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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.
Fig. 1; also known as calcitriol) is the active hormonal form of vitamin D 3 (1); it regulates calcium and phosphorus homeostasis and exhibits potent antiproliferative activity.1-4) Its activity is regulated by the cytochrome oxidase P450 family member CYP24A1, which oxidizes 2 at the C24 and C23 positions to afford biologically inactive, side-chain-truncated, water-soluble end products.5-7) However, the metabolic stability of 2 can be increased by substitution of side-chain hydrogen with fluorine, which is very similar in size to hydrogen, but has different chemical bonding properties. The highly electron-withdrawing nature of fluorine means that the C-F bond has a marked ionic character, and this blocks the oxidation by CYP24A1. Indeed, 24,24-difluorinated 1α,25-dihydroxyvitamin D 3 showed high metabolic stability and almost 100% absorption in rats, although this enhanced metabolic stability did not yield increased biological activity.8) Many fluorinated derivatives of 2 have already been reported. 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. RESULTS AND DISCUSSIONIn our previous study, we synthesized 1β,3β,25-dihydroxy-19-norvitamin D 3 (5a) and 1α,3α,25-dihydroxy-19-norvitamin D 3 (5b) by means of the Julia-Kocienski coupling with a 1,3-cis type A-ring synthon, followed by separation of the isomers 5a and b.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). Compound 7 was subjected to Horner-Wittig olefination using triethyl phosphonoacetate in the presence of sodium hydride in tetrahydrofuran (THF) to give the α,β-unsaturated ester 8, and the ester was then reduced with diisobutylaluminium hydride (DIBAL)-H in toluene to give the allylic alcohol 9 in 68% yield (2 steps). The allylic alcohol 9 was subjected to the Mitsunobu reaction using 2-mercaptobenzothiazole in the presence of disopropyl azodicarboxylate (DIAD) and triphenylphosphi...
1a-Amino-25-hydroxyvitamin D 3 is of interest because of its low calcemic effect in vivo comparedt o1 ,25-dihydroxyvitamin D 3 and its characteristicinhibitory activity towards sterol regulatory elementb inding protein (SREBP), aregulator of lipogenesis. Here we describe the construction of an ovel A-ring synthon bearing an allylic amine, in which the key reaction is an Ichikawa rearrangemento fa llyl cya-nate generated from an allylic alcohol, which wasd erived from l-malic acid. The diastereomers were separated by silica-gel chromatography,a nd ap alladium-catalyzed coupling reactiono fe ach diastereomer with the CD-rings ynthon afforded 1a-amino-25-hydroxyvitamin D 3 and 1bamino-25-hydroxyvitamin D 3 ,r espectively.Scheme1.Convergent strategy for synthesis of 1a-amino-25-hydroxyvitamin D 3 (2).Scheme2.Synthesis of allylic alcohol 11. Scheme3.Preparation of A-ring precursor 13.
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