2-Fluoroalkyl A-Ring Analogs of 1,25-Dihydroxyvitamin D3. Stereocontrolled Total Synthesis via Intramolecular and Intermolecular Diels-Alder Cycloadditions. Preliminary Biological Testing

Article abstract of DOI:10.1021/jo00119a045

Intramolecular Diels-Alder (IMDA) cycloadditions of electron-rich trans-vinylic silaketal groups tethered via a chiral, nonracemic 1,3-butanediol auxiliary to electron-poor 2-pyrone-3-carboxylates (e.g. (R)-9, (S)-14) were promoted by zinc dibromide and proceeded unexpectedly in a stepwise, ionic fashion to form exclusively cis-4,5-disubstituted bicyclic lactones 10 and 15 with nearly complete asymmetric induction.Confirmation of the stereochemical outcome of these nonconcerted IMDA cycloadditions was achieved by 1H NMR spectroscopy and by X-ray crystallography.Fluorinated bicycloadduct (-)-15a was converted smoothly in 13 steps into the lipophilic calcitriol analog 2β-(3'-fluoropropyl)-1β,25-dihydroxyvitamin D3 ((-)5).Intermolecular, concerted, 11 kbar, inverse-electron-demand 4+2-cycloaddition of bis-silylated Z-enol ether 22c, carrying two different silyl groups, with commercial methyl 2-pyrone-3-carboxylate gave in gram amounts only vicinally cis-disubstituted bicycloadduct (+/-)-23c.Chemospecific monodesilylation using sodium azide and then fluorination using Et2NSF3 (DAST) gave fluoroalkyl bicyclic lactone (+/-)-25.This bicyclic lactone (+/-)-25 was transformed into fluorinated, racemic, A-ring phosphine oxide (+/-)-30 that was coupled with enantiomerically pure C,D-ring ketone (+)-21 to form enantiomerically pure diastereomers (-)-4 and (+)-4' as fluorinated, lipophilic, A-ring analogs of 1,25-dihydroxyvitamin D3 (calcitriol).Preliminary biological testing (Table 1) showed that only those diastereomers having the unnatural 1β-hydroxyl group stereochemistry (i.e. (+)-3', (+)-4', and (-)-5 had relatively high affinities for the calf thymus vitamin D receptor and significant antiproliferative and differentiation-inducing potencies in HL-60 cells.