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

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 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)

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/Diethyl Tartrate

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/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 )

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/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'

~ 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

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

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?

End of Lecture 32Nov. 19, 2010

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