We have recently obtained 1-desoxy and 3-desoxy analogs of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (2MD), a compound exerting significantly enhanced calcemic activity and currently being evaluated as a potential drug for osteoporosis. In order to further explore this class of pharmacologically important vitamin D compounds we have decided to synthesize analogs characterized by the presence of two A-ring exocyclic methylene groups attached to C-2 and C-10. The Sonogashira coupling of a triflate enol of the protected (20R)- or (20S)-25-hydroxy Grundmann ketone and the corresponding dienyne A-ring fragment provided the target compounds. A new synthetic path was elaborated, leading to the desired A-ring synthon, that started from commercially available 1,4-cyclohexanedione monoethylene acetal. Biological in vitro and in vivo activities of the synthesized 25-hydroxy-2-methylene-vitamin D3 compounds, belonging to 20R- and 20S-series, were evaluated and discussed. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
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