Palladium‐Catalyzed Decarbonylative Dehydration for the Synthesis of α‐Vinyl Carbonyl Compounds and Total Synthesis of (−)‐Aspewentins A,B, and C

The direct α‐vinylation of carbonyl compounds to form a quaternary stereocenter is a challenging transformation. It was discovered that δ‐oxocarboxylic acids can serve as masked vinyl compounds and be unveiled by palladium‐catalyzed decarbonylative dehydration. The carboxylic acids are readily available through enantioselective acrylate addition or asymmetric allylic alkylation. A variety of α‐vinyl quaternary carbonyl compounds are obtained in good yields, and an application in the first enantioselective total synthesis of (?)‐aspewentins A, B, and C is demonstrated.     

Heteroannulation of Arynes with α‐Amino Imides: Synthesis of 2,2‐Disubstituted Indolin‐3‐ones and Application to the Enantioselective Total Synthesis of (+)‐Hinckdentine A

A novel heteroannulation reaction between α‐amino imides and in situ generated arynes has been developed for the synthesis of 2,2‐disubstituted indolin‐3‐ones. An enantioselective total synthesis of the marine alkaloid (+)‐hinckdentine A was subsequently accomplished using this reaction as a key step. A catalytic enantioselective Michael addition of an α‐aryl‐α‐isocyanoacetate to phenyl vinyl selenone was employed for the construction of the enantioenriched α‐quaternary α‐amino ester.     

Enantioselective Synthesis of Quaternary α‐Amino Acids Enabled by the Versatility of the Phenylselenonyl Group

A novel Cinchona alkaloid‐catalyzed enantioselective conjugate addition of α‐alkyl substituted α‐nitroacetates to phenyl vinyl selenone was developed. The resulting enantio‐enriched α,α‐dialkyl substituted α‐nitroacetates were subsequently converted to various cyclic and acyclic quaternary α‐amino acids, taking advantage of the rich functionalities of the resulting Michael adducts. Novel protocols allowing chemoselective reduction of phenyl selenone to phenyl selenide and reduction of alkyl phenyl selenones to alkanes are also reported.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Enantioselective Organocatalytic Addition of Oxazolones to 1,1‐Bis(phenylsulfonyl)ethylene: A Convenient Asymmetric Synthesis of Quaternary α‐Amino Acids

A new, easy, and highly enantioselective method for the synthesis of quaternary α‐alkyl‐α‐amino acids based on organocatalysis is reported. The addition of oxazolones to 1,1‐bis(phenylsulfonyl)ethylene is efficiently catalyzed by simple chiral bases or thioureas. The reaction affords α,α‐disubstituted α‐amino acid derivatives with complete C4 regioselectivity and with excellent yields and enantioselectivities. This methodology is complementary to previously reported enantioselective approaches to quaternary α‐amino acids and allows the synthesis of α‐phenyl‐α‐alkyl‐α‐amino acids and α‐tert‐butyl‐α‐alkyl‐α‐amino acids. It has distinct advantages in terms of operational simplicity, enviromentally friendly conditions, and suitability for large‐scale reactions.     

Enantioselective Palladium‐Catalyzed Cross‐Coupling of α‐Bromo Carboxamides and Aryl Boronic Acids

We herein report an enantioselective palladium‐catalyzed cross‐coupling between α‐bromo carboxamides and aryl boronic acids, generating a series of chiral α‐aryl carboxamides in good yields and excellent enantioselectivities. The development of a chiral P,P=O ligand was critical in overcoming the second transmetalation issue and allows the first asymmetric palladium‐catalyzed coupling of α‐bromo carbonyl compounds.     

Chemo‐ and Enantioselective Oxidative α‐Azidation of Carbonyl Compounds

We report high‐performance I⁺/H₂O₂ catalysis for the oxidative or decarboxylative oxidative α‐azidation of carbonyl compounds by using sodium azide under biphasic neutral phase‐transfer conditions. To induce higher reactivity especially for the α‐azidation of 1,3‐dicarbonyl compounds, we designed a structurally compact isoindoline‐derived quaternary ammonium iodide catalyst bearing electron‐withdrawing groups. The nonproductive decomposition pathways of I⁺/H₂O₂ catalysis could be suppressed by the use of a catalytic amount of a radical‐trapping agent. This oxidative coupling tolerates a variety of functional groups and could be readily applied to the late‐stage α‐azidation of structurally diverse complex molecules. Moreover, we achieved the enantioselective α‐azidation of 1,3‐dicarbonyl compounds as the first successful example of enantioselective intermolecular oxidative coupling with a chiral hypoiodite catalyst.     

Rhodium‐Catalyzed Asymmetric Arylation of β,γ‐Unsaturated α‐Ketoamides for the Construction of Nonracemic γ,γ‐Diarylcarbonyl Compounds

A highly regio‐ and enantioselective rhodium‐catalyzed 1,4‐addition of arylboronic acids to β,γ‐unsaturated α‐ketoamides using a simple new chiral sulfinylphosphine ligand is described. This transformation provides an attractive approach to construct chiral nonracemic γ,γ‐diarylsubstituted carbonyl compounds, as exemplified in the concise syntheses of sertraline and tetrahydroquinoline‐2‐carboxylamide.     

PdII‐Catalyzed Enantioselective C(sp3)−H Activation/Cross‐Coupling Reactions of Free Carboxylic Acids

Pd^II‐catalyzed enantioselective C(sp³)?H cross‐coupling of free carboxylic acids with organoborons has been realized using either mono‐protected amino acid (MPAA) ligands or mono‐protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl‐ and vinyl‐boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α‐chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.     

Asymmetric Synthesis of Heterocyclic γ‐Amino‐Acid and Diamine Derivatives by Three‐Component Radical Cascade Reactions

An enantioselective three‐component radical reaction of quinolines or pyridines with enamides and α‐bromo carbonyl compounds by dual photoredox and chiral Brønsted acid catalysis is presented. A range of valuable chiral γ‐amino‐acid derivatives are accessible in high chemo‐, regio‐, and enantioselectivity from simple, readily available starting materials under mild reaction conditions. Using the same strategy, the asymmetric synthesis of 1,2‐diamine derivatives is also reported.     

Enantioselective Synthesis of Acyclic α‐Quaternary Carboxylic Acid Derivatives through Iridium‐Catalyzed Allylic Alkylation

The first highly enantioselective iridium‐catalyzed allylic alkylation that provides access to products bearing an allylic all‐carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one‐pot preparation of α‐quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations.     

Palladium‐Catalyzed Enantioselective Heck Carbonylation with a Monodentate Phosphoramidite Ligand: Asymmetric Synthesis of (+)‐Physostigmine, (+)‐Physovenine,and (+)‐Folicanthine

Reported herein is the development of the first enantioselective monodentate ligand assisted Pd‐catalyzed domino Heck carbonylation reaction with CO. The highly enantioselective domino Heck carbonylation of N‐aryl acrylamides and various nucleophiles, including arylboronic acids, anilines, and alcohols, in the presence of CO was achieved. A novel monodentate phosphoramidite ligand, Xida‐Phos, has been developed for this reaction and it displays excellent reactivity and enantioselectivity. The reaction employs readily available starting materials, tolerates a wide range of functional groups, and provides straightforward access to a diverse array of enantioenriched oxindoles having β‐carbonyl‐substituted all‐carbon quaternary stereocenters, thus providing a facile and complementary method for the asymmetric synthesis of bioactive hexahydropyrroloindole and its dimeric alkaloids.     

Protecting‐Group‐Free Enantioselective Synthesis of (−)‐Pallavicinin and (+)‐Neopallavicinin

The first enantioselective synthesis of (?)‐pallavicinin and (+)‐neopallavicinin has been achieved in 15 steps. The described synthesis avoids protecting‐group manipulations by synthesis designs predicated on highly chemo‐ and stereoselective transformations. Highlights of the synthesis include a palladium‐catalyzed enantioselective decarboxylative allylation to form the chiral all‐carbon quaternary stereocenter, a palladium‐catalyzed oxidative cyclization to assemble the [3.2.1]‐bicyclic moiety, and an unprecedented LiBHEt₃‐induced fragmentation/protonation of an α‐hydroxy epoxide to form the α‐furan ketone with the desired configuration.     

Silver(I)‐Catalyzed Enantioselective [3+2]‐Cycloaddition Reaction of α‐Silylimines: A Facile Route to Quaternary‐Carbon‐Rich Scaffolds

A silver‐catalyzed highly enantioselective 1,3‐dipolar cycloaddition reaction of α‐silylimines with pyrone‐based trisubstituted olefins was developed affording bi‐ and tricyclic α‐quaternary‐carbon‐rich pyrano‐pyrrolidines in excellent yields. The tricyclic benzopyrone adducts thus obtained were efficiently transformed into highly complex tetracyclic scaffolds supporting four consecutive stereogenic centers with three quaternary carbons.     

Bifunctional Brønsted Base Catalyst Enables Regio‐, Diastereo‐, and Enantioselective Cα‐Alkylation of β‐Tetralones and Related Aromatic‐Ring‐Fused Cycloalkanones

The catalytic asymmetric synthesis of both α‐substituted and α,α‐disubstituted (quaternary) β‐tetralones through direct α‐functionalization of the corresponding β‐tetralone precursor remains elusive. A designed Brønsted base‐squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or α‐monosubstituted β‐tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the α‐carbon atom of the β‐tetralone exclusively, but adducts including all‐carbon quaternary centers are also formed in highly diastereo‐ and enantioselective manner.     

Catalytic Asymmetric Construction of Quaternary α‐Amino Acid Containing Pyrrolidines through 1,3‐Dipolar Cycloaddition of Azomethine Ylides to α‐Aminoacrylates

The first catalytic enantioselective 1,3‐dipolar cycloaddition of azomethine ylides to α‐aminoacrylate catalyzed by a AgOAc/ferrocenyl oxazolinylphosphine (FOXAP) system was developed, which exhibits excellent exo‐ and enantioselectivity (92–99 % ee). This process provides efficient access to useful 4‐aminopyrrolidine‐2,4‐dicarboxylic acid (APDC)‐like compounds containing a unique quaternary α‐amino acid unit.     

α‐Carbonyl Cations in Sulfoxide‐Driven Oxidative Cyclizations

The selective, metal‐free generation of α‐carbonyl cations from simple internal alkynes was accomplished by the addition of a sulfoxide to a densely substituted vinyl cation. The high reactivity of the α‐carbonyl cations was found to efficiently induce hydrogen and even carbon shift reactions with unusual selecivities. Complex compounds with highly congested tertiary and all‐carbon‐substituted quartenary carbon centers can thus be accessed in a single step from simple precursors. Mechanistic analysis strongly supports the intermediacy of the title compounds and provides a simple predictive scheme for the migratory aptitude of different substituents.     

Pseudoephedrine‐Directed Asymmetric α‐Arylation of α‐Amino Acid Derivatives

Available α‐amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′‐aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′‐aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy‐metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.     

SpinPhox/Iridium(I)‐Catalyzed Asymmetric Hydrogenation of Cyclic α‐Alkylidene Carbonyl Compounds

Optically active medium‐sized cyclic carbonyl compounds bearing an α‐chiral carbon center are of interest in pharmaceutical sciences and asymmetric synthesis. Herein, SpinPhox/Ir^I catalysts have been demonstrated to be highly enantioselective in the asymmetric hydrogenation of the CC bonds in the exocyclic α,β‐unsaturated cyclic carbonyls, including a broad range of α‐alkylidene lactams, unsaturated cyclic ketones, and lactones. It is noteworthy that the procedure can be successfully used in the asymmetric hydrogenation of the challenging α‐alkylidenelactam substrates with six‐ or seven‐membered rings, thus affording the corresponding optically active carbonyl compounds with an α‐chiral carbon center in generally excellent enantiomeric excesses (up to 98 % ee). Synthetic utility of the protocol has also been demonstrated in the asymmetric synthesis of the anti‐inflammatory drug loxoprofen and its analogue, as well as biologically important ε‐aminocaproic acid derivatives.     

α‐Arylation of Carbonyl Compounds through Oxidative C−C Bond Activation

A synthetically useful approach for the direct α‐arylation of carbonyl compounds through a novel oxidative C?C bond activation is reported. This mechanistically unusual process relies on a 1,2‐aryl shift and results in all‐carbon quaternary centers. The transformation displays broad functional‐group tolerance and can in principle also be applied as an asymmetric variant.