ASYMMETRIC TOTAL SYNTHESIS, X-RAY CRYSTALLOGRAPHY, AND PRELIMINARY BIOLOGICAL EVALUATION OF 1-(1'-HYDROXYETHYL)-25-HYDROXYVITAMIN-D(3) ANALOGS OF NATURAL CALCITRIOL

With 3-bromo-2-pyrone as diene and acrolein as dienophile, thermally mild Diels-Alder cycloaddition led to an isolable bicyclic lactone aldehyde that underwent highly stereocontrolled methyl Grignard addition to form essentially only a single diastereomer of secondary alcohol (+/-)-8a. This bicyclic lactone alcohol (+/-)-8a was converted smoothly into A-ring phosphine oxide (+/-)- 15 which was coupled with the enantiomerically pure C,D-ring chiron 16 to produce separable diastereomers of 1-substituted calcitriol analogs (+)-2 and (-)-3 overall in 15 steps and approximately 4% yield. Single-crystal X-ray diffraction analysis revealed some unusual intermolecular hydrogen-bonding interactions as well as the absolute stereochemistry of diastereomer (+)-2 and therefore also of its companion diastereomer (-)-3. Likewise, I-substituted calcitriol analogs (+)-4 and (-)-5 were prepared with key steps involving mild Diels-Alder cycloaddition of 3-bromo-2-pyrone and methyl vinyl ketone followed by chemospecific reduction of the ketone carbonyl group. Preliminary biological evaluation showed all four of these 1-hydroxyethyl analogs 2-5 to be significant inhibitors of murine keratinocyte growth, with diastereomers (+)-2 and (+)-4 comparable in potency to calcitriol. Significantly, these four homologs of calcitriol were approximately 1000 times less effective than calcitriol in binding to the calf thymus 1,25(OH)2D3 receptor. Also, these analogs were found to open calcium channels via a nongenomic process.