“One-Pot” Methylation of N-Nosyl-α-amino Acid Methyl Esters with Diazomethane and Their Coupling To Prepare N-Methyl Dipeptides

Abstract

N-Nosyl-alpha-amino acid methyl esters are methylated quantitatively with diazomethane. After proper deprotection of the amino function by treatment with the reagent system mercaptoacetic acid/sodium methoxide, the obtained N-methyl amino acid methyl esters are coupled with N-Fmoc amino acid chlorides to afford the corresponding dipeptides. The obtained products do not show any detectable extent of racemization by (1)H NMR and HPLC.

Intramolecular Suzuki–Miyaura Reaction for the Total Synthesis of Signal Peptidase Inhibitors, Arylomycins A2 and B2

“…A range of methods have been developed, which include direct alkylation and reductive aminoalkylation of the parent amino acids. [25,26] However, to the best of our knowledge, biocatalytic kinetic resolution of the N-Me-Hpg amide developed by Wang and co-workers was the only reported method for the synthesis of enantiomerically enriched N-Me-Hpg. [27] Our synthesis of 3-iodo-4-hydroxy-N-methyl arylglycine (12) is shown in Scheme 2.…”

N‐(4‐Nitrophenylsulfonyl)‐ and N‐(Fluorenylmethoxycarbonyl)‐N‐ethyl Amino Acid Methyl Esters – A Practical Approach

“…Thanks to its strong electron-withdrawing character, the nosyl group acts as both an activating and protecting group and enhances the reactivity of the N-H function towards various alkylating agents. [20,21] In addition, the compatibility of the nosyl group with the more practical Fmoc protecting group, commonly used in peptide and amino acid synthesis has been well documented. [20][21][22] On the basis of the above considerations, we initially subjected the N-nosyl-alanine methyl ester, (1a) chosen as a model system, to treatment with 2.5 equivalents of triethyloxonium tetrafluoroborate and 3.5 equivalents of N,N-diisopropylethylamine (DIPEA) in dichloromethane at room temperature (Scheme 1, Table 1).…”

“…[20,21] In addition, the compatibility of the nosyl group with the more practical Fmoc protecting group, commonly used in peptide and amino acid synthesis has been well documented. [20][21][22] On the basis of the above considerations, we initially subjected the N-nosyl-alanine methyl ester, (1a) chosen as a model system, to treatment with 2.5 equivalents of triethyloxonium tetrafluoroborate and 3.5 equivalents of N,N-diisopropylethylamine (DIPEA) in dichloromethane at room temperature (Scheme 1, Table 1). To our delight, the reaction was complete in only ten minutes and TLC analysis clearly showed the total conversion of 1a into a single product; subsequently, a simple workup afforded the corresponding N-ethylated product 2a in excellent yield.…”

“…The N-nosyl α-amino acid methyl esters were prepared as described previously. [20] Synthesis of N-Ethyl-N-nosyl Amino Acid Methyl Esters 2a-l. General Procedure: DIPEA (3.5 mmol) and solid triethyloxonium tetrafluoroborate (2.5 mmol) were added to a solution of 1a-l (150 mg, 1 mmol) in CH 2 Cl 2 (20 mL) under an inert atmosphere. The reaction mixture was stirred at room temperature for 10 min.…”

Amino acid chlorides: a journey from instability and racemization toward broader utility in organic synthesis including peptides and their mimetics

“…On the other hand, coupling employing acid chlorides is more than satisfactory. Preformed acid chlorides, with a variety of N-protecting groups, have been successfully employed to couple not only amino acid chlorides to N-methyl amino acids but also N-methyl amino acid chlorides to N-methyl amino Amino acid chlorides generated in situ have been successfully utilized to assemble even four consecutive N-methyl amino acids in solid phase method.In a preparation of N-methylated dipeptide methyl esters, Di Gioia et al employed Fmocamino acid chlorides as coupling reagents with N-methyl amino acid methyl ester under biphasic NaHCO 3 /CH 2 Cl 2 conditions 229. In addition, the N-methyl di as well as tripeptide could be coupled with N-Fmoc-amino acid chlorides in standard Fmoc solution phase peptide synthesis to obtain corresponding N-Fmoc-tri and tetrapeptides which are N-methylated at the requisite amino acid.…”