Research in the Aron lab is focused on the development of molecular assembly lines as versatile tools for chemical synthesis. Using biosynthetic pathways as both starting point and inspiration, we are working to build reconfigurable multifunctional catalysts that allow specific access to a variety of structures. These efforts are multidisciplinary in nature, encompassing enzymology, protein engineering, directed evolution, peptide folding, nanotechnology, organic methodology and total synthesis.
The idea of hijacking biosynthetic machinery to generate new "natural" products has long been a goal of synthesis-minded biochemists. With the elucidation of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) mechanisms, this idea has become reality. PKS and NRPS are large multimodular enzymes that catalyze the programmable and iterative formation of natural products. Acting as molecular assembly lines, substrates are passed along PKS and NRPS through a series of covalent linkages, controlling substrate interactions with catalytic domains. Our research focuses on expanding the utility of PKS engineering by developing new methods that simplify assembly line modification and engineering new domains to access dramatically different products.
In addition to reengineering biochemical assembly lines, we are interested in developing synthetic assembly lines that can control a series of reactions in a single flask. Enroute toward this end, we are developing molecular conveyer belts that control the location of substrates as well as catalysts that act on these covalently tethered substrates. A representative catalyst that would work both as part of an assembly line and as a stand alone species is shown below. Tethering a chiral thio-Claisen catalyst to a nucleophilic thiol is expected to facilitate the mild and stereoselective formation of a,a-disubstituted amino acids.
Natural products inspire scientists in chemistry, biology and medicine. As we develop new methodologies, we will pursue relevant synthetic targets that both highlight our chemistry and explore important biological problems. Representative targets are shown below.
