Efficient amide bond formation through a rapid and strong activation of carboxylic acids in a microflow reactor

Abstract

The development of highly efficient amide bond forming methods which are devoid of side reactions, including epimerization, is important, and such a method is described herein and is based on the concept of rapid and strong activation of carboxylic acids. Various carboxylic acids are rapidly (0.5 s) converted into highly active species, derived from the inexpensive and less-toxic solid triphosgene, and then rapidly (4.3 s) reacted with various amines to afford the desired peptides in high yields (74%-quant.) without significant epimerization (≤3%). Our process can be carried out at ambient temperature, and only CO2 and HCl salts of diisopropylethyl amine are generated. In the long history of peptide synthesis, a significant number of active coupling reagents have been abandoned because the highly active electrophilic species generated are usually susceptible to side reactions such as epimerization. The concept presented herein should renew interest in the use of these reagents.

Keywords: amides; amino acids; continuous flow; natural products; peptides.

Scheme 1

Amide bond formation based on a conventional concept of the mild activation of carboxylic acids and our concept of rapid and strong activation of carboxylic acids.

Figure 1

Microflow synthesis of peptides based on the concept of rapid and strong activation of carboxylic acids using triphosgene.

Scheme 2

Synthesis of the tetrapeptide 17, a substructure of aurilide (13). a) Batch, AllylBr, K₂CO₃, DMF, RT, 19 h, 93 %. b) Batch, Et₂NH, CH₂Cl₂, RT, 2.5 h. c) Flow A, N-Fmoc-sarcosine, 2 steps 87 %. d) Flow A, N-Fmoc-N-methyl-D-leucine, 2 steps 83 %, epimer <1 %. e) Flow and batch, N-Fmoc-l-valine, 2 steps 60 %, epimer <1 %.