In this work, we describe the use of visible light and a photocatalytic system for the cyclization of iodoaryl vinyl derivatives to tetrahydroquinoline structures. The reaction proceeds under very mild conditions, tolerates different functional groups and more importantly, the method allows the synthesis The synthesis of tetrahydroquinolines (THQs) is of special interest, since they are heterocyclic structures present in natural and unnatural compounds with interesting biological properties (Scheme 1a). [1] For example, tetrahydroquinolines display anti-HIV activity (I), [2] antifungal properties against Cladosporium cladosporioides, yeasts, hialohyphomycetes and dermatophytes (II), [3] and antitumor (III) [4] as well as antidepressant activities (IV). [5] Therefore, new approaches and strategies for the synthesis of this class of molecules are one of the main objectives of the modern synthetic chemistry. [1a] In this regard, among all the synthetic methods available for preparing THQs, radical chemistry has proven to be a straightforward methodology with a good functional group tolerance. In fact, different synthesis of THQs have been reported under radical conditions, most of them using tin sources as hydrogen donor and AIBN as initiator (Scheme 1b). [6] In these methodologies, given the energetic reaction conditions (usually 80-100°C) required, the control in the regioselectivity of the reaction (6 exo-trig vs 7 endo-trig cyclization) is not very predictable, normally giving a mixture of products. Moreover, the protection (PG) of the start-[a
Hybridization of a chiral 3‐hydroxy‐2‐trityl‐pyrrolidine deriving from (R)‐pyrrolidinol with [60]fullerene via click chemistry provides a highly efficient supported enantioselective organocatalyst, which was successfully exploited in a Michael addition of malonates to cinnamaldehydes, via iminium ion activation. The supported organocatalyst was recycled up to six times, with only a moderate decrease in terms of activity and with no loss in enantioselectivity.magnified image
The proline-catalysed asymmetric aldol reaction is usually carried out in highly dipolar aprotic solvents (dimethylsulfoxide, dimethylformamide, acetonitrile) where proline presents an acceptable solubility. Protic solvents are generally characterized by poor stereocontrol (e.g., methanol) or poor reactivity (e.g., water). Here, we report that water/methanol mixtures are exceptionally simple and effective reaction media for the intermolecular organocatalytic aldol reaction using the simple proline as the catalyst.
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.
The construction of a hybrid metal-organo-photoredox catalyst based on the conjugation of an imidazolidinone organocatalyst and Ir(ppy)2(bipy) (ppy = 2-phenylpyridine, bipy = bipyridine) is described.
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