Chemistry 125: Lecture 34

Sharpless Oxidation Catalysts and the Conformation

of Cycloalkanes

Professor Barry Sharpless of Scripps Research Institute describes his Nobel-

prizewinning development of titanium-based catalysts for stereoselective oxidation,

the mechanism of their reactions, and their use in preparing esomeprazole.

Conformational energy of cyclic alkanes illustrates the use of molecular mechanics.

Synchronize when the speaker finishes saying

“Remember what the point of this synthesis was?” Synchrony can be adjusted by using the pause(||) and run(>) controls.

For copyright notice see final page of this file

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'

Nobel Prize 2001

THE HUMAN UMBILICAL CORD

Michaelson and Oshima

Ti V Cr

Mo

W

Mn

Tc

Re

Ru

Os

B C

Si

N

P

O

S

Se

Te

F

Cl

Br

I

Ti(OR)4

HOOC

COOH

OH

HO

R

R

"Weinsaure"

Tsutomu Katsuki’s famous “recipe”Stanford Chemistry Department (1980)

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

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!

"A man in California just won a Nobel Prize for mixing paint and wine!"

Los Angeles Times, October, 2001

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!

+

+ +

The Carvones

O O

(S) - ( + ) (R) - ( - )

Stretch

Bend

Stretch-Bend

Torsion

Non-1,4-VDW

1,4-VDW

TOTAL

Cyclobutane Puckering(by Molecular Mechanics)

Torsion vs. Bend

Relaxed

0.77

16.07

-0.92

11.23

-0.26

2.35

29.24

Planar

0.66

13.48

-0.78

14.81

-0.28

2.27

30.16

Stretch

Bend

Stretch-Bend

Torsion

Non-1,4-VDW

1,4-VDW

TOTAL

Cyclopentane Puckering(by Molecular Mechanics)

"Envelope"

Relaxed

0.31

2.14

-0.09

6.38

-0.51

3.19

11.42

Planar

0.19

0.51

0.02

11.53

-0.48

4.34

16.10

e.g. What is the source of the barrier

to c-hexane ring flip?

two butanegauche eclipsed

(~7 kcal/mole)

But why does the plastic model click?Baeyer Angle Strain

+7°+5°

-3°

+5°

Like a plastic model, molecular mechanics is satisfying because

not only does it say what a structure should be, it can also say “why”.

Are They “True”?

YES

Are Molecular MechanicsPrograms Useful?

NO

End of Lecture 34Dec. 3, 2008

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