Efficient Large-Scale Synthesis of CAT811, a Potent Calpain Inhibitor of Interest in the Treatment of Cataracts

Abstract

A high-yielding, short, and scalable synthesis of a potent calpain 2 inhibitor (CAT811) is reported. The key step in the sequence involves an intramolecular macrocyclization of a 6-iodonorleucine residue to the side chain of tyrosine.

Molecular Modeling: A Search for a Calpain Inhibitor as a New Treatment for Cataractogenesis

“…Ring closing metathesis, a proven route to macrocyclization, could be used to form each macrocycle . We have subsequently explored other routes that have proved to be more amenable to large scale production of compounds that have been shown to be of particular commercial interest …”

ORGANIC-08 Research Highlights

“…natural and non-natural products (Professor Martin Banwell (ANU), 'A Total Synthesis of the Marine Alkaloid Ningalin B from (S)-Proline', [6] Professor Mark Rizzacasa (Melbourne), 'Formal Total Synthesis of (+)-Citrafungin A', [7] and Dr Kate Jollife (Sydney), 'Solid-State and Solution-Phase Conformations of Pseudoproline-Containing Dipeptides' [8] ), natural products chemistry (Professor Mary Garson (Queensland), 'The Absolute Configurations of Haliclonacyclamines A and B Determined by X-Ray CrystallographicAnalysis' [9] ), medicinal chemistry (ProfessorAndrewAbell (Adelaide), 'Efficient Large-Scale Synthesis of CAT811, a Potent Calpain Inhibitor of Interest in the Treatment of Cataracts' [10] ), supramolecular chemistry and nanotechnology (Professor Steven Langford (Monash), 'Synthesis and Photophysical Properties of a Conformationally Flexible Mixed Porphyrin Star-Pentamer', [11] and Dr Pall Thordarson (UNSW), 'The Effect of Unsaturation on the Formation of SelfAssembled Gels from Fatty Acid l-Serine Amides and their Cytotoxicity Towards Caco-2 Cancer Cells' [12] ), and mechanistic and physical organic chemistry (Professor Stephen Glover (UNE), 'S N 2 Substitution Reactions at the Amide Nitrogen in the Anomeric Mutagens, N-Acyloxy-N-alkoxyamides' [13] ).…”