The CTCMLD brings together exceedingly complementary expertise in organic synthesis, featuring a unique collaboration of five synthetic laboratories in three Chicago-area institutions, including Dr. Kozmin, Dr. Yamamoto and Dr. Rawal at the University of Chicago, Dr. Scheidt at Northwestern University and Dr. Gevorgyan at the University of Illinois at Chicago. In addition, the Chicago CMLD provides an effective mechanism for the cross-disciplinary integration of the core synthetic effort with the surface engineering expertise of Dr. Mrksich at Northwestern University and the cheminformatics expertise of Dr. Liang at the University of Illinois at Chicago. The Chicago CMLD brings a significant degree of collaboration within each project, as well as a considerable degree of integration between individual projects and the Core.

Project 1: Practical synthesis of new nitrogen-based heterocyclic libraries

This project focuses on the development of new, complex and drug-like heterocyclic libraries, which will be assembled in a highly practical, parallel manner. Success of this project relies on identifying an arsenal of methods and strategies for rapid, parallel construction of a range of new heterocyclic chemotypes. Newly developed methods and strategies are validated by synthesis of several new heterocyclic libraries for broad high-throughput biological screening.

Project Leaders – Karl Scheidt and Vladimir Gevorgyan

Project 2: Multi-component assembly of polyketide libraries

Polyketide-based natural products have been exceedingly valuable in several therapeutic areas, including infectious diseases (erythromycin A and amphotercin B), as well as immunology and oncology (rapamycin). The main focus of this project is to provide an exceedingly rapid access to polyketide-based compound libraries. Based on the pioneering studies of the Yamamoto laboratory, the team will design a series of new multi-component reactions, which will enable production of complex acyclic and cyclic polyketide arrays with an unprecedented level of efficiency.

Project Leader – Hisashi Yamamoto

Project 3: Assembly of scaffold-unbiased small-molecule libraries

Parallel introduction of scaffold diversity into small molecule libraries is, arguably, the most challenging conceptual problem of modern high-throughput organic synthesis. The resulting libraries are expected to probe a large segment of chemical diversity space increasing the probability of the identifying new bioactive compounds. We are developing several strategies that will enable parallel introduction of many diverse polycyclic scaffolds into new small-molecule libraries. Our approaches feature latest advances in [4+2] cycloadditions, as well as applications of gold and palladium catalysis, which enable a series of highly efficient and chemoselective polycyclization processes for scaffold diversification.

Project Leader – Sergey Kozmin

Project 4 – Development of tailored surfaces for new reaction discovery, miniaturized library synthesis and small molecule immobilazation

The existing methods employing insoluble polymeric supports for library synthesis suffer from several major limitations due to the difficulty of monitoring and optimizing heterogeneous reactions. We are using engineered surfaces of self-assembled monolayers on gold to provide a superior approach for facile, miniaturized library synthesis, which will enable us to efficiently monitor and optimize individual reactions using MALDI-TOF. This unique strategy is used for discovering new multi-component condensations, synthesis of libraries, and surface immobilizations of small-molecule arrays for subsequent biological screening.

Project Leader – Milan Mrksich