2nd Lecture Comb Chem. 5th Year Pharmacy 2016-2017

Combinatorial Chemistry Solid phase synthesis is rapid and efficient 11/17/2018 12:14:34 AM Combinatorial Chemistry Solid phase synthesis is rapid and efficient amino acid AA3 coupling & deprotection AA2 coupling & deprotection AA1 coupling & deprotection AA3 AA2 AA3 AA3 AA2 AA1 cleavage polystyrene bead AA1 AA2 AA3 • Reactions can be driven to completion using excess reagents and multiple couplings • Intermediates do not need to be purified • Final compounds are cleaved from the beads and purified by HPLC as necessary • Some procedures can be machine automated How do we synthesize these in the lab? Bruce Merrifield Nobel Prize Solid phase synthesis DISTRIBUTE BEADS couple amino acids can wash off all of the side products cleave final product one purification automated - when we send out for peptides, done with a machine now Professor R. Bruce Merrifield The Rockefeller University Nobel Prize, 1984

Combinatorial Chemistry Comparison of techniques 11/17/2018 12:14:34 AM Combinatorial Chemistry Comparison of techniques Larger Example: All 20 possibilities at 4 positions  20 x 20 x 20 x 20 = 160,000 possible tetrapeptides • Mixture Synthesis 4 positions x (1 coupling + 1 deprotection) = 8 reactions 1 mixture of 160,000 products • Parallel Synthesis 160,000 products x (4 couplings + 4 deprotections) = 1,280,000 reactions 160,000 individual products • Split–Pool Synthesis (20 possibilities x 4 couplings) + 4 deprotections = 84 reactions 160,000 individual products split–pool reaction arrow

Ground Rules Drug-like molecules Single compounds 20 µmol each. Purity priorities Flexible synthesis methods Automation as needed Drug-like molecules focus on non-peptide molecules Single compounds not mixtures, easier synthesis, to avoid cumulative effects, interferences 20 µmol each. enough to see, get an NMR, crystalize enough for >100 screens Purity priorities Samples free from reactive contaminants Good Quantitation of Compound Amount (biol log vs chem linear) Knowledge of contaminant structures not too worried about polypropylene Absolute purity- more aesthetic appeal than practical appeal Flexible synthesis methods Solid phase, solution phase, combination Automation as needed Investigate all processes manually and automate those that slow you down, hurt your arms or drive you crazy with the greatest priority.

Purification Methods Filtration Extractions Chromatography Salt Removal Covalent and Ionic Scavenging Resin Removal Extractions Liquid-Liquid SPE - Solid Phase Extraction Chromatography Silica C18 Based on using our reactor as a 96 position chromatography column/filter

Multicomponent Reaction 1. Passerini reaction 2. Ugi reaction

Creating a Library Using Ugi Chemistry

Multicomponent Reaction 3. Hantzsch reaction

References Walters, W.P., Stahl, M.T., Murcko, M.A. Drug Discovery Today 1998, 3,160-178. Short notes on Combinatorial Chemistry. By Faris Abachi 2005.