Contemporary Approaches for Amide Bond Formation

Advanced Synthesis & Catalysis, Год журнала: 2023, Номер 365(24), С. 4359 - 4391

Опубликована: Ноя. 7, 2023

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

Язык: Английский

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Competing Reaction Mechanisms of Peptide Bond Formation in Water Revealed by Deep Potential Molecular Dynamics and Path Sampling

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(20), С. 14213 - 14224

Опубликована: Май 13, 2024

The formation of an amide bond is essential step in the synthesis materials and drugs, assembly amino acids to form peptides. mechanism this reaction has been studied extensively, particular understand how it can be catalyzed, but a representation capable explaining all experimental data still lacking. Numerical simulation should provide necessary molecular description, solvent involvement poses number challenges. Here, we combine efficiency accuracy neural network potential-based reactive dynamics with extensive unbiased exploration pathways provided by transition path sampling. Using microsecond-scale simulations at density functional theory level, show that method reveals presence two competing distinct mechanisms for peptide between alanine esters aqueous solution. We describe both pathways, via general base catalysis direct cleavage tetrahedral intermediate respectively, change pH. This result contrasts conventional involving single pathway which only barrier heights are affected new proposal consistent data, discuss implications under prebiotic conditions ribosome. Our work shows integrating deep potential sampling provides powerful approach exploring complex chemical mechanisms.

Язык: Английский

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Recent progress of chemical methods for lysine site-selective modification of peptides and proteins

Chinese Chemical Letters, Год журнала: 2024, Номер unknown, С. 110126 - 110126

Опубликована: Июнь 1, 2024

Язык: Английский

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Peptide and Protein Cysteine Modification Enabled by Hydrosulfuration of Ynamide

ACS Central Science, Год журнала: 2024, Номер 10(9), С. 1742 - 1754

Опубликована: Авг. 21, 2024

Efficient functionalization of peptides and proteins has widespread applications in chemical biology drug discovery. However, the chemoselective site-selective modification remains a daunting task. Herein, highly efficient chemo-, regio-, stereoselective hydrosulfuration ynamide was identified as an method for precise by uniquely targeting thiol group cysteine (Cys) residues. This novel could be facilely operated aqueous buffer fully compatible with wide range proteins, including small model large full-length antibodies, without compromising their integrity functions. Importantly, this reaction provides Z-isomer corresponding conjugates exclusively superior stability, offering approach to peptide protein therapeutics. The potential application further exemplified Cys-bioconjugation variety ynamide-bearing functional molecules such molecule drugs, fluorescent/affinity tags, PEG polymers. It also proved redox proteomic analysis through Cys-alkenylation. Overall, study bioorthogonal tool Cys-specific functionalization, which will find broad synthesis peptide/protein conjugates.

Язык: Английский

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Scalable and sustainable DMF-free solid-phase synthesis of liraglutideby 1-tert-butyl-3-ethylcarbodiimide-mediated couplings and catch-and-release acylation and purification strategies

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

The growing need for sustainable practices in pharmaceutical manufacturing has stimulated advancements peptide synthesis. This study focuses on applying green chemistry principles to the synthesis of Glucagon-Like Peptide-1 analog liraglutide, using novel and solid-phase synthetic strategies. By adopting safer coupling reagent 1-tert-butyl-3-ethylcarbodiimide (T-Bec®) combination with eco-friendly binary solvents like dimethyl sulfoxide butyl acetate, we demonstrated that it is possible significantly reduce environmental impact while maintaining high efficiency quality T-Bec® minimizes hazardous byproducts, such as hydrogen cyanide, enhances solvent compatibility, achieving crude purities yields comparable conventional syntheses. Two strategies were developed liraglutide production. first strategy based a “direct synthesis”, incorporating lipidated lysine building block into sequence, 86% HPLC purity after catch-and-release purification. second “catch-lipidation-and-release” approach, allowed obtain precursor without lipid moiety, which was later linked during controlled lipidation step. latter yielded exceeding 90% reduced reliance preparative HPLC. These findings highlight effectiveness systems optimize scalable SPPS processes. methods improve resource impact, allow viable pathway produce therapeutic ingredients liraglutide. work underscores potential align innovation responsibility.

Язык: Английский

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An Electrochemical Design for a General Catalytic Carboxylic Acid Substitution Platform via Anhydrides at Room Temperature: Amidation, Esterification, and Thioesterification

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

An original concept for catalytic electrochemical dehydration has enabled a suite of acid substitutions, including amidation, esterification, and thioesterification, through linchpin anhydride formed in situ. By avoiding stoichiometric dehydrating agents, this method addresses leading challenge organic synthesis green chemistry. It also proceeds without additives at room temperature, accesses diverse range product structures, is easily scaled, the first example peptide coupling temperature.

Язык: Английский

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Rapid peptide synthesis using a methylimidazolium sulfinyl fluoride salt

Communications Chemistry, Год журнала: 2025, Номер 8(1)

Опубликована: Фев. 22, 2025

Peptide couplings have been a subject of investigation for over century, with modern research seeking to discover new methodologies that minimize purification steps, reagent expense, and/or decrease reaction times. Of the numerous coupling reagents available, sulfur(IV) fluorides potential as they can effectively transform carboxylic acids reactive intermediates, and sulfite by-products be removed through aqueous washes. Here we demonstrate formation capture key acyl fluorosulfite intermediates peptide in 15 min total, without epimerization or column chromatography purification. Dipeptides were obtained 40–94% yields. This approach was expanded longer chains iterative couplings, oligopeptides 24–57% yields, each within 2 days. Mechanistic studies indicate does not proceed fluoride instead involves nucleophilic catalysis. The mild conditions are tolerant wide range protecting groups canonical non-canonical amino acids. Peptides known important therapeutics; however, minimizing times methods remains challenging. Here, authors use reagent, demonstrating rapid purification, achieving yields dipeptides oligopeptide formation.

Язык: Английский

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Scalable and Sustainable DMF-Free Solid-Phase Synthesis of Liraglutide by 1-Tert-Butyl-3-Ethylcarbodiimide-Mediated Couplings and Catch-and-Release Acylation and Purification Strategies

International Journal of Peptide Research and Therapeutics, Год журнала: 2025, Номер 31(3)

Опубликована: Фев. 22, 2025

Язык: Английский

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Synthesis of Mono-Boc-2,5-Diketopiperazine: A Key Building Block for Amide and Peptide Synthesis

The Journal of Organic Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Diketopiperazine (DKP), a versatile scaffold, is extensively used in the synthesis of complex natural products, bioactive molecules, and smart materials organic chemistry. Recently, activated DKPs, such as Boc-DKPs, have emerged key building blocks for peptide elongation synthesis. In this study, we developed facile protocol synthesizing mono-Boc-protected DKPs from readily accessible N-4-methoxybenzyl (N-PMB)-amino acids amino acid methyl esters. This involved sequence reactions encompassing formation dipeptides N-PMB-amino esters, cyclization N-PMB-dipeptides to form PMB-DKPs, Boc-protection subsequent PMB-deprotection PMB-DKP-Boc afford mono-Boc-DKPs. The demonstrated broad substrate scope, accommodating diverse with various side chains, affording mono-Boc-DKPs good yields excellent stereoselectivities (>20:1 dr). synthetic utility was showcased by pentapeptide Boc-l-Tyr(t-Bu)-Gly-l-Phe-Gly-l-Val-OtBu 2-fold two Furthermore, synthesized Leu-enkephalin reacting cyclo(Boc-l-Tyr(t-Bu)-Gly-) H-Gly-l-Phe-l-Leu-Ot-Bu, resulting yield optical purity.

Язык: Английский

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A Thiourea-Based Rotaxane Catalyst: Nucleophilic Fluorination Phase-Transfer Process Unlocked by the Mechanical Bond

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Март 18, 2025

We report a five-component clipping approach using activated isophthaloyl-derived esters to synthesize an amide-based thiourea rotaxane. This method overcomes acyl chloride limitations with nucleophilic threads. The steric hindrance of the mechanical bond enables, for first time, interlocked as hydrogen-bonding phase-transfer organocatalyst in fluorinations. highlights how bonds expand catalysis processes previously incompatible conventional catalysts.

Язык: Английский

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