TETRAHEDRON:
ASYMMETRY
Tetrahedron: Asymmetry 14 (2003) 689–700 Pergamon
Asymmetric synthesis of 2H -aziridine phosphonates, and - or
-aminophosphonates from enantiomerically enriched 2H -azirines
Francisco Palacios,* Domitila Aparicio, Ana Marı ´a Ochoa de Retana, Jesu ´s M. de los Santos,
Jose ´ I. Gil and Rafael Lo ´ pez de Munain
Departamento de Quı ´mica Orga ´nica I, Facultad de Farmacia, Universidad del Paı ´s Vasco, Apartado 450, 01080 Vitoria, Spain
Received 31 October 2002; revised 9 January 2003; accepted 22 January 2003
Abstract—A simple and efficient method for asymmetric synthesis of 2H-azirine-2-phosphonates 6 is described. The key step is
a base-mediated Neber reaction of p -toluenesulfonyloximes 4 derived from phosphonates. Triethylamine 5, alkaloids 7 and
solid-phase bound achiral 8 or chiral amines 9 are used. Reduction of 2H-azirines 6 with sodium borohydride in ethanol gives
cis -aziridine-phosphonates 10. Ring opening of aziridines 10 and 11 leads to the formation of enantiomerically enriched -12 and
14 and -aminophosphonates 13 and 15. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2H -Azirine ring systems represent an important class of
compounds because of their high reactivity.
1
They can
be used as key intermediates in organic synthesis in the
preparation of acyclic functionalized amino
derivatives
2a–c
and heterocycles
2d–h
since all three bonds
of the azirine ring can be cleaved, depending on the
experimental conditions used. In particular, 2H -azirines
containing a carboxylic ester group (I, Fig. 1) are
constituents of naturally occurring antibiotics
1a
and are
excellent reagents for the preparation of functionalized
aziridines
1,3
and -
3b,4a–e
and -amino acid deriva-
tives.
3b,4f–h
Furthermore, fosfomycin IIIa (X=O) (Fig.
1), a three ring heterocycle containing a phosphorus
substituent is a broad spectrum antibiotic,
5a,b
which has
been used in vitro
5c,d
and clinically.
5e
It is also known
that phosphorus substituents regulate important biolog-
ical functions,
6
and that molecular modifications
involving the introduction of organophosphorus func-
tionalities could increase their biological activity in a
similar manner to that reported for other pharmaceuti-
cals.
6
Some procedures for the synthesis of 2H -azirines
have been reported,
1
and enantiomerically enriched 2H -
azirine carboxylates I have been prepared from chiral
N -substituted aziridine 2-carboxylic esters,
7a,b
and by
using the Neber reaction.
7c,d
However, despite the
potential utility of 2H -azirines,
1
these three-membered
heterocycles directly substituted with a phosphorus con-
taining functional group have received little attention.
8
For these reasons, the development of new processes
for the asymmetric synthesis of functionalized azirines
containing a phosphorus substituent at the 2 position
(II, Fig. 1) may represent an important tool in organic
synthesis because these heterocycles are expected to
play a similar role to that of their isosteric analogues I,
and therefore could be used as starting materials for the
preparation of phosphorus substituted aziridines IIIb
and in the enantioselective synthesis of - and -
aminophosphorus derivatives. -Aminophosphonates
9
can be considered as surrogates for -amino acids,
10a
and have been used as haptens for the generation of
catalytic antibodies,
10b,c
as antibacterial agents,
10d,e
and
as nucleosides,
10f
or as phosphapeptide enzyme
inhibitors,
10g–k
whereas -aminophosphonate deriva-
tives, some of them naturally occurring,
9b,11a–c
have
been used for the preparation of hydroxy deriva-
tives,
12a–c
of peptide-based enzyme inhibitors
12d–g
and as
agrochemicals
12h
or pharmaceuticals.
12i–k
Figure 1.
* Corresponding author. Tel.: +34-945-013103; fax: +34-945-013049;
e-mail: qoppagaf@vf.ehu.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00089-2