.0, 8.0 Hz, 2H), 7.42 (t, J = 8.0
Hz, 2H), 7.39 – 7.18 (m, 15H), 7.09 (t, J = 7.5 Hz, 1H), 5.39 (s, 1H), 5.05 (d, J = 3.5 Hz, 1H), 4.04 (s,
2H), 4.17 (d, J = 18.5 Hz, 1H), 4.07 – 4.00 (m, 3H), 3.76 (dd, J = 5.0, 15.0 Hz, 1H), 3.72 (d, J = 13.5
13
Hz, 1H), 3.43 – 3.34 (m, 3H), 2.19 – 2.16 (m, 1H), 1.97 (q, J = 12.0 Hz, 1H); C NMR (125 MHz,
CDCl3)
δ 195.8, 141.7, 138.0, 137.5, 137.4, 137.0, 133.0, 129.6, 129.1, 128.8, 128.6, 128.4, 128.3,
128.1, 127.9, 127.8, 127.7, 127.4, 127.2, 126.3, 125.9, 101.8, 92.5, 82.2, 76.9, 74.6, 71.0, 69.1, 64.8,
46.1, 43.1, 29.8; ESIHRMS calcd for C42H40O6SNa [M + Na]+ 695.2443, found 695.2449.
Acknowledgment. We thank the NIH (GM62160) for support of this work.
1
13
Supporting Information Available. Copies of the H and C NMR spectra of compounds 3α, and
9ꢀ14. This material is available free of charge via the Internet at http://pubs.acs.org
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References
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Glycoside Synthesis; Postema, M. H. D., Ed.; CRC: Boca Raton, 1995; c) Postema, M. H. D.;
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(14) For the reaction of 1 with allyltrimethylsilane and allyltributylstannane to give 5 we previously
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o
reported yields of 58 and 61%, respectively, with α:β ratios of 1:5 and 1:8, respectively, at ꢀ60 C. The
4
5
6
7
8
formation of comparably minor amounts of the αꢀanomer of 5 in the present can not be excluded but
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9
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180ꢀ190.
(40) For interesting discussions on diastereoselectivity induced by the size, shape, and orientation of
protecting groups at the 2ꢀpositions see: a) Kumar, R. Whitfield, D. M. J. Org. Chem. 2012, 77, 3724ꢀ
3739. b) Ionescu, A. R.; Whitfield, D. M.; Zgierski, M. Z. Carbohydr. Res. 2007, 342, 2793ꢀ2800.
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