Synlett 2018; 29(10): 1257-1271
DOI: 10.1055/s-0036-1591579
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© Georg Thieme Verlag Stuttgart · New York

Enantioselective Bromocyclization of Allylic Amides Mediated by Phosphorus Catalysis

Yuji Kawato
School of Pharmaceutical Sciences, University of Shizuoka, Japan   Email: hamashima@u-shizuoka-ken.ac.jp
,
Yoshitaka Hamashima*
School of Pharmaceutical Sciences, University of Shizuoka, Japan   Email: hamashima@u-shizuoka-ken.ac.jp
› Author Affiliations
This work was supported by JSPS KAKENHI (Grant Number 16H05077 and 16K18848) and a Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts” from MEXT, Japan, and partially supported by Platform Project for Supporting Drug Discovery and Life Science Research from Japan Agency for Medical Research and Development (AMED).
Further Information

Publication History

Received: 06 March 2018

Accepted after revision: 03 April 2018

Publication Date:
14 May 2018 (online)


Abstract

Halocyclization of alkenes is commonly employed to increase molecular complexity during organic synthesis because it enables double installation of heteroatoms on a carbon–carbon double bond. Moreover, stereodefined halogenated compounds are widely found among naturally occurring compounds and can serve as versatile chiral building blocks. Therefore, the development of asymmetric halocyclization reactions is of great interest and, in recent years, there has been remarkable progress in catalytic asymmetric halogenation reactions. This account summarizes recent progress made by our group on phosphorus-­catalyzed enantioselective bromocyclization of allylic amides. Building on a comprehensive study of the reaction mechanism, we discovered an intriguing catalytic reaction in which P+Br species serves as a fine-tuning element for substrate fixation. We also describe the application of this bromocyclization to asymmetric desymmetrization of 1,4-diene substrates and a concise synthesis of the HIV-protease inhibitor ­nelfinavir using the newly developed desymmetrization reaction as a key step.

1 Introduction

2 Enantioselective Bromocyclization of Allylic Amides with a BINAP Catalyst

2.1 Bromocyclization with a P/P Catalyst

2.2 Bromocyclization with a P/P=O Catalyst

3 Desymmetrization of Bisallylic Amides through Enantioselective Bromocyclization

3.1 Desymmetrization of Bisallylic Amides

3.2 Enantioselective Synthesis of Nelfinavir

4 Summary

 
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