Posner G H, Nelson T D, Guyton K Z, Kensler T W
Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland 21218.
J Med Chem. 1992 Aug 21;35(17):3280-7. doi: 10.1021/jm00095a026.
Surprisingly, both of the synthetic 1-(hydroxymethyl)-25-hydroxyvitamin D3 diastereomers (-)-2 and (+)-3 retained the antiproliferative activity of natural calcitriol in murine keratinocytes. Preliminary studies indicated, however, that both of these synthetic diastereomers were less than 0.1% as effective as calcitriol for binding to the 1,25-(OH)2-D3 receptor and that they were less than 0.1% as potent as calcitriol for calbindin-D28K induction in organ-cultured embryonic chick duodenum. 1-(Hydroxymethyl)-25-hydroxyvitamin D3 homologs (-)-2 and (+)-3 were synthesized in a convergent manner by combining enantiomerically pure C,D-ring ketone 12 with highly enantiomerically enriched A-ring phosphine oxides (-)-11a and (+)-11b. These A-ring chirons were prepared starting from thermal [2 + 4] cycloaddition of 3-bromo-2-pyrone and acrolein.
令人惊讶的是，两种合成的1-(羟甲基)-25-羟基维生素D3非对映异构体(-)-2和(+)-3在小鼠角质形成细胞中均保留了天然骨化三醇的抗增殖活性。然而，初步研究表明，这两种合成非对映异构体与1,25-(OH)2-D3受体结合的效力不到骨化三醇的0.1%，并且在器官培养的胚胎鸡十二指肠中诱导钙结合蛋白-D28K的效力也不到骨化三醇的0.1%。通过将对映体纯的C、D环酮12与高度对映体富集的A环氧化膦(-)-11a和(+)-11b结合，以汇聚方式合成了1-(羟甲基)-25-羟基维生素D3同系物(-)-2和(+)-3。这些A环手性试剂是从3-溴-2-吡喃酮和丙烯醛的热[2 + 4]环加成反应开始制备的。
