La-Hydroxyvitamin

Whereas the intermolecular Heck reaction is limited to unhindered alkenes, the intramolecular version permits the participation of even hindered substituted alkenes, and many cyclic compounds can be prepared by the intramolecular Heck reaction [37]. The stereospecific synthesis of an A ring synthon of la-hydroxyvitamin D has been carried out. Cyclization of the (7T)-alkene 88 gives the (fT)-exo-diene 90, and the (Z)-alkene 91 affords the (Z)-exo-diene 92 [38]. These reactions are stereospecific, and can be understood by cis carbopalladation to form 89 and the. sun-elimination mechanism. 

Therapeutic Function Calcium regulator. Vitamin Chemical Name 9,10-Secocholesta-5,7,10(19)-triene-l,3-diol Common Name la-Hydroxycholecalciferol la-Hydroxyvitamin D3 Structural Formula ... 

Doxercalciferol (la-hydroxyvitamin D2) is under investigation for osteoporosis treatment. 

Tsuji, M. et al. (1994) la-hydroxyvitamin D3 inhibits type II collagen-induced arthritis in rats. FEBS Letters, 337, 248-250. 

Tabata, T. et al. (1986) The effect of la-hydroxyvitamin D3 on cell-mediated immunity in hemodialyzed patients. The Journal of Clinical Endocrinology and Metabolism, 63, 1218-1221. 

Morimoto, S. and Kumahara, Y. (1985) A patient with psoriasis cured by la-hydroxyvitamin D3. Medical Journal of Osaka University, 35, 51-54. 

Morimoto, S. et al. (1986) Treatment of psoriasis vulgaris by oral administration of la-hydroxyvitamin D3 - open-design study. Calcified Tissue International, 39, 209-212. 

Cycloaddition of 2-pyrones 5 to vinyl ethers 6 serves a key reaction in the synthesis of the important chiron 9, being an A-ring precursor to la-hydroxyvitamin D3. The best diastereose-lectivities were obtained when the appropriate chiral auxiliary was used in the diene component22 or a stereochemically matched pair of chiral diene and chiral catalyst was applied22. 

The MS-free BINOL-Ti complex 21 catalyzes the inverse-electron-demand Diels Alder reaction of methyl 2-pyrone-3-carboxylate (23) with vinyl ethers 24, yielding adducts 25 in 95-98% ee and excellent yields39. The adducts are converted into an important synthon for la-hydroxyvitamin D3. 

P450 llAl has now been foimd to be less specific than originally thought. Vitamin D3 is oxidized to a munber of different products, on the side chain, by P450 llAl, mainly 20-hydroxy- and 20,23-dihydroxyvitamin D3 [1943, 1944]. In addition, 23-hydroxy-, 17a-ltydroxy-, 17a,20-dihydroxy- [1944], and 20,22-dihy-droxyvitamin D3 [1945] are produced [1946]. la-Hydroxyvitamin D3 can yield la,20-diltydroxyvitamin Dj [1947], Several of these products have biological activities [1945, 1948] and are formed in vivo (animal models) [1949]. 

Expanding on the previous discussion, P450 27A1 catalyzes the 25-hydroxylation of vitamin D3 (Fig. 9.29), la-hydroxyvitamin Dj, vitamin D2, and la-hydroxyvitamin D2 and also the 27-hydroxylation of cholesterol and several derivatives (Fig. 9.31) [2563, 2564]. The cholesterol alcohols are further oxidized by the enzyme to aldehydes and then carboxylic acids [2565]. The available information suggests release of the intermediates in the pathway [2565]. The regi-oselectivity of the enzyme is considered to be a function of the distance of the hydroxylation site to the end of the side chain [2566]. 

Saarem K, Pedersen J1 (1985) 25-hydroxylation of la-hydroxyvitamin Dj in rat and human liver. 

Both the synthetic analog, la-hydroxyvitamin D3 (7), and la,25-hydroxyvitamin D3 are potent stimulators of intestinal calcium absorption in organ culture 37, 58) in rats and chickens 26,36,69,145,146,198) fed vitamin D3 and calcium deficient diets. The ratio of activities of la-hydroxy- and la,25-dihydroxyvitamin D3 compared to the activity of vitamin D3 itself reaches 1000 in parathyroidectomixed-thyroidectomized animals 146). However, what these ratios mean as regards the therapeutic value of la-hydroxyvitamin D3 or la,25-dihydroxyvitamin D3 is not easy to assess. In clinical situations of impaired calcium utilization, there normally would be an adequate supply of calcium, phosphorous, and vitamin D3 in the diet. However, in certain metabolic dysfunctions (see Section 6) both la- and la,25-dihydroxyvitamin D3 have been clearly demonstrated to have therapeutic value. 

Both la-hydroxyvitamin D3 and la,25-dihydroxyvitamin D3 increase bone formation and bone resorption in vitro and in the rachitic animal 100,153,183,188,197). 

The advances in our understanding of vitamin D3 metabolism which have been described in the previous sections have promoted the rapid use of some of these compounds in the clinic. Both la-hydroxyvitamin D3 and la,25-dihydroxyvitamin D3 have been studied in several disease states, such as chronic renal failure 28, 32, 33, 51, 71, 115, 144), hypoparathyroidism 74, 159), osteomalacia 23, 87), osteoporosis 106), and neonatal hypocalcemia 47,96). 

In osteomalacia associated with malabsorption problems and nutritional osteomalacia, small doses of la-hydroxyvitamin D3 and la,25-di-hydroxyvitamin D3 are efficacious. Clinical response is impressive even during the first week with doses as low as 0.25 pg daily. 

Bordier, P., M. M. Pechet, R. Hesse, P. Marie, and H. Rosenson Response of Adult Patients with Osteomalacia to Treatment with Crystalline la-Hydroxyvitamin D3. New Engl. J. Med. 291,866 (1974). 

Harmeyer, J., and H. F. DeLuca Calcium Binding Protein and Calcium Absorption after Vitamin D Administration. Arch. Biochem. Biophys. 133, 247 (1969). Harrison, I. T., and B. Lythgoe Calciferol and its Relatives. Part III. Partial Synthesis of Calciferol and of Epicalciferol. J. Chem. Soc. (London) 1958, 837. Harrison, R. G., B. Lythgoe, and P. W. Wright Calciferol and its Relatives. Part XVIII. Total Synthesis of la-Hydroxyvitamin D3. J. Chem. Soc. Perkin I 1974, 2654. 

Okamura, W. H., M. N. Mitra, R. M. Wing, and A. W. Norman Chemical Syntheses and Biological Activity of 3-Deoxy-la-hydroxyvitamin D3 an Analog of la,25-Di-hydroxyvitamin D3, the Active Form of Vitamin D3. Biochem. Biophys. Res. Comm. 60, 179 (1974). 

The Biological Activities of Pure Crystalline la-Hydroxyvitamin D3 and la,25-Dihydroxyvitamin D3. Mol. Cell Endo. 1, 305 (1974). 

---