Uniform Preparation of (4R)- and (4S)-Fluoro-l-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 Z-Asp-OBn and led to a separable mixture of (4R)- and (4S)-epimers of 4-hydroxylysine, with protected amino groups (α-Z, ϵ-Boc) and carboxyl groups (as tert-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 SN2 reaction with PyFluor followed by manipulation with protecting groups; they were carried out separately and resulted in (4R)- and (4S)-fluoro-l-lysine isomers. Orthogonally protected α-Fmoc-ε-Boc-4-fluoro-l-lysines as (4R)- and (4S)-epimers were prepared as compounds with a set of protecting groups compatible with the conditions of solid-phase peptide synthesis.