Highly stereoselective synthesis of primary, secondary, and tertiary α-S-sialosides under lewis acidic conditions

Article abstract of DOI:10.1021/ol301779e

N-Acetyl 4-O,5-N-oxazolidinone protected sialyl phosphates of either anomeric configuration are excellent donors for the formation of α-S-sialosides at -78 °C in dichloromethane with primary, secondary, and tertiary thiols including galactose 3-, 4-, and

Full text of DOI:10.1021/ol301779e

ORGANIC
LETTERS
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Vol. XX, No. XX
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Highly Stereoselective Synthesis of
Primary, Secondary, and Tertiary
r‑S‑Sialosides under Lewis Acidic
Conditions
Amandine Noel,† Bernard Delpech,† and David Crich*,†,‡
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS,
1 Avenue de la Terrasse, 91190 Gif-sur-Yvette, France, and Department of Chemistry,
Wayne State University, Detroit, Michigan 48202, United States
dcrich@chem.wayne.edu
Received June 28, 2012
ABSTRACT
N-Acetyl 4-O,5-N-oxazolidinone protected sialyl phosphates of either anomeric configuration are excellent donors for the formation of R-S-sialosides
at À78 °C in dichloromethane with primary, secondary, and tertiary thiols including galactose 3-, 4-, and 6-thiols. The reactions, which proceed under
typical Lewis acid promoted glycosylation conditions, are highly R-selective and do not suffer from competing elimination of the phosphate.
Thioglycosides, including the thiosialosides, have been
widely exploited as nonhydrolyzable mimics of O-glyco-
sides for use in the study of glycosidase enzymes for which
they are both potential inhibitors and stable substrate
analogs that facilitate crystallographic studies.1 The
stereoselective synthesis of the R-O-sialosides has been a
notoriously difficult problem in carbohydrate chemistry,2
to which we and others recently introduced a practical
stereoselective solution based on the use of 4-O-5-N-ox-
azolidinone protected sialyl donors3 and their N-acetyl
counterparts.4 More recently, we extended this chemistry
to encompass the highly stereoselective synthesis of the
R-C-sialosides using allyltributylstannane and trimethylsilyl
enol ethers as nucleophiles.5 We now show that these same
† Centre de Recherche de Gif.
‡ Wayne State University.
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10.1021/ol301779e
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donors are applicable to the highly stereoselective synthesis
of the R-S-sialosides for which surprisingly few syntheses by
sialylation of thiols have been reported,1g,6 with the more
common approach being alkylation of 2-mercapto sialic
acid derivatives.1eÀg,7 Interestingly, the few syntheses of
R-S-sialosides that have been reported by the sialylation
of thiols made use of alkali metal thiolates with which to
displace chloride from the anomeric position of a β-sialyl
chloride, conditions which are limited in functional group
compatibility and require the isolation of a single diaster-
eomerically pure sialyl chloride.1g,i,6 Indeed, other authors
have described problems arising from elimination reactions
of the sialyl chloride under these conditions.7g
Scheme 2. Synthesis of a 3-Mercaptogalactopyranoside
To test the applicability of the N-acetyl oxazolidinone-
protected sialyl donors for the formation of R-S-sialosides,
we prepared three deoxy mercapto sugars as acceptors by
standard methods. Thus, the galactose 6-thiol 3 was
obtained by the Mitsunobu reaction on the corresponding
alcohol 1,8 via the thioacetate 2, employing thioacetic acid
as a nucleophile (Scheme 1).9
Finally, to probe the effect of steric hindrance on
glycosylation, we prepared the galactose 4-thiol derivative
10 from the glucose derivative 8.11 Triflation of 8 was
best accomplished with Comins’ reagent, N-(5-chloro-
2-pyridyl)bis(trifluoromethanesulf donimide),12 followed
by displacement with potassium thioacetate giving the
thioester 9, from which 10 was obtained on exposure to
hydrazine acetate (Scheme 3).
Scheme 1. Synthesis of a 6-Mercaptogalactopyranoside
Scheme 3. Synthesis of a 4-Mercaptogalactopyranoside
A galactose 3-thiol was obtained from the 4,6-O-benzy-
lidene protected galactose 3-OH derivative 410 by adapta-
tion of the syntheses of related thiols described previously
by the Schmidt6b,c and Bundle1g groups. Thus, triflation of
4 with triflic anhydride followed by displacement with
tetrabutylammonium nitrite gave the gulose derivative 5,
from which the thiol 7 was obtained by a second inversion
and subsequent hydrazinolysis of the intermediate thioa-
cetate 6 (Scheme 2).
Turning to the sialidation reaction, we elected to work
with the sialyl phosphates introduced by the Wong group4e
and prepared from the N-acetyl oxazolidinone protected
sialyl thioglycosides4a,b in a single step. This choice was
made to avoid potential complications arising from the
reaction of thiophilic reagents, needed for thioglycoside
activation, with the thiol nucleophiles. We note, however,
based on previous work from our laboratory that the Kahne
sulfoxide glycosylation method13 is generally compatible
with the use of thiols as nucleophiles and, thus, with the
formation of thioglycosides.14 Thus, as the N-acetyl oxazo-
lidinone protecting system has very recently been shown to
enable the isolation of stable sialyl sulfoxides for the first
time,4h the sulfoxide method presents a potential but as yet
untested alternative to the use of the sialyl phosphates.
Initial experiments were conducted with the R-config-
ured donor 11r4e,5 in dichloromethane at À78 °C using
trimethylsilyl trifluoromethanesulfonate (TMSOTf) as the
(6) (a) Lubineau, A.; LeGallic, J. J. Carbohydr. Chem. 1991, 10, 263–
268. (b) Eisele, T.; Schmidt, R. R. Liebigs Ann./Recl. 1997, 1303–1313.
(c) Eisele, T.; Toepfer, A.; Kretzschmar, G.; Schmidt, R. R. Tetrahedron
Lett. 1996, 37, 1389–1392. (d) Marra, A.; Sinay, P. Carbohydr. Res. 1989,
187, 35–42.
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(b) Bennett, S.; von Itzstein, M.; Kiefel, M. J. Carbohydr. Res. 1994, 259,
293–299. (c) Park, W. K. C.; Meunier, S. J.; Zanini, D.; Roy, R.
Carbohydr. Lett. 1995, 1, 179–184. (d) Angus, D. I.; von Itzstein, M.
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Chem. 1998, 63, 3486–3491. (f) Abo, S.; Ciccotosto, S.; Alafaci, A.; von
Itzstein, M. Carbohydr. Res. 1999, 322, 201–208. (g) Turnbull, W. B.;
Field, R. A. J. Chem. Soc., Perkin Trans. 1 2000, 1859–1866. (h) Zhang,
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C.-Y.; Hung, S.-C. Angew. Chem., Int. Ed. 2005, 44, 1665–1668.
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(9) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119–3122.
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B
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Table 1. Electrophilic S-Sialylation and Subsequent Oxazolidinone Cleavage
a brsm, based on recovered starting material. b An additional treatment with Dowex 50 was employed after the saponification resulting in cleavage of
the benzylidene acetal.
promoter and benzyl mercaptan as the acceptor (Table 1).
With 1 equiv of thiol and 1 equiv of promoter (Table 1,
entry 1), a 45% yield of a single anomer of the product 12
was obtained together with 40% of recovered donor,
corresponding to a 75% yield of the product based on
recovered starting material. The anomeric stereochemistry
of 12, and of all other thioglycosides obtained subsequently,
was assigned in the standard manner15 following the mea-
3
surement of the JC,H coupling constant between the car-
boxyl carbon or methoxy carbonyl and the axial proton at
(15) (a) Hori, H.; Nakajima, T.; Nishida, Y.; Ohrui, H.; Meguro, H.
Tetrahedron Lett. 1988, 29, 6317–6320. (b) Haverkamp, J.; Spoormaker,
T.; Dorland, L.; Vliegenthart, J. F. G.; Schauer, R. J. Am. Chem. Soc.
1979, 101, 4851–4853.
Org. Lett., Vol. XX, No. XX, XXXX
C

C3 in the sialic acid ring. Increasing the amount of TMSOTf
employed led to a more complex reaction mixture and a
lower yield, albeit with retention of the excellent stereose-
lectivity for the formation of 12 (Table 1, entry 2). The use
of 2 equiv each of acceptor and promoter was also not
beneficial (Table 1, entry 3). However, the employment of
2 equiv of thiol and 1 equiv of promoter gave a clean
reaction mixture and an 80% yield of pure 12r (Table 1,
entry 4). Interestingly, an attempt to further improve the
yield through the use of 5 equiv of thiol resulted in cleavage
of the oxazolidinone ring and isolation of the β-thioglyco-
side 13 in high yield and selectivity (Table 1, entry 5). As
careful monitoring of the reaction mixture by TLC and
mass spectrometry revealed, cleavage of the oxazolidinone
ring required the presence of both the promoter and an
excess of thiol, allowing Lewis acid promoted removal of
the oxazolidinone ring by the excess thiol subsequent to
thioglycoside formation followed by equilibration of the
anomeric stereochemistry. The essentially pure β-nature
of the thioglycoside formed under these conditions is con-
sistent with the very strong thermodynamic preference for
the axial glycoside in the sialic acid series.16 Equilibration of
the anomeric stereochemistry is much more likely to occur
on the more highly armed system following cleavage of the
oxazolidinone ring. The use of 4-methoxythiophenol and
of tert-butyl mercaptan as acceptors under the optimum
conditions of 2 equiv of acceptor and 1 equiv of TMSOTf
also gave excellent yields of the corresponding thiosialo-
sides, 14 and 15, respectively, both as single R-anomers
(Table 1, entries 6 and 7).
With the focus turned toward the carbohydrate-based
thiols 3, 7, and 10, use of the galactose 6-thiol 3 as the
acceptor resulted in the formation of the thioglycoside 16
in moderate to good yield and in the form of a single
equatorial anomer (Table 1, entries 8 and 9). This result
was independent of the configuration of the donor and
applied both in neat dichloromethane as solvent and in a
mixture of dichloromethane and acetonitrile, such as is
common in other sialylation protocols. Directly compar-
able results were obtained with the galactose 3-thiol 7
(entries 10 and 11), again from both isomers of the donor.
Finally, the highly hindered galactose 4-thiol 10 was
demonstrated to be a competent acceptor in this chemistry,
giving the thioglycoside 18 in good yield as a single
anomer from either stereoisomeric donor (Table 1, entries
12 and 13).17 Deprotection of the thioglycosides 16À18
(Table 1, entries 8, 10, and 12) was achieved in the usual
manner,4 with clean removal of the oxazolidinone ring, by
treatment with sodium methoxide in methanol.
The stereoselectivities observed in these reactions, with
the exception of the example reported in Table 1, entry 5
discussed above, very strongly favor the R-anomer and
more so than the already highly R-selective coupling to
corresponding alcohols.4 This is most consistent with an
associative mechanism facilated by the use of the more
powerful thiols as nucleophiles, which involves displace-
ment of a covalent activated β-donor, possibly a sialyl
triflate, with inversion of configuration. The alternative
possibility of nucleophilic attack on a sialyl oxocarbenium
ion is considered less likely on the grounds that the
stereoselectivity of such systems diminishes with the use
of more powerful nucleophiles and as the diffusion con-
trolled limit is approached.18 Although SN2 processes are
considered to be highly disfavored at tertiary centers, there
is strong literature precedent, both stereochemical and
kinetic, for the existence of such processes with good
nucleophiles when one of the substituents is a carboxylate
ester.19 Finally, several clear demonstrations of associative
glycosylation reactions have been reported in the recent
literature.20
Overall, we demonstrate a practical method for the
highly selective synthesis of R-S-sialosides that proceeds
under typical glycosylation conditions and functions with
either anomer of the donor. The reaction is applicable
to primary, secondary, and tertiary thiols, whether simple
or carbohydrate-based, and is somewhat immune to steric
hindrance in the thiol. The type of competing elimination
that plagues many sialylation methods, including S-siali-
dation with other donors, does not compete to any sig-
nificant extent with the glycosylation reaction. As the
thiosialosides have been reported to be excellent stable
analogs for binding to a number of protein targets and
for the inhibition of sialidase enzymes,1dÀf,h,i,7a,7dÀ7f,7h,21
we anticipate that this novel, practical chemistry will find
application.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Beaver, M. G.; Woerpel, K. A. J. Org. Chem. 2010, 75, 1107–
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McCarthy, J. R. Org. Lett. 2009, 11, 807–810. (b) Peng, C.-H.; Kong, J.;
Seeliger, F.; Matyjaszewski, K. Macromolecules 2011, 44, 7546–7557.
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D. A.; Crich, D. Nat. Chem. 2012, 4, 663–667. (b) Gouliaras, C.; Lee, D.;
Chan, L.; Taylor, M. S. J. Am. Chem. Soc. 2011, 133, 13926–13929. (c)
Wurst, J. M.; Liu, G.; Tan, D. S. J. Am. Chem. Soc. 2011, 133, 7916–
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1997, 53, 3933–3942. (b) Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002,
102, 471–490. (c) Wilson, J. C.; Angus, D. I.; von Itzstein, M. J. Am.
Chem. Soc. 1995, 117, 4214–4217.
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(17) Note, however, that better yields were obtained in several
instances with the R-donor than with its β-isomer. This is consistent
with the observations of Wong and co-workers for O-glycoside synthesis
from the same donors.4e
The authors declare no competing financial interest.
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