Catalytic Asymmetric ‘Clip-Cycle’ Reactions: Synthesis of Heterocycles Important in Drug Discovery

Cyclic ethers and amines are ubiquitous in biologically active natural and non-natural products. However, despite this prevalence and importance, there is no strategy for their asymmetric synthesis which is independent of heteroatom and/or ring size. We propose to address this challenge by the development of the ‘clip-cycle’ procedure. ‘Clip-Cycle’ provides a new modular, catalytic and experimentally simple route to functionalised cyclic ethers and amines of different ring sizes. ‘Clip-Cycle’ uses the robust catalytic alkene metathesis reaction to ‘clip’ an activating unsaturated thioester group to an unactivated ‘allyl’ alcohol or amine unit. The ring size of the heterocycle formed is dependent only on the length of the tether between the alkene and the heteroatom, making this one strategy applicable to the synthesis of different ring sizes. The ‘clip’ metathesis reaction of the thioester is followed, in the same pot, by the ‘cycle’ hetero-Michael reaction, which is catalysed by a chiral Brønsted acid. Unsaturated thioesters are preferred as the electrophile as they sit in the “Goldilocks zone” of reactivity, and they can be easily converted into a wide variety of different functional groups. Unsaturated ketones and aldehdyes are more reactive, but can suffer from higher levels of uncatalysed background hetero-Michael reaction, or the formation of alternative cyclic structures as a result of reaction with the carbonyl group. Unsaturated oxoesters, however, tend to require more forcing conditions to affect cyclisation, and can lead to decomposition of the substrate and lower enantioselectivities as a result. Our proof of principle studies on the asymmetric synthesis of pyrrolidines is reported Org. Lett. 2020, 22, 8116 and Tetrahedron, 2021, 78, 131789. This project will investigate ‘clip-cycle’ synthesis of piperidines, THPs, THFs, piperazines, morpholines and 1,4-dioxanes.

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