Methods For Amide Bond Formation Research Articles

Contemporary Approaches for Amide Bond Formation

AbstractAmide bond construction has garnered significant interest in recent decades due to amides being one of the most prevalent functional groups among bioactive molecules. Out of the thirty‐seven new drugs approved by the FDA in 2022, eleven are small molecules containing at least one amide bond. Additionally, there are nineteen large molecules approved as new drugs, some of which have peptide structures, and therefore, also bear amide bonds. In recent years, multiple teams have embraced the challenge of developing more efficient methods for amide bond formation. This dedication has led to numerous publications appearing monthly in prestigious journals, showcasing significant advancements in this field. The primary goal of this review is to present the most viable strategies for constructing the amide bond. It is crucial to differentiate between amide bond formation and amide synthesis; hence, the focus is on describing specific methods for forming new C(O)−N bonds. In particular, this review concentrates on the methods developed within the last six years. There is a particular emphasis on new approaches that consider the thought process when selecting the starting materials and functional groups. This approach ensures coverage of all the most common chemical transformations that yield new amide bonds.

A Sustainable Green Enzymatic Method for Amide Bond Formation.

A sustainable enzymatic strategy for the preparation of amides by using Candida antarctica lipase B as the biocatalyst and cyclopentyl methyl ether as a green and safe solvent was devised. The method is simple and efficient and it produces amides with excellent conversions and yields without the need for intensive purification steps. The scope of the reaction was extended to the preparation of 28 diverse amides using four different free carboxylic acids and seven primary and secondary amines, including cyclic amines. This enzymatic methodology has the potential to become a green and industrially reliable process for direct amide synthesis.

Catalytic and Sustainable Amide Bond Formation using a DABCO/Dichlorotriazine System

AbstractAmides are one of the most important functional groups in organic chemistry and play essential roles in both the pharmaceutical industry and life sciences. However, due to the natural reactivity of carboxylic acids and amines, their direct coupling is challenging and often leads to reactions that are not atom‐economic and produce large amounts of non‐recoverable by‐products. Despite the impressive number of coupling reagents available, sustainable methods for amide bond formation are still needed. To address this challenge, a new catalytic approach for the direct preparation of amides from carboxylic acids and amines is reported here. This method combines organocatalysis with a substoichiometric amount of activating agent under mild conditions (open air, room temperature, green solvents). This method was applied with good efficiency on a wide range of substrates, without epimerization of chiral stereocenters and on SPPS.

Amide bond formation: beyond the dilemma between activation and racemisation.

The development of methods for amide bond formation without recourse to typical condensation reagents has become an emerging research area and has been actively explored in the past quarter century. Inspired by the structure of vitamin B12, we have developed a metal-templated macrolactamisation that generates a new wave towards classical macrolactam synthesis. Further, distinct from the extensively used methods with condensation reagents or catalysts based on catalyst/reagent control our metal-catalysed methods based on substrate control can effectively address long-standing challenges such as racemisation in the field of peptide chemistry. In addition, the substrate-controlled strategy demonstrates the feasibility of "remote" peptide bond-forming reaction catalysed by a metal-ligand complex. Moreover, an originally designed hydrosilane/aminosilane system can avoid not only racemisation but also unnecessary waste production. This feature article documents our discovery and application of our original approaches in amide bond formation.

Sodium N-(3,5-Bis(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-4-carbonyl)-l-methioninate

The development of the methods for amide bond formation is important for various uses in the laboratory and industrial applications. The compounds combined in their structures 1,4-dihydroisonicotinic acids and amino acids linked with an amide bond can be considered as “privileged structures” due to their broad range of biological activities. Herein, the formation of amide bond between 1,4-dihydroisonicotinic acid and l-methionine is reported. The coupling of l-methionine with pentafluorophenyl active ester of 1,4-dihydroisonicotinic acid appears to be a convenient and effective method for amide bond formation. Sodium N-(3,5-bis(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-4-carbonyl)-l-methioninate has been successfully synthesized via a procedure where the key step is amide formation from 5-diethyl 4-(perfluorophenyl) 2,6-dimethyl-1,4-dihydropyridine-3,4,5-tricarboxylate and l-methionine. Sodium salt formation was performed to improve physicochemical properties, such as solubility of the l-methionine-derived 1,4-dihydroisonicotinamide. The obtained target compound was fully characterized by UV, IR, 1H NMR, 13C NMR, MS, and microanalysis.

Sustainable Amidation Reactions – Recent Advances

Due to the widespread occurrence of amides in modern pharmaceuticals and biologically active compounds, amidation reaction is one of the most important reactions in organic chemistry. Traditional methods to form amide bonds involve the coupling of a carboxylic acid with an amine and require the pre‐activation of the carboxylic acid moiety. Sustainable routes are replacing these existing methods since large amounts of waste are produced. Recently, novel reagents and methods for amide bond formation have emerged with the development of boron reagents, as well as the use of more sustainable metallic and organometallic catalysts. This review compiles the most recent efforts towards sustainable approaches that contribute to solving the problems associated with traditional methods. The new routes are based on promising reagents to performed more versatile and efficient amidation reactions.

Enzyme‐Catalysed Synthesis of Secondary and Tertiary Amides

AbstractThe synthesis of the amide bond between an amine and a carboxylic acid is one of the most significant reactions in industrial pharmaceutical synthesis. Despite the apparent simplicity of synthetic methods for amide bond formation, many of these are disadvantaged by their requirement for toxic or hazardous reagents for the activation of the acid component, or poor atom economy resulting from the need for stoichiometric amounts of coupling reagents. In this context, biocatalysis has emerged as an alternative catalytic method for amide bond formation, presenting the advantages of both environmentally benign reagents and conditions and also atom economy. In this review we detail developments in the enzyme‐catalysed preparation of secondary and tertiary amides for the synthesis of pharmaceutical‐type molecules and review the applications of hydrolases, such as lipases and penicillin acylases, to these reactions. We also summarise the activity of ATP‐dependent enzymes for amide bond formation and assess their potential for the preparative synthesis of amides from carboxylic acids and amines in aqueous media.magnified image

A New Wave of Amide Bond Formations for Peptide Synthesis

The construction of peptidic amide bonds has become a daily laboratory practice by virtue of well-established ‘coupling reagents’. Nonetheless, inherent limitations connected to these classical coupling methods in terms of waste, safety and expense have yet to be conquered. Research efforts have been devoted to synthetic methods able to surpass these limitations. This short review focuses on the advances made in these ‘non-classical’ methods for amide bond formation with a specific application in peptide chemistry. It consists of two main sections: (i) novel carboxylic activation reagents, and (ii) carboxylic acid and amine surrogates.1 Introduction2 Alternative Carboxylic acid Activation Reagents3 Carboxylic Acid and Amine Surrogates4 Conclusion and Perspectives

The mechanism and structure-activity relationship of amide bond formation by silane derivatives: a computational study.

The condensation of carboxylic acids and amines mediated by silane derivatives provided a straightforward and sustainable method for amide bond formation with minimal waste. However, the detailed mechanism and structure-activity relationship of substrates, the topics that are of interest for both academic and industrial applications, were not clear. Herein, a systematic computational study was conducted to solve the two questions. We found that the two previously proposed mechanisms involving intramolecular acyl transfer or silanolate were less likely because the associated silanone intermediate and zwitterion adducts were too unstable with higher overall energy barriers. By comparison, the mechanism involving deprotonation of carboxylic acids, addition of carboxylates on silane reagents, dihydrogen formation to afford an acyloxysilane intermediate, carboxylic-acid-assisted addition of amines, and concerted proton transfer/amide formation, was found to be more favorable with overall energy barriers varying between 24 and 28 kcal mol-1 for the different calculated cases. Meanwhile, the dihydrogen formation and amide formation processes are both potential rate-determining steps. Energy composition, atomic charge, and distortion-interaction analyses indicated that the steric effect of silane reagents was more important than the electronic effect, making less bulky silane reagents more reactive. On the other hand, the dihydrogen formation process was mainly controlled by the electronic effect of the substituents of carboxylic acids and amines while the amide formation process was mainly influenced by their steric effect. As a result, less bulky, less acidic alkyl carboxylic acids are more reactive than unsaturated carboxylic acids, and less bulky, medium basic primary alkyl amines are more reactive than secondary alkyl amines and primary aryl amines. The related results provided deeper mechanistic insights into the amide bond formation mediated by silane derivatives and can act as a reference for further experimental design.

The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides

Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides.

The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides

AbstractAmide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides.

Mechanism and Rate-Determining Factors of Amide Bond Formation through Acyl Transfer of Mixed Carboxylic-Carbamic Anhydrides: A Computational Study.

Acyl transfer of in situ-generated mixed anhydrides is an important method for amide bond formation from short linkages with the easily removed byproduct CO2. To improve our understanding of the inherently difficult acyl transfer hindered by the large ring strain, a density functional theory study was performed. The calculations indicate that the amidation of activated α-aminoesters and N-protected amino acids is more likely to proceed via the self-catalytic nucleophilic substitution of the two substrates and the subsequent 1,3-acyl transfer. By comparison, the mechanism involving 1,5-acyl transfer is less kinetically favored because of the slow homocoupling of activated α-aminoesters. Furthermore, we found that the detailed mechanism of 1,3-acyl transfer on the mixed carboxylic-carbamic anhydrides depends on the catalysts. Strong acidic catalysts and bifunctional catalysts both lead to stepwise pathways, but their elementary steps are different. Basic catalysts cause a concerted C-N bond formation/decarboxylation pathway. The calculations successfully explain the reported performances of different Brønsted-type catalysts and substrates, which validates the proposed mechanism and reveals the dependence of the reaction rates on the acid-base property of catalysts and the acidity of substrates.

A chemoenzymatic process for amide bond formation by an adenylating enzyme-mediated mechanism

Amide bond formation serves as a fundamental reaction in chemistry, and is practically useful for the synthesis of peptides, food additives, and polymers. However, current methods for amide bond formation essentially generate wastes and suffer from poor atom economy under harsh conditions. To solve these issues, we demonstrated an alternative synthesis method for diverse tryptophyl-N-alkylamides by the combination of the first adenylation domain of tyrocidine synthetase 1 with primary or secondary amines as nucleophiles. Moreover, the physiological role of this domain is l-phenylalanine adenylation; however, we revealed that it displayed broad substrate flexibility from mono-substituted tryptophan analogues to even d-tryptophan. To the best of our knowledge, this is the first evidence for an adenylating enzyme-mediated direct amide bond formation via a sequential enzymatic activation of amino acids followed by nucleophilic substitution by general amines. These findings facilitate the design of a promising tool for biocatalytic straightforward amide bond formation with less side products.

Collision-induced dissociation of phenethylamides: role of ion-neutral complexes.

Phenethylamides are a large group of naturally occurring molecules found both in the plant and animal kingdoms. In addition, they are used as intermediates for the synthesis of pharmaceutically important dihydro- and tetrahydroisoquinolines. To enable efficient characterization of this class of molecules, a detailed mass spectrometric fragmentation study of a broad series of analogs was carried out. The test compounds were synthesized using standard methods for amide bond formation. Low-energy high-resolution tandem mass spectra were acquired on a hybrid quadrupole/time-of-flight mass spectrometer using positive ion electrospray ionization. A total of 26 analogs were investigated in the study. Fragmentation of phenethylamides was found to proceed via intermediate ion-neutral complexes. The complexes can break down via multiple pathways including dissociation, proton transfer, Friedel-Crafts acylation, and single electron transfer. The relative contribution of each of these pathways strongly depends on the structure of the coupling amine and acid. A general scheme for the fragmentation of phenethylamides was developed. This study further extends the knowledge base of the ion-neutral complex by discovering Friedel-Crafts acylation as a novel reaction. The strong influence of minor structural modifications on the fragmentation patterns highlights the importance of testing many analogs in order to fully predict a fragmentation pattern of a particular class of molecules.

Protein assembly by orthogonal chemical ligation methods.

Chemical synthesis harbors the potential to provide ready access to natural proteins as well as to create nonnatural ones. The Staudinger ligation of a peptide containing a C-terminal phosphinothioester with a peptide containing an N-terminal azide gives an amide with no residual atoms. This method for amide bond formation is orthogonal and complementary to other ligation methods. Herein, we describe the first use of the Staudinger ligation to couple peptides on a solid support. The fragment thus produced is used to assemble functional ribonuclease A via native chemical ligation. The synthesis of a protein by this route expands the versatility of chemical approaches to protein production.