Protecting‐Group‐Free Amidation of Amino Acids using Lewis Acid Catalysts

Abstract

Amidation of unprotected amino acids has been investigated using a variety of ‘classical“ coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions.

A green chemistry perspective on catalytic amide bond formation

“…Although it was shown to be less reactive than the zirconium catalysts, Ti(O i Pr)4 is an inexpensive bulk chemical, and has perhaps been somewhat overlooked as an amidation catalyst since the original report 20 , especially given the fact that it is relatively non-hazardous. To date, no efficient large-scale application has been reported, even though it does show reasonable reactivity with functionalised substrates including amino acid derivatives 20,24 ; no information regarding its reactivity with heterocycles/anilines has yet been published. Cp2ZrCl2 and ZrCl4 are reported to be more effective catalysts which have been applied to a wider substrate range (some anilines, but few heterocycles), and a reaction with improved efficiency has been demonstrated on a 20 mmol scale 19 .…”

“…Cp2ZrCl2 and ZrCl4 are reported to be more effective catalysts which have been applied to a wider substrate range (some anilines, but few heterocycles), and a reaction with improved efficiency has been demonstrated on a 20 mmol scale 19 . Whilst molecular sieves were used for dehydration in the vast majority of these reactions, azeotropic water removal has also been shown to be feasible using PhMe as solvent 18,24 . The corresponding hafnium catalyst 21 did not offer any significant benefits over titanium or zirconium catalysts which could outweigh the increased cost of this relatively rare metal.…”

“…The main drawback is the lack of catalyst activity with more challenging substrates (anilines, heterocyclics, amino acids). Commercially available borate esters can offer considerable improvements in reactivity and scope 23 , with many pharmaceutically relevant amides being prepared including those derived from poorly nucleophilic anilines, heterocyclic compounds, and amino acids (including unprotected amino acids 24 ). These reactions can be scaled up to access multigram quantities of amide with very high efficiency (PMI from [5][6][7][8][9][10][11][12][13].…”

All Non‐Carbon B3NO2 Exotic Heterocycles: Synthesis, Dynamics, and Catalysis

“…Amide bond construction is generally rendered in reagent‐driven reaction settings, offering reliable and short‐period delivery of the amide products of interest, although the inevitable coproduction of reagent‐derived waste significantly decreases the sustainability. Since the first demonstration by Yamamoto and co‐workers rendering amide bond formation catalytic with boronic acids, two decades of intense research have disclosed boronic acid (and boric acid and borate) based catalysts as well as Group 4 metal catalysts . A recent mechanistic investigation led by Whiting provided more in‐depth information regarding boronic acid catalysis, in which dimerized boronates were responsible for effective catalysis .…”

Sustainable Peptide Synthesis Enabled by a Transient Protecting Group

“…A number of alternative approaches have been proposed to overcome this hurdle, among them peptide synthesis in less harmful organic solvents or those referred to as “green” ones (cyrene, diethyl carbonate, anisole, etc. ), solvent‐free methods based on ball‐milling, and the application of some water‐compatible systems with appropriate protecting groups and solvents . However, the scope of these procedures is often limited in terms of peptide length, choice of amino acid derivatives, orthogonality, and compatibility with the desired synthetic step.…”