ORGANIC
LETTERS
2
004
Vol. 6, No. 1
39-141
Three-Component Homo 3 + 2 Dipolar
Cycloaddition. A Diversity-Oriented
Synthesis of Tetrahydro-1,2-oxazines
and FR900482 Skeletal Congeners
1
Ian S. Young and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London,
Ontario, Canada N6A 5B7
Received November 24, 2003
ABSTRACT
The reaction of nitrones, formed in situ by reaction of hydroxylamines with aldehydes, with 1,1-cyclopropanediesters results in the formation
of tetrahydro-1,2-oxazines via a homo 3 + 2 dipolar cycloaddition. This three-component coupling allows for the formation of a diverse array
of cycloadducts with excellent diastereoselectivity (>95%) and yields (66−96%). The procedure has been used in the two-step preparation of
congeners of the FR900482 skeleton.
1
5
The antitumor, antibiotic natural products FR900482 and
tions of which are not abundant. A flexible synthesis of this
2
FR66979, structurally related to the anticancer drug mito-
mycin C, have emerged as promising therapeutic candidates.
As with the synthetic derivatives FK317 and FK973, they
heterocycle would aid in the synthesis of these natural targets
and their evaluation as a drug scaffolds.
3
are thought to act as minor groove-binding cross-linkers.
Not surprisingly there has been significant activity toward
4
the synthesis of these molecules in pursuit of preparing
analogues with improved biological profiles. An equally
compelling motivation for their synthesis lies in their unique
and formidable structure, its central feature being the
relatively uncommon tetrahydro-1,2-oxazine ring, prepara-
Recently, we reported the first cycloaddition reaction
between a nitrone 5 and a 1,1-cyclopropane diester 6 to yield
a tetrahydro-1,2-oxazine 7, always as the cis isomer exclu-
(1) Uchida, I.; Shigehiro, T.; Hiroshi, K.; Sumio, K.; Hashimoto, M.;
Tada, T.; Shigetaka, K.; Morimoto, Y. J. Am. Chem. Soc. 1987, 109, 4108-
4
109.
6
sively (Scheme 1). The exact nature of this fundamentally
(2) Terano, H.; Takase, S.; Hosoda, J.; Kohsaka, M. J. Antibiot. 1989,
4
2, 145-148.
unique reaction is under investigation (stepwise annulative
vs concerted cycloaddition); however, the synthetic utility
is clearly evident, with tetrahydro-1,2-oxazines being pre-
pared in excellent yields with virtually complete diastereo-
selectivity.
(
3) Judd, T. C.; Williams, R. M. Org. Lett. 2002, 4, 3711-3714 and
references therein.
4) Racemic total syntheses: (a) Fukuyama, T.; Xu, L.; Goto, S. J. Am.
Chem. Soc. 1992, 114, 383-385. (b) Schkeryantz, J. M.; Danishefsky, S.
J. J. Am. Chem. Soc. 1995, 117, 4722-4723. Enantioselective total
syntheses: (c) Kato, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron
(
1
997, 53, 10253-10270. (d) Judd, T. C.; Williams, R. M. Angew. Chem.,
Int. Ed. 2002, 41, 4683-4685. (e) Suzuki, M.; Kambe, J.; Tokuyama, H.;
Fukuyama, T. Angew. Chem., Int. Ed. 2002, 41, 4686-4688. (f) Paleo, M.
R.; Aurrecoechea, N.; Jung, K.-Y.; Rapoport, H. J. Org. Chem. 2003, 68,
(5) (a) Tsoungas, P. G. Heterocycles 2002, 57, 1149-1178. (b) Gilchrist,
T. L.; Wood, J. E. In ComprehensiVe Heterocyclic Chemistry II; Elsevier:
Oxford, UK, 1996; Vol. 6, pp 279-299, 1177-1307.
(6) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 26, 3023-
3026.
1
30-138. For a synthesis of related racemic FR66979, see: (g) Ducray,
R.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2002, 41, 4688-4691.
1
0.1021/ol0362919 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/13/2003