Lactones Mevalonolactone

The dihydroxy acid that is formed in this step cyclizes to the S-lactone mevalonolactone. 

Scheme 11.40. A representation of the reduction of (35 )-3-hydroxy-3-methylglutaryl CoA to (R)-mevalonic acid [(R)-3,5-dihydroxy-3-methylpentanoic acid] by the enzyme hydroxymethylglutaryl-CoA reductase (EC 1.1.1.34). The corresponding lactone mevalonolactone is also shown.

CPO has been used occasionally in complex syntheses. An important application of CPO as an enantioselective epoxidation catalyst is the efficient synthesis of (R)-2-mevalonolactone (Scheme 2.26a) [270]. A survey of the literature revealed that the previous methods required many steps to produce the lactone, in low overall yield, with moderate ee, in addition to expensive starting materials. Meanwhile, a retro-synthetic analysis starting with an appropriately functionalized epoxide provided confidence that CPO could rescue the situation if used in the key stereogenic step. Another completed synthesis is depicted in Scheme 2.26b. Again, the epoxide is generated in high yield with conversion to (R)-dimethyl-2-methylaziridine-l,2-dicarboxylate, which may serve as a synthon for P-methylamino acids [283],... 

M. Fetizon, M. Golfier, and J. M. Louis, Highly selective oxidations of diols by silver carbonate, Chem. Commun., (1969) 1102 A new synthesis of lactones application to ( )-mevalonolactone, ibid., (1969) 1118-1119. 

Isolation. Tschesche et al.1 found that mevaloside is the glucoside of R( — )-mevalonolactone and can be isolated in 1.75 % yield. By enzymic hydrolysis the lactone is obtainable with ease from medlar leaves in yield of 0.63%. 

S) -( — )-2-Methyl-2-hydroxy-y-butyrolactone (176a) is a useful synthon for the asymmetric construction of acyclic tertiary a-hydroxy acids found in natural products such as the pheromone frontalin and mevalonolactone, the biosynthetic precursor of terpenoids and steroids. This compound is readily prepared from lactone (175) using the asymmetric enolate oxidation protocol and dimethoxy oxaziridine ( + )-(158) <95JOC6l48>. The a-hydroxy lactone (176b), isolated as the benzoate, was obtained in 84% ee and 70% yield. A single crystallization from ethyl acetate improved the ee to >94% (Equation (41)). 

Kaufman (32) has studied and determined the rate and equilibrium constants for the acid catalyzed hydrolysis of mevalonolactone, lovastatin and other structurally related HMG CoA reductase inhibitors in pH 2.0 buffer at 37°C. Under these conditions lactone concentrations decrease with time but do not approach zero indicating that the hydrolysis is reversible. The equilibrium nature of the reaction was further confirmed by repeating the experiment with hydroxyacid as starting material in the same system and demonstrating that an equilibrium composition is achieved that is identical to that achieved starting with lactone. Kinetic points in all studies were carried out to 15 hours and data obtained indicate that... 

A large number of 1,4-, 1,5-, and 1,6-diols is converted to lactones on treatment with silver carbonate on celite in refluxing benzene mevalonolactone is thus prepared in 74% yield. 

Reactions.—Asymmetric syntheses involving cr-sulphinyl carbanions have been described, including the preparation of /ff-methoxy-)ff-phenylacetaldehyde via a chiral dithioacetal mono-5-oxide anion " and of lactones, -hydroxy-lactones, and esters such as (i )-mevalonolactone. or-Sulphinyl carbanions are intermediates in the reaction of sulphines with carbanions (thiophilic addition) which can lead ultimately to ketones or olefins - (see also Chap. 3, Pt II, p. 162). 

Valerolactones.—During a total synthesis of ( )-Malyngolide (120), thermolysis (reflux in cyclohexane) of the epoxy-acid (119) was found to give (120) stereoselectively in 50% yield.A new route to mevalonolactone has been developed which could prove especially useful for the introduction of labels at the C-3 and 3-CH3 positions. Yet another synthesis of the Prelog-Djerassi lactone has been reported. 

Of the simpler 8-lactone natural products, syntheses of malyngolide, mevalonolactone, and an oviposition-attractant pheromone of a mosquito ... 

Figure 6.5 The key compounds mevalonic acid and its lactone, with fluoro-mevalonolactone, an inhibitor of the terpene pathway...

A couple of template-directed approaches have been developed for the synthesis of mevalonolactone [90]. In the first approach, the spiro-fused lactone 225 constructed from diacetone-o-glucose was subjected to a stereoselective epoxida-tion and then reduction to provide diol 226 (Scheme 46). Cleavage of the acetals followed by exhaustive oxidation allowed the cleavage of the carbon skeleton from the template, providing (/ )-mevalonolactone 10 in moderate yield. 

Based on the CPO-catalyzed stereoselective epoxidation of terminal alkenes, Lakner et al. designed a concise synthetic route for the preparation of the natural lactone (R)-mevalonolactone 27 (Scheme 13.5). The key step of the sequence was the epoxidation of ethyl 3-methyl-3-butenoate catalyze by CPO, which yielded the corresponding (R)-24 in 67% yield and 93% ee. Tlie final product was achieved in 57% overall yield and identical purity (Scheme 13.5) [87]. 

In the presence of a strong base such as LDA, the a-carbon of acetic acid esters can react with the carbonyl group of aldehydes or ketones to give j8-hydroxy esters, which may or may not be dehydrated to a,j8-unsaturated esters. This type of reaction has been exploited for the preparation of racemic [2- C]mevalonolactone (64) (Figure 6.25) and the benzofuran[l- C]acetamide PD 126,212 (67)". In the first case a-deprotonated trimethyl-silyl [2- C]acetate was treated with l-trimethylsilyloxy-3-butanone. Acidic work-up resulted in hydrolytic cleavage of the TMS groups and formation of the lactone system... 

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