Asymmetric Cascade Reaction to Allylic Sulfonamides from Allylic Alcohols by Palladium(II)/Base‐Catalyzed Rearrangement of Allylic Carbamates

A regio‐ and enantioselective tandem reaction is reported capable of directly transforming readily accessible achiral allylic alcohols into chiral sulfonyl‐protected allylic amines. The reaction is catalyzed by the cooperative action of a chiral ferrocene palladacycle and a tertiary amine base and combines high step‐economy with operational simplicity (e.g. no need for inert‐gas atmosphere or catalyst activation). Mechanistic studies support a Pd^II‐catalyzed [3,3] rearrangement of allylic carbamates—generated in situ from the allylic alcohol and an isocyanate—as the key step, which is followed by a decarboxylation.     

Highly Enantioselective Nickel‐Catalyzed Intramolecular Reductive Cyclization of Alkynones

The first asymmetric nickel‐catalyzed intramolecular reductive cyclization of alkynones is reported. A P‐chiral monophosphine and triethylsilane were used as the ligand and the reducing reagent, respectively, to form a series of tertiary allylic alcohols bearing furan/pyran rings in excellent yields and enantioselectivities. This reaction has a broad substrate scope and enabled the efficient synthesis of dehydroxycubebin and chiral dibenzocyclooctadiene skeletons.     

Synthesis of (+) or (-)-2-(8′-Diphenylphosphino-1′-naphthyl)oxazoline Ligands and Their Application in Pd-Catalyzed Allylic Alkylation Reaction

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Chiral Phosphoric Acid Catalyzed Kinetic Resolution of 2‐Amido Benzyl Alcohols: Asymmetric Synthesis of 4H‐3,1‐Benzoxazines

An efficient method for the asymmetric synthesis of 4H‐3,1‐benzoxazines was developed by kinetic resolution of 2‐amido benzyl alcohols using chiral phosphoric acid catalyzed intramolecular cyclizations. A broad range of benzyl alcohols (both secondary and tertiary alcohols) were kinetically resolved with high selectivities, with an s factor of up to 94. Mechanistic studies were performed to elucidate the mechanism of these reactions, wherein the amide moieties reacted as the electrophiles. Gram‐scale reaction and facile transformations of the chiral products demonstrate the potential of this method in asymmetric synthesis of biologically active chiral heterocycles.     

Asymmetric Allylic Alkylation of β‐Ketoesters with Allylic Alcohols by a Nickel/Diphosphine Catalyst

Asymmetric allylic alkylation of β‐ketoesters with allylic alcohols catalyzed by [Ni(cod)₂]/(S)‐H₈‐BINAP was found to be a superior synthetic protocol for constructing quaternary chiral centers at the α‐position of β‐ketoesters. The reaction proceeded in high yield and with high enantioselectivity using various β‐ketoesters and allylic alcohols, without any additional activators. The versatility of this methodology for accessing useful and enantioenriched products was demonstrated.     

Multicomponent Synthesis of Chiral Bidentate Unsymmetrical Unsaturated N‐Heterocyclic Carbenes: Copper‐Catalyzed Asymmetric CC Bond Formation

A multicomponent strategy was applied to the synthesis of chiral bidentate unsaturated hydroxyalkyl‐ and carboxyalkyl‐N‐heterocyclic carbene (NHC) precursors. The newly developed low‐cost chiral ligands derived from amino alcohols and amino acids were evaluated in copper‐catalyzed asymmetric conjugated addition and asymmetric allylic alkylation, which afforded the desired tertiary and quaternary carbon stereocenters with excellent regio‐ and enantioselectivities (up to 99:1 e.r.).     

Enantioselective Alkynylation of Ketones Promoted by β-Sulfonamide Alcohol-Titanium Complexes

A readily available β-sulfonamide alcohol-titanium complex was found to be effective on promoting the asymmetric addition reaction of an alkynylzinc reagent to unactivated simple ketones under very mild conditions. And the corresponding chiral tertiary propargylic alcohols were obtained with enantiomeric excesses of up to 86%, which provided a simple, practical and inexpensive method to generate chiral tertiary propargylic alcohols.     

Lewis Acid Catalyzed Asymmetric Three‐Component Coupling Reaction: Facile Synthesis of α‐Fluoromethylated Tertiary Alcohols

A chiral dicationic palladium complex is found to be an efficient Lewis acid catalyst for the synthesis of α‐fluoromethyl‐substituted tertiary alcohols using a three‐component coupling reaction. The reaction transforms three simple and readily available components (terminal alkyne, arene, and fluoromethylpyruvate) to valuable chiral organofluorine compounds. This strategy is completely atom‐economical and results in perfect regioselectivities and high enantioselectivities of the corresponding tertiary allylic alcohols in good to excellent yields.     

Copper‐Catalyzed Enantioselective Allyl–Allyl Coupling between Allylic Boronates and Phosphates with a Phenol/N‐Heterocyclic Carbene Chiral Ligand

Copper‐catalyzed enantioselective allyl–allyl coupling between allylboronates and either Z‐acyclic or cyclic allylic phosphates using a new chiral N‐heterocyclic carbene ligand, bearing a phenolic hydroxy, is reported. This reaction occurs with exceptional S_N2′‐type regioselectivities and high enantioselectivities to deliver chiral 1,5‐diene derivatives with a tertiary stereogenic center at the allylic/homoallylic position.     

Transition‐Metal‐Free Borylation of Allylic and Propargylic Alcohols

The base‐catalyzed allylic borylation of tertiary allylic alcohols allows the synthesis of 1,1‐disubstituted allyl boronates, in moderate to high yield. The unexpected tandem performance of the Lewis acid–base adduct, [Hbase]⁺[MeO‐B₂pin₂]^? favored the formation of 1,2,3‐triborylated species from the tertiary allylic alcohols and 1‐propargylic cyclohexanol at 90 °C.     

Direct Regiospecific and Highly Enantioselective Intermolecular α‐Allylic Alkylation of Aldehydes by a Combination of Transition‐Metal and Chiral Amine Catalysts

The first direct intermolecular regiospecific and highly enantioselective α‐allylic alkylation of linear aldehydes by a combination of achiral bench‐stable Pd⁰ complexes and simple chiral amines as co‐catalysts is disclosed. The co‐catalytic asymmetric chemoselective and regiospecific α‐allylic alkylation reaction is linked in tandem with in situ reduction to give the corresponding 2‐alkyl alcohols with high enantiomeric ratios (up to 98:2 e.r.; e.r.=enantiomeric ratio). It is also an expeditious entry to valuable 2‐alkyl substituted hemiacetals, 2‐alkyl‐butane‐1,4‐diols, and amines. The concise co‐catalytic asymmetric total syntheses of biologically active natural products (e.g., Arundic acid) are disclosed.     

Enantio‐ and Diastereoselective Dehydrative “One‐Step” Construction of Spirocarbocycles via a Ru/H+‐Catalyzed Tsuji–Trost Approach

Chiral spirocarbocyclic skeletons are ubiquitous in natural products. An intramolecular Tsuji–Trost (T–T) α‐allylation of simple cyclic ketones is a reasonable approach to construct chiral spriocarbocyclic motifs; however, it has been a challenging approach despite many excellent intermolecular examples. For the first time, this has been achieved by a Ru/H⁺ combined catalyst that dehydratively cyclizes racemic allylic alcohols comprising a simple ketone via simultaneous activation of the C=O and OH groups. This chiral technology facilitates the construction of various spirocarbocycles containing two contiguous spiro all‐carbon quaternary and tertiary stereocenters. Among four possible stereoisomers, one stereoisomer can be selectively produced in high yield, enhancing the feasibility of the T–T strategy, particularly in the synthesis of spirocarbocycles.     

Lewis Base/Brønsted Acid Co‐catalyzed Enantioselective Sulfenylation/Semipinacol Rearrangement of Di‐ and Trisubstituted Allylic Alcohols

An enantioselective sulfenylation/semipinacol rearrangement of 1,1‐disubstituted and trisubstituted allylic alcohols was accomplished with a chiral Lewis base and a chiral Brønsted acid as cocatalysts, generating various β‐arylthio ketones bearing an all‐carbon quaternary center in moderate to excellent yields and excellent enantioselectivities. These chiral arylthio ketone products are common intermediates with many applications, for example, in the design of new chiral catalysts/ligands and the total synthesis of natural products. Computational studies (DFT calculations) were carried out to explain the enantioselectivity and the role of the chiral Brønsted acid. Additionally, the synthetic utility of this method was exemplified by an enantioselective total synthesis of (?)‐herbertene and a one‐pot synthesis of a chiral sulfoxide and sulfone.     

Gold(I)/Chiral N,N′‐Dioxide–Nickel(II) Relay Catalysis for Asymmetric Tandem Intermolecular Hydroalkoxylation/Claisen Rearrangement

A highly efficient asymmetric cascade reaction between alkynyl esters and allylic alcohols has been realized. Key to success was the combination of a hydroalkoxylation reaction catalyzed by a π‐acidic gold(I) complex with a Claisen rearrangement catalyzed by a chiral Lewis acidic N,N′‐dioxide–nickel(II) complex. A range of acyclic α‐allyl β‐keto esters were synthesized in high yields (up to 99 %) with good diastereoselectivities (up to 97:3) and excellent enantioselectivities (up to 99 % ee ) under mild reaction conditions. These products can be easily transformed into optically active β‐hydroxy esters, β‐hydroxy acids, or 1,3‐diols.     

Access to 1,3‐Dinitriles by Enantioselective Auto‐tandem Catalysis: Merging Allylic Cyanation with Asymmetric Hydrocyanation

Enantioselective auto‐tandem catalysis represents a challenging yet highlight attractive topic in the field of asymmetric catalysis. In this context, we describe a dual catalytic cycle that merges allylic cyanation and asymmetric hydrocyanation. The one‐pot conversion of a broad array of allylic alcohols into their corresponding 1,3‐dinitriles proceeds in good yield with high enantioselectivity. The products are densely functionalized and can be easily transformed to chiral diamines, dinitriles, diesters, and piperidines. Mechanistic studies clearly support a novel sequential cyanation/hydrocyanation pathway.     

From allylic alcohols to chiral tertiary homoallylic alcohol: palladium-catalyzed asymmetric allylation of isatins

A palladium-catalyzed asymmetric allylation of isatins with allylic alcohols as an allyl donor was developed by using chiral spiro phosphoramidite ligands. A variety of chiral tertiary homoallylic alcohols 3-allyl-3-hydroxy-2-oxindoles were prepared directly from allylic alcohols in one step with excellent yields and moderate enantioselectivities. This represents the first catalytic asymmetric allylation of ketones with allylic alcohol as the allylating agent.     

Iridium‐Catalyzed Intermolecular Asymmetric Dearomatization of β‐Naphthols with Allyl Alcohols or Allyl Ethers

An Ir‐catalyzed intermolecular asymmetric dearomatization reaction of β‐naphthols with allyl alcohols or allyl ethers was developed. When an iridium catalyst generated from [Ir(COD)Cl]₂ (COD=cyclooctadiene) and a chiral P/olefin ligand is employed, highly functionalized β‐naphthalenone compounds bearing an all‐carbon‐substituted quaternary chiral center were obtained in up to 92 % yield and 98 % ee . The direct utilization of allyl alcohols as electrophiles represents an improvement from the viewpoint of atom economy. Allyl ethers were found to undergo asymmetric allylic substitution reaction under Ir catalysis for the first time. The diverse transformations of the dearomatized product to various motifs render this method attractive.     

Pseudo‐Stereodivergent Synthesis of Enantioenriched Tetrasubstituted Alkenes by Cascade 1,3‐Oxo‐Allylation/Cope Rearrangement

The catalytic diastereodivergent construction of stereoisomers having two or more stereogenic centers has been extensively studied. In contrast, the switchable introduction of another stereogenic element, that is, Z/E configuration involving a polysubstituted alkene group, into the optically active stereoisomers, has not been recognized yet. Disclosed here is the pseudo‐stereodivergent synthesis of highly enantioenriched tetrasubstituted alkene architectures from isatin‐based Morita–Baylis–Hillman carbonates and allylic derivatives, under the cooperative catalysis of a tertiary amine and a chiral iridium complex. The success of the switchable construction of the tetrasubstituted alkene motif relies on the diastereodivergent 1,3‐oxo‐allylation reaction between N‐allylic ylides and chiral π‐allyliridium complex intermediates by ligand and substrate control, followed by the stereoselective concerted 3,3‐Cope rearrangement process.     

Transition‐Metal‐Free Hydrogen Autotransfer: Diastereoselective N‐Alkylation of Amines with Racemic Alcohols

A practical method for the synthesis of α‐chiral amines by alkylation of amines with alcohols in the absence of any transition‐metal catalysts has been developed. Under the co‐catalysis of a ketone and NaOH, racemic secondary alcohols reacted with Ellman's chiral tert‐butanesulfinamide by a hydrogen autotransfer process to afford chiral amines with high diastereoselectivities (up to >99:1). Broad substrate scope and up to a 10 gram scale production of chiral amines were demonstrated. The method was applied to the synthesis of chiral deuterium‐labelled amines with high deuterium incorporation and optical purity, including examples of chiral deuterated drugs. The configuration of amine products is found to be determined solely by the configuration of the chiral tert‐butanesulfinamide regardless of that of alcohols, and this is corroborated by DFT calculations. Further mechanistic studies showed that the reaction is initiated by the ketone catalyst and involves a transition state similar to that proposed for the Meerwein–Ponndorf–Verley (MPV) reduction, and importantly, it is the interaction of the sodium cation of the base with both the nitrogen and oxygen atoms of the sulfinamide moiety that makes feasible, and determines the diastereoselectivity of, the reaction.     

Phosphite‐Catalyzed C−H Allylation of Azaarenes via an Enantioselective [2,3]‐Aza‐Wittig Rearrangement

A phosphite‐mediated [2,3]‐aza‐Wittig rearrangement has been developed for the regio‐ and enantioselective allylic alkylation of six‐membered heteroaromatic compounds (azaarenes). The nucleophilic phosphite adducts of N‐allyl salts undergo a stereoselective base‐mediated aza‐Wittig rearrangement and dissociation of the chiral phosphite for overall C?H functionalization of azaarenes. This method provides efficient access to tertiary and quaternary chiral centers in isoquinoline, quinoline, and pyridine systems, tolerating a broad variety of substituents on both the allyl part and azaarenes. Catalysis with chiral phosphites is also demonstrated with synthetically useful yields and enantioselectivities.