Catalytic Enantioselective Reductive Cross Coupling of Electron-Deficient Olefins

Abstract

We report an enantioselective reductive cross coupling of electron-deficient olefins. Using a visible-light-driven cooperative photoredox and chiral Brønsted acid-catalyzed reaction with a Hantzsch ester as the terminal reductant, various cyclic and acyclic enones with 2-vinylpyridines were converted in high yields (up to 93%) to a wide range of enantioenriched pyridine derivatives featuring diverse γ-tertiary carbon stereocenters with good to excellent enantioselectivities (up to >99% ee).

Asymmetric Catalytic Synthesis by Synergistic Chiral Phosphoric Acid Photoredox Catalyzed Reactions

“…The reaction demonstrated good enantioselectivity with up to 93% ee and high yields, reaching up to 97% yield. This was accomplished through a tandem radical conjugate addition and enantioselective protonation process using various hydrocarbons and silanes (40) reacting with different α-branched 2-vinylazaarenes (39). The reaction employed TBADT (PC-6) as a photocatalyst and (S)-SPINOL-based CPA-12 or -13 as a hydrogen bonding catalyst, enabling the desired outcomes.…”

“…The reaction displayed high yields (up to 93%) and yielded pyridine derivatives with diverse γ-tertiary carbon stereocenters, exhibiting good to excellent enantioselectivities (up to > 99% ee). (Scheme 31) [39] Jiang's team have successfully developed an enantioselective intermolecular [3 + 2] cycloaddition reaction of N-arylcyclopropylamines (91) with 2-aryl acrylates/ketones (92) in 2023. This breakthrough was achieved through the employment of a cooperative photoredox and chiral hydrogen bonding catalysis strategy.…”

A Benzophenothiazine/Boronic Acid Hybrid Photocatalyst Enables the Single Electron Transfer (SET) to Carboxy Groups: SET-Initiated Cyclization of α,β-Unsaturated Carboxylic Acids

“…In addition to the [2 + 2] cycloaddition, it was also possible to conduct a reductive cyclization to obtain monocyclic products in the presence of a Hantzsch ester (HEH) as a reductant. , Notably, we found that the dual and hybrid catalyst systems showed reactivity patterns different from those observed in the [2 + 2] cycloaddition (Table ). 1a was reacted in the presence of HEH and MS5A in toluene under irradiation with a 427 nm LED.…”

Pyridylmethyl Radicals for Enantioselective Alkene Hydroalkylation Using “Ene”-Reductases

“…Pyridine-based scaffolds are indispensable among pharmaceutically relevant small molecules, and methods for their derivatization are mainstays in the medicinal synthetic toolkit. , Many strategies toward the synthesis of substituted pyridines have been developed, employing both ring-building and derivatization approaches. − However, many of these methods cannot introduce stereochemical information, as is the case with most azine C–H functionalization , and cross-coupling strategies . Pyridines’ ligand functionality has long stymied the development of metal-catalyzed methods, and when asymmetric methods are successful, control over the new stereocenter is usually confined to proximal α- or β-positions. − Strategies to access γ-stereoenriched pyridines are substantially more rare, relying on the asymmetric addition of prochiral radicals into vinylpyridines. − As drug discovery ventures into three-dimensional space, more diverse methods will be required to access these sp 3 -rich molecules with high selectivity rapidly . Our group envisioned that a biocatalytic method could impart control over constructing a remote pyridyl γ-stereocenter from readily available α-halopyridines, efficiently increasing the complexity of simple heterocyclic structures.…”