Synthesis of 1 α‐ and 1 β‐amino‐25‐hydroxyvitamin D₃

Abstract

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.

Synthetic Chemical Probes That Dissect Vitamin D Activities

“…In our effort to delineate VD 3 activity, we initially searched for VD 3 analogs that activate VDR but lack SREBP inhibitory activity. An in-house library of 250 vitamin D congeners − was screened for their ability to inhibit the activity of an SREBP-responsive luciferase reporter, in which expression of luciferase is controlled by three SREBP binding sites. We found that a series of vitamin D analogs, bearing alkyltriazole and alkyltetrazole substituents at C2 ( 4 – 9 ) (Figure ), displayed limited SREBP inhibitory activities (Figure A).…”

Pd(0)‐Catalyzed‐Mediated Synthesis of Vitamin D Compounds

“…The relevance of this short pathway to 1,25D 3 analogs has been demonstrated by the intense synthetic activity used for the preparation of substituted A-ring-enyne synthons [68][69] and vitamin D analogs modified at the A-ring. [70][71][72][73][74][75][76][77][78][79][80] The relative high temperature (reflux in triethyl amine-toluene) required for the Pd(0)-catalyzed alkylative cyclization is unsuitable for the formation of vitamin D analogs that undergo thermal equilibration to the previtamin D form such as 6-methyl-25hydroxyvitamin D 3 , [43,81] and aromatic-D-ring analogs. [44,45]…”