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A highly enantioselective synthetic method towards the α2c-adrenoceptor antagonist ORM-10921

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Abstract

The preparation of ORM-10921, a selective α2C-adrenoceptor antagonist with promising anti-psychotic properties, was successfully achieved using asymmetric α-alkylation of α,β-unsaturated imide and Bischler–Napieralski cyclization/asymmetric reduction as the key steps. When the tetracyclic iminium 11S was used in the reduction, the diastereo-selectivity was poor, from which four stereoisomers of ORM-10921 were obtained, respectively. However, the diastereoselectivity could be significantly improved (with dr up to >97 : 3) when the tricyclic imine substrate 19S was applied in this reduction, suggesting an additional chelation from the side-chain methoxy group in the transition state. According to this protocol, ORM-10921 was accomplished in a highly enantioselective manner. In addition, two analogs 26Aa and 26Ba were prepared using this novel method, and the absolute configurations were unambiguously assigned by single crystal X-ray crystallography.

Graphical abstract: A highly enantioselective synthetic method towards the α2c-adrenoceptor antagonist ORM-10921

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Publication details

The article was received on 27 Oct 2018, accepted on 29 Jan 2019 and first published on 30 Jan 2019


Article type: Research Article
DOI: 10.1039/C8QO01166D
Citation: Org. Chem. Front., 2019, Advance Article

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    A highly enantioselective synthetic method towards the α2c-adrenoceptor antagonist ORM-10921

    Q. Ma, X. Yang, X. Lei and G. Lin, Org. Chem. Front., 2019, Advance Article , DOI: 10.1039/C8QO01166D

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