Alkene Epoxidations: Peracids: The Prilezhaev (Prileschajew) Reaction

Alkene Epoxidations
A huge topic which we will only skim the surface of

References will be include for those who want more detail
Peracids: The Prilezhaev (Prileschajew) Reaction

Reagent:
O
R
for the Caddick group with

their love of named reactions
Transformation:
O
General Mechanism
R'
R'
O
R"
R
O
R'
R"
O
R"
Use in Synthesis
Peracids much weaker acids than carboxylic acids (pKa 8.2 vs 4.8)
But carboxylic acid is a by-product so buffer with NaHCO3
Peracids are electrophilic so electron withdrawing groups on R good (mCPBA)
Electron-rich alkenes more reactive
Hydrogen-bonding can direct epoxidations
Ar
O
OH
ArCO3H
OH
H
O
O
Hydroperoxides
H2O2 & alkyl hydroperoxides require the presence of a transition metal to initiate epoxidation
tBuO2H (TBHP) favoured as safe, soluble and stable in anhydrous solvents and cheap
R
O
M O
R
O
+
R
M O
O
O
M OR
R
O
O
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
16
Directed Epoxidations Utilising Hydroperoxides

93CR1307 (directed reactions)
The use of transition metals can allow directed epoxidations
Use to control chemoselectivity
OH
OH
mCPBA:
TBHP / VO(acac)2
1
49
:
:
2
1
chemo- and
stereoselective
Used to control stereoselectivity

Cl
MeO
H
N
OH
Cl
H
N
MeO
OH
O
TBHP
VO(acac)2
O
N
H
OH
N
H
OMe
OMe
Mechanism
O
tBuOOH
O
O
tBuOH
O
O
HO
HO
internal delivery
VO(acac)2
TBHP rapid ligand exchange
O
O
V
O
O
OO
tBu
O
activation of
peroxide
V O
tBu
O
O O
tBu
O
O
V
O
O
OO
17
Acyclic systems also show good selectivity
TBHP
VO(acac)2
OH
OH
TBHP
VO(acac)2
tBu
biggest effect is R"'
OH
OH
2.5 : 1
erythro
O
V
O
R"'
R
19 : 1
erythro
R'
iv
Rv
therefore use temporary blocking group

SiMe3
SiMe3
TBHP
VO(acac)2
OH
TBAF
O
O
OH
OH
25 : 1
erythro
85CC1636
this all leads on to probably the most famous epoxidation system
18
19
Use in Synthesis
DCM is an uniquely efficient solvent
Complex can not be stored
Catalyst must be aged
Substrates
R2
R2
OH
Yield = good
e.e. = 90 %
OH
R3
R1
R1
R2
OH
OH
few examples
but generally good
R3
R3
R2
OH
Poor
substrate
TsOH
Ti(OiPr)4,
(+)-DET, TBHP
HO
HO
HO
HO
Kinetic resolution
R1
must stop reaction before

100% completion or you will just
recover a different racemate
both enantiomers react just at
different rates
R2
OH
R3
R group hinders attack and

slows epoxidation down
slow
fast
"O" ()-DET
R2
R2
R1
R
R3
R1
H
R3
OH
OH
produced faster
R1
R1
R2
R2
OH
R
OH
R3
R3
If allylic alcohol is the desired product use 0.6 equiv. TBHP

If epoxy alcohol is the desired product use 0.45 equiv. TBHP
20
Although very useful, kinetic resolution only allows a maximum of 50 % yield

Desymmetrisations allow a theoretical 100 % yield
desymmetrisation
preferentially forms one isomer
OH
Fast
Slow
OH
OH
O
OH
Slow
Fast
O
kinetic resolution
removes unwanted isomer
Attractive strategy due to combining initial desymmetrisation with a subsequent kinetic

resolution to result in very impressive enantiomeric excesses
e.e. of desired product increases with time (84 % 3hrs >97 % 140 hrs)
NHPh
OH
OBn
OH
()-DIPT,
Ti(OiPr)4,
OBn
TBHP
OBn
PhNCO,
pyr
OBn
OBn
OBn
BF3.OEt2
O
HO
HO2C
OH
O
OH
OH
OH
OBn
HO
OBn
KDO
What have we learnt?

Peracids and hydroperoxides are good epoxidising reagents
Use of transition metals allows directed epoxidations
SAE is the cornerstone of many total synthesis
It works well for the majority of trans allylic alcohols
It can be used in kinetic resolution or desymmetrisation reactions
References:
directed: 93CR1307
Sharpless: 87JACS5765(good), Comp.Org.Syn. Vol.7, Ch.3.2, 91CR437
Resolution: 81JACS464
Desymmetrisation: 87JACS1525, 94ACR9
KDO: 90T4793
21
Two building blocks from KC Nicolaou's synthesis of amphotericin B show the power of SAE
(+)-DET, Ti(OiPr)4,
TBHP
HO
OH
BnO
BnO
OH
OH
OTBS
OBn
(-)-DET, Ti(OiPr)4,
TBHP
OBn
HO
OBn
1. Swern
2. Wittig
MeO 2C
1. DIBAL
2. tBuCOCl
3. TPSCl
4. DIBAL
OBn
OBn
1. Red-Al
2. tBuCOCl
tBuOCO
OH
OH
OH
OTPS
OBn
(-)-DET,
Ti(OiPr)4,
TBHP
OH
OTPS
22
Dioxirane Epoxidations
Reagent:
O
R1
Transformation:
cis-spiro
transition state
syn-addition
General Mechanism
O
R
concerted
mechanism
H
R
H
H
Preparation
Most common dioxirane is dimethyldioxirane (DMDO)

Prepared as a pale yellow solution in acetone by the action of oxone or caroate KHSO5
H
O
SO3
"SO4"
O
O
SO3
~0.080.10 M acetone solution "distilled" off with carrier gas to prevent further reaction of
oxone and DMDO
Use in Synthesis
cis-alkenes react more efficiently for steric reasons (~7-9 times more reactive)
R
O
O
O
O
Stereocentrol is a result of steric interactions

Addition of DCM or H2O decreases stability therefore increases reactivity
Used at low temperature and neutral conditions (as generates acetone as a by-product)
Mild so can generate very sensitive epoxides
O
tBu
tBu
84 %
Disadvantages: VERY reactive, heteroatoms and hydroxyl groups can be oxidised

Disadvantages: Even unactivated CH can be oxidised
23
O
O
HO
HO
97 %
O
O
O
O
OH
OH
Catalytic Variant
As the dioxirane precursor, the ketone, is regenerated during the reaction only a catalytic
quantity is required if dioxirane generated in situ
Possible if pH is kept between 7.0 7.5 with phosphate or bicarbonate buffer
if pH too low then dioxirane formation can not proceed (deprotonation impossible viva supra)
if pH too high dioxirane destroyed by oxone
O
O
O
O
SO3
SO4
Catalytic Asymmetric Variant

Shi has developed an asymmetric variant using a chiral sugar derivative
97JOC2328
Ph
Ph
0.2 0.3 eq. cat.

oxone ph 7-8
H2O / MeCN
O
Ph
Ph
yield 75 %
e.e. 97 %
O
O
High catalyst loadings are required as the ketone decomposes via Baeyer-Villiger reaction
R
O
R1
SO3
O
R1
SO3
R1
Armstrong has developed a more robust catalyst (00TA2057)

Operates < 10 mol% and up to 76 % e.e.
CO2Et
N
F
H
O

Dioxiranes are extremely powerful oxidants that function under very mild conditions
Readily generated from ketones
Ketones can be used catalytically
Asymmetric variant now possible
24
JacobsenKatsuki Epoxidation
Aim to develop an asymmetric epoxidation catalyst which would operate on substrates with no
functionality for preco-ordination
A number of reasonably efficient porphyrin based oxotransfer reagents were developed but
the real success story has been the us of SALENbased reagents
Reagent:
R2 R2
R1
N
R1
N
Mn
R3
R3
NaOCl
(bleach)
Transformation:
O
General Mechanism
Still contraversial
97Ang2060
Possibilities
R1
R1
R
O
concerted
stepwise
(radical or polar)
M
R1
oxametallocycle
oxidations proceed with a degree of scrambling of geometry

tBu
Ph
Et
CO2Et
> 99 : 1 cis : trans epoxide

78 : 22 cis : trans epoxide
TMS
29 : 71 cis : trans epoxide
Suggests that concerted mechanism is not occurring

Present believe is probably radical - stepwise mechanism (00Ang589)
25
Stereoselectivity
My interpretation would again suggest that Katsuki and Jacobsen disagree on this
Both agree that alkene approaches metal oxo complexes side-on
R1
R1
R
O
approach so that -HOMO

of alkene overlaps with
*-LUMO of oxo
O
tBu
RS
RL
RSMALL
RLARGE
N
O Mn N
tBu
cis alkenes work well

trans alkenes generally bad
small substituent
passes axial proton
tBu
R1
H
N
N
Mn
tBu
tBu
bulky tBu groups block

attack from front or sides
O
tBu
tBu
tBu
Jacobsen implies attack on oxo-species occurs from the back face over the diamine bidge
Katsuki implies that skewed shape of salen complex results in attack from the side
skewed shape of salen
complex shields one side
of nucleophile
back face blocked by H

of cyclohexane group
RL
RS
RL
O
N
O H
Mn
RS
H
N
O
large substituent far

from bulky front face
bulky tBu groups block

approach from front
26
Use in Synthesis
other oxidants
can be used
R O
0.1-4.0 mol % cat.

NaOCl
R1
Wide range of substrates tolerated

Cis better than trans
H
N
Yields = 63-87 %
e.e. = 86-98 %
cis-alkenes
N
Mn
tBu
Cl O
tBu
tBu
tBu
Yields = 41-91 %
e.e. = 83-99 %
cis-alkenes
limited success with
trans-alkenes (e.e. 50%)
N
Mn
Cl O
PhPh
Recent Development
O2N
AcHN
2 % achiral salen, 40 %
()-sparteine
PhIO; e.e. 73 %
O2N
AcHN
use of an achiral salen complex in conjunction with a second ligand gives good (and
cheaper, control

Unfunctionalised alkenes can be catalytically epoxidised with good selectivity
27

Alkene Epoxidations: Peracids: The Prilezhaev (Prileschajew) Reaction

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Alkene Epoxidations

A huge topic which we will only skim the surface of

Peracids: The Prilezhaev (Prileschajew) Reaction

for the Caddick group with

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Directed Epoxidations Utilising Hydroperoxides

Used to control stereoselectivity

TBHP rapid ligand exchange

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Acyclic systems also show good selectivity

biggest effect is R"'

therefore use temporary blocking group

this all leads on to probably the most famous epoxidation system

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

must stop reaction before

R group hinders attack and

If allylic alcohol is the desired product use 0.6 equiv. TBHP

Although very useful, kinetic resolution only allows a maximum of 50 % yield

Attractive strategy due to combining initial desymmetrisation with a subsequent kinetic

What have we learnt?

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Most common dioxirane is dimethyldioxirane (DMDO)

Stereocentrol is a result of steric interactions

Disadvantages: VERY reactive, heteroatoms and hydroxyl groups can be oxidised

Catalytic Asymmetric Variant

0.2 0.3 eq. cat.

Armstrong has developed a more robust catalyst (00TA2057)

What have we learnt?

oxidations proceed with a degree of scrambling of geometry

> 99 : 1 cis : trans epoxide

29 : 71 cis : trans epoxide

Suggests that concerted mechanism is not occurring

approach so that -HOMO

cis alkenes work well

bulky tBu groups block

back face blocked by H

large substituent far

bulky tBu groups block

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

0.1-4.0 mol % cat.

Wide range of substrates tolerated

What have we learnt?

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

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