Secondary Α-amino Acids Research Articles

A three-component [3 + 2]-cycloaddition/elimination cascade for the synthesis of spirooxindole-pyrrolizines.

A three-component synthesis of novel spirooxindole-tetrahydropyrrolizines from secondary α-aminoacids, isatins and vinyl selenones has been disclosed. Products were formed in good yields and high diastereoselectivity by 1,3-dipolar cycloaddition of in situ generated azomethine ylides followed by spontaneous elimination of benzeneseleninic acid. Good regioselectivities with aryl substituted vinyl selenones were observed. The method showed good functional group tolerance, providing a direct approach to biologically relevant spirooxindoles under mild reaction conditions.

Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis.

The synthesis of complex alkyl boronic esters through conjunctive cross-coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross-coupling cascade of vinyl boronic esters. Excellent functional-group tolerance is displayed, and application of a range of carboxylic acids, including secondary α-amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross-coupling was also applied to the synthesis of sedum alkaloids.

Synthesis of oxetane/azetidine containing spirocycles via the 1,3-dipolar cycloaddition reaction

Silver catalyzed 1,3-dipolar cycloaddition reactions between methyl 2-(oxetane/azetidine-3 ylidene)acetate as dipolarophiles and imines derived from α-amino acid methyl esters, 2-aminomethyl pyridine, and 2-aminomethyl pyrazine afforded oxetane/azetidine containing spirocycles in 40–77% yield. The use of 3-oxetanone used as the carbonyl compound thermal 1,3-dipolar cycloaddition reactions with secondary α-amino acids or methyl esters resulted in oxetane spirocycles in 62–90% yield.

Molecular diversity of the three-component reaction of α-amino acids, dialkyl acetylenedicarboxylates and N-substituted maleimides

The one-pot three-component reaction of secondary α-amino acids, including proline, thiazolidine-4-carboxylic acid, and piperidine-2-carboxylic acid sarcosine with dialkyl acetylenedicarboxylate and N-substituted maleimides in refluxing ethanol afforded functionalized pyrrolo[3,4-a]pyrrolizines, pyrrolo[3',4':3,4]pyrrolo[1,2-c]thiazoles, pyrrolo[3,4-a]indolizines and octahydropyrrolo[3,4-c]pyrroles in good yields and with high diastereoselectivity. On the other hand, the similar three-component reaction containing primary α-amino acids, such as glycine, alanine, phenylalanine and leucine, with N-substituted maleimides and two molecules of dialkyl acetylenedicarboxylate obtained the corresponding hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)maleates.

A facile synthesis of glyco 3-nitrochromane hybrid pyrrolidinyl spiro heterocycles via [3+2] cycloaddition of azomethine ylides

A series of diverse glyco 3-nitrochromane hybrid pyrrolidinyl spiro heterocycles have been synthesized by [3+2] cycloaddition reaction of azomethine ylides generated in situ by the condensation of diketones (isatin or acenaphthenequinone)/indenoquinoxalinone and secondary α-amino acids with glyco 3-nitrochromenes as dipolarophiles. This method is simple and provides biologically interesting products. The regio- and stereochemical outcome of the cycloaddition reaction is ascertained by X-ray crystallographic analysis.

A tactical 1,3-dipolar cycloaddition approach for the synthesis of carbohydrate derived polycyclic spiro heterocycles

A facile one-pot synthesis of carbohydrate derived spiro heterocycles via [3+2] cycloaddition reaction of azomethine ylides is described. A unique dipolarophile synthesized from d-glucose reacted with azomethine ylide generated in situ from secondary α-amino acids (sarcosine, proline, or pipecolinic acid) and 1,2-diketone (isatin/acenaphthoquinone)/indenoquinoxalinone to give their corresponding cycloadducts in good yield. The regio- and stereochemical outcome of the cycloaddition reaction is ascertained by X-ray crystallographic analysis.

The chlorinating behaviour of WCl₆ towards α-aminoacids.

Cl/O interchange took place when WCl6 was allowed to interact with a series of α-aminoacids. The α-ammonium-acylchloride salts [NH2(CH2)3CHC(O)Cl][WOCl5], 1a, and [MeNH2CH2C(O)Cl][WOCl5], 1b, were afforded in ca. 55% yields from the reactions of WCl6 with, respectively, L-proline and sarcosine in CH2Cl2. By using other reaction media (hexane or CHCl3), the α-amino-acylchloride complexes WOCl4[O=C(Cl)CH(CH2)3NH2], 5a, and WOCl4[O=C(Cl)CH(R)NHR'] (R = H, R' = Me, 5b; R = R' = H, 5c; R = Me, R' = H, 5d) were isolated in moderate to good yields from WCl6 and, respectively, L-proline, sarcosine, glycine and L-alanine. The formation of 5a,b is basically the result of HCl release from the parent compounds 1a,b. 5a represents a key intermediate in the course of the reaction leading to (WOCl4)2[μ:κ(2)(O)-dkp], 2, dkp = (S,S)-octahydrodipyrrolo[1,2-a:1',2'-d]pyrazine-5,10-dione. 2 was optimally prepared from WCl6/L-proline under high temperature conditions. Hydrolytic treatment of 2 afforded the L-proline-derived 2,5-diketopiperazine (dkp), which was finally isolated with an overall yield of 70%. 1a,b were characterized by X-ray diffractometry, thus providing very rare examples of crystallographically characterized acylchloride derivatives of α-aminoacids. DFT calculations were extensively carried out in order to shed light on structural and mechanistic features.

Convenient synthesis of functionalized spiro[indoline-3,2'-pyrrolizines] or spiro[indoline-3,3'-pyrrolidines] via multicomponent reactions.

A general and practical route for the in situ generation of a new type of azomethine ylide and its sequential 1,3-dipolar cycloaddition reaction was successfully established. The three-component reaction of secondary α-amino acids including proline, sarcosine, thiazolidine-4-carboxylic acid with dialkyl acetylenedicarboxylate and 3-methyleneoxindoles in refluxing ethanol afforded the functionalized spiro[indoline-3,2'-pyrrolizines], spiro[indoline-3,3'-pyrrolidines] and spiro[indoline-3,6'-pyrrolo[1,2-c]thiazoles] in good yields and with high diastereoselectivity. Furthermore, similar multicomponent reactions using primary α-amino acids such as glycine, alanine and phenylalanine resulted in the corresponding (spiro[indoline-3,3'-pyrrolidine]-1'-yl)maleates.

Microwave-promoted, metal- and catalyst-free decarboxylative α,β-difunctionlization of secondary α-amino acids via pseudo-four-component reactions.

A microwave-promoted, metal- and catalyst-free decarboxylative α,β-difunctionlization of secondary α-amino acids via a pseudo-four-component coupling of proline, aldehyde, and 1,3-diketone to generate multifunctionalized pyrano[2,3-b]pyrrole and pyrrolizinone derivatives is reported.

Direct high-performance liquid chromatographic enantioseparation of secondary amino acids on Cinchona alkaloid-based chiral zwitterionic stationary phases. Unusual temperature behavior

Two chiral stationary phases containing a quinine- or a quinidine-based zwitterionic ion-exchanger as chiral selector were applied for the enantioseparation of 27 unusual cyclic secondary α-amino acids. The effects of the nature and concentration of the bulk solvent, the acid and base additives, the structures of the analytes and temperature on the enantioresolution were investigated. To study the effects of temperature and to obtain thermodynamic parameters, experiments were carried out at constant mobile phase compositions in the temperature range −5 to 55°C. The thermodynamic parameters indicated that in most cases the separations were enthalpy-driven, but some entropy-driven separations were also observed. The sequence of elution of the enantiomers was determined in most cases.

Conformational Properties of Secondary Amino Acids: Replacement of Pipecolic Acid by N‐Methyl‐L‐alanine in Efrapeptin C

The efrapeptins, a family of naturally occurring peptides with inhibitory activities against ATPases, contain several α,α-disubstituted α-amino acids such as α-aminoisobutyric acid (Aib) or isovaline (Iva) besides pipecolic acid (Pip), β-Ala, Leu, Gly, and a C-terminal heterocyclic residue. Secondary α-amino acids such as proline are known to stabilize discrete conformations in peptides. A similar influence is ascribed to N-alkyl α-amino acids. We synthesized two efrapeptin C analogs with replacement of Pip by N-methyl-L-alanine (MeAla) using a combination of solid- and solution-phase techniques in a fragment-condensation strategy to compare the conformational bias of both secondary amino acids. The solution conformation was investigated by vibrational circular dichroism (VCD) to probe whether the analogs adopt a 310 -helical conformation. The MeAla-containing analogs [MeAla(1,3) ]efrapeptin C and [MeAla(1,3,11) ]efrapeptin C inhibit ATP hydrolysis by the A3 B3 complex of A1 A0 -ATP synthase from Methanosarcina mazei Gö1.

Stereoselective Synthesis and Semiempirical Studies of Spiro Bridgehead Bicyclic N‐Heterocycles via 1,3‐Dipolar Cycloaddition Reactions of Azomethine Ylides.

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3 + 2]‐Cycloaddition Reactions of Thioisatin with L‐Proline and (R)‐(‐)‐Thiaproline.

AbstractFor Abstract see ChemInform Abstract in Full Text.

3+2]-CYCLOADDITION REACTIONS OF THIOISATIN WITH L-PROLINE AND (R)-(−)-THIAPROLINE

The [3+2]-cycloaddition reactions of cyclic secondary α-amino acids viz L-proline and (R)-(−)-thiaproline with 5-methylthioisatin via azomethine ylide in the presence of dipolarophiles afford azabicyclooctane derivatives in moderate-to-good yields. The cycloadducts have been characterized by elemental analysis and spectral techniques viz IR, 1H NMR, 13C NMR, MASS. In addition, stereochemical aspects of the cycloaddition have been ascertained by MOPAC-6 calculations using AM1 hamiltonians.

Direct high-performance liquid chromatographic separation of unusual secondary amino acids and a comparison of the performances of Chirobiotic T and TAG columns

Two macrocyclic glycopeptide antibiotic-type chiral stationary phases (CSPs) based on native teicoplanin and teicoplanin aglycone, Chirobiotic T and TAG, respectively, were evaluated with regard to the high-performance liquid chromatographic separation of the enantiomers of 10 secondary α-amino acids (imino acids). The chromatographic results are given as the retention, separation and resolution factors, together with the enantioselective free energy difference corresponding to the separation of the enantiomers. By application of these two CSPs, excellent resolutions were achieved for the investigated compounds by using reversed-phase mobile mode systems. The separation conditions were optimized by variation of the mobile phase composition. The difference in enantioselective free energy between the aglycone CSP and the teicoplanin CSP for these particular amino acids ranged between 0.70 and −1.83 kJ mol −1. It was established that better enantioseparations of the secondary α-amino acids were attained in most cases on the aglycone CSP.

X=Y-ZH systems as potential 1,3-dipoles. Part 42. Decarboxylative three carbon ring expansion of cyclic secondary α-amino acids via azomethine ylide formation.

Cyclic 5- and 6-membered secondary α-amino acids react with formaldehyde and acetylenic dipolarophiles via azomethine ylide formation, cycloaddition and subsequent ring expansion to give 8- and 9- membered rings respectively. Ring expansion occurs by reaction of the bridgehead nitrogen of the initial bicyclic cycloadduct with a further molecule of dipolarophile to give a zwitterion which triggers the ring expansion. Dynamic p.m.r. studies show that ring inversion between pairs of mirror image conformations of the medium ring products are occurring with inversion barriers of 13-14.6 kcal/mol.

Unusual reactions of secondary amino acids with trifluoroacetic anhydride: A novel access to α-trifluoromethylated acyloins

A new fragmentation reaction of secondary α-amino acids with trifluoroacetic anhydride under Dakin-West reaction conditions proceeds through oxazolium salt intermediates followed by ring cleavage to form α-trifluoromethylated acyloins in good yields.

Chiral induction in cycloaddition reactions of azomethine ylides derived from secondary α-amino acids by the decarboxylative route

Cyclic secondary α-amino acids react with isatin and menthyl acrylate via decarboxylative azomethine ylide formation and subsequent cycloaddition involving an endo-transition state to give cycloadducts in 67-82% d.e. The stereochemistry of the major cycloadduct is assigned from a single crystal X-ray structure and a transition state model is proposed for the process.

XY–ZH systems as potential 1,3-dipoles. Part 11. Stereochemistry of 1,3-dipoles generated by the decarboxylative route to azomethine ylides

The decarboxylative reaction of aryl aldehydes with cyclic secondary α-amino acids or primary α-amino acids in the presence of N-methyl- or N-phenyl-maleimide leads, via an intermediate azomethine ylide, to mixtures of bicyclic pyrrolidine cycloadducts in good yield. Cyclic secondary α-amino acids, where the carboxylic group is non-benzylic, give cycloadducts arising from a stereospecifically generated anti-dipole. Acyclic α-amino acids, and cyclic secondary α-amino acids with the carboxylic group located at a benzylic site, give rise to cycloadducts derived from both anti- and syn-configurations of the intermediate azomethine glides. The reactions show little discrimination between endo- and exo-transition states for the cycloadditions.

X=Y-ZH Systems as potential 1,3-dipoles: Part 19. Intramolecular cycloadditions of non-stabilised azomethine ylides generated via the decarboxylative route from α- amino acids

Heating a range of acyclic and cyclic secondary α-amino acids with aryl aldehydes containing a proximate terminal alkene or alkyne results in consecutive condensation and decarboxylation, followed by intramolecular cycloaddtion of the resultant non-stabilised azomethine ylides. Evidence is produced for syn-anti dipole equilibration and it is found that intramolecular cycloadditions to a terminal alkyne involve only the anti-dipole and proceed via an exotransition state to give a single cycloadduct. In contrast, intramolecular cycloaddition to a terminal alkene involves both anti- and syn-dipoles, with trapping of the former being slightly energetically preferred resulting in mixtures of two stereoisomeric cycloadducts. Intramolecular cycloadditions of terminal alkenes to anti-dipoles proceed via exo-transition states whilst analogous reactions of the syn-dipole involve endotransition states.