roacetimidates as leaving groups11 compliments the Schmidt
glycosylation in this respect and compares favorably with
the previous direct sialylation protocols.2 The preliminary
results are herewith presented.
Sialyl imidates 2a and 2b were purified by silica gel column
chromatography and were stable to storage at 4 °C for several
weeks.
The donor property of 2a was first examined with primary
sugar alcohol 3a as an acceptor (Scheme 2). Thus, to a
Initially, we investigated the preparation of trifluoroace-
timidates 2a-c to evaluate their potential for undergoing
efficient glycosylation (Scheme 1). Treatment of methyl
Scheme 2
Scheme 1
stirring mixture of 2a (∼ 80 mg), 3a (1.5 eq), and 3Å MS
in CH2Cl2 at -30 °C under argon, was added TMSOTf (0.2
eq). TLC indicated the completion of the reaction in 1.5 h.
Usual workup provided the desired coupling product 4a in
74% yield. The dominance of the â anomer was proved by
1H NMR analysis (Table 1, entry 1).2 Replacement of CH2-
Cl2 with CH3CN as solvent afforded 4a (80%) with the R
anomer being the major product (R/â ) 3:1) (entry 2). Lower
reaction temperature was found to favor the R glycosidation
presumably via the intermediacy of an axial â sialyl nitrilium
ion intermediate.6b Indeed, the coupling reaction in CH2Cl2/
CH3CN (1:1) at -65 °C in 1.5 h produced 4a (79%) with
an improved R/â ratio of 6.6:1 (entry 3).14 Similar results
were obtained when 2b was used as donor (entries 4-5) or
the primary sugar alcohols 3b15 and 3c as acceptors (entries
6-9).
Neu5Ac tetraacetate 112 with N-phenyltrifluoroacetimidoyl
chloride (10 equiv) in the presence of K2CO3 (3.0 equiv) in
acetone at room temperature for 3 h provided the desired
sialyl imidate 2a in 82% yield (R/â ) 1:1). The reaction
between 1 with N-(p-nitrophenyl)trifluoroacetimidoyl chlo-
ride was complete within 15 min, affording 2b (77%) as
predominantly the â anomer. The reaction between 1 and
N-(p-methoxyphenyl)trifluoroacetimidoyl chloride led to a
mixture of products in which 2c could hardly be detected.13
Next, a variety of the secondary alcohols (3d-g) were
examined as acceptors to couple with 2a under the fixed
conditions (0.2 equiv of TMSOTf, 1:1 CH2Cl2/CH3CN,
3 Å MS, Ar, -65 °C) (entries 10-13). Sialylation of
triterpenoids and spirostan steroids has not been previously
practiced, while sialylation of 3d and 3e with imidate 2a
led to the coupling products (4d and 4e) in 80% and 77%
yields, respectively, with R/â ratios > 3.5:1 (entries 10
and 11). For the hindered alcohol 3f, the sialylation pro-
duct 4f could still be obtained in a satisfactory 59%
yield and R/â ratio ) 6.8:1 (entry 12). Regioselective
sialylation of galactopyranoside 3,4-diols and 2,4,6-triols
analogous to 3g and 3h, to produce the naturally occur-
ring R2-3 and R2-6 linkages, has been successful with
previous sialylation protocols.5a,e,6,8 Coupling with the present
(5) For earlier reports, see: (a) Murase, T.; Ishida, H.; Kiso, M.;
Hasegawa, A. Carbohydr. Res. 1988, 184, C1. (b) Kirchner, E.; Thiem, F.;
Dernick, R.; Heukeshoven, J.; Thiem, J. J. Carbohydr. Chem. 1988, 7, 453.
(c) Kanie, O.; Kiso, M.; Hasegawa, A. J. Carbohydr. Chem. 1988, 7, 501.
(d) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1988, 29, 1061. (e) Ito, Y.; Ogawa,
T. Carbohydr. Res. 1990, 202, 165. (e) Hasegawa, A.; Nagahama, T.; Ohki,
H.; Hotta, K.; Ishida, H.; Kiso, M. J. Carbohydr. Chem. 1991, 10, 493.
(f) Roy, R.; Andersson, F. O.; Letellier, M. Tetrahedron Lett. 1992, 33,
6053.
(6) For earlier reports, see: (a) Marra, A.; Sinay¨, P. Carbohydr. Res.
1990, 195, 303. (b) Birberg, W.; Lo¨nn, H. Tetrahedron Lett. 1991, 32,
7453. (c) Martichonok, V.; Whitesides, G. M. J. Org. Chem. 1996, 61,
1702.
(7) For earlier reports, see: (a) Martin, T. J.; Schmidt, R. R. Tetrahedron
Lett. 1992, 33, 6123. (b) Kondo, H.; Ichikawa, Y.; Wong, C.-H. J. Am.
Chem. Soc. 1992, 114, 8746.
(8) The latest development for direct sialylation involves dehydrative
coupling of C2-hemiketal sialyl donors, see: Haberman, J. M.; Gin, D. Y.
Org. Lett. 2003, 5, 2539.
(9) (a) Schmidt, R. R.; Rucker, E. Tetrahedron Lett. 1980, 21, 1421.
(b) Ratcliffe, A. J.; Fraser-Reid, B. J. Chem. Soc., Perkin Trans. 1 1990,
747.
(10) (a) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem.
1994, 50, 21. (b) Schmidt, R. R.; Jung, K.-J. In PreparatiVe Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York, 1997; p
283.
(11) (a) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2505. (b) Yu, B.;
Tao, H. J. Org. Chem. 2002, 67, 9099. (c) Adinolfi, M.; Barone, G.; Iadonisi,
A.; Schiattarella, M. Org. Lett. 2003, 5, 987.
(12) Marra, A.; Sinay¨, P. Carbohydr. Res. 1989, 190, 317.
(13) Condensation of 1 with Cl3CCN under similar conditions also failed,
probably due to the lability of the resulting Neu5Ac 2-imidate.10b
(14) It was reported that sialylation of 3a (1.5 equiv) with methyl
tetra-O-acetyl-Neu5Ac 2-dibenzyl phosphite (0.2 equiv of TMSOTf,
CH3CN, -42 °C) provided 4a in 80% yield and R/â ) 5:1;7b sialylation
with 2-diethyl phosphite (0.1 equiv of TMSOTf, CH3CN, -40 °C)
gave 4a in 70% yield and R/â ) 4:1;7a sialylation with 2-SMe (1.5
equiv of PhSeOTf, CH3CN, -35 °C) gave 4a in 78% yield and R/â )
4.5:1.5e
(15) It was reported that sialylation of 3b (1.0 equiv) with methyl
tetra-O-acetyl-Neu5Ac 2-SMe (PhHgOTf, 1:1 CH3CN/PhCH3, rt) gave
4b in 24% yield and R/â ) 5:1;5b sialylation with 2-SPhOMe-p (NIS/TfOH,
2:1 CH3CN/CH2Cl2, -15 °C) gave 4b in 89% yield and R/â )
2.6:1.5g
3828
Org. Lett., Vol. 5, No. 21, 2003