New approach to exclusive formation of both enantiomers of β-amino acid derivatives

A highly selective two-step approach to chiral β-amino esters via the hydride reductive amination of chiral allenes is reported. β-Enamino esters were obtained from the nucleophilic addition of amines to 2,3-allenoates bearing a chiral auxiliary. The reduction of the (1R)-(−)-10-phenylsulfonylisobornyl β-enamino esters gave the corresponding β-amino esters with S configuration whereas the reduction of the (1S)-(+)-10-phenylsulfonylisobornyl β-enamino esters led to β-amino esters with R configuration. The rationalization of the observed selectivity was supported by semi-empirical molecular orbital calculations (PM3).     

Diastereochemical differentiation of some cyclic and bicyclic β-amino acids, via the kinetic method

Stereochemical differentiation of five diastereomeric pairs of β-amino acids, di-endo- and di-exo-2,3-disubstituted norbornane and norbornene amino acids, cis- and trans-2-aminocyclohexane-, 2-amino-4-cyclohexene-, and 2-aminocyclopentanecarboxylic acids, was investigated via the kinetic method with metal-bound trimeric complexes. This is the first time that diastereomers (di-endo/di-exo and cis/trans) have been differentiated with metal-bound trimeric complexes and the kinetic method. Moreover, determination of diastereochemical excess by the kinetic method was applied to norbornane β-amino acids and cyclopentane β-amino acids. Experiments showed that a remarkable differentiation of the studied diastereomers was achieved. It was observed that better selectivity values correlated to more rigid structures. The reference compounds for the studied β-amino acids varied from α-amino acids to some β-amino acids. In addition, variation of the metal ion (Cu²⁺ and Ni²⁺) had some role in the selectivity values obtained. Ab initio and hybrid density functional theory calculations were performed to clarify the results obtained by mass spectrometry.     

Synthesis and characterization of novel β-amino acid derivatives

In the work discussed in this paper, novel β-amino acid derivatives were prepared by Michael addition between 3-substituted-2-propenic acid and hydrazine hydrate. The optimum reaction conditions were determined by analyzing the effects of the ratio of the starting materials, temperature, and reaction time. The conclusions were: reaction temperature 80 °C, reaction time 8 h, n (3-substituted-2-propenic acid)/n (hydrazine hydrate) = 1:15. Products were characterized by measurement of melting point, elemental analysis, and IR and ¹H NMR spectroscopy.     

Synthesis of orthogonally protected azepane β-amino ester enantiomers

A simple and convenient route is presented for the preparation of regio- and stereoisomers of novel azepane β-amino esters, starting from bicyclic β-lactam isomers. The synthetic procedure consists of dihydroxylation of the olefinic bond of the alicyclic amino esters, followed by NaIO₄-mediated cleavage of the diol intermediate and reductive ring closure, which furnishes novel regioisomeric 5-aminoazepane-4-carboxylate and 3-aminoazepane-4-carboxylates. This method also allows the preparation of amino esters with an azepane skeleton in enantiomerically pure form.     

Synthesis of β3-amino acid and peptides from D-ribose

Synthesis of new β³-amino acid, peptides and conformational analysis are reported from d-ribose, using Wittig olefination and Aza-Michael addition.     

Intramolecular ester enolate-imine cyclization reactions for the asymmetric synthesis of polycyclic β-lactams and cyclic β-amino acid derivatives

Enolates of chiral N-(α-methyl-p-methoxybenzyl)-ω-imino-esters undergo intramolecular cyclization reactions to afford (syn)-aza-anions of β-amino esters in high dr that cyclize to afford N-(α-methyl-p-methoxybenzyl)-β-lactams that can be readily deprotected to afford their corresponding cyclic NH-β-lactams, β-amino esters, or β-amino acids.     

Glycosylation-induced asymmetric synthesis: β-amino acid esters via Mannich reactions

Activation of Schiff bases by N-glycosylation induces asymmetric Mannich reactions with O-silyl ketene acetals to give β-amino acid esters in good yields.     

High-performance liquid chromatography of α-amino acid enantiomers on eremomycin-modified silica

The chromatographic behavior of enantiomers of α-amino acids was studied on new chiral stationary phases based on silica gel with macrocyclic glycopeptide antibiotic eremomycin and its aglycone immobilized on the surface. The retention of adsorbates and enantioselectivity of their separation were studied as functions of the structure of the side group of α-amino acids, eluant pH, concentration of organic modifier in the eluant, and temperature. The mechanism of the chiral recognition of α-amino acid enantiomers is discussed.     

A comparative study of the multicomponent Ugi reactions of an oxabicycloheptene-based β-amino acid in water and in methanol

Di-exo-3-amino-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid 1, five aldehydes and two isocyanides were reacted both in methanol and in water to prepare a 10-membered β-lactam library via a Ugi-4-centre-3-component reaction. The yields were found to be similar in water and methanol. The diastereoselectivities of the aqueous reactions were similar, though in a few cases higher than those in methanol. The benefits of water are the facile isolation of the precipitated product and the shorter reaction time.     

Synthesis of both enantiomers of methylenolactocin,nephrosterinic acid and protolichesterinic acid via tandem aldol–lactonization reactions

Both forms of the enantiomerically pure methylenolactocin, nephrosterinic and protolichesterinic acid have been synthesized via tandem aldol–lactonization reactions from corresponding optically active itaconate–anthracene adducts.     

Chiral separation of α-cyclohexylmandelic acid enantiomers using ionic liquid/salt aqueous two-phase system

In this paper, an ionic liquid-based aqueous two-phase system (ILATPS) was applied to the chiral separation of α-cyclohexylmandelic acid (α-CHMA) enantiomers with hydroxypropyl-β-cyclodextrin (HP-β-CD) as the chiral selector. Several influencing parameters were investigated including the types and concentration of ionic liquids, the amount of phase-forming salt, temperature, mixing time, pH, and the content of HP-β-CD. The results showed that not all ILATPS had the ability to chirally recognise the selected enantiomers and that [C₄mim]BF₄/(NH₄)₂SO₄-based ATPS possessed the best enantioseparation ability of the investigated ILATPSs. Under optimal conditions, the separation factor (α) attained 1.59 in a single-step extraction. ILATPS is much “greener” than other liquid-liquid extraction systems, showing its potential for application to the chiral separation.     

A novel green synthesis of α/β-amino acid functionalized pyrimidinone peptidomimetics using triazole ligation through click-multi-component reactions

An innovative synthetic pathway for the preparation of a new series of triazole-decorated dihydropyrimidinone peptidomimetics with skeletal α or β-amino acid residue is reported. The protocol involves two synthetic steps with an initial solvent-free and catalyst-free synthesis of propargylated dihydropyrimidinone precursors using Biginelli condensations. The subsequent cycloaddition reactions of pyrimidinone alkynes with small peptide like azides prepared from Ugi or alternate Mannich type multi-component reactions afforded the triazole decorated pyrimidinone peptide conjugates in excellent yield with high regio and stereospecificities. In total, a scaffold diversity contains 11 new pyrimidinone alkynes and 18 new pyrimidinone peptidomimetics were introduced into the chemical space.     

Structure and energy of formation of β- and γ-cyclodextrin complexes with amino acid enantiomers

The interaction between cyclodextrins (CyD), β-CyD, and γ-CyD, and the L- and D-optical isomers of several amino acids (Ala, Leu, His, Phe) are calculated using DFT. It is found that the L-forms of the investigated amino acids bond more strongly to CyD, due to the different numbers of hydrogen bonds that form. The structures of the resulting complexes are analyzed.     

Alternative cocrystallization of “almost” enantiomers and true enantiomers in some cis-β-organocobalt salen-type complexes with α-amino acids

The reaction of a chiral cis-β-organocobalt salen-type complex, 1, racemic mixture of Δ and Λ enantiomers, with enantiomerically pure l-histidine and a non-chiral monocationic cobalt complex, 3, resulted quite unexpectedly in the cocrystallization of diastereomers. Each diastereomer is a dicobalt monocationic complex, where four positions around one metal center are occupied by the tetradentate ligand in a cis fashion, the remaining two positions being occupied by l-histidinate. Histidinate further axially coordinates the other Co atom through the nitrogen of the imidazole residue. The two diastereomers are related by a quasi-symmetry center. In this case, the opposite helical chirality of the metal complex 1 prevails over the identical configuration of the asymmetric carbon in the crystallization process and the diastereomers behave as if they were enantiomers.The reaction of the same cobalt complexes 1 and 3 with dl-histidine led to the formation of two pairs of enantiomers, which crystallized separately as racemic compound. Therefore, in this case, the chirality of the asymmetric center is the property that allows the mutual selective recognition of the “true” enantiomers and drives their cocrystallization.     

A novel oxidative ring-opening reaction of isoxazolidines: syntheses of β-amino ketones and β-amino acid esters from secondary amines

A novel oxidative ring-opening reaction of isoxazolidines upon treatment with an electrophile and subsequently with a basegives β-amino ketones and β-amino acid esters highly efficiently.     

Stereoselective synthesis of 3,4,5,6-tetrahydroxycyclohexyl β-amino acid derivatives

Stereoselective syntheses of racemic (1S,2R,3R,4R,5S,6R)- and (1S,2R,3R,4S,5S,6R)-3,4,5,6-tetrahydroxy derivatives of 2-aminocyclohexanecarboxylic acid have been achieved by a stereospecific Diels-Alder reaction between furan and maleic anhydride, a Curtius rearrangement and hydroxylation reactions.     

Stereocontrolled transformation of cyclohexene β-amino esters into syn- or anti-difunctionalized acyclic β-amino acid derivatives

A stereocontrolled approach to functionalized acyclic β^2,3-amino acid derivatives was accomplished from cis- or trans-2-aminocyclohexenecarboxylates derived from bicyclic β-lactam regioisomers. The transformations were based on oxidative ring cleavage through the ring C–C double bond of the cyclohexene β-amino esters, followed by functionalization of the dialdehyde intermediates with different phosphoranes. This stereospecific and stereocontrolled procedure was applied to the synthesis of acylic β^2,3-amino acid derivatives functionalized with ester, nitrile, keto, alkyl or arylalkyl groups.     

Spontaneous and diastereoselective aldol reactions of cyclic β-amino ketones in the presence of water

Direct aldol reactions of 4-methyl-1-piperidone, tropinone and granatanone (pseudopelletierine) take place spontaneously in the presence of water without any catalyst or additional reagents. The anti/syn-diastereoselectivity of the aqueous aldol reaction depends on the amount of water used. The syn-selectivity of the reaction is probably due to the thermodynamic control. Excellent atom economy and low E factors together with anti-selectivity as high as 98:2 for the tropinone aldol were obtained.     

Diastereochemical differentiation of β-amino acids using host-guest complexes studied by fourier transform ion cyclotron resonance mass spectrometry

Host-guest complexes where tetraethyl resorcarene was the host molecule were used to study the stereoselectivity of diasteromeric pairs of di-endo- and di-exo-2,3-disubstituted norbornane and norbornene amino acids by ion-molecule reactions and collision-induced dissociation with electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS). Both methods showed stereoselectivity for the diastereomeric pairs. Particularly high selectivity was achieved for di-endo- and di-exo-2,3-disubstituted norbornane amino acids with ion-molecule reactions. Also, ab initio and hybrid density functional theory calculations were performed to study the different structures of the host-guest complexes. Hydrogen bonding was crucial for the calculated lowest energy structures, and sterical considerations satisfactorily explained the ion-molecule reaction results.     

Diastereoselective synthesis of β-amino ketone and acid derivatives by palladium-catalyzed conjugate addition

The first diastereoselective synthesis of β-amino ketone and β-amino acid derivatives by palladium-catalyzed conjugate addition of arylboronic acids to chiral β-enamino ketones and β-enamino esters is reported. The catalytic system employing (S)-4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary in water under an air atmosphere provides β-amino ketone and β-amino acid derivatives in high yields with excellent diastereoselectivity.