Enantioselective Synthesis of Fmoc-Protected (2S,3R)-3,4-Dimethyl-2-(methylamino)pentanoic Acid

Abzena and Regeneron co-authored a recent journal publication that describes the first asymmetric synthesis of a unique, Fmoc-Protected, amino acid present in a handful of bioactive natural products that show cytotoxic activity at very low concentrations. The Abzena chemistry team, comprised of Francisco Velazquez, PhD., Po-Cheng Yu, Nurul H. Ansari, PhD., and Jerry Taylor, in collaboration with Thomas Nittoli, PhD., from Regeneron, utilized their expertise and skill in asymmetric organic chemistry to design an efficient synthetic route for gram-scale production of this rare amino acid. Having this unique amino acid available allowed the investigation of SAR for novel bioactive molecules.

Publication Abstract

The first enantioselective synthesis of the Fmoc-protected rare amino acid, 3,4-dimethyl-2-(methylamino)pentanoic acid, is disclosed. The synthesis utilized the chiral oxazolidinone to introduce the first chiral center (>95:5 ee), and then swapped the auxiliary to Ellman’s N-sulfinylimine for setting up the chiral α-amino group (95:5 dr). The newly formed chiral centers were confirmed by X-ray crystallography. With this unique amino acid on hand, naturally occurring macrocyclic peptides will become synthetically accessible.

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