New Insights into Cyclobutenone Rearrangements: A Total Synthesis of the Natural ROS‐Generating Anti‐Cancer Agent Cribrostatin 6

Abstract

Aryl- and heteroarylcyclobutenone rearrangements proceed in excellent yield under continuous-flow conditions. The former shows a Hammett correlation with σ(I) providing strong evidence that electrocyclisation is the rate-determining step and has a late transition state. The reaction has been modelled by using DFT and CCSD(T) methods, with the latter giving excellent correlation with the experimental rate constant. A short and efficient total synthesis of cribrostatin 6, an anti-neoplastic and anti-microbial agent, provides a topical demonstration of the value of this method.

An Efficient Flow‐Photochemical Synthesis of 5H‐Furanones Leads to an Understanding of Torquoselectivity in Cyclobutenone Rearrangements

“…[1][2][3] A classic example is the rearrangement of arylcyclobutenone 1 a! [1][2][3] A classic example is the rearrangement of arylcyclobutenone 1 a!…”

“…[1][2][3] A classic example is the rearrangement of arylcyclobutenone 1 a! [2,4] In principle, such criteria could also be met by the related photochemical rearrangement of 1 a to 5H-furanone 4 a, yet this reaction has lain almost dormant since its introduction by because of the low yields attained in each of the published examples (27-51 %, Scheme 2). [2,4] In principle, such criteria could also be met by the related photochemical rearrangement of 1 a to 5H-furanone 4 a, yet this reaction has lain almost dormant since its introduction by because of the low yields attained in each of the published examples (27-51 %, Scheme 2).…”

Cycloaddition and Electrocyclic Reactions of Vinylketenes, Allenylketenes, and Alkynylketenes

“…9,10 Thermal generation of arylvinylketenes in a flow reactor proceeds efficiently to provide 1,4-naphthoquinones in high yield after exposure to air to convert any hydroquinone to the quinone (Scheme 15). 48 The rates of the reactions of substituted derivatives, determined using 1 H NMR analysis, show a reasonable correlation with σ p parameters for the substituent R, a result interpreted in terms of reversible ring opening of the cyclobutenone, with electrocyclization as the rate-limiting step. When the reactions are conducted with photochemical activation of the cyclobutenone, a different course is followed and furanones (Scheme 16, R = alkyl, aryl, heteroaryl, and alkynyl) are formed.…”

Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS

“…Thus, the brominated core, imidazo[1,5-a]pyridine 4, was prepared in three steps from 3-bromo-2-cyanopyridine 1 as previously described (20). Contemporaneously, a series of cyclobutenediones 8 were prepared as surrogates for the quinone ring each bearing alkoxy and organyl residues at C3 and C4 respectively.…”