Mevinolin structure

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. 

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... 

HMG-CoA reductase. Some are analogs of the isoprene precursor while others are NADP(H) analogs. Analogs such as mevinolin have been extremely useful in evaluating the role of the enzyme and in manipulating the concentration of the enzyme in vivo and finally in stabilizing HMG-CoA reductase during purification (for example, see ref. 32). Several effective competitive inhibitors and their structural similarities are shown in Fig. 5. 

Mevinolin [161] and compactin [162] (structures given in Chapter 1) are two inhibitors of HMG-CoA reductase activity with similar properties. Both are fungal metabolites which are competitive inhibitors of HMG-CoA reductase with low X jS of about 1 nM. 

The specificity of the inhibition by mevinolin through its high affinity for HlK-CoA reductase may also serve as a model to develop highly effective and specific artificial biocides and to stinulate research in this topic. For example, citrinin, another antibiotic having a bicyclic structure produced by Pentctllium citrinum has been shown to inhibit sterol biosynthesis (143) at the site of acetoacetyl-CoA thiolase (EC 2.3.2.9) and HMG-CoA... 

It was discovered by the Merck Sharp Dohme Research Laboratories that a strain of Aspergillus terreus obtained from a soil sample produced the cholesterol lowering fungal metabolite lovastatin (initially named mevinolin). Details of the isolation, structural characterization and biochemicai properties of iovastatin have been summarized by Alberts et al. (1). Lovastatin is identicai to monacoiin K isoiated independently from Monascus ruber by Endo (2). 

The serum cholesterol-lowering agent mevinolin (lovastatin) is shown here. Identify the ester and lactone functional groups of lovastatin, and for each, write the structures of the carboxylic acid and alcohol from which the ester and lactone are formed. 

Figure 8.48 Structural similarity between mevinolinic acid and FlMG-CoA.

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