Compactin and mevinolin

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. 

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. 

Another target, that at first seems to be unfavorable since it is principally common for all organisms, is the enzyme HMG-CoA-reduc-tase which is the regulatory enzyme in terpenoid biosynthesis. Results from trials with naturally produced inhibitors for that enzyme, such as Compactine and Mevinoline, indicate that these compounds are able to lower the cholesterol content in mammals, but not markedly depress sterol synthesis in fungi U3). 

The recently discovered title compound BMY-22089, 167, is more potent than the natural products compactin and mevinolin in lowering the serum cholesterol levels in both animals and man by inhibiting the action of enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) which determines the biosynthesis of cholesterol. It has been prepared in 20% overall yield in various steps starting with the tetrazol 168 (equation 58), for pharmacokinetic and drug distribution studies. 

Enantiomerically enriched hetero Diels-Alder cycloadducts have found applications in the synthesis of other pharmaceutical intermediates such as compactin and mevinolin [4, 5]. The strategy described in this work should be applicable to these and similar compounds. 

To judge the relative merits of an anellation versus a bicyclization strategy, it is instructive to look at the many syntheses [101] of compactin and mevinolin, which represented a popular synthesis target in the early 1980s (Scheme 6.27). 

Scheme 6.27 Anellation versus bicyclization during syntheses of compactin and mevinolin...

Roberts et al. [48] have used the other diol enantiopode 155, derived from (+)-150, to construct the hydroxylactone moiety (156) of mevinic acids such as compactin and mevinolin ... 

Hiyama et al. have reported an enantioselective synthesis of p-hydroxy 5-lactones as simplified analogs of compactin and mevinolin [47] (Scheme 10). The p,5-diketo ester 54 derived from Taber s chiral alcohol 57 was subjected to a stereoselective reduction with sodium borohydride in the presence of Et2BOMe to afford a syn diol, which upon saponification and then heating in dry toluene led to the chiral lactone 56. 

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