Streamlined Synthesis of C(sp³)-Rich N-Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis

Abstract

We report a general visible-light-mediated strategy that enables the construction of complex C(sp 3)rich N-heterospirocycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C(sp 3)-rich N-heterospirocycles displaying structural and functional features relevant to fragment-based lead identification programs.

A modular and divergent approach to spirocyclic pyrrolidines

“…7 In this context, Gaunt and coworkers recently disclosed a general spirocyclisation method employing photoredox catalysis to generate a-amino radicals capable of 5-exo-trig/dig cyclisations (Scheme 1B( 1)). 8 From another access point, and focussing on the role these scaffolds play in fragment-based drug discovery, Spring and co-workers reported the use of a ring-closing metathesis strategy to afford a broad class of spirocyclic structures. 9 The group went on to highlight qualitatively the molecules' favourable physicochemical properties as well as the diverse 3D chemical space these products occupy (Scheme 1B(2)).…”

Radical‐Mediated Non‐Dearomative Strategies in Construction of Spiro Compounds

“…In this context, Gaunt group developed interesting approach to synthesis of structurally varied small C(sp 3 )-rich N-heterospirocycles 142 by means of visible-light-induced catalysis. [60] Reported strategy relies on the usage of feedstock aliphatic aldehydes or ketones with simple alkenes containing secondary amine group in the presence of 1,4-cyclohexadiene and Hantzsch ester and highly reducing Ir-photoredox catalyst under blue LED irradiation (Scheme 40). In this approach, a broad library of aliphatic rich spirocycles displaying variety of structural, functional, and physical features can be obtained in reasonable yields (29-97%) and d.r.…”

“…Design of novel, small spirocyclic molecules displaying diverse functionality can help for identifying promising candidates in screening process of finding new therapeutic agents. In this context, Gaunt group developed interesting approach to synthesis of structurally varied small C( sp 3 )‐rich N ‐heterospirocycles 142 by means of visible‐light‐induced catalysis [60] . Reported strategy relies on the usage of feedstock aliphatic aldehydes or ketones with simple alkenes containing secondary amine group in the presence of 1,4‐cyclohexadiene and Hantzsch ester and highly reducing Ir‐photoredox catalyst under blue LED irradiation (Scheme 40).…”

Facile Synthesis of Spirocyclic Lactams via [3+2] and [3+3] Aza‐Annulation Reactions

“…[40] Gaunt reported a visible-light-mediated synthesis of aza-sprirocycles using photocatalytic single electron transfer (SET) reduction of iminium intermediate-radical cycliza-tion sequence. [41] Bode employed catalytic hydrogen atom transfer reduction of electron-rich olefins with a generation of C-centered radicals in the presence of imines for the intramolecular radical cyclization with the formation of spirocyclic morpholines. [42] Recently Krasavin group reported several spirocyclization procedures based on α-diazolactam chemistry.…”