Epoxides, vinyl Esters, 3-keto

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

Substituted phenethyl isocyanates undergo cyclization to lactams when treated with BF3 Et20 [65]. Vinyl ether epoxides (Eq. 37) [66], vinyl aldehydes [67], and epoxyjS-keto esters [68] all undergo cyclization with BF3 Et20. 

Coupling of the two fragments 92 and 98 took place via lithiation of the vinyl stannane and conversion to the cuprate, followed by addition to epoxide 92 to give 99 in 89% yield. Conversion of 99 (R = MTM) to bis-silyl ether 100 was accomplished in 85% yield utilizing conventional methods. Homologation by a two-carbon unit was achieved by metalation of the dithiane group followed by the addition of dimethyloxalate to give the a-keto ester 101 in 96% yield. 

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