Enantio- and Diastereoselective Synthesis of Chiral Tetrasubstituted α-Amino Allenoates Bearing a Vicinal All-Carbon Quaternary Stereocenter with Dual-Copper-Catalysis

The skeletons of chiral tetrasubstituted allenes bearing a vicinal all-carbon quaternary stereocenter are of importance but still challenging to synthesize. Herein, we report enantio- and diastereoselective γ-additions of 1-alkynyl ketimines with dual-copper-catalysis under mild conditions, affording chiral tetrasubstituted α-amino allenoates bearing a vicinal all-carbon quaternary stereocenter in high yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) and diastereoselectivities (up to >20 : 1 dr). Importantly, the stereodivergent synthesis of the products was realized by the asymmetric γ-addition reaction and the Grignard reagent promoted epimerization. Moreover, the dual-copper-catalyzed γ-addition reactions were smoothly applied to a gram-scale reaction and adopted to introduce chiral tetrasubstituted allenyl moieties into bioactive molecules. Mechanistic experiments and density functional theory (DFT) calculations demonstrated that the asymmetric γ-addition reactions were catalyzed by double chiral copper catalysts.     

A diastereoselective Mannich reaction of α-fluoroketones with ketimines: Construction of β-fluoroamine motifs with vicinal tetrasubstituted stereocenters

A diastereoselective Mannich reaction has been developed for the synthesis of chiral β-fluoroamine motifs by the reaction of α-fluoroketones with ketimines, including isatin-derived ketimines and phenylglyoxylate-derived ketimines. This method provides a concise route to a variety of biologically important 3-aminooxindoles and α-amino acids featuring fluorine-containing vicinal tetrasubstituted stereocenters.     

Consecutive Intermolecular Reductive Amination/Asymmetric Hydrogenation: Facile Access to Sterically Tunable Chiral Vicinal Diamines and N‐Heterocyclic Carbenes

A highly enantioselective iridium‐ or ruthenium‐catalyzed intermolecular reductive amination/asymmetric hydrogenation relay with 2‐quinoline aldehydes and aromatic amines has been developed. A broad range of sterically tunable chiral N,N′‐diaryl vicinal diamines were obtained in high yields (up to 95 %) with excellent enantioselectivity (up to >99 % ee). The resulting chiral diamines could be readily transformed into sterically hindered chiral N‐heterocyclic carbene (NHC) precursors, which are otherwise difficult to access. The usefulness of this synthetic approach was further demonstrated by the successful application of one of the chiral vicinal diamines and chiral NHC ligands in a transition‐metal‐catalyzed asymmetric Suzuki–Miyaura cross‐coupling reaction and asymmetric ring‐opening cross‐metathesis, respectively.     

新金鸡纳生物碱衍生物配体的合成及其在烯烃的不对称双羟化反应中的应用

以简便的方法高产率地合成四种金鸡纳生物碱的对甲苯磺酸酯类配体，并将其应用于烯烃的不对称双羟化反应中，取得了较好的不对称诱导效果，双羟化反应的化学产率为82％～95％，对映体过量最高达93％ee．     

Enantioselective Construction of Vicinal Tetrasubstituted Stereocenters by the Mannich Reaction of Silyl Ketene Imines with Isatin‐Derived Ketimines

A highly enantioselective Mannich reaction of silyl ketene imines with isatin‐derived ketimines has been realized by using a chiral N,N′‐dioxide/Zn^II catalyst. A variety of β‐amino nitriles containing congested vicinal tetrasubstituted stereocenters were obtained with excellent outcomes (up to 98 % yield, >19:1 d.r. and 99 % ee). Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.     

Asymmetric synthesis of pyrrolo[1,2-a]indoles via organocatalytic[3 + 2] annulation of substituted 2-vinylindoles with azlactones

The chiral phosphoric acid catalyzed asymmetric[3+2]annulation of substituted 2-vinylindoles with azlactones has been established.This reaction represented a practical approach for the synthesis of structurally diverse pyrrolo[1,2-a]indoles with two vicinal stereocenters including one tetrasubstituted stereocenter in good yields and good stereoselectivities under mild conditions.     

Chiral Zinc(II)‐Catalyzed Enantioselective Tandem α‐Alkenyl Addition/Proton Shift Reaction of Silyl Enol Ethers with Ketimines

A new catalytic asymmetric tandem α‐alkenyl addition/proton shift reaction of silyl enol ethers with ketimines was serendipitously discovered in the presence of chiral N,N′‐dioxide/Zn^II complexes. The proton shift preferentially proceeded instead of a silyl shift after α‐alkenyl addition of silyl enol ether to the ketimine. A wide range of β‐amino silyl enol ethers were synthesized in high yields with good to excellent ee values. Control experiments suggest that the Mukaiyama–Mannich reaction and tandem α‐alkenyl addition/proton shift reaction are competitive reactions in the current catalytic system. The obtained β‐amino silyl enol ethers were easily transformed into β‐fluoroamines containing two vicinal tetrasubstituted carbon centers.     

光学活性胺膦配体的合成与在不对称催化中的应用

用邻二苯基膦苯甲醛与不同的手性二胺缩合,高产率地制备了一系列手性双胺双膦配体。这些配体分别与Ru(DMSO)4Cl2或[Rh(COD)Cl]2等反应,可制备相应的手性双胺双膦钌、铑配合物。在异丙醇溶液中,该C2-对称的手性双胺双膦钌、铑配合物是多种芳香酮不对称转移氢化的优化催化剂,反应产物手性芳香醇的转华裔经和对映选择性分别高达99%和98ee。     

Catalytic Asymmetric Mannich‐Type Reaction of N‐Alkylidene‐α‐Aminoacetonitrile with Ketimines

Optically active vicinal diamines are versatile chiral building blocks in organic synthesis. A soft Lewis acid/hard Brønsted base cooperative catalyst allows for an efficient stereoselective coupling of N‐alkylidene‐α‐aminoacetonitrile and ketimines to access this class of compounds bearing consecutive tetra‐ and trisubstituted stereogenic centers. The strategic use of a soft Lewis basic thiophosphinoyl group for ketimines is the key to promoting the reaction, and aliphatic ketimines serve as suitable substrates with as little as 3 mol % catalyst loading.     

Enantioselective Friedel–Crafts Alkylation Reaction of Heteroarenes with N-Unprotected Trifluoromethyl Ketimines by Means of Chiral Phosphoric Acid

An enantioselective Friedel–Crafts alkylation reaction of pyrroles and indoles with N-unprotected trifluoromethyl ketimines by use of chiral phosphoric acid provided α-trifluoromethylated primary amines bearing chiral tetrasubstituted carbon centers in high yields and with high to excellent enantioselectivities. The present reaction is unique to N-unprotected trifluoromethyl ketimines. No reaction took place with N-p-methoxyphenyl (PMP)-substituted ketimine. Corresponding α-trifluoromethylated amines were transformed without loss of enantioselectivity.     

Highly Enantioselective Direct Synthesis of Endocyclic Vicinal Diamines through Chiral Ru(diamine)‐Catalyzed Hydrogenation of 2,2′‐Bisquinoline Derivatives

An asymmetric hydrogenation of 2,2′‐bisquinoline and bisquinoxaline derivatives, catalyzed by chiral cationic ruthenium diamine complexes, was developed. A broad range of chiral endocyclic vicinal diamines were obtained in high yields with excellent diastereo‐ and enantioselectivity (up to 93:7 dl/meso and >99 % ee). These chiral diamines could be easily transformed into a new class of chiral N‐heterocyclic carbenes (NHCs), which are important but difficult to access.     

Palladium-Catalyzed Asymmetric Hydrogenolysis of Aryl Triflates for Construction of Axially Chiral Biaryls

Here we report the first palladium-catalyzed asymmetric hydrogenolysis of readily available aryl triflates via desymmetrization and kinetic resolution for facile construction of axially chiral biaryl scaffolds with excellent enantioselectivities and s selectivity factors. The axially chiral monophosphine ligands could be prepared from these chiral biaryl compounds and were further applied to palladium-catalyzed asymmetric allylic alkylation with excellent ee values and high branched and linear ratio, which demonstrated the potential utility of this methodology.     

Stereocontrolled synthesis of vicinal diamines by organocatalytic asymmetric Mannich reaction of N-protected aminoacetaldehydes: formal synthesis of (-)-agelastatin A

The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich reactions of N-protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected aminoacetaldehyde as a new entry of α-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (-)-agelastatin A.     

Chiral vicinal diols as platforms for separable diastereomers in Johnson-Claisen rearrangement: a new short route to (−)-nor-canadensolide, (−)-canadensolide and (−)-sporothriolide

The chiral vicinal diols prepared by asymmetric dihydroxylation in high enantioselectivities provide an excellent platform for separable diastereomers in the Johnson-Claisen rearrangement. The separated syn-diastereomers were converted into the advanced γ-(lactone-lactol) intermediates (in six steps, 26-27% overall yields) for the synthesis of (−)-nor-canadensolide, (−)-canadensolide and (−)-sporothriolide.     

Samarium diiodide-induced asymmetric synthesis of optically pure unsymmetrical vicinal diamines by reductive cross-coupling of nitrones with N-tert-butanesulfinyl imines

[reaction: see text] An efficient method for the preparation of optically pure unsymmetrical vicinal diamines by the SmI(2)-induced reductive cross-coupling of nitrones with chiral N-tert-butanesulfinyl imines was developed. This is the first successful example of the highly diastereoselective and enantioselective cross-coupling between two different imine species. It provides a straightforward access to enantiopure unsymmetrical vicinal diamines that are widely applicable in asymmetric synthesis.     

Organocatalytic Nucleophilic Addition of Hydrazones to Imines: Synthesis of Enantioenriched Vicinal Diamines

In the presence of a catalytic amount of chiral phosphoric acid, nucleophilic addition of N ‐monosubstituted hydrazones to N ‐Boc imines affords differentially protected vicinal diamines in the form of β‐amino N ,N ′‐dialkyldiazenes in excellent yields with high chemo‐, diastereo‐, and enantioselectivity. This catalytic asymmetric aza‐Mannich reaction represents the first example in which N ‐alkyl hydrazones serve as α‐azo carbanion equivalents to provide vicinal diamines with control of the two contiguous stereocenters. The adducts are readily converted into the monoprotected or free diamines and derivatives thereof.     

Synthesis of hindered chiral guanidine bases starting from (S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN

An efficient method for the preparation of hindered chiral guanidines using cyanogen bromide is described. The reaction between BrCN and vicinal diamines derived from (S)-2-(N,N-dialkyl-aminomethyl)-pyrrolidines provides chiral substituted cyanamides. The cyanamide derivatives reacted with secondary amines in hexafluoroisopropanol at reflux to form chiral hindered guanidines, which were isolated in good to excellent yields (70–96%). The chiral guanidines were prepared in an effort to design sophisticated chiral guanidine catalysts for asymmetric synthesis.     

Asymmetric Synthesis of Heterocyclic Chloroamines and Aziridines by Enantioselective Protonation of Catalytically Generated Enamines**

We report a method for the synthesis of chiral vicinal chloroamines via asymmetric protonation of catalytically generated prochiral chloroenamines using chiral Brønsted acids. The process is highly enantioselective, with the origin of asymmetry and catalyst substituent effects elucidated by DFT calculations. We show the utility of the method as an approach to the synthesis of a broad range of heterocycle-substituted aziridines by treatment of the chloroamines with base in a one-pot process, as well as the utility of the process to allow access to vicinal diamines.     

Ruthenium-catalysed asymmetric transfer hydrogenation of N-(tert-butanesulfinyl)imines

The ruthenium complex prepared from [RuCl₂(p-cymene)]₂ and (1S,2R)-1-amino-2-indanol is a very efficient catalyst for the asymmetric transfer hydrogenation of (R)-N-(tert-butanesulfinyl)ketimines in isopropanol. By carefully removing all possible moisture from the reaction medium, chiral primary amines with very high optical purities (up to >99% ee) can be easily prepared in excellent yields by the diastereoselective reduction of the imines followed by removal of the sulfinyl group under mild acidic conditions. Reaction times of 1-4 h were needed to complete the reduction reactions when they were performed at 40 °C.     

High Performance of a Palladium Phosphinooxazoline Catalyst in the Asymmetric Arylation of Cyclic N‐Sulfonyl Ketimines

A cationic palladium complex with a chiral phosphine‐oxazoline ligand (iPr‐phox) showed high catalytic activity and enantioselectivity in the asymmetric addition of arylboronic acids to six‐membered cyclic N‐sulfonyl ketimines to give high yields of the corresponding chiral cyclic sulfamidates with 96–99.9 % ee. The products have tetrasubstituted stereogenic centers with an amino group and a triaryl or alkyldiaryl group as substituents.