Combinatorial Chemistry - High Throughput Organic Synthesis

Wright State University
City, State: 
Detroit, MI
Daniel Ketcha (Wright State University) and Richard T. Taylor (Miami University)

This workshop is intended to familiarize participants with the concepts, terminology and basic experimental techniques associated with the emerging approach to organic synthesis termed "Combinatorial Chemistry". For all practical purposes, this general term is best appreciated as the myriad techniques designed for the rapid and efficient synthesis, analysis and evaluation of diverse collections of compounds (libraries). While commonplace in industrial settings such as the pharmaceutical industry, such techniques are not normally encountered in academic research or teaching laboratories. Therefore, the goal of this workshop is to promote and encourage the acceptance of such technologies into the general undergraduate and graduate curricula in order to better train students for industrial careers. For while many college graduates entering the chemical industry routinely will employ the synthesis and purification techniques associated with multiple-parallel synthesis, few would likely have had prior experience therein since the area of solid-phase synthesis is distinctly different from the normal instructional laboratory milieu, having it's own repertoire of solid-supports, linkers and reaction types. The present workshop will provide hands-on exposure to both solid-phase and solution-phase techniques most adaptable to an academic setting.

Day 1 Lectures: Introduction to Combinatorial Chemistry and Solid-Phase Organic Synthesis; Equipment Employed for Multiple-Parallel Synthesis

Day 2 Lectures: Resins and Linkers; Small Molecule Libraries

Day 3 Lectures: Solution-Phase Synthesis; Polymer Supported Reagents and Scavengers

Day 4 Lectures: Solution-Phase Synthesis; Catch and Release Methods; Purification Strategies

Day 5 Lectures: Review: Discussion of Technology Transfer to Undergraduate Laboratories

The planned laboratory activities include:

  • Solid-Phase Suzuki Coupling Reaction: Participants will use a platform shaker and peptide reaction vessels to attach iodobenzoic acids to Wang resin by normal coupling procedures. Palladium-catalyzed coupling with boronic acids and cleavage from the solid-support will provide biary compounds.  
  • Catalyst Development: Participants will use a 96 well format to prepare a small library of catalysts for the dehydration of an aldol at pH 7 and the library will be screened by UV spectroscopy
  • Hydantoin Library: Participants will utilize a Quest 210 automatic synthesizer to prepare a hydantoin library from Wang supported amino acids and isocyanates utilizing a cyclizative cleavage step to release the products from the resin. The completeness of each step in the process will be monitored using the Kaiser color test. Catch and Release
  • Synthesis of Amides and Sulfonamides: Participants will utilize the Advanced Chemtech Labmate for the solution-phase acylation of amines using inexpensive ion-exchange resins.
  • Azo Dyes: Participants will use a 96 well format to prepare a variety of azo dyes using polymer bound nitrite along with scavenger resins.  

The laboratory will be held at the Wright State Combinatorial Chemistry Facility. This facility is equipped with a variety of multiple-parallel synthesizers including an Argonaut Technologies Quest 210, Advanced Chemtech Labmates (2), and Argonaut First-Mate systems. As mentioned above, the laboratory portion of this workshop will strive to foster competence in the now standard protocols for the rapid creation of chemical diversity while avoiding heavy reliance on automated technologies not likely to adopted by academic laboratories. Therefore, several more economical formats including shaker vessels will be used in conjunction with the automated synthesizers described above. Resources available for this workshop include a HP diode array UV spectrophotometer, HP GC/MS with an 8 sample autosampler, PE LC with Waters photodiode array detector, a Chromatron, and LC/MS.