Volume 21, Issue 52 p. 19208-19222
Full Paper

Organocatalytic Asymmetric Conjugate Additions to Cyclopent-1-enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core

Dr. Luca Bernardi

Corresponding Author

Dr. Luca Bernardi

Department of Industrial Chemistry “Toso Montanari” and, INSTM RU Bologna, Alma Mater Studiorum – University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy)

Luca Bernardi, Department of Industrial Chemistry “Toso Montanari” and, INSTM RU Bologna, Alma Mater Studiorum – University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy)

Armando Carlone, Chirotech Technology Centre, Dr. Reddy's Laboratories, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE (UK)

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Dr. Mariafrancesca Fochi

Dr. Mariafrancesca Fochi

Department of Industrial Chemistry “Toso Montanari” and, INSTM RU Bologna, Alma Mater Studiorum – University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy)

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Riccardo Carbone

Riccardo Carbone

Department of Industrial Chemistry “Toso Montanari” and, INSTM RU Bologna, Alma Mater Studiorum – University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy)

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Ada Martinelli

Ada Martinelli

Department of Industrial Chemistry “Toso Montanari” and, INSTM RU Bologna, Alma Mater Studiorum – University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy)

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Dr. Martin E. Fox

Dr. Martin E. Fox

Chirotech Technology Centre, Dr. Reddy's Laboratories, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE (UK)

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Dr. Christopher J. Cobley

Dr. Christopher J. Cobley

Chirotech Technology Centre, Dr. Reddy's Laboratories, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE (UK)

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Bhaskar Kandagatla

Bhaskar Kandagatla

Center for Process Research & Innovation, Dr. Reddy's Institute of Life Science, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Telangana (India)

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Dr. Srinivas Oruganti

Dr. Srinivas Oruganti

Center for Process Research & Innovation, Dr. Reddy's Institute of Life Science, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Telangana (India)

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Dr. Vilas H. Dahanukar

Dr. Vilas H. Dahanukar

Innovation Plaza, Integrated Product Development Organization, Dr. Reddy's Laboratories Ltd. Bachupally, Qutubullapur Hyderabad 500 090, Telangana (India)

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Dr. Armando Carlone

Corresponding Author

Dr. Armando Carlone

Chirotech Technology Centre, Dr. Reddy's Laboratories, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE (UK)

Luca Bernardi, Department of Industrial Chemistry “Toso Montanari” and, INSTM RU Bologna, Alma Mater Studiorum – University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy)

Armando Carlone, Chirotech Technology Centre, Dr. Reddy's Laboratories, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE (UK)

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First published: 25 November 2015
Citations: 14

Graphical Abstract

Organic bicycle: From a manufacturing perspective, eight organocatalytic approaches delivering advanced intermediates towards the challenging bicyclic amino acid core of telaprevir (see scheme) were identified and explored, highlighting the potential of organocatalytic technologies for a cost-effective preparation of pharmaceuticals.

Abstract

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol % in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals.