Organic Synthesis

Asymmetric catalysis is used for the generation of compounds that fulfil the requirements of lead-oriented synthesis, i.e. mw = 200-350, LogP < 3, and an absence of electrophilic or redox active groups.1 Initial screening with compounds fulfilling these requirements increases the odds that further developments to improve drug-like characteristics will eventually lead to a usable medicine. Our work is mainly on the development of new methodologies for the synthesis of novel enantioenriched nitrogen heterocycles. Catalysis is employed sequentially and/or for multiple bond formation to generate rapidly the required structure. An earlier example of this approach used palladacycle catalyst COP-Cl to give (S)-1 from which were generated, following functionalisation and ring-closing metathesis, a series of chiral bicyclic nitrogen heterocycles (S)-2, (S)-3 and (S)-4.2 Stereoselective enone or alkene functionalisation will provide access to a diverse range of lead-like structures. Related programmes have also resulted in the synthesis of novel chiral isoquinolinones and dihydroindoles.3

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1. A. Nadin, C. Hattotuwagama and I. Churcher, Angew. Chem. Int. Ed. 2012, 51, 1114.
2. H. Nomura and C. J. Richards, Org. Lett. 2009, 11, 2892.
3. C. J. Richards, et. al. in preparation.