Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts.

Marco T Sabatini,Matthew Badland,Rachel M Lanigan,Valerija Karaluka,Tom D Sheppard,Lee T Boulton

doi:10.1002/chem.201800372

Abstract

Amidation of unprotected amino acids has been investigated using a variety of ‘classical“ coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions.

Highlights

Chemical reactions for the formation of amide bonds are among the most commonly employed transformations in organic chemistry; amides featuring in 25 % of industrially important pharmaceuticals as well as a wide selection of bioactive natural products and polymeric materials.[1]
While the synthesis of amino amides by the assembly of N-protected a-amino acids and amines is a well-known and accepted methodology,[2] the synthesis of amides directly derived from unprotected amino acids (Scheme 1 B) is rare, despite shortening the synthetic sequence by two steps
We have recently reported that the borate ester B(OCH2CF3)3 is an effective reagent for the direct synthesis of a-amino amides from unprotected amino acids and amines.[13,14]

Summary

Introduction

Chemical reactions for the formation of amide bonds are among the most commonly employed transformations in organic chemistry; amides featuring in 25 % of industrially important pharmaceuticals as well as a wide selection of bioactive natural products and polymeric materials.[1]. While the synthesis of amino amides by the assembly of N-protected a-amino acids and amines is a well-known and accepted methodology,[2] the synthesis of amides directly derived from unprotected amino acids (Scheme 1 B) is rare, despite shortening the synthetic sequence by two steps. This class of amidation reaction presents issues relating to control of reactivity, but the lack of research effort in this area is probably due to the preconception that such a reaction would not work (Scheme 1 C).

Objectives

Results

Conclusion