Regiodivergent and Enantioselective Synthesis of Cyclic Sulfones via Ligand-Controlled Nickel-Catalyzed Hydroalkylation.

Cyclic sulfones have demonstrated important applications in drug discovery. However, the catalytic and enantioselective synthesis of chiral cyclic sulfones remains challenging. Herein, we develop nickel-catalyzed regiodivergent and enantioselective hydroalkylation of sulfolenes to streamline the synthesis of chiral alkyl cyclic sulfones. The method has broad scope and high functional group tolerance. The regioselectivity can be controlled by ligands only. A neutral PYROX ligand favors C3-alkylation whereas an anionic BOX ligand favors C2-alkylation. This control is kinetic in origin as the C2-bound Ni intermediates are always thermodynamically more stable. Reactivity study of a wide range of relevant Ni intermediates reveal a NiI/NiIII catalytic cycle with a NiII-H species as the resting state. The regio- and enantio-determining step is the insertion of this NiII-H species into 2-sulfolene. This work provides an efficient catalytic method for the synthesis of an important class of organic compounds and enhances the mechanistic understanding of Ni-catalyzed stereoselective hydroalkylation.

Catalytic asymmetric construction of helicenes via transformation of biaryls.

This review showcases a systematic overview of the available tools for the catalytic asymmetric transformation of biaryl substrates toward the construction of challenging enantioenriched helicenes and the conceptual aspects associated with each type of transformation. Depending on the properties of the biaryl and the nature of the process, several methodologies have been developed, including olefin metathesis, hydroarylation of alkynes, C-X (X = C, O, N) coupling, and C-H functionalization. Pioneering studies and an array of representative reactions are discussed to underscore the potential of these synthetic protocols.

Enantioselective synthesis of N-alkylindoles enabled by nickel-catalyzed C-C coupling.

Enantioenriched N-alkylindole compounds, in which nitrogen is bound to a stereogenic sp3 carbon, are an important entity of target molecules in the fields of biological, medicinal, and organic chemistry. Despite considerable efforts aimed at inventing methods for stereoselective indole functionalization, straightforward access to a diverse range of chiral N-alkylindoles in an intermolecular catalytic fashion from readily available indole substrates remains an ongoing challenge. In sharp contrast to existing C-N bond-forming strategies, here, we describe a modular nickel-catalyzed C-C coupling protocol that couples a broad array of N-indolyl-substituted alkenes with aryl/alkenyl/alkynyl bromides to produce chiral N-alkylindole adducts in single regioisomeric form, in up to 91% yield and 97% ee. The process is amenable to proceed under mild conditions and exhibit broad scope and high functional group compatibility. Utility is highlighted through late-stage functionalization of natural products and drug molecules, preparation of chiral building blocks.

Chiral Alkyl Amine Synthesis via Catalytic Enantioselective Hydroalkylation of Enecarbamates.

Chiral alkyl amines are omnipresent as bioactive molecules and synthetic intermediates. The catalytic and enantioselective synthesis of alkyl amines from readily accessible precursors is challenging. Here we develop a nickel-catalyzed hydroalkylation method to assemble a wide range of chiral alkyl amines from enecarbamates (N-Cbz-protected enamines) and alkyl halides with high regio- and enantioselectivity. The method works for both nonactivated and activated alkyl halides and is able to produce enantiomerically enriched amines with two minimally differentiated α-alkyl substituents. The mild conditions lead to high functional group tolerance, which is demonstrated in the postproduct functionalization of many natural products and drug molecules, as well as the synthesis of chiral building blocks and key intermediates to bioactive compounds.

Yne-Enones Enable Diversity-Oriented Catalytic Cascade Reactions: A Rapid Assembly of Complexity.

A small-molecule collection with structural diversity and complexity is a prerequisite to using either drug candidates or chemical probes for drug discovery and chemical-biology investigations, respectively. Over the past 12 years, we have engaged in developing efficient diversity-oriented cascade strategies for the synthesis of topologically diverse skeletons incorporating biologically relevant structural motifs such as O- and N-heterocycles, fused polycycles, and multifunctionalized allenes. In particular, we have highlighted the use of simple, linear, and densely functionalized molecular platforms in these reactions.This account details our efforts in the design of novel molecular platforms for use in metal- and organo-catalyzed cascade reactions, which include 2-(1-alknyl)-2-alken-1-ones (yne-enones) for heterocyclization/cross-coupling cascades, heterocyclization/cycloaddition cascades, nucleophilic addition/cross-coupling cascades, nucleophilic addition/heterocyclization cascades, and so on. Moreover, this Account outlines corresponding mechanistic insights, computational information, and applications of these cascades in the construction of various highly substituted carbo- and heterocycles as well as highly functionalized acyclic compounds, e.g., allenes and dienes. In addition to yne-enones, we evolved the functional groups of our original yne-enones to provide a series of yne-enone variants, which resulted in products with complementary reactivities.The reactivity profile of the yne-enones is defined by the presence of an alkyne moiety and a conjugated enone unit and their mutual through-bond connectivity. Owing to the conceptually rapid development of carbophilic activation, we have identified a series of efficient catalytic systems consisting of metal catalysts, including Pd, Au, and Rh complexes, for diversity-oriented cascade catalysis, allowing various unprecedented reactions to be achieved through different-types of reaction intermediates, including all-carbon metal 1,n-dipoles, furan-based o-quinodimethanes (oQDMs), and allenyl-metal species. In addition to commonly known transition-metal catalytic activity, the Lewis acidity of these complexes is crucial to accomplish the corresponding transformation. In addition, highly enantioselective gold(I)-catalyzed heterocyclization/cycloaddition cascades of yne-enones and their variants were achieved by the application of bisphosphines (e.g., Cn-TunePhos), monophosphines, and our developed "Ming-Phos" as chiral ligands. Importantly, Ming-Phos ligands exhibited excellent performance in gold-catalyzed mechanistically distinct [3 + n]-cycloaddition reactions, in which the chiral sulfinamide moiety is possibly responsible for the interaction with the substrate to control enantioselectivity. Subsequently, we demonstrated that the easily prepared polymer-supported Ming-Phos ligand could be applied for heterogeneously gold(I)-catalyzed asymmetric cycloaddition with good stereocontrol. With metal-free catalysis, the divergent functionalization of yne-enones provides numerous synthetic outlets for structure diversification. For example, yne-enones are particularly attractive for use as precursors of various chiral and achiral heterocycles, such as pyrazoles, isoxazoles, pyrroles, and pyrans, etc.

Ligand-Controlled Regiodivergent Hydroalkylation of Pyrrolines.

Nickel hydride (NiH) catalyzed hydrocarbonation has emerged as an efficient approach to construct new C-C bonds containing at least one C(sp3 ) center. However, the regioselectivity of this reaction is by far dictated by substrates. Described here is a strategy to achieve two different regioselectivites of hydroalkylation of the same substrates by using ligand control. This strategy enables the first regiodivergent hydroalkylation of 3-pyrrolines, yielding both 2- and 3-alkylated pyrrolidines, valuable synthetic intermediates and common motifs in many bioactive molecules. This method demonstrates broad scope and high functional-group tolerance, and can be applied in late-stage functionalizations.

Organocatalytic Enantioconvergent Synthesis of Tetrasubstituted Allenes via Asymmetric 1,8-Addition to aza-para-Quinone Methides.

In contrast to the well-explored quinone methides (QMs) and aza-ortho-QMs, aza-para-QMs have been rarely studied in terms of their asymmetric transformations. Herein, a highly efficient enantioconvergent asymmetric 1,8-addition of aza-para-QMs is described. Featuring remarkable remote stereocontrol, this reaction provides expedient access to chiral tetrasubstituted allenes bearing an adjacent all-carbon quaternary stereocenter with high enantioselectivity and diastereoselectivity.

Recent Progress in Asymmetric Ion-Pairing Catalysis with Ammonium Salts.

Quaternary ammonium salts play an important role in asymmetric catalysis. In this Minireview, how asymmetric ion-pairing catalysis with ammonium ions has been utilized in organic synthesis is explained, particularly in the design of novel catalytic cycles. This includes the use of chiral ammonium-based catalysts for the construction of challenging stereogenic centers. Ammonium-derived electrophilic reagents, typically formed in situ and in the context of phase-transfer catalysis (PTC), have also been utilized in asymmetric bond-forming reactions. Furthermore, ammonium salts have been employed as substrates in several stereocontrolled C-N bond cleavage processes, leading to enantioenriched products by using novel asymmetric induction modes. In addition, merging ammonium ion-pairing catalysis with other catalytic approaches has also emerged as a new platform for achieving previously less straightforward reactions, thereby allowing new synthetic applications.

Counterion-Induced Asymmetric Control in Ring-Opening of Azetidiniums: Facile Access to Chiral Amines.

Counterion-induced stereocontrol is a powerful tool in organic synthesis. However, such enantiocontrol on tetrahedral ammonium cations remains challenging. Described here is the first example of using chiral anion phase-transfer catalysis to achieve intermolecular ring-opening of azetidiniums with excellent enantioselectivity (up to 97 % ee). Precise control over the formation and reaction of the chiral ion pair as well as inhibition of the background reaction by the biphasic system is key to the success of the reaction.

Organocatalytic synthesis of chiral tetrasubstituted allenes from racemic propargylic alcohols.

Although chiral allene preparation via formal SN2' nucleophilic substitutions of enantioenriched propargylic derivatives or metal-catalyzed reactions of racemic propargylic derivatives has attracted considerable attention and found applications in many areas of research, direct use of propargylic alcohols instead of propargylic derivatives for catalytic asymmetric allene synthesis is unknown. Here, we show that a highly enantioselective synthesis of tetrasubstituted allenes from racemic propargylic alcohols has been realized by organocatalysis with good efficiency (up to 96% yield and 97% ee). The intermolecular C-C and C-S bond formation was achieved efficiently with simultaneous stereocontrol over the axial chirality. Furthermore, an adjacent quaternary stereocenter could also be constructed. Mechanistically, the reaction may involve efficient stereocontrol on the propargylic cation by its chiral counter anion or 1,8-conjugate addition of para-quinone methides. In sharp contrast to previous central chirality construction, this process employs quinone methides for axial chirality construction.Axially chiral allenes that are normally present in natural products, bioactive molecules, organocatalysts, and functional materials are usually produced from propargylic derivatives. Here, the authors show direct use of propargylic alcohols for catalytic asymmetric allene synthesis.

Highly Regio-, Diastereo-, and Enantioselective Gold(I)-Catalyzed Intermolecular Annulations with N-Allenamides at the Proximal C=C Bond.

A highly enantioselective gold(I)-catalyzed intermolecular annulation of 2-(1-alkynyl)-2-alken-1-ones with N-allenamides is presented. The present work represents the first example of a gold-catalyzed annulation with the proximal C=C bond of an N-allenamide, and is distinctly different from the previously observed annulations at the distal C=C bond. Interestingly, both enantiomers of the products could be obtained in good yields with high regio-, diastereo-, and enantioselectivity by using either diastereomer of a binol-derived phosphoramidite as a chiral ligand.

Gold-catalyzed cyclopropanation reactions using a carbenoid precursor toolbox.

Homogeneous gold-catalyzed cyclopropanation has emerged as a powerful method in organic synthesis due to its rich chemistry and fascinating reactivity. This thriving strategy is remarkable for its mild conditions, good selectivity, and high efficiency, which provides complementarity and orthogonality to traditional metal-catalyzed cyclopropanation. This review summarizes recent advances in gold-catalyzed cyclopropanation divided by the type of carbenoid precursors. Besides the commonly used diazo compounds, current approaches enable readily available enynes, propargyl esters, cyclopropenes, cycloheptatrienes, alkynes, and sulfonium ylides as safer surrogates in the realm of gold carbenoid chemistry. Meanwhile, these reactions allow for the rapid building of molecular complexity including synthetically useful and intricate cyclic, heterocyclic, and polycyclic skeletons. The combination of the new reactivity of gold complexes with their capability to catalyze cyclopropanations may lead to myriad opportunities for the design of new reactions. Furthermore, the synthetic utilities of such superior methods have also been illustrated by the total syntheses of selected natural and biologically interesting products and the asymmetric formation of challenging target molecules.

Gold(I)-catalyzed highly diastereo- and enantioselective alkyne oxidation/cyclopropanation of 1,6-enynes.

A highly enantioselective oxidative cyclopropanation of 1,6-enynes catalyzed by cationic Au(I)/chiral phophoramidite complexes is presented. The new method provides convenient access to densely functionalized bicyclo[3.1.0]hexanes bearing three contiguous quaternary and tertiary stereogenic centers with high enantioselectivity (up to e.r. 98:2). Control experiments suggest that the quinoline moiety of the ß-gold vinyloxyquinolinium intermediate in the reaction plays an important role in promoting good enantioselectivity through a transitional auxiliary effect in the transition state.

Gold-catalyzed cascade reactions for synthesis of carbo- and heterocycles: selectivity and diversity.

This account describes our recent efforts devoted to gold chemistry since 2009. Based on furyl-Au 1,3-dipole analogues and related gold carbene intermediates, a rich variety of gold-catalyzed cascade reactions have been developed, which provide facile access to a diverse range of novel carbo- and heterocycles. In these reactions, the selectivity can be well controlled by the catalyst (ligand and metal), substrate or reagent. In addition, we have also developed the corresponding enantioselective variants, which are guided by bis(phosphinegold) complexes derived from axially chiral scaffolds and asymmetric gold/chiral Brønsted acid relay catalysis.

Catalytic oxidation/C-H functionalization of N-arylpropiolamides by means of gold carbenoids: concise route to 3-acyloxindoles.

An efficient catalytic C-H functionalization by means of gold carbenoids for the one-step synthesis of 3-acyloxindole derivatives has been developed. The reaction proceeds efficiently with extremely good substrate scope and significant opportunities for structural diversification.

A gold(I)-catalyzed intramolecular oxidation-cyclopropanation sequence of 1,6-enynes: a convenient access to [n.1.0]bicycloalkanes.

A gold(I)-catalyzed tandem oxidation/cyclopropanation reaction of 1,6-enynes with an external oxidant has been developed. This quite simple and rapid strategy will provide a safe, mild and versatile avenue to numerous carbo- and hetero [n.1.0]bicyclic frameworks.

Au(I)/Au(III)-catalyzed Sonogashira-type reactions of functionalized terminal alkynes with arylboronic acids under mild conditions.

A straightforward, efficient, and reliable redox catalyst system for the Au(I)/Au(III)-catalyzed Sonogashira cross-coupling reaction of functionalized terminal alkynes with arylboronic acids under mild conditions has been developed.