Total Synthesis of Natural PI-091, a New Platelet Aggregation Inhibitor of Microbial Origin

The total synthesis of a new platelet aggregation-inhibiting γ-lactam PI-091 (1) gave a 1:1 diastereomeric mixture at the γ-ketal carbon. The high-yielding aldol reaction of an appropriately protected 1,3,4-trihydroxy-4-methyldecan-2-one 42, prepared from d-glucose, with the kinetically generated enolate of 3-methyl-2-butanone provided 43. The resulting diastereomeric mixture of the aldol adduct 43 was converted to a 2,4-alkylated furan 45 via an intramolecular ketalization followed by dehydration. The addition of a singlet oxygen to the α-trimethylsilylated furan 48 derived from 45 under photochemical conditions efficiently provided an α,γ-dialkylated γ-hydroxy γ-lactone 47. The transformation of methyl ketal 52 prepared from 47 into γ-hydroxy γ-lactam 53 was achieved by exposure to liquid ammonia in MeOH. The total synthesis of 1 was achieved from 52 through the Dess−Martin periodinane oxidation of the secondary hydroxy group in the side chain. The present total synthesis revealed that the stereogenic carbon center in the side chain in natural 1 is S.