chemistry 125: lecture 32 november 19, 2010 resolution, chiral catalysis, and conformational energy...
TRANSCRIPT
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Chemistry 125: Lecture 32November 19, 2010
Resolution, Chiral Catalysis,and Conformational Energy
Discussion of configuration concludes using esomeprazole as an example of three
general methods for producing single enantiomers. A modification of Sharpless chiral
catalyst for allylic epoxidation is used to prepare esomeprazole commercially.
Conformational isomerism is more subtle than configurational 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. How high is the barrier to
rotation about the C-C bond of ethane? If we knew we could estimate the rate of
rotation using the 10^(13-3/4 H*) trick. For copyright notice see final page of this file
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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.
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1267-page“Bible” of
Stereochemistry(1994)
8 pp. on“Biological Properties”
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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.
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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
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Back to Chemistry
To test and manufacture Nexium AstraZeneca had to prepare
the single enantiomer
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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
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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 nearly enough for one 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)
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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
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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
Gen
eral
ly lo
se h
alf
of th
e m
ater
ial
(but see Levene’s 1,3-butandiol)
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OR
ORO
OEtO
O CO2Et
RO Ti
O
3) Chiral Catalysis by Titanium/Diethyl Tartrate
R
+RO
Ligand Exchange
Double Exchange with Diethyltartrate makes catalyst chiral
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CH2CHO
HCC
H
OH
CH2
H
OR
ORO
OEtO
O CO2Et
TiRO
O
3) Chiral Catalysis by Titanium/Diethyl Tartrate
R
ROO ••
RO+Ti
O
O
O
R
OEtO
CO2Et
O
RO
Ti
O
O
O OEtO
CO2Et
*
RCH2
HC
CCH
H
allyl alcohol
(R)-“epoxide”
(S)-epoxide precursor
Chiral“Oxidizing Agent”
LUMO?
HOMO?
is diastereomeric!
( also pO + *C=C )
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R''R
R' OH
R'' R
O
R'OH
70 - 90% yield > 90% ee
(CH 3 ) 3 COOH, Ti (O i Pr) 4
CH2Cl2 , – 20°C
"O"
"O" L - (+) - diisopropyl tartrate (natural)
D - (–) - diisopropyl tartrate (unnatural)
Asymmetric Epoxidation of olefins
Tsutomu Katsuki’s discovery -- a memorable day
in 1980 at Stanford University!
K. B
Sha
rple
ss, w
ith
perm
issi
on
General !
i.e. 95:5
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K. B
Sha
rple
ss, w
ith
perm
issi
on
5% L-Tartaric Acid
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K. B
Sha
rple
ss, w
ith
perm
issi
on
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K. B
Sha
rple
ss, w
ith
perm
issi
on
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N
S N
N
O
O
H
OO*
H
EtOOCCOOEt
OH
OH
N
S N
N
*O
O
O
H
(S)
(S)-Omeprazole 'Nexium'
TT ii (OiPr)4
(D)-(-)-Diethyl Tartrate
Launched by AstraZeneca in 2000
$$$
Tsutomu Katsuki's now Famous Recipe-- He discovered it on January 18th, 2002 at Stanford University!
+
+ +
K. B
Sha
rple
ss, w
ith
perm
issi
on
1980
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RO
~ racemic• •
OR
ORO
OEtO
O CO2Et
TiRO
O
3) Chiral Catalysis by Titanium/Diethyl Tartrate
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
LUMO*
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'
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~ racemic• •
OR
ORO
OEtO
O CO2Et
TiRO
O
3) Chiral Catalysis by Titanium/Diethyl Tartrate
Ti(etc)
ROO ••
RO+Ti
O
O
O
Ti(etc)
OEtO
CO2Et
O
RO:
Ti
O
O
O
Ti(etc)
OEtO
CO2EtRO
94% e.e. (3% R)• •
add
iPr2NEtAstraZeneca (2000)
H
H H
H
LUMO *
RSR'
O Ti
O
O
O
Ti(etc)
OEtO
CO2Et
+
(for no obvious reason)
catalyticcycle
RO
ROO
SR R'
Chiral “Oxidizing
Agent”
RSR'
nO
RSR'
O
RSR'
add
H2O!Kagan, Pitchen
(1983)+R
O
RO
Still
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DFT calculation bySzabó, et al. (2009)
N(CH3)3CH3-O-O
Ti
R-S-CH3
CRUNCH!
Something New inthe Molecular Model!
O
O
bent by 7°SS
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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
EASYConformation
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19th Century Organic Stereochemistry was
Qualitative.
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Conformationinvolving rotational
isomerism about single bonds is more subtle,requiring quantitative
thought about equilibria, rates, & energies.
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GenealogyBottomPhysical-Organic
Chemistry
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Genealogy TopPhysical-Organic
Chemistry
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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)
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Principles of Chemistry
An Introduction to all Chemical Textbooks
by
Wilhelm Ostwald
1907
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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.”
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Dedication ofSterling Chemistry Laboratory
April, 1923
G. N.Lewis
(Student of Richards)
T. W.Richards
WilderBancroft
Students ofOstwald
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“ 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.”
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High St. Gibbs
Ostwald became fixated on energy because he was so impressed by
the man who lived here.
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JosiahWillardGibbs
(1839-1904)
~1855
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Physical Chemists were (and are)
Quantitativeabout
Equilibrium Constant (K)
Rate Constant (k)
Energy (E, or H, or G)
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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
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Conformationinvolves
rotational isomerism about single bonds.
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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
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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 (but rare)
by p
erm
issi
on J
. D. R
ober
ts
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IUPAC "Basic Terminology of Stereochemistry"
Pure Appl. Chem. 68, 2193-2222 (1996)
prettypedantic
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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?
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End of Lecture 32Nov. 19, 2010
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