From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis

Sarah J Chambers; Graeme Coulthard; William P Unsworth; Peter O'Brien; Richard J K Taylor

doi:10.1002/chem.201600823

From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis

Chemistry. 2016 May 4;22(19):6496-500. doi: 10.1002/chem.201600823. Epub 2016 Mar 23.

Authors

Sarah J Chambers¹, Graeme Coulthard¹, William P Unsworth¹, Peter O'Brien¹, Richard J K Taylor²

Affiliations

¹ Department of Chemistry, University of York, York, UK.
² Department of Chemistry, University of York, York, UK. richard.taylor@york.ac.uk.

Abstract

Heteroaromatic carboxylic acids have been directly coupled with imines using propylphosphonic anhydride (T3P) and NEt(iPr)2 to form azaspirocycles via intermediate N-acyliminium ions. Spirocyclic indolenines (3H-indoles), azaindolenines, 2H-pyrroles and 3H-pyrroles were all accessed using this metal-free approach. The reactions typically proceed with high diastereoselectivity and 3D shape analysis confirms that the products formed occupy areas of chemical space that are under-represented in existing drugs and high throughput screening libraries.

Keywords: 3D space; N-acyliminium ions; dearomatisation; lead identification; spirocycles.

Publication types

Research Support, Non-U.S. Gov't