E. Leclerc et al.
coconjugate analogues because it would allow the introduc-
tion of various aglycon moieties in the pseudo-anomeric po-
sition through a simple, mild, and convergent process. The
synthesis of difluorinated a-C-galactosylceramides and a
thorough conformational study of a-CF2-galactosides are
currently under investigation. Results in these areas will be
reported in due course.
Experimental Section
Representative procedure for the reductive acyl chain transfer: nBuLi
(1.53m in hexane, 0.337 mL, 0.52 mmol) was added dropwise to a solution
of acetate 13 (0.260 g, 0.43 mmol; obtained by acetylation of 9 using
Ac2O/NEt3/cat. 4-dimethylaminopyridine (DMAP)) in THF (5 mL) at
À788C under an argon atmosphere. The mixture was stirred for 1 h at
À788C then quenched with 1m HCl (5 mL) and extracted with EtOAc
(3ꢄ10 mL). The combined organic layers were washed with water
(10 mL) and brine (10 mL), dried over Na2SO4, and evaporated. Chroma-
tography on a flash purification system (3–30% EtOAc in cyclohexane)
gave intermediate 14 as a colorless oil (0.171 g, 75%). The two diastereo-
mers could not be separated at this stage. NaBH4 (0.019 g, 0.50 mmol)
was added to a solution of 14 (0.171 g, 0.32 mmol) in MeOH (5 mL) at
08C. The mixture was stirred for 3 h at 08C, at which point TLC monitor-
ing showed complete conversion of 14 (eluent: cyclohexane/EtOAc
70:30). The mixture was then warmed up to RT, quenched with sat.
NH4Cl and extracted with EtOAc (3ꢄ10 mL). The combined organic
layers were washed with brine (10 mL), dried over Na2SO4, and evaporat-
ed. Chromatography on a flash purification system (7–60% EtOAc in cy-
clohexane) gave 15 as a colorless oil (0.098 g, 58%).
Scheme 4. Br/Li exchange and intramolecular trapping with an electro-
phile. Boc=tert-butoxycarbonyl.
peared as a method of choice to circumvent the potential
problem of stability. To challenge this intramolecular strat-
egy, acetate 13 was thus prepared from 9 by using a standard
acetylation procedure (Ac2O/NEt3). We were pleased to see
that a Br/Li exchange on 13 indeed resulted in the immedi-
ate trapping of the lithium species by the neighboring ace-
tate to afford the stable hemiketal species 14 in 75%
yield.[14] A reduction of this intermediate provided the alco-
hol 15 in 68% yield and the global transformation can be
analyzed as a formal addition of the lithiated anion of 9 to
acetaldehyde. This reductive migration of an ester from O-2
to C-1’ appeared to be a good approach to O-glycoconjugate
analogues, if a highly functionalized ester was introduced at
the 2-position of 9. Ester 16 was thus prepared from 9 and
from the corresponding d-serine-derived acid (through an
N,N’-diisopropylcarbodiimide (DIPC)-mediated coupling,
85% yield) to challenge this hypothesis. To our delight, a
Br/Li exchange with nBuLi at À788C provided hemiketal 17
in 57% yield, which could be reduced to the desired a-C-
galactoside 18 in 57% yield. If the intermolecular trapping
of the lithiated anion at low temperature can still be investi-
gated, this last intramolecular strategy appears much more
preferable for the synthesis of highly functionalized glyco-
conjugate analogues. The high chemical and configurational
stability of a-aminoesters and acids compared with a-amino-
aldehydes is indeed appreciable for the preparation of the
aglyconic moiety.
Acknowledgements
Prof. Dr. A. Vasella is deeply acknowledged for his fruitful suggestions
regarding the reduction reaction. We also thank the Agence Nationale de
la Recherche (ANR) for a PhD grant to S.C. and for funding, and the
Rꢀgion Haute-Normandie (CRUNCH network) for funding.
Keywords: fluorine
· glycoconjugates · organolithium ·
radical reactions · reduction
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Wong) Wiley-VCH, Weinheim, 2003, pp. 381–406.
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