Efficient Methodology for the Synthesis
of 2-C-Branched Glyco-amino Acids by
Ring Opening of
1,2-Cyclopropanecarboxylated Sugars
Perali Ramu Sridhar, K. Chinna Ashalu, and S. Chandrasekaran*
Department of Organic Chemistry, Indian Institute of Science, Bangalore, India
scn@orgchem.iisc.ernet.in
Received March 21, 2004
ABSTRACT
An efficient methodology for the synthesis of 2-C-branched glyco-amino acid derivatives by diastereoselective ring opening of 1,2-
cyclopropanecarboxylated sugars in good yields is reported.
The past decade has seen several methods being introduced
for the stereocontrolled cyclopropanation of glycals.
1
1,2-
Cyclopropanated sugars undergo ring opening to give 2-C-
branched sugars when subjected to solvolysis in the presence
of a stoichiometric amount of mercury(II) salts,
2
strong acid,
3
or halonium ions.
4
Recently, Madsen et al.,
5
synthesized 2-C-
branched carbohydrate derivatives using a Zeise reagent
([Pt(C
2
H
4
)Cl
2
]
2
) catalyzed ring opening of 1,2-cyclopropan-
ated sugars with O-nucleophiles. Their results prompted us
to use 1,2-cyclopropanecarboxylated sugars as synthons for
the synthesis of glyco-amino acids (GAAs),
6
utilizing their
ability to undergo, in the presence of a protic solvent,
electrophilic ring opening assisted by the adjacent oxygen
to furnish a 2-deoxy-2-C-branched glycoside with defined
C-2 stereochemistry, inherently present in the cyclopropane-
carboxylate.
Toward this end, tri-O-benzyl-D-glucal 1 was treated with
methyl diazoacetate (MDA) in dichloromethane with cata-
lytic rhodium acetate (rt, 90 min) to furnish the 1,5-anhydro-
2-deoxy-1,2-C-(exo-carbomethoxymethylene)-3,4,6-tri-O-
benzyl-R-D-glucitol 2
9
in 59% yield. Treatment of 2 with
NIS/MeOH (28 °C, 8 h) afforded methyl-3,4,6-tri-O-benzyl-
2-deoxy-2-C-(iodomethyl acetate)--D-glucopyranoside 3 in
75% yield as a single diastereomer
7
in which two new
stereocenters were introduced in a single reaction (Scheme
1). Further reaction of 3 with NaN
3
/DMF (28 °C, 24 h)
afforded azide 4 in 96% yield. The reduction of azide 4 to
the amine was unsuccessful under various hydrogenation
conditions when 5% Pd/C was used as the catalyst. Reduction
did occur satisfactorily using Ph
3
P/THF/H
2
O (Staudinger
reaction conditions), the amine 5 typically being isolated in
95% yield. It is interesting to note that our benzyltriethyl-
ammonium tetrathiomolybdate reduction methodology
8
was
(1) For a recent review on the preparation and ring opening of
cyclopropanated carbohydrates, see: Cousins, G. S.; Hoberg. J. O. Chem.
Soc. ReV. 2000, 29, 165.
(2) Scott, R. W.; Heathcock, C. H. Carbohydr. Res. 1996, 291, 205.
(3) (a) Kim, C.; Hoang, R.; Theodorakis, E. A. Org. Lett. 1999, 1, 1295.
(b) Hoberg, J. O.; Lcaffey, D. J. Tetrahedron Lett. 1996, 37, 2533.
(4) (a) Ramana, C. V.; Nagarajan, M. Carbohydr. Lett. 1998, 3, 117.
(b) Ramana, C. V.; Nagarajan, M. Synlett 1997, 763. (c) Bertinato, P.;
Sorensen, E. J.; Meng, D.; Danishefsky, S. J. J. Org. Chem. 1996, 61, 8000.
(5) (a) Beyer, J.; Madsen, R. J. Am. Chem. Soc. 1998, 120, 12137. (b)
Beyer, J.; Skaanderup, R.; Madsen, R. J. Am. Chem. Soc. 2000, 122, 9575.
(6) A glyco-amino acid (GAA) is a saccharide attached to a single amino
acid by any kind of covalent bond. McDevitt, J. P., Jr.; Lansbury, P. T. J.
Am. Chem. Soc. 1996, 118, 3818.
(7) The
13
C NMR spectra of compound 3 showed only 13 lines in addition
to the aromatic signals.
(8) Sridhar, P. R.; Prabhu, K. R.; Chandrasekaran, S. J. Org. Chem. 2003,
68, 5261.
ORGANIC
LETTERS
2004
Vol. 6, No. 11
1777-1779
10.1021/ol049467v CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/30/2004