Catalytic Asymmetric α-Alkylation of Ketones with Unactivated Alkyl Halides.

A catalytic, enantioselective method for direct α-alkylation of ketones with unactivated alkyl halides is realized by employing an α-enolizable ketone in a nickel-catalyzed C(sp3)-C(sp3) cross-coupling reaction. The key to the success is attributed to a unique bimetallic ligand. A variety of acyclic ketones and unactivated alkyl iodides can serve as suitable substrates under mild conditions to generate chiral ketones with α-quaternary carbon stereocenters in high yields with good enantioselectivities. A range of transformations based on the ketone moiety are also demonstrated to show the potential application of this method. Preliminary mechanistic studies support a dinickel-catalyzed cross-coupling mechanism.

Catalytic, Enantioselective syn-Diamination of Alkenes.

The enantioselective, vicinal diamination of alkenes represents one of the stereocontrolled additions that remains an outstanding challenge in organic synthesis. A general solution to this problem would enable the efficient and selective preparation of widely useful, enantioenriched diamines for applications in medicinal chemistry and catalysis. In this article, we describe the first enantioselective, syn-diamination of simple alkenes mediated by a chiral, enantioenriched organoselenium catalyst together with a N,N'-bistosyl urea as the bifunctional nucleophile and N-fluorocollidinium tetrafluoroborate as the stoichiometric oxidant. Diaryl, aryl-alkyl, and alkyl-alkyl olefins bearing a variety of substituents are all diaminated in consistently high enantioselectivities but variable yields. The reaction likely proceeds through a Se(II)/Se(IV) redox catalytic cycle reminiscent of the syn-dichlorination reported previously. Furthermore, the syn-stereospecificity of the transformation shows promise for highly enantioselective diaminations of alkenes with no strong steric or electronic bias.

Enantioselective, Lewis Base-Catalyzed Carbosulfenylation of Alkenylboronates by 1,2-Boronate Migration.

A catalytic, enantioselective method for the preparation of chiral, non-racemic, alkylboronic esters bearing two vicinal stereogenic centers is described. The reaction proceeds via a 1,2-migration of a zwitterionic thiiranium-boronate complex to give exclusively anti carbosulfenylation products. A broad scope of aryl groups migrate with good yield and excellent enantioselectivity (up to 99:1 e.r.). Similarly, a range of di- and trisubstituted alkenylboronic esters are competent reaction partners. This method provides access to both secondary and tertiary chiral alkylboronic esters.

Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes.

A sulfenium-ion-initiated, catalytic, enantioselective polyene cyclization is described. Homogeranylarenes and ortho-geranylphenols undergo polycyclization in good yield, diastereoselectivity, and enantioselectivity. The stereodetermining step is the generation of an enantiomerically enriched thiiranium ion from a terminal alkene and a sulfenylating agent in the presence of a chiral Lewis basic catalyst. The use of hexafluoroisopropyl alcohol as the solvent is crucial to obtain good yields. The thioether moiety resulting from the reaction can be subsequently transformed into diverse oxygen and carbon functionality postcyclization. The utility of this method is demonstrated by the enantioselective syntheses of (+)-ferruginol and (+)-hinokiol.

Enantioselective [4 + 1] cycloaddition of ortho-quinone methides and bromomalonates under phase-transfer catalysis.

An enantioselective [4 + 1] cycloaddition reaction of ortho-quinone methides and bromomalonates using a quinine and BINOL derived phase-transfer catalyst is described. With high yields and enantioselectivities, the method provided a variety of optically active dihydrobenzofurans, which represent a valuable structural motif present in numerous naturally occurring and biologically active molecules.

Highly Enantioselective Allylic C-H Alkylation of Terminal Olefins with Pyrazol-5-ones Enabled by Cooperative Catalysis of Palladium Complex and Brønsted Acid.

A highly enantioselective allylic C-H alkylation reaction of allylarenes with pyrazol-5-ones has been established by the cooperative catalysis of a chiral palladium complex and chiral Brønsted acid to afford a wide spectrum of functionalized chiral N-heterocycles with an all-carbon quaternary stereogenic center in high yields and with high levels of enantioselectivity (up to 96% ee), wherein the chiral ligand and phosphoric acid showed synergistic effect on the control of stereoselectivity. In addition, a palladium-catalyzed asymmetric allylic C-H alkylation of 1,4-pentadienes with pyrazol-5-ones has been realized to furnish highly functionalized pyrazol-5-ones in high enantioselectivities. In this case, the chiral ligand controls the stereoselectivity while the achiral Bronsted acid, 2-fluorobenzoic acid, turns out to be a better cocatalyst than the chiral phosphoric acid. The installation of electron-deficient substituents at 3,3'-positions of binaphthyl backbone of chiral phosphoramidites is actually beneficial to the allylic C-H oxidation due to their survival in the presence of quinone derivative oxidants. These allylic C-H alkylation reactions undergo smoothly under mild conditions and tolerate a wide range of substrates. The resultant highly functionalized chiral pyrazol-5-ones have been applied to the preparation of more structurally diverse heterocycles by classical transformations.

Catalytic Enantioselective Assembly of Homoallylic Alcohols from Dienes, Aryldiazonium Salts, and Aldehydes.

A highly selective multicomponent carbonyl allylation reaction of 1,3-butadienes, aryldiazonium tetrafluoroborates, and aldehydes has been established under the combined catalysis of palladium acetate and chiral anion phase transfer to render the favorable assembly of chiral Z-configured homoallylic alcohols in high yields and with excellent levels of enantioselectivity.

Diastereoselective carbonyl allylation with simple olefins enabled by palladium complex-catalyzed C-H oxidative borylation.

A highly diastereoselective Pd-catalyzed carbonyl allylation of aldehydes and isatins directly using simple acyclic olefins as allylating reagents is described. This transformation is actually a sequential process consisting of a Pd-catalyzed oxidative allylic C-H borylation and an allylboration of carbonyls accelerated by phosphoric acid, wherein a wide scope of olefins could be tolerated. The oxidant is revealed to play a key role in the successful realization of the allylic C-H activation-based allylation.

Quinine-catalyzed highly enantioselective cycloannulation of o-quinone methides with malononitrile.

2-Amino-3-cyano-4H-chromenes show great potential as novel anticancer agents. Here we report a quinine-catalyzed highly enantioselective formal 4 + 2 cycloaddition of ortho-quinone methides and malononitrile, providing a unique approach to 4-arylvinyl, 4-aryl and 4-vinyl 2-amino-3-cyano-4H-chromenes with excellent yields and enantioselectivities. Moreover, this reaction can be performed in up to 6 mmol scale without any noticeable loss of yield and stereoselectivity.

Pd-catalyzed asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols: the role of the chiral phosphoric acid in C-O bond cleavage and stereocontrol.

The combination of a palladium complex with a chiral phosphoramidite ligand and a chiral phosphoric acid enables the first highly efficient asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols, affording multiply functionalized heterocyclic products in high yields with excellent enantioselectivities that would be of great potential in the synthesis of pharmaceutically interesting molecules.

Scaffold-inspired enantioselective synthesis of biologically important spiro[pyrrolidin-3,2'-oxindoles] with structural diversity through catalytic isatin-derived 1,3-dipolar cycloadditions.

Catalytic asymmetric construction of the biologically important spiro[pyrrolidin-3,2'-oxindole] scaffold with contiguous quaternary stereogenic centers in excellent stereoselectivities (up to >99:1 d.r., 98% ee) has been established by using an organocatalytic 1,3-dipolar cycloaddition of isatin-based azomethine ylides. This protocol represents the first example of catalytic asymmetric 1,3-dipolar cycloadditions involving azomethine ylides generated in situ from unsymmetrical cyclic ketones. In addition, theoretical calculations were performed on the transition state of the reaction to understand the stereochemistry. Preliminary bioassays with these spiro[pyrrolidin-3,2'-oxindole] revealed that several compounds showed moderate cytotoxicity to SW116 cells.

An asymmetric organocatalytic Povarov reaction with 2-hydroxystyrenes.

An organocatalytic asymmetric three-component Povarov reaction involving 2-hydroxystyrenes has been established to provide an efficient method to access structurally diverse cis-disubstituted tetrahydroquinolines in high stereoselectivities of up to >99:1 dr and 97% ee. This protocol also provides an easy access to tetrahydroquinolines with chiral quaternary stereocenters upon using α-alkyl 2-hydroxystyrenes as substrates. The theoretical studies revealed that the Povarov reaction proceeded through a sequential vinylogous Mannich reaction and an intramolecular Friedel-Crafts reaction, wherein the phosphoric acid acted as bifunctional catalyst to activate 2-hydroxystyrene and aldimine simultaneously.

Double Chiral Induction Enables a Stereoselective Carbonyl Allylation with Simple Alkenes under the Sequential Catalysis of Palladium Complex and Chiral Phosphoric Acid.

An enantioselective carbonyl allylation of aldehydes with simple alkenes has been achieved via a one-pot protocol consisting of a Pd-catalyzed allylic C-H borylation with bis(pinanediolato)diboron and a chiral Brønsted acid catalyzed asymmetric allylborylation, delivering homoallylic alcohols in high yields and with excellent diastereo- and enantioselectivities. The double chiral induction of chiral allylic borate and chiral phosphoric acid allows the reaction to give excellent stereoselectivities.

The catalytic asymmetric 1,3-dipolar cycloaddition of ynones with azomethine ylides.

The first catalytic asymmetric 1,3-dipolar cycloaddition of electron-deficient carbon-carbon triple bonds with azomethine ylides has been established. This reaction provides an unprecedented approach to access novel 2,5-dihydropyrrole derivatives with potential bioactivities in perfect enantioselectivities of up to >99% ee.