Catalytic Peptide Synthesis: Amidation of N-Hydroxyimino Esters

Abstract

A catalytic method for the formation of amide bonds was developed in which the amidation of N-hydroxyimino esters with a broad range of amino acid tert-butyl esters is promoted by a niobium catalyst in the absence of solvent. Contrary to the predominant protocol based on reagent control commonly applied to amidation reactions, this study provides insight into an approach based on substrate control. This system affords the corresponding amides in high yields in addition to being both highly atom efficient and racemization-free. An advantage of this system is shown in that the Lewis acid catalysis proceeds chemoselectively in the presence of nonactivated esters. Furthermore, the resulting amides are easily transformed into their corresponding di-and tripeptides with high diastereoselectivities under simple hydrogenation conditions.

Total Synthesis of the Natural Herbicide MBH‐001 and Analogues

“…Based on the literature precedence we hoped that aldehydes would react better with 2‐hydroxyimino esters as compared to ketones. First, methyl l ‐leucinate ( 27 ) was oxidized with H 2 O 2 in the presence of sodium tungstate to oxime 28 . In the next step, oxime 28 was treated with acetaldehyde under basic conditions by adding 0.1 m NaOH in portions to the mixture.…”

“…Methyl 2‐(Hydroxyimino)‐4‐methylpentanoate (28): According to general procedure 2, methyl leucinate ( 27 ) (10.0 g, 0.07 mol, 1 equiv.) was oxidized to pure oxime 28 (10.3 g, 94 %), white powder. R f = 0.23 (petroleum ether/EtOAc, 4:1); 1 H NMR (400 MHz, CDCl 3 ): δ = 0.92 (d, J = 6.7 Hz, 6H, 5‐H), 2.04 (qqt, J = 6.9, 6.9, 6.8 Hz, 1H, 4‐H), 2.53 (d, J = 7.5 Hz, 2H, 3‐H), 3.83 (s, 3H, OCH 3 ), 8.70 (br s, 1H, OH) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ = 22.6 (C‐5), 26.5 (C‐4), 33.3 (C‐3), 52.6 (OCH 3 ), 152.5 (C‐2), 164.2 (C‐1) ppm; HRMS (ESI‐TOF): calcd.…”

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

“…The successful amidation of Boc-Glu-OtBu illustrated that the tBu ester and Boc protecting groups were compatible in the current catalytic system (24). a,b-Unsaturated acids served as suitable substrates irrespective of the presence of the a-a nd/or b-substituents, and the polyene system remained intact (25,26). A3 0% aqueous solution of 3-hydroxypropanoic acid could be directly submitted to the amidation protocol, affording hydroxyamide 27 in high yield.…”

“…[24] Yamamoto has recently disclosed that Group 5m etal salts exert ap articular catalytic function to promotee ster-amide exchange as ap ractical alternative to efficientlyp roduce high-value amides and oligopeptides. [25] Given the increasing focus on reliable waste-free catalytic amidation protocols in industry, [26,27] the development of ar eadily availabler obustc atalytic system that offers ab road substrate scope with practical tolerance is in high demand.…”

Flow‐based SPPS for protein synthesis: A perspective

“…Can these methods be used in AFPS and can we develop even more reactive active esters? Can catalytical methods for amide bond formation [ 130–134,135 ] be translated into flow chemistry? And can these methods be used for the synthesis of long peptides or even proteins?…”