title: Organocatalytic Asymmetric Conjugate Additions to Cyclopent-1-enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core.
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.
authors.affiliation: Department of Industrial Chemistry "Toso Montanari" and, INSTM RU Bologna, Alma Mater Studiorum - University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy). luca.bernardi2@unibo.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Bernardi
authors.affiliation: Department of Industrial Chemistry "Toso Montanari" and, INSTM RU Bologna, Alma Mater Studiorum - University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy).
authors.forename: Mariafrancesca
authors.initials: M
authors.lastname: Fochi
authors.affiliation: Department of Industrial Chemistry "Toso Montanari" and, INSTM RU Bologna, Alma Mater Studiorum - University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy).
authors.forename: Riccardo
authors.initials: R
authors.lastname: Carbone
authors.affiliation: Department of Industrial Chemistry "Toso Montanari" and, INSTM RU Bologna, Alma Mater Studiorum - University of Bologna, V. Risorgimento 4, 40136 Bologna (Italy).
authors.forename: Ada
authors.initials: A
authors.lastname: Martinelli
authors.affiliation: Chirotech Technology Centre, Dr. Reddy's Laboratories, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE (UK).
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fox
authors.affiliation: Chirotech Technology Centre, Dr. Reddy's Laboratories, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE (UK).
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cobley
authors.affiliation: Center for Process Research & Innovation, Dr. Reddy's Institute of Life Science, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Telangana (India).
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kandagatla
authors.affiliation: Center for Process Research & Innovation, Dr. Reddy's Institute of Life Science, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Telangana (India).
authors.forename: Srinivas
authors.initials: S
authors.lastname: Oruganti
authors.affiliation: Innovation Plaza, Integrated Product Development Organization, Dr. Reddy's Laboratories Ltd. Bachupally, Qutubullapur Hyderabad 500 090, Telangana (India).
authors.forename: Vilas H
authors.initials: VH
authors.lastname: Dahanukar
authors.affiliation: Chirotech Technology Centre, Dr. Reddy's Laboratories, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE (UK). acarlone@drreddys.com.
authors.forename: Armando
authors.initials: A
authors.lastname: Carlone
keywords: Michael addition; asymmetric synthesis; enantioselectivity; organocatalysis; telaprevir