Calbistrin, which was independently isolated and characterized by four groups at the almost same time exhibits antifungal and NGF production enhancing activities. The absolute structures of the octahydronaphthopyranone skeleton and the conjugated tetraene dicarboxylic acid side chain, however, remained undetermined. We now report here the synthesis of these fragments to confirm their absolute configurations. The tetrahydronaphthalene moiety 8 was synthesized by intramolecular Diels-Alder reaction of silyl dienol ether 7 prepared from methyl α-D-mannopyranoside in 23 steps as shown in Scheme 2. Through conversion into the diene, introduction of a C2 unit, construction of lactol ring and oxidation was obtained the diketone 12, which was identical with naturally derived compound [IV] in all respects. Stereoselective reduction of 12 and regio selective oxidation provided the hyrdoxy ketone 14, completing the synthesis of the octahydronaphthopyranone skeleton of calbistrin. The anti (20) and syn isomers of the rasemic side chain, tetraene carboxylic acid dimethyl ester, were synthesized from allyl alcohol 15, which was prepared by the aldol reaction of trans-2-methyl-2-butenal and methyl propionate (Scheme 4). By comparison with the naturally derived diester [I], the stereochemistry of the side chain was confirmed to be anti configuration. Finally, in the similar manner, the optically active acetate 24 obtained by optical resolution with lipase, gave the anti compound 26 identical with the diester [I]. The final stage of the total synthesis of calbistrin is now in progress.
