long literature talk: recent advances in enantioselective ......ar ar o o p o o chiral cation...
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Ar
Ar
OO
POO
Chiral CationPhase-Transfer
Chiral AnionPhase-Transfer
Na
N
N
OHBr
CF3
Long Literature Talk:
Recent Advances in Enantioselective Phase-Transfer Catalysis: Merging Two Catalytic Cycles
Jose M. MedinaEngle Laboratory
02/28/2018 Group Meeting
• Intro to phase-transfer catalysis
Presentation Overview
• The merging of CAPT and enamine catalysis
• The merging of CAPT and palladium catalysis
• The merging of CAPT and palladium catalysis
– Chiral cation phase-transfer catalysis (CCPT)
– Chiral anion phase-transfer catalysis (CAPT)
– α-Fluorinated ketones
– Benzylic boronic esters
– Homoallylic alcohols
O
Ph
OF
O OMe
O
(pin)B
Ph
BnPh
OHBnO
*
*
**
What is a Phase-Transfer Catalyst
Hughes, D. L.; Dolling, U.-H; Ryan, K. M.; Schoenwaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745.
Phase-transfer catalysts facilitate the migration of a reactant from one phase into another where the reaction occurs.
Aqueous phaseSolid phase
Organic phaseOrganic phase
What is a Phase-Transfer Catalyst
Hughes, D. L.; Dolling, U.-H; Ryan, K. M.; Schoenwaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745.
Phase-transfer catalysts facilitate the migration of a reactant from one phase into another where the reaction occurs.
Aqueous phaseSolid phase
Organic phaseOrganic phase
MeCO2Na
MeMe
Me
Me Me
Me
SO3Na
Me Me
SO3Na
Mechanism of Phase-Transfer
Hughes, D. L.; Dolling, U.-H; Ryan, K. M.; Schoenwaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745.
O
ON
Ph
PhtBu
O
ON
Ph
PhtBu
NaOH
NaOH
Interface
Aqueous phase
Organic phase
Mechanism of Phase-Transfer
Hughes, D. L.; Dolling, U.-H; Ryan, K. M.; Schoenwaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745.
O
ON
Ph
PhtBu
O
ON
Ph
PhtBuO
ON
Ph
PhtBu
Na
NaOH
+ H2O
NaOH
Interface
Aqueous phase
Organic phase
Mechanism of Phase-Transfer
Hughes, D. L.; Dolling, U.-H; Ryan, K. M.; Schoenwaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745.
O
ON
Ph
PhtBu
O
ON
Ph
PhtBu
O
ON
Ph
PhtBu
Q*
O
ON
Ph
PhtBu
Na
O
ON
Ph
PhtBu
Bn
*
NaOH
+ H2O
NaOH
Interface
Aqueous phase
Organic phaseQ* Br
NaBr
BnBr
Key Benefits of Phase-Transfer Catalysis
Maurin, L. J. U.S. Patent 4418232, Nov. 29, 1983.
Use of simple and inexpensive reagents (ie. NaOH vs. KHMDS)
High yields and purity of products
Processes are highly scalable
Reduction of organic solvents (cost benefit for large process / Green chemistry)
Key Benefits of Phase-Transfer Catalysis
Maurin, L. J. U.S. Patent 4418232, Nov. 29, 1983.
Use of simple and inexpensive reagents (ie. NaOH vs. KHMDS)
High yields and purity of products
Processes are highly scalable
Reduction of organic solvents (cost benefit for large process / Green chemistry)
Dehydrohalogenation Application of PTC
ClClCl
Tetrabutylammonium chloride (1000 ppm)
NaOH (1.08 equiv)
(99.2% yield) Productivity: 16 tons / hr
Cost effectiveEfficientGreen
Solution to synthetic problems?
Enantioselective Alkylation of Indanones
O
Ph
ClCl
MeO
Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106 , 446.
3-step sequence Complex procedure Stoichiometric chiral auxiliaries
Enantioselective Alkylation of Indanones
O
Ph
ClCl
MeO
OClCl
MeO
Me
Ph
N
N
OHBr
CF3
MeClToluene : aq NaOH (5:1)
20 °C, 18 h
(10 mol%)
95% yield92% ee
MK-0197
Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106 , 446.
3-step sequence Complex procedure Stoichiometric chiral auxiliaries
High enantioinductionthrough electrostatic
interactions
Enantioselective Alkylation of Indanones
Tan, J.; Yasuda, N. Org. Process Res. Dev. 2015, 19 , 1731.
O
Ph
ClCl
MeO
OClCl
MeO
Me
Ph
N
N
OHBr
CF3
MeClToluene : aq NaOH (5:1)
20 °C, 18 h
(10 mol%)
95% yield92% ee
MK-0197
Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106 , 446.
Alkylations Conjugate additions Epoxidations Phosphorylations Desymmetrizations
Contemporary Asymmetric Phase-Transfer Catalysis:Large-Scale Industrial Applications
3-step sequence Complex procedure Stoichiometric chiral auxiliaries
High enantioinductionthrough electrostatic
interactions
Selected Examples of Phase-Transfer Catalysts
N
N
OHBr
CF3Merck
JACS 1984106 , 446.
Selected Examples of Phase-Transfer Catalysts
N
N
OHBr
CF3
N
Br
N O
MerckJACS 1984106 , 446.
CoreyJACS 1997119 , 12414.
Selected Examples of Phase-Transfer Catalysts
N
N
OHBr
CF3
N
Br
N O
ShibasakiACIE 200544, 4564.
Ar
Ar
N
Br
O
OMetBu
MerckJACS 1984106 , 446.
N
N
Me
Me
Ar
ArAr
Ar
2 I
CoreyJACS 1997119 , 12414.
MaruokaChem. Commun.
2007, 1487.
First Example of Enantioselective Chiral Anion Phase-Transfer Catalysis
Hamilton, G. L.; Kanai, T.; Toste, F. D. J. Am. Chem. Soc. 2008, 130 , 14984.
Ph
NPh
Cl
R
R
Ph
NPh
OR'
R
R
Ar
Ar
OO
POOH
(15 mol%)
Ag2CO3 (0.6 equiv), 4A MStoluene, 50 °C, 24h°
R'OH+
Ar = 2,4,6-triisopropylphenyl
• Reaction served as proof of concept
• Solution to reactions involving cationic intermediates with no basic site
50–95% yield90–99% ee
CAPT Catalysis in Enantioselective Fluorinations
Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681.
NN
Cl
F
Selectfluor (Insoluble)
BF4 BF4
CAPT Catalysis in Enantioselective Fluorinations
Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681.
NN
Cl
F
POO
OO**
OO
OOP
Soluble chiral fluorinating agent
CAPT Catalysis in Enantioselective Fluorinations
Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681.
Ar
Ar
OO
POOH
Cat. A (10 mol%)Selectfluor (1.5 equiv)
Proton Sponge (1.1 equiv)
C6H5F, –20 °C
(87% yield)
Ar = 4-NO2-C6H4
NH
O
Br
N
O
F
Br
>20:1 d.r, 93% ee
Cat. A
NN
Cl
F
POO
OO**
OO
OOP
Soluble chiral fluorinating agent
CAPT Catalysis in Enantioselective Fluorinations
Ar
Ar
OO
POOH
Ar = 4-NO2-C6H4
Cat. A
NN
Cl
F
POO
OO**
OO
OOP
Soluble chiral fluorinating agent
OO
P
Ar
Ar
O
O
Ar
Ar
NN
POO
Ar'
Ar'
Commonly Employed CAPT CatalystsAr
Ar
OO
POO
• Intro to phase-transfer catalysis
Presentation Overview
• The merging of CAPT and enamine catalysis
• The merging of CAPT and palladium catalysis
• The merging of CAPT and palladium catalysis
– Chiral cation phase-transfer catalysis (CCPT)
– Chiral anion phase-transfer catalysis (CAPT)
– α-Fluorinated ketones
– Benzylic boronic esters
– Homoallylic alcohols
O
Ph
OF
O OMe
O
(pin)B
Ph
BnPh
OHBnO
*
*
**
Asymmetric Fluorination of α-Branched Cyclohexanones
Expand the scope of chiral anion phase-transfer catalysis
Achieve the fluorination of alpha-branched cyclic ketones
Chiral enamine catalysis successful for alpha-fluorination of aldehydes
Asymmetric Fluorination of α-Branched Cyclohexanones
Expand the scope of chiral anion phase-transfer catalysis
Achieve the fluorination of alpha-branched cyclic ketones
Chiral enamine catalysis successful for alpha-fluorination of aldehydes
Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133 , 1738.
O O
O
NSO2PhPhO2S
FO O
OF
N
N
OMe
H2N
Et
(10 mol%)
Na2CO3 (1.5 equiv)THF, –20 °C
(82% yield, 97% ee)
+
Ketones proved to be more challenging substrates
EnamineCatalysis
Proposed Dual Catalytic Cycle for the Enantioselective Fluorination of Ketones
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
NH2*RO
PhNH
Ph
*R
H2O
EnamineCatalysis
Proposed Dual Catalytic Cycle for the Enantioselective Fluorination of Ketones
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
NH2*RO
PhNH
Ph
*R
H2O
CAPTCatalysis
NN Cl
FP
OO
OO*
2
NN Cl
F BF42
H2O
EnamineCatalysis
Proposed Dual Catalytic Cycle for the Enantioselective Fluorination of Ketones
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
N*R
FPh
OFPh
NH2*RO
PhNH
Ph
*R
H2O
CAPTCatalysis
NN Cl
FP
OO
OO*
2
NN Cl
F BF42
POO
OO*
Reaction Optimization Studies
PhO
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
(5 mol%)
Amine Catalyst (20 mol%)
Na2CO3 or Na2CO3•H2OToluene (0.1M), 23 °C, 20h
Ph
OF
Ar
Ar
OO
POOH
Cat. A
R = C8H17, Ar = 2,4,6-triisopropylphenyl
R
R
OMe
O
NH3 Cl
NN Cl
F BF42
+
Ph
phosphoric acid amine yield eeentry
Cat. A none 5% –21Cat. A 29% –32Cat. A 1 63–73% +63–783Cat. A 1 (dry Na2CO3) 50% +324Cat. A 1 (Na2CO3•H2O) 74% +885
BnNH2
1
Reaction Optimization Studies
PhO
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
(5 mol%)
Amine Catalyst (20 mol%)
Na2CO3•H2OToluene (0.1M), 23 °C, 20h
Ph
OF
Ar
Ar
OO
POOH
Cat. A
R = C8H17, Ar = 2,4,6-triisopropylphenyl
R
R
OMe
O
NH3 Cl
NN Cl
F BF42
+
Ph
phosphoric acid amine yield eeentry
2
Cat. A 2 70% –406
Reaction Optimization Studies
PhO
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
(5 mol%)
Amine Catalyst (20 mol%)
Na2CO3•H2OToluene (0.1M), 23 °C, 20h
Ph
OF
Ar
Ar
OO
POOH
Cat. A
R = C8H17, Ar = 2,4,6-triisopropylphenyl
R
R
OMe
O
NH3 Cl
NN Cl
F BF42
+
Ph
phosphoric acid amine yield eeentry
1
Cat. A 2 70% –406
none 10% +107 1
Reaction Optimization Studies
PhO
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
(5 mol%)
Amine Catalyst (20 mol%)
Na2CO3•H2OToluene (0.1M), 23 °C, 20h
Ph
OF
Ar
Ar
OO
POOH
Cat. A
R = C8H17, Ar = 2,4,6-triisopropylphenyl
R
R
OMe
O
NH3 Cl
NN Cl
F BF42
+
Ph
phosphoric acid amine yield eeentry
1
Cat. A 2 70% –406
none 10% +107
AP 1 57% +208
1
(5 mol%)
t-But-Bu
t-Bu t-Bu
OO
POOH
Reaction Optimization Studies
PhO
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
(5 mol%)
Amine Catalyst (20 mol%)
Na2CO3•H2OToluene (0.1M), 23 °C, 20h
Ph
OF
Ar
Ar
OO
POOH
Cat. A
R = C8H17, Ar = 2,4,6-triisopropylphenyl
R
R
OMe
O
NH3 Cl
NN Cl
F BF42
+
Np
phosphoric acid amine yield eeentry
3
Cat. A 2 70% –406
none 10% +107
AP 1 57% +208
Cat. A 3 62% +949
1
Substrate Scope
RO
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
(5 mol%)
Amine Catalyst (20 mol%)
Na2CO3•H2OToluene (0.1M), 23 °C, 20h
R
OF
Ar
Ar
OO
POOH
Cat. A
R = C8H17, Ar = 2,4,6-triisopropylphenyl
R
R
OMe
O
NH3 Cl
NN Cl
F BF42
+
Np
3
17 examples
OF
O
O
Ph
OF
NBoc
Ph
OF
OF
57% yield91% ee
62% yield89% ee
55% yield86% ee
48% yield86% ee
Substrate Scope
RO
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
(5 mol%)
Amine Catalyst (20 mol%)
Na2CO3•H2OToluene (0.1M), 23 °C, 20h
R
OF
Ar
Ar
OO
POOH
Cat. A
R = C8H17, Ar = 2,4,6-triisopropylphenyl
R
R
OMe
O
NH3 Cl
NN Cl
F BF42
+
Np
3
17 examples
OF
OF
OF
OF
52% yield86% ee
70% yield85% ee
86% yield78% ee
77% yield77% ee
Ph nBu
Big step toward controlled fluorinations of simple substrates
Substrate Scope
RO
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
(5 mol%)
Amine Catalyst (20 mol%)
Na2CO3•H2OToluene (0.1M), 23 °C, 20h
R
OF
Ar
Ar
OO
POOH
Cat. A
R = C8H17, Ar = 2,4,6-triisopropylphenyl
R
R
OMe
O
NH3 Cl
NN Cl
F BF42
+
Np
3
17 examples
LimitationsFluorination limited to branched cyclohexanones
Methodology not amenable to 2-alkyl cyclohexanones
No fluorination of acyclic or non-branched ketones
Substrate Scope
RO
Yang, X.; Phipps, R. J.; Toste, F. D. J. Am. Chem. Soc. 2014, 136 , 5225.
(5 mol%)
Amine Catalyst (20 mol%)
Na2CO3•H2OToluene (0.1M), 23 °C, 20h
R
OF
Ar
Ar
OO
POOH
Cat. A
R = C8H17, Ar = 2,4,6-triisopropylphenyl
R
R
OMe
O
NH3 Cl
NN Cl
F BF42
+
Np
3
17 examples
AccomplishmentsDeveloped the fluorination of branched cyclohexanones
Established the compatibility of CAPT and enamine catalysis
Among the first reports to combine two chiral organocatalytic cycles
• Intro to phase-transfer catalysis
Presentation Overview
• The merging of CAPT and enamine catalysis
• The merging of CAPT and palladium catalysis
• The merging of CAPT and palladium catalysis
– Chiral cation phase-transfer catalysis (CCPT)
– Chiral anion phase-transfer catalysis (CAPT)
– α-Fluorinated ketones
– Benzylic boronic esters
– Homoallylic alcohols
O
Ph
OF
O OMe
O
(pin)B
Ph
BnPh
OHBnO
*
*
**
Recent Approaches to Enantioenriched Benzylic Boronic Esters
Benzylic boronic esters as building blocks for the formation of C–C, C–O, and C–N
Recent Approaches to Enantioenriched Benzylic Boronic Esters
Feng, X.; Jeon, H.; Yun, J. Angew. Chem., Int. Ed. 2013, 52, 3989.
Benzylic boronic esters as building blocks for the formation of C–C, C–O, and C–N
Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3, 894.
OMe
OOMe
O
(dan)B B(pin)
OMe
O
(dan)B Ar
4 steps 2 steps
B(dan)
B(pin)
B(dan)
Ar
3 steps 2 steps
Recent Approaches to Enantioenriched Benzylic Boronic Esters
Benzylic boronic esters as building blocks for the formation of C–C, C–O, and C–N
Sun, C.; Potter, B.; Morken, J. P. J. Am. Chem. Soc. 2014, 136 , 6534.
2 steps 1 step
R B(pin)
B(pin)
R Ar
B(pin)R O
Recent Approaches to Enantioenriched Benzylic Boronic Esters
Saini, V.; Liao, L.; Wang, Q.; Jana, R.; Sigman, M. S. Org. Lett. 2013, 15 , 5008.
Benzylic boronic esters as building blocks for the formation of C–C, C–O, and C–N
Sun, C.; Potter, B.; Morken, J. P. J. Am. Chem. Soc. 2014, 136 , 6534.
2 steps 1 step
R B(pin)
B(pin)
R Ar
B(pin)R O
1,1-diarylation of simple alkenes
OMe
(HO)2BOCO2Ph
OCO2Ph
Ph
OMe
Pd2dba3•CHCl3NaHCO3
t-BuOH (.05M)
80 °C, 4h
(75% yield)
+N2BF4
Ph+
Recent Approaches to Enantioenriched Benzylic Boronic Esters
Nelson, H. M.; Williams, B. D.; Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
Benzylic boronic esters as building blocks for the formation of C–C, C–O, and C–N
Sun, C.; Potter, B.; Morken, J. P. J. Am. Chem. Soc. 2014, 136 , 6534.
2 steps 1 step
R B(pin)
B(pin)
R Ar
B(pin)R O
Single step 1,1-arylboration of simple alkenes
R1 step
R
B(pin)
B2(pin)2 ++ *N2BF4
Enantioselectivity via CAPT
Proposed Dual Catalytic Cycle for 1,1-Arylborylation
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
POO
OO*N2
POO
OO*
CAPTCatalysisAr N2BF4
Proposed Dual Catalytic Cycle for 1,1-Arylborylation
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PdCatalysis
POO
OO*
LnPd0N2
PdLn POO
OO*
POO
OO*
CAPTCatalysisAr N2BF4
Proposed Dual Catalytic Cycle for 1,1-Arylborylation
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PdCatalysis
POO
OO*
LnPd0N2
PdLn POO
OO*
PdLnR POO
OO*R
POO
OO*
CAPTCatalysisAr N2BF4
Proposed Dual Catalytic Cycle for 1,1-Arylborylation
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PdCatalysis
POO
OO*
LnPd0N2
PdLn POO
OO*
PdLnR POO
OO*R
R
POO
OO*PdLn
POO
OO*
CAPTCatalysisAr N2BF4
Proposed Dual Catalytic Cycle for 1,1-Arylborylation
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PdCatalysis
POO
OO*
LnPd0N2
PdLn POO
OO*
PdLnR POO
OO*R
R
POO
OO*PdLn
B2pin2
R
BpinP
OO
OO* P
OO
OO*Bpin
base+
CAPTCatalysisAr N2BF4
Non-enantioselective Reaction ScopeAryldiazonium Partner
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
Pd2(dba)3 (2.5 mol%)NaHCO3 (1.2 equiv)
THF, 23 °CR
(pin)B
ArRN2BF4Ar B2(pin)2+ +
Non-enantioselective Reaction ScopeAryldiazonium Partner
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
Pd2(dba)3 (2.5 mol%)NaHCO3 (1.2 equiv)
THF, 23 °CR
(pin)B
ArRN2BF4Ar B2(pin)2+ +
OMe
(pin)B O OMe
O
CF3
(pin)B O OMe
O(pin)B O OMe
O
72% yield 90% yield 71% yield
Non-enantioselective Reaction ScopeAlkene Partner
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
Pd2(dba)3 (2.5 mol%)NaHCO3 (1.2 equiv)
THF, 23 °CR
(pin)B
ArRN2BF4Ar B2(pin)2+ +
OMe
(pin)B
OMe
(pin)B(pin)B
91% yield 99% yield 46% yield
OMe
NHTs
CN
PhPh
O
OEt
Enantioselective Reaction Optimization Studies
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PhN2BF4, B2(pin)2Pd2(dba)3 (5 mol%)
base, additivesolvent, 23 °C
(10 mol%)
Ar
Ar
OO
POOH
CAPT cat. 1
Ar = 2,4,6-(i-Pr)3C6H2
O OMe
O
O OMe
O
(pin)B
Ph
Enantioselective Reaction Optimization Studies
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PhN2BF4, B2(pin)2Pd2(dba)3 (5 mol%)
base, additivesolvent, 23 °C
(10 mol%)
Ar
Ar
OO
POOH
CAPT cat. 1
Ar = 2,4,6-(i-Pr)3C6H2
CAPT cat. base yield eeentry
1 5% –11 72% < 521 45% 333
NaHCO3
NaHCO3
additive
–––
solvent
THFhexanes
Et2O NaHCO3
O OMe
O
O OMe
O
(pin)B
Ph
Enantioselective Reaction Optimization Studies
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PhN2BF4, B2(pin)2Pd2(dba)3 (5 mol%)
base, additivesolvent, 23 °C
(10 mol%)
Ar
Ar
OO
POOH
CAPT cat. 2
Ar = 2,4,6-(Cy)3C6H2
CAPT cat. base yield eeentry
1 5% –11 72% < 521 45% 3332 25% 884
NaHCO3
NaHCO3
additive
––
––
solvent
THFhexanes
Et2OEt2O
NaHCO3
NaHCO3
O OMe
O
O OMe
O
(pin)B
Ph
Enantioselective Reaction Optimization Studies
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PhN2BF4, B2(pin)2Pd2(dba)3 (5 mol%)
base, additivesolvent, 23 °C
(10 mol%)
Ar
Ar
OO
POOH
CAPT cat. 2
Ar = 2,4,6-(Cy)3C6H2
CAPT cat. base yield eeentry
1 5% –11 72% < 521 45% 3332 25% 8842 26% 935
NaHCO3
NaHCO3
additive
––
––
–
solvent
THFhexanes
Et2OEt2OEt2O
NaHCO3
NaHCO3
Na3PO4
O OMe
O
O OMe
O
(pin)B
Ph
Enantioselective Reaction Optimization Studies
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PhN2BF4, B2(pin)2Pd2(dba)3 (5 mol%)
base, additivesolvent, 23 °C
(10 mol%)
Ar
Ar
OO
POOH
CAPT cat. 2
Ar = 2,4,6-(Cy)3C6H2
CAPT cat. base yield eeentry
1 5% –11 72% < 521 45% 3332 25% 8842 26% 935
NaHCO3
2 39% 906
NaHCO3
additive
––
––
–A
solvent
THFhexanes
Et2OEt2OEt2OEt2O
NaHCO3
NaHCO3
Na3PO4
Na3PO4
O OMe
O
O OMe
O
(pin)B
Ph
O
CF3 CF3A
Reaction Scope - Aryldiazonium Partner
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PhN2BF4, B2(pin)2Pd2(dba)3 (5 mol%)
base, additivesolvent, 23 °C
(10 mol%)
Ar
Ar
OO
POOH
CAPT cat. 2
Ar = 2,4,6-(Cy)3C6H2
O OMe
O
O OMe
O
(pin)B
Ph
O
CF3 CF3A
(pin)B
58% yield87% ee
O OMe
O
MeO
(pin)B O OMe
O
t-Bu32% yield96% ee
(pin)B O OMe
O
40% yield98% ee
Reaction Scope - Alkene Partner
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PhN2BF4, B2(pin)2Pd2(dba)3 (5 mol%)
base, additivesolvent, 23 °C
(10 mol%)
Ar
Ar
OO
POOH
CAPT cat. 2
Ar = 2,4,6-(Cy)3C6H2
O O(pin)B
Ar'
(pin)B
47% yield89% ee
O(pin)B O
OPiv
40% yield97% ee
(pin)B
t-Bu
33% yield98% ee
OEtOEt
OEt
O
OEtOEt
Reaction Scope - Alkene Partner
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PhN2BF4, B2(pin)2Pd2(dba)3 (5 mol%)
base, additivesolvent, 23 °C
(10 mol%)
Ar
Ar
OO
POOH
CAPT cat. 2
Ar = 2,4,6-(Cy)3C6H2
O O(pin)B
Ar' OEtOEt
Limitations
Yields range from low to synthetically useful
Limited scope in terms of functional group tolerance and alkene partners
Reaction Scope - Alkene Partner
Nelson, H. M.; Williams, B. D., Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.
PhN2BF4, B2(pin)2Pd2(dba)3 (5 mol%)
base, additivesolvent, 23 °C
(10 mol%)
Ar
Ar
OO
POOH
CAPT cat. 2
Ar = 2,4,6-(Cy)3C6H2
O O(pin)B
Ar' OEtOEt
Accomplishments
Modular and step-economical method for access to chiral benzylic boronates
Process rendered enantioselective via chiral anion phase-transfer
Alternative strategy for achieving enantioinduction
• Intro to phase-transfer catalysis
Presentation Overview
• The merging of CAPT and enamine catalysis
• The merging of CAPT and palladium catalysis
• The merging of CAPT and palladium catalysis
– Chiral cation phase-transfer catalysis (CCPT)
– Chiral anion phase-transfer catalysis (CAPT)
– α-Fluorinated ketones
– Benzylic boronic esters
– Homoallylic alcohols
O
Ph
OF
O OMe
O
(pin)B
Ph
BnPh
OHBnO
*
*
**
Prevalence of Homoallylic Alcohols
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
Homoallylic alcohols are present in many pharmaceuticals and natural products
OHO
MeOH
OH
Me
O
OH OH
monomarinomycin A
HOH
OO
NHMe
OCl
salinosporamide A
Prevalence of Homoallylic Alcohols
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
Homoallylic alcohols are present in many pharmaceuticals and natural products
OHO
MeOH
OH
Me
O
OH OH
monomarinomycin A
HOH
OO
NHMe
OCl
salinosporamide A
R
OH
R'R'
O
HCat•R
MX
R
XMor
pre-formed in-situ generated
+
Asymmetric allylation of carbonyls
Prevalence of Homoallylic Alcohols
Tao, Z.-L.; Li, X.-H.; Han, Z.-Y.; Gong, L.-Z. J. Am. Chem. Soc. 2015, 137 , 4054.
Homoallylic alcohols are present in many pharmaceuticals and natural products
OHO
MeOH
OH
Me
O
OH OH
monomarinomycin A
HOH
OO
NHMe
OCl
salinosporamide A
O2N
H
O
Ph
H
O2N
OH
Ph
Pd(dba)2 (10 mol%)PPh3 (20 mol%)
PA cat. (20 mol%)
B2(pin)2 (2.0 equiv)NFSI (2.0 equiv)Toluene, 23 °C
+
65% yield, >20:1 dr67% ee
Prevalence of Homoallylic Alcohols
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
Homoallylic alcohols are present in many pharmaceuticals and natural products
OHO
MeOH
OH
Me
O
OH OH
monomarinomycin A
HOH
OO
NHMe
OCl
salinosporamide A
R'
OH
RR' H
O
R
PdLn / *B H
(RO)2B–B(OR)2Base
++N2BF4
Multicomponent asymmetric allylation of carbonyls
* *
Two new C–C bondsTwo new vicinal stereocenters
Proposed Dual Catalytic Cycle - Carbonyl Allylation
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
POO
OO*Ph N2
POO
OO*
CAPTCatalysisPh N2BF4
Proposed Dual Catalytic Cycle - Carbonyl Allylation
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
PdCatalysis
POO
OO*
LnPd0Ph N2
Ph PdLn POO
OO*
POO
OO*
CAPTCatalysisPh N2BF4
Proposed Dual Catalytic Cycle - Carbonyl Allylation
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
PdCatalysis
POO
OO*
LnPd0Ph N2
Ph PdLn POO
OO*
POO
OO*
POO
OO*
CAPTCatalysisPh N2BF4
R
RPh
PdLn
Proposed Dual Catalytic Cycle - Carbonyl Allylation
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
PdCatalysis
POO
OO*
LnPd0Ph N2
Ph PdLn POO
OO*
POO
OO*
POO
OO*
CAPTCatalysisPh N2BF4
R
RPh
PdLn
POO
OO*
RPh
PdLn
Proposed Dual Catalytic Cycle - Carbonyl Allylation
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
PdCatalysis
POO
OO*
LnPd0Ph N2
Ph PdLn POO
OO*
POO
OO*
POO
OO* P
OO
OO*B
base
+
CAPTCatalysisPh N2BF4
R
RPh
PdLn
POO
OO*
RPh
PdLn
B2(OR)2
RPh
RPh
B(OR)2 B(OR)2
* *(RO)2
Proposed Dual Catalytic Cycle - Carbonyl Allylation
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
PdCatalysis
POO
OO*
LnPd0Ph N2
Ph PdLn POO
OO*
POO
OO*
+
R
RPh
PdLn
POO
OO*
RPh
PdLn
B2(OR)2
RPh
RPh
B(OR)2 B(OR)2
* *+ RPh
RPh
* *R' O
R' OHOHR'
Reaction Optimization Studies
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
diborate 1 / 2 eeentry
1.3:1 –1 Pd(dba)2
yield
70%
phosphoric acid
PA 1
A
Pd
1:2
Z / E
A
Ar
OHBn
Ph
Ar
OHPh
Bn
1
2
+
Ar H
O
Ph
N2BF4
Ph++
B BO
OO
O Me
Me
Me
Me
t-Bu t-Bu
t-Bu t-Bu
O
OP
O
OH(10 mol%)
Reaction Optimization Studies
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
diborate 1 / 2 eeentry
1.3:1 –1
2.7:1 –2 Pd(dba)2
Pd(dba)2
yield
90%
70%
phosphoric acid
PA 1
PA 1
B
Pd
1.7:1
1:2
Z / E
A
B
Ar
OHBn
Ph
Ar
OHPh
Bn
1
2
+
Ar H
O
Ph
N2BF4
Ph++
B BO
OO
OMe
Me
MeMe
MeMe
MeMe
t-Bu t-Bu
t-Bu t-Bu
O
OP
O
OH(10 mol%)
Reaction Optimization Studies
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
diborate 1 / 2 eeentry
1.3:1 –1
2.7:1 –2
>20:1 –3
Pd(dba)2
Pd(dba)2
yield
99%
90%
70%
phosphoric acid
PA 1
PA 1
PA 1 Pd(dba)2
C
Pd
1.7:1
1:2
>20:1
Z / E
A
B
C
Ar
OHBn
Ph
Ar
OHPh
Bn
1
2
+
Ar H
O
Ph
N2BF4
Ph++
B BO
OO
OPh
Ph
PhPh
PhPh
PhPh
t-Bu t-Bu
t-Bu t-Bu
O
OP
O
OH(10 mol%)
Reaction Optimization Studies
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
PA 2Ar = 2,4,6-(i-Pr)3C6H2
diborate 1 / 2 eeentry
1.3:1 –1
2.7:1 –2
>20:1 –3
Pd(dba)2
>20:1 82%4
Pd(dba)2
yield
99%
90%
70%
99%
phosphoric acid
PA 1
PA 1
PA 1
PA 2
Pd(dba)2
Pd(dba)2
C
Pd
1.7:1
1:2
>20:1
>20:1
Z / E
A
B
C
C
Ar
OHBn
Ph
Ar
OHPh
Bn
1
2
+
Ar H
O
Ph
N2BF4
Ph++
B BO
OO
OPh
Ph
PhPh
PhPh
PhPh
OO
P
Ar
Ar
O
OH(10 mol%)
Reaction Optimization Studies
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
PA 2Ar = 2,4,6-(i-Pr)3C6H2
diborate 1 / 2 eeentry
1.3:1 –1
2.7:1 –2
>20:1 –3
Pd(dba)2
>20:1 82%4
Pd(dba)2
yield
99%
90%
70%
99%
phosphoric acid
PA 1
PA 1
PA 1
PA 2
Pd(dba)2
Pd(dba)2
C
Pd
1.7:1
1:2
>20:1
>20:1
Z / E
>20:1 93%5 99%PA 2 Pd(OAc)2 >20:1
A
B
C
C
C
Ar
OHBn
Ph
Ar
OHPh
Bn
1
2
+
Ar H
O
Ph
N2BF4
Ph++
B BO
OO
OPh
Ph
PhPh
PhPh
PhPh
OO
P
Ar
Ar
O
OH(10 mol%)
Reaction Scope - 1,3-Butadienes
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
Ar = 2,4,6-(i-Pr)3C6H2
Ar'
OH
RAr' H
O
R
N2BF4
Ph++
B BO
OO
OPh
Ph
PhPh
PhPh
PhPh
OO
P
Ar
Ar
O
OH(10 mol%)
Bn
14 examples
Reaction Scope - 1,3-Butadienes
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
Ar = 2,4,6-(i-Pr)3C6H2
Ar'
OH
RAr' H
O
R
N2BF4
Ph++
B BO
OO
OPh
Ph
PhPh
PhPh
PhPh
OO
P
Ar
Ar
O
OH(10 mol%)
Bn
Ar'
OH
Bn
Ar' = 4-NO2-C6H4
Ar'
OH
BnBr
Ar'
OH
Bn
Me
Ar'
OH
Bn
Et Et99% yield90% ee
99% yield89% ee
96% yield88% ee
74% yield88% ee
14 examples
Reaction Scope - Aryldiazonium Tetrafluoroborate
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
Ar = 2,4,6-(i-Pr)3C6H2
Ar'
OH
PhAr' H
O
Ph
N2BF4
Ar++
B BO
OO
OPh
Ph
PhPh
PhPh
PhPh
OO
P
Ar
Ar
O
OH(10 mol%)
14 examples
Ar
Ar' = 4-NO2-C6H4
Ar'
OH
Ph
99% yield87% ee
OMe
Ar'
OH
Ph
40% yield90% ee
CF3
Ar'
OH
Ph
90% yield94% ee
MeO
Reaction Scope - Aldehydes
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
Ar = 2,4,6-(i-Pr)3C6H2
R
OH
PhR H
O
Ph
N2BF4
Ph++
B BO
OO
OPh
Ph
PhPh
PhPh
PhPh
OO
P
Ar
Ar
O
OH(10 mol%)
Bn
12 examples
OH
Ph Bn
OH
Ph Bn
O
OH
Ph Bn
OH
Ph Bn
BocHN
99% yield90% ee
99% yield92% ee
99% yield92% ee
99% yield94% ee
Reaction Scope - Aldehydes
Tao, Z.-L.; Adili, A.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Angew. Chem., Int. Ed. 2016, 55, 4322.
B2(OR)2Pd source (10 mol%)
NaHCO3Toluene, 23 °C
Ar = 2,4,6-(i-Pr)3C6H2
R
OH
PhR H
O
Ph
N2BF4
Ph++
B BO
OO
OPh
Ph
PhPh
PhPh
PhPh
OO
P
Ar
Ar
O
OH(10 mol%)
Bn
12 examples
Accomplishments
Over 40 different enantioenriched homoallylic alcohols synthesized
Most complex application of CAPT in cooperative catalysis
New strategy for the asymmetric functionalization of 1,3-dienes
Enantioselective Heck–Matsuda Arylations
Ar = 2,4,6-(Cy)3C6H2
MeO2C CO2MeMeO2C CO2Me
Ar
Ar–N2BF4Pd2(dba)3 (5 mol%)PA cat. A (10 mol%)
K2CO3PhH:MTBE (3:2)
24h, 10 ºC5, 6, and
7-membered ringsup to 94% yield
94% ee>25 examples
Ar
Ar
OO
POOH
Avila, C. M.; Patel, J. S.; Reddi, Y.; Saito, M.; Nelson, H. M.; Shunatona, H. P.;Sigman, M. S.; Sunoj, R. B.; Toste, F. D. Angew. Chem., Int. Ed. 2017, 56, 5806.
PA cat. A
Enantioselective Heck–Matsuda Arylations
Ar = 2,4,6-(Cy)3C6H2
Enantioselective 1,1-Diarylation of Acrylates
Yamamoto, E.; Hilton, M. J.; Orlandi, M.; Saini, V.; Toste, F. D.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 15877.
MeO2C CO2MeMeO2C CO2Me
Ar
Ar–N2BF4Pd2(dba)3 (5 mol%)PA cat. A (10 mol%)
K2CO3PhH:MTBE (3:2)
24h, 10 ºC5, 6, and
7-membered ringsup to 94% yield
94% ee>25 examples
Ar
Ar
OO
POOH
Avila, C. M.; Patel, J. S.; Reddi, Y.; Saito, M.; Nelson, H. M.; Shunatona, H. P.;Sigman, M. S.; Sunoj, R. B.; Toste, F. D. Angew. Chem., Int. Ed. 2017, 56, 5806.
BnO
O O Ar’
Ar
Ar’–N2BF4Ar–B(OH)2
Pd2(dba)3 CHCl3 (3 mol%)PA cat. B (6 mol%)
NaHCO3, Et2O20h, 20 ºC
PA cat. A
BnOup to 68% yield
98:2 er>15 examples
Ar = 9-anthracenylPA cat. B
• Intro to phase-transfer catalysis
Summary
• The merging of CAPT and enamine catalysis
• The merging of CAPT and palladium catalysis
• The merging of CAPT and palladium catalysis
– How the catalysts work
– Industrial applications
– α-Fluorinated ketones
J. Am. Chem. Soc. 2014, 136, 5225.
– Benzylic boronic esters
J. Am. Chem. Soc. 2015, 137, 3213.
– Homoallylic alcohols
Angew. Chem., Int. Ed. 2016, 55, 4322.
O
Ph
OF
O OMe
O
(pin)B
Ph
BnPh
OHBnO
*
*
**
PTC is a widely used process in industry and academia
Conclusions
O
Ph
OF O OMe
O
(pin)B
Ph BnPh
OHBnO* * **
Cost effective and green process
Recent cooperative catalysis approach enabled complex molecule synthesis
MeO2C CO2Me
Ar
O Ar’
ArBnO* *
PTC is a widely used process in industry and academia
Conclusions
O
Ph
OF O OMe
O
(pin)B
Ph BnPh
OHBnO* * **
Future Directions
Cost effective and green process
Recent cooperative catalysis approach enabled complex molecule synthesis
Expansion of cooperative catalysis work to include other types of catalysis
Development of new reagents and catalysts tailored for PTC
Application of CCPT in enantioselective cooperative catalysis
MeO2C CO2Me
Ar
O Ar’
ArBnO* *
AcknowledgmentsInstitution:
TSRI
Advisor:
Prof. Keary M. Engle
Group Members:
Dr. De-Wei GaoDr. Miriam O’Duill
Dr. Sri Krishna NimmagaddaDr. Malkanthi K. Karunananda
Joseph DerosaZhen Liu
John A. GurakRei Matsuura
Tanner JankinsAndrew Romine
Mingyu LiuVan Tran
Denise KahlerYiyang (Elaine) Xiao
Huiqi NiPusu Yang
Vincent van der PuylTian (May) Zeng
Hermione
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