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Angew Chem Int Ed Engl. 2015 Oct 5;54(41):12044-8. doi: 10.1002/anie.201505604. Epub 2015 Aug 17.

Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade.

Author information

1
Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA).
2
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569 (USA).
3
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569 (USA). houk@chem.ucla.edu.
4
Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA). jonathan.ellman@yale.edu.

Abstract

The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A Rh(I) -catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6π electrocyclization. The computational results demonstrate that a conformational effect is responsible for the observed selectivity. The ketone functionality and final ring are introduced in a single step by a redox-neutral acid-catalyzed rearrangement of a vicinal diol to give the requisite carbonyl, followed by intramolecular Friedel-Crafts alkylation.

KEYWORDS:

CH activation; alkaloids; asymmetric synthesis; heterocycles; torquoselectivity

PMID:
26385263
PMCID:
PMC4676713
DOI:
10.1002/anie.201505604
[Indexed for MEDLINE]
Free PMC Article

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