Chemoenzymatic Synthesis of Each Enantiomer of Orthogonally Protected 4,4-Difluoroglutamic Acid: A Candidate Monomer for Chiral Brønsted Acid Peptide-Based Catalysts

Abstract

We have accomplished an asymmetric synthesis of each enantiomer of 4,4-difluoroglutamic acid. This α-amino acid has been of interest in medicinal chemistry circles. Key features of the synthesis include highly scalable procedures, a Reformatsky-based coupling reaction, and straightforward functional group manipulations to make the parent amino acid. Enantioenrichment derives from an enzymatic resolution of the synthetic material. Conversion of the optically enriched compounds to orthogonally protected forms allows selective formation of peptide bonds. 4,4- Difluoroglutamic acid, in a suitably protected form, is also shown to exhibit enhanced catalytic activity in both an oxidation reaction and a reduction reaction, in comparison to the analogous glutamic acid derivative.

Modulating the Nucleophile of a Glycoside Hydrolase through Site-Specific Incorporation of Fluoroglutamic Acids

“…Synthesis of Optically Pure Fluoroglutamic Acid Building Blocks. The optimized large-scale synthesis of orthogonally protected, optically pure N-Cbz-δOtBu-L-4,4-difluoroglutamic acid from chlorodifluoroacetic acid published by Miller et al 33 proved straightforward in our hands, with an overall yield of 11%. Exchange of the amine protection group (Cbz) for Fmoc to produce building block 2 was accomplished using standard protocols (Supporting Information).…”

“…While synthetic routes for both 4-fluoroglutamic acid − and 4,4-difluoroglutamic acid − have been established, to the best of our knowledge there is no report of the site-selective incorporation of these unnatural amino acids into a peptide or an active enzyme. In this manuscript we describe the methodology we developed to synthesize these molecules as well as the kinetic characterization of resultant Bcx constructs carrying 4-fluoro- and 4,4-difluoroglutamic acids as their catalytic nucleophile.…”

Hot off the press

“…Multi-gram quantities of both enantiomers of orthogonally protected 4,4-difluoroglutamic acid have been prepared using an enzymatic kinetic resolution as the key step. 29 Using DMSO and phosphate buffer as co-solvents, the racemic 4,4-difluoroglutamic acid derivative was resolved with subtilisin Carlsberg in excellent yield and enantioselectivity (Scheme 7). A one-pot synthesis of tetrahydrochromene derivatives catalysed by lipase from Porcine pancreas (PPL) has been developed.…”

Photocatalytic Reductive Olefin Hydrodifluoroalkylation Enabled by Tertiary Amine Reductants Compatible with Complex Systems

“…Furthermore, the synthetic community has made use of NCAAs as chiral catalysts and ligands for stereoselective methodologies in small molecule synthesis . Thus, access to ever-increasing diversity in NCAAs contributes to a wide swath of science …”