Sharpless Asymmetric Epoxidation: Mechanism, Catalyst, and Applications, Study notes of Chemistry

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Sharpless Asymmetric

Epoxidation

R

O

H

R

R

R

O

R

O

H

R

R

R

"Magic"

Karl Barry Sharpless

Born in Philadephia in 1941

Ph.D from StanfordUniversity in 1968

Postdoc at Harvard and atStanford

Research on chiral synthesisand catalysts at the ScrippsInstitute

Received Nobel Prize in 2001for his work onstereoselective oxidationreactions

The Reaction

The catalyst is titanium tetra(isopropoxide) withdiethyltartrate.

The use of + or – tartrate will yield different enantiomers

Tertbutylperoxide is used as the oxidizing agent

Dichloromethane solvent and -20ºC temperature

R

OH

R

R

R

O

R

OH

R

R

R

Ti(O

i

Pr)

• (+) - DET

tBuOOH

R

OH

R

R

R

O

R

OH

R

R

R

Ti(O

i

Pr)

• (-) - DET

tBuOOH

CH

Cl

, -20ºC

CH

Cl

, -20ºC

The Catalyst

Via rapid ligand exchange of O

i

Pr and diethyl tartrate

O

O

O

O

Ti

C

H

3

CH

3

C

H

3

C

H

3

CH

3

CH

3

CH

3

C

H

3

OH

C

H

3

O

O

O

OH

O

CH

3

CO

Et

EtO

C

EtO

OiPr

O

O OiPr

O

iPrO

OiPr

O

O

O

Ti

Ti

OEt

Diethyl Tartrate (DET)Chirally controls reaction

Ti(O

i

Pr)

catalyst

Transition State

C

H

H

OEt

O

EtOOC

O O

O O

O

Ti

tBu

CH

H

OEt

O

EtOOC

O

O

O O

O

Ti

tBu

CH

Products

EtOOC

EtOOC

O O

OiPr

OiPr

OiPr OiPr Ti

CH

2

H

OEt

O

EtOOC

O

O

O

O

O

Ti

tBu

CH

CO

2

Et

EtO

2

C

EtO

OiPr

O

O

OiPr

O

iPrO

OiPr

O

O

O

Ti

Ti

OEt

tBuOH

H

H

H

O

OH

Improvements

• Many potential areas of improvement to the

original reaction

• Possible problems:
  • Stoichiometric amount of catalyst required– Water soluble substrates (Polymer Support)

cannot be isolated after reaction

• Requirement for low temperatures (high cost

for SAE)

• Some substrates react very slowly– Heterogeneous reaction?

Molecular Sieves

Original reaction requires stoichiometric amount ofTi(

i

OPr)

4

catalyst

Very reactive allyl alcohols need 50% catalysts – stillsignificant

Major reasons for failure of SAE reactions:

• Water destroys catalyst– Water ring-opens epoxide

3Å molecular sieves absorb water improving yield

Requirement of Ti catalyst reduced to <10% and thetartrate ester to <13%

Allyl alcohol concentration can be kept high since sidereactions are minimized (no ring opening)

Polymer Support

Metal catalyst is mounted on a polymer which makes it(usually) heterogeneous

Advantages:

• Lab scale: facilitate workup and isolation– Industry: continuous process– Minimizes catalyst loss during workup

Possible Polymers:

• silica gel (H

2

O

2

catalysts)

• alkaloid polymers– Polystyrene (heterogeneous Jacobson epoxidation)

Polymer support vital with water-soluble substrates

Polymer Support

• Early work with polystyrene had low %ee• A Scottish group used linear chiral poly(tartrate

esters)

• Combining benefits of polymer support with the

active functionality built in

• Reaction gives good yields and %ee• Branched poly(tartrate esters) were found to be

even more selective and had higher yields

Higher Temperatures SAE

• But the titanocene-tartrate cannot form

through ligand exchange (Ti-halidestable)

• Titanocene tartrate is generated before

the reaction:

In Situ Modification

• Ideal use for SAE is to make low molecular

weight chiral products – synthetic utility

• Low molecular weight substrates react slowly –

product is lost during workup

• The epoxide formed may also be ring-opened

during workup

• With molecular sieves, the catalyst

concentration is reduced, so solubility ofproduct also decreases

• Better solution is

in-situ

derivatization

Other Modifications

• Numerous minor modifications

to the classic SAE

• Ageing the catalyst: the catalyst

is synthesized fresh and “aged”for 30 minutes

• Alternative solvents: isooctane,

toluene

• The ester: diethyl tartrate vs.

diisopropyl tartrate

• Mesoporous silica support for

heterogeneous catalysis (MCM-41)

Structure

of catalytic

center

of

MCM

‐

41

Competing Methods

• Many competing

reactions forgenerating epoxides:

• Jacobsen-Katsuki

epoxidation

• Prilezhaev reaction• Shi expoxidation

R

1

R

2

aq. NaOCl

Mn-salen catalyst

CH

2

Cl

2

R

1

R

2

O

H

H

R

1

R

2

R

3

R

3

CO

3

H

R

2

O

H

R

3

R

1

R

1

R

2

Oxone

H

2

O,CH

3

CN

pH 10.

R

2

R

1

O

O

O

O

O

O

C

H

3

CH

3

O

C

H

3

CH

3