Novel Method for the Enantioselective Synthesis of β-Lactams

A novel method for the enantioselective synthesis of β-lactams is described in this study. 2,3-Dihydrobenzooxazin-4-one derived from salicylamide and L-menthone was used as the chiral auxiliary, which reacted with a-bromo-acyl bromides in the presence of pyridine to give carboximides 2. The stereo-controlled Reformatsky-type reactions of carboximides with imines yielded the corresponding trans β-lactams with high enantioselectivities（e.e. 75%-86%） and high chemical yields（63%-85%）, meanwhile, the chiral auxiliary dihydrobenzooxazin-4-one was released and recovered.     

Synthesis of Novel Derivatives of （R）-Cysteine and Their Application in Asymmetric Reduction of Prochiral Ketones

ovel chiral β-amino alcohols containing sulfide or sulfonyl groups were synthesized from （R）-cysteine. Their chiral induction in the asymmetric borane reduction of prochiral ketones was investigated. Optically active secondary alcohols with moderate or high e. e. values were obtained, and the causes of different enantioselectivities between these two sulfur-containing chiral β-amino alcohols were researched.     

Study of chiral recognition mechanism of O,O-diethyl (p-methylbenzenesulfonamindo)-aryl(alkyl)-methylphosphonates by HPLC with a series of CSPs

Five chiral stationary phases (CSPs) were used to separate the enantiomers of a series of O,O-diethyl (p-methyl-benzenesulfonamindo)- aryl(alkyl)-methylphosphonates. A chiral recognition mechanism was presented to explain the resolution of these compounds. Results show that CSP with strong π-acceptor 3,5-dinitrobenzoyl group and high steric hindrance has the best resolution ability in chiral separation of O,O-diethyi (p-methyl-benzenesulfonamindo)- aryl(alkyl)-methylphosphonates. When a CSP has just a strong π-acceptor 3,5-dinitrobenzoyl or high steric hindrance it does not have good chiral resolution ability. The chiral recognition is more difficult when the CSP has more than one asymmetric center.     

The first catalytic asymmetric addition of diethylzinc to aldehyde promoted by chiral thiourea

A series of C₂-symmetric and asymmetric chiral thiourea derivatives were synthesized from commercial L-phenylalanine.All of the new compounds have been fully characterized by IR,¹H NMR,¹³C NMR,MS spectra and elemental analyses.The chiral thioureas were used as chiral ligands in the catalytic enantioselective ethylation of aldehydes with diethylzinc,the corresponding sec-alcohols were gained with excellent enantioselectivities（up to 87.1%ee） and high yields（up to 76.7%） after the conditions were optimized.     

Synthesis of the major isomers of Aprepitant and Fosaprepitant

The synthesis of two isomers of Aprepitant （APT） and three isomers of Fosaprepitant （FPT）, crucial components for quality control in manufacturing, is described. Herein, three chiral centers in the isomers of Aprepitant are established in high yield by induced crystallization and chiral reduction. Additionally, the isomers of Aprepitant are utilized to synthesize the isomers of Fosaprepitant with the same stereochemistry. All the target compounds were confirmed by elemental analyses, 1R, NMR and MS data analysis.     

Preparation and chiral recognition of a novel chiral stationary phase for HPLC,based on mono（6A-N- 1-（2-hydroxyl）- phenylethylimino-6A-deoxy）-β-cyclodextrin and covalently bonded silica gel

A novel chiral stationary phase （CSP） was prepared by immobilizing mono（6A-N-1-（2-hydroxyl）-phenylethylimino-6A- deoxy）-β-cyclodextrin onto the surface of silica gel via a longer spacer. This chiral stationary phase exhibited good enantioselectivity for a variety of chiral compounds under reversed-phase conditions.     

A Mild and Efficient Synthesis of Chiral N-Boc-a-aminoaldehydes

A series of chiral N-Boc-α-aminoaldehydes were synthesized in good yields and high purity via esterification of Boc-L-amino acids followed by reduction with sodium bis （2-methoxy- ethoxy）aluminum hydride.     

Asymmetric Synthesis of the C（17）——C（28） Subunit of Didemnaketal B

The stereocontrolled synthesis of the C（17）--C（28） fragment 3 of didemnaketal B was accomplished in 21 steps from the natural （R）-（＋）-pulegone and （S）-（--）-citronellal. The key steps involved diastereoselective construction of two chiral carbon centers through the intramolecular chiral induction and uncommon Julia olefination of ketone forming the E-trisubstituted C（22）--C（23） double bound.     

Synthesis of novel chiral N, P-containing multidentate ligands and their applications in asymmetric transfer hydrogenation

Novel chiral PN₄-type multidentate aminophosphine ligands have been successfully synthesized by Schiff-base condensation of bis（o-formylphenyl）phenylphosphane and various chiral amino-sulfonamides.Their structures were fully characterized by IR,EI-MS and NMR.The catalytic systems,prepared in situ from the multidentate ligands and iridium（I） complexes,showed high activity in asymmetric transfer hydrogenation of propiophenone in 2-propanol solution,leading to corresponding optical alcohol with up to 75%ee.     

Asymmetric Addition of Diethylzinc to Aldehydes Catalyzed by Chiral γ_Amino Alcohols

Although the asymmetric additions of diethylzinc to aldehydes have been extensively studied in the presence of chiral catalyst, most of the chiral ligands tested are b-amino alcohols1. In this report, the synthesis of chiral gamino alcohols 1-4 from the reaction of (+)-camphor and (-)-menthone with 2-lithiomethyl-6-methyl-pyridine or 2-picolly- lithium2, which give a single diasteromer as determined by 1H NMR with high yields (Scheme 1)3, and their application in the enantioselective additio…     

Synthesis of cis-1,2-diol-type chiral ligands and their dioxaborinane derivatives: Application for the asymmetric transfer hydrogenation of various ketones and biological evaluation

Two cis-1,2-diol-type chiral ligands (T ₁ and T ₂ ) and their tri-coordinated chiral dioxaborinane (T _(1–2) B _(1–2) ) and four-coordinated chiral dioxaborinane adducts with 4-tert-butyl pyridine sustained by N → B dative bonds (T _(1–2) B _(1–2) -N) were synthesized and characterized by various spectroscopic techniques such as NMR (¹H, ¹³C, and ¹¹B), FT-IR and UV–Vis spectroscopy, LC–MS/MS, and elemental analysis. It was suggested that both ferrocene and trifluoromethyl groups played key roles in the catalytic and biological studies because they could tune the solubility of the chiral dioxaborinane complexes and adjust the strength of intermolecular interactions. To assess the biological activities of newly synthesized chiral dioxaborinane compounds, DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging, reducing power, antibacterial, DNA binding, and DNA cleavage activities were tested. Then, all chiral dioxaborinane complexes were investigated as catalysts for the asymmetric transfer hydrogenation of various ketones under suitable conditions. The results indicated that the chiral dioxaborinane catalysts performed well with high yields.     

Organocatalytic Asymmetric Annulation of ortho‐Alkynylanilines: Synthesis of Axially Chiral Naphthyl‐C2‐indoles

A chiral Brønsted base catalyzed asymmetric annulation of ortho‐alkynylanilines has been developed to access axially chiral naphthyl‐C2‐indoles via vinylidene ortho‐quinone methide (VQM) intermediates. This strategy provides a unique organocatalytic atroposelective route to axially chiral aryl‐C2‐indole skeletons with excellent enantioselectivity and functional‐group tolerance. This transformation was applicable to decagram‐scale preparation (50.0 g) with perfect enantioselectivity through simple recrystallization. Moreover, the utility of this reaction was demonstrated by a variety of transformations towards chiral naphthyl‐C2‐indoles for a series of carbon–heteroatom bond formations. Furthermore, the prepared axially chiral naphthyl‐C2‐indoles were applied as a chiral skeleton for organocatalytic aza‐Baylis–Hillman reaction and asymmetric formal [4+2] tandem cyclization to give the corresponding adducts in high yields with improved enantioselectivity and diastereoselectivity.     

Asymmetric Hydrogenation of In Situ Generated Isochromenylium Intermediates by Copper/Ruthenium Tandem Catalysis

The first asymmetric hydrogenation of in situ generated isochromenylium derivatives is enabled by tandem catalysis with a binary system consisting of Cu(OTf)₂ and a chiral cationic ruthenium–diamine complex. A range of chiral 1H ‐isochromenes were obtained in high yields with good to excellent enantioselectivity. These chiral 1H ‐isochromenes could be easily transformed into isochromanes, which represent an important structural motif in natural products and biologically active compounds. The chiral induction was rationalized by density functional theory calculations.     

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.     

Enantioselective Twofold C−H Annulation of Formamides and Alkynes without Built‐in Chelating Groups

Twofold C?H annulation of readily available formamides and alkynes without built‐in chelating groups was achieved. Ni?Al bimetallic catalysis enabled by a bulky BINOL‐derived chiral secondary phosphine oxide (SPO) ligand proved to be critical for high reactivity and high selectivity. This reaction uses readily available formamides as starting materials and provides a concise synthetic pathway to a broad range of chiral ferrocenes in 40–98 % yield and 93–99 % ee.     

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.     

Enantioselective Twofold C−H Annulation of Formamides and Alkynes without Built-in Chelating Groups

Twofold C−H annulation of readily available formamides and alkynes without built-in chelating groups was achieved. Ni−Al bimetallic catalysis enabled by a bulky BINOL-derived chiral secondary phosphine oxide (SPO) ligand proved to be critical for high reactivity and high selectivity. This reaction uses readily available formamides as starting materials and provides a concise synthetic pathway to a broad range of chiral ferrocenes in 40–98 % yield and 93–99 % ee.     

Asymmetric Synthesis of Some Chiral Aryl and Hetero Aryl-Substituted β-, γ-, δ-Hydroxy Esters

Sixteen chiral β-, γ-, and δ-hydroxy esters with aryl, substituted aryl, and heteroaryl groups 2a–2s were synthesized by the asymmetric reduction of their corresponding keto esters 1a–1s as chiral pure reference compounds and starting materials. The asymmetric reduction was achieved by (R)-Me-CBS-oxazaborolidine. Ten new chiral γ- and δ-hydroxy esters 2d, 2e, and 2j–2s were obtained with high ee values and characterized by infrared, NMR (¹H and ¹³C), mass spectrometry, chiral high-performance liquid chromatography, and specific rotation.     

Enantioselective Addition of Organometallic Reagents to Carbonyl Compounds: Chirality Transfer,Multiplication, and Amplification

Nucleophilic addition of organometallic reagents to carbonyl substrates constitutes one of the most fundamental operations in organic synthesis. Modification of the organometallic compounds by chiral, nonracemic auxiliaries offers a general opportunity to create optically active alcohols, and the catalytic version in particular provides maximum synthetic efficiency. The use of organozinc chemistry, unlike conventional organolithium or -magnesium chemistry, has realized an ideal catalytic enantioselective alkylation of aldehydes leading to a diverse array of secondary alcohols of high optical purity. A combination of dialkylzinc compounds and certain sterically constrained β-dialkylamino alcohols, such as (–)-3-exo-dimethylaminoiso- borneol [(–)-DAIB], as chiral inducers affords the best result (up to 99% ee). The alkyl transfer reaction occurs via a dinuclear Zn complex containing a chiral amino alkoxide, an aldehyde ligand, and three alkyl groups. The chiral multiplication method exhibits enormous chiral amplification: a high level of enantioselection (up to 98%) is attainable by use of DAIB in 14% ee. This unusual nonlinear effect is a result of a marked difference in chemical properties of the diastereomeric (homochiral and heterochiral) dinuclear complexes formed from the dialkylzinc and the DAIB auxiliary. This phenomenon may be the beginning of a new generation of enantioselective organic reactions.     

Access to Chiral Hydropyrimidines through Palladium‐Catalyzed Asymmetric Allylic C−H Amination

A palladium‐catalyzed asymmetric intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N ‐sulfonyl amides bearing an arylethene‐1‐sulfonyl group underwent a sequential allylic C−H amination and intramolecular Diels–Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.