La-Hydroxycholesterol

A shorter but less selective route to la-hydroxycholesterol has been described by Kaneko (90). Cholesta-l,4-dien-3-one (90) was deconjugated to its -isomer and then reduced with borohydride to give 3P-hydroxy-cholesta-1,5-diene (91). Selective hydroboration followed by alkaline peroxide treatment afforded a 30% yield of a separable 1 1 mixture of la- and 2a-hydroxycholesterol (89) and (93). If the acetate (92) was hydrated by an oxymercuration-demercuration procedure, a mixture of the 2 3-hydroxycholesterol (94) (14%) and la-hydroxycholesterol (89) (26%) was isolated after saponification (118). When starting with the readily available cholesta-l,4,6-trien-3-one, the deconjugation and reduction afforded 3P-hydroxycholesta-l,5,7-triene (95) (59). The 5,7-diene system was then protected as its 4-phenyl-l,2,4-triazoline-3,5-dione (PTD) adduct (96). Treatment of (96) with m-chloroperbenzoic acid gave a 5 3 mixture of the lp,2p- and la,2a-epoxides (98). More recently, Whalley and his co-workers have found that if the dimethyl-t-... 

A unique and surprisingly efficient synthesis of la-hydroxycholesterol has been described by Mihailovic and co-workers 114). The 5a-hydroxy-cholestanyl acetate (100), obtainable in high yield from cholesterol, was converted by irradiation with visible light in the presence of mercuric oxide and iodine into the 5,10-secosterol (101). Irradiation of (101) with a high pressure mercury lamp resulted in intramolecular cyclization to give the oxetane (102) as the major product. Treatment of this material with hydroiodic acid in acetic acid afforded la-hydroxycholesterol 3-acetate (103) in 20% overall yield from cholesterol. 

Morisaki, M., K. Bannai, and N. Ikekawa Synthesis of Active Forms of Vitamin D. II. Synthesis of la-Hydroxycholesterol. Chem. Pharm. Bull. 21, 1853 (1973). 

The C-24 configurations of the isomeric 24-hydroxy-cholesterols have been firmly established5 by chemical correlation with the known 24R,25- and 24S,25-epoxyderivatives, and by the modified Horeau method.6 With the configurations known, differences in 13C n.m.r. spectra and in polarity were used to establish the configurations of the la,24-dihydroxy-derivatives of vitamin D3.5 Cerebrosterol , isolated from brain tissue, is 24S-hydroxycholesterol,6a but the natural 24,25-dihydroxy-vitamin D3 has the (24R) configuration. The C-24 isomeric 24,25-dihydroxy-cholesterols have also been separated and characterized.7... 

Recent findings show that vitamin D3 must be hydroxylated at C-25 by the liver and then at C-la by the kidney to 1 a,25-dihydroxy-vitamin D3 before it can induce calcium transport. It is therefore not surprising to find several reports on the synthesis of both the la,25-dihydroxy-vitamin and la,25-hydroxycholesterol. 

Mast N, Norcross R, Andersson U, Shou M, Na-kayama K, Bjorkhem I, Pikuleva lA (2003) Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry 42 14284-14292 Bjorkhem I, Starck L, Andersson U, Lutjohann D, von Bahr S, Pikuleva I, Babiker A, Diczfalusy U (2001) Oxysterols in the circulation of patients with the Smith-Lemli-Opitz syndrome abnormal levels of 24S- and 27-hydroxycholesterol. J Lipid Res 42 366-371... 

The bile acid derivative, 3P-acetoxychol-5-en-24-oic acid (32), has been converted in two steps in high yield to 25-hydroxycholesterol (80). The homocholenic acid derivative (33) prepared by a photochemical Wolff rearrangement in this transformation served as a key early intermediate in the first chemical synthesis of la,25-dihydroxycholecalciferol (171). Lithocholic acid, likewise, has been converted to an intermediate (16) used for the preparation of the dihydroxyvitamin (35). Hyodeoxy-cholic acid (34) also shows promise of being a desirable starting material for 25-hydroxycholesterol (132). 

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