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

High Resolution Image Download MS PowerPoint Slide 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 (4 R )- and (4 S )-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 C 4 –OH epimer included the S N 2 reaction with PyFluor followed by manipulation with protecting groups; they were carried out separately and resulted in (4 R )- and (4 S )-fluoro- l -lysine isomers. Orthogonally protected α-Fmoc-ε-Boc-4-fluoro- l -lysines as (4 R )- and (4 S )-epimers were prepared as compounds with a set of protecting groups compatible with the conditions of solid-phase peptide synthesis.