Inverse Peptide Synthesis via Activated α‐Aminoesters

Abstract

A mild, practical, and simple procedure for peptide-bond formation is reported. Instead of activation of the carboxylic acid functionality, the reaction involves an unprecedented use of activated α-aminoesters. The method provides a straightforward entry to dipeptides and was effective when a sensitive cysteine residue was used, as no epimerization was detected in this case. The applicability of this method to iterative peptide synthesis was illustrated by the synthesis of a model tetrapeptide in the challenging reverse N→C direction.

[3,3]‐Sigmatropic Rearrangement of Cyclopropenylcarbinyl Cyanates: Access to Alkylidene(aminocyclopropane) Derivatives

“…Addition of an excess of pyrrolidine [pyrrolidine/CH 2 Cl 2 (1:4)] to isocyanate 5 a delivered urea 7 in good yield (80 %) (Table , entry 1). The N ‐carbamoyl imidazole derivative 8 , potentially amenable in peptide coupling‐type reactions, was isolated in 69 % yield upon addition of imidazole (10 equiv) to the reaction mixture (Table , entry 2). The addition of various alcohols was then examined.…”

“…Addition of an excess of pyrrolidine [pyrrolidine/CH 2 Cl 2 (1:4)] to isocyanate 5a delivered urea 7 in good yield (80 %) ( amenable in peptidec oupling-type reactions, [40] was isolatedi n 69 %y ield upon addition of imidazole (10 equiv) to the reaction mixture ( . Isocyanate 5a could also be involved in aG oldschmidt-Wick coupling reaction with N-Boc glycine in the presence of DMAP [41] which afforded, after rearrangement of the initial adduct 14 and decarboxylation, a-aminoamide 15 in 70 % yield (Scheme5).…”

9‐Silafluorenyl Dichlorides as Chemically Ligating Coupling Agents and Their Application in Peptide Synthesis

“…[3] In light of this,a mide bond formation was recently recognized as akey transformation in which the development of more efficient processes is required. [12] However,a lthough promising and generally efficient, all of these methods still suffer from the same major limitation:t he requirement for prior elaboration of one of the coupling partners to generate ar eactive enough species for the formation of the amide bond. [12] However,a lthough promising and generally efficient, all of these methods still suffer from the same major limitation:t he requirement for prior elaboration of one of the coupling partners to generate ar eactive enough species for the formation of the amide bond.…”

9‐Silafluorenyl Dichlorides as Chemically Ligating Coupling Agents and Their Application in Peptide Synthesis

“…[4] In recent years,anumber of pioneering new strategies have been reported for the synthesis of peptide bonds,such as the catalytic generation of activated carboxylate surrogates from aldehydes, [5] alcohols, [6] and alkynes, [7] the oxidative coupling of a-bromo nitroalkanes with amines, [8] theu se of reactive amine surrogates,s uch as the coupling of isonitriles with carboxylic acids or thioacids, [9] thecoupling of thioacids with azides, [10] the coupling of isocyanates with carboxylic acids, [11] and, very recently,t he coupling of CDI activated amino esters with carboxylic acids. [12] However,a lthough promising and generally efficient, all of these methods still suffer from the same major limitation:t he requirement for prior elaboration of one of the coupling partners to generate ar eactive enough species for the formation of the amide bond. One further and particularly promising method that avoids the use of superstoichiometric activating agents is the use of electron-deficient boronic or borinic acids as catalysts to generate an activated carboxylate.First reported in 1996, [13] and with many recent improvements, [14] these methods still generally require the use of ah ighly functionalized organoboron derivative,f orcing conditions,a nd ad ilute reaction medium to achieve good yields.…”