Vitamin D3 analogs

Fluorinated Vitamin D3 Analog with in vivo Anticancer Activity ... 

Madsen and Hyldtoft proposed a novel zinc-mediated domino reaction to give functionalized dienes.267 Using a Barbier reaction, different approaches of interesting compounds have been reported vitamin D3 analogs, 1 bicy-... 

Cl. Campbell, M. J., Reddy, G. S., and Koeffler, H. P., Vitamin D3 analogs and their 24-oxo metabolites equally inhibit clonal proliferation of a variety of cancer cells but have differing molecular effects. J. Cell. Biochem. 66,413-425 (1997). 

D13. De Vos, S., Holden, S., Heber, D., Elstner, E., Binderup, L., et al., Effects of potent vitamin D3 analogs on clonal proliferation of human prostate cells lines. Prostate 31, 77—83 (1997). 

Skowronski, R. J., Peehl, D. M., and Feldman, D., Actions of vitamin D3, analogs on human prostate cancer cell lines comparison with 1,25-dihydroxy vitamin D3. Endocrinology 136, 20-26(1995). 

Sulfolenes are valuable precursors of 1,3-dienes. Thermolytic desulfonylations of 2,S-disubstituted derivatives lead exclusively to ( ,Z)-dienes in agreement with the symmetry rules. The stereoselectivity of the reaction is dramatically changed however by carrying out the reaction in a protic solvent and in the presence of a base (which probably isomerizes the trans sulfolene to the cis isomer), since ( , )-dienes are now obtained exclusively and contrary to the symmetry rules. a-Metallo sulfolenes may be viewed therefore as masked 1,3-dienyl anion equivalents ( C =>C—C =C—R). The above mentioned set of reactions has been used for the regioselective syntheses of 6- and 16-alkyl-substituted vitamin D3 analogs, as well as rrani-3-ocimene and oi-famesene. ... 

Intermolecular alkyl-alkyl couplings have been performed with a complex molecule, e g., a fragment of vitamin D, attached to a sohd support via a sulfonate linkage, and an alkyl Grignard reagent such as (89) [207]. The Cu-catalyzed reaction was designed to attach various alkyl chains at the 22-position of atom Tl of vitamin D3 analogs (88) (Scheme 20). 

ZnBr2-catalyzed IMDA cycloaddition of the 2-pyrone 152 (Scheme 37), tethered with a chiral enol silaketal, provided (+)-153-exo in 74% yield, along with a small amount of (-)- 5 i-endo <95JOC1617>. In this case, the -geometry of the dienophile was not preserved during the cycloaddition, as in the cycloaddition of 3,5-dibromo-2-pyrone with dimethyl maleate (cf. entry 9, Table 2), implying a stepwise reaetion mechanism. The isolated exo product (+)-153 was used as the key intermediate for the asymmetric total synthesis of a 2-alkyl-vitamin D3 analog. 

Calcitriol is a highly potent vitamin D3 analog (see Figure) used in the therapy of secondary hypoparathyroidism and osteomalacia. 

Search for and development of active vitamin D3 analogs 05Y728. 

Evidence for antarafacial [1,7] hydrogen shifts in a vitamin D3 analog. (Adapted from reference 52.)... 

In addition, 19-nor vitamin D3 analogs are substrates [2480], The products of the reactions of P450 llAl on vitamin D3 are also substrates [2645, 2646],... 

FIGURE 10.2 Building blocks for the combinatorial synthesis of vitamin D3 analogs. 

In Chapter 10, Doi and Takahashi describe several classes of natural product-based libraries prepared in their group including vitamin D3 analogs, trisaccharides, macrosphelide analogs, and cyclic depsipeptides. 

Yukohiri, S., Posner, G.H., and Guggino S. 1996. Vitamin D3 analogs stimulate calcium currents in rat osteosarcoma cells. J. Biol. Chem. 269 23889-93. 

New vitamin D3 analogs 2alpha-(2,3-Dihydroxypropoxy)- and 2alpha-(2-hydroxypropoxy)-active vitamin D3 with highly potent VDR agonism... 

Synthesis of Vitamin D3 Core 248 Phosphine oxide 245 (1.1 equiv) was dissolved in anhydrous THF, cooled to —50°C, and treated with nBuLi (1.0 equiv) under argon. The mixture was then transferred via cannula to a solution of resin-bound ketone 244 (0.72 equiv) in anhydrous THF and reacted at —40°C to — 10°C for 3 hours to yield immobilized triene 246. Concomitant alkylation and cleavage from the polymer-support occurred via a copper-promoted Grignard reaction with 247 at room temperature for 3 hours. The crude protected product was then immediately treated with CSA in methanol and water at room temperature for 6 hours to afford vitamin D3 analog 248 in 47% yield (from 244). 

SCHEME 3.44. Synthesis of a 72-membered library of vitamin D3 analogs. 

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