Synthesis of 17-epi-Calcitriol from a Common Androstane Derivative, Involving the Ring B Photochemical Opening and the Intermediate Triene Ozonolysis

Abstract

An efficient synthesis of 17-epi-calcitriol 2, an epimer of natural hormone, via 17-epi-cholesterol 5a is described. Synthesis of 5a includes palladium-catalyzed cyclopropanation of the common androstane derivative 7 with an alkyl diazoacetate, reductive fission of the less shielded side of cyclopropane carboxylic acid esters 6, oxidation of the products into acid 11a, and alkylation of ester 11b. Photolysis of 7,8-dedydro-17-epi-25-hydroxycholesterol 19b and consecutive thermal rearrangement gave a mixture of several products that was subjected to ozonolysis to provide, after chromatography, hydroxy ketone 3a. The silyl derivative 3b was coupled with the respective ring A building block.

Steroids: partial synthesis in medicinal chemistry

“…The ability of calcidiol (25-hydroxyvitamin D 3 ) to inhibit cell growth and control cell differentiation and proliferation, together with the association between vitamin D 3 levels and a reduced risk of prostate cancer, has attracted considerable interest. 130 Syntheses of a number of vitamin D analogues including 17epi-calcitriol, 131 derivatives of 1a,25-dihydroxy-19-norvitamin D 3 bearing substituents at C-2, 132,133 and other ring A analogues, 134,135 have been reported. The effect of modifications of the side chain have continued to be explored.…”

Total Synthesis of a CD-Ring: Side-Chain Building Block for Preparing 17-epi-Calcitriol Derivatives from the Hajos–Parrish Dione

“…Oxidation of 22 with PDC 19 afforded the hydroxy ketone 4 identical in all respects with the product obtained previously from a steroid starting material. 2 In conclusion, the trans-hydrindan derivative 4, being a key building block for the synthesis of 17-epi-calcitriol 2, has been prepared from the HajosÀParrish dione 3 in 24 steps, 14.97% overall yield. The method for transforming of 3 into 6 has been improved and amended to a gram-scale operations.…”

“…Eventually, the ketone 9 was transformed into enol triflate 10, and this derivative was treated with tributylammonium formate in the presence of Pd(PPh 3 ) 2 (OAc) 2 to afford 11 (86% in two steps). 11 The usual modus operandi for cyclopropanation of alkene 11 would involve its reaction with ethyl diazoacetate induced by a rhodium 12 or palladium catalyst 2,13 [often Pd(OAc) 2 or Rh 2 -(AcO) 4 ]. After some experimentation, we have found that an inexpensive and easy to prepare copper catalyst, 14 CuI 3 P-(OMe) 3 , gives the best results with regard to both the product purity and the yield.…”

1,3‐Chirality Transfer by Fragmentation of Allylsulfinic Acids: A Diastereoselective Approach to Vinyl Bromides Related to trans‐Hydrindane or trans‐Decalin

“…Vinyl halides are important intermediates in convergent syntheses owning to their applications in various cross‐coupling reactions 1. In conjunction with our work in the field of vitamin D synthesis,2,3 we were interested in developing a synthetic approach to vinyl bromides related to trans ‐hydrindane4 ( i , n = 1, Figure 1). Bromoallylic alcohols ii ( n = 2) appear to be plausible intermediates in the synthesis as these compounds are easily accessible from common α,β‐unsaturated ketones iii ( n = 1).…”