The Selective O‐Acylation of Hydroxyproline as a Convenient Method for the Large‐Scale Preparation of Novel Proline Polymers and Amphiphiles

Abstract

In this work we show how a direct O-acylation of trans-4-hydroxy-L-proline with acyl chlorides in trifluoroacetic acid makes a range of novel proline derivatives readily available on large-scale. No protecting groups or chromatographic techniques are involved in any of the procedures, and certain amphiphilic proline derivatives, which recently have received interest in synthesis, are now potentially some of the

Proline Editing: A General and Practical Approach to the Synthesis of Functionally and Structurally Diverse Peptides. Analysis of Steric versus Stereoelectronic Effects of 4-Substituted Prolines on Conformation within Peptides

“…57, 61 Four types of reactions were examined for peptide modification at proline under metal-free conditions: native chemical ligation reaction via 1,2-aminothiol ( 116 ), Diels-Alder reaction via maleimide ( 117 ), inverse electron demand tetrazine-trans-cyclooctene cycloaddition via conjugated tetrazine ( 118 ) (Scheme 19), and oxime reactions (Scheme 20) via 4-aminoxyproline ( 119 - 122 ) or via 4-oxoproline ( 123 ). 42, 51a-d, 62 All model reactions proceeded cleanly in high conversion. The oxime reaction with 4-oxoproline proceeded more slowly and required aniline as a nucleophilic catalyst to achieve high conversion ( 123 ).…”

“…Functionalities thus introduced via acylation reactions included α-bromo acetates ( 74 , 75 ) for S N 2 reactions, biotin ( 76 , 77 ) for affinity recognition, maleimide ( 78 ) for Michael reaction with thiols or for Diels-Alder reactions, alkyne ( 79 ) for Huisgen [3+2] cycloaddition, NHS ester ( 80 ) for reaction with amine nucleophiles, acrylate ( 81 ) for polymerization, and tetrazine ( 82 ) for tetrazine-trans-cyclooctene ligation. 51 These reactions were all conducted on solid phase, and the peptides containing reactive functionalities isolated in good yield after standard TFA cleavage/deprotection (typically using TFA/TIS/H 2 O and avoiding thiol additives such as ethanedithiol that could react with these functional groups, particularly maleimide, fumarate, alkyne, and NHS esters). The acrylate ester was particularly sensitive to reaction and cleavage/deprotection conditions, requiring oxygen and hydroquinone as inhibitors of polymerization; even under these conditions the acrylate exhibited evidence of polymerization and substantially lower overall desired product formation than other reactions, though the peptide was still isolable and characterized by NMR.…”

“…The azidoproline-containing peptides also reacted on solid phase with phenyl acetylene to form either the 4- or 5-substituted triazoles ( 108 , 109 , 112 , 113 ), depending on the use of copper or ruthenium catalyst. 51e, 56 The azidoproline peptides also readily underwent copper-mediated azide-alkyne coupling with 1-ocytne ( 110 , 111 ). These approaches may be useful for solid phase diversification of peptide ligands in medicinal chemistry and other applications.…”

“…Compound 118 results from isomerization of an initial 1,3-diene product. 51a R N = Ac-Thr-Tyr-, R C = -Asn-NH 2 .…”

Ester-prodrugs of ethambutol control its antibacterial activity and provide rapid screening for mycobacterial hydrolase activity

“…Compounds were prepared from commercially-available (S,S)-ethambutol dihydrochloride 1 and a corresponding acid chloride as outlined in Figure 2, following a procedure developed for selective O -acylation of amino alcohols. 27 Acid chlorides were either commercially sourced or prepared from the precursor carboxylic acid using oxalyl chloride in dichloromethane and catalytic DMF. Ethambutol derivatives were prepared by adding the desired acid chloride to a solution of 1 dissolved in trifluoroacetic acid, which was stirred at room temperature for ten minutes.…”