Iterative Catalyst-Controlled Diastereoselective Matteson Homologations Enable the Selective Synthesis of Benzestrol Isomers

We report the development of an iterative Matteson homologation reaction with catalyst-controlled diastereoselectivity through the design of a new catalyst. This reaction was applied to the selective synthesis of each stereoisomer of benzestrol, a bioactive compound with estrogenic activity featurin...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2024-11, Vol.146 (45), p.30771-30777
Main Authors: Angle, Samantha R., Sharma, Hayden A., Choi, Christie K., Carlson, Kathryn E., Hou, Yingwei, Nwachukwu, Jerome C., Kim, Sung Hoon, Katzenellenbogen, Benita S., Nettles, Kendall W., Katzenellenbogen, John A., Jacobsen, Eric N.
Format: Article
Language:English
Subjects:
Catalysis
Estrogen Receptor alpha - chemistry
Estrogen Receptor alpha - metabolism
Humans
Molecular Structure
Stereoisomerism
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Summary:We report the development of an iterative Matteson homologation reaction with catalyst-controlled diastereoselectivity through the design of a new catalyst. This reaction was applied to the selective synthesis of each stereoisomer of benzestrol, a bioactive compound with estrogenic activity featuring three contiguous stereocenters. The different stereoisomers were assayed to determine their binding affinity for the estrogen receptor α (ERα), and the absolute configuration of the compound having uniquely high activity was determined. This research lays a framework for the catalytic synthesis and study of complete stereoisomeric sets of other bioactive molecules and chemical probes containing contiguous stereocenters.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.4c12857