Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

Abstract

Backbone-extended amino acids have a variety of potential applications in peptide and protein science, particularly if the geometry of the amino acid is controllable. Here we describe the synthesis of δ-amino acids that contain three vicinal C–F bonds positioned along the backbone. The ultimately successful synthetic approach emerged through the investigation of several methods based on both electrophilic and nucleophilic fluorination chemistry. We show that different diastereoisomers of this fluorinated δ-amino acid adopt distinct conformations in solution, suggesting that these molecules might have value as shape-controlled building blocks for future applications in peptide science.

Synthesis of complex unnatural fluorine-containing amino acids

“…This selectivity becomes even more pressing when there is a desire to access vicinal multi-fluorinated systems. There have been several reports in which stereoselective vicinal multi-fluorinated amino acids have been accessed [ 150 , 151 , [ 154 , 155 ]. Molecular systems which incorporate vicinal fluorine atoms have been shown to adopt unusual conformations.…”

“…Molecular systems which incorporate vicinal fluorine atoms have been shown to adopt unusual conformations. There have been several examples of amino acids with three vicinal fluorine atoms [ 150 ], and one such example is that of Hunter et al who disclosed the synthesis of α,β,γ-trifluoro- δ -amino acids in 2013 using a sequential deoxyfluorination approach [ 152 ]. The anti, syn amino acid 214 was synthesised using a stereoselective epoxidation followed by deoxyfluorination sequence ( Scheme 41 ).…”