Efficient Enantiospecific Synthesis Of Key A-Ring Synthon For The Preparation Of 1α, 25-Dihydroxyvitamin D₃

The hormone 1α, 25-dihydroxyvitamin D₃ (Figure 1-2, 1) is the most potent natural metabolite of vitamin D₃ and shows a broad spectrum of biological activities. The most prominent physiological role of 1 is the regulation of calcium and phosphorus metabolism as well as bone remodeling via its action in the bone, intestine and kidney. The major reason for therapeutic limitation of 1 is calcemic and phosphatemic activities. Thus, 1 can cause serious side effects such as hypercalcemia and hyperphosphatemia. Therefore, to find the new vitamin D analogs, which are more efficacious, safer, and more selective than the natural 1, numerous analogs of 1 have been developed. Although more than 3000 vitamin D analogs have been synthesized, most of the synthetic studies of the vitamin D₃ analogs have involved side-chain modification. On the other hand, it was found that some functionalization of C-2 position on the A-ring increased the binding affinity for VDR with potent agonistic activity. With this background, we have developed a novel strategy to synthesize the A ring and studied its potential application in modification of A ring at C-2 position:(1) The new, efficient process gave key precursor A-ring 201 in 12 synthetic steps in 20% overall yield and only 3 isolations were needed.(2) In the key synthetic step, a highly regio- and diastereoselective Ene reaction which also bears high atom economy was employed.(3) The scope and potential of the new synthetic approach was assessed by introducing methyl group and hydroxyl group into the C-2 position of A-ring respectively. We found that it is potential to prepare both C-2αand C-2βvitamin D₃ epimers utilizing the new strategy from the same starting material (L)-carvone.(4) A chiral molecule triol 224 was obtained from ozonolysis of vitamin D2. It is the first time to find another useful molecule besides the CD-ring part from this famous reaction system. The potential of the new molecule was also investigated by preparation of the derivative chiral building block with a few synthetic steps.In addition to the investigation of the A-ring, we also studied the CD-ring part by both the linear route and the convergent route. An efficient one-pot strategy was utilized in the preparation ofα,β-unsaturated aldehyde CD-ring.