Synfacts 2021; 17(12): 1317
DOI: 10.1055/s-0041-1737106
Synthesis of Heterocycles

Demonstrated 6-endo-tet Cyclizations!

(Pfizer) Contributor(s):
Paul Richardson
Vartanova AE, Ploduhkin AY, Ratmanova NK, Andreev IA, Anisimov MN, Gudimchuk NB, Rybakov VB, Levina II, Ivanova OA, *, Trushkov IV, *, Alabugin IV. * Florida State University, USA; N. D. Zelinsky Institute of Organic Chemistry, Moscow and Moscow State University, Russian Federation
Expanding Stereoelectronic Limits of endo-tet Cyclizations: Synthesis of Benz[b]azepines from Donor–Acceptor Cyclopropanes.

J. Am. Chem. Soc. 2021;
143: 13952-13961
DOI: 10.1021/jacs.1c07088.
 

Significance

Baldwin’s rules represent established dogma when considering the chances of a specific cyclization reaction occurring, and are based on the geometric restraints within the cyclic transition states (TSs) associated with the ideal trajectories for engagement of the reacting centers. These constraints are particularly strong when the attack of a nucleophile at an electrophilic sp3-carbon atom takes place to break a bond inside a cyclic TS (an endo-tet cyclization) that has fewer than eight atoms, and although there is some debate ­regarding 7-endo-tet reactions, the 5-endo-tet and 6-endo-tet TSs are clearly disfavored. The current report describes a genuine 6-endo-tet process to form a seven-membered ring through intramolecular ring opening of donor–acceptor cyclopropanes to form biologically significant tetrahydrobenz[b]azepin-2-ones.


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Comment

Optimization experiments focused on the screening of Lewis acids, a number of which were identified as capable of promoting the reaction, leading to several general methods being developed, the best of which, in terms of yield and ­diastereoselectivity, depended on the nature of the substrate. These experiments also showed that under otherwise constant conditions, increasing the reaction time led to the formation of the trans isomers through isomerization of the kinetically controlled cis products. The SN2 nature of the process was confirmed through the observed inversion of stereochemistry at the electrophilic carbon atom in the formation of 8, thereby proving that the reaction constituted a genuine endo-tet cyclization, while DFT calculations supported this hypothesis in demonstrating that the proposed mechanism does not involve carbocationic intermediates.


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Publication History

Publication Date:
17 November 2021 (online)

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