Sharpless Asymmetric

Epoxidation
2 3
R R O
"Magic" 2 3
R R
1 4 1 4
R R R R
HO HO
 Karl Barry Sharpless
• Born in Philadephia in 1941
• Ph.D from Stanford
University in 1968
• Postdoc at Harvard and at
Stanford
• Research on chiral synthesis
and catalysts at the Scripps
Institute
• Received Nobel Prize in 2001
for his work on
stereoselective oxidation
reactions
 Sharpless Asymmetric Epoxidation
(SAE)
3
R 3
R
1 O
R OH 1
R OH
2 4 2 4
R R R R

- Converts primary and secondary allylic alcohols

into 2,3 epoxyalcohols
-The reaction is enantioselective (only one
enantiomer produced)
-Enantiomer formed depends on stereochemistry of
catalyst
 2 1
The Reaction R
2
1
R R R
Ti(OiPr)4 - (+) - DET
OH O
3 OH
R tBuOOH
R
4 CH2Cl2, -20ºC R
3
4
R
2 1 2
R R R 1
R
Ti(OiPr)4 - (-) - DET
OH O
3 OH
R tBuOOH
R
4 CH2Cl2, -20ºC R
3
4
R
• The catalyst is titanium tetra(isopropoxide) with
diethyltartrate.
• The use of + or – tartrate will yield different enantiomers
• Tertbutylperoxide is used as the oxidizing agent
• Dichloromethane solvent and -20ºC temperature
 The Catalyst
CH3
H3C
O CH3
H3C O
Ti EtO
O CH3
H3C O O CO2Et
CH3 O
H3C OiPr
Ti(OiPr)4 catalyst O O OEt
Ti Ti
OH O
iPrO O
OiPr O OiPr
H3C O
O CH3
O OH EtO 2C
Diethyl Tartrate (DET)
Chirally controls reaction
• Via rapid ligand exchange of OiPr and diethyl tartrate
 The Mechanism

EtO
O CO2Et O H
O OEt O tBu
OiPr O
O O OEt O
HO
Ti Ti
Ti CH3 EtOOC O
iPrO
OiPr O OiPr O + O CH3 + H2C O

HO CH3
CH2
EtO 2C +
EtOOC OiPr
O OiPr
Ti
O OiPr
EtOOC
OiPr
 Transition State

O H
O H
OEt O
tBu OEt O tBu
O O O
O
Ti
EtOOC O Ti CH
O
EtOOC O
O
H2C
CH2
 Products
EtO
EtOOC OiPr CO2Et
O
O OiPr O
Ti OiPr
OiPr O O OEt
O
Ti Ti
EtOOC
OiPr iPrO
O O
OiPr OiPr
O H
OEt O tBu EtO 2C

O O
Ti CH +
EtOOC O tBuOH
O
+
CH2 O
H
OH

H H
 OiPr

Ln Ti Titanium complex
made through ligand exchange
OiPr
Product

OH O
O
HO Ln Ti
O

O
tBu

O
Catalytic
Ln Ti O
Ln Ti

O
OH

tBu
Cycle O+

O
tBu

O O

Ln Ti O+ Ln Ti O+
O O+
Transition State
tBu tBu
 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 of
Ti(iOPr)4 catalyst
• Very reactive allyl alcohols need 50% catalysts – still
significant
• 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 the
tartrate ester to <13%
• Allyl alcohol concentration can be kept high since side
reactions are minimized (no ring opening)
 Molecular Sieves
• Advantages:
– Economy – less catalyst required
– Somewhat milder conditions
– Ease of isolation
– Increased yields
– Possible in-situ derivatization
• Problem: the substrate may not be soluble in
the solvent (low propoxide ion concentration)
 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 (H2O2 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
• Problem: High cost due low temperatures
• Solution: Titanocene-tartrate (TT) catalyst
• Very good catalytic activity and decent
enantioselectivity at higher temperatures
• TT has bulky cyclopentadienyl rings which
create steric hindrance, inducing chirality
(compare with BINOL)
• In classic SAE, the tartrate-titanium
complex forms through ligand exchange
 Higher Temperatures SAE
• But the titanocene-tartrate cannot form
through ligand exchange (Ti-halide
stable)
• 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 of
product also decreases
• Better solution is in-situ derivatization
 In Situ Modification
• Epoxy-alcohol product is converted to an ester
derivative:
– p-toluene sulfonyl and 2-naphthalene sulfonyl
– t-butyl diphenyl silyl and t-butyl dimethyl silyl
• The derivatives are
– Easily un-doable (good leaving group)
– Functionally equivalent to parent for reactions
• Further chemistry can be done on the epoxy-“alcohol”
without loss of yield
• Derivative may be isolable in high yield and then
converted back to alcohol
 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- Structure of catalytic center of
41) MCM‐41
 Competing Methods
• Many competing R
2
R
1
aq. NaOCl
Mn-salen catalyst
R
1
R
2

reactions for CH2Cl2 H

O
H

generating epoxides:
2 1
R R 3 O
R3CO3H R R
1

2
3 H R
R

• Jacobsen-Katsuki H3C
CH3

epoxidation O
O
O

• Prilezhaev reaction
O
O 1 O
2 H3C R
1 R CH3
2
R R
Oxone
• Shi expoxidation H2O,CH3CN
pH 10.5
 Jacobsen-Katsuki Epoxidation
• Uses cis alkene as a reactant
• Allows broader scope of substrate (R: Ar,
alkenyl, alkynyl; R': Me, alkyl)
• Mn-salen catalyst and a stoichiometric oxidant
H H
+
+ N
N
3-
Mn
O Cl O
H3C
CH3
H3C CH3 H3C
CH3 H3C CHCH3
H3C CH3 CH3 3
 Jacobsen-Katsuki Epoxidation
• Mechanism’s catalytic cycle shows the formation
of an Mn(V)-oxo complex
• Good yields with high enatomeric excess
 Prilezhaev Reaction
• Reaction of an alkene with a peracid
2 1
R R 3 O
R3CO3H R R
1

2
3 H R
• meta-chloroperoxybenzoic
R
acid (m-CPBA) is
most commonly used as the peracid
• Magnesium mono-perphthalate and peracetic
acid

N. K. Jana, J. G. Verkade, Org. Lett., 2003, 5, 3787-3790.

 Shi Epoxidation
• Reaction involving a trans alkene
• Oxone is another main component
• Fructose derived catalyst used
• High enatiomeric excess yields
H3C
CH3
O
O
O

O O
O 1 O
2 H3C R
1 R CH3
2
R R
Oxone
H2O,CH3CN
pH 10.5
 Uses of the Reaction
• The Sharpless Asymmetric Epoxidation converts
alkenes into chirally active epoxides
• Innumerable syntheses published that use the SAE
• Chiral epoxides easily converted into:
– 1,2 Diols
– Make carbon-carbon bonds (stereospecifically)
– Aminoalcohols
• Two examples considered:
– A complex synthesis of Venustatriol by EJ Corey
– Simpler synthesis of Untenone by Mizutani et al.
 Venustatriol
• Marine-derived natural product discovered initially
in 1986
• Found in red alga Laurencia venusta
• Derived in vivo from squalene, made as a triterpene
• Shown to have antiviral and anti-inflammatory
properties
• Structure contains repeated polyether moieties
• Key problems: multiple stereocenters and
polyether moieties.
• Corey proposed a “simple and straightforward”
disconnection
Venustatriol - Reterosynthetic Analysis

Fragment B

Fragment A
Fragment A
Fragment B
Final Step - Venustatriol
 Untenone
• Isolated from a marine sponge in 1993
• Exhibits inhibitory activity against mammalian
DNA polymerases
• These enzymes are important for DNA
replication, repair and cell divisions (cancer
implications)
• Biosynthetic pathway not investigated
• The critical part of the synthesis is the
introduction of a quaternary carbon center (done
via SAE)
• The total synthesis is 15 steps
Untenone - Reterosynthetic Analysis

steps

steps
Untenone Synthesis
 References
• Kurti, L. and Czako, B. Strategic Application of
Named Reactions in Organic Synthesis: Elsevier
Academic Press, 2005
• s