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Chemistry 125: Lecture 32November 20, 2009
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. Curiously,
the barrier to rotation about the C-C bond of ethane was established by measuring its heat capacity.
For copyright notice see final page of this file
Resolution of Omeprazole
1) Chromatography on SiO2 coated with trisphenylcarbamoylcellulose (1990)
Six Chromatograpy Injections 3 mg (+) , 4 mg (-)
Enough to Measure Racemization t1/2 : 1 hr at 75°C , ~100 hr at 37°CNot enough for Human Dose (~20 mg)
n
R
R
R
RR
Ph-N C=O
H
R = R
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
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)
OR
ORO
OEtO
O CO2Et
RO Ti
O
3) Chiral Catalysis by Titanium/Diethyltartrate
R
+RO
Ligand Exchange
Double Exchange with Diethyltartrate makes catalyst chiral
CH2CHO
HCC
H
OH
CH2
H
OR
ORO
OEtO
O CO2Et
TiRO
O
3) Chiral Catalysis by Titanium/Diethyltartrate
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 )
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
K. B
Sha
rple
ss, w
ith
perm
issi
on
5% L-Tartaric Acid
K. B
Sha
rple
ss, w
ith
perm
issi
on
K. B
Sha
rple
ss, w
ith
perm
issi
on
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
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'
~ 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
CO2EtRO
94% e.e. (3% R)• •
add
iPr2NEtAstraZeneca (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'
add
H2O!Kagan, Pitchen
(1983)+R
O
RO
Still
DFT calc. bySzabó, et al. (2009)
N(CH3)3CH3-O-O
Ti
R-S-CH3
CRUNCH!
Something New inthe Molecular Model!
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
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 (but rare)
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%
Is the Minimum eclipsed or staggered?
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
3 kcal/mol
End of Lecture 32Nov. 20, 2009
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