Absbuct: A synthetic approach to the marine alkaloid Zmnthamine is outlined Starting with (-)perillyl alcohol, the C-II to C-2Ofragment % has been synthesized in 12 oprratiotts and >3096 ovemll yiela! M&l sttuiics for a proposed intnmwlmdar DieMider strategy are also &scribed Zoanthamine (1) is the first memberla of a new class of alkaloidslb-c isolated from an unidentified marine zoanthid of the genus Zounthus found on the coast of India. The structure of zoantbamine was elucidatedlhb via a combination of NMR spectroscopic methods and X-ray crystallography, but the absolute configuration remains unknown, as does the biosynthetic origin of this intriguing molecule. Zoanthamine and its congeners (e.g. zoanthamide and 28deoxyzoanthenamine) were isolated in an attempt to determine the structures of inflammatory agents produced by the zoanthid, but the alkaloids were actually found1b.c to inhibit phorbol my&ate acetate induced inflammation of the mouse ear; as far as we are aware, the mode of biological action has not yet been defined in detail. Ztmnthamiie, 1 zlanthamide 28-Deoxyzoanthenamine 9135 9136 D. TANNER et al. These interesting biosynthetic and pharmacological issues combined with stemochemically complex molecular structures make this family of compounds attractive targets for synthesis. Our goal was thus development of a stereocontrolled synthetic route which would: (i) be flexible enough to provide access to several members of the alkaloid class, (ii) allow the preparation of simpler analogues for biological testing, in order to define the pharmacophore, and (iii) permit the assignment of absolute stereochemistry via direct comparison with the natural product itself or materials derived therefrom. In this paper we present our synthetic plan and some results relating to the C-9 to C-22 portion of zoanthamine. The retrosynthetic analysis is shown in Scheme 1. Scheme 1. RetrosyntJxtic analysis of Zoanthamine. (X = protected carbonyl; Y = umpoled carhonyl; L and L' = potential leaving group; M = metal). Simultaneous disconnection of the four carbon-heteroatom bonds indicated above unravels the "lower" portion of the target, to give structure A*. Further retrosynthetic analysis (Scheme 1) defines a convergent route to A, the "upper" portion of zoanthamine being embedded in key intermediates B, C and D. Thus, with the C-17 carbonyl (zoanthamine numbering) of B protected, the vicinal methyls on C-22 and C-9 of the target would be introduced by a conjugate addition-enolate trapping sequence on the less-hindered @) face of the enone. (Inspection of molecular models suggests that nucleophilic attack on the a face is hindered by the axial methyl on C-12). Intermediate B is itself projected to arise from D via intramolecular Diels-Alder reaction of C, the cycloaddition process setting up the stereochemistry at both C-12 and C-21, with one of the controlling factors being the stereochemistry at C-19.