The Synthesis of Methyl-Substituted Spirocyclic Piperidine-Azetidine (2,7-Diazaspiro[3.5]nonane) and Spirocyclic Piperidine-Pyrrolidine (2,8-Diazaspiro[4.5]decane) Ring Systems
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- 作者：Aaron C. Smith ; Shawn Cabral ; Daniel W. Kung ; Colin R. Rose ; James A. Southers ; Carmen N. García-Irizarry ; David B. Damon ; Scott W. Bagley ; David A. Griffith
- 刊名：Journal of Organic Chemistry
- 出版年：2016
- 出版时间：May 6, 2016
- 年：2016
- 卷：81
- 期：9
- 页码：3509-3519
- 全文大小：447K
- 年卷期：0
- ISSN：1520-6904
文摘
The synthesis of a series of pharmaceutically important N-protected methyl-substituted spirocyclic piperidine-azetidine (2,7-diazaspiro[3.5]nonane) and spirocyclic piperidine-pyrrolidine (2,8-diazaspiro[4.5]decane) ring systems was developed. These motifs contain two differentiated sites (protected secondary amines) to allow for further functionalization via reductive amination, amidation, or other chemistry. The methyl-substituted spiroazetidine ring systems were accessed using nitrile lithiation/alkylation chemistry while the methyl-substituted spiropyrrolidines were synthesized by 1,4-addition reactions with nitroalkanes, followed by reduction and cyclization. These conditions were then scaled for the synthesis of 1-methyl spirocyclic piperidine-pyrrolidine with a classical resolution of the product using a tartaric acid derivative to isolate a single enantiomer.