Lecture 4a

Enantioselective Epoxidation I

Catalyst Design I• The catalyst possesses an asymmetric bridge that controls the access of

the alkene• Approach 1: Jacobsen• Approach 2: Katsuki• Main catalyst features

– Tert.-butyl groups in 3- and 5-position block the access from the front and the sides

– The asymmetric cyclohexane bridge controls the orientation of alkene during the approach: the smaller ligand R2 is preferentially oriented to the left side in both cases, which results in an e.e.-value < 100 %

NN

OO

Mn

L

HH

O

R1R2

R1

R2

1

4 4

3

2

R1 = large substituentR2 = small substituentL = promoter

1

2

Catalyst Design II

• Reactivity of catalyst– Donor groups i.e., methoxy, phenoxy, etc. attached to the benzene ring

lower its reactivity – Additives i.e., 4-phenylpyridine N-oxide (=PPNO) lower its reactivity

as well (=L in the diagram on the previous slide)– Both type of ligands above are electron-donating and increase the

electron-density on the Mn(III)-ion slightly, which decreases its electrophilic character

• The Mulliken charge on Mn atom according (Spartan, PM6) when X is located in 5,5’-position

Substituent Charge on Mn

H 1.985

tert.-Bu 1.982

OMe 1.981

NO2 1.987

Catalyst Design III• The activation energy of the first step will increase if an electron-

donating group is attached to the benzene ring

• This leads to an improved stereoselectivity in many reactions due to a late transition state (Hammond Postulate)– The stereochemical aspect during the approach of the alkene to the active

specie becomes more important because the oxo-ligand is transferred at a later stage because the Mn=O bond is stronger

– Example: 2,2-dimethylchromene: X=OCH3 (98 % ee), X=tert.-Bu (83 % ee), X=NO2 (66 % ee)

O

2,2-dimethylchromene

Catalytic Cycle

• The Jacobsen catalyst is oxidized with suitable oxidant i.e., bleach (r.t.), iodosobenzene (r.t.), m-CPBA (-78 oC) to form a manganese(V) oxo specie

• Due to its shallow nature, Jacobsen’s catalyst works well for cis, tri- and tetra-substituted alkenes, with the e.e.-values for these alkene exceeding often 90 %

R2

R3R4

R1R2

R3R4

R1

O

MnIII

O

N N

O

Cl

MnV

O

N N

O

O

L

Oxidant Cl-

Oxidant: NaOCl, PhIO, mCPBAL: Solvent, promoter

Mechanistic Studies I

• If cis alkenes are used as substrates, several pathways are possible.

R2

R1

(I)

MnV

O (II)

O

R1 R2

Mn

R1

OMn

R2

O

Mn

R1

R2

O

R1 R2

(III)

O

R1 R2

O

R1 R2

+

cis epoxide

trans epoxide

cis epoxide

(I) = concerted mechanism(II) = radical mechanism(III) = via manganoxetane intermediatea: R1 = alkyl, alkenyl, arylb: R1=R2=alkyl

Mechanistic Studies II

• Example 1: Cis/trans ratio for substituted cis-cinnamates

• Bottom line: – Electron-withdrawing ligands favor the formation of trans epoxide

over cis epoxides due to the longer life-time of the radical

R-group cis/trans eecis eetrans

OCH3 11.7 72 66CH3 7.0 79 41H 5.7 85 62CF3 0.8 79 55NO2 0.27 91 53

R

COOMe

R

COOMe

R

COOMe

O O

+(R,R)-JC

Mechanistic Studies III

• Example 2: Reactivity of dienes with Jacobsen’s catalyst

• Bottom line: – Cis alkenes are significantly more reactive than trans

alkenes (~5:1 above) – Donor substituted alkene functions are much more reactive

than acceptor substituted alkenes (~6:1 above)

n-Bun-Bu n-BuCOOEt

COOEtn-Bu n-Pent COOEt

17 83 85 15

70 30 >95 <5

Epoxide Chemistry

• Epoxides are very reactive good starting materials for many reaction, but also difficult to handle

• Example 1: Acid catalyzed hydrolysis leading to trans diols

• Example 2: Base catalyzed hydrolysis leading to diols

• Example 3: Acid catalyzed rearrangement i.e., silica column

O H+

OHOH2

OH

OH2-H+

OH

OH

O OH- O-

CH2OHOH2

OH

CH2OH

Ph

R1

R2

NaOCl

catayst Ph

R1

R2

O H+

Ph

R1

R2

O

Industrial Examples I

• Example 4: Diltiazem (anti-hypertensive, angina pectoris)

• Example 5: Ohmefentanyl (very powerful analgesic, used to tranquilize large animals i.e., elephants)

COO(i-Pr)

MeO

(R,R)COO(i-Pr)

O

MeO

NaOCl

96% ee

N

S

OAc

OMe

O

NMe2*HCl

N N

OOH

Industrial Examples II

• Example 6: Taxol (anti-cancer drug)• From 1967 to 1993 it was isolated from the bark of Pacific yew tree (Taxus

brevifolia) very negative environmental impact

• Bristol-Myers Squibb uses plant fermentation technology

R,R-JC/ 4-PPNO, NaOCl

96% ee

NH3/EtOH

Ph NH2

NH2

OH

O

1. Ba(OH)22. H2SO4

Ph OH

NH2

OH

O1. PhCOCl/ NaHCO32. HCl

Ph OH

NH

OH

O

O

Ph

AcO OH

OAcOPh O

NH

OH

O

O

Ph

OH

O

OOCPh

H

Ph COOEt

O

Ph COOEt