Synthesis of 24,24-Ethanovitamin D₃ Lactones Using Ruthenium-Catalyzed Intermolecular Enyne Metathesis: Potent Vitamin D Receptor Antagonists

Abstract

Novel vitamin D receptor antagonists, 24,24-ethanovitamin D3-26,23-lactones 6 and 7 and their 2α-functionalized analogues 6a-c and 7a-c were synthesized and their biological activities were evaluated. The triene structure of vitamin D3 was constructed using Pd-catalyzed alkenylative cyclization of A-ring precursor enynes 12 and 12a-c with the CD-ring bromo-olefin counterpart having 24,24-ethano-α-methylene-γ-lactone on the side chain (21 or 22). The CD-ring precursors 21 and 22 were efficiently synthesized via Ru-catalyzed intermolecular enyne metathesis of 15 with ethylene to give dienone 17 followed by cyclopropanation. The VDR antagonistic activity of the newly designed vitamin D3 lactones 6 and 7 increased to 2.8 times that of TEI-9647 (2) in a HL-60 cell differentiation evaluating system. Moreover, introduction of three substituents, that is, a methyl (6a and 7a), a 3-hydroxypropyl (6b and 7b), or a 3-hydroxypropoxyl group (6c and 7c) into the C2α position of 6 and 7, resulted in marked enhancement, up to 19 times, of the antagonistic activity toward VDR.