Enantioselective Cross-[4 + 2]-Cycloaddition/Decarboxylation of 2-Pyrones by Cooperative Catalysis of the Pd(0)/NHC Complex and Chiral Phosphoric Acid.

Here, we describe a cooperative Pd(0)/chiral phosphoric acid catalytic system that allows us to realize the first chemo-, regio-, and enantioselective sequential cross-[4 + 2]-cycloaddition/decarboxylation reaction between 2-pyrones and unactivated acyclic 1,3-dienes. The key to the success of this transformation is the utilization of an achiral N-heterocyclic carbene (NHC) as the ligand and a newly developed chiral phosphoric acid as the cocatalyst. Experimental investigations and computational studies support the idea that the Pd(0)/NHC complex acts as a π-Lewis base to increase the nucleophilicity of 1,3-dienes via η2 coordination, while the chiral phosphoric acid simultaneously increases the electrophilicity of 2-pyrones by hydrogen bonding. By this synergistic catalysis, the sequential cross-[4 + 2]-cycloaddition and decarboxylation reaction proceeds efficiently, enabling the preparation of a wide range of chiral vinyl-substituted 1,3-cyclohexadienes in good yields and enantioselectivities. The synthetic utility of this reaction is demonstrated by synthetic transformations of the product to various valuable chiral six-membered carbocycles.

Enantioselective Synthesis of cis-Decalins by Merging the Birch Reduction and Inverse-Electron-Demand Diels-Alder Reaction.

Herein, we show that the combination of the Birch reduction of readily available anisole derivatives and the catalytic asymmetric inverse-electron-demand Diels-Alder reaction of 2-pyrones can serve as a powerful platform for the diverse synthesis of synthetically important cis-decalin scaffolds. Enabled by a well-modified chiral bis(oxazoline) ligand/CuII complex, a wide range of polysubstituted cis-decalin scaffolds with up to six contiguous stereocenters were generated efficiently. The synthetic potential of this method is demonstrated by the concise synthesis of the sesquiterpene (+)-occidentalol and a key intermediate for seven triterpenes. Mechanistic studies suggest the 1,3-cyclohexadienes formed in situ are the key intermediates, and efficient kinetic resolution occurs when C2- and/or C3-substituted 1,4-cyclohexadienes are utilized as substrates. DFT calculations elucidated that the Diels-Alder reaction proceeds in a stepwise fashion and revealed the origins of the stereoselectivities.

Construction of gem-Difluoroenol Esters through Catalytic O-Selective Addition of Difluoroenoxysilanes to Ketenes.

The O-site reactivity of difluoroenoxysilanes is disclosed for the first time, which enabled the direct construction of versatile gem-difluoroalkenes through an unprecedented highly efficient addition reaction with ketenes. A series of valuable gem-difluoroenol esters were achieved in good to excellent yields. The synthetic versatility of this protocol is further demonstrated by the gram-scale synthesis and good functional group tolerance.

Catalyst-Free and Solvent-Controlled Divergent Synthesis of Difluoromethylene-Containing S-Heterocycles.

An unprecedented catalyst-free reaction of benzo[b]thiophene-2,3-diones with difluoroenoxysilanes has been developed using either MeOH or H2O as the solvent, which constitutes a facile and efficient protocol for the solvent-controlled divergent synthesis of five- and seven-membered S-heterocycles featuring a gem-difluoromethylene group. A gram-scale synthesis and the diversification of the product transformations to other difluorinated S-heterocycles further highlight its utility.

Regioselective Markovnikov hydrodifluoroalkylation of alkenes using difluoroenoxysilanes.

Alkene hydrodifluoroalkylation is a fruitful strategy for synthesizing difluoromethylated compounds that are interesting for developing new medicinal agents, agrochemicals, and advanced materials. Whereas the anti-Markovnikov hydrodifluoroalkylation to linear-type products is developed, employing radical-based processes, the Markovnikov synthesis of branched adducts remains unexplored. Herein, we describe acid-catalyzed processes involving carbocation intermediates as a promising strategy to secure the Markovnikov regioselectivity. Accordingly, the Markovnikov hydrodifluoroalkylation of mono-, di-, tri-, and tetrasubstituted alkenes using difluoroenoxysilanes, catalyzed by Mg(ClO4)2·6H2O, is achieved. This allows the diversity-oriented synthesis of α,α-difluoroketones with a quaternary or tertiary carbon at the ß-position that are otherwise difficult to access. The method is applied to the modification of natural products and drug derivatives. The resulting α,α-difluorinated ketones could be converted to the corresponding α,α-difluorinated esters or alcohols, or organofluorine compounds featuring a CF2H or CF2CF2Ph moiety. Mechanistic studies support that Mg(ClO4)2·6H2O functions as a hidden Brønsted acid catalyst.