Enantioselective Total Synthesis of the Proposed Structure of Furan-Containing Polyketide

Abstract

Enantioselective total synthesis of the proposed structure of furan-containing polyketide was accomplished. The key features include a chemo-and enantioselective epoxidation of 1,4-cyclohexadiene by Shi asymmetric epoxidation, a regioselective epoxide ring opening, chemo-and diastereoselective dihydroxylation of the conjugated dienone derivative, and vinylation of the lactone accompanied by formation of the furan ring.Key words enantioselective synthesis; polyketide; Shi asymmetric epoxidation; regioselective epoxide ring opening Fungi produce many kinds of metabolites such as terpenes, alkaloids, and polyketides, which are rich sources for new drug candidates.1-3) Fungal polyketides possess various biological activities and their attractive structures, such as macrolides, polyethers, and aromatic compounds, are classified as polyketides. [4][5][6] In 1997, a novel polyketide 1, possessing inhibitory activity of intercellular adhesion molecule-1 (ICAM-1) expression, was isolated from Phialomyces macrosporus MCI3226. 7) From this report, the structure of polyketide 1 was proposed, having a dihydroisobenzofuranone skeleton involving an aromatic furan ring as depicted in Fig. 1. Recently, a polyketide 2 exhibiting anti-proliferative activity against human non-small cell lung cancer A549 cells was isolated from Aspergillus nidulans, and named asperfuranone. [8][9][10][11] Its structure also was proposed to contain a dihydroisobenzofuranone skeleton involving an aromatic furan ring as in polyketide 1. In the anti-proliferative activity of asperfuranone (2), the Fas/FasL apoptotic system plays an important role. 9)To our knowledge, there have been no synthetic studies of these polyketides consisting of the dihydroisobenzofuranone skeleton and side chain to date. The structural features and biological activities of these two polyketides 1 and 2 attracted our attention, and synthetic studies of these dihydroisobenzofuranone polyketides based on a divergent synthetic methodology using a key intermediate were started. Very recently, we reported the total synthesis of the proposed structure of polyketide 1 in racemic form, and suggested that the proposed structure of natural polyketide from Phialomyces macrosporus required revision.12) This report describes the stereo-and enantioselective synthesis of the proposed structure of polyketide 1 using a key intermediate having a dihydroisobenzofuranone skeleton.The synthetic strategy for this dihydroisobenzofuranone polyketide 1 is outlined in Chart 1. Target polyketide could be synthesized by the installation of the corresponding side chain to the Weinreb amide 3, 13,14) which is the key intermediate, followed by several transformation steps. The Weinreb amide 3 would be derived from the vinyl furan derivative 4, produced by vinylation of bicyclic lactone 5, accompanied by furan ring formation. The functionalized bicyclic lactone 5 would be constructed from the allyl alcohol 6 in three steps involving protection of the secondary hydroxyl group of 6, chemo-and diastereoselectiv...

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