3a-Cholestanol

Chloro-5-thiophenethiol, 50,106 3a-Cholestanol, 50, IS Chromium(II)-en perchlorate, 52, 62 Chromium(II) salts, standardization procedure for solutions, 52, 64 Chromium trioxide-pyridine complex, 52,5... 

An entirely different approach to specific dehydrogenation has been reported by R. Breslow39 and by J. E. Baldwin.4,1 By means of this approach it was possible, for example, to convert 3a-cholestanol (2) to 5a-cholest-14-en-Ja-ol (3). thus introducing a double bond... 

We used the radical relay process, chlorinating C-9 and then generating the 9(11) double bond, in a synthesis of cortisone 91 [158]. This is a substitute for manufacturing processes in which C-9 or C-ll are hydroxylated by biological fermentation. Also, with templates that directed the chlorination to C-17 of 3a-cholestanol, such as that in 90, we were able to remove the steroid sidechain [159-162]. Using an electrochemical oxidation process, we could direct chlorination by simple chloride ion with an iodo-phenyl template [163]. A general review of the processes with iodophenyl templates has been published [164]. 

Remote functionalization of steroids (4,264-265 5,352-353). Breslow et al have modified their earlier procedure for chlorination of steroids at C9 or Ci4 by use of an external source of chlorine radicals, lodobenzene dichloride or sulfuryl chloride. Thus irradiation of the m-iodobenzoate of 3a-cholestanol (1) and lodobenzene dichloride in methylene chloride for 28 min. at 25° followed by saponification and acetylation leads to a mixture of 3a-cholestanyl acetate (18.4%) and the acetate of A -cholestene-3a-ol (2, 66%). Application of the... 

Scheme 6-2 Photochemical remote functionalization of 3a-cholestanol using a tethered benzophenone.

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-... 

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... 

The sulfur atom of thiophene can function as a template for radical-relay chlorinations. An excellent application of this concept is in the regiospecific chlorination of a steroid molecule <82JA2045>. Reaction of (2-thienyl)trichlorosilane with 3a-cholestanol gave the tris(cholestanyl)-silylether (623). When this was irradiated in CH2CI2 solution with 2 equiv. of sulfuryl chloride and a catalytic amount of AIBN, the 9(1 l)-olefin was produced in 45% yield after alkaline hydrolysis and elimination of HCl. Apparently, a chlorine atom becomes attached to the sulfur of the thiophene ... 

Recently, Jones and Grayshan have reported the reaction of lithiodithiane derivatives with steroidal epoxides to effect preparation of modified steroids. Treatment of 2 ,3a-oxiranyl-5a-cholestane (46) with 2-lithio-l,3-dithiane, followed by desulphurization, yielded the 2j8-methyl-3a-cholestanol 47 (equation 48). Conversely, reaction with the epimeric epoxide 48 furnished 3a-methyl-5a-cholcstan-2j8-ol (49) (equation 49) . 

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. 

Dilithium derivatives 102-105 were generated by reductive opening of epoxides derived from D-glucose, D-fmctose, estrone and cholestanone, respectively, and trapped with different electrophiles. In this way, 6C-substituted 6-deoxy-D-glucose, 3C-substituted D-psycose [85], 17C-substituted-17/8-estradiol and 3C-substi-tuted-3a-cholestanol [91] derivatives were prepared. 

Epicoprostanol (5/3-cholcstan-3a-ol), cholestanol (5 -cholcslan-3/3-ol), cholesterol (cholesta-5-en-3/hol), lathosterol (cholesta-7-en-3/i-ol), desmosterol (cholesta-5,24-dien-3/hol), and 7-dehydrocholesterol (cholesla-5,7-dien-3/3-ol) (Sigma). 

Further experiments, made using a template selective for position 3, permitted a high stereocontrol of the reaction involving the natural substrate cholestan-3-one (22). This was reduced to the corresponding, less readily available, cholestanol 3a-OH, with a ratio 3a-OH/3/i-OH = 72/28. The corresponding result for a hydride reduction in solution usually gave 3oc-OH/3/ -OH = 10/90. 

Alcchols - iodides. Aliphatic primary and secondary alcohols react with (1) in THF, benzene, or hexane at 35-50° to give the corresponding iodides, usually in high yield. Even sierically hindered alcohols react, although in somewhat low yields. The reaction proceeds with inversion thus 3j5-cholestanol is converted into 3 -iodocholes-tane in 84% yield. Cholesterol is converted into the previously unknown 3a-iodo-A -cholestene (40% yield). 

This selectivity for axial alcohol oxidation is not, apparently, universal since both the 3a- (18) and the 3P-cholestanol (19) are oxidized to cholestanone (20) with a better yield obtained on oxidation of the equatorial, 3p-alcohol (Eqn. 21.31). Selectivity in the platinum catalyzed oxidation of steroid alcohols. 

OH - I. Verheyden and Moffatt1 recommend DMF rather than the commonly used benzene as solvent for conversion of alcohols into iodides by this reagent. The reaction in this solvent occurs at room temperature and is usually rapid. Cholestanol is converted by the reagent in anhydrous DMF in 2 hr. at 25° into 3a-iodocholestane in 57% yield. The reaction of the reagent with alcohols is believed to proceed via... 

Other clinical signs consist of progressive neurologic dysfunction, cataracts, and premature atherosclerosis (SI). The disease is inherited as an autosomal recessive trait, but is usually only detected in adults when cholesterol and cholestanol have accumulated over many years (S2). Biochemical features of the disease include striking elevations in tissue levels of cholesterol and cholestanol and the presence of unusual bile acids, termed bile alcohols, in bile. These bile alcohols are mainly 5 -cholestane-3a,7a,12a,24S, 25-pentol, Sp-diolestane-3a,7a,12a,23 ,25-pentol and 5P-du)lestane-3a,7a,12a,25-tetrol (S2). As chenodeoxycholic acid is deficient in the bile of patients with CTX, it was postulated that early bile salt precursors are diverted into the cholic acid pathway and 12a-hydroxy bile alcohols with an intact side chain accumulate because of impaired cleavage of the cholesterol side chain and decreased bile acid production (S2). HMG-CoA reductase and cholesterol 7a-hydroxylase activity are elevated in subjects with CTX (N4, N5), so that sufficient 7a-hydroxycholesterol should be available for bile acid synthesis. 

This rare inherited hpid storage disease is characterized by xanthomas, progressive neurological dysfunction, cataracts and the development of xanthomatous lesions in the brain and lung. In contrast to other diseases with tendon xanthomatosis, plasma cholesterol levels are remarkably low. Large deposits of cholesterol and cholestanol are present in most tissues, and the concentration of cholestanol is 10-100 times higher than normal. Salen and collaborators have made extensive and elegant studies on the various metabolic aspects of this disease [184,185,187-192]. They have conclusively shown that there is a subnormal synthesis of bile acids and that the metabolic defect is an impaired oxidation of the cholesterol side chain. The synthesis of chenodeoxycholic acid is reduced more than that of cholic acid. These patients excrete considerable amounts of bile alcohol in bile and faeces. The bile alcohols have been identified as 5)S-cholestane-3a,7a,12a,25-tetrol, 5 8-cholestane-3a,7a,12a,24,25-pentol and 5/8-cholestane-3 ,7a,12a,23,25-pentol. Two different explanations for the accumulation of these bile alcohols have been presented. 

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