DOI: 10.1002/anie.201100076
Glycosylation
Dimethylformamide: An Unusual Glycosylation Modulator**
Shao-Ru Lu, Yen-Hsun Lai, Jiun-Han Chen, Chih-Yueh Liu, and Kwok-Kong Tony Mong*
Dedicated to Professor Chi-Huey Wong
The key steps in oligosaccharide synthesis are protecting-
group manipulation and stereoselective glycosylation.[1] Var-
ious strategies have emerged to expedite glycosylation, and
some of these strategies have been elaborated for automated
solid-phase synthesis[2] and one-pot cascade glycosylation.[3]
Most glycosylation strategies rely on traditional methods for
stereochemical control over glycosidic-bond formation.
Although such tactics work well for the formation of 1,2-
trans b-glycosidic bonds,[4] there is no straightforward solution
for the formation of a 1,2-cis a-glycosidic bond.[1a,5] Existing
methods often require extensive optimization of the reaction
the activation of a thioglycoside generates an oxocarbenium
ion pair, which upon trapping by nucleophilic DMF gives rise
to an equilibrium mixture of a-/b-glycosyl imidates. Assuming
that the b imidate is more reactive than its a counterpart;
subsequent coupling of the b imidate with an acceptor
produces the desired a anomer as the major product
(Scheme 1). Since DMF has a modulating function in the
reaction, we coined the term DMF-modulated glycosylation
strategy for this approach.
conditions, including the selection of an ethereal solvent,[6]
a
transition-metal-complex promoting system,[7] a remote par-
ticipating group,[8] a silylidene protecting group,[9] and a chiral
or achiral accessory group at the C2 position,[10–13] or the
installation of a fluoride substituent at the C2 position.[14]
However, most of these methods require additional steps for
the installation of a specific functionality and are therefore
less convenient for routine synthesis. Herein, we report a
simple and general a-glycosylation method in which N,N-
dimethylformamide (DMF) is used as a modulating molecule
to direct the stereochemical course of glycosylation. Further
elaboration of this approach led to a practical a-selective
procedure based on preactivation that is useful for the
glycosylaton of both O-glycoside and thioglycoside acceptors.
In a previous study of the chlorination of glycosyl
hemiacetals, we observed that residual DMF in the glyco-
sylation mixture promoted the formation of 1,2-cis a-glyco-
sidic bonds.[15] A search of the literature revealed that DMF
has been utilized as a glycosylation solvent[16] and as a
component in the Vilsmeier–Haack reaction for glycosyla-
tions.[17] Koto et al. reported the use of DMF as an additive to
effect a-glycosylation; however, this protocol suffered from
undesired glycosyl formate formation.[17d] Lemieux and
Driguez employed DMF (20–30 vol%) as one component
of a mixed solvent system in particular glycosylations;
however, such reactions required 4 days to reach completion,
and the role of DMF was not stated.[18] We hypothesized that
Scheme 1. Proposed mechanism of the DMF-modulated glycosylation.
Initially, we examined two DMF-modulated procedures
(Scheme 2a,b). In procedure A, adapted from a standard
glycosylation protocol, a mixture of a thioglycosyl donor, a
glycosyl acceptor, and DMF is treated with N-iodosuccin-
imide (NIS) and trimethylsilyl triflate (TMSOTf) (Sche-
me 2a).[19] In procedure B, the thioglycosyl donor is first
preactivated with NIS and TMSOTf in the presence of DMF.
Following activation, the glycosyl acceptor is added and reacts
with the glycosyl imidate to furnish the desired glycosylation
product (Scheme 2b).
At the outset, we followed procedure A to couple the
commercially available galactosyl acceptor 3 with the per-
benzyl thiogalactoside 1.[20] After some experimentation, we
found that one molar equivalent of TMSOTf (with respect to
the glycosyl donor) was required for effective activation of the
donor, probably owing to the mild Lewis basicity of DMF.
DMF exhibited an a-directing effect in glycosylation reac-
tions: a result which is in line with our previous findings.[15] We
observed a quantity–selectivity dependence between the
stoichiometric amount of DMF added and the degree of
glycosylation selectivity. Explicitly, when the amount of DMF
was increased from 0 to 1.5 equivalents, the a/b-anomer ratio
of the glycosylation product 4 increased from 1:1 to 3:1
[*] S.-R. Lu, Y.-H. Lai, J.-H. Chen, C.-Y. Liu, Prof. K.-K. T. Mong
Applied Chemistry Department, National Chiao Tung University
1001, Ta Hsueh Road, Hsinchu, Taiwan, 300 (R.O.C.)
Fax: (+886)3-513-1204
E-mail: tmong@mail.nctu.edu.tw
[**] We thank the National Science Council of Taiwan for support (grant
no. NSC 99-2113M-009-009), Dr. C.-W. Chang (Academia Sinica)
and Dr. C.-S. Chao (NCTU) for initial studies. We are indebted to
Prof. W.-C. Cheng (Academia Sinica), Prof. C.-H. Lin (Academia
Sinica), and Prof. Y.-C. Chen (NCTU) for HRMS analysis.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 7315 –7320
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7315