Novel Synthesis of Optically Active 2‐Ethylhexanoic Acid, 2‐Ethylhexanol,and 2‐Ethylhexylamine via the Asymmetric Favorskii Rearrangement

The asymmetric Favorskii rearrangement of optically active α‐haloketones, which are easily prepared from chiral menthyl‐4‐toluenesulfoxide in several steps using primary or secondary amines, yields their corresponding secondary or tertiary chiral amides. The secondary chiral amides were converted to acids or amines using acylation followed by hydrolysis or reduction. In addition, the tertiary amides were directly reduced to alcohol with Super‐Hydride^®.     

Synthesis of enantiopure β-amino amides via a practical reductive amination of the corresponding β-keto amides

A convenient and efficient reductive amination for the preparation of chiral β-amino amides is developed utilizing microwave heating. A variety of chiral β-keto amides react with ammonium acetate and sodium cyanoborohydride to afford the desired functionalized amines in good yields. This improved procedure takes advantage of microwave heating to significantly accelerate the reaction and offers a convenient and effective method to access some interesting molecules containing primary amine functionalities.     

Asymmetric synthesis of delta-substituted alpha,beta-unsaturated delta-lactams by ring closing metathesis of enantiomerically pure N-acryloyl-homoallylic amines

Optically pure secondary homoallylic amines, obtained by highly diastereoselective addition of allylmetal reagents to imines derived from chiral amines, were N-dealkylated, and the primary amines were converted to N-acryloyl amides. Then, ring closing metathesis gave delta-substituted delta-lactams in good overall yields.     

An atom efficient and solvent-free synthesis of structurally diverse amides using microwaves

An array of structurally diverse amides was synthesized efficiently by combining (primary and secondary) amines and carboxylic acids in one-pot under solvent-free microwave (MW) conditions. In most cases, no racemization was observed with optically active inputs and chiral amides were obtained in high ee or de.     

A new method for the preparation of functionalized unnatural α-H-α-amino acid derivatives

A new method for the preparation of α-H-α-amino acids is reported based on the α-alkylation of iminoacetic acid esters or amides. These imines are readily available by the reaction of glyoxylic acid esters with branched primary amines. The subsequent reaction with methanolic ammonia gave the corresponding iminoacetic acid amides. α-Alkylation of these imines with various electrophiles under basic conditions, followed by an acidic hydrolysis, gave α-amino acids, esters, or amides in up to 93% yield. α-Alkylation under chiral PTC conditions resulted in mono-alkylated amino acids with 90% ee.     

Favorskii rearrangement of a highly functionalized meso-dihaloketone

This paper describes studies on the feasibility of an asymmetric Favorskii rearrangement of a meso-dihaloketone substrate. In the racemic series, metal amide bases in the presence of amines give poor to reasonable yields of ring-contracted unsaturated cyclopentyl amides, whilst amines in aqueous solvent mixtures afford cyclopentyl amides in good to excellent yields. A range of chiral non-racemic amines are screened, a tiny diastereo-bias is observed and a tentative mechanistic rationale for the diastereoselective process is proposed.     

High-throughput purification of combinatorial libraries II: Automated separation of single diastereomers from a 4-amido-pyrrolidone library containing intentional diastereomer pairs

A 4-amido-pyrrolidone library that was intentionally synthesized as pairs of diastereomers was produced by solution-phase parallel syntheses and purified by an automated high-throughput purification system. A total of 2592 4-amido-pyrrolidinones were ultimately isolated as single diastereomers from a matrix of 1920 syntheses. After the four-step synthesis and HPLC purification, the average yield of a single diastereomer was 36.6%. The average chemical purity was >90%, and the average diastereomeric purity was >87%. The choice of chiral amines used to make amides with heterocyclic acid chlorides had a dramatic effect on success. Analysis of the relationship between amines used for synthesis and the diastereomeric separation showed that amides made from chiral 1,2-amino alcohols gave superior separation to amides from chiral morpholines. The presence of a hydrogen bond donor on the amide side chain seems to be required for a better diastereomeric separation.     

Steric and electronic effects in the resolution of enantiomeric amides on a commercially available Pirkle-type high-performance liquid chromatographic chiral stationary phase

The steric and electronic effects in the resolution of enantiomeric amides on a commercially available (R)-N-(3,5-dinitrobenzoyl)phenylglycine chiral stationary phase (CSP) have been investigated. Several homologous series of enantiomeric amides were synthesized from alkyl and aromatic amines and from alkyl and aromatic acids. The results of the study indicate that chiral recognition is based on the formation of diastereomeric solute-CSP complexes that are due to attractive interactions located on a single bond in both the solute and CSP and on steric interactions within the complexes. The magnitude of the chiral resolution appears to depend on the steric bulk at the chiral center. In addition, when the amides synthesized from chiral amines were chromatographed, the (R)-enantiomers eluted first, whereas the opposite elution order was found for the amides synthesized from enantiomeric carboxylic acids. Thus, the amide moiety not only provides the sites of attractive interaction between the solute and CSP, but also influences the spatial orientation of the two molecules, thereby affecting the relative stabilities of the two diastereomeric complexes and determining the enantiomeric elution order.     

The use of MPA amide for the assignment of absolute configuration of a sterically hindered cyclic secondary amine by 'mix and shake' NMR method

We present here a new method using methoxyphenylacetic acid (MPA) as the chiral derivatizing agent (CDA) for the assignment of absolute configuration of cyclic secondary amines. The MPA amides were prepared using the purification-free 'mix and shake' method. A detailed conformational analysis for the two diastereomeric amides was conducted by 2D NMR experiments and molecular mechanics calculations. We have established that, in the most stable conformation of each syn rotamer of MPA amides, the H-alpha in the MPA moiety is oriented toward the bulky substituent group at the asymmetric carbon in the chiral amine, presumably to avoid steric and/or electrostatic interactions. The observed NMR data were correlated with the conformational model to allow unambiguous assignment of absolute configuration of secondary amines. The results demonstrate that the MPA can be used as a useful CDA in the case of sterically crowded cyclic secondary amines from which the MTPA amides are usually difficult to make.     

Enantioselective Hydroamidation of Enals by Trapping of a Transient Acyl Species

An enantioselective synthesis of β‐chiral amides through asymmetric and redox‐neutral hydroamidation of enals is reported. In this reaction, a chiral N‐heterocyclic carbene (NHC) catalyst reacts with enals to generate the homoenolate intermediate. Upon highly enantioselective β‐protonation through proton‐shuttle catalysis, the resulting azolium intermediate reacts with imidazole to yield the key β‐chiral acyl species. This transient intermediate provides access to diversified β‐chiral carbonyl derivatives, such as amides, hydrazides, acids, esters, and thioesters. In particular, β‐chiral amides can be prepared in excellent yield and ee (40 chiral amides, up to 95 % yield and 99 % ee). This modular strategy overcomes the challenge of disruption of the highly selective proton‐shuttling process by basic amines.     

Palladium catalysts on alkaline-earth supports for racemization and dynamic kinetic resolution of benzylic amines

Palladium catalysts on alkaline-earth supports were studied as new heterogeneous catalysts for racemization of chiral benzylic amines such as 1-phenylethylamine. Particularly 5 % Pd/BaSO(4) and 5 % Pd/CaCO(3) were able to selectively racemize amines, with minimal formation of secondary amines or hydrogenolysis to ethylbenzene. In contrast, these side reactions were pronounced on Pd/C. A reaction mechanism is proposed that is consistent with the reaction kinetics. The catalyst activity was found to depend on the number of available surface Pd atoms, determined by titration with CO. The selectivity crucially depends on the rate of condensation of the amine and the primary imine, which is highest on Pd/C. The racemization catalysts were combined in one pot with an immobilized lipase to perform dynamic kinetic resolution of chiral amines. High yields (up to 88 %) of essentially enantiopure amides were obtained in a single step. The chemo-enzymatic catalyst system proved to be stable and could be reused without losing the initial activity.     

Synthesis of Polymer-supported Chiral Lithium Amide Bases and Application in Asymmetric Deprotonation of Prochiral Cyclic Ketones

Polymer-supported chiral amines were effectively prepared from amino acid derivatives and Merrifield resin. Treatment of polymer-supported amines with n-butyllithium gave the corresponding polymer-suppported chiral lithium amide bases, which were tested in the asymmetric deprotonation reactions of prochiral ketones. The trimethylsilyl enol ethers were obtained in up to 82% ee at room temperature. The polymer-supported chiral lithium amides can be readily recycled and reused without any significant loss of reactivity or selectivity.     

Acide 2-fluoro-2- phenylacetique. Partie 3 [1]. Correlation entre la configuration de ses amides d''amines chirales et les deplacements chimiques du proton et du fluor

Proton and fluorine chemical shifts of amides from PhCHFCO₂H (used as a chiral derivatizing agent) and amines L¹CH(NH₂)L² are correlated with configuration in order to assign configuration of chiral amines by ¹⁹F NMR spectroscopy.     

Diastereoselective preparation of (R)- and (S)-2-methoxy-2-phenylpent-3-ynoic acids and their use as reliable chiral derivatizing agents

Benzoyl-S,O-acetals 1a and 1b were used as chiral auxiliaries to achieve the diastereoselective preparation of both enantiomers of 2-methoxy-2-phenylpent-3-ynoic acids (MPPAs). The latter were condensed with several chiral secondary alcohols and some primary amines to evaluate their potential as chiral derivatizing agents (CDAs). The (1)H NMR spectra of the corresponding esters and amides showed strong consistency with the absolute configuration of the carbinol and amine moieties, whose observed ΔδL(1) and ΔδL(2) values were in the ranges of 0.1-0.4 and 0.02-0.12 ppm, respectively.     

Enantioselective alkylation of aldehydes with chiral organomagnesium amides (COMAs)

[reaction: see text] Dialkylmagnesiums react with chiral secondary amines to form chiral organomagnesium amides (COMAs). These reagents alkylate aldehydes to form secondary alcohols with enantioselectivities up to 91:9 er.     

Chirality transfer during alkylation of chiral amides

Chiral amides derived from O-methyl mandelic acid and achiral amines underwent enantioselective alpha-methylation on treatment with LTMP followed by addition of methyl iodide; chirality transfer from an undeprotonated chiral amide into an achiral enolate in a mixed aggregate is supposed to be responsible for the asymmetric induction.     

Copper-catalyzed coupling of tertiary aliphatic amines with terminal alkynes to propargylamines via C-H activation

We have developed a convenient and efficient method for coupling of tertiary aliphatic amines with terminal alkynes to propargylamines via C-H activation. The protocol uses CuBr as the catalyst, NBS as the free radical initiator, CH(3)CN as the solvent, and the alkynylation was selectively performed on the methyl of tertiary aliphatic amines at 80 degrees C. This is an economical and practical method for the synthesis of propargylamines.     

Reductive hydroxyalkylation/alkylation of amines with lactones/esters

We have developed a one-pot method for the direct intermolecular reductive hydroxyalkylation or alkylation of amines using lactones or esters as the hydroxyalkylating/alkylating reagents. The method is based on the in situ amidation of lactones/esters with DIBAL-H-amine complex (for primary amines) or DIBAL-H-amine hydrochloride salt complex (for secondary amines), followed by reduction of the amides with an excess of DIBAL-H. Different from the reduction of Weinreb amides with DIBAL-H where aldehydes are formed, the reduction of the in situ formed Weinreb amides yielded amines. Moreover, this method is not limited to Weinreb amides, instead, it also works for other amides in general. A plausible mechanism is suggested to account for the outcome of the reactions.     

Enantioselective Intermolecular Radical Amidation and Amination of Benzylic C−H Bonds via Dual Copper and Photocatalysis

A method for direct access to enantioenriched benzylic amides and carbamate-protected primary benzylamines by C−H functionalization is reported. The C−H substrate is used as limiting reagent with only a small excess of the unactivated amide or carbamate nucleophile. The enantioselective intermolecular dehydrogenative C−N bond formation is enabled by a combination of a chiral copper catalyst, a photocatalyst, and an oxidant, and it takes place under mild conditions, which allow for a broad substrate scope. The method is compatible with late-stage C−H functionalization, and it provides easy access to ¹⁵N-labeled amides and amines starting from cheap ¹⁵NH₄Cl.     

Synthetic macrocyclic receptors in chiral analysis and separation

Chiral synthetic macrocyclic receptors that can achieve chiral discrimination by NMR spectroscopy and/or chiral separation by HPLC are overviewed. Synthetic macrocycles introduced here include crown ethers, calixarenes/calixresorcinarenes/calixpyrroles, macrocyclic amides/amines, and porphyrins. These macrocyclic frameworks are advantageous because intermolecular interactions can take place effectively, such as the ion–dipole interactions in crown ethers, the CH/π and π–π interactions in calixarenes, hydrogen bonding and salt formation in macrocyclic amides and amines, and π–π stacking and metal coordination in porphyrins. Additional functional groups on the periphery of the macrocyclic platforms not only make the whole molecule chiral but also act as the interaction sites. Chiral macrocyclic receptors can show a high degree of chiral recognition/discrimination by using the peripheral functional groups as well as the macrocyclic skeletons (preorganization). Both hosts and guests are shown in the figures to quickly overview the molecular recognition scope of synthetic macrocyclic receptors in chiral analysis and separation.