Compactin

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. 

Scli ir 3.S. Siiylcuprate conjugate addition in cynthecec of (4)-compactin, (4)-mevinolin, and (4)-pravactatin [45]. 

This method is especially useful as part of a three-component condensation of optically active y-alkoxycyclopentenones leading to prostaglandin and compactin precursors268. 

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 adduct derived from (a-benzyloxyacetaldehyde (97 % ee) is an important intermediate en route to compactin and mevinolin [76]. In contrast, modest enantioselectivity was attained when the cycloadditions were catalyzed by a chiral BINOL-ytterbium-derived catalyst [77]. Pyridines were used as additives, and the best enantioselection (93% ee) was attained only in the case of p-methoxybenzaldehyde using 2,6-lutidine. 

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]. 

Intramolecular [4 + 2]-cycloadditions of vinylallenes have been utilized in the synthesis of complex molecules including natural products such as compactin. Heating the vinylallene 208 at 140 °C gave hexahydronaphthalene 209. The crude mixture was immediately reduced with LiB(sBu)3H because of the instability of /3,y-unsatu-rated ketones [175]. 

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. 

Endo A. (1985) Compactin (ML-236B) and related compounds as potential cholesterol-lowering agents that inhibit HMG-CoA reductase. J Med Chem 28 401 05. 

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...

The first generation of statins to be approved for the treatment of hypercholesterolemia was based upon the natural product compactin, an HMG-CoA reductase inhibitor originally isolated from cultures of Penicillium. The most widely prescribed of these first-generation statins are simvastatin (4, Fig. 12.2), marketed as Zocor , and pravastatin (5), marketed as Pravacol . Based in large part on the clinical effectiveness of these early... 

In the synthesis of the compactin lactone precursor 76, an aldol—> 1,3-diol conversion was included in the usual sequence, and the required aldehyde function... 

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