Published on Web 01/05/2006
An Intramolecular Diels-Alder Approach to the Eunicellins:
Enantioselective Total Syntheses of Ophirin B and
Astrogorgin
Michael T. Crimmins,*,† Brandon H. Brown,‡,1 and Hilary R. Plake†
Contribution from the Department of Chemistry, Venable and Kenan Laboratories of Chemistry,
UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, and
Gilead Sciences, Inc., Foster City, California, 94404
Received September 14, 2005; E-mail: crimmins@email.unc.edu.
Abstract: The enantioselective syntheses of the eunicellins ophirin B and astrogorgin have been completed.
Ring-closing metatheses provide efficient access to the oxonene rings, and highly diastereoselective
intramolecular Diels-Alder reactions resulted in the formation of the hydrobenzofuran portion of the
molecules.
Introduction
chemical synthesis of members of these subclasses has piqued
in recent years due to their novel structures and diverse
The eunicellins, briarellins, asbestinins, and sarcodyctins are
related subclasses of the C2,C11-cyclized cembranoid diterpenes
isolated as secondary metabolites of gorgonian octocoral found
in the Caribbean and West Pacific Ocean.2-4 The presence of
all four structural types of natural products in the same organism
provides circumstantial evidence for the biosynthetic pathway
proposed by Faulkner in which a cembrane skeleton is the
precursor to all these metabolites. An unusual oxatricyclic ring
system containing a hydroisobenzofuran and an oxacyclononane
unit with stereogenic centers at C1-3, 9, 10, and 14 are common
to the eunicellins, briarellins, and asbestinins. However, the
location of the cyclohexyl methyl groups (C11 vs C12) and the
oxidation level of the six- and nine-membered rings differ
among the three classes. It has been postulated that upon
oxidation at C16, the eunicellins (cladiellins) are converted to
the briarellins (Scheme 1). Further, a suprafacial 1,2-methyl shift
from C11 to C12 could transform the briarellins to the
asbestinins.
Since the original report of the isolation of eunicellin from
Eunicella stricta appeared in 1968,5 extensive investigation of
gorgonian soft coral has resulted in the isolation of over 50
novel secondary metabolites in the class. Preliminary investiga-
tions into the biological activity have shown that a variety of
the eunicellin, briarellin, and asbestinin metabolites exhibit insect
growth inhibition activity and in vitro cytotoxity against several
cancer cell lines. On the basis of mollusk and fish lethality
assays, the natural role of C2-C11-cyclized cembranoids has
been suggested to be predatory deterrence. Interest in the
biological activities.6-9
The first total synthesis of a eunicellin diterpene was the
synthesis of (-)-7-deacetoxyalcyonin acetate reported by Over-
man in 1995 (Figure 1).10,11 The subsequent synthesis and
structural reassignment of sclerophytin A by both the Paquette12,13
and Overman11,14,15 laboratories was followed by Molander’s16
disclosure of the second synthesis of (-)-7-deacetoxyalcyonin
acetate. Briarellins E and F are the only members of the
briarellin class that have been prepared by chemical synthe-
sis.17,18 Each of the early synthetic approaches to the eunicellins
and briarellins employed a strategy where the hydroisobenzo-
furan unit was incorporated prior to oxonene ring formation.19
While these strategies were clearly effective, an alternate
approach was envisioned wherein the medium ring ether moiety
might be used as a stereochemical control element for stereo-
selective intramolecular Diels-Alder reaction to construct the
(6) Yamada, K.; Ogata, N.; Ryu, K.; Miyamoto, T.; Komori, T.; Higuchi, R.
J. Nat. Prod. 1997, 60, 393-396.
(7) Kusumi, T.; Uchida, H.; Ishitsuka, M. O.; Yamamoto, H.; Kakisawa, H.
Chem. Lett. 1988, 1077-1078.
(8) Ochi, M.; Yamada, K.; Futatsugi, K.; Kotsuki, H.; Shibata, K. Heterocycles
1991, 32, 29-32.
(9) Ochi, M.; Yamada, K.; Shirase, K.; Kotsuki, H.; Shibata, K. Heterocycles
1991, 32, 19-21.
(10) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117, 10391-
10392.
(11) MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem.
Soc. 2001, 123, 9033-9044.
(12) Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T. Org. Lett. 2000,
2, 1875-1878.
(13) Bernardelli, P.; Moradei, O. M.; Friedrich, D.; Yang, J.; Gallou, F.; Dyck,
B. P.; Doskotch, R. W.; Lange, T.; Paquette, L. A. J. Am. Chem. Soc.
2001, 123, 9021-9032.
(14) Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683-2686.
(15) Gallou, F.; MacMillan, D. W. C.; Overman, L. E.; Paquette, L. A.;
Pennington, L. D.; Yang, J. Org. Lett. 2001, 3, 135-137.
(16) Molander, G. A.; St. Jean, D. J., Jr.; Haas, J. J. Am. Chem. Soc. 2004, 126,
1642-1643.
† University of North Carolina at Chapel Hill.
‡ Gilead Sciences, Inc.
(1) Abstracted from the Ph.D. Thesis of B. H. Brown, University of North
Carolina at Chapel Hill, 2004.
(2) Sung, P.-J.; Chen, M.-C. Heterocycles 2002, 57, 1705-1715.
(3) Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49, 531-556.
(4) Rodriguez, A. D. Tetrahedron 1995, 51, 4571-4618.
(5) Kennard, O.; Watson, D. G.; Riva di Sanseverino, L.; Tursch, B.; Bosmans,
R.; Djerassi, C. Tetrahedron Lett. 1968, 9, 2879-2884.
(17) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. Org. Lett. 2003, 5,
1543-1546.
(18) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc.
2003, 125, 6650-6652.
(19) Chai, Y.; Vicic, D. A.; McIntosh, M. C. Org. Lett. 2003, 5, 1039-1042.
9
10.1021/ja056334b CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 1371-1378
1371