Chemistry 125: Lecture 30November 16, 2009
Preparing Single Enantiomers
Methods of resolution are described. The aldol reaction. 3D visualization. Omeprazole.
For copyright notice see final page of this file
Epimerization
(R,R)-Tartaric Acid meso-Tartaric Acid
(R,R) (R,S)
COOH
COOH
OH
OH
H
H
COOH
COOH
OH
H
H
HO
Change at One Center of Two (or many)
Racemization (R) (RS)Resolution
(S)+
1) Pasteur “Conglomerate”
Chiral-Resolved Seeding
Chiral-Resolved Poison
Crystalin Equilibrium withSaturated Solution
Crystal at EquilibriumInterior Molecules more stable than in solutionSurface Molecules less stable than in solution
Average Molecule same as solution
Lengthening Rate Depends on WidthMetastable(in solution)
Averagemoleculeless stable
than in solution
“Critical” NucleusAveragemolecule
more stablethan in solution
Resolution (R) (RS)
(S)+
1) Pasteur Conglomerate
Chiral-Resolved Seeding
Chiral-Resolved Poison
2) Temporary DiastereomersChromatography with Chiral-Resolved Support
Compound with Chiral-Resolved Mate
cont.
Influence nucleation
van’t HoffPrediction
1874C C C
C6H5
C10H7
OCOCH2COOH
C6H5
Brucine
KohlerWalkerTishler 1935
“Alkaloids”organic bases isolated from
plants
used to make diastereomeric
salts withracemic acids
KohlerWalkerTishler 1935
Levo144-146°C[]D -28.4°
mixed mp195°C
Mole ratiobrucine/acid
1.08
42% yield
Pasteur's"Bargain-Basement"Moldy Racemic Acidfrom Thann Pharmacy
(probably apocryphal anecdote via L. F. Fieser ~1960)
Penicillium glaucum had "eaten" (R,R)
Purified l-(S,S)-Tartaric Acid ???
(Remember the smell of carvones!)
React with One Enantiomer
Diastereomeric ReactionsHave Different Rates
React Racemate withResolved Chiral Reagentor Catalyst (e.g. Enzyme)
Nature's WayPrepare only one Enantiomer
Use resolved starting material
Or resolved reagent/catalyst
Nature can be Subtle and Surprising
“A reaction that Prof. McBride will talk about later on called the ‘aldol’ reaction…”
“What Levene did was to reduce it with yeast & sugar.”[add H2 to get optically active product!]
“It’ll reduce this.”
“The compound we want to get.”
“I confuse myself sometimes.”“What did I do wrong?”
CH2CH3
OC
H
OC
HCH3
H
O
O
C
H
CH3
H
H
H catalyst
as in Levene’s preparation of (R)-Butane-1,3-diol
The yeast may have oxidized the alcohol before reducing the aldehyde, and then reduced the ketone back to the alcohol.
CH2
^
“enolate”
CH2
OC
H
O
C
H
CH3
H CH2
OC
H
O
C
H
CH3
H
The yeast may have oxidized the alcohol before reducing the aldehyde, and then reduced the ketone back to the alcohol.
CH2
^
or
CH3 CH2
O
C
H
H OH
C
H
H
OH
C
H
HCH2
O
C
H
CH3
H
OC
H
O
C
H
CH3
H
CH2 CHO
CH
C
H
CH3
Enantiospecific reduction of (R) by yeast/sugar
(R)(S)What happens
to the (S)?
Eisai - 7389Purchase 5 stereocenters.Make the rest.1 by chiral Simulated Bed Chromatography.2 by allyl silane additions.2 by asymmetric dihydroxylations.2 by oxy-michael reactions.3 by asymmetric Ni/Cr reactions.1 by Jacobsen epoxidation.1 by conjugate reduction.1 by enolate alkylation1 by ketal formation
Best regards,
Frank
Only One Chiral Separation
Specific or general selective reactions that preferentially
form one isomer.
In starting materials
19 Stereocenters
Who Cares?Living Things
Food & Drug Administration
Drug Companiestheir Lawyers & USPTO (Patent Office)
"Chiral Switch"
Pain Reliever
COOH
Isobutyl
PropionicAcidPhenyl
Ibuprofen (Advil, Motrin)
(S) Active Pain Reliever
(R) Inactive
Sold as racemate
Sedative
Thalidomide
(S) Sedative
(R) Teratogen
Sold as racemate (1957-62)
N
N
OOO
O
H
(S) (R) 0.12 / hr (R) (S) 0.17 / hr
(S) eliminated 0.24 / hr (R) eliminated 0.08 / hr
in vivo racemization (human)
10,000 birth defects
?
O••
5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}1H-benzimidazole
Gastric Proton Pump Inhibitor (Acid Reflux)
World's largest selling drug in 2000 ($6.2B)
"Omeprazole""Prilosec"
omeprazole1
2
34
5
6 12
34
5
67
8
9
BenzimidazolePyridine
OTC ?
O••
5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}1H-benzimidazole
"Nexium"
O•• ••
Gastric Proton Pump Inhibitor (Acid Reflux)
World's largest selling drug in 2000 ($6.2B)
"Omeprazole""Prilosec"
"esomeprazole"
(racemate)
(S)
N
N
O
O
O
S T E R E OB I N O C U L A R S T E R E O
N
N
O
O
O
Stereoviewing
from X-rayof Ohishi et al. 1989 fromX-ray of Ohishi et al. 1989
(S)-Omeprazole - Stereopair View
left eye right eye
(S)-Omeprazole - Stereopair View
from X-ray ofOhishi et al. 1989
right-eye view left-eye view
Central frame perceived in stereo
How it should look when you
stare dreamily into the distance
“through” the stereo-pair above
until the blue lines “swim” together and superimpose.
Sulfide Sulfoxide
SRR'
••
••
SRR'
O
••
Gives Racemate of Course
End of Lecture 30Nov. 16, 2009
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