Highly potent 2-methylene analogs of 1α,25-dihydroxyvitamin D3: Synthesis and biological evaluation

Vitamin D and Its Synthetic Analogs

“…The analogs 2-methylene-25-(OH)D 3 ( 34a ) and 2-methylen-20-epi-25-(OH)D 3 ( 34b ) belong to the family of the potent lead compound 2-methylene-1,25(OH) 2 D 3 ( 35 , 2MD ) and were synthesized through a Pd-catalyzed coupling between an enol triflate and an enyne. 48 These molecules are defined by the relocation of the exocyclic methylene group from C-10 to C-2 and the inversion of the C-20 configuration. Compound 34a shows lower affinity for VDR than 1,25(OH) 2 D 3 , lower potency in inducing HL-60 cell differentiation and in reporter gene assays, while compound 34b displays the same affinity for VDR as 1,25(OH) 2 D 3 , higher potency in HL-60 cell differentiation induction, and lower activity in reporter gene assays.…”

“…25-Dehydro-1α-hydroxy-vitamin D 3 -26,23 lactones with double modifications of C-24 and C-2α were synthesized via a convergent approach by Pd-catalyzed ring closure of a enyne and subsequent coupling with a functionalized vinyl bromide.51,52 Numerous analogs have been synthesized with variations in their C-23 configuration, C-24 mono-or disubstitution [H, Me, Et, c-Pr, n-Pr, n-Bu, i-Bu(40,41,48, 50,52,54,56,58,60,62,64,66,68,70,72)] and C-2α substitution [H,…”

Recent Developments Towards the Synthesis of Vitamin D Metabolites

“…Additionally, the CDring alkene boranates 34 can be used via an analogous coupling method originally invented by Suzuki (31). Finally, a cyclic A-ring alkene 35 can be coupled with CD ring triflate 36, according to a coupling method invented by Sonogashira (32).…”

Synthesis of Low Abundant Vitamin D Metabolites and Assaying Their Distribution in Human Serum by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) as a New Tool for Diagnosis and Risk Prediction of Vitamin DRelated Diseases

“…Additionally, CDring alkene boranates 49 can be used via an analogous coupling method originally invented by Suzuki [42]. Finally, a cyclic A-ring enynes, such as 50, can be coupled with CD-ring triflate 50, a coupling method invented by Sonogashira [43]. In all these cases, the CD-ring vinyl bromide 47, boranate 49, or triflate 51 are usually carrying the modified side chain already, before coupling with the acyclic or cyclic A-ring enyne.…”

“…A major drawback of these methods is the fact that synthesis of acyclic or cyclic enynes or other A-ring building blocks not derived from vitamin D 2 involves many synthesis steps, and in some cases separation of diastereomeric mixtures is also necessary to obtain enantiomerically and diastereomerically pure product. However, the suitable starting materials can usually be obtained from the natural chiral pool (i.e., terpenes such as carvone [44], malic acid [45], quinic acid [43], or carbon hydrates such as D-glucose [46] or D-xylose [47]), which are usually readily available. A wide range of substrates are tolerated.…”