Johnson Timothy A, Jang Doo Ok, Slafer Brian W, Curtis Michael D, Beak Peter
Department of Chemistry, Roger Adams Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
J Am Chem Soc. 2002 Oct 2;124(39):11689-98. doi: 10.1021/ja0271375.
(-)-Sparteine mediated lithiations of N-Boc-allylic and benzylic amines provide configurationally stable intermediates which on conjugate additions to nitroalkenes provide highly enantioenriched enecarbamate products in good yields, and with high diastereoselectivities. Straightforward transformations of these adducts offer general routes to substituted 3,4-substituted piperidines, 3,4-substituted pyrrolidines, and 4,5-substituted pyrimidinones. Diastereoselective substitutions of intermediate lactams followed by reduction provide 3,4,5-substituted piperidines and 3,4-trisubstituted pyrrolidines. Lithiation adjacent to nitrogen of 3,4-substituted piperidines and pyrrolidines followed by diastereoselective substitution opens a route to 2,4,5- and 2,4,5,6-substituted piperidines as well as 2,3,4- and 2,3,4,5-substituted pyrrolidines. The enantiomers of the enecarbamate and 3,4-substituted piperidine products may be accessed by stannylation/transmetalation sequences as well as by further manipulation of 4-substituted piperidones. The methodology is used to synthesize both enantiomers of an aspartic peptidase inhibitor intermediate, 3-hydroxy-4-phenylpiperidine, as well as the antidepressant (+)-femoxetine.
（-）-鹰爪豆碱介导的N-叔丁氧羰基烯丙基胺和苄基胺的锂化反应可提供构型稳定的中间体，这些中间体在与硝基烯烃进行共轭加成反应时，能以良好的产率和高非对映选择性提供高度对映体富集的烯氨基甲酸酯产物。这些加合物的直接转化为合成取代的3,4-二取代哌啶、3,4-二取代吡咯烷和4,5-二取代嘧啶酮提供了通用方法。中间体内酰胺的非对映选择性取代反应后再进行还原反应，可得到3,4,5-三取代哌啶和3,4,5-三取代吡咯烷。对3,4-二取代哌啶和吡咯烷的氮原子邻位进行锂化反应，随后进行非对映选择性取代反应，为合成2,4,5-和2,4,5,6-四取代哌啶以及2,3,4-和2,3,4,5-四取代吡咯烷开辟了一条途径。烯氨基甲酸酯和3,4-二取代哌啶产物的对映体可通过锡化/金属转移序列以及对4-取代哌啶酮的进一步操作来获得。该方法用于合成天冬氨酸肽酶抑制剂中间体3-羟基-4-苯基哌啶的两种对映体以及抗抑郁药（+）-非莫西汀。
