Synthesis and Biological Activity of Two C‑7 Methyl Analogues of Vitamin D

Two
novel vitamin D analogues of the hormone 1α,25-(OH)2D3 modified at C-7, namely, 7-methyl-1α,25-(OH)2D3 (12) and 7-methyl-1α,25-(OH)2-19-nor-D3 (26), were synthesized
and biologically evaluated to gain further insights into the structure–function
relationships of vitamin D. Key steps in the synthesis of 12 include the functionalization at C-7 by an efficient regioselective
hydrostannylation of an allene precursor, and the construction of
the triene framework by a palladium-catalyzed intramolecular cyclization-Suzuki–Miyaura
coupling cascade. Since the calcitriol analogue 12 was
prone to conversion into its previtamin D form by thermal equilibration,
the corresponding 19-nor-compound 26 was also synthesized.
The diene moiety of compound 26 was constructed by a
modified Julia coupling. UV data as well as X-ray analysis indicate
that introduction of the methyl group at C-7 results in a significant
deviation from planarity of the 5,7-diene moiety. The new vitamin
D analogues 12 and 26 retained good VDR
binding ability.