epoxidation
epoxide
olefin
epoxide
• Highly reactive because of its structure
• Often used as synthetic intermediate
compound to make something
Prilezhaev Epoxidation
+
+
• Lower pKa, higher reactivity
• Electron-rich alkenes are more reactive
• mCPBA(meta-Chloroperbenzoic acid) are widely
used
(relatively safe, and high reactivity)
Lecture material,
http://www.organic-chemistry.org/chemicals/oxidations/meta-chloroperbenzoicacid.shtm
Alkenes reactivity
Lecture material,
features
In epoxidation…
• Stereochemistry of olefin maintained
• Rate insensitive to solvent polarity
(concerted mechanism, no ionic intermediates)
• Less hindered face of olefin attacked
mCPBA
CH2Cl2
R = H 20 min
R = CH3 24 h
99%
<10%
1%
90%
Lecture material
Exocyclic olefins
• Depends on hinder or not
RCOOOH
Less stable product
Less hindered face
Lecture material
Henbest epoxidation
• If compounds has OH (allylic alcohol)…
RCO3H
91%
If OH = OAc , 57%
9%
43%
Lecture material
Henbest,H.B.; Wilson, R.A. J. Chem. Soc. 1957, 1958-1965.
Butterfly transition state
Mechanism: ‘butterfly
mechanism of Bartlett, involving
the interaction of the nucleophilic
alkene with the electrophilic
peracid.
Bartlett, P.D. Rec. Prog. Chem. 1950, 11, 4751.
• If OH…
Hydrogen bond works to fix
→likely to come same face
Lecture material
Henbest,H.B.; Wilson, R.A. J. Chem. Soc. 1957, 1958-1965.
Freccero, M.; Gandolfi, R.; Sarzi-Amadè, M.; Rastelli, A. J. Org. Chem. 2000, 65, 2030.
Conformation affect
Lecture material
Metal catalyzed epoxidation
• More powerful directing effects
• Rate acceleration up to 1000 x
tBuOOH
VO(acac)2
83%
0%
100%
• May be used to differentiate between an
allylic alcohol and an unactivated olefin.
Lecture material
Metal catalyzed epoxidation
• Chemo/regioselectivity
VO(acac)2
T-BuOOH
benzene
98% isomeric purity
VO(acac)2
T-BuOOH
benzene
95% isomeric purity
Lecture material
Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136.
Catalytic cycle
VO(acac)2 : Vanadyl acetylacetonate
tBuOOH
tBuOH
Ligand exchange
Lecture material
Epoxidation of acyclic allylic alcohol
Lecture material
Sharpless asymmetric epoxidation
D-(–)-diethyltartrate
(S,S)
Ti(OiPr)4
tBuOOH
70-90% yield
>90% ee
L-(+)-diethyltartrate
(R,R)
Lecture material
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I. Ed.; Wiley-VCH: New York; 2000.
Mnemonic model
Point by left hand , thumb…OH
Knuckle…negative
Palm…positive
Lecture material
mechanism
Lecture material, Koskinen, Ari. Asymmetric synthesis of natural products
Commercial synthesis of β-blocker
• B-blocker… medicine for nerve
Ar(Aryl)OH, NaH
1)SAE
2)NsCl
Ns:2Nitrobenzenesulfonyl
iPrNH2
(S)-propranolol
Lecture material
Kinetic resolution
Slow
fast
• Kinetic resolution
Separating racemic mixture by reaction speed
Sharpless, K. B., et al. J. Am. Chem. Soc. 1981, 103, 6237.
Kinetic resolution
(+)-DIPT
Ti(Oi-Pr)4
CH2Cl2
fast
98%
2%
Kfast/Kslow = 100
(+)-DIPT
Ti(Oi-Pr)4
CH2Cl2
slow
38%
62%
At the result
> 96% ee
>96% ee
Sharpless, K. B., et al. J. Am. Chem. Soc. 1981, 103, 6237.
Jacobsen epoxidation
Doesn’t need OH
cis
trans
cis
O is above the Mn
Lecture material
Koskinen, Ari. Asymmetric synthesis of natural products
Jacobsen Epoxidation
Jacobsen, E.J. Tetrahedron 1994, 50, 4323.
Katsuki epoxidation
• Similar compound
Lecture material
Koskinen, Ari. Asymmetric synthesis of natural products
Stepwise mechanism
Lecture material
DMDO (Dimethyl Dioxirane)
• High reactivity at mild condition
• Good for nature, easily removed
• But sometimes react with heteroatoms or
hydroxyl groups
• Can react with tertiary carbon atom
acetone
Lecture material
http://www.chem-station.com/odos/2009/08/-oxidation-with-dioxirane.html (not English)
DMDO reactions
Bn : benzene
Lecture material
Shi epoxidation
• 3-substituted C=C (2-cis, trans in some papers)
• Catalysts break down under acid condition
dioxirane
Lecture material
Using enzymes
Phillip A. Lichtor and Scott J. Miller ,Nat Chem. 2012 Dec; 4(12): 990–995.
Published online 2012 Oct 14. doi: 10.1038/nchem.1469