Synthetic Methodology ● Asymmetric Catalysis ● Chirality Sensing
Dynamic Stereochemistry ● Medicinal Chemistry
Research in the Wolf group is very interdisciplinary and includes organic reaction development, green chemistry, catalysis, chirality, optical sensing, high-throughput screening methodology and drug discovery. The expertise from our role in these highly synergistic research areas puts us in a unique position to push current frontiers in chemistry and in the health sciences. Our main interests lie in asymmetric (organo)catalysis, synthetic methodology development, organofluorine chemistry, stereoselective chemosensing, chiral recognition processes and supramolecular assemblies, transition metal catalyzed carbon-carbon and carbon-heteroatom bond formation and dynamic stereochemistry (especially chiral amplification and racemization reactions). We are also actively involved in several collaborative drug discovery efforts, in particular in anticancer research and in the development of treatments for Parkinson’sand Alzheimer’s disease. Selected examples of our research activities are highlighted below. For additional information, please check our publication list and twitter account. We are grateful for generous financial support from the National Institutes of Health, the National Science Foundation, the Petroleum Research Fund administered by the ACS, the Georgetown Environment Initiative and Merck.
New synthetic methods aimed at high-yielding carbon-carbon and carbon-heteroatom bond formation are developed in our laboratory. These efforts are guided by emerging mechanistic insights and systematic catalyst optimization strategies. The detection, trapping and structural elucidation of key reaction intermediates and products by crystallography, in-situ IR, NMR spectroscopy, mass spectrometry and other techniques often provide invaluable clues for methodology development. Significant emphasis lies on the introduction of new catalytic transformations and sustainable chemistry producing multifunctional building blocks that have broad synthetic utility and may serve as precursors for pharmaceuticals and natural products.
The ever-increasing demand for chiral compounds and the importance of fluorinated and chlorinated pharmaceuticals generate compelling motivation for the development of new synthetic methods that afford practical access to a wide variety of halogenated chiral building blocks. The introduction of new strategies that provide control of the unique stability and reactivity patterns of halogenated nucleophiles and electrophiles offers invaluable opportunities to streamline chemical synthesis of current and future drugs. The distinct chemistry of terminal ynamides as (pre)nucleophiles, which has been barely investigated to date, holds similar promise. With this in mind, we are developing new asymmetric methods for catalytic C-C bond formation using both traditional metal catalysis and organocatalytic methodologies.
It has become routine in academic and industrial laboratories to conduct hundreds of reactions in parallel using modern high-throughput experimentation (HTE) technology. The analysis of hundreds of asymmetric reactions, however, remains challenging as costs, time constraints, availability of only minute sample amounts from small scale reactions and waste management issues need to be considered. The constant quest for new chiral pharmaceuticals, agrochemicals and other biologically active compounds demands analytical means that effectively support asymmetric reaction development and optimization efforts. Our laboratory has developed a variety of (chir)optical chemosensors that allow simultaneous analysis of the absolute configuration, ee and total amount of a wide range of chiral compounds based on rapid UV, fluorescence and CD measurements. With these in hand, we are introducing practical assays that fully exploit the impact of HTE and streamline serendipitous asymmetric reaction screening. Our approach is compatible with modern workflow platforms, minimizes waste production and operational (consumables and labor) costs. The possibility of direct determination of yield, ee and absolute configuration using mg amounts of crude reaction mixtures (no work-up!) has been demonstrated several times by our laboratory.
Asymmetric transformations of the 1st and 2nd kind, (de)racemization, diastereomerization reactions and other stereomutations of chiral compounds play a key role across the chemical sciences and the analysis of these processes affords invaluable guidance for the development of asymmetric reactions and the design of chirality chemosensors. We employ variable-temperature NMR spectroscopy, polarimetry, circular dichroism and chromatographic techniques, in particular DHPLC combined with computer simulation of plateau-shaped HPLC elution profiles, to determine the stereodynamic properties of atropisomers and other chiral compounds. This has been particularly helpful for the development and refinement of several of our chirality sensors and for the study of medicinally relevant compounds such as peptoids and N-aryl glycines.
We have been involved in collaborative projects aimed at understanding drug/target interactions, drug resistance mechanisms and the development of structure-activity relationships that provide guidance for systematic development of anticancer agents and other drugs. We are particularly interested in the introduction of new therapies for Alzheimer’s and Parkinson’s disease. In addition, we develop highly specific molecular probes that detect and quantify important biomarkers such as D-amino acids and other biologically important compounds.