Towards 20,20-difluorinated bryostatin: synthesis and biological evaluation of C17,C27-fragments.
Towards 20,20-difluorinated bryostatin: synthesis and biological evaluation of C17,C27-fragments.
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DOI：
10.1039/c8ob03152e
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发表时间：
2019-02
影响因子：
3.2
通讯作者：
Paul R. Mears;S. Hoekman;Claire E. Rye;F. P. Bailey;D. Byrne;P. Eyers;E. Thomas
中科院分区：
文献类型：
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作者：
Paul R. Mears;S. Hoekman;Claire E. Rye;F. P. Bailey;D. Byrne;P. Eyers;E. Thomas
具有修饰的C17-C27片段的苔藓抑素尚未被广泛研究。因此，20，20-二氟化类似物的合成进行了研究。这种取代将抑制涉及C19-羟基的脱水并稳定闭环半缩醛互变异构体。在初步研究之后，使用烯丙基二氢呋喃来制备二氟化烯醇。α，α-二氟代酮经氧化后进行Wittig反应，得到（E）-α，β-不饱和酯，再经合成得到20，20-二氟代苔藓抑素的C17-C27片段2-羟基四氢吡喃。这些化合物与蛋白激酶Cα同工酶有适度的结合。还尝试合成大环20，20-二氟化类似物。在初步研究期间，使用2-烷基-3-溴-1，1-二氟丙烯进行烯丙基二异丙基化。
Bryostatins with modified C17-C27 fragments have not been widely studied. The synthesis of 20,20-difluorinated analogues was therefore investigated. Such substitution would inhibit dehydration involving the C19-hydroxyl group and stabilise the ring-closed hemiacetal tautomers. Following preliminary studies, allyldifluorination was used to prepare difluorinated alkenols. Oxidation followed by stereoselective Wittig reactions of the resulting α,α-difluorinated ketones gave (E)-α,β-unsaturated esters that were taken through to complete syntheses of 2-hydroxytetrahydropyrans corresponding to C17-C27 fragments of 20,20-difluorinated bryostatin. These compounds showed modest binding to protein kinase Cα isozyme. Attempts were also undertaken to synthesise macrocyclic 20,20-difluorinated analogues. During preliminary studies, allyldifluorination was carried out using a 2-alkyl-3-bromo-1,1-difluoropropene.