The mild cleavage of 2-amino-2-deoxy-D-glucoside methoxycarbonyl derivatives.

Article abstract of DOI:10.1021/ol0063353

The conversion of methyl carbamate to the corresponding free amine is described for a series of 2-amino-2-deoxy-D-glucosamine derivatives. Cleavage of methoxycarbonyl moiety with MeSiCl(3) and triethylamine in dry THF at 60 degrees C and subsequent aqueou

Full text of DOI:10.1021/ol0063353

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3135-3138
The Mild Cleavage of
2-Amino-2-deoxy-D-glucoside
Methoxycarbonyl Derivatives
Bryan K. S. Yeung, Sara L. Adamski-Werner, Jennifer B. Bernard,
Gae1lle Poulenat, and Peter A. Petillo*
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
600 South Mathews AVenue, Urbana, Illinois 61801
alchmist@natasha.scs.uiuc.edu
Received July 15, 2000
ABSTRACT
The conversion of methyl carbamate to the corresponding free amine is described for a series of 2-amino-2-deoxy-D-glucosamine derivatives.
Cleavage of methoxycarbonyl moiety with MeSiCl3 and triethylamine in dry THF at 60 °C and subsequent aqueous hydrolysis yields the free
amine in 54 to 93% yields. The selective cleavage of methyl carbamates with MeSiCl3 in the presence of a 2,2,2-trichloroethoxycarbonyl group
or 2-azido glycosides affords selectively, orthogonal N-deprotected carbohydrates.
N-Acetylglucosamine-containing oligosaccharides are ubiq-
uitous in biological systems and are major constituents of
mucopolysaccharides, peptidoglycans, glycoproteins, and
blood group antigens.1 Consequently, and because of their
biological importance, N-acetylglucosamine oligosaccharides
are important synthetic targets.2 In general, the successful
chemical synthesis of these species requires careful selection
of the N-protecting group on the 2-amino-2-deoxy sugar that
is compatible with the glycosylation methodology employed
and is readily removed in the presence of other carbohydrate
functionality. In general, 2-acetamido glycoside derivatives
are not directly employed because of poor solubility in
organic solvents, and formation of the methyloxazoline3 is
oftentimes the major product isolated, thus making them poor
glycosyl donors.4
carbamates is limited in generality and scope.5 For example,
methoxycarbonyl has not been widely employed, as N-
deprotection typically involves a strong base and/or elevated
reaction temperatures.6 However, recent reports demonstrated
that the methoxycarbonyl moiety is readily cleaved in the
presence of a Lewis acid such as TMSI,7 HSiCl3,8,9 or H2-
SiI2.10 Additionally, different chlorosilanes were shown to
activate carbamates differently, leading to multilevel selectiv-
ity in the cleavage of carbamates to isocyanates.9 This latter
(4) A one-pot glycosylation method was recently reported with methyl-
oxazolines as glycosyl donors. See: Di Bussolo, V.; Liu, J.; Huffman, L.
G.; Gin, D. Y. Angew. Chem., Int. Ed. 2000, 1, 204.
(5) (a) Green, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; John Wiley & Sons: New York, 1991; pp 315-348.
(b) Kocienski, P. J. Protecting Groups; Georg Thiem Verlag: Stuttgart,
1994. (c) Shapiro, G.; Marzi, M. J. Org. Chem. 1997, 62, 7096. (d) Ozaki,
S. Chem. ReV. 1972, 72, 457. (e) Valli, V. L. K.; Alper, H. J. Org. Chem.
1995, 60, 257.
(6) A single report exists on the base-induced cleavage of methoxycar-
bonyl monosaccharide derivatives. See: Kobayashi, Y.; Tsuchiya, T.; Ohgi,
T.; Taneichi, N.; Koyama, Y. Carbohydr. Res. 1992, 230, 89.
(7) (a) Lott, R. S.; Chauhan, V. S.; Stammer, C. H. J. Chem. Soc., Chem.
Commun. 1979, 495. (b) Raucher, S.; Bray, B. L.; Lawrence, R. F. J. Am.
Chem. Soc. 1987, 109, 442. (c) Kende, A. S.; Luzzio, M. J.; Mendoza, J.
S. J. Org. Chem. 1990, 55, 918.
Carbamates that act as protecting groups find widespread
use in the synthesis of N-acetylglucosamine-containing
oligosaccharides.2 Among these, CBz- and TROC-carbam-
ates are commonly employed, although the use of other
(1) Carbohydrate Chemistry; Kennedy, J. F., Ed.; Oxford University
Press: Oxford, 1988.
(2) Yeung, B. K. S.; Chong, P. Y.; Petillo, P. A. The Synthesis of
Glycosaminoglycans. In Glycochemistry: Principles, Synthesis and Ap-
plications; Bertozzi, C., Wang, G., Eds.; Marcel-Dekker, in press.
(3) Banoub, J.; Boullanger, P.; Lafont, D. Chem. ReV. 1992, 92, 1167.
(8) (a) Greber, G.; Kricheldorf, H. R. Angew. Chem., Int. Ed. Engl. 1968,
7, 941. (b) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 2781. (c)
Pirkle, W. H.; Hoekstra, M. S. J. Org. Chem. 19747, 39, 3904. (d) Pirkle,
W. H.; Rinaldi, P. L. J. Org. Chem. 1978, 43, 3808.
10.1021/ol0063353 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/09/2000

observation is of particular importance, as the synthesis of
many nitrogen-containing carbohydrates requires the or-
thogonal protection of multiple nitrogen centers. Demonstra-
tion that methyl carbamates are useful in the synthesis of
complex carbohydrates has yet to be accomplished.
Table 1. Preparation of the Substrate Glycosides
We now report the use of methyl carbamate as an
N-protecting group for 2-amino-2-deoxyglycosides and its
compatibility with commonly employed carbohydrate pro-
tecting groups. Methyl carbamate derivatives of 2-amino-
2-deoxyglycosides are shown to be useful glycosyl donors
and acceptors and provide â-glucosides via C-2 participation
under Koenigs-Knorr and Schmidt trichloroacetimidate
glycosylations. The methoxycarbonyl moiety is readily
converted to the corresponding free amine in the presence
of acid-sensitive protecting groups such as acetals and bis-
ketals. Finally, we establish that methyl carbamates provide
orthogonal nitrogen protection in the presence of TROC-
carbamates and azides.
Preparation of the Glycosyl Donors. The methyl car-
bamate glycosyl donors were prepared from D-glucosamine‚
HCl (1), a solution of methyl chloroformate, and sodium
bicarbonate in chloroform/water (1:1) to afford the corre-
sponding methyl carbamate (Scheme 1). Subsequent per-
Scheme 1a
8a and 9a, and in all other glycosylations, trichloroacetimi-
dates 5-7 were employed using either TMSOTf or BF3‚
Et2O as a catalyst.12 The trichloroacetimidates proved more
reliable than the corresponding glycosyl bromide and resulted
in cleaner glycosylations in higher overall yields. C2-Methyl
carbamate glycosyl donors yielded only â-glycoside deriva-
tives, suggesting anchimeric assistance. For 13a, where
imidate 513 was used as the glycosyl donor, a 1:2 mixture of
R- and â-anomers was isolated, accounting for the 58% yield
observed for the glycosylation step.14
a (a) (1) Methyl chloroformate, NaHCO3, CHCl3:H2O (1:1), 25
°C, 1 h; (2) Ac2O, pyridine, 25 °C; (b) 30% HBr in AcOH, 25 °C,
12 h; (c) (1) NH2NH2‚HOAc, DMF, 25 °C, 2 h; (2) CCl3CN, DBU,
CH2Cl2, 25 °C, 1 h.
Scheme 2
acetylation produced 2 in 90% yield as an anomeric mixture.
Tetraacetate 2 is readily transformed into either glycosyl
donor 311 by treatment with 30% HBr in acetic acid or into
4 by the selective reduction of the 1-O-acetate with hydrazine
acetate followed by treatment with trichloroacetonitrile and
1,8-diaza[5.4.0]bicycloundec-7-ene (DBU).
Preparation of the Substrate Glycosides. The syntheses
of substrate glycosides represent a range of functionality
commonly employed in carbohydrate synthesis (Table 1).
Glycosyl bromide 3 was used to prepare monosaccharides
3136
Org. Lett., Vol. 2, No. 20, 2000

Table 2. Deprotection of Methyl Carbamate Glycosides 8a-15a
Deprotection of Substrate Glycosides. The chlorosilane-
induced cleavage of methyl carbamates was carried out by
treatment of the substrate glycoside (A) with MeSiCl3 and
Et3N to afford isocyanate (D) and methoxymethyldichloro-
silane (Scheme 2). In the first step, an N-silylated species is
generated15 (B), followed by formation of the four-membered
ring transition state (C), which collapses to form the
isocyanate.16 Subsequent hydrolysis of the isocyanate during
aqueous workup forms the carbamic acid, which liberates
CO2 and provides the corresponding free amine.17
Conversion of the methyl carbamate to the corresponding
amine by the action of MeSiCl3 proceeds in moderate to
(11) Boullanger, P.; Jouineau, M.; Bouammali, B.; Lafont, D.; Descotes,
G. Carbohydr. Res. 1990, 202, 151.
(12) Yeung, B. K. S.; Hill, D. C.; Janicka, M.; Petillo, P. A. Org. Lett.
2000, 2, 1279.
(13) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249.
(14) A mixture of anomers is commonly observed for this particular
glycosyl donor with a C2-acetyl group. See: Schmidt, R. R.; Kinzy, W.
AdV. Carbohydr. Chem. Biochem. 1994, 50, 21.
(15) (a) Kricheldorf, H. R. Synthesis 1970, 649. (b) Kricheldorf, H. R.
Liebigs Ann. Chem. 1973, 772. (c) Kricheldorf, H. R. Chem. Ber. 1971,
104, 3146.
(9) (a) Chong, P. Y.; Janicki, S. Z.; Petillo, P. A. J. Org. Chem. 1998,
63, 8515. (b) Chong, P. Y.; Petillo, P. A. Tetrahedron Lett. 1999, 40, 2493.
(c) Chong, P. Y.; Petillo, P. A. Tetrahedron Lett. 1999, 40, 4501.
(10) Gastaldi, S.; Weinreb, S. M.; Stien, D. J. Org. Chem. 2000, 65,
3239.
Org. Lett., Vol. 2, No. 20, 2000
3137

excellent yields and is compatible with a variety of protecting
groups including the acid-labile bis-dimethyl acetal (e.g., 12a)
and acetonides (13a-15a) (Table 2). Partial cleavage of the
acetonide was observed for 15b only during column chro-
matography, as TLC and crude 1H NMRs show no evidence
of acetonide loss after carbamate cleavage. Deprotection of
monosaccharides 8a-10a afforded the free amine after 24
h with no starting material remaining, while disaccharide
substrates 11a-15a required significantly longer reaction
times. Although reaction times vary greatly as a function of
disaccharide, the reactions themselves are exceptionally clean
with only free amine and unreacted starting material recov-
ered in all examples with the exception of 10a. Some
decomposition of 10a was observed, presumably due to direct
activation of the thioglycoside.
results in the formation of a higher Rf product that corre-
sponds to the glycosyl isocyanate D (Scheme 2). Interest-
ingly, the glycosyl isocyanates are remarkably stable as
demonstrated by 9a, which was isolable and completely
characterizable by IR, MS, and NMR spectroscopies. More-
over, a simple aqueous wash proved inadequate for complete
isocyanate hydrolysis, and unless the reaction is quenched
under dilute conditions, any free amine present quickly
condenses with the remaining isocyanate to form the cor-
responding ureido glycoside 22 (Figure 1).18 Only under
Methyl carbamate cleavage carried out in the presence of
other N-protecting groups such as azides and 2,2,2-trichloro-
ethoxycarbonyl demonstrates the selectivity and orthogonality
available with this methodology. Cleavage of the methyl
carbamate in disaccharide 14a proceeded in 93% yield with
complete retention of the TROC carbamate. Although some
loss of the acetonide was observed during purification, the
crude reaction mixture was essentially clean and all func-
tionality except the methoxycarbonyl moiety remained intact.
Conversely, removal of the TROC carbamate in 16a by the
action of Zn dust in AcOH revealed the corresponding free
amine (16b), with complete retention of the methyl carbam-
ate. These observations are consistent with those observed
for simple aromatic carbamates9 and suggest that glycoside
carbamates are also subject to reactivity differences as a
function of silane. Finally, cleavage of the methoxycarbonyl
moiety in 15a proceeded in 81% yield (15b) in the presence
of the alkyl azide. As expected, the reduction of the azide
moiety (17a) occurred quantitatively, leaving the methyl
carbamate untouched (17b).
Figure 1. Ureido glycoside 22.
highly dilute conditions can the isocyanate be hydrolyzed
without intermolecular condensation.19
In summary, we have demonstrated that methoxycarbonyl-
protected 2-amino-2-deoxy glycosides are useful glycosyl
donors, which can be readily N-deprotected in the presence
of acid-sensitive protecting groups by the action of MeSiCl3.
Selective cleavage of the methoxycarbonyl group in the
presence of other protected nitrogen centers occurs without
crossover, suggesting that this methodology may be useful
in the synthesis of differentially functionalized polyamino
carbohydrates.
Acknowledgment. This research was generously sup-
ported by the National Institutes of Health.
Supporting Information Available: Experimental pro-
cedures and complete spectroscopic data for all substrates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Deprotection of methyl carbamates 8a and 9a initially
(16) (a) Mironov, V. F.; Seludjakov, V. D.; Kozjukov, V. P.; Chatuncev,
G. D. Dokl. Akad. Nauk. SSSR 1968, 181, 115. (b) Mironov, V. F.;
Kozyukov, V. P.; Orlov, G. I. J. Gen. Chem. USSR (Engl. Transl.) 1981,
51, 1555. (c) We have recently carried out a kinetic study on the formation
of isocyanates from carbamates with a variety of chlorosilanes.
(17) General procedure: MeSiCl3 (5 equiv) is added to a solution of
the methyl carbamate glycoside (0.02-0.1 M) and Et3N (5 equiv) in dry
THF. The reaction flask is sealed under nitrogen and heated to 60 °C. When
the starting material is consumed, the reaction is diluted (3×-20× reaction
volume) with water or 1:1 THF-water and allowed to stir until the
isocyanate is hydrolyzed as determined by TLC. The free amine can then
be purified or directly acetylated.
OL0063353
(18) Temeriusz, A.; Piekarska-Bartoszewicz, B.; Weychert, M.; Wawer,
I. Pol. J. Chem. 1999, 73, 1011.
(19) We are currently exploring the preparation of other ureido glycosides
with this methodology.
(20) Dullenkopf, W.; Castro-Palomino, J. C.; Manzoni, L.; Schmidt, R.
R. Carbohydr. Res. 1996, 296, 135.
(21) Chong, P. Y.; Petillo, P. A. Org. Lett. 2000, 2, 1093.
3138
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