Mevinoline

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

Lovastatin is administered as an inactive lactone. After oral ingestion, it is hydrolyzed to the active mevinolinic acid, a competitive inhibitor of the reductase with a Ki of 0.6 nM. Mevinolinic acid is thought to behave as a transition-state analog (Chapter 16) of the tetrahedral intermediate formed in the HMG-CoA reductase reaction (see figure). 

The structures of (inactive) lovastatin, (active) mevinolinic acid, mevalonate, and synvinolin. 

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]. 

Appropriate choice of catalyst permitted formation of either of two dihydro derivatives of mevinolin in high yield (67). Hydrogenation of mevinolin over platinum oxide in ethyl acetate gave the tetrahydro derivative as a 1 3 mixture of CIS- and rrd 5-decalin isomers. 

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. 

Prasad and Sirkar (1990) have worked with actual streams obtained from Merck. Their work includes the recovery of mevinolinic acid, obtained by fermentation, which is a precursor to the hypocholestcrmic agent Mevinolin. 

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

Blood/gout/ mevinolin (= lovastatin = methylcompactin)/polyket. Mevacor/ inflammation... 

In the total synthesis of mevinolin,122 a stereoselective conversion of (57) into (58) was called for. Several organocopper reagents were examined, but it was MeCu-BFa which exhibited die highest selectivity (Scheme 26). The reason for the selectivity is not obvious, but the results do indicate that there can be significant differences between the reactivity profile of the various organocopper reagents available. 

The cyclofunctionalization of cycloalkenyl systems where the chain containing the nucleophilic functionality is attached at one end of the double bond leads to spirocyclic structures. Cyclizations of cyclic and acyclic enol ethers to generate spiroacetals are shown in equations (66)168 and (67).169 These reactions generate the thermodynamically more stable products based on anomeric and steric factors.170 Spiroacetal products have also been obtained using isoxazolines as the nucleophilic functionality (cf. Table 14).l4lb Studies of steric and stereoelectronic control in selenoetherification reactions which form spirocyclic tetrahydrofurans have been reported.38 An interesting example of stereoelectronic control in the formation of a spirocyclic lactone has been reported in a recent mevinolin synthesis (equation 68).171... 

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). 

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