Synthesis Of β-Amino Acids Research Articles

Visible-Light-Mediated β-Amino Acid Synthesis from α-Amino Acids

Visible-Light-Mediated β-Amino Acid Synthesis from α-Amino Acids

Straightforward Access to Free β2,3,3-Amino Acids through One Pot C-H Activation/C-C Cleavage.

The first synthesis of unnatural β2,3,3-amino acids with a spirocyclic backbone by one-pot protocol has been presented. This reaction features wide functional group tolerance and feasibility of post-functionalization of natural products and biologically important molecules. Novel dipeptide and tripeptide structures were assembled using this newly developed β2,3,3-amino acid in high efficiency. The combination of C-H activation and C-C cleavage for the synthesis of β-amino acids would trigger more promising synthetic routes for this compound.

Arndt–Eistert Reaction for the Synthesis of β-Amino Acids

Arndt–Eistert Reaction for the Synthesis of β-Amino Acids

Modular synthesis of β-amino acids from alkenes, amines, and CO2 via photoredox/copper dual catalysis

Modular synthesis of β-amino acids from alkenes, amines, and CO2 via photoredox/copper dual catalysis

Microwave Assisted Aza-michael Additions Towards β-amino Acids

Background: β-amino acids are non-natural amino acids, where the amino group is attached to the β-carbon instead of the α-carbon. Peptides containing β-amino acids present with particular secondary structures and remarkable chemical and biological properties. β-peptides are used as peptidomimetics, based on the resistance to hydrolysis in vivo, with various important applications in the field of Medicine. Methods: Several synthetic methods have appeared in recent years, with the Aza- Michael conjugate addition reactions, being a very effective approach towards β-amino acids. Microwave irradiation mediated reactions have also attracted much interest since they significantly improve the reaction yields while reducing the reaction time and avoiding by-products formation. The aim of this project has been the development of a reliable and general synthetic methodology towards β2 and β3 amino acids with the use of conjugate additions of N-nucleophiles to substituted acrylate derivatives. The application of effective catalysts has been also examined here. Results: The results show that the acrylate precursors of β2 and β3 amino acids with side chains corresponding to Phe, Asp, Ile, Leu, Val, and Tyr have been synthesized successfully by using a one-pot Horner-Wadsworth-Emmons reaction, and they have been used for the addition of Nnucleophiles, with a study on conditions and yields optimization. Conclusion: With the main challenge for β-amino acid synthesis being that there is still no general method to synthesize different types of β-amino acids corresponding to all-natural α-amino acids, the proposed synthetic methodology may offer this possibility.

Azumamides A-E: Isolation, Synthesis, Biological Activity, and Structure–Activity Relationship

Cyclic peptides are one of the important chemical groups in the HDAC inhibitor family. Following the success of romidepsin in the clinic, naturally occurring cyclic peptides with a hydrophilic moiety have been intensively studied to test their function as HDAC inhibitors. Azumamides A-E, isolated from Mycale izuensis, are one of the powerful HDAC inhibitor classes. Structurally, azumamides A-E consist of three D-α-amino acids and unnatural β-amino acids such as 3-amino-2-methyl-5-nonenedioic acid-9-amide (Amnna) and 3-amino-2-methyl-5-nonenoic-1,9-diacid (Amnda). Moreover, azumamides have a retro-arrangement peptide backbone, unlike other naturally occurring cyclopeptide HDAC inhibitors, owing to the D-configuration of all residues. This review summarizes the currently available synthetic methods of azumamides A-E focusing on the synthesis of β-amino acids and macrocyclization. In addition, we overview the structure-activity relationship of azumamides A-E based on reported analogs. Collectively, this review highlights the potentiality of azumamides A-E as an HDAC inhibitor and provides further developmental insight into naturally occurring cyclic peptides in HDAC inhibition.

Ammonium Chloride Promoted One-Pot, Three-Component Mannich Reaction: An Efficient Synthesis of β-Amino Ketones and β-Amino Esters

Ammonium chloride was found to efficiently reagent for the one pot-three component Mannich reaction between aromatic aldehyde, ketone and amine in ethanol at room temperature to furnish β-amino ketones in good to excellent yields. The said protocol was further applied for the direct synthesis of β-amino esters, which are important precursors for the synthesis of β-amino acids. This protocol is potentially applicable for the development of a clean and environment-friendly strategy for the synthesis of β-amino ketones and found applications in the synthesis of potent biologically active molecules due to its simple experimental conditions, inexpensive reagents and straight forward product isolation procedure.

Rapid access to β-amino aldehydes by a Ni/Ir dual-catalyzed homologation reaction

In this issue of Chem Catalysis , Glorius and co-workers harness the power of metallaphotoredox catalysis to synthesize valuable β-amino aldehydes from α-amino acids and vinylene carbonate. This one-step protocol provides an attractive alternative to more traditional multistep homologation protocols and will streamline the synthesis of β-amino acids and medicinally relevant scaffolds. In this issue of Chem Catalysis , Glorius and co-workers harness the power of metallaphotoredox catalysis to synthesize valuable β-amino aldehydes from α-amino acids and vinylene carbonate. This one-step protocol provides an attractive alternative to more traditional multistep homologation protocols and will streamline the synthesis of β-amino acids and medicinally relevant scaffolds.

Ligand-Enabled, Copper-Catalyzed Electrophilic Amination for the Asymmetric Synthesis of β-Amino Acids.

Catalytic asymmetric nitrene transfer has emerged as a reliable method for the synthesis of nitrogen-containing chiral compounds. Herein, we report the copper-catalyzed intramolecular asymmetric electrophilic amination of aromatic rings. The reactive intermediate is a copper-alkyl nitrene generated from isoxazolidin-5-ones. Copper catalysis promotes three classes of asymmetric transformations, namely, asymmetric desymmetrization, parallel kinetic resolution, and kinetic resolution, expanding the repertoire of alkyl nitrene transfer and providing various cyclic and linear β-amino acids in their enantioenriched forms.

Critical role of Bronsted acid in Lewis-acid-catalyzed synthesis of Amadori and Heyns compounds of β-amino acids

Amadori and Heyns rearrangement reactions are a century old reactions of the carbohydrates. The great body of literature on these reactions are concentrated on ɑ-amino acids. Reports on the synthesis and chemistry of Amadori and Heyns compounds derived from β-amino acids are scarce. We demonstrate herein, via Lewis-acid catalysis, synthesis of Amadori and Heyns compounds derived from β-amino acids consisting of β-alanine and β-phenylalanine with, D-xylose, D-galactose, D-fructose, D-mannose, D-maltose, D-lactose. The accomplished Lewis-acid catalyzed method is practical and devoid of separation techniques for achieving purity. We also report insight on the mechanism of Lewis-acid catalyzed Amadori and Heyns rearrangement reactions, and reveal the key role of Bronsted acid in Lewis-acid catalyzed Amadori and Heyns synthesis of β-amino acids.

One-Pot Construction of Diverse β-Lactam Scaffolds via the Green Oxidation of Amines and Its Application to the Diastereoselective Synthesis of β-Amino Acids

In this study, a simple one-pot construction of β-lactam scaffolds was successfully achieved via 4,6-dihydroxysalicylic acid-catalyzed organocatalytic oxidation of amines to imines using molecular oxygen. Although some imines are highly unstable and difficult to isolate by conventional methods, the organocatalytic oxidation of amines described herein, followed by their direct reaction with acyl chlorides in the presence of a base, afforded a series of new β-lactam derivatives with excellent cis selectivity, which could not be synthesized and isolated by previously reported methods. Thus, this one-pot protocol will be one of the powerful methods applicable to the synthesis of various potential drug candidates and functional molecules. Furthermore, the subsequent hydrolysis of these β-lactams successfully afforded the corresponding β-amino acids as almost single diastereomers in up to 99% yields.

Crystal Structures and Catalytic Mechanism of l-erythro-3,5-Diaminohexanoate Dehydrogenase and Rational Engineering for Asymmetric Synthesis of β-Amino Acids.

Amino acid dehydrogenases (AADHs) have shown considerable potential as biocatalysts in the asymmetric synthesis of chiral amino acids. However, compared to the widely studied α-AADHs, limited knowledge is available about β-AADHs that enable the synthesis of β-amino acids. Herein, we report the crystal structures of a l-erythro-3,5-diaminohexanoate dehydrogenase and its variants, the only known member of β-AADH family. Crystal structure analysis, site-directed mutagenesis studies and quantum chemical calculations revealed the differences in the substrate binding and catalytic mechanism from α-AADHs. A number of rationally engineered variants were then obtained with improved activity (by 110-800 times) toward various aliphatic β-amino acids without an enantioselectivity trade-off. Two β-amino acids were prepared by using the outstanding variants with excellent enantioselectivity (>99 % ee) and high isolated yields (86-87 %). These results provide important insights into the molecular mechanism of 3,5-DAHDH, and establish a solid foundation for further design of β-AADHs for the asymmetric synthesis of β-amino acids.

Synthesis of β2-Amino Acids from β-Phthalimido-α-xanthylpropionic Acids by Radical Addition

Key words amino acids - phthalimidoxanthylpropionic acid - radical addition - vinylation

Progress in recent development of stereoselective synthesis of β2-amino acid derivatives from β-nitroacrylate derivatives.

The synthesis and properties of β-amino acids have drawn considerable attention owing to their ubiquitous presence in naturally occurring products of biological importance. While β3-amino acids can be readily prepared from α-amino acids via one-carbon homologation, the synthesis of β2-amino acids generally requires multistep efforts. This review focuses on the recent advances in the synthesis of β2-amino acids and their derivatives from substituted β-nitropropionate analogues obtained from the stereoselective transformation of β-nitroacrylates.

Stereoselective Synthesis of β-Amino Acids by Aldol-Type Addition

Stereoselective Synthesis of β-Amino Acids by Aldol-Type Addition

Organocatalytic Enantioselective Mukaiyama–Mannich Reaction of Isatin‐Derived Ketimines for the Synthesis of Oxindolyl‐β3, 3‐Amino Acid Esters

Mukaiyama-Mannich reactions of ester enolate equivalents with aldimines have been elegantly used for the asymmetric synthesis of β-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are unexplored. Herein, the first organocatalytic enantioselective Mukaiyama-Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals is disclosed towards the scalable synthesis of 2-oxoindolinyl-β3, 3 -amino acid esters at room temperature with excellent enantioselectivities (ee >99.5 %). Ultra-low catalyst loadings (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short formal synthesis of pharmaceutically demanded (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.

Cyclic β-Amino Acid Synthesis by Rhodium Catalysis

Cyclic β-Amino Acid Synthesis by Rhodium Catalysis

Structural Analysis of the Glycine Oxidase Homologue CmiS2 Reveals a Unique Substrate Recognition Mechanism for Formation of a β-Amino Acid Starter Unit in Cremimycin Biosynthesis.

The flavin adenine dinucleotide-dependent oxidase CmiS2 catalyzes the oxidation of N-carboxymethyl-3-aminononanoic acid to produce a 3-aminononanoic acid starter unit for the biosynthesis of cremimycin, a macrolactam polyketide. Although the sequence of CmiS2 is similar with that of the well-characterized glycine oxidase ThiO, the chemical structure of the substrate of CmiS2 is different from that of ThiO substrate glycine. Here, we present the biochemical and structural characterization of CmiS2. Kinetic analysis revealed that CmiS2 has a strong preference for N-carboxymethyl-3-aminononanoic acid over other substrates such as N-carboxymethyl-3-aminobutanoic acid and glycine, suggesting that CmiS2 recognizes the nonanoic acid moiety of the substrate as well as the glycine moiety. We determined the crystal structure of CmiS2 in complex with a substrate analogue, namely, S-carboxymethyl-3-thiononanoic acid, which enabled the identification of key amino acid residues involved in substrate recognition. We discovered that Asn49, Arg243, and Arg334 interact with the carboxyl group of the nonanoic acid moiety, while Pro46, Leu52, and Ile335 recognize the alkyl chain of the nonanoic acid moiety via hydrophobic interaction. These residues are highly conserved in CmiS2 homologues involved in the biosynthesis of related macrolactam polyketides but are not conserved in glycine oxidases such as ThiO. These results suggest that CmiS2-type enzymes employ a distinct mechanism of substrate recognition for the synthesis of β-amino acids.

Nickel-Catalyzed Enantioselective Synthesis of β-Amino Acids

Nickel-Catalyzed Enantioselective Synthesis of β-Amino Acids

One-Pot Lipase-Catalyzed Enantioselective Synthesis of (R)-(-)-N-Benzyl-3-(benzylamino)butanamide: The Effect of Solvent Polarity on Enantioselectivity.

The use of the solvent engineering has been applied for controlling the resolution of lipase-catalyzed synthesis of β-aminoacids via Michael addition reactions. The strategy consisted of the thermodynamic control of products at equilibrium using the lipase CalB as a catalyst. The enzymatic chemo- and enantioselective synthesis of (R)-(−)-N-benzyl-3-(benzylamino)butanamide is reported, showing the influence of the solvent on the chemoselectivity of the aza-Michael addition and the subsequent kinetic resolution of the Michael adduct; both processes are catalyzed by CalB and both are influenced by the nature of the solvent medium. This approach allowed us to propose a novel one-pot strategy for the enzymatic synthesis of enantiomerically enriched β-aminoesters and β-aminoacids.