Dj. Witter et Jc. Vederas, PUTATIVE DIELS-ALDER-CATALYZED CYCLIZATION DURING THE BIOSYNTHESIS OFLOVASTATIN, Journal of organic chemistry, 61(8), 1996, pp. 2613-2623
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.