13,13-Dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (2MD): Total synthesis, docking to the VDR, and biological evaluation

摘要: As a continuation of our studies focused on the vitamin D compounds lacking C,D-hydrindane system, 13,13-dimethyl-des-C,D analogues (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (2, 2MD) were prepared by total synthesis. The known cyclohexanone 30, precursor desired A-ring phosphine oxide 11, was synthesized starting with keto acetal 13, whereas aldehyde 12, constituting an acyclic ‘upper’ building block, obtained from isomeric esters 34, previously in laboratory. The commercial 1,4-cyclohexanedione monoethylene ketal (13) enantioselectively α-hydroxylated utilizing α-aminoxylation process catalyzed l-proline, and introduced hydroxy group protected as TBS, TPDPS, SEM ether. Then 15–17 methylenated allylic hydroxylation performed selenium dioxide pyridine N-oxide. After separation isomers, newly hydrolyzed to yield corresponding (3R,5R)-3,5-dihydroxycyclohexanones 30–32. for C,D-fragment first α-methylated, then reduced resulted primary alcohols 36 deoxygenated using Barton-McCombie protocol. Primary diether 38 deprotected oxidized furnish 12. Wittig–Horner coupling latter anion followed hydroxyl deprotection furnished two 2MD (compounds 10 42) differing configuration their 7,8-double bond. Pure isolated HPLC biological activity examined. vitro tests indicated that, compared analogue 7, unsubstituted at C-13, showed markedly improved VDR binding ability, significantly enhanced HL-60 differentiation well increased transcriptional potency. Docking simulations provided rational explanation observed affinity these ligands VDR. Biological vivo proved that des-C,D compound retained some intestinal activity. Its geometrical isomer 42 devoid any