N-Methyl amino acids occur in many natural products. Experimental strategies are presented for a unified approach to the synthesis of N-methyl derivatives through 5-oxazolidinones of the 20 common l-amino acids. The amino acids with reactive side chains that required protecting groups or devoted syntheses for side chain construction for N-methylation to proceed included serine, threonine, tyrosine, cysteine, methionine, tryptophan, asparagine, histidine, and arginine. The studies have provided improved methods for the preparation of N-methyl serine, threonine, and tyrosine. All 20 of the common l-amino acids are now available in suitable forms for solid or solution-phase peptide synthesis.

Protonated threonine and its allo diastereomer exhibit different proportions of collisionally activated dissociation (CAD) product ions. N-Methylation attenuates these differences. Water loss from protonated allo-threonine gives protonated trans-3-methylaziridinecarboxylic acid via an internal S(N)2 pathway, rather than protonated vinylglycine.

The novel metallosurfactant Cu(II)-1-tetradecyldiethylenetriamine (Cu(II)TDET) was prepared, and the hydrolyses of 2-acetoxy-5-nitrobenzoic acid (1), 4-acetoxy-3-nitrobenzoic acid (2), 4-nitrophenyl acetate (3), and 2-nitrophenyl acetate (4) in the presence of micellar Cu(II)TDET were examined. The rate of ester hydrolysis for the series followed the order 1 approximately 2>3>4. The larger observed rate (kpsi) for 1 and 2 was attributed to (i) electrostatic interaction between the carboxylate anion and the cationic metallomicelle surface and (ii) the formation of a ternary complex metal:surfactant ligand:substrate (MLnS). The position of the carboxylate anion in the substrate did not significantly affect catalysis. Similar rates were observed when the carboxylate anion was ortho to the acyl ester 1 or para to the reaction center 2. The absence of a significant difference may be associated with the ternary complex coordination geometry, which unfavorably aligned the ligated substrate and the metal-bound hydroxyl. Mixed micellar solutions containing Cu(II)TDET and MTAB or Triton X-100 were examined. Added cosurfactants have a pronounced effect on the catalytic activity of Cu(II)TDET. At a low concentration of Cu(II)TDET the addition of MTAB or Triton X-100 increased the pseudo-first-order rate constant (kpsi) for the hydrolysis of 1 and 3 relative to the rate in pure Cu(II)TDET. The addition of a cosurfactant increased the total micellar volume (VM), promoting substrate incorporation within the pseudophase. At higher metallosurfactant concentration, the rate enhancement was smaller due to the dilution of the substrate within the co-micellar pseudophase.