Angewandte
Chemie
The generation of nucleophilic glycosyl lithium reagents
by reductive lithiation, a process invented by Cohen and co-
workers,[21] for the stereoselective synthesis of C-glycosides
was reported previously by the research groups of Sinaꢀ,[17c,24]
Beau,[25] Kessler,[26] and others.[27] Although the synthesis of a-
C-glycosides from readily available a-glycosyl lithium inter-
mediates is straightforward, the generation of b-glycosyl
lithium species for the synthesis of b-C-glycosides has
remained a challenge. Previous efforts towards the prepara-
tion of b-glycosyl lithium species involved the synthesis of b-
glycosylstannanes and a subsequent tin–lithium exchange.[28]
Alternatively, the b-C-glycosides can be synthesized by an
indirect approach involving sequential deprotonation of
a glycosylsulfone, electrophile addition, and stereoselective
reductive desulfonation.[29] Therefore, the development of
a more effective method for the selective preparation of b-
glycosyl lithium species is particularly appealing. Further-
more, although these studies[27] highlighted umpolung
approaches in the stereoselective synthesis of C-glycosides,
the sulfenylation of glycosyl lithium intermediates for the
stereoselective synthesis of S-linked glycosides has not been
disclosed thus far.
2-Deoxyglycosyl phenylsulfide donors 4 were prepared
from the corresponding readily available glycals through ReV
catalysis.[20,30] In our hands, compounds 4a, 4b, and 4d were
obtained as a mixture of a and b anomers, whereas 4c, 4e, and
4 f were isolated as the pure a isomer (Scheme 3).[30] Since
both 2-deoxy a- and b-glycosyl phenylsulfides can undergo
reductive lithiation to afford the stereochemically pure axial
lithium (a-lithium) species,[21] a/b anomeric mixtures of 4a,
4b, and 4d were used directly for reductive lithiation.
Furthermore, asymmetric sugar-derived tert-butyldisulfide
acceptors, 6a–d, were synthesized[30] by reactions of thio-
sugars[31] with tert-butyl methanethiosulfonate[32] in the pres-
ence of a tertiary amine base (Scheme 2).[33] For example, l-
fucal (10) was converted into the corresponding methyl
glycoside, which underwent regioselective silyl protection to
afford 11 (59% over two steps). Next, the triflation of 11,
followed by SN2 displacement with cesium thioacetate,
provided thioester 12 (86% over two steps). The reduction
of thioacetate 12 with lithium aluminium hydride furnished
the corresponding thiosugar with concomitant cleavage of the
tert-butyldimethylsilyl ether. The reaction of this thiosugar
with tert-butyl methanethiosulfonate, followed by silyl repro-
tection, gave the disulfide acceptor 6a (78% over three
steps). The sugar-derived C6 disulfide acceptor 6b, C4
disulfide acceptor 6c, and C3 disulfide acceptor 6d were
obtained by a similar strategy.[30]
With 2-deoxyglycosyl phenylsulfides 4a–f and sugar-
derived disulfides 6a–d in hand, we carried out the key S-
glycosylation reactions based on umpolung reactivity. Reduc-
tive lithiation[21,22] of a mixture of 2-deoxy a- and b-glycosyl
donors 4a (1.2 equiv) at ꢀ788C with lithium 4,4’-di-tert-
butylbiphenyl (LiDBB)[34] generated the corresponding
highly stereochemically pure axial-lithium intermediate,
which subsequently reacted with the C6-disulfide acceptor
6b to afford the S-linked disaccharide 13 in 87% yield with
excellent a selectivity (a/b > 40:1; Scheme 3). Under the
same conditions, the S-(1!6)-linked 2-deoxydisaccharides
14 and 15 were prepared in excellent yield with excellent
a selectivity from the 2-deoxyglycosyl phenylsulfide donors
4c and 4d, respectively. The S-(1!4)-linked 2-deoxydisac-
charides 16–21 were also synthesized in good to excellent
yield and with excellent a selectivity from the corresponding
2-deoxy l- or d-glycosyl lithium species and the l- or d-
olivoside-derived C4-disulfide acceptor 6a or 6c. Further-
more, the S-(1!3)-linked 2-deoxydisaccharides 22 and 23
were prepared in good yield with excellent a selectivity from
the corresponding 2-deoxyglycosyl lithium species and the d-
olivoside-derived C3-disulfide acceptor 6d. Under the typical
reaction conditions, only a slight excess of the 2-deoxyglycosyl
phenylsulfide 4, used either pure or as an anomeric mixture,
was necessary for the synthesis of S-linked 2-deoxy-a-glyco-
sides in high yield. Benzyl (Bn) and p-methoxybenzyl (PMB)
ether protecting groups are compatible with this type of S-
glycosylation.
Next, we studied the anomerization of the axial 2-deoxy
glycosyl lithium species 5d to the corresponding equatorial
glycosyl lithium species 8d as well as the synthesis of the S-
linked b-l-olivose-(1!4)-a-l-olivose derivative 24 (Table 1).
Initially, it was found that when the axial 2-deoxyglycosyl
lithium intermediate 5d (1.2 equiv) was allowed to stand at
08C for 30 min before being cooled to ꢀ788C and treated
with the disulfide acceptor 6a, the desired S-(1!4)-linked 2-
deoxydisaccharide 24 was isolated in 32% yield with excellent
anomeric selectivity (b/a > 40:1; Table 1, entry 1). Epimeri-
zation of the axial 2-deoxyglycosyl lithium intermediate 5d
(1.2 equiv) at ꢀ208C for 45 min[35] and subsequent treatment
with disulfide 6a at ꢀ788C improved the yield of 24 to 53%
(b/a > 40:1; Table 1, entry 2). However, incomplete epimeri-
zation of 5d at ꢀ308C for 45 min led to the production of 24
as a mixture of a and b anomers in 54% yield with moderate
stereoselectivity (b/a 4.3:1; Table 1, entry 3). In all these
experiments, the yield of product 24 as calculated on the basis
of recovered disulfide acceptor 6a was nearly quantitative.
Therefore, competitive deprotonation of THF[22] by the
glycosyl lithium species during epimerization was believed
to be the major side reaction. In the hope that the use of less
acidic solvents would suppress competitive deprotonation,[22]
the epimerization was attempted at ꢀ208C in hexane/THF
Scheme 2. Reagents and conditions: a) cat. CSA, MeOH; b) TBSCl,
Et3N, DMF, 59% over two steps; c) Tf2O, pyridine, CH2Cl2, 08C;
d) CsSAc, THF, 86% over two steps; e) LiAlH4, Et2O, ꢀ308C!RT;
f) tBuSSO2Me, Et3N, CH2Cl2, 08C!RT; g) TBSCl, imidazole, DMF,
78% over three steps. CSA=camphorsulfonic acid, DMF=N,N-dime-
thylformamide, TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesul-
fonyl, TMSE=2-trimethylsilylethyl.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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