Efficient Sialylation with Phenyltrifluoroacetimidates as Leaving Groups

Article abstract of DOI:10.1021/ol0353161

(Matrix presented) Sialylation with N-phenyltrifluoroacetimidates as leaving groups and a catalytic amount of TMSOTf as promoter compares favorably with the previous protocols for direct sialylation and expand in essence the scope of the Schmidt glycosyla

Full text of DOI:10.1021/ol0353161

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3827-3830
Efficient Sialylation with
Phenyltrifluoroacetimidates as Leaving
Groups
Sutang Cai and Biao Yu*
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
byu@mail.sioc.ac.cn
Received July 16, 2003
ABSTRACT
Sialylation with N-phenyltrifluoroacetimidates as leaving groups and a catalytic amount of TMSOTf as promoter compares favorably with the
previous protocols for direct sialylation and expand in essence the scope of the Schmidt glycosylation reaction.
Sialic acids constitute a family of 2-keto-3-deoxynononic
acids represented by the most abundant prototypical congener
N-acetylneuraminic acid (Neu5Ac). Neu5Ac occurs es-
sentially at the termini of glycoproteins and glycolipids in
mammalian cellular systems frequently via a R2-3 glyco-
sidic linkage to galactose or R2-6 linkages to galactose and
N-acetylgalactosamine. In fact, as many as 107 Neu5Ac
residues are bound to a single human cell forming a charged
sheath of mechanical importance. These surface Neu5Ac are
a significant recognition site for a variety of hormones,
enzymes, viruses, and toxins, while they can also effectively
block important antigenic sites and recognition markers to
protect them from identification and degradation by the
surrounding immune system.1 Allured by these important
biological functions, synthetic access toward sialic acid
containing oligosaccharides and glycoconjugates has been a
topic of intensive research.2 However, sialylation to make
the equatorial 2-R-ketosidic linkages is one of the most
challenging tasks in glycosylation chemistry.2 The electron-
withdrawing C1 carboxylic function, disfavoring the oxo-
carbenium formation, restricts glycosidation both electroni-
cally and sterically. No neighboring C3 functionality is
present to direct the stereochemical outcome of glycosyla-
tions; thus, formation of the thermodynamically more stable
but unnatural â glycosidic bond prevails. In addition, an
elimination to produce the 2,3-dehydro glycals can be a
significant competing pathway. In fact, only limited glyco-
sylation protocols are applicable for direct sialylation.3 The
classical Koenigs-Knorr glycosylation with 2-chloro deriva-
tives of Neu5Ac provides good yields only when coupled
with simple or primary sugar alcohols.4 Glycosylation with
2-sulfide,5 xanthate,6 and phosphite7 Neu5Ac donors has
enabled the synthesis of those natural linkages of Neu5Ac
in reasonable yields (commonly 30-70%).8 And the R
selectivity is ensured by the nitrile solvent effect.2,9 It is noted
that the most favorable Schmidt glycosylation protocol with
trichloroacetimidate as leaving group is not suitable for
sialylation.10 Fortunately, the recent alternative with trifluo-
(1) (a) Varki, A. Glycobiology 1993, 3, 97. (b) Biology of Sialic Acids;
Rosenberg, A., Ed.; Plenum Press: New York, London, 1995.
(2) (a) Okamoto, K.; Goto, T. Tetrahedron 1990, 46, 5835. (b) DeNinno,
M. P. Synthesis 1991, 583. (c) Boons, G.-J.; Demchenko, A. V. Chem. ReV.
2000, 100, 4539.
(3) Indirect sialylation mostly involves modified sialyl donors that have
a participating functionality at C-3; thus, additional steps are required for
installation and removal.2c
(4) Bromides of Neu5Ac have found limited application in sialyation,
likely due to their low chemical stability.2a
10.1021/ol0353161 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/25/2003

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

Table 1. Sialylation with Trifluoroacetimidate Donors 2a,b
a Key: (A) CH2Cl2, -30 °C; (B) CH3CN, -30 °C; (C) CH2Cl2-CH3CN (1:1), -65 °C; all the reactions were carried out in the presence of 3 Å MS and
1
a positive charge of argon. b Isolated yields, based on donor 2. c Determined by H NMR analysis.
trifluoroacetimidate donor 2a gave comparable or favor-
able yields and R selectivity (entries 13 and 14). In all the
above sialylations, the 2,3-glycal derivative was detected to
be the major side product.
In summary, N-phenyltrifluoroacetimidates were disclosed
as excellent leaving groups for direct sialylation, which
compares favorably with the previous protocols for direct
sialylation with respect to the coupling yields, R-selectivity,
Org. Lett., Vol. 5, No. 21, 2003
3829

and ease of operations. The method also employs a nontoxic
catalytic amount of the promoter.
Supporting Information Available: Experimental pro-
cedures and analytical data for new compounds. Reproduc-
tions of 1H NMR spectra for compounds 2a(R), 2a(â), 2b(â),
4a(R), 4b, 4c, 4d(R), 4e(R), 4f, 4g(R), and 4h(R) and 13C
NMR spectra for compounds 2a(R), 2a(â), 2b(â), 4d(R),
4e(R), 4f, 4g(R), and 4h(R). This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The work described in the paper was
supported by the National Natural Science Foundation of
China (20172068, 29925203), the Committee of Science and
Technology of Shanghai (01JC14053), and the Area of
Excellence Scheme established under the University Grants
Committee of Hong Kong Special Administrative Region,
China (Project No. AoE/P-10/01).
OL0353161
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Org. Lett., Vol. 5, No. 21, 2003