Total Synthesis of the Reputed Structure of Alcyonin and Reassignment of Its Structure † Olivier Corminboeuf, Larry E. Overman,* and Lewis D. Pennington ‡ Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine, California 92697-2025 leoVerma@uci.edu Received March 5, 2003 ABSTRACT Introduction of the C4 hydroxyl group by an epoxy ester rearrangement is a pivotal step in the first total synthesis of the purported structure of alcyonin. As the spectral data for diol acetate 3 do not match those reported for alcyonin, the structure of this marine diterpene must be revised. Reexamination of NMR spectra, MS data, and chemical transformations of natural alcyonin suggests that the structure of this marine metabolite is allylic peroxide 15. A variety of structurally novel diterpene cyclic ethers, some with interesting biological activities, have been isolated from marine invertebrates. 1,2 A recent report from our laboratories described a versatile strategy for enantioselective total synthesis of members of the cladiellin subgroup of these diterpenes exemplified by 6-acetoxycladiell-7(16),11-dien- 3-ol (1) and sclerophytin A (2). 3 In our approach, the condensation of a carvone-derived dienyl diol with an R,- unsaturated aldehyde assembles the hexahydroisobenzofuran core and five of the six invariant stereocenters of these marine metabolites. 3,4 Three cladiellin diterpenes and most briarellin and asbestinin diterpenes (e.g., 4 and 5) 2,5 contain oxygen substitution at C4 of the bridging oxacyclononane ring (Figure 1). Alcyonin, which was isolated by Kakisawa and co-workers in 1988 from the Okinawan soft coral Sinularia flexibilis and assigned structure 3, 6 was chosen as a good target to first explore stereoselective introduction of this additional oxidation. We report herein the initial total synthesis of 3, which necessitates reassignment of the structure of alcyonin. The starting point for the total synthesis of 3, the putative structure of alcyonin, was the known epoxide 6. 7 Using our third-generation strategy, this intermediate is available in 9 steps and 14% overall yield from (S)-dihydrocarvone (Scheme 1). 3,7 Conventional acetylation of 6 provided the correspond- † This paper is dedicated to the memory of John Faulkner, a pioneer in marine natural products chemistry. ‡ Current address: Array BioPharma, 2620 Trade Center Avenue, Longmont, CO 80501. (1) Faulkner, D. J. Nat. Prod. Rep. 2002, 19,1-48. (2) For recent reviews of cladiellin, briarellin, and asbestinin diterpenes, see: (a) Sung, P.-J.; Chen, M.-C. Heterocycles 2002, 57, 1705-1715. (b) Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49, 531-556. (3) MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033-9044. (4) For an alternative approach to the total synthesis of 2, see: 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. (5) (a) Rodrı ´guez, A. D.; Co ´bar, O. M. Tetrahedron 1995, 51, 6869- 6880. (b) Rodrı ´guez, A. D.; Co ´bar, O. M. Chem. Pharm. Bull. 1995, 43, 1853-1858. (c) Stierle, D. B.; Carte ´, B.; Faulkner, D. J.; Tagle, B.; Clardy, J. J. Am. Chem. Soc. 1980, 102, 5088-5092. (d) Selover, S. J.; Crews, P.; Tagle, B.; Clardy, J. J. Org. Chem. 1981, 46, 964-970. (6) Kusumi, T.; Uchida, H.; Ishitsuka, M. O.; Yamamoto, H.; Kakisawa, H. Chem. Lett. 1988, 1077-1078. (7) Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683-2686. ORGANIC LETTERS 2003 Vol. 5, No. 9 1543-1546 10.1021/ol034384k CCC: $25.00 © 2003 American Chemical Society Published on Web 04/04/2003