Oxazolidinone protected 2-amino-2-deoxy-D-glucose derivatives as versatile intermediates in stereoselective oligosaccharide synthesis and the formation of α-linked glycosides [10]

Full text of DOI:10.1021/ja0162109

J. Am. Chem. Soc. 2001, 123, 9461-9462
Oxazolidinone Protected 2-Amino-2-deoxy-D-glucose
9461
Derivatives as Versatile Intermediates in
Stereoselective Oligosaccharide Synthesis and the
Formation of r-Linked Glycosides
Kamel Benakli, Congxiang Zha, and Robert J. Kerns*
Department of Pharmaceutical Sciences
Wayne State UniVersity, Detroit, Michigan 48202
ReceiVed May 16, 2001
Figure 1. Ring-fused oxazolidinones of 2-amino-D-glycopyranosides are
versatile intermediates to R-linked and â-linked saccharides.
Many natural products and biologically significant glycocon-
jugates contain N-substituted 2-amino-2-deoxy-D-glycopyranoside
residues.1 We have recently been exploring the introduction of
structural diversity into one family of these important glycocon-
jugates, the glycosaminoglycans (GAGs).2 A major obstacle to
synthesizing GAG oligosaccharides, as well as other glycocon-
jugates containing 2-amino-2-deoxy-D-glycopyranoside residues,
is the difficulty to readily prepare structurally diverse 2-amino
sugars that also display high stereoselectivity during glycoside
bond-forming reactions. Here, we report the synthesis of ring-
fused 2,3-oxazolidinone derivatives of 1-phenylthio-glycopyran-
osides and demonstrate the utility of these novel glycosyl donors
and synthetic intermediates in stereoselective oligosaccharide
synthesis and the formation of R-linked glycosides.
Scheme 1a
a Reagents and conditions: (a) PhSH, SnCl4, 60 °C, CH2Cl2 (98%).
(b) Boc2O, DMAP, 60 °C, THF (97%). (c) (i) Na0, MeOH (98%); (ii)
TFA, MeOH (80%). (d) NPCC, NaHCO3, CH3CN/H2O (80%). (e) Ac2O,
pyridine (90%). (f) PhCH(OMe)2, CSA, 60 °C, DMF (90%).
While there are a number of strategies to obtain “â-linked”
2-amino-D-glycopyranosides3 (found in hyaluronate and dermatan
sulfate GAGs), the formation of “R-linked” 2-amino-D-glucopy-
ranosides (found in heparin and heparan sulfate (HS) GAGs) relies
almost exclusively on employing 2-azido-glycosyl donors.4 Gly-
cosidation of the 2-azido donors affords R/â-mixtures of the
coupled products, although the R-isomer usually predominates.
Methods to prepare the 2-azido sugars are also generally expensive
and often inefficient, posing limitations to commercialization of
glycoconjugates synthesized via these intermediates.5 Moreover,
the synthesis of oligosaccharides containing multiple different
N-substituted R-linked 2-amino sugars is severely limited because
these syntheses must use 2-azido donors for each glycoside
forming reaction, making it problematic to differentiate the
multiple amine groups. An additional significant obstacle to
preparing galactosamine-containing glycoconjugates (e.g. chon-
droitin sulfates and glycopeptides) is the high cost and inacces-
sibility of galactosamine derivatives as synthetic intermediates.
In an effort to address these problems, we envisioned ring-
fused 2,3-oxazolidinone derivatives of phenyl 2-amino-2-deoxy-
1-thio-glucopyranosides as versatile intermediates for the stereo-
selective synthesis of R-linked and â-linked glycoconjugates.
(Figure 1).
Oxazolidinone 5 was the first common intermediate targeted
(Scheme 1). The phenylthio group protects the anomeric position
until selectively activated for glycoside bond formation.6 Selective
differentiation of all hydroxyl groups in 5 is facilitated by the
fused oxazolidinone ring, which protects and differentiates the
C-3 hydroxyl group.
Two steps in Scheme 1 require comment. First, direct hydroly-
sis of acetamide 2 to form 4 is not efficient on large scale (10 g
or more) because separating 4 from salts and byproducts is
problematic. Converting 2 to tert-butoxycarbonyl (Boc) protected
3, which is readily deacetylated, circumvents this problem.7
Removal of the Boc group affords 4 in excellent yield from 1.
Second, treatment of 4 with p-nitro-phenoxycarbonyl chloride
(NPCC) or phenyl chloroformate using modifications of reported
methods affords oxazolidinone 5 in high yield: 80% and 93%
yield, respectively.8 Synthesis of these ring-fused oxazolidinones
is versatile, efficient, and cost-effective when compared to
preparing the 2-azido counterparts as synthetic intermediates.
Employing phenylsulfenyltriflate (PST) for the activation and
glycosidation of thioglycoside 6 affords the formation of R-linked
glycosides in excellent yield, Table 1.9 In fact, glycoside bond
formation using this novel donor/activator pair proceeds with
nearly 100% stereoselective formation of the R-linked glyco-
sides.10 This very efficient glycosylation strategy rivals, even
surpasses, the stereoselectivity and yields of current methods
utilizing the 2-azido donors to make R-linked glycosides of
2-amino-D-hexopyranosides.
* Corresponding author: (phone) 313-577-0455; (fax) 313-577-2033; (e-
mail) robkerns@wayne.edu.
(1) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
(2) For a recent review of GAGs and their functions in cell-surface
recognition and the regulation of receptor functions and cytotoxic events see:
Bernfield, M.; Gotte, M.; Park, P. W.; Reizes, O.; Fitzgerald, M. L.; Lincecum,
J.; Zako, M. Annu. ReV. Biochem. 1999, 68, 729-77.
(3) A participating group at position 2 of hexopyranoside glycosyl donors
is required to obtain â-linked glycosides. A number of groups for amine
protection have been employed for this purpose, including N-tetrachlorophthal-
oyl (Debenham, J. S.; Madsen, R.; Roberts, C.; Fraser-Reid, B. J. Am. Chem.
Soc. 1995, 117, 3302-3303), N-thiodiglycoloyl (Castro-Palomino, J. C.;
Schmidt, R. R. Tetrahedron Lett. 2000, 41, 629-632), Troc (Yeung, B. K.
S.; Hill, D. C.; Janicka, M.; Petillo, P. A. Org. Lett. 2000, 9, 1279-1282),
methoxycarbonyl (Yeung, B. K. S.; Adamski-Werner, S. L.; Bernard, J. B.;
Poulenat, G.; Petillo, P. A. Org. Lett. 2000, 20, 3135-3138), and acetamido-
glycosylation (Di Bussolo, V.; Liu, J.; Huffman, L. G.; Gin, D. Y. Angew.
Chem., Int. Ed. Engl. 2000, 39, 204-207).
In addition to promoting the stereoselective formation of
R-linked glycosides, the ring-fused oxazolidinone provides a
(6) See: Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(7) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185-4188.
(8) PC Kumar, R.; Remers, W. A. J. Org. Chem. 1978, 43, 3327.
(9) Specific reaction conditions are available in the Supporting Information.
For a discussion of this method to activate phenythioglycosides see: Crich,
D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 455-456.
(4) A nonparticipating group at position 2 of the donor (such as 2-azido)
is required to obtain R-linked glycosides that are then converted to the 2-amino-
2-deoxy-D-glycopyranoside product.
(5) For recent reports regarding the preparation of 2-azido saccharides
see: (a) Seeberger, P. H.; Roehrig, S.; Schell, P.; Wang, Y.; Christ, W.
Carbohydr. Res. 2000, 328, 61-69. (b) Vasella, A.; Witzig, C.; Chiara J. L.;
Martin-Lomas, M. HelV. Chim. Acta 1991, 74, 2073-2077.
(10) â-Glycoside has been observed when sufficiently low temperatures
were not maintained during the course of the reaction.
10.1021/ja0162109 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/01/2001

9462 J. Am. Chem. Soc., Vol. 123, No. 38, 2001
Communications to the Editor
Scheme 3a Synthesis of Deprotected HS Disaccharide
Table 1. Ring-Fused Oxazolidinone of D-Glucosamine Affords the
Stereoselective Formation of R-Linked Glycosides in High Yield
a Reagents and conditions: (a) (i) PST, CH2Cl2, -78 °C (75%); (ii)
NaOH, H2O/THF (80%).
glycosyl acceptor
glycosyl donor
8a 8b 8c
8d
6
6
6
6
for preparing the 3-linked amino-sugars found in hyaluronate, the
chondroitin sulfates, and many glycopeptides/glycoproteins. Simi-
larly, 7 and 12 are ideal intermediates for the preparation of the
4-linked glucosamine residue units present in heparin, heparan
sulfate, bacterial peptidoglycan, and glycosylphosphatidylinositol
anchors.
isolated yield (%) of R-linked disaccharidea 97 75
90 95
a No â-glycoside was detected. A complete discussion of reaction
conditions and procedures is presented in the Supporting Information.
Scheme 2a Oxazolidinone Donors as Versatile Intermediates
A primary reason for exploring the chemistry of ring-fused
2,3-oxazolidinone derivatives of the 1-thio-glucopyranosides was
our need to prepare versatile synthetic intermediates for the
introduction of structural diversity into GAG and GAG-like
oligosaccharides. Indeed, stereoselective coupling of oxazolidi-
none 6 with glucuronic acid 14 followed by hydrolysis readily
affords high yield of the major, R-linked, repeating disaccharide
unit of heparan sulfate in fully deprotected form (15, Scheme 3).
The mild conditions required for oxazolidinone opening do not
promote â-elimination of the 4-linked uronic acid, a significant
limitation of many base-labile protecting groups in GAG synthesis.
In conclusion, ring-fused 2,3-oxazolidinone derivatives of
phenyl 2-amino-2-deoxy-1-thio-glucopyranosides are highly ver-
satile intermediates for stereoselective oligosaccharide synthesis.
Notable advantages of these new synthetic intermediates that will
be applicable to a diverse range of amino-sugar syntheses include
the following:
(1) The ring-fused oxazolidinone moiety is an effective
“nonparticipating” group for the stereoselective synthesis of “R”-
linked glycosides of 2-amino-2-deoxy-D-hexopyranoses.
(2) Highly functionalized galactosamine derivatives are ef-
ficiently synthesized in high yield from oxazolidinonyl-protected
glucosamine intermediates.
(3) Cleavage of the ring-fused oxazolidinones with alcohol
affords an efficient route to “â-selective” glycosyl donors.
(4) The oxazolidinone-containing glycosyl donors and synthetic
intermediates obtained from D-glucosamine can be readily
prepared on large scale, in high yield, at low cost.
a Reagents and conditions: (a) NaOH, H2O/THF, 75-80%. (b)
Cs2CO3, R-OH, 85-95%. (c) NaCNBH3, HCl, Et2O/THF, 98%. (d) (i)
Tf2O, pyridine; (ii) NaOAc, DMF, 86%.
versatile protecting group for 2-amino sugar synthesis.11 Important
functional group interconversions of these 2,3-oxazolidinonyl
glycosyl donors are demonstrated (Scheme 2).
Hydrolytic ring opening (deprotection) of oxazolidinones 5-7
under mild conditions affords 4 and 9, respectively.12 Similarly,
treatment of 6 and 7 with an alcohol in the presence of mild base
readily affords ring-opening deprotection of the C-3 hydroxyl
group with concomitant generation of the C-2 carbamate protected
amine (10, 11). It is notable that this opening of the oxazolidinone
ring with alcohol provides an extremely efficient synthetic route
to differentially protected “â-selective” glycosyl donors.3
Entry into the D-galactosamine series of 2-amino sugars is
readily achieved through regiospecific inversion of stereochem-
istry at C-4 or the ring-fused oxazolidinones (Scheme 2, conver-
sion of 12 to 13).13 This novel route for preparing highly
functionalized galactosamine derivatives, where each position on
the sugar ring is differentially protected, is a significant improve-
ment over current methods to synthesize these valuable, hard to
obtain, intermediates.
We are currently employing ring-fused 2,3-oxazolidinone
derivatives of D-glycopyranoside intermediates in the stereose-
lective synthesis of highly substituted GAG oligosaccharides. The
methods outlined here have broad utility in the synthesis of many
diverse glycoconjugates containing N-substituted 2-amino-2-deoxy
sugar residues.
The highly versatile chemistry and reaction pathways shown
here for the ring-fused oxazolidinones are widely applicable to
efficiently preparing cost-effective intermediates for the synthesis
of many biologically important glycoconjugates. For example,
monosaccharides 10, 11, and 13 are ideal synthetic intermediates
Acknowledgment. This work was supported by a grant from The
American Heart Association, Midwest Affiliate, Inc., and Wayne State
University.
(11) Oxazolidinone protection of other amino alcohols is known.
(12) Molecular modeling shows the ring-fused oxazolidinone ground-state
energy to be higher than similar monocyclic structures.
(13) For the synthesis of galactosamine from glucosamine using similar
chemistry for C-4 inversion see: Chaplin, D.; Crout, D. H. G.; Bornemann,
S.; Hutchinson, D. W. J. Chem. Soc., Perkin Trans. 1 1992, 235-237.
Supporting Information Available: Experimental procedures and
spectral/analytical data for key intermediates and products (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA0162109