Direct site-selective and enantioselective oxyfunctionalization of C(sp3)-H bonds to form alcohols with a general scope, with predictable selectivities, and in preparatively useful yields represents a paradigm shift in the standard logic of synthetic organic chemistry. However, the knowledge of either enzymatic or nonenzymatic asymmetric hydroxylation of tertiary C-H bonds for enantioenriched tertiary alcohol synthesis is sorely lacking. Here, we report a practical manganese-catalyzed enantio-differentiating hydroxylation of tertiary propargylic C-H bonds in acyclic systems, producing a wide range of structurally diverse enantioenriched tertiary propargyl alcohols in high efficiency with extremely efficient chemo- and enantio-discrimination. Other features include the use of C-H substrates as the limiting reagent, noteworthy functional group compatibility, great synthetic utilities, and scalability. The findings serve as a blueprint for the development of metal-catalyzed asymmetric oxidation of challenging substrates.

Chiral N-alkoxy amines are increasingly vital substrates in bioscience. However, asymmetric synthetic strategies for these compounds remain scarce. Catalytic kinetic resolution represents an attractive approach to prepare structurally diverse enantiopure N-alkoxy amines, which has remained elusive due to the notably reduced nucleophilicity of the nitrogen atom together with the low bond dissociation energies of labile NO-C and N-O bonds. We here report a general kinetic resolution of N-alkoxy amines through chemo- and enantioselective oxygenation. The mild and green titanium-catalyzed approach features broad substrate scope (55 examples), noteworthy functional group compatibility, high catalyst turnover number (up to 5200), excellent selectivity factor (s > 150), and scalability.

A manganese-catalyzed highly site- and enantioselective benzylic C-H azidation of indolines has been described. The practical method is applicable for azidation of a tertiary benzylic C-H bond with good functional group tolerance, allowing facile access to structurally diverse tertiary azide-containing indolines in high efficiency with excellent site-, chemo-, and enantioselectivity. The generality of the method was further demonstrated by site- and enantioselective azidation of the secondary benzylic C-H bond for a range of secondary azide-containing indolines. The benzylic C-H azidation method allows to straightforwardly and enantioselectively install a variety of nitrogen-based functional groups and diverse bioactive molecules at the C3 position of indoline frameworks through post-azidation manipulations. Gram-scale synthesis was also demonstrated, further highlighting the synthetic potential of the method. Mechanistic studies by combined experiments and computations elucidated the reaction mechanism and origins of stereoselectivity.

Catalytic nonenzymatic kinetic resolution (KR) of racemates remains one of the most powerful tools to prepare enantiopure compounds, which dominantly relies on the manipulation of reactive functional groups. Moreover, catalytic KR of organic azides represents a formidable challenge due to the small size and instability of the azido group. Here, an effective KR of cyclic benzylic azides through site- and enantioselective C(sp 3 )–H oxidation is described. The manganese catalyzed oxidative KR reaction exhibits good functional group tolerance, and is applicable to a range of tetrahydroquinoline- and indoline-based organic azides with excellent site- and enantio-discrimination. Computational studies elucidate that the effective chiral recognition is derived from hydrogen bonding interaction between substrate and catalyst.

An effective construction of diarylmethanes containing CF3‐ and CN‐substituted all‐carbon quaternary stereocenters via cyanation of δ‐CF3‐δ‐aryl disubstituted para‐quinone methides has been described. The reaction proceeds smoothly under simple and mild conditions and exhibits a broad scope of δ‐CF3‐δ‐aryl disubstituted para‐quinone methides in high efficiency. δ‐CF3‐δ‐alkynyl‐disubstituted para‐quinone methides also proved to be suitable substrates. The rich chemistry of the cyano moiety allows for rapid access to other valuable CF3‐substituted di‐ and triarylmethanes containing all‐carbon quaternary centers that are otherwise difficult to synthesize. The generality of the method was further demonstrated by cyanation of δ‐CN‐substituted para‐quinone methides furnishing diarylmalononitriles in good yields.

We disclose a catalytic method for β-C(sp3)-H functionalization of N-alkylamines for the synthesis of enantiomerically enriched β-substituted amines, entities prevalent in pharmaceutical compounds and used to generate different families of chiral catalysts. We demonstrate that a catalyst system comprising of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg- or Sc-based complex, promotes the highly enantioselective union of N-alkylamines and α,β-unsaturated compounds. An array of δ-amino carbonyl compounds was synthesized under redox-neutral conditions by enantioselective reaction of a N-alkylamine-derived enamine and an electrophile activated by the chiral Lewis acid co-catalyst. The utility of the approach is highlighted by late-stage β-C-H functionalization of bioactive amines. Investigations in regard to the mechanistic nuances of the catalytic processes are described.

A hybrid catalyst system for sequential Conia-ene-type cyclization/Negishi coupling for union of alkynyl ketones and aryl iodides has been developed.

An efficient catalytic method to convert an alpha-C-H bond of N-alkylamines into an alpha-C-alkynyl bond was developed. In the past, such transformations were carried out under oxidative conditions, and the enantioselective variants were confined to tetrahydroisoquinoline derivatives. Here, we disclose a method for union of N-alkylamines and trimethylsilyl alkynes, without the presence of an external oxidant, and promoted through cooperative actions of two Lewis acids, B(C6F5)3 and a Cu-based complex. A variety of propargylamines can be synthesized in high diastereo- and enantioselectivity. The utility of the approach is demonstrated by late-stage site-selective modification of bioactive amines. Kinetic investigations that shed light on various mechanistic nuances of the catalytic process are presented.

An efficient and highly enantioselective Conia-ene-type process has been developed. Reactions are catalyzed by a combination of B(C6F5)3, an N-alkylamine and a BOX-ZnI2 complex. Specifically, through cooperative action of B(C6F5)3 and amine, ketones with poorly acidic α-C-H bonds can be converted in situ to the corresponding enolates. Subsequent enantioselective cyclization involving a BOX-ZnI2-activated alkyne leads to the formation of various cyclopentenes in up to 99% yield and 99:1 er.

Current studies on cross-dehydrogenative coupling of benzylic ethers for new C-C bond construction predominantly focus on primary ether moieties. Oxidative cross-coupling of secondary benzylic ethers remains elusive. Herein, we describe the first cross-dehydrogenative coupling of secondary benzylic ethers with indoles and pyrroles for tertiary ether construction. A broad range of alpha-aryl substituted isochromans react with a variety of electronically varied indoles and pyrroles smoothly under mild metal-free conditions in high efficiency. In addition, the catalytic asymmetric variant was preliminarily explored, and corresponding tertiary ether was obtained in 69% ee. (C) 2019 Elsevier Ltd. All rights reserved.

An efficient deuteration process of beta-amino C-H bonds in various N-alkylamine-based pharmaceutical compounds has been developed. Catalytic reactions begin with the action of Lewis acidic B(C6F5)(3) and Brensted basic N-alkylamine, converting a drug molecule into the corresponding enamine. The acid/base catalysts also promote the dedeuteration of acetone-d(6) to afford a deuterated ammonium ion. Ensuing deuteration of the enamine then leads to the formation of beta-deuterated bioactive amines with up to 99% deuterium incorporation.

The first bimolecular oxidative C–H functionalization of secondary benzylic ethers for tertiary ether synthesis has been established in high efficiency.

Current studies on the oxidative C-H functionalization of benzylic ethers for C-C forging process dominantly focus on primary ethers. The corresponding reaction of secondary ethers remains underdeveloped. Herein, a practical and efficient oxidative C-H cyanation of secondary benzylic ethers with TMSCN in the presence of DDQ is described. The metal-free process is well tolerated with a wide variety of electronically varied alpha-monosubstituted isochromans, facilely furnishing a library of isochromans bearing alpha-aryl alpha-cyano substituent patterns for further diversification and bioactive small molecule identification. (C) 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

An efficient oxidative C-H alkynylation of N-carbamoyl tetrahydroisoquinolines mediated by a TEMPO oxoammonium salt has been established A variety of electronically varied N-carbamoyl tetrahydroisoquinolines reacted with a range of alkynyl potassium trifluoroborates smoothly under mild metal-free conditions Dihydroisoquinolines were also suitable components for the reaction The synthetic applicability of the method for facile access to structurally diverse bioactive molecules was further demonstrated.

Catalytic transformations of α-amino C-H bonds to afford valuable enantiomerically enriched α-substituted amines, entities that are prevalent in pharmaceuticals and bioactive natural products, have been developed. Typically, such processes are carried out under oxidative conditions and require precious metal-based catalysts. Here, we disclose a strategy for an enantioselective union of N-alkylamines and α,β-unsaturated compounds, performed under redox-neutral conditions, and promoted through concerted action of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg-PyBOX complex. Thus, a wide variety of β-amino carbonyl compounds may be synthesized, with complete atom economy, through stereoselective reaction of an in situ-generated enantiomerically enriched Mg-enolate and an appropriate electrophile.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An enantioselective direct Mannich-type reaction catalyzed by a sterically frustrated Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the chiral Lewis acid and achiral Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond-activated aldimines delivers β-aminocarbonyl compounds with high enantiomeric purity.

We have successfully developed a strategy for the first time for the enantioselective Rh-TaniaPhos catalyzed asymmetric hydrogenation of unprotected β-enamine phosphonates to free β-amino phosphonates directly with good enantioselectivities (80%-86% ee) and high conversions (>99% conversion). The resulting chiral free β-amino phosphonates and their derivatives are important intermediates in biochemistry and pharmaceuticals.

Highly regioselective and enantioselective asymmetric hydrogenation of cyclic dienamides catalyzed by an Rh-DuanPhos complex has been developed, which provides a readily accessible method for the synthesis of chiral cyclic allylic amines in excellent enantioselectivities (up to 99% ee). The products are valuable chiral building blocks and could be easily transformed to multisubstituted cyclohexane derivatives.