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 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.
['Phillips|Eric M|EM|', 'Mesganaw|Tehetena|T|', 'Patel|Ashay|A|', 'Duttwyler|Simon|S|', 'Mercado|Brandon Q|BQ|', 'Houk|Kendall N|KN|', 'Ellman|Jonathan A|JA|']
D000475:Alkenes D000701:Analgesics, Opioid D002384:Catalysis D003500:Cyclization D004095:Dihydropyridines D008958:Models, Molecular D010084:Oxidation-Reduction D012238:Rhodium D013237:Stereoisomerism
torquoselectivity asymmetric synthesis CH activation alkaloids heterocycles