Enantioselective Total Synthesis of Marine Alkaloids Stellettamides

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Stellettamid A was first isolated by Fustian in 1990 from a marine sponge of the genus Stelletta collected in Shikinejima of Japan as the first representive of an indolizidine class of marine alkaloids. Subsequently, Shin reported the isolation of the closely related alkaloid stellettamide B from a Korean specimen of Stelletta. Very recently, another alkaloid, stellettamide C was isolated from the Japanese sponge. Stellettamides A-C comprise a common indolizidine skeleton, containing a quaternary nitrogen atom and a variation of the unsaturated side chain, which are connected via an amide linkage. The present investigations were aimed at the first asymmetric total synthesis of stellettamides A, B, and C in an enatiomerically pure form utilizing asymmetric allylation of the chiral N-acyl-N, O-acetalThe tricyclic N-acyl-N, O-acetal incorporating ( R )-2-(1-aminoethyl)phenol as a chiral auxiliary underwent TiCl_4-mediated allylation to give the chiral allylpiperidinone with retention of configuration in high yield and diastereoselectivity. The first total synthesis of (+)-stellettamide A has been achieved by a sequence based on amide coupling of the chiral 1-(aminomethyl)indolizidine fragment, prepared from the (6R)-allylpiperidinone, with the chiral trienoic acid fragment. By employing the same methodology, the syntheses of (-)-stellettamide B and (1S,4S,8aR)-stellettamide C have been achieved. The synthesis of stelletamide B led to revision of the published relative stereochemistry of the natural product and established its absolute stereochemistry to be 1S,4S,8aR,6"R