Coumarin Synthesis H N H O + O OH salicylaldehyde piperidine OEt O O OEt AcOH OEt diethyl malonate O O ethyl coumarin-3-carboxylate O 1) KOH 2) HCl OH O O coumarin-3-carboxylic acid Background: “Privileged Structures” in Drug Design A review of the structures of drug molecules and natural products reveals that there are certain substructure motifs that are frequently encountered. These have been dubbed “Privileged Scaffolds” or “Privileged Structures”.1 Their prevalence is due to a combination of factors. They have structural elements that are predictive for bioactivity (e.g. functional groups capable of hydrogen bonding with a protein). Many of these privileged structures already have arsenals of synthetic strategies for their construction, or are produced in nature by known biosynthetic pathways. There may also be an inherent bias for pharmaceutical chemists to reach for something already in their “bag of tricks” that had previously brought success.2 One such privileged structure, chromone,3 could be seen in the Aldol Lab handout. It forms the core of the flavone structure, which is biosynthesized via a chalcone. An example of a drug containing this substructure is pranlukast, which has been used to treat asthma. 1 Welsch, M.E.; Snyder, S.A.; Stockwell, B.R. Curr. Opin. Chem. Biol. 2010, 14, 347. 2 “Privileged Scaffolds” Derek Lowe Corante http://pipeline.corante.com/archives/2010/03/24/ privileged_scaffolds.php 3 Borges, F. et al. Chem. Rev. in print at time of writing; DOI: 10.1021/cr400265z O O O O chromone a flavone O O O NH N HN N N O pranlukast A similar privileged structure, coumarin, will be synthesized in this week’s lab. An example of an important drug that features this motif is warfarin, an anticoagulant that has also been used as rat poison. Warfarin was the result of research conducted at the University of Wisconsin in the 1930s and -40s, which was funded by the Wisconsin Alumni Research Foundation (hence “warfarin”)4 . The lead compound, dicoumarol, is found in moldy hay; an outbreak of cattle deaths in the 1920s that was caused by spoiled silage led to its discovery.5 OH O O coumarin 4 Meyer, O.O. Circulation 1959, 19, 114. 5 Link, K.P. Circulation 1959, 19, 97. O O O warfarin OH O OH O O dicoumarin O Procedure Hazards: Piperidine is flammable and toxic when ingested, inhaled or through skin contact. It can cause skin burns and eye damage. Piperidine has a powerful stench and can be detected at low concentrations. Use only in a fume hood, and stopper any flasks containing piperidine when moving them from one hood to another. Salicylaldehyde and diethyl malonate are combustible liquids that cause skin and eye irritation, and are harmful if swallowed. Ethanol is a flammable liquid. Acids and bases used are corrosive and can cause burns to eyes and skin. Day 1: ethyl coumarin-3-carboxylate: To a 50-mL round-bottom flask add salicylaldehyde (2.7 mL), diethyl malonate (4.8 mL), and absolute ethanol (12 mL). To this mixture carefully add piperidine (3.0 mL) followed by glacial acetic acid (5 drops). Add a stir bar and fit the flask with a condenser. Heat the solution at reflux for 1 h. Reaction progress may be monitored by TLC, using dichloromethane as the developing solvent. Allow the reaction mixture to cool below 60 °C, then add 15 mL of water to the flask. Chill the reaction mixture in an ice bath. Collect the solid product by suction filtration, washing with a small amount of chilled 50% aqueous ethanol. Transfer your product to a tared 50-mL round-bottom flask, cover the mouth of the flask with a kimwipe and rubber band, label the flask (compound name, your name, and date) and let the product air-dry in your fume hood until next day. Obtain the mass, and set aside a small amount for IR and melting point analysis. Your TA will also select one student’s product for NMR analysis. Day 2: coumarin-3-carboxylic acid: Prepare a solution of 4.0 g of KOH in 20 mL H2O, then add 8 mL of ethanol to this. Add the entire solution to your 50-mL flask containing your product from the previous day. Add a magnetic stir bar and fit the flask with a condenser. Heat the solution at reflux for 30 minutes. While your reaction mixture is being heated, chill 24 mL of 6 M HCl in an ice bath. At the end of the 30 min reaction period, remove the heating mantle, let your reaction mixture cool slightly (until it can be safely handled) and then finish the cooling in an ice bath. Add the cold HCl to the reaction mixture, which will cause your solution to crystallize from solution. Collect the product by suction filtration and allow it to air dry as long as possible before obtaining its mass, melting point, and IR spectrum. Your TA will select one student’s product for NMR analysis.