the development of dioxirane mediated • introduction to...
TRANSCRIPT
The Development of Dioxirane MediatedEnantioselective Epoxidation Reactions
• Introduction to Dioxiranes• Early Epoxidations• Initial Asymmetric Epoxidations• Recent Advances, focusing on the Shi Group
Brian ConnellEvans Group Seminar
9/24/99
Dioxiranes: Cyclic Peroxides
R1
MeMeCF3CF3HPhCF3ClFMes
R2
MeCF3CF3CF2ClHPhPhPhFMes
Known Dioxiranes(Characterized)
Kabal'nova, et al, Reactions of Dioxiranes, Kinetics and Catalysis, v.40, No.2, 1999, 207.
F3C
OLi
OLi
F3C
1) F2(g)
2) low temp GC
F3C
O
O
F3C
The First Synthesis (Talbott & Thompson, 1972):Characterized by:UVIR19F NMRmass spec
H H
H H
O3H
O
O
H
Microwave spectroscopy:
C–H 1.090 ÅC–O 1.387 ÅO–O 1.515 Å
Martiney (1977), Chapman and Hess (1984):
R
C
R
Duncan and Shields (1986):
O2R
O
O
R
Mes
C
Mes
N2
O2
hν
Mes
O
O
Mes
R1
OO
R2
stable for several days
Kirschfield et al (1994):
stable in the gas phase
Burger et al (1994):
R
C
R
O
O hν
F
O
O
F
F2(g) orCl2 or
ClFF
C
F
O
O
Dioxirane NMR Chemical Shift Data
Me
OO
Me Me
OO
CF3
Nucleus
1H13C17O19F
1.6522.73, 22.69, 102.3302
1.9714.51, 97.32, 122.2 (CF3)297-81.5
O
O
104.51
*
• t1/2 = ~7 h (disputed)
• stabilized by the presence of O2
•24.9 kcal/mol ∆G- compare to 15.5 kcal/mol ∆G for O–O bond cleavage in
H
OO
H
• first order kinetics at low concentration (10-2 M); complex kinetics at higher concentrations
• radical pathways confirmed by ESR, spin trapping reagents, oxygen trapping, etc.
Thermal Stability
Me
OO
Me
∆
O
MeO Me+
O
HO Me
O
Me Me
+
+ CO2
O
MeHO
Me
OHO Me
OMe
+ +
Oxone: Background
Oxone; CaroateKHSO5
Available commercially as
Caro's AcidH2SO5
explosive
K2SO4•KHSO4•2 KHSO5
O
SO
OK
O OH
pKa(1): < 0
pKa(2): 9.4
Decomposition pathway:
SO52- + HSO5
-
O
SO
OH
O OH
O
SO
OK
O O O
H
OS
O
O
O
SO42- + O2 + HSO4
-
pKa data: JACS, 1956, 78, 1125.decomp pathway: Inorg. Chem. 1964, 1331; Inorg. Chim Acta, Rev, 1968, v2, 53.
25 kg/$180 from Aldrich
Synthetically Useful Dioxirane Synthesis
oxoneO
Me Me Me
OO
Me
co-distill to give~0.1 M soln of dioxirane in acetone
oxoneO
F3C CF3 F3C
OO
CF3
co-distill to give~0.6 M soln of dioxirane in hexafluoroacetone
Curci, JOC, 1980, 4758 & 1988, 3890; JACS 1991, 7654.
Montgomery had reported that ketones catalyze the decomp of oxone (JACS, 1974, 7820).
2 HSO5 2 H+ + 2 SO4- + O2
Relative rateKetone presentnoneacetonecyclohexanone
N
MeMe
O
11094
14,000
NO3
Only catalytic amounts of ketone were required.
convenient preparation: W. Adam Chem. Ber. 1991, 124, 2377.
Mechanism of Dioxirane Formation with Oxone
O
Me
Me oxone
CO
OSO3HO
MeMefast fast
OH
slow
CO
OSO3O
MeMe
OOMe
Me
+ SO42-
oxoneO
Me
Me+ SO4
- + O2
Formation of an O–O bond seems a bit strange, but all data is consistent with the mechanism shown, including independent 18O labeling of the oxone and ketone.
Ph
CO2H
Ph
CO2H
O
Edwards, Curci et al Photochem. Photobio., v.30, 1979, 63.
Oxone Mediated Epoxidations
MeCO2H
MeCO2H
O
oxone
H2O, rt84%
oxone
H2O/CH3OH, rt91%
O
R
R
R
RO
oxone
H2O/CH2Cl2
70-90%
JOC, 1985, 1544.Recl. Trav. Chim. Pays-Bas. 1985, 350.
rt
Synthetic Epoxidations with Oxone/Acetone
Curci, JOC 1980, 4758.
CO2H
Ph
CO2HPh
MeCO2H
Me
O
95%
>90%
97%
97%
98%
CO2H
Ph O
CO2HPh
O
MeCO2H
O
Me
O
O
O
Standard Reaction Conditions:excess oxone in acetone/water (pH 7.5 phosphate buffer) at ~0 °C for 2 h.
Transition State for the Dioxirane Mediated Olefin Epoxidation
O
O
R
R
planar
O
O
R
R
rotate 90°
spiro
Houk, JACS, 1997, 12982.
stabilizing Olp → π* C=Ccis olefins react ~10 times faster than trans
First "Enantioselective" Version
Curci, JCS Chem Comm, 1984, 155.
Me
Ph
Me
ee's determined using Eu(tfc)3 doped 1H NMR.
Me
Ph
Me
O
O
oxonechiral ketone
oxonechiral ketone
2 chiral ketones explored:
O
Me
H
Ph
Me
Me O
MeMe
H
20-300% ketone usedyields 68-92%ee's 4.2 - 12.5%
"...the use of ketones in substoichiometric amounts with no appreciable loss in selectivity is significant and suggests that further research in this area is certainly well justified." Eric Jacobsen in Catalytic Asymmetric Synthesis, 1993, chap 4.2, Wiley-VCH.
Shi's First Stoichiometric Dioxirane Mediated Epoxidation
O OO
O
O
O
MeMe
MeMe
PCC
93%
O OO
O
O
OH
MeMe
MeMe
HClO4
acetone
O OHOH
HO
HO
OH
D-fructose($15/kg, Aldrich)
enantiomer can be readily prepared from L-sorbose in 3 steps (51%)
Rational design features:
• Stereocenters are close to the reacting center• Fused ring and quaternary center minimize possibility of ketone epimerization• Steric discrimination between faces of carbonyl
53%
JACS, 1996, 9806.
Initial Results
O
O
O
O
O
O
Me
MeMe
Me
R
R
R
R Ooxone, CH3CN-H2OpH 7-8
Dramatic pH Effect Observed
JOC, 1997, 2328.
O
O
O
O
O
O
Me
MeMe
Me
R
R
R
R Ooxone, CH3CN-H2OpH 10.5
High pH Epoxidations
JOC, 1998, 6425.
R3
R1
R2
Me
O
O
Me
pH 10.5
CH3CN/H2O R3
R1
R2
O
O
Me
Me oxone
CO
OSO3HO
MeMefast fast
OH
slow
CO
OSO3O
MeMe
OOMe
Me
+ SO42-
oxoneO
Me
Me+ SO4
- + O2
Ph
CO2H
Ph
CO2H
O
What Causes the pH Effect?
CO
OSO3O
MeMe
A
A
O
Me OMe+ SO4
2-
Proposal:Baeyer-Villiger Competition leads to decomposition of chiral catalyst
Structural Modification of the Ketone
O OO
O
O
O
MeMe
MeMe
O OO
O
O
O
RR
RR
R = Et, -(CH2)4, -(CH2)5, -(CH2)6
JOC, 1998, 8475.JOC, 1999, 6443.
O ORO
O
O
O
MeMe
Cl
Original Ketone
None are better than the original
O
O
O
MeMe
OO
MeMe
R
OOR
O
O
O
MeMe
O
O
O
O
MeMe
O
OO
O
O
O
Me
Me
O
O
O
O
O
O
Me
MeMe
Me
R2
R1
R2
R1 Ooxone, CH3CN-H2OpH 10.5
Representative Disubstituted Olefins
O
O
O
O
O
O
Me
MeMe
Me
R3
R2
R3
R2 Ooxone, CH3CN-H2OpH 10.5
Representative Trisubstituted Olefins
R1 R1
O
O
O
O
O
O
Me
MeMe
Me
R2 R2
Ooxone, CH3CN-H2OpH 10.5
Representative Terminal and Cis Olefins
R1 R1
O
O
O
O
O
O
Me
MeMe
Me
R2
R1
R2
R1 Ooxone, CH3CN-H2OpH 10.5
Origin of Enantioselectivity
JACS, 1997, 11224.
O
O
O
O
O
O
Me
MeMe
Me
R2
R1
R2
R1 Ooxone, CH3CN-H2OpH 10.5
Evidence of Mechanism
Alcohol Substrates
JOC, 1998, 3099.Review of allylic alcohol epoxidation: Org. React. 1996, 48, 1-299.
O
O
O
O
O
O
Me
MeMe
Me
(CH2)nOH
R
(CH2)nOH
R Ooxone, CH3CN-H2OpH > 9
Epoxidation of DienesThe chiral dioxirane is more regioselective than MCPBA,and complementary to the Sharpless epoxidation.
JOC, 1998, 2948.
Enyne Epoxidation
TL, 1998, 4425.JOC, 1999, 7646.
O
O
O
O
O
O
Me
MeMe
Me
oxone, CH3CN-DMMpH 9.3
R1R2
R3
R1R2
R3
O
R1R2
R3
O
Nu:R1
R2
R3
OH
Nu
PdCl2SnCl2
R3 = H
R3P, COO
R1 NuR2
O
Mo(CO)6 O
R1 NuR2
R3 = H
R4CuR4
R3R2
OH
R1
Ag+
O
R2
R4
R3
R1
Enyne Results
O
O
O
O
O
O
Me
MeMe
Me
oxone, CH3CN-DMMpH 9.3
R1R2
R3
R1R2
R3
O
Vinyl Silane Epoxidations
JOC, 1999, 7675.
O
O
O
O
O
O
Me
MeMe
Me
TMS
R2
TMS
R2 Ooxone, CH3CN-H2OpH 10.5
R1 R1 TBAF
R2 O
R1
Epoxidation of Enol Ethers and Esters
TL, 1998, 7819. Applications:JACS, 1999, 4080 & in press.
O
O
O
O
O
O
Me
MeMe
Me
R1 oxone, solventpH 10.5
RO
R2 R1
RO
R2
O
Kinetic Resolutions
JACS, 1999, 7718.
O
O
O
O
O
O
Me
MeMe
Me
oxone, CH3CN-H2OpH 10.5
+
R1
R2
R3
R1
R2
R3
O
R1
R2
R3
Yang System
O
O
O
OO
R2R1 R2
R1
Ooxone, pH 7-7.5
Yang, JACS, 1996, 491 & 1999, 5943.
Conclusions
• Recent advances in asymmetric epoxidation have developed around chiral dioxirane mediated reactions.
• Trans and tri-substituted unfunctionalized olefins can now be epoxidized in good ee.
• Future goals include tetrasubstituted and terminal olefin epoxidation.
• Other goals include higher enatioselectivity & convienient reaction protocol.
• Catalyst stability is a liability.