Substituted sterols

The synthesis of novel 4a-substituted sterols was undertaken in the laboratory of C.H. Robinson. These compounds are potential inhibitors of sterol 4-demethylation. To prepare the desired 4-allenyl-5a-cholestan-3p-ol, the exocyclic olefin precursor was first reacted with bromoform/potassium f-butoxide to afford the geminal dibromo-substituted cyclopropane derivative. Next, methyllithium was used to bring about the rearrangement to afford the allene, and finally acidic conditions were applied for the removal of the THP protecting group. 

Figure 9.3 The figure shows the degradation of the side chain of sterols which have substitutions at C-19. Removal of the C-19 methyl group (eg 19 norchoiesta-1,3,5 (10) triene-3-ol) also prevents ring breakdown. Note, however, hydroxylation of C-19 does not prevent all ring modifications.

Wakamatsu N, Hayashi M, Kawai H, Kondo H, Gotoda Y, et al. 1999. Mutations producing premature termination of translation and an amino acid substitution in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis associated with parkinsonism. J Neurol Neurosurg Psychiatry 67 195-198. 

Intramolecular alkylation has been used in the synthesis of the cyclopropane side chain of the marine sterols Glaucasterol95 and Petrosterol96. During the preparation of the latter the mesylate 1 was reacted with 1.0 equivalent of potassium-tcr -butoxide in tetrahydrofuran/ben-zene at 0°C to give the trans-substituted cyclopropane 2 in >70% yield. 

The proportions of delta 8-cholesterol and desmosterol in the serum rose while those of cholestanol, campesterol and sitosterol dropped, implying a decreased absorption of cholesterol and a compensatory increase in its synthesis. High basal precursor sterol proportions were predictive of a large decrement in titer of LDL cholesterol. It appeared that partial substitution of normal dietary lipid consumption with sitostanol was a safe and effective therapeutic measure for children with FH (Lees et al., 1977 Wang and Ng, 1999). The effect of a small amount of sitosterol, sitostanol and sitostanol esters dissolved in rapeseed oil on serum lipids and cholesterol metabolism in patients with primary hypercholesterolemia and various apolipoprotein E phenotypes on a rapeseed oil diet showed a diminution in TC and LDL-cholesterol levels in the serum (Gylling and Miettinen, 1994). 

Homberg, E. and Bielefeld, B. (1982) Sterols and methylsterols in cocoa butter and cocoa butter substitutes. Deut. Lebensm.-Rundsch., 78(3), 73-77. 

Even though cholesterol (substituted by other sterols in plants) is chemically classified as a lipid, the molecule is better grouped it into a special category, which is distinct from membrane proteins and (phospho- and sphingo-) lipids, when discussing its role in biomembrane stmcture and function. Cholesterol constitutes between 25% and 40% of the total lipid plus cholesterol fraction of most typical cell membranes. These numbers translate into a 33-66% fraction of the noncholesterol lipids, or considering its smaller size, about a 10-20%... 

Other biogenetically distinct cyclopropane side chain substitution patterns are typified by the sponge sterols calysterol (25) isolated from Calyx nicaensis, and petrosterol (19) found in Petrosia. Unlike the biosynthesis of gorgosterol-type (17)... 

Figure 4. Proposed partial model for the AmB-induced pore in the cell membrane. The drug acts as a counterfeit phospholipid, with the C,j hydroxyl, C,g carboxyl, and C g mycosamine groups situated at the membrane-water interface, and the Cj to and C gto chains aligned in parallel within the membrane. The heptaene chain will seek a hydrophobic envi-ronmentwhile the hydroxyl groups will seek a hydrophilic environment Thus, a cylindrical pore will be formed, the inner watt of which consists of the hydroxyl-substituted carbon chains of the AmB molecules, and outer watt of which is formed by the heptaene chains of the molecules and by sterol nuclei.

The general procedures previously outlined in this section for the formation of the carbon to azide bond have been widely employed in the steroid field, particularly as a stage in the stereospecific synthesis of aminosteroids. Bimolecular nucleophilic displacement reactions of sterols substituted with j -toluenesulphonyl, methanesulphonyl or halogeno groups etc. with azide ion proceeds with Walden Inversion and enables the stereospecific introduction of the azido group, which may then be reduced to an amino group. 

Rapson, W. S., Robinson, R. Synthesis of substances related to the sterols. II. New general method for the synthesis of substituted cyclohexenones. J. Chem. Soc. 1935, 1285-1288. 

Steroidal and other rigid alcohols have been used to derive a four-parameter equation for the calculation of 13C chemical shifts due to substitution by the OH group.57 Calculated 13C chemical shifts for all the likely saturated sterol side-chains with from seven to eleven carbon atoms have been tabulated and compared, where possible, with published data.58 Good agreement is found in most cases, with standard deviations of ca. 1 p.p.m. Only C-20, attached to the steroid nucleus, showed serious deviations (ca. + 5 p.p.m.) from calculated values. The results will be useful in future structural assignments of new sterols. 

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