Chiral Amino Group Research Articles

19F NMR enantiodiscrimination and diastereomeric purity determination of amino acids, dipeptides, and amines.

Chiral amino-group compounds are of significance for human health, such as biogenic amino acids (AAs), dipeptides, and even various drugs. Enantiospecific discrimination of these chiral compounds is vital in diagnosing diseases, identifying pathological biomarkers and enhancing pharmaceutical chemistry research. Here, we report a simple and rapid 19F NMR-based strategy to differentiate chiral AAs, dipeptides, and amines, that were derivatized with (R)-2-(2-fluorophenyl)-2-hydroxyacetic acid ((R)-2FHA). As a result, 19 proteinogenic AAs (37 isomers) as well as Gly could be concurrently resolved. Moreover, various mirror-image dipeptides, such as Ser-His, Leu-Leu, and Ala-Ala, were commendably recognized. Intriguingly, we found that the absolute configuration of AAs in the N-terminus of dipeptides decided the relative 19F chemical shifts between two enantiomers. Besides, the ability of this method for enantiodiscrimination was further demonstrated by non-AA amines, including aromatic and aliphatic amines, and even amines having chiral centers several carbons away from the amino-group. The structurally similar antibiotics, amoxicillin and ampicillin, were well discriminated. Furthermore, this method accurately determines the de or dr values of non-racemic mixtures. Therefore, our strategy provides an effective approach for 19F NMR-based enantiodiscrimination and diastereomeric purity determination of amino-group compounds.

Synthesis of chiral pyrazolo[4,3-e][1,2,4]triazine sulfonamides with tyrosinase and urease inhibitory activity

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC50 0.037, 0.044 and 0.042 μM, respectively, while IC50 of thiourea is 20.9 μM.

Recent Developments in the Reduction of Aromatic and Aliphatic Nitro Compounds to Amines

The reduction of the nitro group represents a powerful and widely used transformation that allows to introducing an amino group in the molecule. New synthetic strategies for complex functionalized molecular architectures are deeply needed, including highly efficient and selective nitro reduction methods, tolerant of a diverse array of functional moieties and protecting groups. Since chiral amino groups are ubiquitous in a variety of bioactive molecules such as alkaloids, natural products, drugs, and medical agents, the development of reliable catalytic methodologies for the nitro group reduction is attracting an increasing interest also in the preparation of enantiomerically pure amines. In this context, the modern reduction methods should be chemoselective and respectful of the stereochemical integrity of the stereogenic elements of the molecule. The review will offer an overview of the different possible methodologies available for this fundamental transformation, with special attention on the most rece...

Relaxant effects of selected sildenafil analogues in the rat aorta

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their relaxant effects in the rat aorta. Evaluation of prepared derivatives demonstrated that compound (8a) is probably a non-selective phosphodiesterase (PDE) inhibitor, as it induced aortic relaxation through endothelium-independent mechanism.

Total synthesis of pachastrissamine together with its 4-epi-congener via [3,3]-sigmatropic rearrangements and antiproliferative/cytotoxic evaluation

Synthesis of the HCl salts of two anhydrophytosphingosines, jaspine B (1) and its 4-epi-congener 5 from easily available dimethyl l-tartrate and/or l-arabinose, is described. The key transformations are the efficient incorporation of a chiral amino group via [3,3]-sigmatropic rearrangements, a Wittig olefination for the instalment of the carbon backbone and the acid-promoted building-up of a tetrahydrofuran framework. Evaluation for in vitro antiproliferative/cytotoxic activity with a panel of human tumour cell lines using a MTT assay revealed for some compounds of our strategy noteworthy activity. Compound 1·HCl (IC50: 0. 41–2.35μM), its antipode ent-1·HCl (IC50: 4.07–5.69μM) and also stereoisomer 4·HCl (IC50: 4.28–6.10μM) exhibited significant potency compared with clinically available anticancer drugs such as cisplatin (IC50: 11.4–14.7μM) and etoposide (IC50: 1.2–21.2μM) on MDA-MB-231, MCF-7 and Jurkat cells.

Total synthesis of (−)-jaspine B and its 4-epi-analogue from d-xylose

The total synthesis of the HCl salts of (−)-jaspine B ent-1 and its 4-epi-congener ent-4 was accomplished starting from the common template 13 derived from d-xylose. The cornerstone of our synthesis was [3,3]-heterosigmatropic rearrangements, which effectively provided scaffolds with a chiral amino group. A subsequent Wittig olefination installed a C14 alkyl side chain and acid-mediated ring-closing reaction established the tetrahydrofuran core.

ChemInform Abstract: Trichlorosilane‐Mediated Stereoselective Reduction of C=N Bonds

AbstractReview: 52 refs.

Synthesis of P,N-2,2′-biphenyl derivatives with central chirality

Enantiopure 2-(dicyclohexylphosphino)-1,1′-biphenyl derivatives substituted in the 2′-position by a chiral amino group were prepared. For the compound bearing an acyclic chiral chain, the key step was a Suzuki coupling between bromobenzeneboronic acid and N-Boc-iodoaniline whereas an aromatic nucleophilic substitution allowed the introduction of a chiral pyrrolidine in the 2′-position of the biphenyl backbone. The efficiency of the P,N-biphenyl pyrrolidine derivatives as ligands in Pd-catalyzed arylaminations compares well with that of DavePhos ligand.

Trichlorosilane‐Mediated Stereoselective Reduction of C=N Bonds

AbstractThe reduction of C=N bonds represents a powerful and widely used transformation allowing new nitrogen‐containing stereocenters to be generated. Chiral amino groups are ubiquitous in a variety of bioactive molecules such as alkaloids, natural products, drugs, and medical agents, so the development of a catalytic stereoselective process for the preparation of enantiomerically enriched amines through ketoimine reduction is attracting increasing interest, especially in view of future industrial applications. Great efforts to develop efficient organocatalytic methods to perform enantioselective imine reductions and reductive amination processes have recently been made. In the last few years, trichlorosilane‐mediated reductions have received constantly increasing attention because the potential to generate chiral catalysts for imine reduction simply by coordination of HSiCl3 with a chiral Lewis base has allowed the development of several efficient organocatalytic systems. Here we offer a complete overview of different chiral promoters of stereoselective reductions with trichlorosilane, classified as N‐formyl derivatives, which may be considered historically the first class of compounds developed as chiral activators of trichlorosilane, picolinamide derivatives, and miscellaneous compounds presented in that order.

Dendrimers in solution can have their remote catalytic groups folded back into the core: Enantioselective transaminations by dendritic enzyme mimics-II

PAMAM dendrimers with double thioether arms have been synthesized with a pyridoxamine core and terminal chiral amino groups. Transamination to afford natural isomers of phenylalanine and alanine induced enantioselectivity by the peripheral chiral caps, supporting a computer model that indicates folding of dendrimer chains back into the core.

The synthesis of tetrahydropyridopyrimidones as a new scaffold for HIV-1 integrase inhibitors

An efficient synthesis of methyl 9-amino-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4 H-pyrido[1,2- a]pyrimidine-2-carboxylate as a late stage intermediate for a new class of HIV-1 integrase inhibitors is described. After construction of the bicyclic core scaffold, a stereoselective introduction of the chiral amino group in the 9-position is achieved.

Synthesis of an Optically Active Al(salalen) Complex and Its Application to Catalytic Hydrophosphonylation of Aldehydes and Aldimines

Optically active aluminum(salalen) complex 2 was newly synthesized in a modular synthetic manner, and it was found to serve as an efficient catalyst for hydrophosphonylation of aldehydes and aldimines, giving the corresponding alpha-hydroxy and alpha-amino phosphonates with high enantioselectivity, respectively. The scope of the hydrophosphonylation was wide, and both aliphatic and aromatic aldehydes and aldimines were successfully used as substrates for the reaction. The potent catalysis of the complex is attributed to its unique structure: it adopts a distorted trigonal bipyramidal configuration which allows the salalen ligand to take a cis-beta-like structure wherein the chiral amino group is located close to the metal center.

Synthesis of Alkylated Aminofluorenes by Palladium‐Catalyzed Substitution at Halofluorenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

From α,β‐Unsaturated Fischer Carbene Complexes to Highly Substituted 3‐Ethoxycyclopentadienes, Masked Cyclopentenones

AbstractThe β‐amino‐substituted α,β‐unsaturated Fischer carbene complexes 3 are readily available by a four step one‐pot procedure from terminal alkynes, chromium hexacarbonyl and secondary amines (24 examples with yields of 68−99% and 7 examples with yields of 26−63%). The formal [3+2] cycloadditions of complexes 3 with different alkynes including diynes and enynes performed in donor solvents such as pyridine or acetonitrile afforded highly substituted 5‐(dialkylamino)‐3‐ethoxycyclopentadienes 7, generally in medium to excellent yields (25 examples with yields of 60−95% and 7 examples with yields of 18−53%). The steric and electronic effects of the substituents on the carbene complexes and the incorporated alkynes on the regio‐ and stereoselectivity of the ring‐forming reaction have been elaborated. An interesting 1,5‐ or, more likely, 1,2‐migration of the dimethylamino group was observed for 5‐(dimethylamino)‐3‐ethoxycyclopentadienes with trimethylsilyl and iPr substituents at C‐5. Attempted asymmetric syntheses of cyclopentadienes 7 from complexes 3 with chiral amino groups or substituents were only moderately successful. At a center of chirality in the secondary amino group, complexes of type 3 gave compounds 7 with diastereomeric excesses of, at best, 59% in yields of 54%, and with a stereogenic center in the substituent R1 attached to the vinyl group of 3, diastereomeric excesses as high as 94% could be achieved, but with poor chemical yields (21%). In general, cyclopentenones 21 could be easily obtained from the cyclopentadienes 7 under acidic conditions in very good yields (4 examples with yields of 81−98%, 1 example with an overall yield of 50% from complex 3). Intramolecular aldol reactions of dicarbonyl compounds generated by hydrolysis of cyclopentadienes 7 with acetal‐protected aldehyde or ketone carbonyl groups in either the 5‐substituent R1 or the N‐substituent R2 led to the bicyclic compounds 22 and 23. The dimethylamino group in cyclopentenones 21 could be either eliminated or transformed into other functional groups via the quaternary ammonium salts 24. The elimination product, cyclopentadienone 27 can undergo dimerization either by a formal [4+2] or [2+2] cycloaddition. Cyclopentenone 21naaa with a bromovinyl‐terminated side chain undergoes an intramolecular Heck reaction to form 5‐methyl‐4,6‐dimethylenebicyclo[3.3.0]oct‐1‐en‐3‐one (32) (37% yield). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Synthesis of alkylated aminofluorenes by palladium-catalyzed substitution at halofluorenes.

New N-substituted 2-amino-9,9-dialkylfluorenes optionally bearing electron-withdrawing substituents such as nitro or cyano in position 7 can be synthesized starting from 2-halo-9,9-dialkylfluorenes by Pd-catalyzed substitution with amines. Chiral amino groups can be introduced by this method too. 2-N,N-Dimethylamino-7-nitro-9H-fluorene was obtained in a convenient way by reductive amination. The N-substituted 2-amino-7-nitro-9H-fluorenes are promising candidates for fluorescence probes for femtosecond solvation dynamics.

New Optically Active 2H-Azirin-3-amines as Synthons for Enantiomerically Pure 2,2-Disubstituted Glycines

The synthesis of novel 2,2-disubstituted 2H-azirin-3-amines with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers (1′R,2R)-4a – e and (1′R,2S)-4a – e (Scheme 1, Table 1), which are synthons for the (R)- and (S)-isomers of isovaline, 2-methylvaline, 2-cyclopentylalanine, 2-methylleucine, and 2-(methyl)phenylalanine, respectively. The configuration at C(2) of the synthons was determined by X-ray crystallography relative to the known configuration of the chiral auxiliary group. The reaction of 4 with thiobenzoic acid, benzoic acid, and the dipeptide Z-Leu-Aib-OH (12) yielded the monothiodiamides 10, the diamides 11 (Scheme 2, Table 3), and the tripeptides 13 (Scheme 3, Table 4), respectively.

Optisch aktive 3‐Amino‐2H‐azirine als Bausteine für enantiomerenreine α,α‐disubstituierte α‐Aminosäuren: Synthese des α‐Methylphenylalanin‐Synthons and Einbau in Modell‐Peptide

Optically Active 3‐Amino‐2H‐azirines as Synthons for Enantiomerically Pure αα‐Disubstituted α‐Amino Acids: Synthesis of the α‐Methylphenylalanine Synthons and Some Model PeptidesThe synthesis of a novel 2‐benzyl‐2‐methyl‐3‐amino‐2H‐azirine derivative with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers 9a and 9b (Scheme 4) which are the D‐ and L‐2‐methylphenylalanine ((α‐Me)Phe) synthons, respectively. The reaction of 9a and 9b with thiobenzoic acid and with Z‐leucine yielded the monothiodiamides 10a and 10b (Scheme 5) and the dipeptide derivatives 11a and 11b (Scheme 6), respectively. Methanolysis of 11b yielded 12b. The absolute configuration of 10a was established by X‐ray crystallography. The absolute configuration of (α‐Me)Phe in 12b has been deduced from the known configuration of L‐leucine.

Optisch aktive 3-Amino-2H-azirine als Bausteine für enantiomerenreine alpha,alpha-disubstituierte alpha-Aminosäuren: Synthese des alpha-Methylphenylalanin-Synthons and Einbau in Modell-Peptide

Optically Active 3-Amino-2H-azirines as Synthons for Enantiomerically Pure alpha,alpha-Disubstituted alpha-Amino Acids: Synthesis of the alpha-Methylphenylalanine Synthons and Some Model Peptides The synthesis of a novel 2-benzyl-2-methyl-3-amino-2H-azirine derivative with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers 9a and 9b (Scheme 4 ) which are the D- and L-2-methylphenylalanine ((alpha-Me)Phe) synthons, respectively. The reaction of 9a and 9b with thiobenzoic acid and with Z-leucine yielded the monothiodiamides 10a and 10b (Scheme 5 ) and the dipeptide derivatives 11a and 11b (Scheme 6), respectively. Methanolysis of 11b yielded 12b. The absolute configuration of 10a was established by X-ray crystallography. The absolute configuration of (alpha-Me)Phe in 12b has been deduced from the known configuration of L-leucine.

Aminophosphine—rhodium complexes as catalysts in asymmetric hydrogenation. The influence of the chiral amino groups on the catalyst enantioselectivity.

Aminophosphine—rhodium complexes as catalysts in asymmetric hydrogenation. The influence of the chiral amino groups on the catalyst enantioselectivity.