Citation: Gao Yanjiao, Xiao Zhenhua, Liu Liangxian, Huang Peiqiang. Direct Reductive Cyanation of A 2-Pyrrolidinone Chiral Building Block Bearing An Unprotected Hydroxyl Group: A Stereoselective Synthesis of N-Methyl-2-epi-bulgecinine[J]. Chinese Journal of Organic Chemistry, ;2017, 37(5): 1189-1197. doi: 10.6023/cjoc201703024 shu

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

Fujian Provincial Key Laboratory of Chemical Biology, Collaborative Innovation Centre of Chemistry for Energy Materials, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005

Corresponding author: Liu Liangxian, lxliu@xmu.edu.cn Huang Peiqiang, pqhuang@xmu.edu.cn
Received Date: 13 March 2017
Revised Date: 1 April 2017

Fund Project: by the National Natural Science Foundation of China 21332007

Figures(12)

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 LiAlH₄/KCN combination. The reaction afforded 2, 5-trans-2-cyano-5-hydroxylmethyl-4-benzyloxy-pyrrolidine (5a) 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 between the hydroxymethyl group at C(5) and the incoming cyanide anion on the presumed Δ-1 pyrrolinium ion intermediate. The subsequent hydrolysis of the cyano group of the diastereomeric mixture 5a/5b (trans:cis=69:31) under basic conditions 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.
- amides,
- nitriles,
- iminium ion,
- stereoselective synthesis,
- epimerization
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