Translating planar heterocycles into 3D analogs via photoinduced hydrocarboxylation

Abstract

The rapid preparation of complex three-dimensional (3D) heterocyclic scaffolds is a key challenge in modern medicinal chemistry. Small molecule therapeutic candidates with increased 3D complexity, on average, possess a higher probability of clinical success. However, new drug targets remain dominated by flat molecules due the wealth of robust coupling reactions available for their construction. Heteroarene dearomatization reactions offer an ideal opportunity to transform readily accessible 2D structures into saturated analogs. Broadly employed heteroarene hydrogenation reactions rehybridize C(sp2) sites to C(sp3) without otherwise perturbing the molecular shape. In stark contrast, heteroarene difunctionalization strategies dramatically change the molecular structure. In principle, heteroarene hydrofunctionalization reactions constitute an elusive middle ground by disrupting aromaticity and introducing a single molecular vector. Unfortunately, dearomative hydrofunctionalization reactions remain limited. Herein, we report a new strategy to enable the dearomative hydrocarboxylation of indoles and related heterocycles. This reaction represents a rare example of a heteroarene hydrofunctionalization that meets the numerous requirements for broad implementation in drug discovery. The transformation is highly chemoselective, broad in scope, operationally simple, and readily amenable to high-throughput experimentation (HTE). Accordingly, this process will allow existing libraries of heteroaromatic compounds to be translated into diverse 3D analogs and enable exploration of new classes of medicinally relevant molecules.

Radical Hydrocarboxylation of Unactivated Alkenes via Photocatalytic Formate Activation

“…Substrates bearing a variety of pendant heterocycles, including oxetanes (12), γ-lactones (14), piperidines (15,16), pyrans (17), and imidazoles (18), each underwent the desired transformation. Hydrocarboxylation proceeds smoothly across a series of sterically hindered substrates (11,12,(14)(15)(16)(17)19), which included fully substituted carbon centers in both cyclic (12) and acyclic systems (19). Moderate to high yields of the linear carboxylic acid products were obtained across a series of exocyclic and acyclic 1,1disubstituted alkene substrates upon gentle heating (20−22).…”

“…5−17 Our group has a particular interest in alkene hydrocarboxylation using radical intermediates. 18,19 Carboxylic acids are a readily diversifiable functional handle 20−24 and are themselves a common motif found in natural products, pharmaceuticals, and commodity chemicals. 25−28 We envision that a broad and general radical hydrocarboxylation reaction would offer a powerful complement to transition-metal-catalyzed methods, such as the numerous established CO-based approaches 29−32 and the emerging alternative technologies that proceed through migratory insertion into CO 2 .…”

“…54 This approach has been applied to activated alkene hydrocarboxylation; however, attempts to expand the scope of this process to unactivated alkenes have been categorically unsuccessful. 18,19,40,41 Nonetheless, we recognized that, in principle, this formate-based mechanistic manifold should be uniquely well-matched to address the specific challenges encountered by other approaches to unactivated alkene hydrocarboxylation. Based on our working mechanistic model, CO 2…”

“…Alkene hydrofunctionalization methods that exploit radical intermediates are a fundamental class of synthetic reactions. Radical reactivity offers a complementary regio- and chemoselectivity profile relative to polar pathways. , Despite anti-Markovnikov hydrobromination dating back a century, , the development of radical hydrofunctionalization reactions remains a contemporary area of investigation. − Our group has a particular interest in alkene hydrocarboxylation using radical intermediates. , Carboxylic acids are a readily diversifiable functional handle − and are themselves a common motif found in natural products, pharmaceuticals, and commodity chemicals. − We envision that a broad and general radical hydrocarboxylation reaction would offer a powerful complement to transition-metal-catalyzed methods, such as the numerous established CO-based approaches − and the emerging alternative technologies that proceed through migratory insertion into CO 2 . − However, established approaches to radical hydrocarboxylation have remained largely limited to activated alkenes (Figure A). ,,− Unactivated aliphatic alkenes are an abundant and important substrate class but remain more challenging to engage due to their attenuated reactivity. Indeed, in the past year, Yu and co-workers reported the first and only synthetic methodology that engages unactivated alkenes with CO 2 •– .…”

“…Our group and others , have recently reported a strategy that generates CO 2 •– from inexpensive formate salts via hydrogen atom abstraction (formate C­(sp 2 )–H BDE = 86 kcal/mol) . This approach has been applied to activated alkene hydrocarboxylation; however, attempts to expand the scope of this process to unactivated alkenes have been categorically unsuccessful. ,,, Nonetheless, we recognized that, in principle, this formate-based mechanistic manifold should be uniquely well-matched to address the specific challenges encountered by other approaches to unactivated alkene hydrocarboxylation. Based on our working mechanistic model, CO 2 •– generation is coupled to its consumption, which maintains a low steady-state concentration of the reactive radical intermediate (Figure B).…”