The creativity and varied interests of the students in the Schomaker group have led us to explore a broad range of different projects! These research areas encompass methodology development, the total synthesis of natural and unnatural products with intriguing biological activities, medicinal chemistry, computational and mechanistic studies, design of silver catalysts for tunable, chemo-, regio-, and enantioselective C-H amination reactions. Representative projects are described in the sections below; our publications page contains links to papers for more detailed information.
Oxidative allene amination for the exploration of new complex amine chemical space.
Natural products and pharmaceuticals that exhibit their bioactivity by binding to the ribosome often contain complex amine motifs embedded in arrays of contiguous heteroatom-bearing stereocenters. However, synthetic methods to construct densely functionalized and stereochemically rich amine motifs that might serve as useful building blocks for such compounds are challenging to prepare using conventional methods.
To address the need for new methods to rapidly deliver novel amine-containing molecular scaffolds, our group has developed creative ways to utilize allenes as flexible and convenient starting materials. A simple chemo-, regio- and stereocontrolled intramolecular allene aziridination furnish key bicyclic methylene aziridine intermediates that are easily manipulated to deliver significant diversity in new amine chemical space. The scheme below highlights some of the transformations we have achieved in a few steps from an allene precursor.
Design and syntheses of molecules that bind the ribosome.
The majority of drugs that inhibit protein synthesis by binding to the ribosome are derived from natural product sources, including the tetracyclines, aminoglycoside antibiotics, and macrolide antibiotics. The complexity of the ribosome and the difficulty of carrying out structure-activity relationship studies in molecules based on natural products has stimulated interest in identifying molecules that: 1) are capable of binding to the ribosome, 2) show selectivity in binding pathogen over human ribosomes, and 3) can be readily manipulated using versatile synthetic methods to enable structure-activity relationship studies that shed insight into how useful function can be introduced into new molecular scaffolds. Interestingly, it has been shown that minor changes to the core of pactamycin, an anti-malarial and anti-tumor aminocyclopentitol natural product, can significantly decrease toxicity towards mammalian cells. We are currently targeting analogs of jogyamycin to determine which structural features contribute to toxicity in order to tune selectivity in binding to pathogen over human ribosomes. In addition, we are working towards the first total synthesis of jogyamycin that harnesses a key tandem Ichikawa/[3.3]-sigmatropic rearrangement strategy to install two of the vicinal amine stereocenters
Collaborative studies of a small subset of our novel amine library revealed compounds that show selective binding to E. coli A-site rRNA over human rRNA, stimulating interest in carrying out further SAR and ADMET/PK studies with the UW-Medicinal Chemistry Center and other collaborators. Other promising results showing anti-cancer, anti-tuberculosis, and antimalarial activities will be examined to determine if binding to the ribosome is the primary mechanism of action.
We are interested in investigating analogs of doxorubicin (DOX), a potent anti-tumor drug that displays significant cardiotoxicity and other side effects. The introduction of rationally designed bicyclic aminosugars into the aglycone is proposed to both improve binding specificity and lower the toxicity associated with anthracycline antibiotics in this class of compounds. In addition to the above-described efforts, we continue to seek molecules with stereochemically complex and intriguing molecular architectures with the potential to exhibit selective bioactivities by engaging the ribosome.
Diastereo- and enantioselective methods for the syntheses of highly substituted carbocycles.
In addition to our efforts in oxidative allene amination efforts, we are expanding the impact of our chemistry to engage allenes as convenient three-carbon synthons for the preparation of densely substituted carbocycles. Projects currently under investigation are inspired by molecules with potential neuroprotective activities, including bilobalide and members of the cyathane diterpenoid family of natural products. For example, inspired by the biosynthetic pathway involving the cyclization of a methylene epoxide to a cyclopentenone by allene oxide cyclase, we have developed a method to convert conjugated allenes to α,β-unsaturated cyclopentenimines. Future directions include promoting an enantioselective ‘imino-Nazarov’, other elaborations of the product scaffold, and applications of the method to drugs and natural products.
Catalyst-controlled C-H functionalization reactions.
The C-H bond is ubiquitous in common building blocks for organic synthesis. While significant progress has been made in utilizing substrate control to achieve selectivity in C-H functionalization reactions, predictable and tunable catalyst- or reagent-controlled C-H amidations are rare outside of enzyme evolution. Catalysts designed to target a specific C-H bond in the presence of multiple other reactive C-H bonds could enable new retrosynthetic strategies for complex molecule synthesis and exploit novel chemical space through mild and selective late-stage C-H functionalizations. We have been addressing this long-standing challenge in the field through experimental and computational studies of silver-catalyzed nitrene transfer chemistry, where the diversity of coordination geometries in Ag(I) complexes enables unique and tunable chemo-, regio- and stereoselectivities in transformations of C-H bonds to new C-N bonds. Thus far, we have designed and successfully demonstrated the ability of silver catalysts to achieve: 1) tunable control over chemoselective nitrene transfer to favor either aziridination or C-H bond insertion, 2) tunable, site-selective C-H bond amination, and 3) enantioselective intramolecular aziridination. Ongoing projects are focused on extending the scope and utility of tunable, site-selective intermolecular nitrene transfer, designing new asymmetric catalysts for nitrene transfer, carrying out late-stage amidations of complex molecules and extending our design principles to other metals to transform X-H and C-H bonds to new X-C and C-X bonds.
Cu(I)-catalyzed halogen migration.
In 2012, we described synthetic and mechanistic studies of an unusual Cu-catalyzed 1,3-halogen migration reaction. Computations suggested that the reaction proceeds through an unusual Cu(I)-aryl species.
Current efforts are focused on harnessing the key aryl-Cu(I) species to carry out other transformations, including additions to other coupling partners and transmetallation/cross-coupling reactions. For example, while hydrocupruation and borocupration of styrene derivatives have been explored by others, we are This net cross-electrophile coupling is one of a kind, allowing the retention of a halogen and proceeding through copper catalysis.
Unified strategies for the syntheses of N-heterocycles via aziridinium ylides.
Despite the breadth of synthetic approaches for N-heterocycle synthesis, unified approaches to stereochemically complex four- to seven-membered rings from simple precursors are rare. To meet this need, we are exploring tandem nitrene/carbene transfer reactions that proceed through the intermediacy of an unusual aziridinium ylide. Attractive features of this chemistry include simple precursors, the ability to tap into previously inaccessible bond disconnections, wide catalyst availability for both nitrene and carbene transfer, rapid assembly of molecular complexity, mild reaction conditions, and exciting potential for powerful asymmetric methods.
Exploring the utility of SNO-OCTs, new tunable bioorthogonal labeling reagents.
We have reported heterocyclic strained cyclooctynes (SNO-OCTs) that display unusual properties compared to other cycloalkynes typically used in biorthogonal labeling.
In collaboration with the Raines group, we have prepared 2nd-generation SNO-OCTs and are studying their utility for mutually exclusive bioorthogonal labeling in living cells. Future opportunities will explore the potential of designer SNO-OCTs for the preparation of drug-antibody conjugates, and the application of this tunable scaffold by incorporating SNO-OCTs into biological building blocks (e.g. protein, DNA and RNA) as probes for in vivo studies.
Radical additions to allenes.
In contrast to the addition of radicals to alkenes, the regio- and stereocontrolled addition of similar species to allenes is far less explored. We are currently investigating inter- and intramolecular additions of a variety of recently reported radical sources to allenes with the goal of achieving tunable and selective strategies that enable ready access to highly functionalized synthetic building blocks.
Development of an all-optical electrophysiology system.
In collaboration with the Chanda group in the Department of Neuroscience, we are investigating whether synthetic small molecule ionophores offer unique advantages compared to patch-clamp or optogenetics-based approaches to carrying out electrophysiological measurements. Given their ability to transport ions in biphasic solutions, crown ether azobenzenes and dibenzo crown ether were selected as models to probe ion transport in bilayers. We are also pursuing the design of synthetic ion channels that mimic the biological functions of natural ion channels to achieve both spatial and temporal control in controlling and measuring membrane potential.
For further information, see our articles on the Publications page and, for the latest, our Group News.