Sintesis enantioselectiva de alcaloides del grupo de las madangaminas

Zusammenfassung

SÍNTESIS ENANTIOSELECTIVA DE ALCALOIDES DEL GRUPO DE LAS MADANGAMINAS We herein report our efforts to find a synthetic route to Madangamine D, a complex polycyclic alkaloid isolated from the marine sponge Xestospongia ingens. The basic synthetic plan calls for the construction of the tricyclic ABC core, followed by the annulations of both the saturated 14-membered D ring and the unsaturated 11-membered E ring. In the context of our studies on the enantioselective synthesis of piperidine-containing complex natural products from phenylglycinol-derived bicyclic lactams, we have already reported the enantioselective preparation of functionalized diazatricyclic synthetic precursors 1, common to all madangamines. Recently, an efficient and direct closure of the saturated macrocycle of Madangamine D has been accomplished, providing the unprecedented tetracyclic ABCD system 2. In parallel, a suitable synthetic procedure for the construction of the challenging unsaturated ring E involving i) a (Z)-stereoselective olefination at C-3 and ii) the N-1/C-13 cyclization has been developed from model systems. The application of this synthetic protocol to a diazatricyclic ketone, which already incorporates the 11-carbon chain at C-9 required for the closure of ring D, has now culminated in the assembly of the advanced ABCE system 3 of Madangamine D. From these results, our confidence in completing the total synthesis has grown steadily, and further elaboration of 2 and 3 to deliver the first synthetic sample of a madangamine alkaloid is currently in progress in our laboratory.