Reductive cyclization of δ-hydroxy nitriles: A new synthesis of glycosylamines

Article abstract of DOI:10.1021/ol035111s

(Matrix presented) The stereoselective cyclization of δ-hydroxy nitriles to afford N,O-acetals and the application of this reaction toward the synthesis of glycosylamines is described.

Full text of DOI:10.1021/ol035111s

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3237-3239
Reductive Cyclization of δ-Hydroxy
Nitriles: A New Synthesis of
Glycosylamines†
Andrew D. Dorsey, Jennifer E. Barbarow, and Dirk Trauner*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California-Berkeley, Berkeley, California 94720
trauner@cchem.berkeley.edu
Received June 17, 2003
ABSTRACT
The stereoselective cyclization of δ-hydroxy nitriles to afford N,O-acetals and the application of this reaction toward the synthesis of
glycosylamines is described.
Glycosylamines are a central motif in N-linked glycopeptides
and glycoproteins.1 Their importance in biology has sparked
the development of numerous strategies for their synthesis
involving, among others, glycosyl azides, glycals, and
unprotected reducing oligosaccharides as precursors. Many
of these methods, however, lack generality or suffer from
low diastereoselectivities. The development of new meth-
odology for the synthesis of glycosylamines, therefore,
remains an important goal.
In the course of our ongoing program directed at confor-
mationally restricted proline derivatives and novel ligands
for metabotropic glutamate receptors, we have encountered
a reaction useful to this end (Scheme 1). Exposure of Meyers’
lactam 12 to TMSCN in the presence of a Lewis acid led to
N-acyl aminonitrile 2.3 In an attempt to selectively reduce
its nitrile function via intramolecular participation of the
primary hydroxy group, 2 was exposed to excess sodium
borohydride in ethanol. To our surprise, the stable N,O-acetal
3 was obtained in good yield as a single diastereomer. The
X-ray crystal structure of compound 3 is shown in Figure 1.
In principle, the reductive cyclization of hydroxynitriles
to afford cyclic N,O-acetals is a known reaction.4 The few
reported examples, however, were observed as unexpected
side reactions, which have never been further evaluated for
their synthetic potential. We therefore decided to investigate
the applicability of this reaction to the synthesis of glyco-
sylamines, arguably the most important class of N,O-acetals.
Scheme 1
† This paper is dedicated to the memory of Andrew D. Dorsey (November
2, 1977-August 13, 2001).
(1) (a) Dwek, K. Chem. ReV. 1996, 96, 683. (b) Arsequell, G.; Valencia,
G. Tetrahedron: Asymmetry 1999, 10, 3045. (c) Grogan, M. J.; Pratt, M.
R.; Marcaurelle, L. A.; Bertozzi, C. R. Annu. ReV. Biochem. 2002, 71, 593.
(2) (a) Ragan, J. A.; Claffey, M. C. Heterocycles 1995, 41, 57. (b) Ennis,
M. D.; Hoffman, R. L.; Ghazal, N. B.; Old, D. W.; Mooney, P. A. J. Org.
Chem. 1996, 61, 5813.
(3) Apparently, reactions of TMSCN and Meyers’ lactams have not been
reported. For a review of the chemistry of Meyers’ lactams, see: Meyers,
A. I.; Brengel, G. P. J. Chem. Commun. 1997, 1.
(4) For examples, see: (a) Overman, L. E.; Ricca, D. J.; Tran, V. D. J.
Am. Chem. Soc. 1993, 115, 2042. (b) Deprez, P.; Royer, J.; Husson, H.-P.
Tetrahedron 1993, 49, 3781.
10.1021/ol035111s CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/08/2003

Scheme 3
Figure 1. X-ray structure of compound 3.
We now report a general strategy for the synthesis of
protected pyranosylamines via reductive cyclization of δ-
hydroxynitriles.
Our method is exemplified by the synthesis of â-tetra-O-
benzylglucosylamine 7 shown in Scheme 2.5 Quantitative
Scheme 2
glycosylamine 9, a building block for N-linked glycoproteins,
as the only observed diastereomer. Galactonitrile 10 gave a
1:4 mixture favoring the â-anomer 11, whereas mannonitrile
12 only gave â-glycosylamine 13. In the case of maltonitrile
15, formation of a 1:5 mixture favoring the â-anomer 16
was observed.
Although the methodology performs well in the synthesis
of pyranosylamines, it appears to be somewhat limited to
hydroxynitriles yielding electronically deactivated six-
membered ring products. Attempts to prepare N,O-acetals
18 and 20 and furanosylamine 22 from the corresponding
hydroxynitriles 17, 19, and 21, respectively, through reduc-
tive cyclization failed (Scheme 4). Instead, complex mixtures
conversion of 2,3,4,6-tetra-O-benzylglucose 4 into the cor-
responding oxime 5 was followed by dehydration under the
conditions described by Vasella.6 Exposure of the resulting
known hydroxynitrile 6 to sodium borohydride in ethanol
led to reductive cyclization and precipitation of glycosyl-
amine 7 as a single â-anomer in good yield.
The extension of this methodology to other glycosylamines
is shown in Scheme 3. All substrates are readily available
from the corresponding reducing sugars and are, with the
exception of maltose-derivative 15, known compounds.6,7
Nitrile 15 was obtained from the known oxime 148 under
standard dehydration conditions.
Scheme 4
Upon exposure to sodium borohydride in ethanol, the
δ-hydroxynitriles cyclized to afford the corresponding gly-
cosylamines in moderate to good yields. In all cases, the
reductive cyclization resulted in preferential formation of the
â-anomer. No attempts were made to separate anomeric
mixtures. N-Acetylglucosamine derivative 8 afforded â-
(5) Aebischer, B.; Hanssen, H.; Vasella, A.; Schweizer, W. J. Chem.
Soc., Perkin Trans. 1 1982, 6, 2139.
(6) Ermert, P.; Vasella, A. HelV. Chim. Acta 1991, 74, 2043.
(7) Heightman, T.; Ermert, P.; Klein, D.; Vasella, A. HelV. Chim. Acta
1995, 78, 514.
(8) Yokoyama, M.; Irie, M.; Sujino, K.; Kagemoto, T.; Togo, H.;
Funabashi, M. J. Chem. Soc., Perkin Trans. 1 1992, 16, 2127.
3238
Org. Lett., Vol. 5, No. 18, 2003

of amino alcohols and products of reductive amination were
obtained under these conditions. Note that the simple N,O-
acetals 18 and 20 are unknown and appear to be unstable.
Mechanistically, the reaction presumably involves base-
catalyzed cyclization of the δ-hydroxynitrile to the corre-
sponding imidate (24), followed by reduction of the CdN
double bond and alcoholysis (Scheme 5).9 NMR studies in
Scheme 6
Scheme 5
By contrast, coupling of 9 with 26 using IIDQ afforded 28
as a single diastereomer.13 No anomerizaton was observed
under these conditions.
In summary, a new method for the stereoselective synthesis
of glycosylamines has been developed. Since the δ-hydroxy-
nitriles used as synthetic precursors can be obtained in two
simple steps from the corresponding reducing sugars, the
methodology appears to be practical for large-scale applica-
tions. Future investigations will address the optimization of
yields, the stability of different protecting groups (silyl ethers,
esters) toward the cyclization conditions, and mechanistic
studies.
deuterated ethanol indicate that at the end of the reaction
time, no boron species remains bound to the amino group.
Nitriles per se have been reported to be insensitive toward
sodium borohydride in alcoholic solvents.10
The stereoselectivity of the reaction can be explained by
preferential axial attack of the borohydride onto the imidate.
However, it is unclear whether the product ratio reflects
kinetic or thermodynamic control since glycosylamines are
known to epimerize readily in protic solvents. Due to a less
pronounced anomeric effect, â-glycosylamines are generally
more stable.11 Furthermore, the products are isolated by
precipitation in some cases.
Acknowledgment. We thank Dr. Frederick J. Hollander
and Dr. Allen G. Oliver for the crystal structure determination
of compound 3. Financial support by Merck & Co. is
gratefully acknowledged.
The use of glycosylamines 7 and 9 in the synthesis of
building blocks for N-linked glycopetides and glycoproteins
is shown in Scheme 6. Coupling of pure â-anomer 7 with
protected aspartic acid 26 under DCC/HOBt conditions gave
a 5:1 mixture of N-acylglycosylamine 27 and its R-anomer.12
Supporting Information Available: Spectroscopic and
analytical data for compounds 1-3, 7, 9, 11, 13, 15, 16, 21,
27, and 28, as well as an X-ray structure of compound 3.
This material is available free of charge via the Internet at
http://pubs.acs.org. Crystallographic data for compound 3
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no. CDC 215332.
(9) Attempts to prepare these imidates through acid- or base-mediated
cyclizations of the corresponding hydroxynitriles failed.
(10) Seyden-Peyne, J. Reductions by the Alumino- and Borohydrides in
Organic Synthesis; VCH: New York, 1991; p 129.
(11) Kozar, T.; Tvaroska, I. Biopolymers 1990, 29, 1531.
(12) Torres, O. L.; Haro, I.; Bardaoi, E.; Valencia, G.; Garcia-Anton, O.
M.; Reig, F. Tetrahedron 1988, 44, 6131.
OL035111S
(13) Danishefsky, S.; Hu, S.; Cirillo, P.; Eckhardt, M.; Seeberger, P.
Chem. Eur. J. 1997, 3, 1617.
Org. Lett., Vol. 5, No. 18, 2003
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