Abstract
(+)-Mycoepoxydiene (1) was isolated from the fermentation of a rare fungus in 1999 (Figure). This fungal metabolite is the first natural product reported so far which contains a 9-oxabicyclo|4.2.1|nona-2,4-diene skeleton. On the other hand, 1893A (2) and 1893B (3) were isolated recently from the fermentation broth of a marine endophytic fungus, showing cytotoxic and insecticidal activities. The two new metabolic products, 2 and 3, were found to possess the same oxygen-bridged cyclooctadiene core skeleton. Being interested in their unique structures and the biological activities of 2 and 3, we became involved in synthetic studies of mycoepoxydiene (1) as well as 1893A (2) and 1893B (3). Herein, we describe the asymmetric total syntheses of (+)-1 and (-)-2. The present synthetic strategy features the use of one-pot ring-opening/cross metathesis (ROM/CM) followed by a ring-closing metathesis (RCM) reaction, allowing for the concise construction of 9-oxabicyclo|4.2.1|nona-2,4-diene 16 from 7-oxabicyclo|2.2.1|hept-2-ene 17 and 1,3-butadiene (Schemes 3 and 4). The substrate 17 was prepared in an optically active form through the asymmetric desymmetrization of meso-compound 5 by the enzymatic method (Scheme 1). For the conversion of 16 into the desired natural product (+)-mycoepoxydiene (1), we applied the stereoselective reduction of ketone 19 with L-Selectirde, the oxidative rearrangement of furfuryl alcohol 20 to hydroxylated pyranone 21, and the stereoselective 1,2-reduction of 22 under Luche conditions (Scheme 5). Through the present completion of the total synthesis of (+)-1, the absolute stereochemistry of natural 1 was established. The total synthesis of novel natural product (-)-1893A (2) was also achieved by use of the vinylogous aldol reaction with 2-(trimethylsilyloxy)furan (25) as the introduction of the side chain (Scheme 6). Through the two total syntheses, we have verified that the ROM/CM/RCM strategy is a valuable approach to synthesize oxygen-bridged cyclooctadiene-type natural products.
