Synthesis Of Amides Research Articles

Adapting an acyl CoA ligase from Metallosphaera sedula for lactam formation by structure-guided protein engineering

The CoA ligase from Metallosphaera sedula (MsACL) can be used for the chemoenzymatic synthesis of amides from carboxylic acids. In this CoA-independent conversion, the enzyme catalyzes the adenylation of a carboxylic acid with the help of ATP, followed by the uncatalyzed cleavage of acyl-AMP by a nucleophilic amine to yield an amide. With ω-amino acids as substrates this reaction may result in formation of lactams, but unfortunately the substrate preference of the wild-type enzyme is rather limited. To allow structure-based protein engineering and expand the substrate scope of the enzyme, crystal structures of MsACL were solved in the thioesterification conformational state with AMP, CoA and with the reaction intermediate acetyl-AMP bound in the active site. Using substrate docking and by comparing the crystals structures and sequence of MsACL to those of related CoA ligases, mutations were predicted which increase the affinity in the carboxylic acid binding pocket for ω-amino acids. The resulting mutations transformed a non-active enzyme into an active enzyme for ε-caprolactam synthesis, highlighting the potential of the thermophilic CoA ligase for this synthetic and biotechnologically relevant reaction.

Enzymatic Synthesis of Hydroxycinnamic Acid Amides in Water Using the Promiscuous Hydrolase/Acyltransferase PestE from Pyrobaculum calidifontis VA1

AbstractHydroxycinnamic acid amides are believed to have antioxidant, antidiabetic, cytotoxic, anticancer, neuroprotective, and antiinflammatory properties, making them interesting target molecules for potential applications in the food, cosmetics, and pharmaceutical industries. Here, we describe the synthesis of hydroxycinnamic acid amides starting from hydroxycinnamic acid esters and the corresponding amines by using variants of the promiscuous hydrolase/acyltransferase from Pyrobaculum calidifontis VA1 (PestE) in water as a solvent. Up to 97% conversion within two hours at 60 °C was achieved with methyl ferulate and tyramine as substrates. This is a promising, environmentally friendly alternative strategy to established chemical synthesis routes or enzymatic methods using lipases in nonaqueous organic solvents.

Lanthanide Amide Complexes Supported by the Bis‐tris(pyrazolyl)borate Ligand Environment

AbstractSynthesis of primary lanthanide amides in the bis‐hydrotris(1‐pyrazolyl)borate ligand environment has been achieved. Salt metathesis of [Dy(Tp)2(OTf)] 1‐Dy (OTf=CF3SO3) with K(N′′) (N′′=N(SiMe3)2) in toluene yielded the [bis(silyl)]amide [Dy(Tp)2(N′′)] 2‐Dy. Complexes 1‐Ln and 2‐Ln were both used to access primary lanthanide amides, where either metathesis of 1‐Ln with K(NHArCF3) (ArCF3=C6H3(CF3)2‐3,5) or protonolysis of 2‐Ln with H2NArCF3 in toluene yielded [Ln(Tp)2(NHArCF3)] 3‐Ln (Ln=Y, Dy). The synthesis of parent amides was also attempted, but the metathesis of 1‐Y with NaNH2 yielded complicated reaction mixtures, but from which the dimeric parent amide [{Y(Tp)2(μ‐NH2)}2] 4‐Y and an ‘ate’‐salt [{Y(Tp)2(μ2‐OTf)(μ3‐OTf)Na(THF)2}2] 5‐Y were isolated. Full characterisation data are presented for all complexes, including the structure determination.

Efficient production of copolymerized PA6-based polymer fibers: Oligomer control and direct melt spinning

Synthesis of PA6-based polyester amides (PEAs) is the one of main way to expand the application of PA6. Due to the residual oligomers in the polymer matrix, PEAs are also difficult to achieve directly melt spinning similar to PA6. In this work, the molecular structure designable PEA synthesis method proposed in our previous work was further investigated to control the oligomer content control by end-amino shielding at open-loop stages and efficient de-volatilization at polycondensation stages. The effect of the molecular weight of PA6 segments on oligomer formation was also investigated. The results show that the oligomers, caprolactam, and cyclic dimer contents of PEAs are reduced to 2 wt%, 0.38–0.76 wt%, and 0.2–0.3 wt%, which is lower 75%, 85%, and 50% compared to industrially produced PA6, respectively. It indicates that the molecular weight of PA6 segments, in addition to affecting the physicochemical properties, can also thermodynamically enable regulation of the type of oligomer generated. By adjusting the chain segment structure and controlling the reaction conditions, all PEAs can be directly melting spinning (1200 m/min) and maintains good physical and chemical properties. At the same time, the substantial reduction in oligomers means that PEAs can completely eliminate post-processing such as hydrothermal extraction, fiber production time is shortened from more than 40 h (PA6) to less than 15 h and resource consumption is reduced by more than 30%. This oligomer control method is also applicable to functional PA6, which lays the foundation for efficient and sustainable industrial production of copolymerized PA6 functional fibers on a large scale.

Dehydrative Condensation of Carboxylic Acids with Amines Promoted by HBF4/MS 5A

AbstractThe direct dehydrative condensation of carboxylic acids with amines is one of the most straightforward methods for the synthesis of amides. We discovered that HBF4 effectively promotes the coupling of several N‐protected amino acids in the presence of molecular sieves (MS) 5A to afford the corresponding peptides in good to high yield. Interestingly, the recovered MS 5A could be reused as a catalyst even in the absence of additional HBF4 for the dehydrative condensation. This protocol is not limited to the synthesis of peptides, but generally works for the synthesis of amides from a variety of carboxylic acids and amines.

Nitriles and Amides Synthesis from 1,2-Diols by N-Doped Porous Carbons

Nitriles and Amides Synthesis from 1,2-Diols by N-Doped Porous Carbons

Dual Nickel/Photoredox-Catalyzed Asymmetric Carbamoylation of Benzylic C(sp3 )-H Bonds.

Radical-mediated Hydrogen Atom Abstraction of Csp3 -H bonds has become a powerful tool for the asymmetric functionalization of organic feedstocks. Here, we present an asymmetric synthesis of α-aryl amides via carbamoylation of alkylarenes with isocyanates as electrophiles. The synergistic combination of a photoredox and a chiral nickel-catalyst, enables the use of readily available and neutral reagents under mild reaction conditions and provides straightforward access to pharmacologically relevant motifs in enantiomerically pure form.

Synthesis of Linear Aliphatic Amides via Rh-Catalyzed Hydroamidation of Internal Olefins

Synthesis of Linear Aliphatic Amides via Rh-Catalyzed Hydroamidation of Internal Olefins

Acid-Catalyzed Nitromethane Activation for the Synthesis of Amides and Nitriles

Acid-Catalyzed Nitromethane Activation for the Synthesis of Amides and Nitriles

Synthesis of Amides and Peptides by Employing [4-(Acetylamino) phenyl]imidodisulfuryl Difluoride (AISF) as a Coupling Reagent

AbstractA new synthetic approach for the preparation of amides and peptides containing amino acids as well as aryl acids and amines by employing [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF) as a carboxylic acid activator under mild conditions is delineated. The use of AISF as an acid activator allows the reaction to be performed efficiently. This operationally simple amidation is amenable to a wide variety of carboxylic acids and Nα-protected amino acids. Further, racemization did not occur during the coupling. In addition, a gram-scale reaction is demonstrated.

Identification of novel human CC chemokine receptor 8 (CCR8) antagonists via the synthesis of naphthalene amide and sulfonamide isosteres

The human CC chemokine receptor 8 (CCR8) has been extensively pursued as target for the treatment of various inflammatory disorders. More recently, the importance of CCR8 in the tumor microenvironment has been demonstrated, spurring the interest in CCR8 antagonism as therapeutic strategy in immuno-oncology. On a previously described naphthalene sulfonamide with CCR8 antagonistic properties, the concept of isosterism was applied, leading to the discovery of novel CCR8 antagonists with IC50 values in the nM range in both the CCL1 competition binding and CCR8 calcium mobilization assay. The excellent CCR8 antagonistic activity of the most potent congeners was rationalized by homology molecular modeling.

Synthesis and Antiulcer Activity of Aromatic and Heterocyclic Amides of 3-O-Acetylglycyrrhetic Acid

Synthesis and Antiulcer Activity of Aromatic and Heterocyclic Amides of 3-O-Acetylglycyrrhetic Acid

Discovery and Mechanistic Understanding of a Lipase from Rhizorhabdus dicambivorans for Efficient Ester Aminolysis in Aromatic Amines.

The formation of amide bonds via aminolysis of esters by lipases generates a diverse range of amide frameworks in biosynthetic chemistry. Few lipases have satisfactory activity towards bulky aromatic amines despite numerous attempts to improve the efficiency of this transformation. Here, we report the discovery of a new intracellular lipase (Ndbn) with a broad substrate scope. Ndbn turns over a range of esters and aromatic amines in the presence of water (2 %; v/v), producing a high yield of multiple valuable amides. Remarkably, a higher conversion rate was observed for the synthesis of amides from substrates with aromatic amine rather than aliphatic amines. Molecular dynamics (MD) and quantum mechanical/molecular mechanical (QM/MM) studies showcase the mechanism for the preference for aromatic amines, including a more suitable orientation, shorter catalytic distances in the active site pocket and a lower reaction barrier for aromatic than for aliphatic amines. This unique lipase is thus a promising biocatalyst for the efficient synthesis of aromatic amides.

Divergent Synthesis of Primary Amides via Modular Dearomative Carbamoylations of Arene π-Systems

Divergent Synthesis of Primary Amides via Modular Dearomative Carbamoylations of Arene π-Systems

One pot synthesis of carboxylic acid, ester, and amide derivatives from iodoarenes in aqueous solubilized systems using sodium oleate as surfactant at room temperature

Palladium acetate [Pd(OAc)2] catalyzed reaction of aryl iodide utilizing sodium oleate as surfactant was demonstrated in water under ambient temperature and carbon monoxide pressure. Aryl carboxylic acid with different electron withdrawing and donating substituents, and multi-substituted acid derivatives were synthesized in good to excellent isolated yields. Notably, this protocol was also applicable for one pot synthesis of various amide and ester derivatives. Several drug molecules such as niacin, and mefenamic acid alike compound were also obtained in good, isolated yields.

N‐Carboxyanhydrides (NCAs): Unorthodox and Useful Reagents for Amide Synthesis

AbstractN‐Carboxyanhydrides (NCAs) are compounds derived from the addition of a carboxylic acid to an isocyanate, and are known to form amides readily with the release of CO2 as a by‐product. NCAs have been known for over 120 years, but despite their lengthy history, have remained so far overshadowed by more traditional approaches to amide bond formation. In this review, the potential utility of NCAs in the context of amide bond formation is reviewed and their preparation, reactivity and practical application are also discussed.

A Metal‐Free System for Conversion of Alcohols to Amides Using tert‐Butyl Nitrite

AbstractA transition metal‐free cascade synthesis of amides from alcohols was developed. Various alcohols reacted with N‐hydroxyimides by tert‐butyl nitrite to generate N‐hydroxyimide esters. The resulting active esters were subsequently reacted with amines to generate amides in one pot. Further, we have illustrated the application of the developed protocol in synthesizing anti‐Alzheimer compounds. A detailed mechanistic exploration was also carried out.

Electrochemical Benzylic C(sp3)-H Direct Amidation.

Amide bonds are ubiquitous and found in a myriad of functional molecules. Although formed in a reliable and robust fashion, alternative amide bond disconnections provide flexibility and synthetic control. Herein we describe an electrochemical method to form the non-amide C-N bond from direct benzylic C(sp3)-H amidation. Our approach is applied toward the synthesis of secondary amides by coupling secondary benzylic substrates with substituted primary benzamides. The reaction has been scaled up to a multigram scale in flow.

Design, synthesis, and pharmacological evaluation of indole-piperidine amides as Blood−brain barrier permeable dual cholinesterase and β-secretase inhibitors

Heterocyclic compounds play a crucial role in the discovery of therapeutics. Alzheimer's disease (AD) is an unfathomable sporadic neurodegenerative disorder that involves multiple pathological pathways. The failure of current single-target small molecules to address AD's underlying causes has prompted interest in discovering multi-target directed ligands (MTDLs) to slow down the disease's progression. Herein we report the synthesis and biological evaluation of indole-piperidine amides as MTDLs for AD. The 5,6-dimethoxy-indole N-(2-(1-benzylpiperidine) carboxamide (23a) inhibits hAChE and hBACE-1 with IC50 values of 0.32 and 0.39 μM, respectively. The MTDL 23a is a mixed-type inhibitor of both hAChE and hBACE-1 with Ki values of 0.26 μM and 0.46 μM, respectively. The MD simulation studies revealed that both AChE and BACE-1 experience minor conformational changes on binding with 23a. In the PAMPA-BBB assay, analog 23a demonstrated CNS permeability, indicating the possibility for future investigation in preclinical models of AD.

Broad Spectrum Enantioselective Amide Bond Synthetase from Streptoalloteichus hindustanus.

The synthesis of amide bonds is one of the most frequently performed reactions in pharmaceutical synthesis, but the requirement for stoichiometric quantities of coupling agents and activated substrates in established methods has prompted interest in biocatalytic alternatives. Amide Bond Synthetases (ABSs) actively catalyze both the ATP-dependent adenylation of carboxylic acid substrates and their subsequent amidation using an amine nucleophile, both within the active site of the enzyme, enabling the use of only a small excess of the amine partner. We have assessed the ability of an ABS from Streptoalloteichus hindustanus (ShABS) to couple a range of carboxylic acid substrates and amines to form amine products. ShABS displayed superior activity to a previously studied ABS, McbA, and a remarkable complementary substrate specificity that included the enantioselective formation of a library of amides from racemic acid and amine coupling partners. The X-ray crystallographic structure of ShABS has permitted mutational mapping of the carboxylic acid and amine binding sites, revealing key roles for L207 and F246 in determining the enantioselectivity of the enzyme with respect to chiral acid and amine substrates. ShABS was applied to the synthesis of pharmaceutical amides, including ilepcimide, lazabemide, trimethobenzamide, and cinepazide, the last with 99% conversion and 95% isolated yield. These findings provide a blueprint for enabling a contemporary pharmaceutical synthesis of one of the most significant classes of small molecule drugs using biocatalysis.