Synthesis of Diastereomers of 1,3-<i>cis</i>-25-Dihydroxy-19-norvitamin D₃

Abstract

1β,3β,25-Dihydroxy-19-norvitamin D3 (4a) and 1α,3α,25-dihydroxy-19-norvitamin D3 (4b) were synthesized by employing a new A-ring synthon, (1R,3S)-3-((tert-butyldimethylsilyl)oxy)-5-oxocyclohexyl benzoate (19), which was derived from D-(-)-quinic acid in 12 steps. The A-ring was coupled with the circular dichroism (CD) ring by means of Julia-Kocienski olefination to construct the diene unit. The structures of the products were confirmed by (1)H-NMR and nuclear Overhauser effect (NOE) experiments.

Synthetic Chemical Probes That Dissect Vitamin D Activities

“…Discovery of 32a encouraged us to synthesize the rest of the seven possible regio-and stereoisomers at C1 and C3 in 32a, i.e., 32b−h (Figure 4) (for synthesis of compounds, see Supporting Information). 44 Upon subsequent evaluation, all of the isomers of 32a exhibited potent SREBP inhibitory activity with limited VDR agonistic activity regardless of the regio-and stereochemistry at C1 and C3 (Figure 5). Optimization of Compound 32.…”

Synthesis of 24,24-Difluoro-1,3-<i>cis</i>-25-dihydroxy-19-norvitamin D₃ Derivatives and Evaluation of Their Vitamin D Receptor-Binding Affinity

“…14) Here we adopted similar methodology, using ketone 11 and sulfone 10. The sulfone 10 was synthesized from the Grundmann's ketone 7, which was reported by DeLuca and colleagues 13,15) (Chart 1).…”

“…The relative stereochemistries were assigned by 1 H-NMR and nuclear Overhauser effect (NOE) correlations, as reported previously in the literature. 14,17,18) Each compound was subjected to two-step deprotection using K 2 CO 3 in methanol, followed by hydrogen fluoride·pyridine (HF·Py) in THF, to afford 6a and b, respectively, in 64% yield (Chart 2).…”

“…Among them, falecalcitriol [9][10][11][12] is used to treat hypercalcemia, osteomalacia, and rickets, and is more efficient than calcitriol (2). Recently, DeLuca and colleagues reported 24,24-difluoro-1α,25-(OH) 2 -19-norvitamin D 3 (4), which showed stronger vitamin D receptor (VDR) binding affinity than compound 2 and promoted bone formation more efficiently.13) Thus, although 24-difluoro substitution has little effect on the biological potency of the natural hormone (2), it does alter the biological activity profile of 1α,25-(OH) 2 -19-norvitamin D 3 (3).With this background, we decided to extend our previously reported synthetic studies of 1,3-cis-25-dihydroxy-19-norvitamin D 3 (5a, b) 14) to obtain the 24-difluoro series (6a, b), to investigate the effects of fluoro substitution at the side chain on the biological activities of those ligands. Here, we describe the synthesis of 24,24-difluoro-1β,3β,25-dihydroxy-19-norvitamin D 3 (6a) and 24,24-difluoro-1α,3α,25-dihydroxy-19-norvitamin D 3 (6b), and a comparison of their VDR-binding affinity with that of compounds 5a and b.…”

“…With this background, we decided to extend our previously reported synthetic studies of 1,3-cis-25-dihydroxy-19-norvitamin D 3 (5a, b) 14) to obtain the 24-difluoro series (6a, b), to investigate the effects of fluoro substitution at the side chain on the biological activities of those ligands. Here, we describe the synthesis of 24,24-difluoro-1β,3β,25-dihydroxy-19-norvitamin D 3 (6a) and 24,24-difluoro-1α,3α,25-dihydroxy-19-norvitamin D 3 (6b), and a comparison of their VDR-binding affinity with that of compounds 5a and b.…”