Synthesis of Polysubstituted 2-Oxabicyclo[2.1.1]hexanes via Visible-Light-Induced Energy Transfer

Abstract

Synthesis of bicyclic scaffolds has attracted growing interest because they are of high importance in modern pharmaceutical development. Here we report a strategy to access polysubstituted 2-oxabicyclo[2.1.1]hexanes in a single operation from readily accessible benzoylformate esters and bicyclo[1.1.0]butanes via visible-light-induced triplet energy transfer catalysis. The process is proposed to involve a formal [2π + 2σ] photocycloaddition/backbone C–H abstraction/aryl group migration sequence. A diverse range of (hetero)aryl groups successfully underwent migration to the backbone (C2) position to provide previously inaccessible bicyclic molecules, and the ester group of the product can serve as a handle for downstream manipulation, thus offering opportunities to rapidly build up molecular complexity and access new sp3-rich chemical space.

Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes

“…Synthetic organic chemists have also made great progress in the development of new synthetic methods that provide geometrically complementary meta-substituted arene bioisosteres. However, these architectures have been explored using mainly bridge-substituted BCPs and bicyclo[2.1.1]­hexanes, , although these motifs do not exactly mimic the bond vectors displayed in meta-substituted arenes. Recently, Brown and Glorius presented efficient [2π + 2σ] photocycloaddition protocols for the preparation of bicyclo[2.1.1]­hexanes.…”

Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis

“…Recent developments in the synthesis of more highly functionalised BCBs should also enable more detailed investigations of these scaffolds and the effect that alternative substitution has on BCB reactivity. This is a rapidly developing field and during the review process of this manuscript further investigations towards bridged bicyclic 97,98 , spirocyclic 99 , and other structural motifs 100,101 have been reported. As the preparation of structurally complex architectures becomes more important to our ability to design the next generation of pharmaceuticals, the chemistry of the smallest fused hydrocarbon will certainly have its part to play.…”

Photocatalyzed [3sigma + 2sigma] and [3sigma + 2pi] cycloadditions for the synthesis of bicyclo[3.1.1]heptanes and cyclopentenes.

“…The single crystal structure of 8 is shown in Scheme 3 (CCDC number 2238001). Given the redox potentials of the [Ir] photocatalyst (E1/2 PC*/PC+ = -0.96 V vs SCE; E1/2 PC*/PC-= +0.66 V vs SCE) 39 in comparison with reported values for 1h (E1/2 = -2.01 V vs SCE), 7 styrene (E1/2 = +1.97 V) 39 and BCBs (E1/2 = +1.54 V vs SCE), 34 a single electron transfer mechanism appears less probable. Based on previous studies, the formation of a ketyl radical via a proton-coupled electron transfer (PCET) process in the presence of PA could be favored by 11 kcal/mol compared to the direct electron transfer.…”

“…The synthesis of BCBs is now well developed due to the recent focus of interest in their use as building blocks, especially in photocatalytic processes. [30][31][32][33][34][35][36] While we were working on this project, Molander and co-workers reported the first annulation of cyclopropyl amines (CPAs) and BCBs to give amino BCHs via oxidative activation. 35 Interestingly, this work is highly complementary to our approach, both from the substitution pattern (amine donors vs carbonyl acceptors) and the mode of activation (electron-transfer vs homolytic cleavage).…”