Long Literature Talk: Recent Advances in Enantioselective ......Ar Ar O O P O O Chiral Cation Phase-Transfer Chiral Anion Phase-Transfer Na N N OH Br CF3 Long Literature Talk: Recent

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


– 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


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


O

ON

Ph

PhtBu

O

ON

Ph

PhtBu

NaOH

NaOH

Interface

Aqueous phase

Organic phase



O

ON

Ph

PhtBu

O

ON

Ph

PhtBuO

ON

Ph

PhtBu

Na

NaOH

+ H2O

NaOH

Interface

Aqueous phase

Organic phase



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


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



High enantioinductionthrough electrostatic

interactions


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


Alkylations Conjugate additions Epoxidations Phosphorylations Desymmetrizations

Contemporary Asymmetric Phase-Transfer Catalysis:Large-Scale Industrial Applications


High enantioinductionthrough electrostatic

interactions

Selected Examples of Phase-Transfer Catalysts

N

N

OHBr

CF3Merck

JACS 1984106 , 446.


N

N

OHBr

CF3

N

Br

N O

MerckJACS 1984106 , 446.

CoreyJACS 1997119 , 12414.


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



NN

Cl

F

POO

OO**

OO

OOP

Soluble chiral fluorinating agent



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



Ar

Ar

OO

POOH

Ar = 4-NO2-C6H4

Cat. A

NN

Cl

F

POO

OO**

OO

OOP


OO

P

Ar

Ar

O

O

Ar

Ar

NN

POO

Ar'

Ar'

Commonly Employed CAPT CatalystsAr

Ar

OO

POO











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



NH2*RO

PhNH

Ph

*R

H2O

CAPTCatalysis

NN Cl

FP

OO

OO*

2

NN Cl

F BF42

H2O

EnamineCatalysis



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


(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


PhO


(5 mol%)


Na2CO3•H2OToluene (0.1M), 23 °C, 20h

Ph

OF

Ar

Ar

OO

POOH

Cat. A


R

R

OMe

O

NH3 Cl

NN Cl

F BF42

+

Ph


2

Cat. A 2 70% –406


PhO


(5 mol%)



Ph

OF

Ar

Ar

OO

POOH

Cat. A


R

R

OMe

O

NH3 Cl

NN Cl

F BF42

+

Ph


1

Cat. A 2 70% –406

none 10% +107 1


PhO


(5 mol%)



Ph

OF

Ar

Ar

OO

POOH

Cat. A


R

R

OMe

O

NH3 Cl

NN Cl

F BF42

+

Ph


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


PhO


(5 mol%)



Ph

OF

Ar

Ar

OO

POOH

Cat. A


R

R

OMe

O

NH3 Cl

NN Cl

F BF42

+

Np


3

Cat. A 2 70% –406

none 10% +107

AP 1 57% +208

Cat. A 3 62% +949

1

Substrate Scope

RO


(5 mol%)



R

OF

Ar

Ar

OO

POOH

Cat. A


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


(5 mol%)



R

OF

Ar

Ar

OO

POOH

Cat. A


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


(5 mol%)



R

OF

Ar

Ar

OO

POOH

Cat. A


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


(5 mol%)



R

OF

Ar

Ar

OO

POOH

Cat. A


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











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


Feng, X.; Jeon, H.; Yun, J. Angew. Chem., Int. Ed. 2013, 52, 3989.


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



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


Saini, V.; Liao, L.; Wang, Q.; Jana, R.; Sigman, M. S. Org. Lett. 2013, 15 , 5008.



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+


Nelson, H. M.; Williams, B. D.; Miro, J.; Toste, F. D. J. Am. Chem. Soc. 2015, 137 , 3213.



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



PdCatalysis

POO

OO*

LnPd0N2

PdLn POO

OO*

POO

OO*




PdCatalysis

POO

OO*

LnPd0N2

PdLn POO

OO*

PdLnR POO

OO*R

POO

OO*




PdCatalysis

POO

OO*

LnPd0N2

PdLn POO

OO*

PdLnR POO

OO*R

R

POO

OO*PdLn

POO

OO*




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+


Non-enantioselective Reaction ScopeAryldiazonium Partner


Pd2(dba)3 (2.5 mol%)NaHCO3 (1.2 equiv)

THF, 23 °CR

(pin)B

ArRN2BF4Ar B2(pin)2+ +

Non-enantioselective Reaction ScopeAryldiazonium Partner



THF, 23 °CR

(pin)B


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



THF, 23 °CR

(pin)B


OMe

(pin)B

OMe

(pin)B(pin)B

91% yield 99% yield 46% yield

OMe

NHTs

CN

PhPh

O

OEt

Enantioselective Reaction Optimization Studies


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





(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





(10 mol%)

Ar

Ar

OO

POOH

CAPT cat. 2

Ar = 2,4,6-(Cy)3C6H2


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





(10 mol%)

Ar

Ar

OO

POOH

CAPT cat. 2

Ar = 2,4,6-(Cy)3C6H2


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





(10 mol%)

Ar

Ar

OO

POOH

CAPT cat. 2

Ar = 2,4,6-(Cy)3C6H2


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




(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




(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





(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





(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











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




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


Tao, Z.-L.; Li, X.-H.; Han, Z.-Y.; Gong, L.-Z. J. Am. Chem. Soc. 2015, 137 , 4054.


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




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


POO

OO*Ph N2

POO

OO*

CAPTCatalysisPh N2BF4



PdCatalysis

POO

OO*

LnPd0Ph N2

Ph PdLn POO

OO*

POO

OO*




PdCatalysis

POO

OO*

LnPd0Ph N2

Ph PdLn POO

OO*

POO

OO*

POO

OO*


R

RPh

PdLn



PdCatalysis

POO

OO*

LnPd0Ph N2

Ph PdLn POO

OO*

POO

OO*

POO

OO*


R

RPh

PdLn

POO

OO*

RPh

PdLn



PdCatalysis

POO

OO*

LnPd0Ph N2

Ph PdLn POO

OO*

POO

OO*

POO

OO* P

OO

OO*B

base

+


R

RPh

PdLn

POO

OO*

RPh

PdLn

B2(OR)2

RPh

RPh

B(OR)2 B(OR)2

* *(RO)2



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'



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%)






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%)






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%)





PA 2Ar = 2,4,6-(i-Pr)3C6H2


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%)





PA 2Ar = 2,4,6-(i-Pr)3C6H2


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




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




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




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




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




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


Summary




– How the catalysts work

– Industrial applications


J. Am. Chem. Soc. 2014, 136, 5225.


J. Am. Chem. Soc. 2015, 137, 3213.


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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