Total Synthesis Through the Lens of Chemical Informatics
Natural products (NPs) populate areas of chemical space that are remote from commercial compounds and thus challenging to access, modify and study. Our group develops new chemistry to accelerate access to nodes in NP space. These syntheses can be leveraged to assign mechanism of action, remove structural liabilities and perturb target selectivity. Recently, we developed new cross-coupling methods to access two alkaloids from Galbulimima and used this synthetic platform to discover their biological targets. We also developed short synthetic routes to picrotoxinin (PXN) and a more complex analog (5MePXN) that simplifies synthetic access, stabilizes the scaffold and allows diversification to probe selectivity among ligand-gated ion channels (LGICs).
Exploring Siderophore Scaffolds for Antibacterial Strategies
Siderophores are Fe(III)-chelating secondary metabolites that bacteria deploy to acquire iron, an essential nutrient, from the vertebrate host. We report the design and evaluation of siderophore-antibiotic conjugates based on the siderophore enterobactin. This siderophore is biosynthesized and utilized by enteric bacteria including Escherichia coli, Salmonella and Klebsiella. Antibacterial activity studies demonstrate that enterobactin-modified antibiotics are transported into Escherichia coli by the enterobactin uptake machinery and provide insight into the fate of enterobactin-antibiotic conjugates that have beta-lactam and fluoroquinolone antibiotic cargos. Moreover, we show that siderophore modification allows repurposing of an anticancer drug for targeted bacterial delivery. These studies provide a guide for further investigations of targeting siderophore uptake machinery in the design of non-traditional antibacterial agents.
Catalysis With Earth Abundant Metals as an Enabling Tool for Chemical Synthesis
Transition metal catalysis has revolutionized chemical synthesis. Reactions such as metal-catalyzed cross coupling, asymmetric hydrogenation and C–H functionalization have changed the way chemists approach bond constructions and ultimately expand molecular space. Our group has been studying catalytic transformations with iron and cobalt that exploit the unique electronic structures available to these elements that provide new reactivity or selectivity. My lecture will focus on the ability of iron and cobalt catalysts to promote selective C–H bond functionalization reactions that operate based on electronically-driven site selectivity. Specifically, we have been able to tune the C–H activation step to operate under either kinetic or thermodynamic control of site selectivity and open new areas of molecular space inaccessible by more traditional methods that rely on directing groups. Correlations between M–C bond dissociation energies and C–H bond strengths have been particularly instructive and will be highlighted throughout.
Designing Organic Materials for Electronics and Optoelectronics
Organic/polymer semiconductors are of growing interest towards providing solutions to many societal challenges, including information technologies, human health, and climate change. Organic materials capable of efficient charge transport, light emission, and light absorption can offer opportunities for creative molecular design and synthesis. In this talk, I will use several examples that span small discrete molecules and linear π-conjugated polymers to quasi-2D polymer architectures to illustrate our lab’s ongoing interest in the design of organic materials for electronic and optoelectronic device applications.
Complex Natural Products as a Driving Force for Discovery in Organic Chemistry
Our laboratory is deeply interested in the discovery and development of new reaction methodology en route to the chemical synthesis of complex bioactive molecules. Over the course of many years, research in our group at the California Institute of Technology has been pursued in the general area of synthetic chemistry, with a focus on the development of new strategies for the preparation of complex molecules. Concurrent to this program of target driven synthesis is a strong effort directed toward the development of new catalytic reaction methods, which will be useful for a range of applications. Typically, the complex target structure is used as an inspiration for the discovery of new reactions and technologies that may eventually be regarded as general synthetic methodology. Consequently, this approach provides access to a) novel, medicinally relevant structures, b) a general method for their synthesis, and c) new synthetic methods that will be beneficial for a host of applications. These topics will be discussed in the lecture.