16
J . Org. Chem. 1999, 64, 16-22
Articles
A Biom im etic Ap p r oa ch to th e Discor h a bd in Alk a loid s: Tota l
Syn th eses of Discor h a bd in s C a n d E a n d Deth ia d iscor h a bd in D
Kelly Marshall Aubart and Clayton H. Heathcock*
Department of Chemistry, University of California, Berkeley, California 94720
Received J uly 31, 1998
The characteristic spirodienone structure of the discorhabdin alkaloids is readily formed by reaction
of the tyramine-substituted indoloquinonimines 26, 35, and 36 with cupric chloride, triethylamine,
and oxygen. This cyclization provides a possibly biomimetic route to discorhabdins C and E (41
and 42). The unbrominated spirodienone 40 reacts with hydrogen over Pd/C to give enone 46.
Bromination at the R position gives a mixture of bromoenones that undergo smooth conversion to
dethiadiscorhabdin D (4) upon treatment with basic alumina.
The pyrroloquinoline alkaloids known as the discorhab-
dins1 are found in the sponges of the genus Latrunculia
du Bocage along the New Zealand coast. These quinon-
imine alkaloids are responsible for the pigmentation
possessed by the sponges, and many of the compounds
in this class, along with the structurally related pri-
anosins,2 makaluvamines,3 and epinardins,4 demonstrate
antitumor activity. Because of their cytotoxicity and
unusual ring structures, the discorhabdins have attracted
the synthetic interest of several groups,5 two of which
have completed total syntheses of discorhabdin C (1).6
In this article, we report a biomimetic approach to the
spirodienone core of the discorhabdin alkaloids, resulting
in syntheses of discorhabdins C and E (1 and 2), and
studies directed toward the synthesis of discorhabdin D
(3), resulting in preparation of the dethia analogue 4.
sp. B produced discorhabdin B with elevated 14C incor-
poration.7 But how are these two biogenic amines con-
verted into discorhabdin C and E and eventually into the
bizarre structure of discorhabdin D? We believe that the
early stages of this transformation might proceed along
the lines indicated in Scheme 1. Beginning with an
appropriately oxidized and functionalized tryptamine (6),
coupling of tyramine (5) could occur by a Michael addition
followed by autoxidation to the quinonimine (8). The
regiochemistry of the 1,4-addition leading to 7 might be
the result of enzymic intervention, or it might result from
addition to protonated quinonimine 6. Autoxidation of
p-aminophenols to quinonimines is known to be quite
facile.8 Often, only catalytic base and air are needed for
such oxidations, but metal ions and other quinones can
Inspection of the discorhabdin structures suggests a
biosynthesis from tyrosine and tryptamine, derived from
the amino acids phenylalanine and tryptophan, respec-
tively. Indeed, Munro et al. showed that incubation of
[U-14C]-L-phenylalanine in tissue slices of Latrunculia
(1) (a) Perry, N. B.; Blunt, J . W.; McCombs, J . D.; Munro, M. H. G.
J . Org. Chem. 1986, 51, 5476. (b) Perry, N. B.; Blunt, J . W.; Munro,
M. H. G. Tetrahedron 1988, 44, 1727. (c) Perry, N. B.; Blunt, J . W.;
Munro, M. H. G.; Higa, T.; Sakai, R. J . Org. Chem. 1988, 53, 4127. (d)
Blunt, J . W.; Munro, M. H. G.; Battershill, C. N.; Copp, B. R.;
McCombs, J . D.; Perry, N. B.; Princep, M.; Thompson, A. M. New J .
Chem. 1990, 14, 761. (e) Copp, B. R.; Fulton, K. F.; Perry, N. B.; Blunt,
J . W.; Munro, M. H. G. J . Org. Chem. 1994, 59, 8233. (f) Yang, A.;
Baker, B. J .; Grimwade, J .; Leonard, A.; McClintock, J . B. J . Nat. Prod.
1995, 58, 1596. (g) Six other discorhabdins were presented at the New
Zealand Institute of Chemistry Conference, Auckland, New Zealand,
December 7-10, 1993.
(2) (a) Kobayashi, J .; Cheng, J .; Ishibashi, M.; Nakamura, H.;
Ohizumi, Y.; Hirata, Y.; Sasaki, T.; Lu, H.; Clardy, J . Tetrahedron Lett.
1987, 28, 4939. (b) Chemg, J .; Ohizumi, Y.; Walchli, M. R.; Nakamura,
H.; Hirata, Y.; Sasaki, T.; Kobayashi, J . J . Org. Chem. 1988, 53, 4621.
(3) (a) Radisky, D. C.; Radisky, E. S.; Barrows, L. R.; Copp, B. R.;
Kramer, R. A.; Ireland, C. M. J . Am. Chem. Soc. 1993, 115, 1632. (b)
Carney, J . R.; Scheuer, P. J . Tetrahedron 1993, 49, 8483. (c) White, J .
D.; Yager, K. M.; Yakura, T. J . Am. Chem. Soc. 1994, 116, 1831.
(4) D’Ambrosio, M.; Guerriero, A.; Chiasera, G.; Pietra, F. Tetrahe-
dron 1996, 52, 8899.
(5) (a) Sadanandan, E. V.; Pillai, S. K.; Lakshmikantham, M. V.;
Billimoria, A. D.; Culpepper, J . S.; Cava, M. P. J . Org. Chem. 1995,
60, 1800. (b) Roberts, D.; J oule, J . A.; Bros, M. A.; Alvarez, M. J . Org.
Chem. 1997, 62, 568. (c) White, J . D.; Yager, K. M.; Yakura, T. J . Am.
Chem. Soc. 1994, 116, 1831. (d) Knolker, H. J .; Hartmann, K. Synlett
1991, 428. (e) Kubiak, G. G.; Confalone, P. N. Tetrahedron Lett. 1990,
31, 3845. (f) Roberts, D.; Alvarez, M.; J oule, J . A. Tetrahedron Lett.
1996, 37, 1509.
(6) (a) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T.
J . Am. Chem. Soc. 1992, 114, 2175. (b) Tao, X. L.; Cheng, J .;
Nishiyama, S.; Yamamura, S. Tetrahedron 1994, 50, 2017. (c) Nish-
iyama, S.; Cheng, J . F.; Tao, X. L.; Yamamura, S. Tetrahedron Lett.
1991, 32, 4151.
(7) Lill, R. E.; Major, D. A.; Blunt, J . W.; Munro, M. H. G.;
Battershill, C. N.; McLean, M. G.; Baxter, R. L. J . Nat. Prod. 1995,
58, 306.
(8) (a) J ames, T. H.; Weissberger, A. J . Am. Chem. Soc. 1938, 60,
98. (b) J ames, T. H.; Snell, J . M.; Weissberger, A. J . Am. Chem. Soc.
1938, 60, 2084. (c) Schneider, F. Ber. 1899, 32, 689.
10.1021/jo9815397 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/11/1998