Sugar silanes: Versatile reagents for stereocontrolled glycosylation via intramolecular aglycone delivery

Article abstract of DOI:10.1039/c5sc00810g

A new method for the intramolecular glycosylation of alcohols is described. Utilizing carbohydrate-derived silanes, the catalytic dehydrogenative silylation of alcohols is followed by intramolecular glycosylation. Appropriate combinations of silane positi

Full text of DOI:10.1039/c5sc00810g

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Sugar silanes: versatile reagents for
stereocontrolled glycosylation via intramolecular
aglycone delivery†
Cite this: Chem. Sci., 2015, 6, 3448
*
Jordan T. Walk,‡ Zachary A. Buchan‡§ and John Montgomery
A new method for the intramolecular glycosylation of alcohols is described. Utilizing carbohydrate-derived
silanes, the catalytic dehydrogenative silylation of alcohols is followed by intramolecular glycosylation.
Appropriate combinations of silane position and protecting groups allow highly selective access to b-
manno, a-gluco, or b-gluco stereochemical relationships as well as 2-azido-2-deoxy-b-gluco- and 2-
deoxy-b-glucosides. Intramolecular aglycone delivery from the C-2 or C-6 position provides 1,2-cis or
1,2-trans glycosides, respectively. Multifunctional acceptor substrates such as hydroxyketones and diols
are tolerated and are glycosylated in a site-selective manner.
Received 5th March 2015
Accepted 12th April 2015
DOI: 10.1039/c5sc00810g
www.rsc.org/chemicalscience
substrates (Fig. 1). Our prior efforts have described the direct
reductive glycosylation of carbonyl substrates and the three-
Introduction
component assembly of glycosylated products via the catalytic
union of aldehydes, alkynes, and sugar silanes.7 In order to
provide a more complete toolbox of glycosylation procedures
Despite the enormous progress that has been made in the
development of chemical glycosylation methods, challenges
remain in the efficiency and stereoselectivity of carbohydrate
installation.1 Access to the various 1,2-stereochemical arrange-
ments from a common carbohydrate donor is challenging, as
careful matching of the anomeric leaving group, protecting
groups that inuence stereochemistry and reactivity, and reac-
tion conditions is oen required.2 The vast majority of methods
require that only a single hydroxyl group is unmasked in the
acceptor substrate. Furthermore, utilization of acceptor
substrates other than alcohols and reactive electrophiles are
virtually unexplored.3 Creative developments in intramolecular
aglycone delivery,4 including the silicon-tethered version pio-
neered and developed by Stork5 and Bols,6 have served an
important role in modern glycosylation technology. However,
improved routes to the requisite tethered substrates and
expansion of the range of accessible classes of glycoside prod-
ucts would signicantly broaden the appeal and utility of these
methods.
To address the above challenges and limitations, our labo-
ratory has focused on the development of “sugar silanes” as a
versatile reagent class that enables an array of glycosylation
processes, providing access to numerous 1,2-stereochemical
relationships and utilizing several different types of donor
Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor,
MI, 48109-1055, USA. E-mail: jmontg@umich.edu
† Electronic supplementary information (ESI) available: Experimental details and
copies of NMR spectra. See DOI: 10.1039/c5sc00810g
‡ J.T.W. and Z.A.B. contributed equally.
Fig.
1 Donor–acceptor combinations for sugar silane-based
§ Current address: Discovery Chemistry, R&D, Dow AgroSciences LLC, 9330
Zionsville Rd, Indianapolis, IN 46268.
glycosylations.
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from sugar silanes, and to address the essential issue of site- coupling to afford silane intermediate 4a in near quantitative
selectivity among various reactive functional groups, we now yield. The silyl-linked intermediates were stable to silica gel
report the direct glycosylation of alcohol substrates by the chromatography and were puried prior to glycosylation.
dehydrogenative condensation with sugar silanes. In addition Intramolecular glycosylation with N-iodosuccinimide, trime-
to identifying effective catalysts to promote this new trans- thylsilyl triate, and 2,6-di-(t-butyl)-4-methylpyridine cleanly
formation, utilization of C-25,6 or C-68 intramolecular delivery of afforded a-glucoside 5a as a single stereoisomer in 98% isolated
the glycosyl acceptor enables highly stereoselective access to yield.3b Alternatively, mannose-derived silane 2a allowed the
b-manno, a-gluco, or b-gluco congurations. The work over- production of b-mannoside 5b in excellent overall yield as a
comes challenges that plagued previous strategies for intra- single stereoisomer using either CuCl–IMes or B(C6F5)3 in the
molecular aglycone delivery from the C-6 position. silylation step. Tolerance of acetal and silyl protecting groups
Stereocontrolled access to b-glucosides with benzyloxy or acy- was demonstrated through the formation of a-glucoside 5c as a
loxy C-2 substituents as well as 2-azido and 2-deoxyglycosides is single stereoisomer. The method may be applied to the
made possible by the new procedures described herein.
synthesis of disaccharides as demonstrated by the formation of
a-glucoside 5d as a single stereoisomer. Additionally, the iter-
ative potential of the method is demonstrated by the synthesis
of b-mannoside 5e. In this example, the product 5b is directly
converted with sugar silane 1b to intermediate 4e. Intra-
molecular glycosylation then directly affords product 5e as a
single stereoisomer. Given that the C-2 hydroxyl is deprotected
during glycosylation, this method may be especially attractive
for the synthesis of oligosaccharides that possess repeating C-2
glycosidic linkages. While this method allows glycosylations of
the C-2 hydroxyl of mannose as example 5e illustrates, glyco-
sylations of more hindered secondary hydroxyl sugar acceptors
were not effective. While the above method builds upon the
seminal contributions from Stork and Bols, the streamlined
catalytic access to the silicon-tethered intermediates using
readily accessible sugar silane reagents advances the practi-
cality of the approach.
Given the range of acceptor substrates that are amenable to
glycosylation with sugar silanes (Fig. 1), the chemoselective or
regioselective derivatization of a single functional group in a
multifunctional substrate becomes a signicant question to
address.12 As entropic factors govern the intramolecular glyco-
sylation, the chemoselectivity of the initial attachment of the
sugar silane to a single functional group introduces a strategy
for site-selective glycosylation of complex multifunctional
substrates. Since both ketones and alcohols are competent
substrates for the catalytic addition of sugar silanes, chemo-
and regioselective additions to both hydroxyketones and to
diols would provide important advances towards site-selective
glycosylation. To address this question, the dehydrogenative
silylation of 2-hydroxypinanone was examined. For this
substrate, highly chemoselective dehydrogenative silylation of
the hydroxyl group was observed with both the glucose and
mannose-derived sugar silane to enable the production of
a-glucoside 5f or b-mannoside 5g as single stereoisomers
through the intermediacy of 4f and 4g. To examine a spatial
separation of the ketone and hydroxyl functionalities, the
dehydrogenative silylation of a steroid framework was exam-
ined, with both the silylation and glycosylation proceeding in
excellent yield. In this case, an A-ring hydroxyl was silylated
without affecting the D-ring ketone, enabling the production of
b-mannoside 5h as a single stereoisomer through the interme-
diacy of 4h. Finally, two examples involving the C-6 selective
glycosylation of a sugar diol were illustrated. The reaction of a
4,6-diol derived from glucose underwent selective C-6 silylation
Results and discussion
Given the precedent from Stork and Bols on intramolecular
aglycone delivery from the C-2 position, our efforts rst focused
on the utility of mannose- and glucose-derived glycosyl donors
bearing the requisite silane functionality at the C-2 position.
These reagents are easily accessed in quantitative yield by C-2
protection with commercially available Me2SiHCl (Fig. 2). While
bis-electrophilic reagents are most commonly used in the
assembly of silyl linkages between two hydroxyls,5,6 the use of
Me2SiHCl enjoys the advantage of high heterocoupling effi-
ciency across a range of alcohol substrates.9 Following chloride
displacement by the initially added alcohol, a second alcohol
then condenses with the resulting silyl hydride (losing H2) in
the presence of a transition metal or Lewis acid catalyst, thus
effectively preventing homocoupling across a range of substrate
combinations.
Upon screening numerous catalyst systems to promote the
dehydrogenative coupling with alcohol acceptors, two catalyst
systems were identied as most robust and exhibiting
complementary behavior. While the methods were oen inter-
changeable with similar results, the use of B(C6F5)3 was most
effective with more hindered 2ꢀ and 3ꢀ alcohol substrates,10
whereas a copper–IMes catalyst was most effective with 1ꢀ
alcohols.11 As the following examples illustrate, a range of
hindered and unhindered glycosidic linkages may be created by
this method (Table 1). Couplings of menthol with glucose-
derived silane 1a are effective using either CuCl–IMes or
B(C6F5)3 as catalyst, with the latter allowing dehydrogenative
Fig. 2 Synthesis of thioglycosides with a C-2 silane.
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Table 1 b-Mannosides and a-glucosides by C-2 delivery
a
IMes ¼ 1,3-bis(mesityl)imidazol-2-ylidene. b Diastereoselectivities of glycosylations are >97 : 3 as judged by 1H NMR.
and a-glucosylation to afford 5i. Similarly, reaction of a 2,6-diol that installation of a conformational bias that prevents chair–
derived from mannose underwent selective C-6 silylation and a- chair interconversion should inhibit delivery of the undesired
glucosylation to afford 5j.
C-6 oxygenation. To evaluate this hypothesis, we utilized the
Whereas the synthesis of b-manno and a-gluco stereo- strategy pioneered by Ley to protect the C-3/C-4 trans-diol via the
chemical relationships has been achieved through alternative cyclic bisacetal 7 (Fig. 3).15 This protecting group serves the two
intramolecular methods, an efficient strategy for b-gluco useful purposes of (1) providing streamlined access to the
stereochemical relationships by intramolecular aglycone desired protecting group array, wherein late-stage installation
delivery has not been previously developed.13 Early efforts from of the C-6 silane is easily allowed, and (2) removing the
Bols demonstrated that C-6 delivery is unsuccessful since conformational exibility that allows the undesired [3.2.1]-
bridged bicyclic product 6 is the major product via intra- oxabicyclic product 6 to form. This strategy allows straightfor-
molecular delivery of the internal C-6 oxygen rather than the ward access to a range of thiophenyl sugar silanes 8–10 bearing
desired tethered aglycone (Fig. 3).14 While successes were seen a C-6 silane, a C-3/C-4 trans-diol protected as the bis-acetal, and
with ribose frameworks,14 long-range intramolecular delivery a range of C-2 substituents including benzyloxy, acetoxy, azido,
with pyranosides remains an unsolved problem. We reasoned and hydrogen substituents.
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examples of the C-6 delivery strategy, the intramolecular
glycosylations of butanol and phenethyl alcohol were conducted
using sugar silane 8a. In both cases, b-glucoside products 12a
and 12b were obtained as single stereoisomers (Table 2). Simple
secondary alcohols such as cyclohexanol were effective partici-
pants as evidenced by the production of 12c in good yield as a
single stereoisomer. Unlike the C-2 delivery procedures that
tolerate hindered alcohols, secondary alcohols more hindered
than cyclohexanol were poor substrates for C-6 delivery. More
hindered substrates such as menthol and C-2 hydroxyl accep-
tors derived from glucose underwent glycosylation in moderate
to low yield. Given this limitation, the CuCl–IPr catalyst system
was used in the majority of the C-6 delivery examples as this
method is most effective with the primary acceptor alcohols
employed.
The formation of C-6 linked disaccharides proceeded effi-
ciently, as evidenced by the formation of products 12d and 12e.
In the former case (12d), coupling using B(C6F5)3 avoided the
formation of a homocoupling product derived from partial
hydrolysis of the sugar silane reagent. In the latter case (12e), a
small amount of an impurity derived from dimerization of the
sugar donor 8a was inseparable from intermediate 11e. None-
theless, subjecting the mixture to glycosylation conditions led
to the clean production of product 12e, which was easily puri-
ed. Additionally, an example demonstrated the chemo-
selectivity for hydroxyls over ketones in the production of 12f. In
this case, the site-selective alcohol silylation is best accom-
plished with B(C6F5)3 as the catalyst.
Fig. 3 Synthesis of thioglycosides with a C-6 silane utilizing the Ley
bis-acetal protection.
Silylations of alcohols using sugar silanes 8–10 were typically
conducted with a CuCl–IPr catalyst derived from a 1 : 2 Cu : IPr
ratio (Table 2).16 Reactions of these silanes were most efficiently
accomplished with this hindered catalyst, compared with the
CuCl–IMes catalyst that was utilized with silylations of the more
hindered C-2 sugar silanes 1–3 (Table 1). As a rst pair of
Table 2 b-Glucosides by C-6 delivery
a
b
c
IPr ¼ 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. Diastereoselectivities of glycosylations are >97 : 3 as judged by 1H NMR. Product 11e
was contaminated with a homodimer of sugar silane 8a that was easily removed aer conversion to 12e. d Glycosylation was conducted at ꢁ78 ꢀC.
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glycosidic bonds with the available linkages including those of
the b-manno, a-gluco, or b-gluco type. Additionally, challenging
substrate classes including 2-benzyloxy, 2-azido, and 2-deoxy
sugars are tolerated by the method, with the current procedure
allowing glycosylation of primary hydroxyls. The site-selective
glycosylation of hydroxyketones and sugar diols is enabled
through this approach with proper selection of the dehydro-
genative silylation catalyst. Future work will focus on the utili-
zation of this work in combination with previously developed
methods7 in increasingly complex illustrations of site-selective
glycosylation of polyfunctional substrates.
Fig. 4 Evidence for intramolecularity of glycosylation.
In addition to C-2 benzyloxy examples 12a–f, sugar silanes
possessing C-2 acetoxy substituents, C-2 azido substituents, and
those lacking C-2 substitution were cleanly tolerated in the
production of 12g–i. It should be noted that the directing
inuence of C-2 acetyl and C-2 benzoyl protecting groups is
commonly employed in the facile synthesis of b-glucosides.
However, b-selective glycosylation of donors lacking C-2 acyloxy
substituents, such as benzyloxy, 2-azido-2-deoxy,17 and 2-deox-
yglycosides,2a,18 present much more challenging substrates for
controlled b-selective glycosylation. Interestingly, recent studies
have shown that 3,4-trans-cyclic protecting groups with
2-deoxyglycosides favor a-selective intermolecular glycosyla-
tions, which are thus fully complementary to the b-selective
intramolecular process illustrated herein.18b With the exception
of one example (12g), each of the examples in Table 2 involves
the more challenging classes of substrates that lack a stereo-
chemistry-directing C-2 substituent.
Given the difficulties noted above in prior strategies for C-6
delivery with alternate protecting groups (Fig. 3), control
experiments were conducted to ensure that glycoside formation
proceeds by an intramolecular process. Repeating the conver-
sion of silyl intermediate 11a to glycoside 12a in the presence of
exogenous phenethyl alcohol resulted in the formation of 12a
(16%), 12b (48%), and the a-anomer of 12b (36%) as judged by
analysis of the crude reaction mixture. However, increasing the
amount of TMSOTf (3.2 equiv.) to enable complete silylation of
the exogenous alcohol produced only 12a (Fig. 4). These results
illustrate that silyl cleavage followed by intermolecular glyco-
sylation is not occurring under the standard method reported
(Table 2) since only the intramolecular delivery is b-selective.
Furthermore, addition of excess TMSOTf effectively suppresses
the glycosylation of free alcohols and enables the b-selective
intramolecular delivery to exclusively proceed when an exoge-
nous alcohol is present.
Acknowledgements
We thank the National Institutes of Health (GM57014) for
support of this research.
Notes and references
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