Oxazolidinone protection of N-acetylglucosamine confers high reactivity on the 4-hydroxy group in glycosylation

Article abstract of DOI:10.1021/ol0342305

(Matrix presented) The preparation of a convenient oxazolidinone protected N-acetyl glucosamine 4-OH derivative is reported. This substance exhibits enhanced reactivity as a glycosyl acceptor in a variety of coupling methods, the products of which are con

Full text of DOI:10.1021/ol0342305

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1297-1300
Oxazolidinone Protection of
N-Acetylglucosamine Confers High
Reactivity on the 4-Hydroxy Group in
Glycosylation
David Crich* and A. U. Vinod
Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
dcrich@uic.edu
Received February 7, 2003
ABSTRACT
The preparation of a convenient oxazolidinone protected N-acetyl glucosamine 4-OH derivative is reported. This substance exhibits enhanced
reactivity as a glycosyl acceptor in a variety of coupling methods, the products of which are converted to the target N-acetylglucosaminyl
saccharides under very mild conditions.
Glycosylation of the 4-hydroxyl group of selectively pro-
tected N-acetyl glucosamine derivatives is both extremely
important and notoriously difficult. The importance stems
from the widespread nature of glycosidic bonds to this
hydroxyl group in biologically important polymers in
general,1 but especially in the common core pentasaccharide
of the N-linked glycoproteins.2 The difficulty arises from the
well-known lack of reactivity of this particular alcohol, which
is due to a combination of steric hindrance, common to most
pyranose 4-OH’s,3 and the involvement of the N-acetyl group
in a hydrogen-bonded network.4 Typically, the problem is
addressed through the use of N-phthalimido glucosamine or
2-azido-2-deoxy glucose derivatives, as exemplified by 1 or
2. N,N,-Diacetyl and N-acetyl-N-benzyl protected glu-
cosamine derivatives, e.g. 3 and 4, also show enhanced
reactivity as glycosyl acceptors. Among these four the azide
(2) is the most reactive4 and has proven its value in a
synthesis of the common core trisaccharide of the N-linked
glycans,5 but the most convenient preparation employs triflyl
azide and is inconvenient on a large scale.6 Substances 1, 3,
and 4 suffer from the relatively harsh conditions required to
cleave the phthalimide,7 the instability of 3 toward premature
hydrolysis, and the complex NMR spectra engendered by
the fully substituted amide in 4.4 Interestingly, sulfonamide
protected glucosamine derivatives (5) have proven to be
serviceable glycosyl acceptors whose deprotection may be
conveniently achieved in parallel to benzyl ethers by means
of sodium in liquid ammonia.8 We now show that oxazoli-
dinone protection of N-acetylglucosamine affords a very
convenient and highly reactive glycosyl acceptor that,
(5) Dudkin, V. Y.; Crich, D. Tetrahedron Lett. 2003, 44, 1787.
(6) Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. HelV. Chim.
Acta 1991, 74, 2073.
(7) The tetrachlorophthalimides are easier to cleave but are not considered
as their more crystalline nature renders them insufficiently soluble at the
low temperatures (e60 °C) used for glycosylation in this laboratory.
Debenham, J. S.; Madsen, R.; Roberts, C.; Fraser-Reid, B. J. Am. Chem.
Soc. 1995, 117, 3302.
(8) Wang, Z.-G.; Zhang, Z.; Visser, M.; Live, D.; Zatorski, A.; Iserloh,
U.; Lloyd, K. O.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 1728.
Dudkin, V. Y.; Miller, J. S.; Danishefsky, S. J. Tetrahedron Lett. 2003, 44,
1791.
(1) (a) Lehman, J. Carbohydrates: Structure and Biology; Thieme:
Stuttgart, Germany, 1998. (b) Dwek, R. A. Chem. ReV. 1996, 96, 683. (c)
Varki, A. Glycobiology 1993, 3, 97. (d) Bioorganic Chemistry: Carbohy-
drates; Hecht, S. M., Ed.; OUP: New York, 1999.
(2) Davis, B. G. Chem. ReV. 2002, 102, 579.
(3) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155.
(4) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 123, 6819.
10.1021/ol0342305 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/20/2003

additionally, is converted in a straightforward manner to the
target N-acetyl protected disaccharides post-glycosylation.9,10
Scheme 2. Glycosylation of 9 with Thioglycosides and
BSP/Tf2O
addition of the acceptor and warming to room temperature
(Table 1). After isolation of the disaccharides, the N-acetyl
oxazolidinone moiety was removed with barium hydroxide
in ethanol and the acetamide reinstalled by brief treatment
with acetic anhydride (Scheme 1 and Table 1).
A suitable N-acetyl oxazolidinone (9) was prepared in a
straightforward manner from the known11 glucosamine
derivative 6 as shown in Scheme 1. It is of some interest
All of the couplings presented in Table 1 proceeded
without event, leaving only the stereoselectivities in need
of comment. Coupling to the mannosyl donor 10 was
â-selective as anticipated,13,17 but less so than might have
been expected. Nevertheless, the two anomers were readily
separated thereby providing an entry into the key linkage of
the N-linked glycans. The 4,6-O-benzylidene protected donor
13 afforded a highly R-selective coupling, again in line with
precedent,13,18 thereby providing a convenient entry into the
repeating unit of heparin.1 Interestingly, the 4,6-O-ben-
zylidene protected galactosyl donor 16,19 like its glucose
counterpart but in contrast to the mannose series, was also
highly R-selective and affords the linkage at the core of the
keratin sulfate repeating unit.1 The rhamnosyl donor 19 was
highly R-selective, again in line with precedent,13,20,21 whereas
lower selectivity was obtained with the less rigid tetra-O-
benzyl glucose donor 22.
Scheme 1. Preparation of an Oxazolidinone Protected
Acceptor
that the acid-mediated, regioselective cleavage of the ben-
zylidene acetal12 is fully compatible with the N-acetyl
oxazolidinone group in 8.
Although the broad, general BSP/Tf2O protocol is the
coupling method of choice in our laboratory for glycosidic
bond formation, it is by no means the only method avail-
able.22 We have glycosylated acceptor 9 by three other
methods to test its generality as an improved acceptor alcohol
(Scheme 3, Table 2).
In the event, as is evident from Table 2, acceptor 9
performs well in Kahne’s sulfoxide method,23 Gin’s dehy-
drative coupling sequence,24 and Schmidt’s trichloroacetimi-
date protocol.25
Acceptor 9 was then subjected to coupling with a range
of thioglycosides under the standardized activation conditions
employed in both the solution13 and solid phases14 in this
laboratory (Scheme 2). Thus, the various thioglycosides were
briefly exposed to the combination of 1-benzenesulfinylpi-
peridine (BSP),15 2,4,6-tri-tert-butylpyrimidine (TTBP),15,16
and triflic anhydride in dichloromethane at -60 °C before
(9) Oxazolidinone protection of glucosamine affords an R-selective
glucosamine donor but its use has not been described in glucosamine
acceptors. Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001, 123,
9461.
(10) 2,3-O-Carbonate protection has been applied in glucose acceptors
but without any comment on its ability to enhance or diminish nucleo-
philicity. Zhu, T.; Boons, G.-J. Org. Lett. 2001, 3, 4201.
(11) Bauer, T.; Tarasiuk, J.; Pasiczek, K. Tetrahedron: Asymmetry 2002,
13, 77.
Finally, the question of the reasons underlying the
enhanced reactivity of acceptor 9 obviously arises, aside from
the obvious elimination of the NH bond. The possibility that
(17) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321.
(12) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108,
97. Garegg, P. J. In PreparatiVe Carbohydrate Chemistry; Hanessian, S.,
Ed.; Dekker: New York, 1997; p 53.
(13) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015. Crich,
D.; de la Mora, M. A.; Cruz, R. Tetrahedron 2002, 58, 35. Crich, D.; Li,
H. J. Org. Chem. 2002, 67, 4640. Crich, D.; Picione, J. Org. Lett. 2003, 5,
781-784.
(18) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926.
(19) Sugimura, H.; Watanabe, K. Synth. Commun. 2001, 31, 2313.
(20) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291.
(21) Note that this selectivity contrasts with that obtained for 2,3-O-
carbonyl-protected rhamnosyl bromides by the insoluble silver salt
method: Bachinovsky, L. V.; Balan, N. F.; Shashkov, A. S.; Kochetkov,
N. K. Carbohydr. Res. 1980, 84, 225.
(14) Crich, D.; Smith, M. J. Am. Chem. Soc. 2002, 124, 8867.
(15) Commercially available from www.lakeviewsynthesis.com.
(16) TTBP is a convenient, crystalline alternative to DTBMP: Crich,
D.; Smith, D.; Yao, Q.; Picione, J. Synthesis 2001, 323.
(22) Barresi, F.; Hindsgaul, O. J. Carbohydr. Chem. 1995, 14, 1043.
(23) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239.
(24) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269.
(25) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
1298
Org. Lett., Vol. 5, No. 8, 2003

Table 1. Preparation of 4-O-Glycosylated N-Acetylglucosamines from Acceptor 9 by the Thioglycoside/BSP/Tf2O Method
a Only the â-anomer was deprotected. b In this case the esterification was conducted with Ac2O in pyridine. c Only the R-anomer was deprotected.
the oxazolidinone ring confers a twist, or even an inversion
of conformation, of the pyranose ring thereby exposing the
4-OH more is ruled out by the scalar couplings around the
ring which clearly indicate a standard C1 chair. It seems
most likely, therefore, that the enhanced reactivity of 9
simply arises from the tied back nature of the protection on
O-3, which minimizes steric hindrance about the 4-OH. This
being the case, it is likely that cyclic carbonates spanning
O-2 and O-3 will enhance the reactivity of the 4-OH in other
donors. Indeed, although no formal comparisons were made,
the work of Boons suggests that this may well be the case.10
Similarly, it is likely that 2,3-acetonide (28) and even silylene
4
Scheme 3. Glycosylation of 9 by Alternative Methods
Table 2. Alternative Coupling Methods for the Formation of
23
anomeric
donor
mediator; conditions
ratio (R/â)
% yield
22a
25
26
27
BSP, TTBP, Tf2O; -60 °C
TTBP, Tf2O; -60 °C
Ph2SO, Tf2O, TTBP; -40 °C
TMSOTf; -30 °C
6.2:1
78
63
59
82
R only
R only
3.5/1
a The last entry of Table 1 is reproduced here for convenient com-
parison.
Org. Lett., Vol. 5, No. 8, 2003
1299

(29) protected acceptors will show enhanced reactivity,
Acknowledgment. We thank the NIH (GM 62160) for
although this remains to be tested.
support of this work.
Supporting Information Available: Synthetic details and
characterization for all new molecules. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0342305
1300
Org. Lett., Vol. 5, No. 8, 2003