含未保护羟基2-吡咯烷酮衍生物的直接还原氰基化:N-甲基-2-别-Bulgecinine的立体选择性合成

Direct Reductive Cyanation of A 2-Pyrrolidinone Chiral Building Block Bearing An Unprotected Hydroxyl Group:A Stereoselective Synthesis of N-Methyl-2-epi-bulgecinine

报道手性合成砌块(4S,5R)-N-苄基-4-苄氧基-5-羟甲基-2-吡咯烷酮(3a)的直接还原氰基化及产物的立体化学与转化研究.含未保护羟基的内酰胺用Li Al H4/KCN体系直接还原氰基化,生成比例为69∶31的2,5-反式/顺式非对映立体异构体.与文献类似结果对比显示,氰基负离子对5-羟甲基-(35)-1-吡咯啉鎓中间体的加成主要受立体电子效应和C(5)位取代基(羟甲基)与进攻试剂间烯丙型1,3-位阻控制.该混合物在碱性条件下水解,生成比例为10∶90的2,5-反式/2,5-顺式-bulgecinine衍生物.这一结果表明氰基水解反应伴随着在C(2)位发生了有合成价值的串联差向异构化.由此建立了立体选择性地合成2,5-顺式(-)-N-甲基-2-别-bulgecinine的简便方法.

The direct reductive cyanation of N-benzyl-4-benzyloxy-5-hydroxymethyl-2-pyrrolidinone （3a）, a lactam bearing a free hydroxyl group, has been achieved with the LiA1H4/KCN combination. The reaction afforded 2,5-trans-2-cyano-5- hydroxylmethyl-4-benzyloxy-pyrrolidine （Sa） and its cis-diastereomer 5b in a ratio of 69 ： 31 with a combined yield of 63%. The observed 2,5-trans-stereoselectivity is suggested to be resulted from both stereoelectronic effect and allylic 1,3-strain be- tween the hydroxymethyl group at C（5） and the incoming cyanide anion on the presumed A-1 pyrrolinium ion intermediate. The subsequent hydrolysis of the cyano group of the diastereomeric mixture 5a/Sb （trans ： cis=69 ; 31） under basic condi- tions afforded the corresponding 5-hydroxymethyl-4-benzyloxyproline with 2,5-cis-diastereomer as the major diastereomer （trans ： cis= 10 ： 90）. This result implies that a synthetically useful epimerization at C（2） has occurred concomitantly. This unexpected result afforded a concise and highly stereoselective synthesis of 2,5-cis-（--）-N-methyl-2-epi-bulgecinine.