La-Hydroxy vitamin

The stereospecific synthesis of an A ring synthon of la-hydroxy vitamin D has been carried out. The ( )-allcene is cyclized to give the (E -c.xo-diene 155, and the (Z)-allcene affords the (Z)-e,xo-diene 156 stereospecifically[125,126]. These results can be understood by the cis addition and syn elimination mechanism. 

Reduction.—la,2a-Epoxycholesta-4,6-dien-3-one (63) has been reduced by lithium-liquid ammonia under strictly controlled conditions to give a mixture which included 45% of the la,3/3-dihydroxy-5a-6-ene (64), and 20% of the A5-isomer.88 The A6-compound was used in the preparation of la,3/3-dihydroxycholesta-5,7-diene, required for the synthesis of la-hydroxy-vitamin D3. 

Irradiation of the 5,7-diene gave the previtamin, which was isomerized and saponified to give la-hydroxy-vitamin D3. For the last synthesis of la-hydroxy-7-dehydrocholesterol recorded here, cholesta-l,4,6-triene-3-one was again used as starting steroid.122 Deconjugation of this trienone with strong base followed by immediate reduction with calcium borohydride led to the unstable 3/3-hydroxycholesta-l,5,7-triene which, without isolation, was converted into the 1,4-addition product (265) upon reaction with 4-phenyl-l,2,4-triazoline-3,5-dione. 

Cycloaddition of 4-phenyl-3//-l,2,4-triazole-3,5(4//)-dione to provitamin D3 affords exclusively the product formed by addition to the least hindered a-face of the more reactive diene, the structure was determined by X-ray8. The diastereoselectivity appears to be determined by the steric effect of the rran.v-hydrindane system, although the mechanism has not been elucidated. The cycloaddition of 4-phenyl-3//-l,2,4-triazole-3,5(4//)-dione was exploited to temporarily protect the diene group in the syntheses of la-hydroxy vitamin D3 7 a(X = H)8,9 and la,25-dihydroxy vitamin D3 7b (X = OH, starting from 25-hydroxy provitamin D3)10. Complete stereocontrol was observed in the cycloreversion step. For related cycloadditions to vitamin D3 see Section 7.2,10.3.4. 

As discussed in Sect. 2, a-selanylalkyllithiums, generated from selenoacetals, can react with various electrophilic reagents, i. e. chloromethyl isopropyl ether for the synthesis of la-hydroxy vitamin D analogues [25] and with propargylic chloride derivatives for the preparation of alkynols [26]. A synthesis of vinyl-cyclopropane derivatives from l,4-dichloro-but-2-ene was achieved with trans stereoselectivity (>93%) in 68-89% yield. This one-pot cyclization, via an intramolecular allylic substitution, required the presence of two equivalents of u-BuLi [26] (Scheme 23). 

A connective synthesis of alkynes inspired by the Julia alkenation was developed by Lythgoe and coworkers for the synthesis of la-hydroxy vitamin D3, as shown in Scheme 34. The P-keto sulfone (101) derived by condensation of the the metalated sulfone (99) with the ester (100) was converted to the enol phosphate (102), which on reductive elimination gave the enynene (103). 

H N.m.r. studies show that ring A of vitamin D3 exists in solution as an equimolar mixture of chair conformers, with the 3-hydroxy-group axial and equatorial, respectively. The conformational equilibrium is not appreciably different in la-hydroxy-vitamin D3, and is unaffected by variations in side-chain structure. Added... 

A new synthesis of la-hydroxycholecalciferol (la-hydroxy-vitamin D3) from cholesterol employs transformations in rings A and B which differ only in detail from an earlier sequence for introduction of the la-hydroxy-group the la,2a-epoxy-3j8,6j8-diol derivative (382) was the key intermediate, allowing regeneration of... 

Eine bequeme Synthese fur la-Hydroxy-Vitamin D3 bedient sich der photocheniischeu Stufc von l ,3jS-Diacctoxy-cholestadien-(5,7) znm loc,3f -Diacetoxy-9,10-seco-cholestatrien-(<510,6,< )3. t)ber die bei Bestrahlung von Vitamin D3 in Athanol mit A > 250 nm anfallenden Produkte s. lit.4. 

Saarem, K. and J.I. Pedersen (1985). 25-Hydroxy lation of la-hydroxy vitamin Dj in rat and human liver. Biochim. Biophys. Acta 840, 117-126. 

The protein was expressed in E. coli using an E. co//-optimized cDNA [2670]. The pmified enzyme, reconstituted with recombinant adreno-doxin and NADPH-adrenodoxin reductase, did not catalyze the oxidation of cholesterol, vitamin Dj, la-hydroxy vitamin D3, or 25-hydroxyvita-min D3. In other studies, none of a test set of pro-carcinogens [350] was activated to a genotoxic product. 

Cork, D. J., M. R. Haussler, M. J. Pitt, E. Rizzardo, R. H. Hesse, and M. M. Pechet la-Hydroxy vitamin D3 A Synthetic Sterol which is Highly Active in Preventing Rickets. Endocrin. 94, 1337 (1974). 

Kaneko, C., S. Yamada, A. Sugimoto, Y. Eguchi, M. Ishikawa, T. Suda, M. Suzuki, S. Kakuta, and S. Sasaki Synthesis and Biological Activity of la-Hydroxy vitamin D3. Steroids 23,75 (1974). 

Morisaki, M., A. Saika, K. Bannai, M. Sawamura, J. Rubio-Lightbourn, and N. Ikekawa. Synthesis of Active Forms of Vitamin D. X. Synthesis of la-Hydroxy-vitamin D3. Chem. Pharm. Bull. 23, 3272 (1975). 

Okamura, W. H., M. N. Mitra, M. R. Pirio, A. Mourino, S. C. Carey, and A. W. Norman Studies on Vitamin D and Its Analogs. 13. 3-Deoxy-3a-methyl-la-hydroxy-vitamin D3, 3-Deoxy-3a-methyl-la,25-dihydroxyvitamin D3 and la-Hydroxy-3-... 

Barton DHR, Hesse RH, Pechet, MM, Rizzardo E. Convenient synthesis of la-hydroxy-vitamin D3. J. Am. Chem. Soc. 1973 95 2748-2749. 

During recent years it has become evident that the 1-hydroxylation of vitamin D or 25-hydroxyvitamin D in the kidney is essential for its biological activity. It was therefore conceivable that treatment with synthetic vitamin D analogues with a hydroxyl group in the 1 position would be effective in the treatment of renal osteodystrophy. Both la,25-dihydroxyvitamin D (57 ) and la-hydroxy vitamin D (58, 59 ) have been used succesfuUy, but careful monitoring of serum calcium is necessary since sudden hypercalcaemia can occur. 

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