COMU: scope and limitations of the latest innovation in peptide acyl transfer reagents

Abstract

The methodology for peptide bond formation is undergoing a continuous evolution where the main actors are being renewed. In recent years, coupling reagents based on the Oxyma scaffold, such as the uronium salt COMU, has been a groundbreaking contribution to the field. The advantages of COMU over classic benzotriazole-based reagents (HATU, HBTU, HCTU, TBTU) were proven in terms of solubility and coupling efficiency in bulky junctions in our groups and others. However, some aspects of the use of COMU need to be revised and improved, such as the stability of commercial samples in organic solvents, which hampers the compatibility with long synthesis in automated synthesizers. In this review, an overview of the main features and suggestions to improve the use of COMU are presented, along with a discussion on the best conditions for its use in microwave-assisted peptide robots.

Biosynthetic Products from a Nearshore-Derived Gram-Negative Bacterium Enable Reassessment of the Kailuin Depsipeptides

“…The coupling reagent COMU ((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbe-nium hexafluorophosphate) was used as the cyclization reagent, which afforded complete cyclization of the peptide within 20 min. This represented a tremendous improvement over the commonly reported reaction times of 16 h. 45 It has been reported previously that COMU may not provide an efficient cyclization reagent, 46 but in this system, however, it enabled expedient macrolactamization. Moreover, global side chain deprotection using 50% TFA in CH 2 Cl 2 in the presence of COMU leads to many undesired side reactions (unpublished data).…”

New Methods for Chemical Protein Synthesis

“…Because of the excellent leaving group ability of the Oxyma moiety [50], the great solubility of the morpholino-containing iminium moiety [54], and the high reactivity of the formed uronium salt [55], COMU shows superior performance in the synthesis of many different types of amide bonds in comparison with HATU and HBTU [53]. Unfortunately, COMU degrades more rapidly than HATU or HBTU in DMF, although there has been discussion that this may not be because of the inherent properties of COMU and can easily be overcome by using purer COMU [56]. They also developed another derivative by combining Oxyma with bis (2-oxo-3-oxazolidinyl) phosphorodiamidic chloride (BOP-Cl).…”

Making Solid‐Phase Peptide Synthesis Greener: A Review of the Literature

“…[40] Undoubtedly,A lbericios' lab have made significant contributions in traditional peptides ynthesisa sw ell as in making the protocolg reenera nd safer. [13,15,41] Their results using THF and MeCN instead of DMF for peptides ynthesis were comparable to andi ns ome cases even better than DMF. [42] These solvents despite not being considered green solvents, constitute an environmentally friendlier approacht han DMF and CH 2 Cl 2 .L ater, the lab expanded McMillan's methodology by using 2-MeTHF and CPME as greenera lternatives to THF and MeCN for amide bond formation in peptide synthesis.…”

“…The explosive nature of HOBt and HOAt along with the toxicity of HATU, led Albericios’ lab to investigate and report on the third generation coupling reagents and racemization suppressors . Many researchers have used OxymaPure (ethyl cyanoglyoxalate‐2‐oxime ) and K Oxyma (ethyl (hydroxyimino)cyanoacetate potassium salt) (Figure ) to suppress racemization and COMU– [(1‐cyano‐2‐ethoxy‐2‐oxoethylidenaminooxy)dimethylamino‐morpholino‐carbenium hexafluorophosphate] (Figure ) instead of HCTU and HATU as the coupling reagent with excellent results.…”

“…In some cases, coupling with COMU resulted in better yields compared with HATU and HDMA (1‐[(dimethylamino)(morpholino)methylene]‐1 H ‐[1,2,3]triazolo[4,5‐ b ]pyridine‐1‐ium 3‐oxide hexafluorophosphate) . Preliminary concerns about COMU's stability in DMF and other organic solvents owing to hydrolysis have been recently overcome, with the authors reporting in‐depth studies of COMU's stability in green/greener solvents . Differential scanning calorimetry (DSC), a technique used to detect the kinetics of decompositions, was also performed and the results proved the non‐autocatalytic nature of the morpholonium and oxime‐based COMU in comparison to the autocatalytic nature of the benzotriazole‐based HDMA and HDMB (1‐((dimethylamino)(morpholino)methylene)‐1 H ‐benzotriazolium hexafluorophosphate‐3‐oxide).…”