Bifunctional Iminophosphorane-Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,β-Unsaturated Esters**
Daniel Rozsar
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
Search for more papers by this authorAlistair J. M. Farley
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
These authors contributed equally to this work.
Search for more papers by this authorIain McLauchlan
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
These authors contributed equally to this work.
Search for more papers by this authorBenjamin D. A. Shennan
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
Search for more papers by this authorCorresponding Author
Ken Yamazaki
Division of Applied Chemistry, Okayama University, 700-8530 Tsushimanaka, Okayama, Japan
Search for more papers by this authorCorresponding Author
Darren J. Dixon
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
Search for more papers by this authorDaniel Rozsar
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
Search for more papers by this authorAlistair J. M. Farley
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
These authors contributed equally to this work.
Search for more papers by this authorIain McLauchlan
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
These authors contributed equally to this work.
Search for more papers by this authorBenjamin D. A. Shennan
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
Search for more papers by this authorCorresponding Author
Ken Yamazaki
Division of Applied Chemistry, Okayama University, 700-8530 Tsushimanaka, Okayama, Japan
Search for more papers by this authorCorresponding Author
Darren J. Dixon
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, OX1 3TA Oxford, UK
Search for more papers by this authorA previous version of this manuscript has been deposited on a preprint server (https://doi.org/10.26434/chemrxiv-2022-w1086).
Abstract
Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,β-unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ-nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including β-(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)-rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results.
Conflict of interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available in the Supporting Information of this article.
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