Mevinolin synthesis

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... 

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). 

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. 

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). 

Several of these bioactive natural products have been successfully developed as therapeutics for clinical use. For example, Cyclosporin A is a fungal decapeptide principally used to suppress immune rejection in organ transplant patients. Mevinolin and compatin both control cholesterol synthesis in human. The search for enzyme- or receptor-targeted microbial products does not limit itself to medical use. Several commercially important antibiotics such as Nikkomycin and Avermectin have been found for agricultural applications in recent years. 

Hetero Diels-Alder Reaction. The hetero-Diels-Alder reaction involving glyoxylate as the dienophile provides an efficient access to the asymmetric synthesis of monosaccharides. The hetero Diels-Alder reaction with methoxydienes proceeds smoothly with catalysis by BINOL-TiCl2 to give the cis product in high enantiomeric excess (eq 14). The dibromide affords a higher cis selectivity, however, with a lower enantioselectivity, particularly in the trans adduct. The product thus obtained can be readily converted to the lactone portion of HMG-CoA inhibitors such as mevinolin or compactin. ... 

Kiyooka et al. reported that the 3i-catalyzed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with y3-siloxy aldehyde resulted in the production of syn and anti 1,3-diols with complete stereoselectivity depending on the stereochemistry of the catalyst used [45b]. This methodology was applied to the enantioselective synthesis of the optically pure lactone involving a syn-l,3-diol unit, known to be a mevinic acid lactone derivative of the HMG-CoA reductase inhibitors mevinolin and compac-tin (Sch. 2). 

Several examples of alkynic ketone formation have been recorded since Weinreb s first examples. A Diels-Alder strategy for Ae synthesis of mevinolin required the preparation of alkynic ketone (24). Standard methods, calling for the addition of the alkynide anion to an aldehyde followed by oxidation, lead to extensive degradation and by-product formation. The Weinreb methodology was clearly more effective (Scheme 8). ... 

An additional problem is that polyketide formation requires acetyl-CoA, malonyl-CoA, and NADPH generated by primary metabolic pathways. These precursors and the cofactor are also used for fatty acid biosynthesis. An inverse relationship between the synthesis of fatty acids and polyketide compounds has been found in the mevinolin (lovastatin)-producing species ot Aspergillus (Dutton, 1988 Greenspan and Yudkovitz, 1985). Thus, any regulatory factor that substantially alters the rate or extent of formation of these precursors and cofactor may affect polyketide formation. 

A similar strategy was followed by Konoike et for the enantioselective total synthesis of ( + )-6-epi-mevinolin and its analogues. Intramolecular cycloaddition of chiral (Z)-trienone 73 led to a mixture of r/.s-dccalins 74 and 75 (Scheme 7.17) the most satisfactory result was achieved when the reaction was... 

Araki, Y, and Konoike, T, Enantioselective total synthesis of (+)-6- 77i-mevinolin and its analogs. Efficient construction of the hexahydronaphthalene moiety by high pressure-promoted intramolecular Diels-Alder reaction of (7 ,2Z,8 , 10 )-l-[(fert-butyldimethylsilyl)oxy]-6-methyl-2,8,10-dodecatrien-4-one, 7. Org. Chem., 62, 5299, 1997. 

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. 

An excellent example is the synthesis of mevinolin 126, an HMG-CoA reductase inhibitor that lowers the cholesterol level, by Hirama and Iwashita.19 Their idea was to use a Diels-Alder reaction to close both rings in one step and they therefore disconnected various peripheral fragments to leave the simpler ketone 127. Reversing the Diels-Alder reveals 128 and the starting material was actually one diastereoisomer to ensure stereochemical control in the ring closure. 

The Diels-Alder was successful20 129 but now the methyl group in the SW comer needs to be added by conjugate addition and that requires an enone. Oxidation of the silyl enol ether 130, prepared by kinetic enolate formation with LDA, with catalytic Pd(OAc)2 and benzoquinone as the stoichiometric oxidant gave the required enone 131 in 57% yield. Addition of Me2CuLi was stereoselective to give 132 and the synthesis of mevinolin completed. 

The arrangement of functional groups as well as the erythro configuration of the latent diol makes carbonate 517 an excellent candidate as a compactin lactone synthon (99) and it has in fact been used in the synthesis of both compactin (97) and mevinolin (98) (Scheme 75) [112]. 

In model studies related to the synthesis of compactin (97) and mevinolin (98), the upper-half lactone moiety was constructed from 550 starting with an oxirane ring-opening reaction by vinyl Grignard reagent (Scheme 81) [136]. lodocarbonation of 560 followed by hydrolysis and ketalization affords isomerically pure acetonide 562, the compactin lactone synthon. 

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