Perrey David, Zhang Dehui, Nguyen Thuy, Carroll F Ivy, Ko Mei-Chuan, Zhang Yanan
Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Department of Physiology and Pharmacology, Wake Forest University, Winston-Salem, NC 27157, USA.
European J Org Chem. 2018 Aug 7;2018(29):4006-4012. doi: 10.1002/ejoc.201800517. Epub 2018 May 18.
PZM21 () was recently reported as a biased agonist of the mu-opioid receptor (MOR) with improved antinociceptive effects but reduced side effects than traditional opioid-based analgesics. The original synthesis of PZM21 with the desired (S,S) configuration required the separation of diastereomeric mixture in the final step using chiral HPLC. We have designed a concise synthesis of in the enantiomeric pure form starting with commercially available L-alanine and via a chiral aziridine as a key intermediate. The final product as the (S,S) diastereomer was obtained in 7 steps in 22.5% yield from L-alanine. This synthetic strategy could be readily applied to the development of PZM21 analogs at the thiophenyl position.
PZM21（）最近被报道为μ-阿片受体（MOR）的偏向性激动剂，与传统的阿片类镇痛药相比，其镇痛效果有所改善，但副作用减少。最初合成具有所需（S,S）构型的PZM21需要在最后一步使用手性高效液相色谱法分离非对映体混合物。我们设计了一种简洁的合成方法，以市售的L-丙氨酸为起始原料，通过手性氮丙啶作为关键中间体，合成对映体纯形式的。最终产物作为（S,S）非对映体，以L-丙氨酸为原料，经7步反应得到，产率为22.5%。这种合成策略可以很容易地应用于噻吩基位置的PZM21类似物的开发。
