Tetrahedron report number 740Amide bond formation and peptide coupling
A review of methods and strategies available to the organic chemists to form amide bonds.
Introduction
The amide functionality is a common feature in small or complex synthetic or natural molecules. For example, it is ubiquitous in life, as proteins play a crucial role in virtually all biological processes such as enzymatic catalysis (nearly all known enzymes are proteins), transport/storage (haemoglobin), immune protection (antibodies) and mechanical support (collagen). Amides also play a key role for medicinal chemists. An in-depth analysis of the Comprehensive Medicinal Chemistry database revealed that the carboxamide group appears in more than 25% of known drugs.1 This can be expected, since carboxamides are neutral, are stable and have both hydrogen-bond accepting and donating properties.
In nature, protein synthesis involving a sequence of peptide coupling reactions (amide bond formation between two α-amino acids or peptides) is very complex, probably to safeguard the unique and precisely defined amino acid sequence of every protein. This barrier is overcome in vivo by a selective activation process catalysed by enzymes, where the required amino acid is transformed into an intermediate amino ester. This intermediate is then involved in a process mediated by the coordinated interplay of more than a hundred macromolecules, including mRNAs, tRNAs, activating enzymes and protein factors, in addition to ribosomes.2
Amide or ester bond formation between an acid and, respectively, an amine or an alcohol are formally condensations. The usual esterifications are an equilibrium reaction, whereas, on mixing an amine with a carboxylic acid, an acid–base reaction occurs first to form a stable salt. In other words, the amide bond formation has to fight against adverse thermodynamics as the equilibrium shown in Scheme 1 and lies on the side of hydrolysis rather than synthesis.3
The direct condensation of the salt can be achieved at high temperature (160–180 °C),4 which is usually quite incompatible with the presence of other functionalities (see also Section 2.6.3). Therefore, activation of the acid, attachment of a leaving group to the acyl carbon of the acid, to allow attack by the amino group is necessary (Scheme 2).
Hence, a plethora of methods and strategies have been developed and these are now available for the synthetic, medicinal or combinatorial chemist. Relevant examples of these methods are indicated in this report. The chemist might have to screen a variety of such conditions to find the method best adapted to his situation. For example, due to poor reactivity or steric constraints in some extreme cases, the challenge will be to get the amide formed at all. In other situations, the chemist will require the reaction to avoid racemisation. In general, the aim could also be to optimise the yield, to reduce the amount of by-products, to improve selectivity, to facilitate the final purification, to define a scalable process or to exploit more economical reagents. In the last two decades, the combined rapid development of solid-phase technologies and coupling methods has enabled parallel synthesis to become a tool of choice to produce vast amounts of diverse compounds for early discovery in the pharmaceutical industry.
Section snippets
Amide bond formation: methods and strategies
Carboxy components can be activated as acyl halides, acyl azides, acylimidazoles, anhydrides, esters etc. There are different ways of coupling reactive carboxy derivatives with an amine:
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an intermediate acylating agent is formed and isolated then subjected to aminolysis
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a reactive acylating agent is formed from the acid in a separate step(s), followed by immediate treatment with the amine
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the acylating agent is generated in situ from the acid in the presence of the amine, by the addition of an
Conclusions
Methodologies to form an amide bond have been described since the beginning of organic chemistry, but, in the past two decades, the design and the synthesis of innovating coupling reagents has been an area of intense investigation. Most of these new developments were originally aimed towards the highly demanding and specialised field of peptide synthesis. Indeed, many of these reagents have been developed on purpose, to enable the coupling of specific amino acids, or to work in conjunction with
Acknowledgements
We thank Dr Bob Marmon, Dr Herve Deboves, Dr Tom Coulter and Dr Manuel Cases for helpful discussions.
Christian A. G. N. Montalbetti was born in Baden, Switzerland, in 1967. He graduated from the Ecole Nationale Supérieure de Chimie de Paris in 1992. He pursued his PhD at the same institution under the guidance of Professor Jean Pierre Genet (Synthesis of B-seco-taxoids and carbopalladation reactions of oxanorbornenes). After completing his doctorate in 1996, he was offered a postdoctoral fellowship in the group of Professor Richard F. W. Jackson, at the University of Newcastle upon Tyne
References and notes (154)
- et al.
Tetrahedron Lett.
(1999) - et al.
Acc. Chem. Res.
(1996) - et al.
J. Am. Chem. Soc.
(1990) Chem. Lett.
(1998)- et al.
J. Org. Chem.
(1999) - et al.
Synthesis
(1973) Berichte der Deutschen Chemischen Gesellschaft
(1902)Justus Liebigs Ann. Chem.
(1957)- et al.
Tetrahedron
(1970)
J. Org. Chem.
J. Org. Chem.
J. Med. Chem.
J. Org. Chem.
Synthesis
Tetrahedron Lett.
J. Comb. Chem.
J. Chem. Soc., Perkin Trans. 2
Synth. Commun.
Bioorg. Med. Chem.
J. Am. Chem. Soc.
J. Prakt. Chem. (Leipzig)
Helv. Chim. Acta
Tetrahedron Lett.
Org. Process Res. Dev.
J. Am. Chem. Soc.
J. Chem. Soc., Abstr.
Chem. Commun.
Angew. Chem., Int. Ed. Engl.
Tetrahedron Lett.
J. Chem. Soc., Chem. Commun.
Synlett
Tetrahedron Lett.
Acc. Chem. Res.
Tetrahedron Lett.
Usp. Khim.
Synthesis
Tetrahedron
J. Am. Chem. Soc.
Indian J. Chem. Sect. B
Chem.Commun.
Tetrahedron
Synth. Commun.
Justus Liebigs Ann. Chem.
Tetrahedron Lett.
J. Am. Chem. Soc.
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Christian A. G. N. Montalbetti was born in Baden, Switzerland, in 1967. He graduated from the Ecole Nationale Supérieure de Chimie de Paris in 1992. He pursued his PhD at the same institution under the guidance of Professor Jean Pierre Genet (Synthesis of B-seco-taxoids and carbopalladation reactions of oxanorbornenes). After completing his doctorate in 1996, he was offered a postdoctoral fellowship in the group of Professor Richard F. W. Jackson, at the University of Newcastle upon Tyne (synthesis of unnatural α-aminoacids via Zinc mediated couplings). In 1998, he joined Evotec, where he worked on diverse projects ranging from hit generation (combinatorial synthesis of compound libraries), to hit-to-lead and lead-to-candidate projects (Medicinal Chemistry).
Virginie Falque was born in Boulogne Billancourt, France, in 1969. She attended the University Pierre and Marie Curie, in Paris, where she graduated in chemistry. She received her PhD degree in 1997 working under the guidance of Professor Jean Santamaria and Professor Alain Guy (Applications of a photochemical process to the synthesis of alkaloids). In 1998, she joined Evotec as a Senior Scientist working in Process Research Development and Custom Preparation. Recently, her professional focus shifted towards the early phases of the Drug Discovery process as she is part of the Medicinal Chemistry department of Evotec.