Issue 9, 2024

Strain-enabled radical spirocyclization cascades: rapid access to spirocyclobutyl lactones and – lactams

Abstract

Spirocyclobutane derivatives have gained significant attention in drug discovery programs due to their broad spectrum of biological activities and clinical applications. Ring-strain in organic molecules is a powerful tool to promote reactivity by releasing strain energy, allowing the construction of complex molecules selectively and efficiently. Herein, we report the first strain-enabled radical spirocyclization cascades for the synthesis of functionalized spirocyclobutyl lactones and – lactams, which are finding increasing applications in medicinal chemistry. The reaction of interelement compounds with bicyclobutane (BCB) allyl esters and – amides proceeds with high chemoselectivity under simple, catalyst-free conditions using blue light irradiation. The reaction has been successfully extended to synthesize bis-spirocycles. To introduce a more diverse set of functional groups, we have developed a dual photoredox/nickel catalytic system capable of mediating the carbosulfonylation of BCB allyl amides. The reaction shows broad applicability across various (hetero)aryl halides, aryl sulfinates, and BCB allyl amides, operates under mild conditions and demonstrates excellent functional group compatibility. The functional groups introduced during the cascade reactions served as versatile handles for further synthetic elaboration.

Graphical abstract: Strain-enabled radical spirocyclization cascades: rapid access to spirocyclobutyl lactones and – lactams

Supplementary files

Article information

Article type
Edge Article
Submitted
25 Oct 2023
Accepted
20 Dec 2023
First published
21 Dec 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 3182-3191

Strain-enabled radical spirocyclization cascades: rapid access to spirocyclobutyl lactones and – lactams

K. Das, A. Pedada, T. Singha and D. P. Hari, Chem. Sci., 2024, 15, 3182 DOI: 10.1039/D3SC05700C

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