Asymmetric Synthesis of Unnatural α-Amino Acids: Applications to Natural Products

Florida Atlantic University, Boca Raton FL

Investigators

Linked publications, trials & patents

Abstract

7. Project summary. Given their unique structural features, non-proteinogenic ?-amino acids (Xaas) are prominent building blocks in biologically active molecules, non-ribosomal peptides and other marketed drugs. Even so, numerous classes of non-canonical amino acids remain untapped and their asymmetric syntheses complicated, which make them an exciting starting point for a rich discovery program. Despite enormous advances in the enantioselective synthesis of ?-amino acids, there is still no general and practical solution to the synthesis of enantiopure ?,?-disubstituted Xaas. Hence, we will address this issue by establishing novel maneuvers to synthesize different classes of non-proteinogenic Xaas in a straightforward one-pot fashion (overall aim). Preliminary findings in our laboratory validated two distinct asymmetric strategies to synthesize Xaas from ?-haloglycines: anion-binding catalysis and asymmetric counteranion-directed catalysis. The synthesis of ?-haloglycines was optimized to become operationally simple, practical and amenable to asymmetric functionalizations in the same pot as the main vantage point. This proposal seeks to provide innovative synthetic solutions for the synthesis of unusual ?-amino esters through enantioselective induction using hydrogen bond-donor catalysts and silver phosphates catalysts on glycine- and alanine-like iminium surrogates (aim 1). The asymmetric synthesis of ?,?-disubstituted Xaa to craft a tetrasubstituted ?-stereocenter via arylation is also proposed in a one-pot approach, catalyzed by some designed (thio)ureas anion-binding catalysts. These strategies will ultimately serve to synthesize some biologically active small-molecule natural products in the most expedient way: (+)-sorbicillactone A and (?)-fumimycin (aim 2). Both natural products are architecturally framed around a privileged ?-arylated alanine unit and represent a valid starting point for the biological investigations of anti-leukemic and antibacterial agents. It is anticipated that these studies will establish simple, catalytic and highly enantioselective methods for synthesizing several major classes of non-canonical ?-amino acids (and ???-disubstituted Xaas). Our novel one-pot tactic expands the synthetic toolbox of asymmetric catalysis in a platform for reaction discovery towards ?-amino acids. By providing broader access to these critically important building blocks, we seek to impact antibiotic peptides synthesis which will likely find important applications in biomedical research.