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.

Enantioselective organocatalytic approaches to active pharmaceutical ingredients – selected industrial examples

“…To simplify, we feel that there is a tendency to report organocatalytic reactions in the literature at high (5-20 mol%) loadings, even if higher TONs could readily be achieved. [72,73] Altogether, we believe that asymmetric organocatalysis will have an increasing role in the production of APIs, meeting sustainability and cost requirements; this technology will likely flank other more established methodologies providing exciting opportunities. Society can only have a sustainable development if we exploit modern technologies and asymmetric organocatalysis promises to contribute considerably to it.…”

Influence of the Framework Topology on the Reactivity of Chiral Pyrrolidine Units Inserted in Different Porous Organosilicas

“…Recently, this catalytic process was successfully performed using amino acids adsorbed on inorganic oxides as laponite-type supports that formed active hybrid organic-inorganic chiral heterogeneous catalysts [28]. The preparation of carbonyl and nitrocarbonyl compounds through the asymmetric Michael addition reaction of carbonyl compounds and nitroolefins is a versatile and useful tool in organic synthesis, normally being carried out using homogeneous and heterogeneous catalytic systems containing prolinol active units [29][30][31][32]. The reaction mechanism widely accepted involves, first, the formation of the enamine via the condensation of a chiral amine and a carbonyl substrate.…”

Enantioselective Approaches to 3,4-Annulated Indoles Using Organocatalytic Domino Reactions

“…Following this pathway, the enamine resulting from the Friedel-Crafts-type addition undergoes conjugate addition to the α,β-unsaturated ketone, another transformation where catalysts of type 2a,b have proven to be competent. 20 Furthermore, at the time this work was being developed, we had just completed a collaborative project with Dr. Reddy's Chirotech Technology Centre (Cambridge, UK), 21 that left us samples of these catalysts. Last but not least, we have had a relationship with Professor Karl Anker Jørgensen's laboratory in Aarhus (Denmark) for many years; one of the authors of this account (L.B.)…”