14 コンビナトリアルケミストリーを指向した活性型ビタミンD_3の固相合成研究(口頭発表の部)

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1α, 25-Dihydroxyvitamin D_3 (1α, 25-(OH)_2D_3, calcitriol), the biologically active metabolite of vitamin D_3, is recognized as a steroid hormone. In order to separate these activities, especially cell differentiation and proliferation activity from calcemic activity, and to enhance the specific activities, a number of analogues have been synthesized by many laboratories. In recent years, it has been proven that applications of solid phase chemistry, capable of generating combinatorial natural small molecule libraries, to drug discovery process is extremely effective in terms of searching a wide range of analogues rapidly. Herein, we describe two solid-phase synthesis of the vitamin D_3 system for a three-component library (i.e. the A-ring, the CD-ring, and the side chain) in only four steps including two nucleophilic additions. One is for 11-hydroxy analogues, and the other is for versatile analogues. In the latter strategy, the sulfonate-linked CD-ring 28 was initially immobilized on PS-DES resin to give solid-supported CD-ring 32 (Scheme 4). Similarly, solid-supported CD-ring 32 was prepared by attachment of the CD-ring 25 to the chlorosulfonate resin 33. The vitamin D_3 system was synthesized by Homer-Wadsworth-Emmons reaction of the A-ring phosphine oxide to a solid-supported CD-ring, followed by simultaneous introduction of the side chain and cleavage from resin with a Cu^1-catalyzed Grignard reagent. Parallel synthesis of the vitamin D_3 analogues was accomplished by a split & pool method utilizing radiofrequency encoded combinatorial (REC) chemistry, and a manual parallel synthesizer for side chain diversification and deprotection. In addition, we wish to report an efficient synthesis of various A-ring moieties by means of the Pd(0)-catalyzed intramolecular Mizoroki-Heck reaction.
天然有機化合物討論会の論文
2001-09-01

14 コンビナトリアルケミストリーを指向した活性型ビタミンD_3の固相合成研究(口頭発表の部)

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