Cholestanol esters

In a full paper describing this and other functionalizations of steroids tethered to benzophenones [34], it was revealed that the 3a-cholestanol ester 8 of benzophenone-4-acetic acid afforded, after hydrolytic removal of the tether, A " -3a-cholestenol 4 as the product along with the diphenylcarbinol from reduction of the benzophenone. The short tether did not permit insertion into the C-14-H bond, so after the oxygen atom of excit-... 

The remote photochemical oxidation by means of a rigid benzophenone reagent attached to a hydroxy-group" has been further investigated with the cholestanol ester (314) as well as other steroid molecules (see Chapter 1, ref. 360). " ... 

The values below refer to total plasma cholestanol concentration determined by GC-MS analysis following hydrolysis of cholestanol esters. 

Only one of these methods, namely the reaction of halides with lithium aluminum deuteride, is a true displacement reaction, following the same course as the previously discussed displacement of sulfonate esters (section Vl-A). Thus, lithium aluminum deuteride treatment of 7a- and 7jS-bromo-3 -benzoyloxy-5a-cholestanes (195) and (196) gives the corresponding deuterium labeled cholestanols (197) and (198) respectively." ... 

The liver plays a decisive role in the cholesterol metabolism. The liver accounts for 90% of the overall endogenic cholesterol and its esters the liver is also impli-cated in the biliary secretion of cholesterol and in the distribution of cholesterol among other organs, since the liver is responsible for the synthesis of apoproteins for pre-p-lipoproteins, a-lipoproteins, and P-lipoproteins which transport the secreted cholesterol in the blood. In part, cholesterol is decomposed by intestinal micro-flora however, its major part is reduced to coprostanol and cholestanol which, together with a small amount of nonconverted cholesterol, are excreted in the feces. 

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). 

SN2-Suhf.titutions. The configuration of secondary alcohols can be inverted by reaction of the mesylate with cesium propionate (65-100% yield). The reagent reacts with secondary alkyl halides to form the ester of the inverted alcohol (85 100% yield). Some elimination occurs in reaction of the mesylates of menthol and cholestanol. ... 

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). 

Remote chlorination (6, 298-300). Breslow has extended his remote functionalization of steroids to a double functionalization at C, and Cn of cholestanol. Thus the ester (2) of cholestanol, prepared from a p-iodophenylnicotinic acid, when treated with 1 (1.2 equiv.) is chlorinated selectively at C9 chlorination of the same ester with 3 equiv. of C6H5IC12 results in chlorination at C9 and at C17 in quantitative yield. The para-iodo group of the ester plays an important role in this remote chlorination. 

Turning now to the reactions of cholestanols, it has been shown that when dilute solutions of non-activated carboxylic esters such as 3/3-acetoxy-5a-cholestane are irradiated at 254 nm in aqueous HMPA the corresponding alkanes are formed in high yields.150... 

The selectivity of the radical relay chlorination is striking. In the case of the enone (13 Sdieme 18), and in related compounds with A-ring dienones, the m-iodobenzoate template at C-17 directs chlorination to C-9 and not to die preexisting functional groups of (13). The selective chlorination of C-9 seems to be quantitative, although in the first report the A "Lalkene (14) was isolated in only 77% yield. Later work has shown that the overall introduction of this double bond can have yields in the 90-93% range, and good yields for this reaction have also been reported from another laboratory. Template-directed radical relay chlorination on the a-face of steroids has also been successful in the a/b cu-coprostanol steroid series,and in the cholestanol series with iodophenyl templates linked by amide, ether, or sulfonate functions rather than carboxylic esters. ... 

Esters of cholesterol cannot be directly attacked by the enzyme [60,61]. Rat liver microsomes catalyse 7a-hydroxylation of cholestanol at a rate comparable to that of cholesterol [62]. Since 7a-hydroxylation of cholestanol is stimulated after treatment with cholestyramine, it appears likely that the same enzyme is involved as in hydroxylation of cholesterol. Shght changes in the side chain lead to marked loss of activity [63,64]. Loss of a terminal methyl group reduces the rate to about 50% and addition of an ethyl group at C-24 (sitosterol) leads to almost complete loss of the activity. From a study with a great number of structurally closely related steroids, Aringer concluded that cholesterol 7a-hydroxylase requires a rather flat steroid (A", A or 5a) and an equatorial or quasi-equatorial hydroxyl group at C-3 [65]. 

Ethers, Esters, and Related Derivatives of Alcohols.—5a-Cholestanyl methyl ether has been cleaved inter alia) and converted into 5a-cholestanol by successive treatment with trimethylsilyl iodide and water.Pyridinium toluene-p-sulphonate has been reported as an efficient and mild catalyst for the conversion of alcohols into their tetrahydropyranyl ethers.Bile acids were efficiently performylated by treatment with 90% HCO2H-HCIO4. Selective base-catalysed... 

Breriow et air have since extended this remote halogenation to the conversion of /3-cholestanol into androsterone (11) by selective halogenation at C17. In order to place the internal chlorinating reagent in proximity to the Civposition, 30-cholestanol is converted, with inversion, into the ester (7). Irradiation of (7) and iodobenzene dichloride gives an intermediate Cn-chloro compound that is... 

We irradiated a solution of phenyliodine dichloride with the w-iodobenzoate ester 12 of 3a-cholestanol and found that C-9 chlorination occurred selectively, while no such selectivity was seen without the iodine atom on the benzoate ester [37]. Various controls established that we were not simply converting the attached iodoaryl template to its... 

Trlfluoroacetylation. Trifluoroacetylation of a hydroxyl group was first observed as a side reaction in the epoxidation of an unsaturated hindered alcohol with trifluoroperacetic acid at room temperature. This reaction is apparently general thus trifluoroacetylation was observed in the case of cyclohexylmethanol (557 ) and 3/S-cholestanol (60%). The esters are easily hydrolyzed by chromatography on silica gel. ... 

The ester of 3-a-cholestanol with p-iodophenylacetic acid held the iodine in such a position that an attached chlorine atom could reach the hydrogen of C-14, but not... 

Several synthetic glycosides of adrenal corticosteroids have been prepared (W). The deoxycorticosterone glucoside is more soluble in water than the aglycon and exhibits full physiological activity in maintaining the life of adrenalectomized rats (21). Synthetic glucosides of cholestanol and epi-cholestanol (22) and the methyl esters of several sterol gaJactosiduronic acids (23) are reported. 

What has been described as biomimetic control of chemical selectivity is already possible. When the steroid 3a-cholestanol is esterified with 4-iodophenylacetic acid and treated with chlorine in the dark the iododichloride can generate free radicals which attack the C-17 of the steroid. The shorter ester derived from benzoic acid attacks C-9 (Figure 6.33). In another context metal porphyrin complexes have been devised which can hydroxylate hydrocarbons (Figure 6.34). Many more ideas of this kind are likely to follow a better understanding of the mechanisms of enzyme catalysis. 

Figure 6.33 The biomimetic chlorination of steroids. The dichloride of 3a- (4-iodophenylacetyl)-cholestanol (1) activates the C-14 of the steroid nucleus, while the dichloride of the shorter 3-iodobenzoate ester (2) activates C-9. A chloride radical is delivered to these carbon atoms from a second molecule of the respective iodochlorides, and for this reason the chlorine atom derived from (1) lies above the plane of the steroid nucleus, while that derived from (2) lies below it. After Breslow, R. (1980) Acc. Chem. Res. 13, 170...

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