Recent Progress in the Chemical Synthesis of Antibiotics and Related Microbial Products

Abstract

The lactonic part of (+)-compactin and (+I-mevinolin as well as a compactin analogue were synthesized in an enantioselective way from a j3,d-diketo sulfoxide easily obtained by the reaction of the trianion of methyl 3,5-dioxohexanoate with (-)-menthyl (S)-p-toluenesulfinate. The main reaction was the two-step stereoselective reduction of /?,&diketo sulfoxide without any protective group-Since their discovery at the end of the seventies, compactin (la) and mevinolin (lb) have attracted a growing interest for their biological activity as potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). As seen from their structure, the lactonic moiety, a masked dihydroxy acid, is closely related to the natural substrates of HMGR, which catalyzes the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid. This enzyme is one of the most important enzymes involved in the biosynthesis of cholesterol in the cells, and its regulation for the control of cholesterol level in the blood is of prime imp0rtance.l Many syntheses of these substances have been already reported and reviewed2 as well as the synthesis of new analogues in which only the lactonic part, which, in its open form mimics mevalonic acid, was retained, the southern lipophilic moiety being replaced by more accessible aromatic derivatives.2 A large number of publications reported mainly the synthesis of the lactonic moiety of compactin with two asymmetric carbons in the (RS) configuration. Different strategies have been used: many started from the chiral pool [(SI-malic acid,3a L-glutamic acid,3b*C tartaric acid,3d or carbohydrate~~~-gI; others described asymmetric syntheses [asymmetric Diels-Alder reaction,3b diastereose-lective aldol condensation,3' or enantioselective reduction + On leave from the Centro CNR per lo studio Lett. 1984,25,2101. (b) Hanessian, S.; Roy, P. J.; Petrini, M.; Hodges, P. J.; Di Fabio, R.; Carganico, G. J. Org. Chem. 1990, 55, 5766. (c) Menges, M.; Brlickner, R. Synlett 1993, 901. (d) Minami, T.; Takahashi, K.; Hiyama, T. Tetrahedron Lett. 1993, 34, 513. (e) Miyazawa, K.; Yoshida, N. Chem. Lett. 1993, 1529. (0 Ernolenko, M. S.; Olesker, A.; Luckacs, G. Tetrahedron Lett. 1994, 35, 711. (g) Emolenko, M. S.; Olesker, A.; Luckacs, G. Tetrahedron Lett. 1994,35, 715. (h) Terada, M.; Mikami, K.; Nakai, T. Tetrahedron Lett. 1991,32, 935. (i) Lynch, J. E.; Volante R. P.; Wttley, R. V.; Sinkai, I. Tetrahedron Lett. 1987, 28,1385. (j) Shao, L.; Seki, T.; Kwano, H.; Saburi, M. Figure 1. of /?,&diketo esters with a chiral Ruthenium catalyst3j or bakers' y e a ~ t ~ ~ J 1. We report in this paper a short and efficient asym-metric synthesis of a compactin analogue (+)-(R3)-2, based on the stereoselective reduction of (+)-(R) methyl 3,5-dioxo-6-(p-tolylsulfinyl)hexanoate (4) as shown on the retrosynthetic Scheme 1. Compound 4 was prepared in one step by reaction of the trianion of methyl 3,5-dioxohexanoate with (-)-menthyl (SI-p-toluenesulfinate. The diketo ester 6 was readily obtained in one step by a known procedure4 from commercially available de-hydro acetic acid 5 (Scheme 2). The trianion of 6, prepared in THF at 0 "C with 1 equiv of NaH and 2 equiv of t-BuLi or sec-BuLi, reacted rapidly at 0 "C with (-1-menthyl (S)-p-toluenesulfinate5 to afford the corresponding diketo sulfoxide (+)-(R)-4. This new method is a convenient and short route to diketo sulfoxides which were obtained in our previous studies either by reaction of the anion of (R)-methyl-p-tolyl sulfoxide6 on a /?-keto ester, or dianions of j3-diketonesl on menthyl p-toluene-sulfinate, or dianion of (R)-(p-tolylsulfinyl)-2-propanones on an ester. IH NMR of compound 4 showed as expected6-8 that only the 8-carbonyl was entirely enolized (one vinylic hydrogen giving a singlet at 5.65 ppm). Therefore, following our previous results,6-8 the enanti-oselective reduction of the /I-carbonyl of the (R)-/?,d-dicarbonyl sulfoxide 4 was carried out with 2 equiv of DIBAL in THF at-78 "C. Only one diastereomer of the resulting [B(S),S(R)]-methyl 5-hydroxy-3-oxo-6-(p-tolyl-sulfinyl)hexanoate, 7, was detected by 200 MHz l H NMR of the crude product. The yield in isolated product was (4) Batelaan,