Enantioselective β-Protonation of Enals via a Shuttling Strategy

Abstract

Remote asymmetric protonation is a longstanding challenge due to the small size of protons. Reactions involving electron-deficient olefins pose a further difficulty due to the electrophilic nature of these substrates. We report a shuttling system that delivers a proton in a highly enantioselective manner to the β-carbon of enals using a chiral N-heterocyclic carbene (NHC) catalyst. Choices of a Brønsted base shuttle and a Brønsted acid cocatalyst are critical for highly stereoselective β-protonation of the homoenolate intermediate and regeneration of the NHC catalyst results in functionalization of the carbonyl group. Thioesters with a β-chiral center were prepared in a redox-neutral transformation with an excellent yield and ee.

Aerobic Oxidation/Annulation Cascades through Synergistic Catalysis of RuCl3 and N‐Heterocyclic Carbenes

“…Reacting the enal ( 1 a ) with a catalytic amount of an NHC precursor and a base in the presence of MeOH and O 2 leads to formation of the saturated methyl ester ( 3 a′ ) as the major product in 32 % yield (Table ). The desired oxidation product, methyl cinnamate ( 3 a ), is isolated in 9 % yield, a result suggesting that the β‐protonation pathway is faster than direct aerobic oxidation of the homoenolate . In order to accelerate the oxidation pathway, we tested several saturated Ru species that are known to be single electron transfer (SET) oxidants.…”

Enantio‐ and Diastereoselective Hydrofluorination of Enals by N‐Heterocyclic Carbene Catalysis

“…[6] If the b-protonation occurs with low enantioselectivity for b,bdisubstitued enals,amixture of diastereomeric products will Table 2: Scope with respect to b-aryl enals in the enantioselective hydrofluorination. Although the NHC precursor 4 induces excellent discrimination in the a-fluorination step,a symmetric control of the b-protonation is likely to be compromised when ac arboxylate is used as ap roton-transfer agent.…”

Enantio‐ and Diastereoselective Hydrofluorination of Enals by N‐Heterocyclic Carbene Catalysis

“…[5] In 2017, our group reported enantioselective hydrogenation of enals using bridgehead nitrogen amines as as elective proton-transfer agent. [6] Subsequently,w ed iscovered that the same transformation can be accomplished with ab roader substrate scope by using acombination of an achiral NHC and achiral phosphoric acid. [7] We recently applied this strategy to the synthesis of b-chiral amides,hydrazides,acid, esters,peresters, and heterocycles.…”