Nickel-Mediated Conjugate Addition. Elaboration of Calcitriol from Ergocalciferol

Article abstract of DOI:10.1021/jo00125a051

A convenient method for introduction the side chain of the hormone calcitriol (3) was achieved by coupling the nickel(0) complex derived from ethyl acrylate with the C-22 iodides 15, 16, 27, and 30 to give the corresponding esters 18, 21, 28, and 23 in yields of 73-82percent.Iodide 15 was also coupled with the Ni(0) complex derived from methyl vinyl ketone.The C-22 iodides 15 and 27 were obtained from ergocalciferol (6) and the 1(S),3(R)-bis<(tert-butyldimethylsilyl)oxy>-(5E,7E)-ergocalciferol derivative 24, respectively, by selective ozonolysis of their SO2 adducts, followed by in situ reduction of the ozonides with NaBH4 and iodination of the derived alcohols 14 and 26 with I2/PPh3/imidazole.The triene iodide 16 was prepared by extrusion of SO2 from 15, while 30 was obtained from the corresponding alcohol 29.Extrusion of SO2 from 21 and 28 gave the 5(E),7(E)-trienes 18 and 23, respectively.The latter was also made from the former by C-1 hydroxylation with selenium dioxide followed by silylation with tert-butyldimethylsilyl chloride and chromatographic separation.Completion of the synthesis of 3 was accomplished by treating 23 with methylmagnesium bromide to give 31, followed by desilylation with n-Bu4NF and triplet-sensitized photoisomerization.Alternatively, 31 was photoisomerized to 33, desilylation of which gave 3.Alcohol 33 was also prepared by the reaction of the 5Z,7E-triene ester 34, which was obtained by the photoisomerization of 23, with methylmagnesium bromide.