Combined Theoretical and Experimental Studies Unravel Multiple Pathways to Convergent Asymmetric Hydrogenation of Enamides.

We present a highly efficient convergent asymmetric hydrogenation of E/Z mixtures of enamides catalyzed by N,P-iridium complexes supported by mechanistic studies. It was found that reduction of the olefinic isomers (E and Z geometries) produces chiral amides with the same absolute configuration (enantioconvergent hydrogenation). This allowed the hydrogenation of a wide range of E/Z mixtures of trisubstituted enamides with excellent enantioselectivity (up to 99% ee). A detailed mechanistic study using deuterium labeling and kinetic experiments revealed two different pathways for the observed enantioconvergence. For α-aryl enamides, fast isomerization of the double bond takes place, and the overall process results in kinetic resolution of the two isomers. For α-alkyl enamides, no double bond isomerization is detected, and competition experiments suggested that substrate chelation is responsible for the enantioconvergent stereochemical outcome. DFT calculations were performed to predict the correct absolute configuration of the products and strengthen the proposed mechanism of the iridium-catalyzed isomerization pathway.

Asymmetric Synthesis of Alkyl Fluorides: Hydrogenation of Fluorinated Olefins.

The development of new general methods for the synthesis of chiral fluorine-containing molecules is important for several scientific disciplines. We herein disclose a straightforward method for the preparation of chiral organofluorine molecules that is based on the iridium-catalyzed asymmetric hydrogenation of trisubstituted alkenyl fluorides. This catalytic asymmetric process enables the synthesis of chiral fluorine molecules with or without carbonyl substitution. Owing to the tunable steric and electronic properties of the azabicyclo thiazole-phosphine iridium catalyst, this stereoselective reaction could be optimized and was found to be compatible with various aromatic, aliphatic, and heterocyclic systems with a variety of functional groups, providing the highly desirable products in excellent yields and enantioselectivities.

Diastereo- and Enantioselective Synthesis of Fluorine Motifs with Two Contiguous Stereogenic Centers.

The synthesis of chiral fluorine containing motifs, in particular, chiral fluorine molecules with two contiguous stereogenic centers, has attracted much interest in research due to the limited number of methods available for their preparation. Herein, we report an atom-economical and highly stereoselective synthesis of chiral fluorine molecules with two contiguous stereogenic centers via azabicyclo iridium-oxazoline-phosphine-catalyzed hydrogenation of readily available vinyl fluorides. Various aromatic, aliphatic, and heterocyclic systems with a variety of functional groups were found to be compatible with the reaction and provide the highly desirable product as single diastereomers with excellent enantioselectivities.

HNTf2-catalyzed regioselective preparation of polysubstituted naphthalene derivatives through alkyne-aldehyde coupling.

We report herein the preparation of polysubstituted naphthalene derivatives by the original Brønsted-acid-catalyzed benzannulation reaction of phenylacetaldehydes with alkynes. This reaction, which was usually performed with Lewis acids under thermal activation, is efficiently promoted by 15 mol % of triflimide (HNTf2) at room temperature under metal-free and mild reaction conditions and leads with a perfect regioselectivity to a wide variety of diversely functionalized naphthalenes in 41-78% yield. A catalytic cycle is proposed together with some further applications of this catalytic system in the related benzannulation transformations of epoxide and acetal derivatives.

Catalytic enantioselective synthesis of fluoromethylated stereocenters by asymmetric hydrogenation.

Fluoromethyl groups possess specific steric and electronic properties and serve as a bioisostere of alcohol, thiol, nitro, and other functional groups, which are important in an assortment of molecular recognition processes. Herein we report a catalytic method for the asymmetric synthesis of a variety of enantioenriched products bearing fluoromethylated stereocenters with excellent yields and enantioselectivities. Various N,P-ligands were designed and applied in the hydrogenation of fluoromethylated olefins and vinyl fluorides.

Asymmetric synthesis of 1,2-fluorohydrin: iridium catalyzed hydrogenation of fluorinated allylic alcohol.

We have developed a simple protocol for the preparation of 1,2-fluorohydrin by asymmetric hydrogenation of fluorinated allylic alcohols using an efficient azabicyclo thiazole-phosphine iridium complex. The iridium-catalyzed asymmetric synthesis of chiral 1,2-fluorohydrin molecules was carried out at ambient temperature with operational simplicity, and scalability. This method was compatible with various aromatic, aliphatic, and heterocyclic fluorinated compounds as well as a variety of polyfluorinated compounds, providing the corresponding products in excellent yields and enantioselectivities.

Asymmetric preparation of polysubstituted cyclopentanes by synergistic Pd(0)/amine catalyzed formal [3+2] cycloadditions of vinyl cyclopropanes with enals.

We report herein a novel diastereo- and enantiocontrolled preparation of polysubstituted cyclopentanes by the formal [3+2] cycloadditions of vinyl cyclopropanes with enals. In constrast with previously developed strategies, our original approach is based on the synergistic merger of iminium/enamine organocatalysis with palladium(0) catalysis.

TiCl4-Mediated Preparation of Thiophthalide Derivatives via Formal Thio-Passerini Reactions.

By the formal extension of the Passerini reaction to thiocarbonyl derivatives, the straightforward preparation of thiophthalides is disclosed. This method involves the intermediate formation of a sulfanyl-phthalide and a titanium tetrachloride mediated isocyanide insertion reaction. When tert-butyl thiol is used, thanks to the deprotection of the tert-butyl group, a thiophthalide resulting from a 1,5-Mumm rearrangement is isolated. Owing to the multifaceted activity of TiCl4, all steps may conveniently be performed in one pot, starting directly from 2-formylbenzoic acids, tert-butyl thiol, and various isocyanides.

Synthesis of novel pyrano[3,2-f]quinoline, phenanthroline derivatives and studies of their interactions with proteins: an application in mammalian cell imaging.

A series of tri-cyclic pyrano[3,2-f]quinoline and phenanthroline derivatives have been synthesized by a HCl-mediated 6-'endo-trig' Michael type ring closure reaction of 6-amino-5-(3-hydroxy-3-methylbut-1-ynyl)-2H-chromen-2-one in excellent yields. The process is very simple, facile and inexpensive and can provide a diverse range of substituted quinoline derivatives from simple and easily available starting materials. Moreover, the synthesized derivatives exhibit staining property to the cultured HeLa cells after fixing and can be used as fluorophores which can bind with protein molecule.