Efficient methodology for the synthesis of 2-C-branched glyco-amino acids by ring opening of 1,2-cyclopropanecarboxylated sugars

Article abstract of DOI:10.1021/ol049467v

Matrix presented. 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.

Full text of DOI:10.1021/ol049467v

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1777-1779
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(C2H4)Cl2]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 29 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)-â-D-glucopyranoside 3 in
75% yield as a single diastereomer7 in which two new
stereocenters were introduced in a single reaction (Scheme
1). Further reaction of 3 with NaN3/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 Ph3P/THF/H2O (Staudinger
reaction conditions), the amine 5 typically being isolated in
95% yield. It is interesting to note that our benzyltriethyl-
ammonium tetrathiomolybdate reduction methodology8 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 13C 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.
10.1021/ol049467v CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/30/2004

Scheme 1. General Strategy for the Synthesis of a
Gluco-amino Acid from 3,4,6-Tri-O-benzyl-D-glucal
Scheme 2
the newly formed C-1 and C-7 stereocenters (Table 1). The
large coupling constant (J ∼ 8.8 Hz) for the anomeric proton
in all the ring-opened products showed that the sugar
derivatives had a 1,2-trans configuration.9 The stereochem-
istry at C-2 was defined on the basis of the stereochemistry
present in the 1,2-cyclopropanecarboxylated sugar precursors.
However, in the case of 1,5-anhydro-2-deoxy-1,2-C-(exo-
carbomethoxymethylene)-3,4,6-tri-O-benzyl-R-D-galactol 10,
the ring-opened product gave a mixture of R,â-diastereomers
in a ratio of 30:7010 (Table 1, entry 2). Treatment of
compound 18 with NIS in anhydrous acetonitrile (4 Å
molecular sieves) furnished the corresponding levoglucosan
derivative 19 in good yield, which once again corroborated
the 1,2-trans selectivity at the anomeric center. The iodide
19 was then converted to the azide 20 and this reduced under
Staudinger reaction conditions or with tetrathiomolybdate to
afford the levoglucosan-derived glyco-amino acid ester 21
in excellent yield (95%).
also effective for converting 4 into 5 (CH3CN, ))))), 28 °C,
6 h, 94%) (Scheme 1).
The aforementioned ring-opening of 1,2-cyclopropane-
carboxylates could also be extended to the sugar derivatives.
Thus, 6, 10, and 14 gave rise to the 2-C-branched gluco-
amino acid derivatives 9, 13, and 17, respectively, in good
yields (65-85%) and with very high diastereoselectivity at
To ascertain the exact stereochemistry at C-7, the GAA
derivative 17 was treated with phosgene (Et3N/CH2Cl2, 0
°C, 3 h) to furnish the corresponding urea derivative 22 as
a crystalline solid (Scheme 2), and it was subjected to X-ray
crystallographic analysis. The crystal structure of compound
22 (Figure 1) was in accord with our stereochemical
assignment for the ring-opened products.11
Table 1. Ring Opening of 1,2-Cyclopropanecarboxylated
Sugar Derivatives: Synthesis of GAAs
Figure 1. ORTEP diagram of compound 2212.
a TBDMS has been completely deprotected under NIS-mediated sol-
volytic ring opening of 1,2-cyclopropanecarboxylated sugar 6. b Isolated
yield after column chromatography. c The free OH in 8 was acetylated prior
to reduction of the azide.
In conclusion, we have developed an effective method for
the synthesis of 2-C-branched glyco-amino acid derivatives
1778
Org. Lett., Vol. 6, No. 11, 2004

by diastereoselective ring opening of 1,2-cyclopropane-
carboxylated sugars. Further studies on the application of
these new GAAs and the synthesis of glycopeptides by the
above methodology are currently under investigation.
Supporting Information Available: 1H and 13C NMR
data for all the ring-opened products, azides, and GAA
derivatives, 1H 1H COSY spectra for compounds 15, 16, and
17, and crystallographic data for compound 22. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. P.R.S. thanks the Council of Scientific
and Industrial Research, India, for a senior research fellow-
ship.
OL049467V
(12) One molecule of water was observed in the crystal structure. Crystal
data for 22 (C49H62N2O14): Mr ) 908, monoclinic, space group P21, a )
12.1940 Å, b ) 19.8738 Å, c ) 17.5201 Å, â ) 93.670(10)°, V )
2499.75(27) Å3, Z ) 2, Mo KR radiation (λ ) 0.710 73 Å), T ) 293(2) K;
R1 ) 0.0578, wR2 ) 0.115 (I > 2σ(I)); R1 ) 0.102, wR2 ) 0.132 (all
data).
(9) The high diastereoselectivity at the anomeric center may be attributed
to the neighboring group (COOMe) participation.
1
(10) Based on HPLC and H NMR spectroscopy.
(11) The configuration of all GAA derivatives were assigned on the basis
of the coupling constants and also the structure of compound 22.
Org. Lett., Vol. 6, No. 11, 2004
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