Chiral Catalysis for Therapeutic DrugsI. Organisms sense the chirality of bioactive compounds

A. Carvone enantiomers bind different chiral taste and odor sensors:

1) (S)-Carvone is a component of Dill and Caraway flavor

2) (R)-Carvone is a component of Spearmint flavor

B. Limonene enantiomers bind different chiral taste and odor sensors:

1) (R)-Limonene is a component of Orange flavor

2) (S)-Limonene is a component of Lemon flavor

C. Aspartame enantiomers bind different chiral taste and odor sensors:

1) One enantiomer of Aspartame is 160 times sweeter than sugar

2) The other enatiomer tastes bitter

II. Chiral DrugsA. Drugs are (or have been) frequently prepared as Racemic Mixtures

1) Usually, only one enantiomer is biologically active

2) The other was generally assumed to be completely inactive

B. Thalidomide is an example where the “silent” enantiomer was actually deadly

III. Origins of Chirality in OrganismsA. Several theories exist about how organisms became so stereoselective

1) Circularly polarized light is produced by some stars.

a) Differential interaction with enantiomers by polarized light

b) Destruction of one enantiomer by photoreactions results in enrichment of the other enantiomer

c) Organisms evolve in an environment containing enriched enantiomer

2) Resolution of racemic amino acids by chiral mineral faces

a) Some minerals crystallize with chiral crystal faces: CaCO3, calcite

b) Amino acids are strongly adsorbed to solid calcite

c) Evolving Organisms may have (by chance) grown on/near a certain chiral face of such a mineral where amino acids were resolved

B. All of our proteins are made from single enantiomer amino acids

1) Organisms only use L-amino acids

2) Organisms primarily use D-sugars

L-amino acid D-amino acid

IV. Chiral Transition Metal Catalysts help produce single enantiomer drugsA. Changes in the Drug Industry

1) Currently, each enantiomer of a chiral drug must be tested and approved independently

2) Drug companies want to avoid racemic mixtures because of the added cost and potential for undesirable side effects

3) The percentage of single enantiomer drugs grew rapidly between 1989-2000

B. Organisms’ responses to enantiomers

1) Drug receptor sites (usually proteins) are themselves chiral

2) Chiral drugs may not be able to bind effectively to elicit the correct response

C. Production of a single enantiomer drug via chiral transition metal catalysts

1) Asymmetric Synthesis = production of a single enantiomer

2) Chiral ligands (“chiral auxiliary”) controls the way reactants can bind to the metal ion during a synthetic step catalyzed by the metal ion

3) The chiral auxiliary must be a pure enantiomer itself, so that only one enantiomer of the product is formed

4) Catalysts use one chiral ligand to produce (turnover) many molecules of a chiral product

5) Sharpless, Noyori, and Knowles won the 2001 Nobel Prize for this idea

D. Asymmetric Hydrogenation

1. Chiral ligands on hydrogenation catalysts can force interaction with only one face of a double bond during hydrogenation

2. Asymmetric Hydrogenation in the Synthesis of Naproxen

a. (S)-Naproxen is a well-known anti-inflammatory

b. (R)-Naproxen causes liver damage

c. (S)-BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) is used to make a chiral Ru catalyst (Noyori)

d. Reaction and Proposed Mechanism

3) Rhodium Catalyzed Synthesis of L-DOPA

a) L-DOPA is used in the treatment of Parkinson’s Disease

b) D-DOPA is not active, but becomes toxic when it builds up

c) Chiral DiPAMP Ligand used to make a chiral Rh(I) Catalyst (Knowles)

d) Stereoselective Hydrogenation yields L-DOPA

E. Asymmetric Oxidations

1. Salen Complexes for Assymetric Epoxidations

a. Chiral centers close to the metal center

b. Simple to prepare—substituted salicylaldehyde plus chiral diamine

c. Stable to oxidation; range of oxidants can be used

d. Mechanism

2. Process Scale Production of a Potassium Ion Channel Activator

Iodosobenzene

2) Sharpless Asymmetric Epoxidation

a) Uses Titanium complex of a chiral tartrate diester

b) Catalyst Strucure is thought to be a dimer

c) Used to produce chiral intermediates for several chiral drugs