asymmetricbi,andtri,func2onalorganocatalysis ...€¦ ·...

Asymmetric bi-‐ and tri-‐func2onal organocatalysis: Mechanis2c inves2ga2ons toward the elucida2on

of reac2on mechanisms

Nastaran Salehi Marzijarani

Graduate Seminar

Department of Chemistry Michigan State University

Oct. 26th, 2011 1

E

2

Links between asymmetric organocatalysis & nature

How does nature accomplish so many transformaEons so efficiently and selec2vely?

Asymmetric monofuncEonal organocatalysis

Asymmetric mulEple organocatalysis

Asymmetric mulEfuncEonal organocatalysis

3 -‐Knowles, R. R.; Jacobsen, E. N.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724.

-‐ Chook, Y. M.; ke, H.; Lipscomb, W. H.; Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8600-‐8603. -‐ Sharon, T. C.; Liu, D. R.; Pastor, R. M.; Schultz, P. G.; J. Am. Chem. Soc. 1996, 118, 1787-‐1788.

Learning from nature: chorismate mutase

O COOOH

COO

OH

OOC

O

COOChorismatemutase

Chorismate Prephenate

HO

COOH

NH2

COOH

NH2



OO2CChorismate mutaseCO2

HO

CO2

OCO2

HOO

O

O

OH

O

O

O COOOH

COO

OH

OOC

O

COOChorismatemutase

Chorismate Prephenate




Chorismate mutase ac2ve site from Bacillus Sub+lis


Tyr 108OHH2N N

HH2N

HNArg 90

H2N

NH2

O

OGlu 78 S

H

Cys 75

O

O

O

OH

O

O

Arg 7

Phe 57

6

Learning from nature: enzyme catalysis

•  Mul2ple amino acids in an enzyme parEcipate in the reacEon!!!

Hydrogen bonding

Acid-‐base catalysis Covalent (nucleophilic) catalysis

-‐ R. B. Silverman, The Organic Chemistry of Enzyme-‐catalyzed ReacFons, Academic Press, New York, 2002

B

BHO

RY

HO H

7

Rate accelera2on: o  Stabilizing the transiEon

state

o  DestabilizaEon of enzyme-‐substarte complex (ES)

o  Proximity and orientaEon

Learning from nature: enzyme catalysis

-‐ R. B. Silverman, The Organic Chemistry of Enzyme-‐catalyzed ReacFons, Academic Press, New York, 2002

•  Mul2ple amino acids in an enzyme parEcipate in the reacEon!!!

ES EP S P

Energy

Progress of reacEon

8

Links between asymmetric organocatalysis & nature (Enzymes catalysis)

How does nature accomplish so many transformaEons so efficiently and selec2vely?

Asymmetric monofunc2onal organocatalysis


Asymmetric mulEfuncEonal organocatalysis

9 -‐ Seayad, J.; List, B.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724.

Asymmetric monofunc2onal organocatalysis: five major classes

•  Lewis Base Catalysis (LB)

•  Lewis Acid Catalysis (LA)

•  BrØnsted Base Catalysis (BB)

•  BrØnsted Acid Catalysis (BA)

•  Hydrogen-‐bonding catalysis (HB)

S

*P

Cat . S

Cat . P* Cat.

Asymmetric organocatalysis: five major classes






-‐ Zhu, G.; Chen, Z.; Jiang, Q.; Xia, D.; Cao, P.; Zhang, X.; J. Am. Chem. Soc. 1997, 119 (16), 3836-‐3827. -‐ Seayad, J.; List, B.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724.

10

.H

H H

COOR1

COOR2

H

H

HCOOR2

COOR1

i-PrP

Ph

i-Pr

R2OOC

.H

H H

COOR1

COOR1PR3

!!

11







-‐ Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T.; J. Org. Chem. 2003, 68 (26), 10046-‐10057. -‐ Seayad, J.; List, B.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724

R1 R2

O

StBu

OTMS

tBuS

O

R2

OR1

R2

O

R1

OB

N Ph

Ts

O

O

O

StBu

OTMS

12







-‐ Dobish, M. C.; Johnston, J. N.; Org. LeK. 2010, 12 (24), 5744-‐5747-‐. -‐ Seayad, J.; List, B.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724.

NH

R1

R2Ts

NH

R1

R3

NO2R2

R3 NO2K2CO3

NN

N

N

N

N

HH

H

PBAM

H

13







-‐ Dobish, M. C.; Johnston, J. N.; Org. LeK. 2010, 12 (24), 5744-‐5747-‐. -‐ Seayad, J.; List, B.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724.

NH

R1

R2Ts

NH

R1

R3

NO2R2

R3 NO2K2CO3

NR1

R2H

R3 NO2

HPBAM!!

Ts

14







-‐ Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R. M.; Angew. Chem. Int. Ed. 2008, 47, 6798-‐6801. -‐ Schenker, S.; Zamfir, A.; Freund, M.; Tsogoeva, S. B.; Eur. J. Org. Chem. 2011, 12, 2209-‐2222.

-‐ Seayad, J.; List, B.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724.

R F3C

O

CO2Et R CO2Et

OHF3C

OO

PO

NH

Tf

p-MeOC6H4

p-MeOC6H4

15







-‐ Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R. M.; Angew. Chem. Int. Ed. 2008, 47, 6798-‐6801. -‐ Schenker, S.; Zamfir, A.; Freund, M.; Tsogoeva, S. B.; Eur. J. Org. Chem. 2011, 12, 2209-‐2222.

-‐ Seayad, J.; List, B.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724.

R F3C

O

CO2Et R CO2Et

OHF3C

OO

PO

N Tf

p-MeOC6H4

p-MeOC6H4

B!!

F3C CO2Et

O H

R

B!!

16






•  Hydrogen-‐Bonding Catalysis (HB)

-‐ Uyeda, C.; Jacobsen, E. N.; J. Am. Chem. Soc. 2011, 133 (13), 5062-‐5075. -‐ Uyeda, C.; Jacobsen, E. N.; J. Am. Chem. Soc. 2008, 130 (29), 9228-‐9229.

-‐ Seayad, J.; List, B.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724. -‐ Schreiner, P. R.; Chem. Soc. Rev., 2003, 32, 289–296.

NH

NH

NH2

Ph

B

CF3

CF34

Ph

OR1

R2R4

R3

MeO

O

MeO!!

!!

O

O

R1

R3 R4

R2

17






•  Hydrogen-‐Bonding Catalysis (HB)

-‐ Uyeda, C.; Jacobsen, E. N.; J. Am. Chem. Soc. 2011, 133 (13), 5062-‐5075. -‐ Uyeda, C.; Jacobsen, E. N.; J. Am. Chem. Soc. 2008, 130 (29), 9228-‐9229.

-‐ Seayad, J.; List, B.; Org. Biomol. Chem. 2005, 3 (5), 719-‐724. -‐ Schreiner, P. R.; Chem. Soc. Rev., 2003, 32, 289–296.

δ+

H

H

N

N

R!!

R!!

H2N

O

OMeO

R2

R4R3

R1

OR1

R2R4

R3

MeO

O

MeO!!

!!

O

O

R1

R3 R4

R2

18

Links between asymmetric organocatalysis & nature (Enzymes catalysis)

How does nature accomplish so many transformaEons efficiently and selec2vely?

Asymmetric monofuncEonal organocatalysis


Asymmetric mul2func2onal organocatalysis

19

+ + + + LA BB BA Mul2ple organocatalysis

LB HB

LA

Mul2func2onal organocatalysis LB BA

BB HB

A single organic molecule with two or more funcEonal groups, each one having a different catalyEc acEvity, is a mulEfuncEonal organocatalyst. (mulEple acEvaEon)

-‐ Piovesana, S.; Schietroma, D. M. S.; Bella, M.; Angew. Chem. Int. Ed. 2011, 50, 6216-‐6232.

Asymmetric mul2func2onal or mul2ple organocatalysis

Asymmetric bi-‐ and tri-‐func2onal organocatalysis

-‐ Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43 (7), 1005-‐1018.

AcEvaEon of Electrophile: Bronsted Acid, Lewis Acid, Hydrogen Bond donor

AcEvaEon of nucleophiles: Lewis Base, Bronsted Base

20

The substrates are bound and oriented at two different acEve centers in a controlled chiral environment (high selecEvity and reacEvity)

Chiral

Backbone

E E

Asymmetric bi-‐ and tri-‐func2onal organocatalysis

-‐ Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43 (7), 1005-‐1018.

AcEvaEon of Electrophile: Bronsted Acid, Lewis Acid, Hydrogen Bond donor

AcEvaEon of nucleophiles: Lewis Base, Bronsted Base

21

The substrates are bound and oriented at two different acEve centers in a controlled chiral environment (high selecEvity and reacEvity)

Chiral

Backbone

E E

22

BA

LB

*

SubstrateB

SubstrateA

*

SubstrateA

SubstrateB

Proximity, orienta2on, Posi2ve coopera2vity, efficient catalysis

SubstrateB + SubstrateA +

Lower entropy loss

Mul2ple catalysis SubstrateA

SubstrateB

SubstrateB + SubstrateA +

BA

LB

*

Asymmetric bifunc2onal organocatalysis

BA

LB *

LB *

BA

23 -‐ Calderone, C. T.; Williams, D. H.; J. Am. Chem. Soc. 2001, 123 (26), 6262-‐6267.

SubstrateA

SubstrateB

•  Non-‐covalent interac2on is important

•  Binding interac2on & Inhibi2on

•  Proximity & orienta2on

•  Posi2ve coopera2vity (efficient catalysis)

BA

LB

* SubstrateB + SubstrateA +

SubstrateB

SubstrateA

*

BA

LB

*


24

SubstrateA

SubstrateB

•  Stabiliza2on of transi2on state

•  Control of enan2oselec2vity

BA

LB


SubstrateB

SubstrateA

*

BA

LB

*


*

SubstrateA

SubstrateB

BA

LB

*

25

BA

LB


SubstrateB

SubstrateA

*

BA

LB

*


*

SubstrateA

SubstrateB

BA

LB

*

B A *

*

SubstrateA

SubstrateB *

•  Binding interac2on & inhibi2on

BA

LB

*

26

² Catalyst Quenching

Factors to consider in asymmetric mul2func2onal organocatalysis

BA

BB

LA

LB

-‐ Jang, H. B.; Rho, H. S.; Oh, J. S.; Nam, E. H.; Park, S. E.; Bae, H. Y.; Song, C. E.; Org. Biomol. Chem. 2010, 8, 3918-‐3922.

27

² Catalyst Quenching ² The distance or angle between the acEve sites

² Self aggregaEon of bifuncEonal organocatalysts

² Lower order/non-‐cooperaEve behavior

Factors to consider in asymmetric mul2func2onal organocatalysis

-‐ Jang, H. B.; Rho, H. S.; Oh, J. S.; Nam, E. H.; Park, S. E.; Bae, H. Y.; Song, C. E.; Org. Biomol. Chem. 2010, 8, 3918-‐3922.

v  Asymmetric Aza-‐Morita-‐Baylis-‐Hillman

v  Asymmetric Cyanosilyla2on of Ketones

28

Importance of bi-‐ and tri-‐func2onal organocatalysis in two reac2ons

Covalent interac2on

Non-‐covalent interac2on

OH

PPh2

R

MeHN

NH

NH

O

S

Nn-Prn-Pr

But-s

Aza-‐Morita-‐Baylis-‐Hillman (Aza-‐MBH) reac2on

29 -‐ Perlmuper, P.; Teo, C.C.; Tetrahedron LeK. 1984, 25 (51), 5951-‐5952. -‐ Shi, M.; Xu, Y. M.; Angew. Chem. Int. Ed. 2002, 41, 4507-‐4510.

Ø  Racemic synthesis was developed by Perlmuper and Teo in 1984

Ø  First enanEselecEve reacEon developed in 2002 by Shi et al.

§  Slow reacEon rates §  Limited substrate scope §  Poor conversion §  Low enanEoselecEvity

Ar CH=N R

O

R

O

!!Ar

NHPGCatalyst

SolventPG

30

Aza-‐Morita-‐Baylis-‐Hillman reac2on mechanism

-‐ Mansilla, J.; Saa, J. M., Molecules 2010, 15 (2), 709-‐734. -‐ Raheem, I. T.; Jacobsen, E. N.; Adv. Synth. Catal. 2005, 347, 1701-‐1708.

-‐ Regiani, T.; Santos, V. G.; Godoi, M. N.; Vaz, B. G.; Eberlin, M. N.; Coelho, F.; Chem. Commun. 2011, 47, 6593-‐6595.

RDS

Nu

R1

O

Step 1

ONu

R1

Step 2 R2-CH=N-PG

O

R1Nu

R2N

O

R1Nu

R2HNPGPG

O

R1

R2HNPG

Step 3

Step 4

H

kH/kD = 3.81

31 -‐ Mansilla, J.; Saa, J. M., Molecules 2010, 15 (2), 709-‐734.

Role of Bronsted acid addi2ve in Aza-‐Morita-‐Baylis-‐Hillman reac2on

-‐ Roy, D.; Patel, C.; Sunoj, R.; J. Org. Chem. 2009, 74 (18), 6936-‐6943. -‐ Buskens, P.; Klankermayer, J.; Leitner, W.; J. Am. Chem. Soc. 2005, 127 (48), 16762-‐16763.

O R

H

R OH

Bronsted acid addi2ve

R2 N

HO

R1 Nu

PG

HOR

Nu

R1

O

Step 1

ONu

R1

Step 2 R2-CH=N-PG

O

R1Nu

R2N

O

R1Nu

R2HNPGPG

O

R1

R2HNPG

Step 3

Step 4

32

Complex mechanis2c nature of Aza-‐Morita-‐Baylis-‐Hillman reac2on

-‐ Raheem, I. T.; Jacobsen, E. N.; Adv. Synth. Catal. 2005, 347, 1701-‐1708.

Ar= C6H5, m-‐MeC6H4, m-‐MeOC6H4, p-‐ClC6H4, m-‐ClC6H4,

m-‐BrC6H4, 1-‐Naphthyl, 2-‐Thiophenyl, 3-‐Furyl

25-‐49 % yield

87-‐99 ee %

16-‐36 h

Ar H

NNs CO2Me

Catalyst (10 mol %)DABCO, xylenes, 3 Å sieves, 4 °C

CO2MeAr

HNNs

BnN

N NO

S

N

But-s

H H

Me

HO

t-Bu t-Bu

33 -‐ Raheem, I. T.; Jacobsen, E. N.; Adv. Synth. Catal. 2005, 347, 1701-‐1708.

NuR

O

Nu

O

RR'

NHPG

R' R

ON

Nu

PG

R' R

ON

Nu

PG

R' R

ONH

Nu

PG

Chiral catalyst.R' H

NPG

Cat.. Cat..

R

O

R'

NPGH

CORNu

R'

NPGH

COR

Nu

Chiral catalyst

Syn AntiHigh ee, Low yield

Low ee, High yield

ppt.

accelerate

34

Asymmetric mul2func2onal organocatalysis in Aza-‐Morita-‐Baylis-‐Hillman

Design of a bifuncEonal organocatalyst in Aza-‐MBH reacEon: 1-‐ Lewis base unit to iniEate the Aza-‐MBH reacEon 2-‐ Bronsted Acid unit to facilitate the proton transfer 3-‐ Chiral environment to induce enanEoselecEvity

BA

LB

O

NPG

RChiral

-‐ Shi, M.; Chen, L. H.; Chem. Commun. 2003, (11), 1310-‐1311.

35

Asymmetric Aza-‐MBH by bifunc2onal BINOL-‐derived organocatalysts

Ar= C6H5, p-‐MeC6H4, p-‐EtC6H4, p-‐FC6H4, p-‐ClC6H4, p-‐BrC6H4, m-‐FC6H4, m-‐ClC6H4, p-‐NO2C6H4, m-‐NO2C6H4, o-‐NO2C6H4,

o-‐ClC6H4, trans-‐C6H4CH=CH

79-‐92 % ee

82-‐96 % yield

-‐ Shi, M.; Chen, L. H.; Chem. Commun. 2003, (11), 1310-‐1311.

-‐ Shi, M.; Chen, L. H.; Li, C. Q.; J. Am. Chem. Soc. 2005, 127(11), 3790-‐3800

OHPPh2

Ar CH=NTsO O

Ar

NHTs

S

Catalyst (10 mol %)

THF, -30 °C, MS 4 Å

36

31P NMR Analysis

-‐ Shi, M.; Chen, L. H.; Pure Appl. Chem. 2005, 77 (12), 2105-‐2110. -‐ Shi, M.; Chen, L. H.; Li, C. Q.; J. Am. Chem. Soc. 2005, 127 (11), 3790-‐3800.

-‐13.16 ppm

-‐13.16 ppm +25.30 ppm

OHPPh2

O

PPh2

OH

+26.07 ppm OH

PPh2

O

I

37

31P NMR Analysis

-‐ Shi, M.; Chen, L. H.; Pure Appl. Chem. 2005, 77 (12), 2105-‐2110. -‐ Shi, M.; Chen, L. H.; Li, C. Q.; J. Am. Chem. Soc. 2005, 127 (11), 3790-‐3800.

-‐13.16 ppm

-‐13.16 ppm +25.30 ppm

OHPPh2

O

PPh2

OH

-‐13.16 ppm +25.30 ppm OMe

PPh2

O

38

Elucida2on of the reac2on mechanism by control catalysts

38

Yield: 13 % 35 % 72 % ee: 20 % 39 % 94 %

-‐ Shi, M.; Chen, L. H.; Pure Appl. Chem. 2005, 77 (12), 2105-‐2110. -‐ Shi, M.; Chen, L. H.; Li, C. Q.; J. Am. Chem. Soc. 2005, 127(11), 3790-‐3800

SH

PPh2

OMe

PPh2

OH

PPh2

p-ClC6H4 CH=NTs

O O

!!p-ClC6H4

NHTsCatalyst (10 mol %)

THF, 0 °C

39

Elucida2on of the reac2on mechanism by control catalysts

-‐ Shi, M.; Chen, L. H.; Pure Appl. Chem. 2005, 77 (12), 2105-‐2110. -‐ Shi, M.; Chen, L. H.; Li, C. Q.; J. Am. Chem. Soc. 2005, 127(11), 3790-‐3800

Yield: no reacEon no reacEon 72 % ee: -‐ -‐ 94 %

PPh2

PPh2

OH

P

OH

PPh2

p-ClC6H4 CH=NTs

O O

!!p-ClC6H4


THF, 0 °C

40

Proposed pathway

-‐ Shi, M.; Chen, L. H.; Li, C. Q.; J. Am. Chem. Soc. 2005, 127(11), 3790-‐3800

Favored

OHPPh2

Bronsted acid

Lewis base

OO

PPh2

O

ArCH=NTsArCH=NTs

A

ONH

Ar

Ts ONH

Ar

Ts

H

O

PPh2

HO

NTs

H

H

Ar

C

O

PPh2

HO

NTs

Ar

H

H

B

Ar

H

NTs

H

O

PPhPh

O H

E

H

Ar

NTs

H

O

PPhPh

O H

D

TheoreEcal Analysis ?!!

41 -‐ Buskens, P.; Klankermayer, J.; Leitner, W.; J. Am. Chem. Soc. 2005, 127 (48), 16762-‐16763.

Racemiza2on of Aza-‐MBH: Dual catalysis vs. Bifunc2onal system

OHPPh2

PPh3 +

ee %

2me (hr)

OH

F3C CF3

p-BrC6H4 CH=NTs

OO

p-BrC6H4


THF, RT

O

p-BrC6H4

NHTs

PPh3, bis-3,5-(CF3)phenol

THF, RT

O

p-BrC6H4

NHTsO

p-BrC6H4

NHTs

42

Importance of the two ac2ve sites: design of the new catalysts

Design of new catalysts

§  Nucleophilicity of Lewis Base

§  Hydrogen bonding

§  Acidity of Bronsted Acid

§  Proper posiEon of acid-‐base moieEes

§  Chiral backbone

OH

PPh2

Bronsted Acid as Hydrogen bond donor

Lewis Base

43

Design of the new catalysts

-‐ Matsui, K.; Takizawa, S.; Sasai, H.; J. Am. Chem. Soc. 2005, 127, 3680-‐3681. -‐ Qi, M. J.; Ai, T.; Shi, M.; Li, G.; Tetrahedron 2008, 64, 1181-‐1186. -‐ Lei, Z. Y.; Ma, G. N.; Shi, M.; Eur. J. Org. Chem. 2008, 3817-‐3820.

-‐ Takizawa, S.; Kiriyama, K.; Ieki, K.; Sasai, H.; Chem. Commun. 2011, 47, 9227-‐9229.

61-‐92 % ee

84-‐96 % yield

18 – 24 h

Ar = EWG

61-‐91 % ee

80-‐99 % yield

7 – 48 h

61-‐91 % ee

89-‐98 % yield

1 – 2 h

Ar CH=NTs

OO

Ar

NHTsCatalyst (5-10 mol %)

Solvent

OH

PPh2

NHAc

PPh2

OH

Pn-Bu

44

87-‐97 % ee

72-‐99 % yield

96 – 216 h

88-‐95 % ee

88-‐96 % yield

12 – 96 h


Ar = EWG

61-‐92 % ee

84-‐96 % yield

18 – 24 h

OH

PPh2

-‐ Matsui, K.; Takizawa, S.; Sasai, H.; J. Am. Chem. Soc. 2005, 127, 3680-‐3681. -‐ Qi, M. J.; Ai, T.; Shi, M.; Li, G.; Tetrahedron 2008, 64, 1181-‐1186. -‐ Lei, Z. Y.; Ma, G. N.; Shi, M.; Eur. J. Org. Chem. 2008, 3817-‐3820.

-‐ Takizawa, S.; Kiriyama, K.; Ieki, K.; Sasai, H.; Chem. Commun. 2011, 47, 9227-‐9229.

PPh2

OHOH

OH

NN

Ar CH=NTs

OO

Ar


Solvent

45


61-‐92 % ee

84-‐96 % yield

18 – 24 h

-‐ Liu, Y. H.; Chen, L. H.; Shi, M.; Adv. Synth. Catal. 2006, 348, 973-‐979.

90-‐96 % ee

83-‐97 % yield

24 – 36 h

Ar CH=NTs

OO

Ar


Solvent

O

OH HO

HOPPh2

OH

PPh2

Ar = EWG

46 -‐ Liu, Y. H.; Chen, L. H.; Shi, M.; Adv. Synth. Catal. 2006, 348, 973-‐979.

Bifunc2onal BINOL-‐derived organocatalysts with mul2ple units

98 % yield, 92 % ee 55 % yield, 88 % ee

O

OH HO

HOPPh2

O

OH MeO

MeOPPh2

p-ClC6H4 CH=NTs

OO

!!p-ClC6H4


THF, -20 °C

47

31P NMR Analysis


-‐12.07 ppm

+26.36 ppm

O

OH HO

HOPPh2

O

O O

OPOPh

Ph

H H

H

48

31P NMR Analysis


+26.36 ppm

-‐13.16 ppm +25.30 ppm

-‐13.16 ppm +25.30 ppm

O

O O

OPOPh

Ph

H H

H

O

PPh2

OH

OMe

PPh2

O

49

Trifunc2onal organocatalyst-‐promoted counterion catalysis

-‐ Garnier, J. M.; Liu, F.; Org. Biomol. Chem. 2009, 7, 1272-‐1275. -‐ AnsEss, C.; Liu, F.; Tetrahedron. 2010, 66, 5486-‐5491.

Bronsted Acid

Lewis Base

X H

Nu

Bronsted Acid

Lewis Base

X H

Nu

Bronsted Base

NH

PPh2

NHHO

R1

R2

OHPPh2

50


-‐ Garnier, J. M.; AnsEss, .C.; Adv. Synth. Catal. 2009, 351, 331-‐338.

62-‐95 % Conv.

87-‐ 94 % ee

30 min-‐ 900 min

Ar= m-‐NO2C6H4, p-‐BrC6H4, p-‐ClC6H4, o-‐ClC6H4, p-‐FC6H4, o-‐NO2C6H4, p-‐NO2C6H4, p-‐MeC6H4, o-‐MeOC6H4,

m-‐MeOC6H4,

PPh2

NHHO

t-Bu

NO2

Ar CH=NTs

O O

Ar

NHTs

R

Catalyst (10 mol %)

CH2Cl2, RT

Benzoic Acid (10 mol %)

51


-‐ Garnier, J. M.; AnsEss, .C.; Adv. Synth. Catal. 2009, 351, 331-‐338.

62-‐95 % Conv.

87-‐ 94 % ee

30 min-‐ 900 min

Ar= m-‐NO2C6H4, p-‐BrC6H4, p-‐ClC6H4, o-‐ClC6H4, p-‐FC6H4, o-‐NO2C6H4, p-‐NO2C6H4, p-‐MeC6H4, o-‐MeOC6H4,

m-‐MeOC6H4,

Ar CH=NTs

O O

Ar

NHTs

R

Catalyst (10 mol %)

CH2Cl2, RT


PPh2

NHHO

t-Bu

NO2

52

The role of the acid ac2va2on in kine2c and induc2on of asymmetry

-‐ AnsEss, C.; Garnier, J. M.; Liu, F.; Org. Biomol. Chem. 2010, 8, 4400-‐4407.

Entry Benzoic acid Time/min Conv. (%) ee (%)

1 -‐ 90 90 16

2 10 mol % 30 >95 88

3 10 mol % with a 30 min delay 60 95 48

Ar= p-‐NO2C6H4

PPh2

NHHO

F

Br

Ar CH=NTs

OO

Ar

NHTs

R

Catalyst (10 mol %)

CH2Cl2, RT


53


-‐ Garnier, J. M.; Liu, F.; Org. Biomol. Chem. 2009, 7, 1272-‐1275. -‐ AnsEss, C.; Liu, F.; Tetrahedron. 2010, 66, 5486-‐5491.

Off On

Bronsted Acid

Lewis Base

X H

Nu

Bronsted Base

NH

H A

Activation

X H

Nu

NH

HA

Counterion

Bronsted AcidBronsted Acid

Lewis Base

54

Importance of acid ac2va2on and roles of func2onal groups

-‐ Garnier, J. M.; Liu, F.; Org. Biomol. Chem. 2009, 7, 1272-‐1275.

Counterion (A ) = Benzoate

31P NMR analysis?!!

O

Ar-CH=N-Ts

O

R3P!!

ArN

Ts

H

OR3P

PR3

PN

OtBu

NO2

H

H

HAPh2

O

55

Importance of acid ac2va2on and roles of func2onal groups

-‐ Garnier, J. M.; Liu, F.; Org. Biomol. Chem. 2009, 7, 1272-‐1275.

Counterion (A ) = Benzoate

O

Ar-CH=N-Ts

O

R3P!!

ArN

Ts

H

OR3P

PR3

PPh2

N

OtBu

NO2

H

H

H

NTs

H

Ar O

A

56 -‐ Garnier, J. M.; AnsEss, .C.; Adv. Synth. Catal. 2009, 351, 331-‐338.

Basis for enan2oselec2vity in trifunc2onal organocatalyst

favored disfavored

NH

ArH

TsO

P HOH

NH

A

tBu

NO2

HN

ArH

O

P HO

H

NH

A

TstBu

NO2

O

Ar

NHTs

R

57 -‐ AnsEss, C.; Garnier, J. M.; Liu, F.; Org. Biomol. Chem. 2010, 8, 4400-‐4407.

Ini2al rate studies of the asymmetric trifunc2onal organocatalysis

t = 50 min

t = 0 min

Hprod HC

MVK HStandard

p-BrC6H4 CH=NTs

O O

p-BrC6H4

NHTsCatalyst, Benzoic acid

HcmvkHprod

CD2Cl2


Catalyst : 12-‐ 24 mM

Benzoic acid

36 mM 36 mM

Catalyst

Kine2c studies in the trifunc2onal organocatalyst

[catalyst]

p-BrC6H4 CH=NTs

OO

p-BrC6H4

NHTs

HcmvkHprod

CD2Cl2

PPh2

NHHO

t-Bu

NO2


Catalyst : 12 mM

Benzoic acid

25-‐75 mM 36 mM


[imine]

p-BrC6H4 CH=NTs

OO

p-BrC6H4

NHTs

HcmvkHprod

CD2Cl2

PPh2

NHHO

t-Bu

NO2

Catalyst


36 mM 45-‐75 mM


[MVK]

p-BrC6H4 CH=NTs

OO

p-BrC6H4

NHTs

HcmvkHprod

CD2Cl2

Catalyst : 12 mM

Benzoic acid

PPh2

NHHO

t-Bu

NO2

Catalyst

61 -‐ Buskens, P.; Klankermayer, J.; Leitner, W.; J. Am. Chem. Soc. 2005, 127 (48), 16762-‐16763.


RDS

Monofunc2onal catalysis

Ar-CH=N-Ts

O!!

Ar

NHTs

O

Ar

NTs

Ph3P

OO

Ph3P

A B

C

PPh3



Trifunc2onal catalysis

Ar-CH=N-Ts

O

!!Ar

NHTs

O

Ar

NTs

P

OO

Ph2P

A B

CN

OH

PPh2

NH2

OHHH

N

OH

HH

Ph2

Rate = kobs [A]1[B]1 Catalyst design:

Nucleophilicity of the

phosphine

RDS

63

Ø  StabilizaEon of high energy charged-‐separated intermediates Ø  AcceleraEon of the proton transfer step Ø  AcceleraEon of the enanEoselecEve C-‐C bond forming step Ø  High enanEoselecEvity and high yield

Ø Minimizing racemizaEon and reversibility issues

Importance of mul2func2onal organocatalyts in asymmetric Aza-‐MBH reac2on

64

•  One of the oldest carbon-‐carbon bond-‐forming reacEon (Winkler, 1832)

Cyanosilyla2on of carbonyl compounds by asymmetric organocatalysis

-‐ Winkler, F. W.; Liebigs Ann. Chem. 1832, 4, 246-‐249. -‐ Tian, S. K.; Hong, R.; Deng, L.; J. Am. Chem. Soc. 2003, 125 (33), 9900-‐9901.

Asymmetric monofuncEonal organocatalysis: Lewis Base catalysis

Up to 98 % ee

Up to 99 % yield

16 – 94 h

R1

O

R2TMSCN

R1 !! R2

TMSO CN

Catalyst =

O O

N

MeO

N

OMe

Et

OO

NEt

N

HH

R1

O

TMSCNR1 !!

TMSO CNOR2

OR2

Catalyst (2 mol %)OR2

OR2

CHCl3, -40 or -50 °C

65 -‐ Denmark, S. E.; Chung, W. J.; J. Org. Chem. 2006 ,71 (10), 4002-‐4005.

Problems associated with asymmetric lewis base organocatalysis

R1

O

R2TMSCN

R1 !! R2

TMSO CNLB* catalyst

TMSCN

Me3Si LB!!

CNi

Ph H

O

Ph H

OSi

Me

MeMe

LB!!

CN

Ph!!

CN

OSiMe3

LB!!

Cycle A Cycle B

LB!!

NC Ph

OSiMe3

LB!!

SiMe3

NC Ph

O

66 -‐ Fuerst, D. E.; Jacobsen, E. N.; J. Am. Chem. Soc. 2005, 127, 8964-‐8965.

Asymmetric bifunc2onal ketone cyanosilyla2on

ee : 86-‐98 % yield : 81-‐98 % 2me : 12 h-‐ 48 h

Me

O

R

OMe

O

R

Me

O

Me

OO

Me

O

N

S

MeMe

R

O

Me

O

BrO

O

R = o-‐Me, p-‐Me, m-‐OMe, p-‐OMe, p-‐Br

R = n-‐Bu, Me

R = i-‐Pr, Me, Et

MeN

N NO

S

Nn-Prn-Pr

But-s

H H

H

R1

O

R2 R1!! R2

TMSO CNCatalyst (5 mol%), CH2Cl2

TMSCN, CF3CH2OH, -78 °C

67 -‐ Zuend, S. J.; Jacobsen, E. N.; J. Am. Chem. Soc. 2007, 129, 15872-‐15883.

-‐ Hisaki, I.; Sasaki, S. I.; Hirose, K.; Tobe, Y.; Eur. J. Org. Chem. 2007, 607-‐615. -‐ Schreiner,P. R.; Wipkopp, A.; Org. LeK. 2002, 4(2), 217-‐220.

Role of func2onal groups in the catalyst

Spectroscopic data of detectable intermediates

N N

S

H HO

O N

O

i-Pr

MeN

N NO

S

Nn-Prn-Pr

But-C

H H

H

MeN

N NO

S

Nn-Prn-Pr

Bu

H H

H t-c

E

68

Anion-‐binding proper2es of the thiourea moiety

-‐ Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N.; J. Am. Chem. Soc. 2008, 130 (23), 7198-‐7199.

R'!!

N N

SR"!!

H H

ClO

OR

Cl R

thiourea OR1

OR2

R2

SiR3

O

Cl

OR1

OSiR3

R2

R2

RO

R

R2R2

CO2R1

Catalyst (10 mol %)

TBME, -78 °C

N N

S

!!

H H

!!N

O

But-

CF3

CF3

F

69

-‐ Okino, T.; Hoashi, Y.; Takemoto, Y.; J. Am. Chem. Soc. 2003, 125, 12672-‐12673. -‐ Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y.; J. Am. Chem. Soc. 2005, 127 (1), 119-‐125.

-‐ Hamza, A.; Schubert, G.; Soos, T.; Papai, I.; J. Am. Chem. Soc. 2006, 128, 13151-‐13160.

Role of thiourea moiety in nucleophilic ac2va2on

R1

O

R2

O

R3NO2

R3NO2

R1

O

R2

O

NH

CF3

F3C NH

S

N

70

-‐ Okino, T.; Hoashi, Y.; Takemoto, Y.; J. Am. Chem. Soc. 2003, 125, 12672-‐12673. -‐ Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y.; J. Am. Chem. Soc. 2005, 127 (1), 119-‐125.

-‐ Hamza, A.; Schubert, G.; Soos, T.; Papai, I.; J. Am. Chem. Soc. 2006, 128, 13151-‐13160.

Role of thiourea moiety in nucleophilic ac2va2on

Takemoto’s mechanism Papai’s mechanism

E Nu ENu

R1

O

R2

O

R3NO2

R3NO2

R1

O

R2

O

N

CF3

F3C N

S

NH H

O

ON

O

R1 R2

O H

R3

N

CF3

F3C N

S

NH H

O ON

R3

HO

R1 R2

O

71

Kine2c studies

-‐ Zuend, S. J.; Jacobsen, E. N.; J. Am. Chem. Soc. 2007, 129, 15872-‐15883. -‐ Blackmond, D. G.; Angew. Chem. Int. Ed. 2005, 44, 4302-‐4320.

97 % yield, 97 % ee 12 h

rate =k [cat]1 [sub]1 [HCN]1 [TMSCN]0

O

CH3H3CO Catalyst (5 mol%), CH2Cl2

TMSCN, CF3CH2OH, -78 °C!! CH3

TMSO CNH3CO

MeN

N NO

S

Nn-Prn-Pr

But-s

H H

H

72

Kine2c studies

-‐ Zuend, S. J.; Jacobsen, E. N.; J. Am. Chem. Soc. 2007, 129, 15872-‐15883. -‐ Blackmond, D. G.; Angew. Chem. Int. Ed. 2005, 44, 4302-‐4320.

cat.(cat)2.HCN

cat.HCN

cat.(HCN)2

k4 cat HCN

k3 2HCN

k1 HCN

k2 HCN sub cat.HCN.subkcat cat.HCN.sub

97 % yield, 97 % ee 12 h

73

Mechanis2c possibili2es

-‐ Zuend, S. J.; Jacobsen, E. N.; J. Am. Chem. Soc. 2007, 129, 15872-‐15883.

(cat)2.HCN

cat.(HCN)2

Nn-Pr

n-PrHN

H

S

NH

H

t-BuO

NHH3C

N OC

RR'

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

O

R'R

HCN

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

HC

N

N

n-Pr

n-PrNH

S

NH

H

t-Bu

HCN

NC

H

OHN

CH3

cat.HCN

cat.HCN.sub

cat.HCN

Mechanism A

Mechanism B

+ Sub

+ Sub

+ HCN

+ cat

NMe

MeHN

H

S

NH

H

t-BuO

NHH3C

O

R'

CN

R

MeN

N NO

S

N(n-Pr)2

But-c

H H

H

HCN

74



(cat)2.HCN

cat.(HCN)2

Nn-Pr

n-PrHN

H

S

NH

H

t-BuO

NHH3C

N OC

RR'

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

O

R'R

HCN

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

HC

N

N

n-Pr

n-PrNH

S

NH

H

t-Bu

HCN

NC

H

OHN

CH3

cat.HCN

cat.HCN.sub

cat.HCN

Mechanism A

Mechanism B

+ Sub

+ Sub

+ HCN

+ cat

N

n-Pr

n-PrNH

S

NH

H

t-Bu

HCN

NC

H

OHN

CH3NMe

MeHN

H

S

NH

H

t-BuO

NHH3C

O

R'

CN

R

MeN

N NO

S

N(n-Pr)2

But-c

H H

H

HCN

75

Inhibi2on: effect of added CH3CN


97 % ee

Rate X 105 (M

/S)

[CH3CN] (M)

20 % 50 % 80 %

O

CH3H3CO Catalyst, CH3CN

HCN, TMSCN, CH2Cl2!! CH3

TMSO CNH3CO

Nn-Pr

n-PrNH

S

NH

H

t-BuHCN

NC

H

OHN

CH3

76

Inhibi2on: medium effect or a direct direc2on


97 % ee

N t-But-Bu

N CH3H3C

N

Rate X 105 (M

/S)

[subs2tuted pyridine] (M)

O

CH3H3CO Catalyst, Substituted Pyridines


TMSO CNH3CO

Nn-Pr

n-PrNH

S

NH

H

t-BuHCN

NC

H

OHN

CH3


(cat)2.HCN

cat.(HCN)2

Nn-Pr

n-PrHN

H

S

NH

H

t-BuO

NHH3C

N OC

RR'

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

O

R'R

HCN

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

HC

N

N

n-Pr

n-PrNH

S

NH

H

t-Bu

HCN

NC

H

OHN

CH3

cat.HCN

cat.HCN.sub

cat.HCN

Mechanism A

Mechanism B

+ Sub

+ Sub

+ HCN

+ Cat


NMe

MeHN

H

S

NH

H

t-BuO

NHH3C

O

R'

CN

R

MeN

N NO

S

N(n-Pr)2

But-c

H H

H

HCN


Role of trialkylamine por2on of the catalyst

Me2NEt

i-‐Pr2NEt

Et3N

ee (%

)

[amine] (M) [amine] (M)

Rate X 105 (M

/S)

O

CH3H3CO Catalyst, !"#$!%#&'()*+%!'


TMSO CNH3CO


Effect of added exogenous trialkylamines

MeOCH3

TMSO CN NC

NHR3

MeOO

CH3

TMSCN

NR3Me

HN

N NO

S

N

But-c

H HNR3

n-Pr n-Pr

+ Cat.

HCN

NC

NHR3

inactive

MeHN

N NO

S

N

But-c

H Hn-Pr n-Pr

inactive

NC

HNR3

+ Cat.


Effect of added exogenous trialkylamines

MeN

N NO

S

Nn-Prn-Pr

But-s

H H

H

MeN

N NO

S

NMeMe

But-s

H H

H

O

CH3H3CO Catalyst (5 mol%), CH2Cl2

TMSCN, CF3CH2OH, -78 °C!! CH3

TMSO CNH3CO

20 2mes faster

ee: 97 %

ee: 95 %


(cat)2.HCN

cat.(HCN)2

Nn-Pr

n-PrHN

H

S

NH

H

t-BuO

NHH3C

N OC

RR'

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

O

R'R

HCN

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

HC

N

N

n-Pr

n-PrNH

S

NH

H

t-Bu

HCN

NC

H

OHN

CH3

cat.HCN

cat.HCN.sub

cat.HCN

Mechanism A

Mechanism B

+ Sub

+ Sub

+ HCN

+ cat


NMe

MeHN

H

S

NH

H

t-BuO

NHH3C

O

R'

CN

R

MeN

N NO

S

N(n-Pr)2

But-c

H H

H

HCN


Mechanis2c studies to dis2nguish between mechanisms A and B

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

O

R'R

HCNMechanism A

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

HC

N

Mechanism B

+ Sub

Nn-Pr

n-PrHN

H

S

NH

H

t-BuO

NHH3C

O

R'

CN

R

Nn-Pr

n-PrHN

H

S

NH

H

t-BuO

NHH3C

N OC

RR'

83



Mechanism A

Mechanism B

+ Sub

Nn-Pr

n-PrNH

S

NH

H

R1O

NHR2

O

R'R

HCN

Nn-Pr

n-PrNH

S

NH

H

R1O

NHR2

HC

N

Nn-Pr

n-PrHN

H

S

NH

H

R2O

NHR1

N OC

RR'

ΔΔE≠ (calculated) Size of the amide por2on of the catalyst

ee % (experimental)

Nn-Pr

n-PrHN

H

S

NH

H

R1O

NHR2

O

R'

CN

R

84



Mechanism A

Mechanism B

+ Sub

ΔΔE≠ (calculated) Size of R and R’ ee % (experimental)

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

O

R'R

HCN

Nn-Pr

n-PrNH

S

NH

H

t-BuO

NHH3C

HC

N

Nn-Pr

n-PrHN

H

S

NH

H

t-BuO

NHH3C

N OC

RR'

Nn-Pr

n-PrHN

H

S

NH

H

t-BuO

NHH3C

O

R'

CN

R

85

Importance of different parts of the catalyst

-‐ Zuend, S. J.; Jacobsen, E. N.; J. Am. Chem. Soc. 2007, 129, 15872-‐15883

97 % ee

79 % ee 90 % ee

90 % ee

Ph

O

CH3

Catalyst (10 mol%)

Solvent, CF3CH2OH Ph !! CH3

TMSO CNTMSCN

N N

S

N

CH3

H Hn-Prn-Pr

O

NMe

H

Me N N

S

Nn-Prn-Pr

But-c

H HMe

NN N

O

S

Nn-Prn-Pr

But-C

H H

H

i-PrN N

S

NH Hn-Prn-Pr

86

Calculated transi2on structures: basis for enan2oselec2vity


Major

Minor

NCH3

CH3HN

H

S

NH

H

t-BuO

NHH3C

O

H3C

CN

NCH3

CH3HN

H

S

NH

H

t-BuO

NHH3C

O CN

CH3

87

Coopera2ve mechanism and design of new catalyst

-‐ Zuend, S. J.; Jacobsen, E. N.; J. Am. Chem. Soc. 2007, 129, 15872-‐15883. -‐ Corey, E. J.; Helal, C. J.; Angew. Chem. Int. Ed. 1998, 37, 1986-‐2012.

R1 R2

OLA!!

H

CNO

R1R2

Bronsted Base

Hydrogen bond donor

NR3

R3NH

S

NH

H

t-BuO

NH

H3C

88

Coopera2ve mechanism and design of new catalyst

-‐ Zuend, S. J.; Jacobsen, E. N.; J. Am. Chem. Soc. 2007, 129, 15872-‐15883. -‐ Corey, E. J.; Helal, C. J.; Angew. Chem. Int. Ed. 1998, 37, 1986-‐2012.

Design of new catalysts

H

CNO

R1R2

Nn-Pr

n-PrHN

H

S

NH

Ht-BuO

NHO

R1

CN

R2

N

i-PrO

CH3H3C

NR3

R3NH

S

NH

H

t-BuO

NH

H3C

89

Conclusion

•  Asymmetric mul2func2onal organocatalysis: o  Aspiring to imitate enzymaEc synergisEc cooperaEon of mulEcenters

o  PromoEng the rate of the reacEon while hindering spaEally the compeEng pathways

§  Proximity, orientaEon, and enhancement of the mutual chemical reacEvity

§  Pre-‐organizaEon of the substrates

§  StabilizaEon of charge-‐separated intermediates §  StabilizaEon of transiEon state structure

90

•  Asymmetric mul2func2onal organocatalysis:

o  High enanEoselecEvity:

§  ConformaEonal constraints for high stereoinducEon

§  EnergeEc differenEaEon by:

Ø  DestabilizaEon through repulsive steric and/or electronic interacEons

Ø  StabilizaEon of one enanEomer by mulEple hydrogen bonding

o  A greater mechanisEc understanding of the subtleEes of these processes is necessary for advancement

Conclusion

91

Acknowledgements: u  Prof. Borhan

u  Prof. Wulff

u  Prof. Jackson u  Chrysoula, Marina

u  Labmates: Arvind, Atefeh, Roozbeh,

Carmin, Calvin, Camille, Kumar, Ipek, Tanya, Wenjing, Meisam, Sarah, Mercy

u Mathew, Afrand, Rafida, Anil, Behnaz

93 -‐ Pascal Buskens, Ph.D. Thesis, Germany, 2006. -‐ Stewart, I. C.; Bergman, R. G.; Toste, F. D.; J. Am. Chem. Soc. 2003, 125, 8696-‐8697.

Racemiza2on of Aza-‐MBH

PPh3R

OHTsHN

R

OHTsHN

PPh3

O

PPh3

HTsHNH

R

ONHHTs

OH

F3C CF3

O

CF3F3C

?

94

!!

R

OHTsHN

R

O

HTsHN

HOHPPh2

P OPh2

-‐ Pascal Buskens, Ph.D. Thesis, University, Germany, 2006. -‐ Stewart, I. C.; Bergman, R. G.; Toste, F. D.; J. Am. Chem. Soc. 2003, 125, 8696-‐8697.

Racemiza2on of Aza-‐MBH: importance of Bifunc2onal system

asymmetric*bi,*and*tri,func2onal*organocatalysis ...€¦ ·...

Documents

asymmetricbi,andtri,func2onalorganocatalysis ...€¦ ·...