Of -compactin

Decalin unit 121, an intermediate in the total synthesis of compactin, has been prepared by intramolecular cycloaddition reaction [117] of trienone-carboxylic acid 122 carried out under either thermal conditions or microwave irradiation. The desired cxo-adduct 123 was the major stereoisomer (Equation 2.34). Similar results were observed in the cycloadditions of the corresponding esters. 

The synthesis of the decalin unit of compactin (59), a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which acts as an effective hypocholesterolemic agent, was planned to incorporate an intramolecular Diels-Alder reaction (Scheme 9.15) [57]. 

A well-designed synthesis of the bottom portion of (+)-compactin (44) was reported by Keck and Kachensky using a vinylallene as the diene in an intramolecular Diels-Alder reaction (Scheme 19.10) [12]. This was done at a time when there was very little literature precedent on the use of vinylallenes as dienes. Based on examination of molecular models, it was reasoned that the transition state for the... 

Still, occasionally the other fuctional groups react as well, for example in 38 under basic conditions the propargylic alcohol isomerizes to the a,/3-unsaturated ketone [73] (Scheme 1.15), whereas in a closely related substrate from the synthesis of a subunit of compactin an allylic alcohol remains unchanged [74],... 

Scheme 3.S. Silylcuprate conjugate addition in syntheses of (+)-compactin, (-l-)-mevinolin, and (+)-pravastatin [45].

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. 

MacMillan reported a short and effective synthesis of spiculisporic acid which elegantly exemplified his Mukaiyama-Michael addition of silyloxyfurans to a,P-unsatu-rated aldehydes [88], Robichaud and Tremblay augmented this in a formal synthesis of compactin [224], Within this report it was shown that low enantioselectivities were obtained in the conjugate addition to aCTolein. Use of p-silyl acrolein 177 circumvented this and gave butenohde 178 in 95% yield and 82% ee. Conversion of adduct 178 to the decaUn (179) in eight steps resulted in a formal synthesis (Scheme 71). 

Scheme 71 Iminium ion catalysed Mukaiyama-Michael reaction in the synthesis of compactin...

Chumpolkulwong, N. Kakizono, T. Handa, T. Nishio, N. (1997) Isolation and characterization of compactin resistant mutants of an astaxanthin synthesizing green alga Haematococcus pluvialis. Biotechnol. Lett., 19, 299-302. 

The hexahydronaphthalene ring system of compactin has been constructed by a nitrile oxide cycliza-tion strategy (Scheme 24).42 Thus, cyclization of either (83) or (84) via nitrile oxide intermediates led to... 

Pravastatin, a 3-hydroxy-3-methyl glutaryl CoA reductase inhibitor applied as a therapeutic agent for hypercholesterolemia, can be synthesized by stereo- and regioselective hydroxylation of compactin by the soil microorganism Streptomyces sp. Y-110 (Fig. 22) [152]. The fermentative production of pravastatin has already been applied on an industrial scale by Sankyo Co. using different Streptomyces bacteria strains [153, 154]. 

Robichaud J, Tremblay F (2006) Formal enantioselective synthesis of (+)-compactin. Org Lett 8 597-600... 

Park J-W, Lee J-K et al (2003) Bioconversion of compactin into pravastatin by Streptomyces sp. Biotechnol Lett 25 1827-1831... 

Heathcock, C. H. Davis, B. R. Hadley, C. R. Synthesis and biological evaluation of a mono-cyclic, fully functional analogue of compactin. /. Med. Chem. 1989, 32, 197-202. 

Reduction of 30 with the mild reducing agent Zn/HOAc at 0°C gives the oxime 31 that can be hydrolysed directly to the ketone 32 without isolation.8 This ketone was used in a synthesis of compactin.9... 

Octahydronapthalene synthesis.1 An intramolecular version of this annelation using a Michael addition to a vinyl sulfone provides the octahydronapthalene unit (1) of compactin (2), a mevinic acid of interest as an inhibitor of cholesterol synthesis. 

However, excellent simple (exo endo = 95 5) and induced diastereoselectivity (94 6) was obtained by Jurczak [88] by applying the bornane sulfone amide derivative of glyoxylic acid 2-23 in the presence of a catalytic amount of a europium salt. Reaction of 2-23 with 1-methoxy-1,3-butadiene 2-24 gave predominantly 2-25 a which was transformed into the lactone 2-26 aiming towards the synthesis of compactin (Fig. 2-7)[89]. 

Compactin exhibits AJH activity in several insects (5,6,29) and seems to function as an inhibitor of 3-hydroxyl-3-methylglut-aryl-CoA reductase in both the rat (44,45) and M. sexta 5). Although the methyl ester of compactin was inactive as an AJH in our bioassay, two of its analogs (L-643,049-01K01 and L-643,737-... 

S03) did display AJH activity. Thus, for T. ni, analogs of compactin would appear to be good candidates for continued exploration as potential AJHs. 

Few synthetically useful examples of the oxidation of ethers by oxygen or ozone have been publish-ed.7 96 Q0 In 1978, Ourisson and coworkers reported that ozonization of the natural product cedrane oxide (43) on silica gel at -78 °C led to the formation of the corresponding lactone (44) in 30% yield (equation 32).A small amount of the tertiary alcohol (45) was also produced. Later, in the course of a chiral total synthesis of compactin, Hirama examined the ozonolysis of the alkene (46 equation 33). ° Under carefully controlled conditions, selective ozonolysis of the double bond could be achieved in 88% yield. However, when excess ozone was employed, significant amounts of the benzoate (47) were obtained, even at -78 C. In subsequent studies, benzyl ethers of primary and secondary alcohols,and carbohydrates were oxidized to the corresponding benzoates in excellent yields. Surprisingly, no further synthetic rqrplications of this reaction have been reported. 

Epoxidation of a,/J-unsaturated -lactone 6 giving single epoxide 7 in 73% yield allowed the stereoselective introduction of the hydroxy group at C-4 of the sugar portion 8 of compactin and mevinolin70. 

The discovery of compactin and lovastatin prompted efforts to develop derivatives with improved biological properties (163, 164). Modification of the methylbutyryl side chain of lovastatin led to a series of new ester derivatives with varying potency and, in particular, introduction of an additional methyl group a to the carbonyl gave a compound with 2.5 times the intrinsic enzyme activity of lovastatin (165). The new derivative, named simvastatin (124), was the second HMG-CoA reductase inhibitor to be marketed by Merck. Both lovastatin and simvastatin are prodrugs and are hydrolyzed to their active open-chain dihydroxy acid forms in the liver (166). A third compound, pravastatin (125), launched by Sankyo and Squibb in 1989, is the open hy-droxyacid form of compactin that was first identified as a urinary metabolite in dogs. Pravastatin is produced by microbial biotransformation of compactin. 

Easily prepared from glycols, enones have been investigated as dienophiles. They react with butadiene under Lewis acid catalysis to form chiral cyclohexenes used in the synthesis of compactin analogs [353]. Levoglucosenone has been used in a Diels-Alder reaction with acetoxy-butadiene to construct a part of the indole alkaloid reserpine [354], and in synthetic studies toward tetrodotoxin [355]. Analogs of the anthracycline rhodomycinone have been similarly prepared [356]. [4 + 2]-Cycloaddition of the same enone with silyloxydiene allowed the creation of the fused ring system present in actinobolin [357]. 

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