ORGANIC
LETTERS
2010
Vol. 12, No. 4
672-675
Formal Synthesis of Belactosin A and
Hormaomycin via a Diastereoselective
Intramolecular Cyclopropanation of an
r-Nitro Diazoester
Se´bastien F. Vanier, Guillaume Larouche, Ryan P. Wurz, and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
Received November 17, 2009
ABSTRACT
An efficient and convenient methodology for the synthesis of the 3-(trans-2-aminocyclopropyl) alanine and 3-(trans-2-nitrocyclopropyl) alanine
moieties found in the core of belactosin A and hormaomycin, respectively, is reported. By using an enantioenriched substituted r-nitro
diazoester in a diastereoselective intramolecular cyclopropanation reaction, the trans-nitrocyclopropyl alanine moiety can be obtained efficiently
in five steps from the initial r-nitrocyclopropyl lactone unit, thus achieving the synthesis of the cyclopropane core of the two natural products.
Nature displays a wide range of chemical diversity through
a variety of architecturally complex molecules. Among these
designs, the unique structure of the cyclopropane subunit is
common to many compounds of biological and pharmaco-
logical relevance. As such, there have been significant efforts
toward the synthesis of functionalized cyclopropanes as well
as their applications in synthesis.1,2
are both structurally related, as they contain 3-(trans-2-
aminocyclopropyl) alanine [(AcP)Ala, 3]5 and 3-(trans-2-
nitrocyclopropyl) alanine [(NcP)Ala, 4]5a,6 as part of their
central core (Figure 1). Furthermore, current investigations
of the biological activities of belactosin A (1) and hormao-
mycin (2) derivatives illustrate the importance of more
efficient enantioselective methods to synthesize these cyclo-
propyl subunits.6
Belactosin A (1, Figure 1) is a naturally occurring molecule
demonstrating moderate antitumor activity against cell-cycle
progression at the G2/M phase.3 Additionally, hormaomycin
(2), produced by the strain W384 Streptomyces griseoflaVus,
has a direct impact on the secondary metabolite proliferation
of certain micro-organisms.4 These two unusual compounds
(4) (a) Andres, N.; Wolf, H.; Za¨hner, H.; Ro¨ssner, E.; Zeeck, A.; Ko¨nig,
W. A.; Sinnwell, V. HelV. Chim. Acta 1989, 72, 426–437. (b) Ro¨ssner, E.;
Zeeck, A.; Ko¨nig, W. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 64–65.
(5) For the synthesis of 1 and 3, see: (a) de Meijere, A.; Larionov, O. V.
In Asymmetric Synthesis - The Essentials; Christmann, M., Braese, S., Eds.;
Wiley-VCH: Weinheim, 2007; pp 67-71 and references therein. (b)
Armstrong, A.; Scutt, J. N. Chem. Commun. 2004, 510–511. (c) Larionov,
O. V.; Kozhushkov, S. I.; Brandl, M.; de Meijere, A. MendeleeV Commun.
2003, 199–200. (d) Jain, R. P.; Vederas, J. C. Org. Lett. 2003, 5, 4669–
4672. (e) Be´gis, G.; Sheppard, T. D.; Cladingboel, D. E.; Motherwell, W. B.;
Tocher, D. A. Synthesis 2005, 3186–3188. (f) Yoshida, K.; Yamaguchi,
K.; Sone, T.; Unno, Y.; Asai, A.; Yokosawa, H.; Matsuda, A.; Arisawa,
M.; Shuto, S. Org. Lett. 2008, 10, 3571–3574.
(1) (a) Salau¨n, J.; Baird, M. S. Curr. Med. Chem. 1995, 2, 511–542. (b)
Crews, C. M.; Mohan, R. Curr. Opin. Chem. Biol. 2000, 4, 47–53. (c)
Salau¨n, J. Top. Curr. Chem. 2000, 207, 1–67
.
(2) For recent reviews on 1-aminocyclopropanecarboxylic acids, see:
(a) Brackmann, F.; de Meijere, A. Chem. ReV. 2007, 107, 4493–4537. (b)
Brackmann, F.; de Meijere, A. Chem. ReV. 2007, 107, 4538–4583
.
(6) (a) Yoshida, K.; Yamaguchi, K.; Mizuno, A.; Unno, Y.; Asai, A.;
Sone, T.; Yokosawa, H.; Matsuda, A.; Arisawa, M.; Shuto, S. Org. Biomol.
Chem. 2009, 7, 1868–1877. (b) Hasegawa, M.; Kinoshita, K.; Nishimura,
C.; Matsumura, U.; Shionyu, M.; Ikeda, S.; Mizukami, T. Bio. Med. Chem.
(3) (a) Asai, A.; Hasegawa, A.; Ochiai, K.; Yamashita, Y.; Mizukami,
T. J. Antibiot. 2000, 53, 81–83. (b) Asai, A.; Tsujita, T.; Sharma, S. V.;
Yamashita, Y.; Akinaga, S.; Funakoshi, M.; Kobayashi, H.; Mizukami, T.
Biochem. Pharmacol. 2004, 67, 227–234.
Lett. 2008, 18, 5668–5671
.
10.1021/ol9026528 2010 American Chemical Society
Published on Web 01/07/2010