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Organocatalytic Asymmetric Conjugate Additions to Cyclopent‐1‐enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core
Author(s) -
Bernardi Luca,
Fochi Mariafrancesca,
Carbone Riccardo,
Martinelli Ada,
Fox Martin E.,
Cobley Christopher J.,
Kandagatla Bhaskar,
Oruganti Srinivas,
Dahanukar Vilas H.,
Carlone Armando
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201503352
Subject(s) - conjugate , telaprevir , bicyclic molecule , organocatalysis , core (optical fiber) , chemistry , computer science , catalysis , stereochemistry , enantioselective synthesis , mathematics , organic chemistry , biochemistry , mathematical analysis , ribavirin , genotype , gene , telecommunications
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.