Synthesis of 19-norcalcitriol analogs with elongated side chain

Publication date: Available online 18 August 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Pawel Brzeminski, Adrian Fabisiak, Katarzyna Sektas, Klaudia Berkowska, Ewa Marcinkowska, Rafal R. Sicinski
Pronounced biological potency of 19-norvitamin D compounds as well as interesting biological action of the vitamin D analogs possessing elongated side chains encouraged us to expand the scope of our structure-activity studies to encompass such modifications of the 1α,25-(OH)2D3 (calcitriol) molecule. The aim of our studies was the synthesis of calcitriol analog, designed on the basis of results of molecular modeling and docking experiments, and characterized by a presence of a long, nitrogen-containing substituent attached to carbon 26, and an exomethylene moiety transferred from C-10 to C-2. The convergent synthesis of such 19-norcalcitriol compound, described in this communication, consisted of the preparation and combining four building blocks. The crucial point of the synthesis, coupling of the known A-ring phosphine oxide and the synthesized Grundmann ketone analog, was achieved using Wittig-Horner protocol. It provided the protected analog of 2-methylene-1α,25-dihydroxy-19-norvitamin D3 which was further transformed into the target compound.

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