Uniform Preparation of (4 <i>R</i> )- and (4 <i>S</i> )-Fluoro- <scp>l</scp> -lysines from One Precursor: Retrosynthesis Software Approach and the Route of a Chemist

Fluorine-containing analogues of natural amino acids are becoming increasingly important as constituents of peptides, building blocks for new drugs, and drug candidates. We experimentally verified the synthesis of 4-fluoro-l-lysine proposed by SYNTHIA software, found the step which did not work as predicted, and modified it. Hereby, we found that α-iodoketones may be used in C-alkylation of enolates generated from (chiral) glycine derivatives. Eventually, a successful route was developed by us. It started from <i>Z</i>-Asp-OBn and led to a separable mixture of (4<i>R</i>)- and (4<i>S</i>)-epimers of 4-hydroxylysine, with protected amino groups (α-<i>Z</i>, ϵ-Boc) and carboxyl groups (as <i>tert</i>-butyl ester). These compounds were obtained from the common precursor (a 4-oxo-l-lysine derivative). Further transformations of each C⁴-OH epimer included the S_N2 reaction with PyFluor followed by manipulation with protecting groups; they were carried out separately and resulted in (4<i>R</i>)- and (4<i>S</i>)-fluoro-l-lysine isomers. Orthogonally protected α-Fmoc-ε-Boc-4-fluoro-l-lysines as (4<i>R</i>)- and (4<i>S</i>)-epimers were prepared as compounds with a set of protecting groups compatible with the conditions of solid-phase peptide synthesis.