Synthesis of ent-Ketorfanol via a C-H Alkenylation/Torquoselective 6[pi] Electrocyclization Cascade

The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A RhI-catalyzed intramolecular CH alkenylation/torquoselective 6πelectrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. Computational studies were perfor...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2015-10, Vol.54 (41), p.12044
Main Authors: Phillips, Eric M, Mesganaw, Tehetena, Patel, Ashay, Duttwyler, Simon, Mercado, Brandon Q, Houk, Kendall N, Ellman, Jonathan A
Format: Article
Language:English
Online Access:Get full text
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Summary:The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A RhI-catalyzed intramolecular CH alkenylation/torquoselective 6πelectrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6πelectrocyclization. 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.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201505604