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 LiAlH 4 /KCN combination. The reaction afforded 2,5-trans-2-cyano-5hydroxylmethyl-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. Keywords amides; nitriles; iminium ion; stereoselective synthesis; epimerization α-氰胺是一类多用途的复合官能团 [1] , 其多样的化 学已在 Husson 著名的氰基调控构型方法学中全面展 示 [2]. 此外, α-氰胺结构单元存在于许多药物和活性天 然 产 物 及 其 类 似 物 中 [3] (图 1), 例 如 , 沙 格 列 汀 (Saxagliptin, D-1) 和 地格列 汀 甲苯 磺酸 盐 (Denagliptin tosylate, D-2)均为四型二肽酶(DPP IV)抑制剂, 前者作 为高效地治疗二型糖尿病的药物于 2009 年获批准上 市 [4] , 后者正在被开发为治疗二型糖尿病的药物 [5]. 化 合物 D-3 是一种苯并二氮杂受体拮抗剂 [3]. Lahadinine A (N-1) [6] 和 Cyanosafracin B (N-2)均为天然产物, 后者 被用作合成抗癌药 Ecteinascidin 743 工业生产的原料 [7]. DX-52-1 (N-3)表现出显著的抗肿瘤活性 [1b] .