A new method for the stereoselective synthesis of α- and β-glycosylamines using the Burgess reagent

Article abstract of DOI:10.1021/ja049293c

Although glycosylamines constitute an important group of carbohydrates from the standpoint of biology and medicine, methods for their synthesis typically lack substrate generality and/or result in variable stereoselectivity, especially in complex contexts

Full text of DOI:10.1021/ja049293c

Published on Web 04/29/2004
A New Method for the Stereoselective Synthesis of r- and â-Glycosylamines
Using the Burgess Reagent
K. C. Nicolaou,* Scott A. Snyder, Annie Z. Nalbandian, and Deborah A. Longbottom
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and Biochemistry, UniVersity
of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093
Received February 9, 2004; E-mail: kcn@scripps.edu
Table 1. Synthesis of Sulfamidates on Carbohydrate Templatesa
Even though our knowledge concerning many classes of
carbohydrates has expanded dramatically over the past decade,
glycosylamines persist as an understudied group, especially in light
of their prominence in glycopeptides and glycoproteins and their
potential as selective RNA-binding agents.1 This state of affairs
primarily reflects the difficulty in achieving their synthesis, as
available methods, based on the use of glycosyl azides, glycals,2
Kochetkov aminations,3 and R-hydroxy nitriles,4 among others,5
lack substrate generality and often result in variable stereoselectivity,
especially in complex contexts. In this communication, we report
an operationally simple method for the synthesis of both R- and
â-glycosylamines that overcomes many of these limitations in a
bare minimum of synthetic steps.
Drawing insight from our recent explorations6 into the novel
chemistry that can be achieved with Burgess-type reagents (1, 2,
or 3, Scheme 1), we anticipated that exposing a carbohydrate of
general structure 4 to an excess amount of one of these salts would
lead to the formation of a sulfamidate product (6) with complete
regio- and stereocontrol. Such an outcome is in accordance with
the established preference6a of the more activated hydroxyl group
to depart in the cyclization event, either by the indicated SN2
mechanism or via an oxonium alternative, with the C-2 group
orchestrating the stereoselective delivery of nitrogen. Once con-
structed, the newly installed sulfamidate ring could then be opened
with a variety of heteroatomic nucleophiles to afford 1,2-trans-
difunctionalized glycosylamine products.6a,7 Thus, based on this
model, a starting material derived from D-glucose would provide
a All reactions were performed using 2.5 equiv of the appropriate
Burgess-type reagent (1, 2, or 3) in THF/CH2Cl2 (4:1) with heating at reflux
for 6 h.
Scheme 1
an R-glycosylamine product (7), arguably the more difficult
glycosylamine anomer to synthesize in a controlled manner.
Alternatively, if lactols bearing C-2 protection (8) were exposed
to the same general reaction conditions, it would be reasonable to
expect that these materials would afford N,O-acetal products instead
of sulfamidates through the indicated mechanism, with stereocontrol
in this “self-displacement” reaction arising from the established
preference for anomeric triflates to exist as R-anomers (10) over
their â-disposed counterparts (9).8 As such, D-glucose-based materi-
als would afford only â-glycosylamine products (11) in this reaction
paradigm.
Gratifyingly, when these propositions were tested in the labora-
tory, they proved to be highly accurate. Indeed, as shown in Table
1, a variety of diols on diverse carbohydrate templates (D-glucose,
D-galactose, L-rhamnose) were smoothly converted into their
R-disposed sulfamidate counterparts over the course of 6 h upon
the action of 2.5 equiv of 1, 2, or 3 in refluxing THF/CH2Cl2
(4:1). As revealed through the selected examples in Scheme 2, these
products could be subsequently opened with nucleophiles to afford
R-disposed glycosylamines such as 24 or, alternatively, converted
into functionalized sulfamidates such as 25 simply by removing
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J. AM. CHEM. SOC. 2004, 126, 6234-6235
10.1021/ja049293c CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
furanose substrates performed equally well (entries 5 and 6), with
anomeric stereochemistry in these products presumably controlled
by the orientation of the C-2 substituent on a level commensurate
to its bulk.9 Finally, it is important to note that, in addition to
generating highly predictable products within this reaction manifold,
Alloc-protected amines were readily liberated to afford free
glycosylamines for additional synthetic applications. For example,
Alloc-protected 29 was transformed into 2,3,4,6-tetra-O-benzyl-â-
D-glucosylamine in near quantitative yield (95%) using conditions10
that did not initiate any anomerization.
In conclusion, we have developed a new approach for the
synthesis of both R- and â-glycosylamines on a wide variety of
carbohydrate scaffolds using a reaction protocol that is exceedingly
mild, operationally simple, and tolerant of numerous functional and
protecting groups.11 In addition, these reactions appear to be
applicable for large-scale syntheses (reactions up to 5 mmol have
been performed with no drop in efficiency) and late-stage operations
relevant to the synthesis of complex aminoglycosides and/or
N-linked glycopeptides. Accordingly, this synthetic technology
provides certain advantages over those currently available and
should enhance our capability to study the chemical biology of both
natural and designed glycosylamines. Equally important, this
methodology continues to underscore the impressive power of the
Burgess reagent (1) and its relatives (2, 3) to effect transformations
of critical importance in chemical synthesis.12
a Reagents and conditions: (a) NaN3 (5.0 equiv), DMF, 60 °C, 5 h, 83%;
(b) Pd(OAc)2 (0.1 equiv), TPPTS (0.2 equiv), Et2NH (40 equiv), MeCNH2O
(1:1), 25 °C, 30 min; (c) NaH (5.0 equiv), DMF, 25 °C, 5 min, then allyl
bromide (4.0 equiv), 25 °C, 15 min, 73% over two steps.
Table 2. Direct Conversion of Anomeric Alcohols to Aminesa
Acknowledgment. We thank Drs. D. H. Huang and G. Siuzdak
for NMR spectroscopic and mass spectrometric assistance, respec-
tively. Financial support for this work was provided by The Skaggs
Institute for Chemical Biology, the National Institutes of Health
(U.S.A.), predoctoral fellowships from the National Science
Foundation, Pfizer, and Bristol-Myers Squibb (all to S.A.S.), and
a grant from American Biosciences.
Supporting Information Available: Detailed experimental pro-
cedures and full characterization for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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a All reactions were performed using 1.5 equiv of the appropriate
Burgess-type reagent (1, 2, or 3) in THF/CH2Cl2 (4:1) with heating at reflux
for 6 h.
(7) For a review, see: Melendez, R. E.; Lubell, W. D. Tetrahedron 2003,
the Alloc protecting group and alkylating. Although both of these
manipulations should prove important in future applications relevant
to chemical biology and medicinal chemistry, compounds of type
25 offer several unique advantages as their sulfamidate ring provides
untapped structural novelty and ensures that the disposition of the
N-atom cannot anomerize (as often occurs with unprotected
R-glycosylamines simply upon standing in solution). As indicated
in Table 2, C-2 protected lactols reacted with Burgess-type reagents
in a level of smoothness that matched their diol counterparts,
affording a â-disposed, protected glycosylamine on every six-
membered carbohydrate probed (entries 1-4), as verified by both
X-ray crystallographic and 1H NMR analyses. Five-membered
53, 2581.
(8) Crich, D. J. Carbohydr. Chem. 2002, 21, 667.
(9) It is important to note that this protocol does not provide a general synthesis
of aminals from lactols, as a number of conventional lactols gave
inconsistent yields of the desired products.
(10) Geneˆt, J. P.; Blart, E.; Savignac, M.; Lemeure, S.; Paris, J.-M. Tetrahedron
Lett. 1993, 34, 4189.
(11) The only incompatibility that we have identified is the presence of
carbonyl-based protecting groups such as acetate or benzoate at the C-3
position.
(12) For reviews on the chemistry of the Burgess reagent, see: (a) Taibe, P.;
Mobashery, S. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L.A., Ed.; John Wiley & Sons: Chichester, 1995; Vol. 5, pp
3345-3347. (b) Burckhardt, S. Synlett 2000, 559.
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