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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