Synlett 2019; 30(01): 1-11
DOI: 10.1055/s-0037-1610314
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© Georg Thieme Verlag Stuttgart · New York

Recent Advances in the Synthetic Chemistry of Bicyclo[1.1.1]pentane

a  Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan   Email: junichiro.kanazawa@jt.com
b  Cluster of Pioneering Research (CPR), Advanced Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
,
b  Cluster of Pioneering Research (CPR), Advanced Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
c  Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan   Email: uchiyama@mol.f.u-tokyo.ac.jp
› Author Affiliations
Financial support for experimental work on radical multicomponent carboamination of [1.1.1]propellane was provided by Japan Tobacco Inc. This work was also supported by a JSPS KAKENHI (S) (No. 17H06173), JSPS Grant-in-Aid for Scientific Research on Innovative Areas (No. 17H05430), and grants from Asahi Glass Foundation and Kobayashi International Scholarship Foundation (to M.U.).
Further Information

Publication History

Received: 11 October 2018

Accepted after revision: 12 October 2018

Publication Date:
15 November 2018 (online)

Abstract

Utilization of three-dimensional cyclic scaffolds is important in modern drug discovery, both to provide greater opportunities for optimizing drug candidates and to expand the available chemical space of drugs. Among these scaffolds, bicyclo[1.1.1]pentane (BCP) is a high-value bioisostere for 1,4-disubstituted phenyl rings, internal alkynes, and the tert-butyl group, generally offering high passive permeability, high water solubility, and improved metabolic stability. However, the lack of methods for functionalizing BCP remains a significant challenge, and in particular, a versatile strategy for synthesizing a wide range of unsymmetrically 1,3-difunctionalized BCP derivatives has been lacking. In this account, we review recent advances in the synthetic chemistry of BCP, focusing especially on our recently developed radical multicomponent carboamination of [1.1.1]propellane.

1 Introduction

2 Overview of the Synthetic Chemistry of [1.1.1]Propellane, the Most Promising Precursor of Bicyclo[1.1.1]pentane

3 Recent Advances in the Synthetic Chemistry of Unsymmetrically 1,3-Disubstituted Bicyclo[1.1.1]pentane Derivatives

4 Radical Multicomponent Carboamination of [1.1.1]Propellane Permits Direct Synthesis of 3-Substituted Bicyclo[1.1.1]pent-1-ylamine Derivatives

5 Conclusion

 
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