Skoda Erin M, Davis Gary C, Wipf Peter
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Org Process Res Dev. 2012;16(1):26-34. doi: 10.1021/op2002613.
Nucleophilic imine additions with vinyl organometallics have developed into efficient, high yielding, and robust methodologies to generate structurally diverse allylic amines. We have used the hydrozirconation-transmetalation-imine addition protocol in the synthesis of allylic amine intermediates for peptide bond isosteres, phosphatase inhibitors, and mitochondria-targeted peptide mimetics. The gramicidin S-derived XJB-5-131 and JP4-039 and their analogs have been prepared on up to 160 g scale for preclinical studies. These (E)-alkene peptide isosteres adopt type II' β-turn secondary structures and display impressive biological properties, including selective reactions with reactive oxygen species (ROS) and prevention of apoptosis.
亲核亚胺与乙烯基有机金属化合物的加成反应已发展成为生成结构多样的烯丙基胺的高效、高产率且稳健的方法。我们已将锆氢化-转金属化-亚胺加成协议用于合成肽键等电子体、磷酸酶抑制剂和线粒体靶向肽模拟物的烯丙基胺中间体。已制备了高达160克规模的短杆菌肽S衍生的XJB-5-131和JP4-039及其类似物用于临床前研究。这些（E）-烯烃肽等电子体采用II'型β-转角二级结构，并表现出令人印象深刻的生物学特性，包括与活性氧（ROS）的选择性反应和细胞凋亡的预防。
