ORGANIC
LETTERS
2004
Vol. 6, No. 21
3781-3784
Stereocontrolled Synthesis of Onchidins
Yungui Peng,† Heung Wing Pang,† and Tao Ye*,†,‡
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong,
and Open Laboratory of Chirotechnology of the Institute of Molecular Technology
for Drug DiscoVery & Synthesis and Department of Applied Biology &
Chemical Technology, The Hong Kong Polytechnic UniVersity, Hung Hom,
Kowloon, Hong Kong, China
Received August 6, 2004
ABSTRACT
The first total synthesis of a molecule possessing the stereochemistry proposed for onchidin is described. The structure synthesized appears
to be different from that of the marine natural product.
Marine cyanobacteria have produced a wide variety of natural
products, many of which have shown striking biological
activity.1-3 Consequently, they are key synthetic targets in
the quest for new leads in the pharmaceutical industry.4 To
date, the compounds extracted have shown anticancer,
antifungal, antiviral, and cytotoxic activity, and the diversity
of structure exhibited by these secondary metabolites also
makes them appealing to synthetic chemists. We have been
interested for some time in the metabolites of these bacteria,
and view their syntheses as a key route to structural
modification and subsequent activity control. In an earlier
paper, we were able to amend the stereochemistry of
yanucamide A,5 and here we report on our studies toward
the synthesis of onchidin.
to be of cyanobacterial biosynthesis, due to structural
similarities between it and other metabolites of this species,
and because it is a known constituent of the mollusc’s diet.8
Its structure was determined by a combination of chemical
degradation, chiral chromatography and spectroscopic analy-
sis. The relative stereochemistry at positions 7 and 9 on the
novel R-methyl-â-amino octynoic acid portion was assigned
through NOE observations. This was also the case for
assigning the absolute stereochemistry of the alkyne-contain-
ing chain; an enhancement was observed between the
(4) Proksch, P.; Edrada, R. A.; Ebel, R. Appl. Microbiol. Biotechnol.
2002, 59, 125-134. Frenz, J. L.; Kohl, A. C.; Kerr, R. G. Expert Opin.
Ther. Pat. 2004, 14, 17-33.
(5) Xu, Z. S.; Peng, Y. G.; Ye, T. Org. Lett. 2003, 5, 2821-2824.
(6) Rodriguez, J.; Fernandez, R.; Quinoa, E.; Riguera, R.; Debitus, C.;
Bouchet, P. Tetrahedron Lett. 1994, 35, 9239-9242.
Onchidin (1) was isolated and structurally assigned in 1994
by Riguera,6 and it is known to show cytotoxic activity
(P-388 cells, IC50 ) 8 µg/mL).7 Although it was extracted
from the marine mollusc Onchidium sp., it is firmly believed
(7) Fernandez, R.; Rodriguez, J.; Quinoa, E.; Quinoa, E.; Riguera, R.;
Munoz, L.; Fernandez-Suarez, M.; Debitus, C. J. Am. Chem. Soc. 1996,
118, 11635-11643.
(8) Nakao, Y.; Yoshida, W. Y.; Szabo, C. M.; Baker, B. J.; Scheuer, P.
J. J. Org. Chem. 1998, 63, 3272-3280. Reese, M. T.; Gulavita, N. K.;
Nakao, Y.; Hamann, M. T.; Yoshida, W. Y.; Coval, S. J.; Scheuer, P. J. J.
Am. Chem. Soc. 1996, 118, 11081-11084. Kimura, J.; Takada, Y.; Inayoshi,
T.; Nakao, Y.; Goetz, G.; Yoshida, W. Y.; Scheuer, P. J. J. Org. Chem.
2002, 67, 1760-1767. Tan, L. T.; Sitachitta, N.; Gerwick, W. H. J. Nat.
Prod. 2003, 66, 764-771. Williams, P. G.; Yoshida, W. Y.; Quon, M. K.;
Moore, R. E.; Paul, V. J. J. Nat. Prod. 2003, 66, 651-654. Luesch, H.;
Harrigan, G. G.; Goetz, G.; Horgen, F. D. Curr. Med. Chem. 2002, 9, 1791-
1806. Wan, F.; Erickson, K. L. J. Nat. Prod. 2001, 64, 143-146.
† The University of Hong Kong.
‡ The Hong Kong Polytechnic University.
(1) Burja, A. M.; Banaigs, B.; Abou-Mansour, E.; Burgess, J. G.; Wright,
P. C. Tetrahedron 2001, 57, 9347-9377.
(2) Gerwick, W. H.; Tan, L. T.; Sitachitta, N. Alkaloids (Academic Press)
2001, 57, 75-184.
(3) Luesch, H.; Harrigan, G. G.; Goetz, G.; Horgen, F. D. Curr. Med.
Chem. 2002, 9, 1791-1806.
10.1021/ol048437p CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/17/2004