Synthetic Studies on Highly Functionalized γ-Lactam Natural Products, PI-091 and Epolactaene
Ryota SHIRAKI and Kin-ichi TADANO*
Department of Applied Chemistry, Keio University; 3-14-1 Hiyoshi, Kohoku-ku, Yokohama-shi 223-8522 Japan
From the aspect of their unique structures and important biological activities, highly functionalized γ-lactam natural products have attracted much attention to synthetic chemist in recent years. On the other hand, the usefulness of carbohydrate-derived enantiomerically pure building blocks to enantioselective synthesis of complex natural products has been well recognized. In this paper, we describe the synthesis of two highly functionalized γ-lactam natural products, PI-091 and epolactaene, in enantiomerically pure form. PI-091 was isolated from Paecilomyces sp. F-3430 by the group of Taisho Pharmaceutical Co. in 1990, and exhibits a platelet aggregation inhibitory activity against rabbit platelet in vitro. We started our total synthesis of PI-091 from D-glucose. In the early stage of this synthesis, all carbons in PI-091 were assembled by featuring an aldol carbon-elongation. Then an intramolecular ketalization and successive dehydration gave a 2,4-alkylated furan, which was transformed to a γ-lactam skeleton by the photochemical singlet oxygen addition to the furan derivative, followed by a γ-lactone --γ-lactam transformation. The absolute structure of PI-091 was determined through the present synthesis. Epolactaene was isolated by Osada et al. from the culture broth of Penicillium sp. BM1689-P in 1995. It shows the neurite outgrowth activity of a human neuroblastoma cell line, SH-SY5Y cells. Owing to the similarity of their structures between PI-091 and epolactaene, we planned to synthesize epolactaene using the similar synthetic pathway employed to the total synthesis of PI-091. The synthetic achievements on these novel antibiotics are described herein.
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