Cholestanol formation

The PCBM methyl ester can be used for coupling amine-containing ligands after removal of the methyl group and activation of the carboxylate using a number of different reaction strategies. Hummelen et al. (1995) successfully coupled cholestanol and histamine to the fuller-ene-PCBM derivative (after acid chloride formation) for use in fabrication of photodetectors and biological studies, respectively. For specific applications of PCBM-fullerenes, see Shaheen et al. (2001), Brabec et al. (2001), Yu et al. (1995), Mecher et al. (2002), Meijer et al. (2003), van Duren et al. (2004), and Anthopoulos et al. (2004). 

The relative reactivity of primary and secondary positions adjacent to oxygen can be strongly dependent on the nature of the oxidant. For example, treatment of the methyl ethers (8) and (10) with chromium trioxide in acetic acid leads to the formation of the formates (9) and (11), respectively (equations 13 and 14). In direct contrast, n-decyl methyl ether is oxidized exclusively to methyl n-decanoate (83% yield) by ruthenium tetroxide (equation 11). Under similar reaction conations, 3 -cholestanol methyl ether gives cholestan-3-one as the mqjor product, togedier with traces of the corresponding formate. Therefore, at least in the case of ruthenium tetroxide, primary positions appear to be more reactive than tertiary. 

This disease is caused by an autosomal recessive gene mutation (localization on chromosome 2) and leads to an enzyme defect in mitochondrial steroid-27 hydroxylase. The enzyme itself is responsible for the breakdown of cholesterol side-chains in bile acid synthesis. Such a defect results in the formation of cholestanol, a reduction product of cholesterol. It is deposited in various organs, particularly in the tendons and in the nervous system, because the substance cannot be broken down adequately. Deposition takes place conjointly with cholesterol. (209, 210)... 

A specific finding in patients with CTX is the accumulation of cholestanol. The major pathway in the formation of cholestanol from cholesterol seems to involve intermediary formation of 4-cholesten-3-one and 5 -cholesten-3-one. The rate-limiting step in this conversion is probably the formation of 4-cholesten-3-one from cholesterol [196-198]. It is difficult to understand, however, how the oxidation of... 

These results were confirmed by Caira et al. (85,133), who found gallstones in New Zealand rabbits of both sexes fed 0.5 g cholestanol for 9 days or more. They observed that the newly formed stones were gelatinous in consistency and were accompanied by marked mucosal inflammatory changes (edema, round cell infiltration, and fibrosis). Choledocholithiasis developed readily in cholecystectomized animals, indicating that the liver bile itself was abnormal and that a gallbladder was not essential for stone formation. Similar concretions formed in two of 20 guinea pigs fed 0.25 g cholestanol daily, but none formed in rats fed 0.125 g daily. 

Mosbach and Bevans (134) showed that cholestanol-induced cholecystitis and cholelithiasis could be inhibited by the simultaneous administration of dehydrocholic acid and that the extent of inhibition depended on the relative concentrations of the two steroids. Similar observations were made by Ricci et al, (135). Deoxycholic and cholic acids were also effective inhibitors (136), but hyodeoxycholic acid did not suppress gallstone formation and appeared to increase biliary tract inffammation. Several non-bile acid choleretics were without inhibitory effects (136). Lindelof and van der Linden (32) found that intravenous injections of cholecystokinin every 8 hr did not suppress and may actually have enhanced gallstone formation. The inhibition of cholelithiasis by dehydrocholic, deoxycholic, and cholic acids was not accompanied by a decrease in cholestanol absorption but did result in increased tissue cholestanol levels, suggesting a decrease in the conversion of this sterol to bile acids (134,136). Conversely, methyl testosterone apparently inhibited stone formation by interfering with cholestanol absorption, since tissue and serum levels of cholestanol were reduced (137). Olive oil has been shown to facilitate stone formation (138), perhaps by enhancing cholestanol absorption (137). 

Hydroxycholesterol is converted into both tigogenin (64) and solasodine (46). 16p-Hydroxy-5a-cholestanol (60), 16p,26-dihydroxy-5a-cholestanol (61), and 16p-hydroxy-22-oxo-5a-cholestanol (62) are convertible into spirostanes [such as tigogenin (64)], but not into spirosolanes (such as 52 and 46). TTie 16-hydroxy group appears to be introduced after formation of the oxaazaspirane unit (ring F) (Fig. 36.15). 

A report describes the stereoretentive chlorination of cyclic alcohols with thionyl chloride and TiCl4. Evidence suggests formation of a nonplanar carbocation and frontside attack of the chloride nucleophile. The proposed mechanism is supported by product studies and DFT calculations. The studies include stereoselective chlorinations of Z-menthol and cholestanol derivatives. 

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