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
O
O
H
Transformation:
O
General Mechanism
R'
R'
O
R"
R
O
R
O
O
O
O
H
H
R'
O
R"
R
O
H
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
O
H
O
OH
H
O
O
H
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
O
+
R
M O
O
O
+
M OR
R
O
O
M
M
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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Directed Epoxidations Utilising Hydroperoxides
93CR1307 (directed reactions)
• The use of transition metals can allow directed epoxidations
• Use to control chemoselectivity
OH
OH
O
mCPBA:
TBHP / VO(acac)2
1
49
:
:
2
1
• chemo- and
stereoselective
• Used to control stereoselectivity
Cl
MeO
H
N
O
OH
Cl
H
N
MeO
O
OH
O
TBHP
VO(acac)2
O
N
H
OH
O
O
O
N
H
OMe
O
OMe
Mechanism
O
tBuOOH
V
O
O
tBuOH
O
O
HO
HO
• internal delivery
O
VO(acac)2
• TBHP rapid ligand exchange
O
O
V
O
O
OO
O
tBu
O
• activation of
peroxide
V O
tBu
O
O O
tBu
O
O
V
O
O
OO
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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Acyclic systems also show good selectivity
TBHP
VO(acac)2
O
OH
OH
TBHP
VO(acac)2
tBu
• biggest effect is R"'
L
O
OH
OH
2.5 : 1
erythro
O
V
O
L
R"'
R
19 : 1
erythro
R'
iv
O
R
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…
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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
3
R
TsOH
Ti(OiPr)4,
(+)-DET, TBHP
HO
O
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
R
R2
OH
R3
• R group hinders attack and
slows epoxidation down
H
slow
fast
"O" (–)-DET
R2
R2
R1
R
R3
R1
H
R3
OH
OH
H
R
• produced faster
R1
R1
R
R2
O
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
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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• 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
O
OH
OH
O
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
O
OBn
O
PhNCO,
pyr
OBn
O
O
OBn
OBn
BF3.OEt2
O
HO
HO2C
O
OH
O
OH
O
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
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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• 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
O
OH
OH
OTBS
OBn
(-)-DET, Ti(OiPr)4,
TBHP
OBn
HO
OBn
O
1. Swern
2. Wittig
MeO 2C
O
1. DIBAL
2. tBuCOCl
3. TPSCl
4. DIBAL
OBn
OBn
1. Red-Al
2. tBuCOCl
tBuOCO
OH
OH
OH
O
OTPS
OBn
(-)-DET,
Ti(OiPr)4,
TBHP
OH
OTPS
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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Dioxirane Epoxidations
Reagent:
O
O
R
R1
Transformation:
O
• cis-spiro
transition state
•syn-addition
General Mechanism
O
R
O
H
R
• concerted
mechanism
O
R
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
H
O
SO3
O
2–
"SO4"
O
O
O
O
O
SO3
• ~0.08–0.10 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
R
O
O
R
O
O
R
• 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
O
O
•
tBu
•
H
84 %
O
H
• Disadvantages: VERY reactive, heteroatoms and hydroxyl groups can be oxidised
• Disadvantages: Even unactivated C–H can be oxidised
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O
O
S
S
O
HO
HO
N
N
97 %
O
O
O
O
O
OH
OH
O
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
O
O
SO3
SO4
O
2–
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
O
O
Ph
Ph
yield 75 %
e.e. 97 %
O
O
O
O
• High catalyst loadings are required as the ketone decomposes via Baeyer-Villiger reaction
R
O
R1
O
O
R
O
O
SO3
O
R1
O
SO3
R
O
R1
• Armstrong has developed a more robust catalyst (00TA2057)
• Operates < 10 mol% and up to 76 % e.e.
CO2Et
N
F
H
O
What have we learnt?
• Dioxiranes are extremely powerful oxidants that function under very mild conditions
• Readily generated from ketones
• Ketones can be used catalytically
• Asymmetric variant now possible
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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Jacobsen–Katsuki 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 oxo–transfer reagents were developed but
the real success story has been the us of SALEN–based reagents
Reagent:
R2 R2
R1
N
R1
N
Mn
O
O
R3
R3
NaOCl
(bleach)
Transformation:
O
General Mechanism
• Still contraversial
97Ang2060
•Possibilities
R1
R
R1
R
R
O
O
O
M
M
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)
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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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
R
R
O
O
O
M
M
M
• approach so that π-HOMO
of alkene overlaps with
π*-LUMO of oxo
O
tBu
O
RS
RL
RSMALL
H
RLARGE
N
O Mn N
tBu
• cis alkenes work well
• trans alkenes generally bad
• small substituent
passes axial proton
tBu
R1
H
H
N
H
N
Mn
tBu
tBu
• bulky tBu groups block
attack from front or sides
O
tBu
O
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
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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Use in Synthesis
• other oxidants
can be used
1
R
R
H
H
R O
0.1-4.0 mol % cat.
NaOCl
R1
H
• Wide range of substrates tolerated
• Cis better than trans
H
H
N
Yields = 63-87 %
e.e. = 86-98 %
cis-alkenes
N
Mn
tBu
O
Cl O
tBu
tBu
tBu
N
Yields = 41-91 %
e.e. = 83-99 %
cis-alkenes
limited success with
trans-alkenes (e.e. 50%)
N
Mn
O
Cl O
PhPh
Recent Development
O2N
AcHN
O
2 % achiral salen, 40 %
(–)-sparteine
PhIO; e.e. 73 %
O2N
AcHN
O
O
• use of an achiral salen complex in conjunction with a second ligand gives good (and
cheaper, control
What have we learnt?
• Unfunctionalised alkenes can be catalytically epoxidised with good selectivity
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
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