ORGANIC
LETTERS
2006
Vol. 8, No. 10
1975-1978
Total Synthesis of Stephanotic Acid
Methyl Ester
David J. Bentley,† Alexandra M. Z. Slawin,‡ and Christopher J. Moody*,†,§
Department of Chemistry, UniVersity of Exeter, Stocker Road, Exeter, EX4 4QD, U.K.,
School of Chemistry, UniVersity of St. Andrews, Fife, Scotland, KY16 9ST, U.K., and
School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham,
NG7 2RD, U.K.
Received January 19, 2006
ABSTRACT
The methyl ester of the naturally occurring macrocyclic pentapeptide stephanotic acid, containing an unusual â-substituted r-amino acid with
a tryptophan C-6 to leucine
â
-carbon link, has been synthesized. The key steps include the formation of this amino acid through a thioxo-
oxazolidine intermediate and a Horner
−
Wadsworth Emmons reaction using a phosphonoglycine, derived by a dirhodium(II)-catalyzed N
−
−H
insertion reaction, to give a dehydroamino acid and subsequent rhodium(I)-catalyzed asymmetric hydrogenation to introduce the modified
tryptophan residue.
Natural products of the moroidin family, many of which are
potent inhibitors of tubulin polymerization, are characterized
by the presence of a highly modified tryptophan within a
macrocyclic peptide array. Thus, moroidin 1 itself (Figure
1), originally isolated from the leaves of the Australian rain
forest bush Laportea moroides, and the structure determined
by a combination of molecular modeling and detailed NMR
experiments by the Williams group in Cambridge, contains
the highly unusual direct linkages of the tryptophan C-2 and
C-6 to the imidazole N-1 of histidine and the â-carbon of a
leucine residue, respectively.1 More recently, moroidin has
been reisolated from the seeds of Celosia argentia, along
with the closely related celogentins, for example, celogentin
A 2, which share a similar structural motif based on the same
tryptophan core.2 The simplest member of this family of
cyclic peptides, stephanotic acid 3, isolated from Stephanotis
floribunda, lacks the right-hand histidine-containing ring of
moroidin and has a leucine-isoleucine substitution.3
Despite their fascinating structures, these cyclic peptides
have attracted little attention from synthetic chemists,
although over a decade ago we developed a route to simple
N-(2-indolyl)imidazoles4 and subsequently used this meth-
odology to prepare the right-hand cycle of moroidin.5 Castle
(2) Morita, H.; Shimbo, K.; Shigemori, H.; Kobayashi, J. Bioorg. Med.
Chem. Lett. 2000, 10, 469-471. Kobayashi, J.; Suzuki, H.; Shimbo, K.;
Takeya, K.; Morita, H. J. Org. Chem. 2001, 66, 6626-6633. Suzuki, H.;
Morita, H.; Iwasaki, S.; Kobayashi, J. Tetrahedron 2003, 59, 5307-5315.
Suzuki, H.; Morita, H.; Shiro, M.; Kobayashi, J. Tetrahedron 2004, 60,
2489-2495. Morita, H.; Suzuki, H.; Kobayashi, J. J. Nat. Prod. 2004, 67,
1628-1630.
(3) Yoshikawa, K.; Tao, S.; Arihara, A. J. Nat. Prod. 2000, 63, 540-
542.
(4) Comber, M. F.; Moody, C. J. Synthesis 1992, 731-733.
(5) Harrison, J. R.; Moody, C. J. Tetrahedron Lett. 2003, 44, 5189-
5191.
† University of Exeter.
‡ University of St. Andrews.
§ University of Nottingham.
(1) Leung, T.-W. C.; Williams, D. H.; Barna, J. C. J.; Foti, S.; Oelrichs,
P. B. Tetrahedron 1986, 42, 3333-3348. Kahn, S. D.; Booth, P. M.; Waltho,
J. P.; Williams, D. H. J. Org. Chem. 1989, 54, 1901-1904. Kahn, S. D.;
Booth, P. M.; Waltho, J. P.; Williams, D. H. J. Org. Chem. 2000, 65, 8406-
8406.
10.1021/ol060153c CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/21/2006