Compactin, structure

The dihydropyrones are not produced directly in the initial BINOL-titanium(IV)-cat-alyzed reaction. The major product at this stage is the Mukaiyama aldol product which is subsequently cyclized by treatment with TFA [19fj. The formal cycloaddition product 3d (97% ee) obtained from a-(benzyloxy)acetaldehyde is an important intermediate for compactin and mevinolin. Scheme 4.13 outlines how the structural subunit 13 is available in three steps via this cycloaddition approach [19 fj. 

Brown AG Smale TC, King TJ, Hasenkamp R, Thompson RH. (1976) Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium Brevicompactum. J Chem Soc, Perkin Trans 1 1165-1170. 

Pravastatin (10) is another HMG-CoA reductase for the inhibition of cholesterol biosynthesis it is marketed by Sanyo and Bristol Myers Squibb under the trade names Mevalotin and Pravachol.87 It has a close structural relationship to lovastatin and simvastatin. It is produced by a two-step sequence. First, mevastatin (11), also known as ML-236B or compactin, is prepared by fermentation of Penicillium citrinum ss it is then enzymatically hydroxylated to produce 11 (Scheme 31.7).88-101... 

An excellent application of the Narasaka reduction is a diastereoselective synthesis by Merck scientists of 7, a structurally novel analog of the natural product compactin (8)7, which is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase8 (Scheme 4.1e). The key step in the construction of the P-hydroxy-8-lactone moiety in 7 is the highly diastereoselective reduction of the P-hydroxy ketone 9 using a triethyl borane/sodium borohydride system. The yyn-diol 10 was obtained in high yield and with a remarkably high level of diastereoselectivity. 

Sato/Kaneko [104] and Carreira [105] have independently employed acetoacetate-derived O-silyl dienolates as Si-substituted nucleophiles in asymmetric catalytic aldol reactions. The aldol products, d-hydroxy-/3-ketoesters, and the derived syn- and anti-yS,d-diol esters are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotics. These structural subunits are also found in chemotherapeutics, most notably compactin analogs [106] that have been studied as... 

A promising natural product, compactin, was discovered in a screen of compounds from a fermentation broth from Fenicillium citrinum in a search for antibacterial agents. In some, but not all, animal studies, compactin was found to inhibit HMG-CoA reductase and to lower serum cholesterol levels. In 1982, a new HMG-CoA reductase inhibitor was discovered in a fermentation broth from Aspergillus cereus. This compound, now called lovastatin, was found to be structurally very similar to compactin, bearing one additional methyl group. 

Moorhoff, C.M., and Schneider, D.F., Comments on the reaction of ethyl 4-(diethoxyphosphinyl)-3-oxobutanoate and related phosphonate esters with enals. Tetrahedron Lett., 28, 559, 1987. Heathcock, C.H., Hadley, C.R., Rosen, T., Theisen, P.D., and Hecker, S.J., Total synthesis and biological evaluation of structural analogues of compactin and dihydromevinolin, 7. Med. Chem., 30, 1858, 1987. 

Mevinolin [161] and compactin [162] (structures given in Chapter 1) are two inhibitors of HMG-CoA reductase activity with similar properties. Both are fungal metabolites which are competitive inhibitors of HMG-CoA reductase with low X jS of about 1 nM. 

The development and use of HMGRIs began in 1976 with the discovery of mevastatin. Originally named compactin, this fungal metabolite was isolated from two different species of Penicillium and demonstrated potent, competitive inhibition of HMG-CoA reductase. Its affinity for the enzyme was shown to be 10,000-fold greater than that of the substrate HMG-CoA (22). Several years later, a structurally similar compound was isolated from Monascus ruber and Aspergillus terreus. This compound was originally known as... 

Heathcock CH, Hadley CR, Rosen T, et al. Total synthesis and biological evaluation of structural analogues of compactin and dihydromevinolin. J Med Chem 1987 30 1858-1873. 

Fig. 9.7 Chemical structures of statins. Lipitor (a) crestor (b) zocor (c) pravachof (d) and compactin (e)...

C24H36O5, Mr 404.55, cryst., mp. 174°C, [a] +323° (CH3CN), a polyketide. M. is a potent inhibitor (K,= 1 nM) of HMG-CoA-reductase, the key enzyme in the biosynthesis of higher terpenes and steroids such as, e. g., cholesterol. It is produced by Aspergillus terreus and various Monascus species. Thus, e. g., the plasma cholesterol concentration (a major risk factor for the occurrence of arteriosclerosis) decreases by ca. 50% in patients under medication with M. In the terpene metabolism HMG-CoA-reductase reduces 3-hydroxy-3-methy Iglutary 1-CoA to mevalonate. M. mimics the substrate and thus leads to inhibition of the enzyme. M. is commercially available under the tradename Meva-cor . M. was the lead structure for numerous synthetic HMG-CoA-reductase inhibitors that are now available or are being developed (Atorvastatin, Cerivastatin, Fluvastatin, Pravastatin, Simvastatin). In these derivatives the hexahydronaphthalene structure is replaced by heterocylic ring systems, see also compactin. 

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