Fmoc-N-methyl-D-leucine

A highly efficient method for amide bond formation used a microflow reactor, based on the concept of rapid and strong activation of carboxylic acids. An inexpensive solid triphosphate activates carboxylic acids within 0.5 seconds to form symmetric anhydrides, which then react with amines in 4.3 seconds at ambient temperature. The method minimizes epimerization and produces only CO₂ and HCl salts as byproducts.
To demonstrate the utility of this approach, the authors synthesized a tetrapeptide fragment of the depsipeptide natural product auliride, which contains two N-methyl amino acids. After initial esterification and Fmoc deprotection of intermediate 14, microflow amidation with N-Fmoc sarcosine gave dipeptide 15 in 87% yield over two steps. Significantly, the subsequent coupling of N-Fmoc-N-methyl-D-leucine with the less-nucleophilic dipeptide 15 proceeded smoothly under microflow conditions, affording tripeptide 16 in 83% yield over two steps without detectable epimerization. The final coupling with N-Fmoc-L-valine required a brief batch extension but still delivered the desired tetrapeptide 17 in 60% yield without epimerization.

Fig. 1 Fmoc-N-methyl-D-leucine for the synthesis of tetrapeptide 17. (Fuse S.; et al. 2014)