Cholesterol, biosynthesis stereochemistry

Nobel Prize, Physiology/ Medicine, 1964, cholesterol biosynthesis) JohnCornfbrth (Australia, Nobel Prize, Chemistry, 1975 isoprenoid biosynthesis, stereochemistry) George Popjak (cholesterol biosynthesis)... 

Details of cholesterol biosynthesis continue to be explored. Further details of work concerning the stereochemistry of the rearrangement of the methyl group at C-15 of squalene (which migrates to C-13 of Ianosterol) during the biosynthesis of cholesterol by rat liver are available.Cholesterol, biosynthesized independently... 

Stereochemistry of hydrogen elimination from C-15 during cholesterol biosynthesis. J. Chem. Soc. Chem. Commun. 1458-1460. 

Comforth and his colleagues have investigated the stereochemistry of isomerization of isopentenyl to dimethylallyl pyrophosphate in isoprenoid biosynthesis. They find that the prototropic change involved is stereochemically different from the superficially analogous association of C5 units. Bisabolene appears to be excluded as an intermediate in the biosynthesis of helicobasidin and trichothecin by recent labelling studies (see also Vol. 1, p. 232, ref. 81) and a 1,4-hydride shift in the initially formed intermediate is indicated. The loss of the C-14 methyl group in cholesterol biosynthesis differs from loss of the C-4 methyl groups. The 32-carbon atom is released at the aldehyde oxidation level as formic acid. 

Further exploration125 of the stereochemistry associated with modification of the steroidal side-chain into that of steroidal alkaloids such as solanidine (139) and tomatidine (140) has revealed that on formation of the furan ring in (140) tritium in the 16/8-configuration of cholesterol [as (143)] is retained but appears now in the 16a-configuration. Retention of the tritium excludes a C-16-oxo-intermediate, and the fact that an inversion of configuration is observed excludes hydroxylation with normal retention of configuration. Examination of the fate of the cholesterol 16/S-proton on incorporation into solanidine (139) revealed that during solanidine biosynthesis this proton is lost. 

It is interesting to note that this Rh-catalyzed isomerization mimics a similar double bond migration found in nature in the biosynthesis of cholesterol and terpenes in which isopen-tenyl diphosphate (92) is converted reversibly to dimethylallyl diphosphate (93), shown in equation 9.48.119The stereochemistry ofthis reaction is also suprafacial. 

Bergstrom S, Lindstredt S, Samuelson B, Corey EJ, Gregoriou GA (1958) The stereochemistry of 7a-hydroxylation in the biosynthesis of cholic acid from cholesterol. J Am Chem Soc 80 2337-2338... 

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