A facile synthesis of optically pure disubstituted amino acids

Monomerchem, Inc., Durham NC

Investigators

Abstract

Project Summary Enantiopure ?,?-disubstituted amino acids (EDAAs) are valuable fundamental building blocks for medical research in both academics and industry. When an EDAA is incorporated into the framework of a peptide or a small molecule, both substituents attached to the ? carbon contribute to the molecule's shape, biological activity and physical properties. EDAAs can be used to optimize stability, clogP, and solubility, providing a drug candidate with a vastly improved cellular potency (EC50) and pharmacokinetic profile (PK). The commercial availability of diverse collections of these unique and three dimensional building blocks will allow for the production of libraries of peptides and small molecules that have the ability explore new conformational space. The unique properties and shapes have the potential to interact with a wide range of drug targets. However, commercially available EDAAs are confined to simple alanine derivatives. Reason: No general method for the preparation of diverse EDAAs is available. We will introduce a new general method for the preparation of ?,?-disubstituted amino acids with a wide scope of functional groups (overall aim). Preliminary findings in our laboratory have validated the new method for producing an EDAA in 3 steps from a ketone and gave both antipodes with equal and opposite optical rotations. The reagents and conditions for each of the 3 steps of this new process will be presented and potential solutions to optimize for yield, scope, and efficiency will be proposed. This simple, straightforward 3-step method begins with simple ketones that are designed to test the impact of these parameters (aim 1). We will produce a library of EDAAs from a diverse set of commercially available ketones using the optimized general method (aim 2). Complete characterization of the EDAA library using modern analytical techniques [NMR (for structure and ee), LCMS, optical rotation] will be undertaken (aim 3). We have observed in the literature that EDAAs have been used in academic research in protein/peptide function and in drug discovery in both academics and in the pharmaceutical industry. Here, in particular, we know that a library of commercially available EDAAs would have a dramatic impact on medicinal chemistry SAR campaigns. We predict that availability of these diverse quaternary amino acids will produce fundamental achievements in science and medicine to benefit society, providing better drugs with fewer side effects.