Palladium-catalyzed regio- and enantioselective migratory allylic C(sp3)-H functionalization

Abstract

Transition metal-catalyzed asymmetric allylic substitution with a suitably pre-stored leaving group in the substrate is widely used in organic synthesis. In contrast, the enantioselective allylic C(sp3)-H functionalization is more straightforward but far less explored. Here we report a catalytic protocol for the long-standing challenging enantioselective allylic C(sp3)-H functionalization. Through palladium hydride-catalyzed chain-walking and allylic substitution, allylic C-H functionalization of a wide range of acyclic nonconjugated dienes is achieved in high yields (up to 93% yield), high enantioselectivities (up to 98:2 er), and with 100% atom efficiency. Exploring the reactivity of substrates with varying pKa values uncovers a reasonable scope of nucleophiles and potential factors controlling the reaction. A set of efficient downstream transformations to enantiopure skeletons showcase the practical value of the methodology. Mechanistic experiments corroborate the PdH-catalyzed asymmetric migratory allylic substitution process.

Heteroatom-Assisted Regio- and Stereoselective Palladium-Catalyzed Carboxylation of 9-Allyl Adenine

“…Such a strategy would create the possibility to form two regioisomeric products (A and A′) as shown in Figure . Fine-tuning of the reaction conditions could promote the formation of the desired linear product (A′) via S N 2′ attack of the carboxylate ion on site a′ rather than on site a of the σ-allyl Pd­(II) complex.…”

“…The catalytic Pd­(II) species ( I ) would next undergo substrate coordination binding the reactive ene-moiety of 9-allyladenine ( 1 ) with assistance from the chelation available through the N -3 nitrogen atom (Figure , II ). Insertion of the Pd­(II) species into the N -allyl functionality results in the formation of a σ-allyl Pd­(II) complex that can possibly convert to the desired product via either an inner-sphere mechanism or an outer-sphere mechanism (Figure , III ). Given the high regioselectivity observed in the given transformation, an outer-sphere mechanism involving the S N 2′ of the nucleophile (acetate ion) looks more plausible than the inner-sphere.…”

Computational insights into the [Ni]H-catalyzed remote C(sp3)–H hydroamidation of alkenes: mechanism and insertion selectivity

“…In recent years, the chain-walking strategy has attracted considerable interest as it allows for the consecutive migration of the CC bond along the hydrocarbon chain, achieving remote C(sp 3 )–H functionalization such as hydroformylation, hydroboration, and hydroarylation. 12–15 Metal hydride species such as PdH, 16–19 CoH, 20 RhH, 21,22 and especially NiH 23–26 are commonly considered catalysts for these chain-walking reactions. Notably, very recently, the NiH-catalyzed chain-walking strategy has been employed in hydroamidation reactions by Yu and co-workers, obtaining remote C(sp 3 )–H hydroamidation products.…”

Catalytic Asymmetric Hydroalkoxylation and Formal Hydration and Hydroaminoxylation of Conjugated Dienes

“…As a part of our group’s ongoing efforts in asymmetric hydrofunctionalizations, ,, we envisioned that novel ligands would need to be designed to resolve the aforementioned challenges that have persisted for half a century (Scheme c). Most recently, an elegant Ni-catalyzed enantioselective hydroalkoxylation of conjugated dienes was published by Dong and Yang (Scheme b) .…”