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
1957 Germany.
Anti-morning sickness.
60% fatality due to
Birth defects—limb
malformation major
outcome.
Never approved in U.S.

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

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. 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
Iodosobenzene

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