Synthesis of ent-Ketorfanol via a C-H Alkenylation/Torquoselective 6π Electrocyclization Cascade

The asymmetric synthesis of ent‐ketorfanol from simple and commercially available precursors is reported. A RhI‐catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2‐dihydropyridine as a key intermediate. Computational studies were perf...

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Bibliographic Details
Published in:Angewandte Chemie 2015-10, Vol.127 (41), p.12212-12216
Main Authors: Phillips, Eric M., Mesganaw, Tehetena, Patel, Ashay, Duttwyler, Simon, Mercado, Brandon Q., Houk, Kendall N., Ellman, Jonathan A.
Format: Article
Language:English
Subjects:
Alkaloide
Alkylation
Asymmetrische Synthesen
Asymmetry
C-H-Aktivierung
Cascades
Computation
Diols
Heterocyclen
Ketones
Precursors
Synthesis
Torquoselektivität
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Summary:The asymmetric synthesis of ent‐ketorfanol from simple and commercially available precursors is reported. A RhI‐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. Die asymmetrische Synthese von ent‐Ketorfanol ausgehend von käuflichen Vorstufen beruht auf einer Kaskade aus RhI‐katalysierter intramolekularer C‐H‐Alkenylierung und torquoselektiver 6π‐Elektrocyclisierung zum Aufbau einer bicyclischen 1,2‐Dihydropyridin‐Zwischenstufe. Die Ketofunktion und der letzte Ring werden in einem Schritt durch die redoxneutrale säurekatalysierte Umlagerung eines vicinalen Diols mit anschließender intramolekularer Friedel‐Crafts‐Alkylierung eingeführt.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201505604