Chiral Catalysis for Therapeutic Drugs

1. Chiral Catalysis for Therapeutic Drugs • Organisms sense the chirality of bioactive compounds • Carvone enantiomers bind different chiral taste and odor sensors: • (S)-Carvone is a component of Dill and Caraway flavor • (R)-Carvone is a component of Spearmint flavor • Limonene enantiomers bind different chiral taste and odor sensors: • (R)-Limonene is a component of Orange flavor • (S)-Limonene is a component of Lemon flavor

2. Aspartame enantiomers bind different chiral taste and odor sensors: • One enantiomer of Aspartame is 160 times sweeter than sugar • The other enatiomer tastes bitter II. Chiral Drugs • Drugs are (or have been) frequently prepared as Racemic Mixtures • Usually, only one enantiomer is biologically active • The other was generally assumed to be completely inactive • Thalidomide is an example where the “silent” enantiomer was actually deadly

3. III. Origins of Chirality in Organisms • Several theories exist about how organisms became so stereoselective • Circularly polarized light is produced by some stars. • Differential interaction with enantiomers by polarized light • Destruction of one enantiomer by photoreactions results in enrichment of the other enantiomer • Organisms evolve in an environment containing enriched enantiomer • Resolution of racemic amino acids by chiral mineral faces • Some minerals crystallize with chiral crystal faces: CaCO3, calcite • Amino acids are strongly adsorbed to solid calcite • Evolving Organisms may have (by chance) grown on/near a certain chiral face of such a mineral where amino acids were resolved

4. All of our proteins are made from single enantiomer amino acids • Organisms only use L-amino acids 2) Organisms primarily use D-sugars L-amino acid D-amino acid

5. Chiral Transition Metal Catalysts help produce single enantiomer drugs • Changes in the Drug Industry • Currently, each enantiomer of a chiral drug must be tested and approved independently • Drug companies want to avoid racemic mixtures because of the added cost and potential for undesirable side effects • The percentage of single enantiomer drugs grew rapidly between 1989-2000

6. Organisms’ responses to enantiomers • Drug receptor sites (usually proteins) are themselves chiral • Chiral drugs may not be able to bind effectively to elicit the correct response

7. Production of a single enantiomer drug via chiral transition metal catalysts • Asymmetric Synthesis = production of a single enantiomer • Chiral ligands (“chiral auxiliary”) controls the way reactants can bind to the metal ion during a synthetic step catalyzed by the metal ion • The chiral auxiliary must be a pure enantiomer itself, so that only one enantiomer of the product is formed • Catalysts use one chiral ligand to produce (turnover) many molecules of a chiral product • Sharpless, Noyori, and Knowles won the 2001 Nobel Prize for this idea

8. Asymmetric Hydrogenation • Chiral ligands on hydrogenation catalysts can force interaction with only one face of a double bond during hydrogenation • Asymmetric Hydrogenation in the Synthesis of Naproxen • (S)-Naproxen is a well-known anti-inflammatory • (R)-Naproxen causes liver damage • (S)-BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) is used to make a chiral Ru catalyst (Noyori)

9. d. Reaction and Proposed Mechanism

10. Rhodium Catalyzed Synthesis of L-DOPA • L-DOPA is used in the treatment of Parkinson’s Disease • D-DOPA is not active, but becomes toxic when it builds up • Chiral DiPAMP Ligand used to make a chiral Rh(I) Catalyst (Knowles) • Stereoselective Hydrogenation yields L-DOPA

11. Iodosobenzene • Asymmetric Oxidations • Salen Complexes for Assymetric Epoxidations • Chiral centers close to the metal center • Simple to prepare—substituted salicylaldehyde plus chiral diamine • Stable to oxidation; range of oxidants can be used • Mechanism • Process Scale Production of a Potassium Ion Channel Activator

12. Sharpless Asymmetric Epoxidation • Uses Titanium complex of a chiral tartrate diester • Catalyst Strucure is thought to be a dimer c) Used to produce chiral intermediates for several chiral drugs