Mevalonolactone, biosynthesis

In view of the importance of mevalonate in the biosynthesis of terpenes and steroids, it is not surprising that numerous syntheses of mevalonolactone are available. These are briefly itemized in the detailed procedure for the synthesis of (i ,S)-mevalonolactone labelled at C-2 with 13C (Scheme 215) (81OS(60)92>. 

The typical secondary metabolites of soft corals are diterpenoids, although some species also produce sesquiterpenoids. The sesquiterpene portion of furoquinol (Structure 2.102) is labeled by [2-3H]mevalonolactone in Sinularia capillosa,m while Heteroxenia sp. converts acetate and meva-lonate into cubebol (Structure 2.103) and clavukerin A (Structure 2.104).188 In contrast, acetate is used for cetyl palmitate synthesis in Alcyonium molle, but not for de novo diterpene biosynthesis.188... 

Jeffrey pine beetle, Dendroctonus jeffreyi Hopkins, which had been previously treated with juvenile hormone III (JH III, 2.2 pg/beetle in acetone) and then placed in an aeration tube for 25 to 30 h. Ips paraconfusus and I. pini were each injected with 0.2 pCi of sodium [1-14C]acetate prior to placement in cut pine logs and volatile collection, while D. jeffreyi were each injected with 3.8 (male) and 3.7 (female) pCi of sodium [1-14C]acetate 6.4 (male) and 10.7 (female) h after JH application. (G) The role of the mevalonate pathway in frontalin biosynthesis is supported by the incorporation of radiolabel from [2-14C]mevalonolactone into frontalin by male D. jeffreyi (2.2 pg JH 11 l/beetle in acetone, 10 h incubation and volatile collection, 1.1 pCi of [2 14C] mevalonolactone injected, 20 h volatile collection). Figures adapted from Seybold et al. (1995b) and Barkawi (2002). 

The biosynthesis of virginiamycin Ml in Streptomyces virginiae has been studied using both radiolabeled precursors (63) and stable isotope techniques (45, 63-65). Incorporation of [2-l4C]acetate, L-[methyl-3H]methionine, dl-3-14C]serine, L-[3,4-3H2]proline, and [2-14C]glycine established these compounds as the main precursors (63). The assumption that carbons 2, 26, 27, and 28 arose from valine was supported by the observation that no incorporation of appropriately labeled mevalonolactone was observed (65). On the basis of the radio-... 

Eguchi, T. Morita, M., and Kakinuma, K., Multigram synthesis of mevalonolactone-rf, and its application to stereochemical analysis by H NMR of the saturation reaction in the biosynthesis of the 2,3-di-O-phytanyl-5 -glycerol core of the Archaeal membrane lipid, 7. Am. Chem. Soc., 120, 5427, 1998. 

Corsino et al. [22] reported that friedelane and quinonemethide biosynthesis is compartmentalized in Maytenus aquifolium and Salacia campestris, indicating cyclase activity in the leaves but not in the root bark. In order to confirm the possible translocation of friedelin derivatives, from the leaves to root bark, a solution of ( )5-3H-mevalonolactone was administered to the leaves of M. aquifolium seedlings. No labeled friedelin was detected in the root bark but, nevertheless, label quinonemethides were found. 

An excellent example of the use of n.m.r. spectroscopy for biosynthetic studies is seen in the work of Stothers et al., who have provided very good evidence for the involvement of a hydride shift in the biosynthesis of capsidiol (577). Thus incorporation experiments with [4,4- H2]mevalonolactone revealed the presence of deuterium atoms at C-1, C-4, and C-7 and this has been interpreted in terms of Scheme 45. 

Seo, S., Y. Tomita, and K. Tori Biosynthesis of Oleanene- and Ursene-Type Triterpenes from [4- C]Mevalonolactone and [1,2- C2]Acetate in Tissue Cultures of Isodon japonicus Hara. J. Am. Chem. Soc. 103, 2075 (1981). 

Recently, Li et al. also studied the biosynthesis of iridoid glucoside lamalbid (106) in Lamium harbatum using C-labeled intermediates of MEP and MVA pathways, namely, [3,4,5- C3] 1-deoxy o-xylulose 5-phosphate and [2- Ci] mevalonolactone (MVL), and observed that only the former was incorporated into lamalbid (Scheme 97.12) [132]. 

Seiler, M., Acklin, W. and Arigoni (1970) Biosynthesis of ergot alkaloids from (5R)-and (5S)-[5- Hi]-Mevalonolactones./. Chem. Soc. Chem. Commun., 1394-1395. 

Mevalonic acid, the key intermediate in solving the terpene biosynthesis pathway is an oily liquid, in solution it is in equilibrium with mevalonolactone (Figure 6.5), a crystalline solid, so the latter is used in biosynthetic studies. Fluoromevalonolactone, and the corresponding acid, are powerful inhibitors of terpene formation. If addition of fluoromevalonate to a biosynthesizing system blocks the formation of a compound, then it can be concluded that that compound has a terpene origin. 

A final example shows a process called desymmetrization (Figure 15.25). We start with a raeso-compound (remember this is a molecule that contains asymmetric carbon atoms but is not chiral, because it has a plane of symmetry) with two identical functional groups. Under enzymatic hydrolysis, only one of these reacts, so a chiral compound is produced, and all the material is used, without any need to recycle. The enzyme used in this reaction is electric eel acetylcholinesterase (EEAc). Pig liver esterase is also commonly used, as a relatively crude extract is inexpensive and gives good results. An example is shown in Figure 15.26, in the synthesis of 7 -mevalonolactone, important in the biosynthesis of terpenes and steroids. 

Finally, natural (/ )-(—)-mevalonolactone, a key intermediate in the biosynthesis of a broad spectrum of compounds such as sterols, terpenes, and carotenoids, was synthesized via eight steps in 55% overall yield and more than 99% e.e. (Scheme 22). In the key step, the aforementioned enantioconvergent chemoenzymatic deracemization route was applied. Thus, 2-methyl-2-benzyl oxirane ( )-2.8 was deracemized on a large scale (10 g) using lyophilized cells of Nocardia EHl and sulfuric acid. The product (S j-diol was isolated in 94% chemical yield and 94% optical purity [133]. 

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