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Epoxidation of Alkenes
Peracids: ! ! !
• most common reagents
• reaction is stereospecific
R O
O
OHO
R OH
O+ +
CH2Cl2
CH3 OOH
O
CF3 OOH
OOOH
OCl
peraceticacid
pertrifluoroaceticacid
m-chloroperbenzoicacid (mCPBA)
increasing reactivity
RmCPBACH2Cl2 R
OR
mCPBACH2Cl2 R
O
Epoxidation of Alkenes
• regio- & chemoselectivity
C CH
H
H
HC C
R
H
H
HC C
R
H
R
HC C
R
R
H
HC C
R
R
R
HC C
R
R
R
R< < <≤ <
krel 1 24 500 500 6500 even faster
OMeRO
< <
very slow
OMemCPBA(1 equiv)
OMeOO
mCPBA(1 equiv)
mCPBACHO CHO
O
Epoxidation of Alkenes
• diastereoselectivity (cyclic systems)
R R R R R R
+mCPBA
HH
O H
OH
R = HR = CH3
99 : 1 < 10 : > 90
mCPBA
O
OTBSmCPBA OTBSO OTBSO
7 : 1
Epoxidation of Alkenes
• diastereoselectivity (cyclic systems) directing effects
OTBSmCPBA OTBSO OTBSO
7 : 1
OHmCPBA OHO OHO
9 : 91
OAcmCPBA OAcO OAcO
43 : 57
Epoxidation of Alkenes
Alkyl Hydroperoxides: ! ! !
• common catalysts
• chemoselectivity
OH OHOtBuOOHTM catalyst
R R
VO(acac)2, Mo(CO)6, Ti(OiPr)4
OH tBuOOHVO(acac)2
OH
O
OH
O
mCPBA
Epoxidation of Alkenes
• mechanism
HOO V
OR
OROR
tBuOOHO V
OO
RO O tBuO V
O
RO
OO
O V
O
RO
OO
tBu
O VO
OOR tBu
tBu
O
slow
tBuOOHHO
HO O+ tBuOH
Epoxidation of Alkenes
• diastereoselectivity
HOH
HOH
HOHO O
mCPBATBHP, V5+
4 : 3100 : 0
+
Me
MeOHHMe
MeOHHMe
MeOHH+
O O
mCPBATBHP, V5+
95 : 5 70 : 30
Epoxidation of Alkenes
• diastereoselectivity
Me
H
OVHMeH
Me
MeH OHtBuOOH
(VO(acac)2
Me
MeH OH
Me
MeH OH+
O O
70 : 30
Me
Me
H OV
H
H
OV
MeHMeH
Me
H
H Me
OV
45° ≡≡
Epoxidation of Alkenes
• diastereoselectivity – homoallylic alcohols
Ph
OH
OBPS
Ph
OH
OBPS
tBuOOHVO(acac)2
O
VO O OtBuPhMe
OBPS
LL
Epoxidation of Alkenes
• Sharpless Asymmetric Epoxidation (SAE)
Empirical Rule:
R2 OH
R1
R3Ti(OiPr)4, (+)-DETtBuOOH, 3Å MSCH2Cl2, -20°C
R2 OH
R1
R3
O
EtO2CCO2Et
OH
OH(-)-DET
(+)-DET
EtO2CCO2Et
OH
OH
Epoxidation of Alkenes
• Sharpless Asymmetric Epoxidation (SAE)
R2 OH
R1
R3Ti(OiPr)4, (+)-DETtBuOOH, 3Å MSCH2Cl2, -20°C
R2 OH
R1
R3
O
Epoxidation of Alkenes
• Sharpless Asymmetric Epoxidation
OHSAE
(+)-DETSAE
(-)-DET OHOHO O
the following substrate types show excellent selectivity
(Z)-disubstituted olefins are less selective
OH OH
OH
OH OH
OHOH
OH
rxn not compatible with: Ar-OH, CO2H, most amines, phosphines
Epoxidation of Alkenes
• Sharpless Asymmetric Epoxidation (SAE)
C8H17
OH
C8H17 OH
C8H17
OH
C8H17 OH
O
OSAE(+)-DET
SAE(+)-DET
78%; 94% ee
63%, 80% ee
OHO
OHOPh OHO
77%; 93% ee 95%; 91% ee 79%; 98% ee
Epoxidation of Alkenes
Dimethyldioxirane (DMDO): ! ! !
• prep
• utility
OOK+ -O S OOH
O
O
O
oxone
+ + KSO4H
dimethyldioxirane
CF3
OO
trifluorodimethyldioxirane (TFDO)
O O
DMDOacetone
+
80 : 20
O O
DMDOacetone O O
O
Epoxidation of Alkenes
Hydrogen Peroxide: ! ! !
• oxidation of electron deficient alkenes
• chemoselectivity
O
H2O2NaOH
O
O
H
OH2O2NaOH
H
O
O
Epoxidation of Alkenes
Other Methods: ! ! !
• From Halohydrins
• From Diols
R OHOH TsCl (1 eq)
pyridine R OTsOH NaH
RO
• Darzon’s Condensation
O Cl OEt
O
KOtBuCO2Et
O
Br2H2O
NaH
OH
BrO
+ regioisomer
Epoxidation of Alkenes
Sulfur Ylides (Corey-Chaykovsky Reaction): ! ! !
• dimethylsulfonium methylide
preparation
reactivity
irreversible addition to carbonyl
CH3SCH3
MeICH3
SCH3
MenBuLiI
CH3SCH2
Me
OS
Me
Me
O
CH3S CH3+
O SMe2
Epoxidation of Alkenes
Sulfur Ylides (Corey-Chaykovsky Reaction): ! ! !
• dimethylsulfoxonium methylide
preparation
reactivity
reversible addition to carbonyl
CH3S CH3
MeICH3
S CH3
OnBuLiI
CH3S CH2
OO
Me Me
Me SO
Me
O O
CH3S CH3+
O
Epoxidation of Alkenes
Sulfur Ylides (Corey-Chaykovsky Reaction): ! ! !
• mechanistic consquences
stereoselectivity
cyclopropanation of enones
tBu
O
tBu tBu+
Me2S=CH2Me2S(O)=CH2
87 : 13 0 : 100
OO
O OMe S
O
Me
SO MeMe
O
Epoxidation of Alkenes
Further Digression: Simmons Smith Reaction ! ! !
• cyclopropanation
• selectivity
OTMS OTMS
Zn(Cu)CH2I2
HClMeOH
O
Zn(Cu)CH2I2
R RZn(Cu)CH2I2
OH
Zn(Cu)CH2I2
OH
-NR2, -CO2R also direct
Dihydroxylation of Alkenes
Osmium Tetraoxide (OsO4) ! ! !
• reactivity
• mechanism
OOs
O
OO
OOsO O
O
VIVII
OH
OH
OOs
O
O
N+NMe Me O-
VI
OsO4NMO
OH
OH
stoichiometric or catalytic in the presence of a reoxidant e.g. NMO; UpJohn Process)
Dihydroxylation of Alkenes
Osmium Tetraoxide (OsO4) ! ! !
• diastereoselectivity (cyclic systems)
OsO4NMO
OH
OH
MeH
E
Me
H
OsO4NMO
OH
OH
EOH
H
OH
OH
Dihydroxylation of Alkenes
Osmium Tetraoxide (OsO4) ! ! !
• diastereoselectivity (acyclic systems)
BnOBnO
OsO4NMO
BnOBnO
BnOBnO
+
OH
OHOH
OH
9 : 1
HBnO
BnO
L
M
OsO4
HBnO
BnOHO OH
Dihydroxylation of Alkenes
Sharpless Asymmetric Dihydroxylation (SAD) ! !
Empirical Rule:
HRMRS
RL
AD-mix β
AD-mix α
Ph CO2Et AD-mix αtBuOH/H2O
AD-mix βtBuOH/H2O Ph CO2Et
OH
OHPh CO2Et
OH
OH 97% ee 95% ee
Dihydroxylation of Alkenes
Sharpless Asymmetric Dihydroxylation ! !
alkaloid ligands:
• AD-mix: K3Fe(CN)6 K2OsO2(OH)6 K2CO3 alkaloid ligand
(DHQD)2-PHALligand for AD-mix β
(DHQ)2-PHALligand for AD-mix α
these substrates do not work well:
R1 R2 R2 R4
R1 R3
Dihydroxylation of Alkenes
Epoxide Opening ! !
O
MeH
Me
H
MeH
Me
HO
Nu (axial attack)
OH
OH
mCPBA H3O+
or NaOH
Oxidative Cleavage of Alkenes
Ozonolysis ! ! ! • reactivity
O3;DMS or Zn/AcOH or PPh3
O3;H2O2
O3;NaBH4
OO
OH
CO2H CHO
OH
R R
O OO
OO
O
R R
OO
O
R RO
OO
R
R
OO
O
R
R
Criegeeintermediate ozonidemolozonide
products
mechanism:
Oxidative Cleavage of Alkenes
Ozonolysis ! ! ! • reactivity differentiated products
O3;ROH, NaHCO3
O3;ROH, pTsOH
OOHCHO
OR
Ac2OEt3N O
CHO
OR
OOH
OR
OR
ORNaHCO3DMS
Ac2OEt3N O
OR
OR
OR
CHO
OR
OR
best used on symmetrical olefins
Oxidative Cleavage of Alkenes
KMnO4 or RuO4, NaIO4 ! ! ! • reactivity
KMnO4 orRuO4, NaIO4
OH
OH CO2HCO2H
note:
OH OH
O
OH OH
O
R
OH
OH
R' R
O
O
R' R
OH
O
R' not R
OR"
O
R'
Oxidative Cleavage of Alkenes
OsO4 / NaIO4 ! ! !
• reactivity
Johnson-Lemieux Procedure:
OsO4 (cat)NaIO4, tBuOH/H2O O
O
H H+
notHOO
R2NO
OO OH OH
OH
OH
CHOOsO4O
NaIO4
Allylic Oxidation
Selenium Dioxide (SeO2) ! ! !
• reactivity
OHSeO2
• regioselectivity SeO2
HO
HO+
SeO2HO
SeO2OH
then prefered order of reactivity is CH2 > CH3 > CH
Recommended