PUTATIVE DIELS-ALDER-CATALYZED CYCLIZATION DURING THE BIOSYNTHESIS OFLOVASTATIN

A Diels-Alder cyclization proposed to occur during polyketide synthase assembly of the bicyclic core of lovastatin (1) (mevinolin) by Asperg illus terreus MF 4845 was examined via the synthesis of the N-acetylcy steamine (NAC) thioester of 13(2)]-(E,E,E)-(R)-6-methyldodecatri-2,8,1 0-enoate (5a). In vitro Diels-Alder cyclization of the corresponding u nlabeled NAC ester 5b, ethyl ester 18b, and acid 20b yielded two analo gous diastereomers in each case, under either thermal or Lewis acid-ca talyzed conditions. The reaction of thioester 5 proceeds readily at 22 degrees C in aqueous media. For 18b, one product is trans-fused ethyl 8a-octahydro-2,6-dimethylnaphthalene-1-carboxylate (30) (endo product ), and the other is cis-fused ethyl (1R,2S, 8a-octahydro-2,6-dimethyln aphthalene-1-carboxylate (31) (exo product). Isomer 21 with stereochem istry analogous to 4a,5-dihydromonacolin L (2), a precursor of 1, was made by transformation of a tricyclic lactone, ,8a-octahydro-2-methyl- 6,8-naphthalenecarbolactone (22) using reduction and Barton deoxygenat ion. Comparison of 21 with 30 and 31 confirmed the structural assignme nts and showed that the nonenzymatic 4 + 2 cyclizations of 5, 18, and 20 proceed via chairlike exo and endo transition states with the methy l substituent pseudoequatorial. The proposed biosynthetic Diels-Alder leading to lovastatin (1) would require an endo conformation with the methyl substituent pseudoaxial. Intact incorporation of the labeled he xaketide triene 5a into 1 was not achieved because of rapid degradatio n by A. terreus cells.