Sugar-derived aziridines: Functionalization via lithiation of the aziridine ring

Article abstract of DOI:10.1021/ol990841e

(Matrix Presented) Stereoselective preparation of a new arabinose-derived aziridine and functionalization of the corresponding N-BH₃ complex are described. Regio-and stereoselective aspects are discussed.

Full text of DOI:10.1021/ol990841e

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1181-1182
Sugar-Derived Aziridines:
Functionalization via Lithiation of the
Aziridine Ring
,†
Philippe Bisseret,* Claire Bouix-Peter, Olivier Jacques, Ste´phanie Henriot, and
Jacques Eustache*
Laboratoire de Synthe`se Organique et de Chimie Microbienne - CNRS UPRESA 7015,
UniVersite´ de Haute-Alsace, Ecole Nationale Supe´rieure de Chimie de Mulhouse,
3, Rue Alfred Werner, F-68093 Mulhouse Cedex, France
j.eustache@uniV-mulhouse.fr
Received July 21, 1999
ABSTRACT
Stereoselective preparation of a new arabinose-derived aziridine and functionalization of the corresponding N-BH complex are described.
3
Regio- and stereoselective aspects are discussed.
In the course of a project aimed at identifying inhibitors of
mycobacterial arabinosyltransferases, we needed to prepare
a series of bicyclic sugar-derived aziridines (1; Figure 1).
reported.2 The key step in the synthesis of the latter
compounds was an intramolecular 1,3-dipolar cycloaddition
of δ-azidoalkenes. This reaction, however, is not general3
and may lead to imines or diazo compounds besides (or
instead of) the desired aziridines. In addition, the use of 1,3-
dipolar cycloadditions for the preparation of each member
of a series of functionalized aziridines, as required in a
medicinal chemistry program, would obviously be cumber-
some.
Vedejs and Kendall’s recent report on the functionalization
of simple aziridine-BH3 complexes by sequential deproto-
Figure 1. Sugar-derived bicyclic aziridines.
(2) Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990,
55, 4683-4687.
(3) The thermal decomposition of olefinic azides is still not well
understood and may yield mixtures of products; see for instance: (a)
Logothetis, A. L. J. Am. Chem. Soc. 1965, 87, 749-753. (b) Bernet, B.;
Bulusu Murty, A. R. C.; Vasella, A. HelV. Chim. Acta 1990, 73, 940-958.
(c) Kru¨lle, T. M.; dela Fuente, C.; Pickering, L.; Aplin, R. T.; Tsitsanou,
K. E.; Zographos, S. E.; Oikonomakos, N. K.; Nash, R. J.; Griffiths, R. C.;
Fleet, G. W. J. Tetrahedron: Asymmetry 1997, 8, 3807-3820.
(4) Vedejs, E.; Kendall, J. T. J. Am. Chem. Soc. 1997, 119, 6941-6942.
(5) Bouix, C.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 1998, 39, 825-
828.
(6) (a) Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. HelV.
Chem. Acta 1991, 74, 2073-2077. (b) Alper, P. B.; Hung, S.-C.; Wong,
C.-H. Tetrahedron Lett. 1996, 34, 6029-6032. The thermal lability of azide
4 (previously prepared once by another route) has been noted: Pearson,
W. H.; Hines, V. A. Tetrahedron Lett. 1991, 32, 5513-5516.
Although simple 1-azabicyclo[3.1.0] octanes are known,3a
few nonsubstituted sugar-derived aziridines (2, R ) H) have
been found1 and, to the best of our knowledge, only two
examples of substituted analogues (2, R * H) have been
† E-mail: p.bisseret@univ-mulhouse.fr.
(1) (a) Martin, O. R.; Saavedra, O. M. Tetrahedron Lett. 1995, 36, 4027-
4030. (b) Martin, O. R.; Saavedra, O. M. Tetrahedron Lett. 1995, 36, 799-
802. (c) Paulsen, H.; Matzke, M.; Orthen, B.; Nuck, R.; Reutter, W. Liebigs
Ann. Chem. 1990, 953-963. (d) Tong, M. K.; Ganem, B. J. Am. Chem.
Soc. 1988, 110, 312-313.
10.1021/ol990841e CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/16/1999

nation and quenching with electrophiles4 suggested an
alternative strategy (Scheme 1). In this approach, a common
Table 1. Functionalization of Aziridine-BH3 Complex 6
solvent
electrophile
7:8
yield (%)
Scheme 1a
THF
D2O
D2O
Bu3SnCl
P(O)(OEt)2Cl
P(OEt)2Cl
1:0
1:1
5:1
1:0
1:0
10
80
50
15
20
cumene
cumene
cumene
cumene
Functionalization of 6 was then examined (see Table 1).
Whereas deprotonation/quenching with D2O was sluggish
in THF, switching to cumene and using (-)-sparteine as a
lithium chelating agent afforded a high yield of deuterated
aziridine-BH3 complexes 7a and 8a in a 1:1 ratio. The poor
regioselectivity was surprising in light of earlier results4 but
was expected to improve for bulkier electrophiles. Accord-
ingly, trapping of lithiated 6 with Bu3SnCl gave a 50% yield
of the 1S and 2R stannylated aziridine-BH3 complexes 7b
and 8b in a 5:1 ratio. This expected stereoselectivity is the
result of a lithiation step syn to the N-B bond followed by
electrophilic attack with retention of configuration, in line
with Vedejs’s results.
a Legend: (i) TfN3, DMAP, CH3CN, 20 °C, 30 min; (ii) 3 h, 40
°C; (iii) BH3-THF, 0 °C, 30 min; (iv), sBuLi (4 equiv), (-)-sparteine
(4 equiv), cumene, -78 °C, 4 h, then electrophile, 30 min, -78 to
20 °C (electrophile: (a) D2O, E ) D; (b) Bu3SnCl, E ) SnBu3; (c)
P(O)(OEt)2Cl or P(OEt)2Cl, E ) P(O)(OEt)2); (v) H2 (P ) 5 bar),
Pd(OH)2/C 10%, AcOEt; (vi) H2 (P ) 50 bar), Pd (OH)2/C 10%,
iPrOH.
Phosphorylation was examined next: using P(O)(OEt)2Cl
or P(OEt)2Cl, the same noncomplexed 1S phosphonate 7c
was obtained in modest yield.8 In the experiment using
P(OEt)2Cl, a spontaneous oxidation obviously takes place
during the workup and/or purification steps.
Thus, the above studies show that functionalization of
sugar-derived aziridine-borane complexes can be effected
by deprotonation followed by quenching with electrophiles.
The reaction appears to be both regio- and stereoselective,
and although the (nonoptimized) yields are modest in some
cases, the approach is competitive in terms of versatility and
should allow a ready access to various classes of substituted
sugar-derived aziridines.
nonsubstituted aziridine is converted to the desired analogues
in one step. We report here the facile preparation of the new
aziridine 5 and its functionalization via the corresponding
borane complex.
Thus, the known primary amine 35 was treated with freshly
prepared triflic azide in the presence of DMAP, to afford
the unstable azide 4,6 which was directly converted to a single
bicyclic aziridine (5) in 55% yield (two steps) upon warming
to 40 °C. The 2R configuration in 5 was established by nOe
measurements and by chemical correlation: hydrogenolysis
of the aziridine ring in 5 and removal of the benzyl groups
afforded pyrrolidine 10, whose NMR data were identical with
those previously described.7 Treatment of 5 with borane in
THF gave complex 6 in 90% yield.
Acknowledgment. We thank Dr. Didier Le Nouen for
help with NMR recording and spectra interpretation and the
“Fondation de l′Ecole Nationale Supe´rieure de Chimie de
Mulhouse” for a fellowship to C.B.-P.
Supporting Information Available: Experimental pro-
cedures for compounds 4-7 and 9-10 and corresponding
1H NMR spectra and HRMS data for 7b and 7c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) Wang, Y.-F.; Dumas, D. P.; Wong, C.-H. Tetrahedron Lett. 1993,
34, 403-406.
(8) Whereas 7a,b were isolated as aziridine-BH3 complexes, 7c was
directly obtained as a free, noncomplexed aziridine. We attribute the
difference between the stability of complexes 7a,b and that of 7c to reduced
electron density on the nitrogen atom in the latter case.
OL990841E
1182
Org. Lett., Vol. 1, No. 8, 1999