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Synfacts 2025; 21(07): 671
DOI: 10.1055/a-2601-4197
Synthesis of Heterocycles

Catalyst-Controlled Cycloaddition for the Synthesis of Bridged Sulfur Heterocycles

Contributor(s):
Paul Richardson (Pfizer)
Tang L, Bai W, Wang K-J, Wu F, Peng Q, Huang G *, Feng J-J *. Tianjin University and Hunan University, Changsha, P. R. China
Lewis Acid-Catalyzed Enantioselective (4 + 3)/Thia-(3 + 2) Cycloadditions of Bicyclobutanes and Enaminothiones: Catalyst-Directed Divergent Synthesis of Bridged Sulfur Heterocycles.

ACS Catal. 2025;
15: 7877-7890
DOI: 10.1021/acscatal.5c02274
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Keywords

Lewis acid catalysis - cycloadditions - strain release - sulfur

Significance

Bridged bicyclic sulfur scaffolds are rarely encountered in medicinal chemistry owing to the challenges in their synthesis. Cycloaddition reactions involving bicyclobutanes (BCBs) are facilitated by the concomitant strain release and have been widely exploited for the synthesis of a range of bridged bicyclo[n.1.1] bioisosteres. The current report extends this work using enaminothiones 1 to incorporate sulfur into the products through a catalyst-controlled synthesis of either thia-bicyclo[2.1.1]hexanes 3 or thia-bicyclo[4.1.1]octanes 4.


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Comment

Catalyst screening demonstrated that ZnCl2 promoted the [3 + 2] cycloaddition with an acidic work-up utilized to mitigate the instability of the initially generated enamine. When Sc(OTf)3 was employed as the catalyst, a total switch in regioselectivity was observed with exclusive formation of the [4 + 3]-based cycloaddition products. An impressive substrate scope was demonstrated for both transformations. Key to the success in developing an enantioselective variant of the [4 + 3]-cycloaddition is utilization of an imidazole-based amide on the BCB-component in conjunction with a nickel catalyst and a PyBIM-based ligand.


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Publication History

Article published online:
23 June 2025

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