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Chemistry 125: Lecture 31
Preparing Single Enantiomers and
Conformational Energy After mentioning some legal implications of chirality, the discussion of configuration concludes using
esomeprazole as an example of three general methods for producing single enantiomers. Conformational
isomerism is more subtle because isomers differ only by rotation about single bonds, which requires
careful physico-chemical consideration of energies and their relation to equilibrium and rate constants.
Conformations have their own notation and nomenclature. Curiously, the barrier to rotation about the C-C
bond of ethane was established by measuring its heat capacity.
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For copyright notice see final page of this file
Legal Considerationsof Stereochemistry
McBride Disclosure
I have served as scientific consultant or expert witness to a number of pharmaceutical companies including Eisai.
I take Lipitor and served as an expert witness for a generic competitor in a case involving the validity of a Canadian Lipitor patent of Pfizer.
My only connection to AstraZeneca or Omeprazole is as an occasional consumer of Prilosec OTC.
1267-page“Bible” of
Stereochemistry(1994)
8 pp. on“Biological Properties”
Court Rejects Suit Over AstraZeneca Nexium Marketing
Tuesday November 8, 2005, 4:38 PM EST
WILMINGTON, Del. - (Dow Jones Newswire) - A federal court in Delaware Tuesday dismissed a class-action lawsuit that alleged AstraZeneca PLC's (AZN) misleading marketing of Nexium added billions to health-care costs.
U.S. District Judge Sue Robinson rejected the suit brought by the Pennsylvania Employee Benefit Trust Fund on behalf of entities that foot the bill in health- care plans.
Court Rejects Suit Over AstraZeneca Nexium Marketing
According to the health plan paying organizations, the big difference between the two drugs is not effectiveness, but advertising. By selling doctors and patients on the idea that patented Nexium is better than Prilosec, which faced generic competition, AstraZeneca was able to preserve billions in sales.
Judge Robinson said that the courts should defer to the U.S. Food and Drug Administration in weighing the differences between drugs and that since the FDA cleared Nexium's label, the lawsuit could not stand.
2003 Nexium mass-media advertising budget $260M
2005 advertising budget $226M; Sales $5.8B
Back to Chemistry
To test and manufacture Nexium AstraZeneca had to prepare
the single enantiomer
Resolutiona) Pasteur Conglomerate
b) Temporary Diastereomers
Destroy One EnantiomerReact Racemate with Resolved
Chiral Reagent or Catalyst
Prepare only one Enantiomera) Use resolved starting material
b) Use resolved reagent/catalyst
Resolution of Omeprazole
1) Chromatography on SiO2 coated with trisphenylcarbamoylcellulose (1990)
from Ph-N=C=O and Cellulose
Six Chromatograpy Injections 3 mg (+) , 4 mg (-)
Enough to Measure Racemization t1/2 : 1 hr at 75°C , ~100 hr at 37°C
Ph-N=C=O
Not enough for Human Dose (~20 mg)
n
R
R
R
RR
Ph-N C=O
H
R = R
Ph-N C=O
H
(like urea from NH3 + H-N=C=O)
H2C=O
OH
O
OHH
Resolution of Omeprazole2) Reversible formation of crystalline
mandelate ester (1994)
Hundreds of mg - enough for biological testing.(R) four times as active as (S) in rats. Reversed in humans!
N
SON
N
OCH3
H3CO
H
(S)-mandelic acid separate diastereomers by crystallization
H HC
OR
ORO
OEtO
O CO2Et
RO Ti
O
3) Chiral Catalysis by Titanium/Diethyltartrate
Ti(etc)
+RO
Ligand Exchange
Double Exchange with Diethyltartrate makes catalyst chiral
RO
~ racemic• •
OR
ORO
OEtO
O CO2Et
TiRO
O
3) Chiral Catalysis by Titanium/Diethyltartrate
Ti(etc)
ROO ••
RO+Ti
O
O
O
Ti(etc)
OEtO
CO2Et
O
RO
Ti
O
O
O
Ti(etc)
OEtO
CO2Et94% e.e. (3% R)• •
with added
iPr2NEt(discovered in 2000)
n
*
RSR'
O Ti
O
O
O
Ti(etc)
OEtO
CO2Et
+
(for no obvious reason)
catalyticcycle
RO
ROO
SR R'
Chiral “Oxidizing
Agent”
RSR'
+O
RSR'
O
RSR'
One "C" to Go
Composition
Constitution
"Stereoisomers"
distinction based onbonding model
Change by breakingbonds (van't Hoff)
Change by rotatingabout single bonds
(Paternó)
Isom
ers
Configuration
Conformation
HARD
EASY
All "isomers" representlocal energy minima
(not just differentphases of vibration)
Conformation
19th Century Organic Stereochemistry was
Qualitative.
Conformationinvolving rotational
isomerism about single bonds is more subtle,requiring quantitative
thought about equilibria, rates, & energies.
GenealogyBottomPhysical-Organic
Chemistry
Genealogy TopPhysical-Organic
Chemistry
In the late 19th Century organic chemists focused their efforts on molecular structure ,
while physical chemists focused on energy.
(sometimes to the exclusion of structure)
Principles of Chemistry
An Introduction to all Chemical Textbooks
by
Wilhelm Ostwald
1907
In all 554 pages Ostwald used the word “atom” only this once
- in the subordinate clauseof a footnote!
Footnote, p. 421
“Dalton, who developed the law of combining weights on the basis of an hypothesis he had pro-posed about the composition of matter from atoms, at first took hydrogen as unity, since it had the smallest ‘atomic weight’, i.e. combining weight.”
Dedication ofSterling Chemistry Laboratory
April, 1923
G. N.Lewis
(Student of Richards)
T. W.Richards
WilderBancroft
Students ofOstwald
“ Ostwald's gift for leadership showed itself in the wayhis pupils regarded him all through their lives.
Ostwald obituary by Wilder Bancroft (1933)
They usually believed whatOstwald said even when theyknew that he was not right.”
High St. Gibbs
Ostwald became fixated on energy because he was so impressed by
the man who lived here.
JosiahWillardGibbs
(1839-1904)
~1855
Physical Chemists were (and are)
Quantitativeabout
Equilibrium Constant (K)
Rate Constant (k)
Energy (E, or H, or G)
Energy determines what can happen (equilibrium)
K = e-E/kT
and how fast (kinetics) 10-(3/4)E kcal/mole
@ room Temp
k (/sec) = 1013e-E /kT‡
‡ 1013-(3/4)E kcal/mole@ room Temp
“activation” energy
Conformationinvolves
rotational isomerism about single bonds.
How Free is Single-Bond Rotation?Paternó (1869)
Not at allvan't Hoff (1874)
Entirely
(Note that all are shown eclipsed)
(Count Isomers) (Don’t Count Isomers)
as are both versions of the ACS
“molecule of the week” L-(+)-Tartaric Acid
H
H HH
H H
Eclipsed
H
H H
H
H H
The Newman Projection (1952)
Melvin Newman1908-1993
Yale '29, Ph.D. '32
YX
Y
X
Y
X
H
HH
H
H H
Staggered
Y
X
Anti
YX
Syn (or fully eclipsed)
YX
Gauche(+)(-)
H
H H
(+)(-)
conventional
by p
erm
issi
on J
. D. R
ober
ts
IUPAC "Basic Terminology of Stereochemistry"
Pure Appl. Chem. 68, 2193-2222 (1996)
prettypedantic
Is 3-Fold Barrier to Rotation Significant?
H
H HH
H HH
H HH
H H
H
HH
H
H H
H
HH
H
H H
H
HH
H
H HH
H HH
H H
H
HH
H
H H
0° 120° 240° 360°Torsional Angle
Ene
rgy
Is Energy Quantized in Triple Minimum?
Absorption of Heat by Ethane (1936)
cal /
mol
e / d
egre
e
Depends on how much Heat is absorbed,
For T = 298.1 K
Barrier (kcal/mole) SCalculated
0.0 56.40.3 56.33.1 54.6
SExperimental
54.8 0.2
€
∫0
T
CP
Td T
S "entropy"
and on the Temperature at which it is absorbed.
With larger quantized spacings, less Heat is
absorbed, and at higher T, smaller S.
1Kcal Harmonic Oscillator at RT
81.9%
2.7%14.8%
0.5% 0.1%
average
Equilibrium ratio of 0:1 quantum (or 1:2, etc.)?
103/4 = 5.6
1Kcal Harmonic Oscillator at RT
364 cal/mol
1.2 cal/mol K@ 300 K
(of 1.8)
average
at 1 kcal
0.8%
4.2%lowest level
33%
59%
6%
2.7%14.8%
81.9%
End of Lecture 31Nov. 19, 2008
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