Chiral Catalysis for Therapeutic Drugs
I.
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 Drugs
A.
B.
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
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.
III. Origins of Chirality in Organisms
A.
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
L-amino acid
2)
Organisms primarily use D-sugars
D-amino acid
IV. Chiral Transition Metal Catalysts help produce single enantiomer drugs
A.
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)
4)
5)
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
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
Iodosobenzene
a.
b.
c.
d.
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
2.
Process Scale Production of a Potassium Ion Channel Activator
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