Expeditious diastereoselective synthesis of elaborated ketones via remote Csp3–H functionalization

Abstract

The quest for selective C–H functionalization reactions, able to provide new strategic opportunities for the rapid assembly of molecular complexity, represents a major focus of the chemical community. Examples of non-directed, remote Csp3–H activation to forge complex carbon frameworks remain scarce due to the kinetic stability and thus intrinsic challenge associated to the chemo-, regio- and stereoselective functionalization of aliphatic C–H bonds. Here we describe a radical-mediated, directing-group-free regioselective 1,5-hydrogen transfer of unactivated Csp3–H bonds followed by a second Csp2–H functionalization to produce, with exquisite stereoselectivity, a variety of elaborated fused ketones. This study demonstrates that aliphatic acids can be strategically harnessed as 1,2-diradical synthons and that secondary aliphatic C–H bonds can be engaged in stereoselective C–C bond-forming reactions, highlighting the potential of this protocol for target-oriented natural product and pharmaceutical synthesis.

Photocatalytic three-component asymmetric sulfonylation via direct C(sp3)-H functionalization

“…Other photocatalysts (PC2-PC4) failed to catalyze this transformation (entries 8-10). In order to improve the reaction e ciency and enantioselectivity, a range of chiral ligands (L2-L11) were screened (entries [11][12][13][14][15][16][17][18][19][20]. Chiral bis(oxazoline) ligands (L2-L4) and a tridentate ligand (L5), which have been successfully used for asymmetric induction in some radical-mediated transformations, 53−56 were found to be ineffective in this photocatalytic reaction (entries 11-14), but replacement of L1 with an indane-derived BOX ligand (L6) led to a full conversion and signi cantly increased enantiomeric excess (82% ee) (entry 15).…”

Catalytic asymmetric synthesis of a nitrogen heterocycle through stereocontrolled direct photoreaction from electronically excited state

“…Inspired by Padwa’s work and other reports on the diverse reactivity of vinyl azides 25 , we develop a herein reported direct [2 + 3] photocycloaddition of photoexcited acceptor-substituted alkenes with vinyl azides in a catalytic and asymmetric manner toward the synthesis of nonracemic chiral 1-pyrrolines with virtually perfect diastereoselectivities and enantioselectivities of up > 99% ee. Although vinyl azides are well-known to act as radical acceptors 26 – 28 or triplet energy acceptors 23 , 29 , their ability to direct undergo cycloaddition with photoexcited alkenes has no precedence. All mechanistic experiments support a scenario in which a visible-light-excited complex out of α,β-unsaturated carbonyl compound and rhodium catalyst directly engages in a reaction with vinyl azides, thereby providing a convenient and unique access to nonracemic chiral 1-pyrrolines with a constitution that differs from related ground-state chemistry.…”

An Update on Distal C(sp3)−H Functionalization Involving 1,5‐HAT Emerging from Nitrogen Radicals

“…In further agreement with Shi's work, Nevado in the year of 2017, thought to use carboxylic acid as a 1,2-diradical synthon in presence of Ag(II) active catalyst and vinyl azide, via radical mediated decarboxylation to generate an iminyl radical after the removal of dinitrogen unit (Scheme 15a). [43] The following reaction goes via formation of C-centered radical through 1,5-HAT enabled by a directing-group free remote C(sp 3 )À H activation, followed by a C(sp 2 )À H function- alization in an intricate radical cascade. Mechanistic study indicates that the 1,5-HAT is connected to the rate-determining step of these transformations.…”