Squalene biosynthesis

Zaragozic acid A (which is also called squalestatin SI and has been shown to lower serum cholesterol levels in test animals by inhibition of squalene biosynthesis) by K. C. Nicolaou (University of California San Diego, Scripps Research Institute) ... 

On the other hand, the amine moiety of daphniphylline (1) is complicated. However, in connection with the co-occurrence of seco-daphniphylline (28), whose stereostructure has also been established, the heterocyclic skeleton of the amine moiety seems to be constructed as shown in Scheme XI in which the distributions of 14C-labeled carbon atoms are based on the squalene biosynthesis from six [2-14C]MVA molecules. 

The details of squalene biosynthesis are on pp. 1442-4. The biosynthesis of chrysanthemic acid requires only the first few steps of this sequence. The greatest simplification is that R in the squalene biosynthesis is now just a methyl group. The stereochemistry in the three-membered ring comes from the stereoselectivity of the enzyme-controlled ring closure reaction. Hydrolysis of the pyrophosphate and oxidation of the alcohol are needed to get the acid. 

The details of squalene biosynthesis were elucidated by Popjak and Comforth by 1966 their conclusions are summarised below since they are fundamental to the understanding of much current work. 

It is possible that an analogous intermediate is involved in phytoene (8) biosynthesis. However, instead of a reductive elimination of pyrophosphate, as in squalene biosynthesis, the 15(15 )-double bond must be derived by elimination. Goodwin and co-workers have shown that both protons of this double bond are labelled by [2- C,3R,5R- H]mevalonic acid. Porter and co-workers have studied the kinetics of an enzyme system from tomatoes for the conversion of geranyl geranyl pyrophosphate (6 n = 3) into phytoene. 

Miscellaneous Applications.— The Wittig reaction of ( ) 6,10-dimethyl 5,9-undecadien-2-ylidenetriphenylphosphorane with ethyl rra/ (2-carboxaldehyde)-cyclopropanecarboxylate yields a 1 1 mixture of ( )- and (Z)-alkenes. The former isomer was converted into an analogue (161) of a proposed intermediate in squalene biosynthesis. (10 ,ll/ )-(+)-Squalene-10,ll-epoxide (164), identical to a constituent of the red algae Laurencia okamuri, was isolated from the isomeric mixture produced from a Wittig reaction of the ylide (162) with the aldehyde (163). ... 

As part of the extensive studies by Cornforth and co-workers of squalene biosynthesis, the stereochemistry of the last step has now been elucidated. This concerns the stereochemistry of proton addition to isopentenyl pyrophosphate with formation of the new methyl group of dimethylallyl pyrophosphate under the influence of isopentenyl isomerase (EC 5.3.3.2). The investigation hinged on the generation of a chiral methyl. CHDT. [2- C,2R- H,3R]- and [2- C,2S- H,3/ ]-mevalonic acid were separately converted in the presence of... 

Fig. 23.3. Presqualene pyrophosphate and chrysanthemic acid and inhibitors for squalene biosynthesis.

The second step in the squalene biosynthesis is the reductive rearrangement of presqualene diphosphate (36a) to squalene. Initial diphosphate abstraction formally gives a primary cyclopropylcarbinyl catimi 37a that rearranges via a secondary cyclobutylium intermediate 38a to the tertiary cyclopropylcarbinyl cation 39a (Scheme 87.12) [176-178]. Hydride attack from NADPH at C3 terminates the squalene biosynthesis. Evidence for the existence of the tertiary... 

The next step in understanding squalene biosynthesis depended on the isolation, from yeast and from rat liver microsomal incubations in the absence of NADPH, of a cyclopropyl compound, presqualene pyrophosphate 4.48) it is established as an intermediate in squalene biosynthesis (in micromosal preparations it is converted into squalene in the presence of NADPH) [57-60]. A reasonable mechanism for the biosynthesis of squalene 4.47) via presqualene pyrophosphate 4.48) is shown in Scheme 4.12 [60-63]. 

Most of the natural carotenoid pigments are tetraterpenes, being formed from two C20 geranylgeranyl pyrophosphate units through phytoene 4.122). The mechanism of phytoene formation has much in common with squalene biosynthesis. In particular, head-on fusion of the two C20 units occurs via prephytoene pyrophosphate 4.120), analogous to presqualene pyrophosphate 4.48) formation from two... 

Coates, R. M., and W. H. Robinson Solvolysis of /ra/i5-2,2-Dimethyl-3-(2 -methyl-propenyl)-cyclobutyl Tosylate. Model Reactions Relevant to Squalene Biosynthesis. J. Amer. Chem. Soc. 94, 5920 (1972). 

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