1

FeN

Me2N

Ph

PhPh

Ph

Ph

Fe

N

Ph

Ph

Ph Me

MeMe

Me

O

FeN

Me

Me

Me

MeMe

OTBSFe

N

N

Me

MeMe

Me

Me

N

Me

N

MeFe

FeMe

Me

Me

MeMe

Me

Me

Me

MeMe

“From Planarity to Chirality”

The research work of Gregory C. Fu

byMaude Poirier

October 2nd, 2007

2

Gregory C. Fu

1963 Born in Galion, Ohio

1984-1985 Researcher with Professor K. Barry Sharpless   MIT

1985-1991Graduate student with Professor David A. Evans   Harvard University

1991-1993 Postdoctoral fellow with Professor Robert H. Grubbs   CALTECH

1993-1996 Assistant Professor of Chemistry   MIT

1996-1998 Firmenich Assistant Professor of Chemistry   MIT

1998-1999 Firmenich Associate Professor of Chemistry   MIT

1999-present Professor of Chemistry   MIT

3

Gregory C. Fu

1963 Born in Galion, Ohio

1984-1985 Researcher with Professor K. Barry Sharpless   MIT

1985-1991Graduate student with Professor David A. Evans   Harvard University

1991-1993 Postdoctoral fellow with Professor Robert H. Grubbs   CALTECH

1993-1996 Assistant Professor of Chemistry   MIT

1996-1998 Firmenich Assistant Professor of Chemistry   MIT

1998-1999 Firmenich Associate Professor of Chemistry   MIT

1999-present Professor of Chemistry   MIT

4

Gregory C. Fu

2007 Fellow, American Academy of Arts and Sciences 2007 Catalysis Science Award, Mitsui Chemicals  2006 Mukaiyama Award, Society of Synthetic Organic Chemistry of Japan  2005 Fellow, Royal Society of Chemistry 2004 Corey Award, American Chemical Society  2001 Springer Award in Organometallic Chemistry 2000 School of Science Undergraduate Teaching Prize, Massachusetts Institute of Technology 2000 Chan Memorial Award in Organic Chemistry 1999 Innovation Recognition Award, Union Carbide 1998 Bristol-Myers Squibb Award 1998 Cope Scholar Award, American Chemical Society 1998 Synthetic Organic Chemistry Award, Pfizer 1997 Camille Dreyfus Teacher-Scholar Award 1997 Alfred P. Sloan Research Fellow 1997 Chemistry Scholar Award, Glaxo Wellcome 1996 Lilly Grantee Award, Eli Lilly 1996 Cottrell Scholar Award, Research Corporation 1995 American Cancer Society Junior Faculty Research Award 1994 National Science Foundation Young Investigator Award 1993 Camille and Henry Dreyfus Foundation New Faculty Award 

5

What is planar chirality ?

1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed. 2006, 45, 968-973.

2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol. 2007, 20, 1046-1052.

OH

O O

NH

OHN

O

OH

NH

NH2

O

O

CH2CH(CH3)2

NHMeHN

O

H

OHN

HO

NH

HO

OHOH

HO

HO2C

Cl

Cl

OHO

HO

OH

(-)-cavicularin

(CH2)n

(CH2)n

cyclophanes

Fe

ferrocenes

vancomicyn aglycon

O

MeO

O

HO

(+)-galeon

HH

trans-cyclooctene

Chirality in molecules devoid of chiral centers

6

What is planar chirality ?

1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed. 2006, 45, 968-973.

2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol. 2007, 20, 1046-1052.

OH

O O

NH

OHN

O

OH

NH

NH2

O

O

CH2CH(CH3)2

NHMeHN

O

H

OHN

HO

NH

HO

OHOH

HO

HO2C

Cl

Cl

OHO

HO

OH

(-)-cavicularin

(CH2)n

(CH2)n

cyclophanes

Fe

ferrocenes

vancomicyn aglycon

O

MeO

O

HO

(+)-galeon

HH

trans-cyclooctene

Chirality in molecules devoid of chiral centers

7

What is planar chirality ?

1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed. 2006, 45, 968-973.

2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol. 2007, 20, 1046-1052.

OH

O O

NH

OHN

O

OH

NH

NH2

O

O

CH2CH(CH3)2

NHMeHN

O

H

OHN

HO

NH

HO

OHOH

HO

HO2C

Cl

Cl

OHO

HO

OH

(-)-cavicularin

(CH2)n

(CH2)n

cyclophanes

Fe

ferrocenes

vancomicyn aglycon

O

MeO

O

HO

(+)-galeon

HH

trans-cyclooctene

Chirality in molecules devoid of chiral centers

8

What is planar chirality ?

1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed. 2006, 45, 968-973.

2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol. 2007, 20, 1046-1052.

OH

O O

NH

OHN

O

OH

NH

NH2

O

O

CH2CH(CH3)2

NHMeHN

O

H

OHN

HO

NH

HO

OHOH

HO

HO2C

Cl

Cl

OHO

HO

OH

(-)-cavicularin

(CH2)n

(CH2)n

cyclophanes

Fe

ferrocenes

vancomicyn aglycon

O

MeO

O

HO

(+)-galeon

HH

trans-cyclooctene

Chirality in molecules devoid of chiral centers

9

Nucleophilic catalyst development

O

OMe Me

O OH

MePh

uncatalyzed

(slow)

O

MePh

O

Me

DMAPcatalyzed

(fast)

N Me

O

Me2N

O Me

O

(fast)OH

MePh

+

NMe2N NMe2NR

H

MLn

NC C

left right

top

bottomNH

MLn

Void

Rtop

bottom

left right

G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420.

10

Nucleophilic catalyst development

Should be electron rich, enhancing the nucleophilicity of the catalyst It’s steric environment should be tunable Should lead to robust planar-chiral complexes for maximum versatility and for ease of handling

Fe

NH

R

FeR

R

R

R

R

N

Me2N

FeN

Me2N

R R

R

R

R R

R R

R

R19 electrons 18 electrons18 electrons

G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420.

11

Planar-Chiral nucleophilic catalyst synthesis

FeCl2

1) CpMe5Li

2)

NK

Fe

N

Me

Me

Me

Me

Me

FeN

R

Me

Me Me

Me

Me

1) CpMe5Li

2)NLi

OLi

Fe

N

Me

Me

Me

Me

Me

OH

TESCl

Et3NFe

N

Me

Me

Me

Me

Me

OTES

1) CpMe5Li

2)

N

R

Li

1

2

3(R=H)4(R=NMe2)

G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420. J. C. Ruble, G. C. Fu, J. Org. Chem. 1996, 61, 7230-7231.

12

Kinetic resolution, basic principles

Enantiomers react at different rates with other chiral compoundsThe more theses rates are fart appart the better isSelectivity factor s :

S =k( fast-reacting enantiomer )

k( slow-reacting enantiomer )

^

10

FeN

Me2N

Me

MeMe

Me

MeOH

MePh r.t.

cat.(-)-4

(-)-4

Me O

O

Me

O

Ph Me

O

O

Me

base

rac

For a review on kinetic resolution, see: H. B. Kagan, J. C. Flaud, Top. Stereochemi. 1988, 18, 249-330.

13

Kinetic resolution, basic principles

PhMe

OH

H

PhMe

H

OH

S

R

FeMe

MeMe

Me

Me

N

NMe2

MeO

OPhMe

NMe2NO

MeO

RLRs

H

CpFe

H

FeMe

MeMe

Me

Me

NNMe2

Me

O

O

H

PhMe

NMe2NO

MeO

RLRs

CpFe

H

Ph Me

O

O

Me

SPh Me

O

O

Me

R

G

Rxn coordinates

N

NMe2

O Me

CpFe

14

Kinetic Resolution of Secondary Alcohols

FeN

Me2N

Me

MeMe

Me

Me

OH

MePh NEt3Toluene r.t.

2% (-)-4

(-)-4

Me O

O

Me

O

Ph Me

O

O

Me

s=1,7

FeN

Me2N

PhPh

PhPh

Ph

(-)-7

OH

MePh NEt3Toluene r.t.

2% (-)-7

Me O

O

Me

O

Ph Me

O

O

Me

s= 12 to52(10substrates)

J. C. Ruble, H. A. Latham, G. C. Fu, J. Am. Chem. Soc. 1997, 119, 1492-1493. J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem. 1998, 63, 2794-2795.B. Tao, J. C. Ruble, D. A. Holc, G. C. Fu, J. Am. Chem. Soc, 1999, 121, 5091-5092.

15

Kinetic Resolution of Secondary Alcohols

OH

RAryl RAlkyl

O

Me O

O

Me

1% (-)-7

NEt3t-amyl alcohol, 0C

O

RAryl RAlkyl

Me

O

Entry Unreacted alcohol s %ee (%conversion)major enantiomer

1234

5

6

7

8

OH

Ph R

R=MeEti-Pri-Bu

43598795

32

71

65

200

^

99(55)99(54)97(52)96(51)

98(56)

98(53)

95(52)

99(51)

OH

PhCl

Me

Me

OH

OH

Me

Me

Me

OH

FeN

Me2N

PhPh

PhPh

Ph

(-)-7

OH

t-amyl alcohol

G. C. Fu, Acc. Chem. Res. 2000, 33, 412-420.

16

Synthesis of Kagan’s ether analogue

BnO

BrOMe

OMe 1) nBuLi, THF, -78C

BnOCHO

2)

BnOCH(OMe)2

OH

OBn

TsOH, CH2Cl2-78Cto rt, 99%

Pd/C, H2MeOH/EtOAc, rt, 99%

O

HO

OH

1)

2)

65%

N B

O

BH2

HPh Ph

Me

BnOCH(OMe)2

OH

OBn

FeN

Me2N

Ph

PhPh

Ph

Ph Et3N, Ac2Ot-amyl alcohol

0C, 50h

BnOCH(OMe)2

OH

OBn

BnOCH(OMe)2

OAc

OBn

LAH 96%

er: 27.6 : 151,7%

er: 9:148,6%

BnOCH(OMe)2

OH

OBn

0,76 mol%

1) Swern Ox

2) CBSred

BnOCH(OMe)2

OH

OBn

7 : 172%

1) TsOH, CH2Cl2-78Cto rt, 99%

Pd/C, H2MeOH/EtOAc, rt, 99%

2)

(R,R)-7

23

4

(R)-5 (S)-5 (R)-5 (S)-5

(R)-6

94%

1) M. Harmata, M. Kahraman, J. Org. Chem. 1999, 64, 4949-4952.

17

Kinetic Resolution of Allylic Alcohols

1) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem. 1998, 63, 2794-2795.2) S. Bellemen-Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem. Commun. 2000, 1009-1010.

FeN

Me2N

Ph

PhPh

PhPh

(-)-1

R

RR

R1

OH 1-2,5% (+)-1

NEt3t-amyl alcohol

0C

R

RR

R1

OH

R

RR

R1

OAc

racemic

R=H, aryl, alkylR1 = alkyl

n-Pr

i-Pr

OH

Ph

Me

OH

R

OH

Me

Me

R

OH

Me

1

2

3 R= n-pentyl

4 R= i-Pr

5 R=Et

6 R= i-Pr

7 i-Pr

OH

n-Bu

8

9

10

11 R= n-pentyl

12 R= i-Pr

13

i-Pr

OH

Ph

Me

OH

Me

Ph

i-Pr

OH

n-Bu

R

OH

Me Me

OH

Me Me

Me Me

Me

5.492%ee

75%conv

6499%ee

54%conv

4.790%ee

77%conv

1092%ee

63%conv

1193%ee

63%conv

1793%ee

58%conv

2594%ee

55%conv

1493%ee

59%conv

8098%ee

53%conv

5.390%ee

73%conv

1297%ee

66%conv

1897%ee

60%conv

2999%ee

59%conv

Entry Alcohol s Entry Alcohol s

18

Epothilone A synthesis

FeN

Me2N

PhPh

PhPh

Ph

(-)-1

MeO

Me

O

Me

OH

Me

1%(+)-1

NEt3t-amyl alcohol

0C

MeO

Me

O

Me

OH

Me

MeO

Me

O

Me

OH

MeAc2O

98% ee, 47%yields= 107

catalyst recovery: 95%racemic

O

O O

OH

OH

N

S

RO

1: Epothilone A; R =H

MeO

MeOH

O

Me Me

1) S. Bellemen-Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem. Commun. 2000, 1009-1010. 2) For the synthesis of Epothilone A, see: S. C. Sinha, C. F. Barbas, III and R. A. Lerner, Proc. Natl. Acad. Sci. USA, 1998, 95, 14603.

19

Epothilone A synthesis

FeN

Me2N

PhPh

PhPh

Ph

(-)-1

MeO

Me

O

Me

OH

Me

1%(+)-1

NEt3t-amyl alcohol

0C

MeO

Me

O

Me

OH

Me

MeO

Me

O

Me

OH

MeAc2O

98%ee, 47%yields= 107

catalyst recovery: 95%racemic

O

O O

OH

OH

N

S

RO

1: Epothilone A; R =H

MeO

MeOH

O

Me Me

1) S. Bellemen-Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem. Commun. 2000, 1009-1010. 2) For the synthesis of Epothilone A, see: S. C. Sinha, C. F. Barbas, III and R. A. Lerner, Proc. Natl. Acad. Sci. USA, 1998, 95, 14603.

20

Kinetic Resolution of Secondary Amines

NH2

Ph Me CHCl3-50C

HN

Ph Me

OMe

O

Entry Amine s Entry Amine s

rac

10%(-)-PPY*

12

27

16

11

NOtBu

O

-Naphthyl

O

OMeFe

N

N

PhPh

PhPh

Ph

(-)-PPY*

1

2

3

4

Me

NH2

Me

NH2

Me

Me

NH2

MeO

Me

NH2

F3C

Me

NH2

MeOMe

NH2

Me

NH2

H2N

O

OCy

Et

NH2

5

6

7

8

13

22

16

11

1) S. Arai, S. Bellemin-Laponnaz, G. C. Fu, Angew. Chem. Int. Ed. 2001, 40, 234-236.

21

Asymmetric nucleophilic catalysist: Planar-chiral heterocycles

Fe

N

Me

Me

Me

Me

Me

OTBS

OC

Ph

MeMeOH10% (+)-2c

Toluene-78C

O

MeOMe

PhH

(+)-2c

56%ee

OC

Ph

MeMeOH10% (+)-2c

Toluene-78C

O

MeOMe

PhH

77%ee

NH

OTf

OC

RS

RL

catalyst

O

catalystRL

RS

O

catalystRL

H RS

ROH

O

RORL

H RS

RO

Step1 Step2

Step3

AB

SuggestedMechanism

B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.

22

Asymmetric nucleophilic catalysist: Planar-chiral heterocycles

Fe

N

Me

Me

Me

Me

Me

OTBS

OC

Ph

MeMeOH10% (+)-2c

Toluene-78C

O

MeOMe

PhH

(+)-2c

56%ee

OC

Ph

MeMeOH10% (+)-2c

Toluene-78C

O

MeOMe

PhH

77%ee

NH

OTf

OC

RS

RL

catalyst

O

catalystRL

RS

O

catalystRL

H RS

ROH

O

RORL

H RS

RO

Step1 Step2

Step3

AB

SuggestedMechanism

B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.

23

Asymmetric nucleophilic catalysist: Planar-chiral heterocycles

OC

RS

RL

catalyst

O

catalystRL

RS

O

catalyst

RL

H RS

ROH

O

RO

RL

H RS

RO

Step1 Step2

Step3

AB

SuggestedMechanism

Fe

N

Me

Me

Me

Me

Me

OTBSO

PhMe

H

Fe

N

Me

Me

Me

Me

Me

OTBSO

Ph Me

H

MeO MeO

O

MeOMe

H Ph

O

MeOPh

H Me

S- Unfavored

Fe

N

Me

Me

Me

Me

Me

OTBSO

MePh

H

Fe

N

Me

Me

Me

Me

Me

OTBSO

Me Ph

H

R- Favored

B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.

24

Asymmetric nucleophilic catalysist: Planar-chiral heterocycles

Entry Subtrate %ee %Yield Entry Substrate %ee %Yield

1

2

3

4

5

6

O

Ph

MeC

O MeC

t-Bu

77 87

77 88

O MeC

OMe

75 80

O MeC

PhO

O

Ph

EtC

OC

74 96

68 92

80 97

OC

Ph

MeMeOH10% (+)-2c

Toluene-78C

O

MeOMe

PhH

77%ee

NH

OTf

Fe

N

Me

Me

Me

Me

Me

OTBS

(+)-2c

B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.

25

Asymmetric Staudinger synthesis of -lactams

1) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 1578-1579.2) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586-11587.

O

C

Ph R

NTs

R1H

NTsO

PhR1

R

10%(-)-6

toluene, r.t.

1.15 equiv

O

C

Ph R

NTf

R1H

NTfO

Ph

R

10%(-)-6

CH2Cl2 and/ortoluene, r.t.1.15 equiv

R1

FeN

N

Me

MeMe

Me

Me

(-)-6

NTsO

catalyst

O

C

R R

O

catalystR

R

NTs

H R

O

catalyst

NTs

RR R

catalyst

NTf

H RR

R R

NTf

H Rcatalyst

OCR

R

NTf

H Rcatalyst

O

R

R

NTfO

R

R R

"imine-first" pathway"ketene-first" pathway

26

Asymmetric Staudinger synthesis of -lactams

1) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 1578-1579.2) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586-11587.

O

C

Ph R

NTs

R1H

NTsO

PhR1

R

10%(-)-6

toluene, r.t.

1.15 equiv

O

C

Ph R

NTf

R1H

NTfO

Ph

R

10%(-)-6

CH2Cl2 and/ortoluene, r.t.1.15 equiv

R1

FeN

N

Me

MeMe

Me

Me

(-)-6

NTsO

catalyst

O

C

R R

O

catalystR

R

NTs

H R

O

catalyst

NTs

RR R

catalyst

NTf

H RR

R R

NTf

H Rcatalyst

OCR

R

NTf

H Rcatalyst

O

R

R

NTfO

R

R R

"imine-first" pathway"ketene-first" pathway

27

Asymmetric Staudinger synthesis of -lactams

O

C

Ph R

NTs

R1H

NTsO

PhR1

R

Entry R R1 dr ee (%) Yield (%)

1

2

3

4

5

6

i-Bu

i-Bu

i-Bu

i-Bu

Et

Et

Ph

O

Ph

O

8 : 1

11 : 1

10 : 1

15 : 1

9 : 1

10 : 1

98

98

98

89

95

98

88

97

95

88

97

98

10%(-)-6

toluene, r.t.

1.15 equivO

C

Ph R

NTf

R1H

NTfO

Ph

R

Entry R R1 dr ee (%) Yield (%)

10%(-)-6

CH2Cl2 and/ortoluene, r.t.1.15 equiv

12345678910

Et Ph 86:14Me Ph 98:2i-Bu Ph 97:3Me 4-FC6H4 96:4Me 4-(CF3)C6H4 97:3Me 4-(OMe)C6H4 81:19Me o-tolyl 81:19Me 2-BrC6H4 80:20Me 2-naphthyl 98:2Ph Ph -

63816385698299849498

60837284807689797662

R1

FeN

N

Me

MeMe

Me

Me

(-)-6

1) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 1578-1579.2) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586-11587.

28

Building quaternary centers

NO

O

R1

R2

O

X N N

NMe2 N

X =alkyl, OR

or

NO

R2

O

X

O

R1

rac

NO

Ar

O

MeBnO

O

H2NOMe

O

Me

95%Ar = 4-MeO-C6H4

BnO2C NH

O

OMe

ONHCOArMe

Me

NaBH4

82%Ar = Ph

BnO2C OHNHCOArMe

dipeptide

protected-methyl serine

Steglich rearrangement

1) W. Steglich, G. Hofle, Tetrahedron Lett. 1970, 4727-4730.2) For a review of asymmetric synthesis of quaternary stereocenter, see: E. J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed. 1998, 37, 388-

401.3) For an overview on the synthesis and significance of a-alkylated a-amino acids, see: T. Wirth, Angew. Chem. Int. Ed. 1997, 36, 225-227.

29

Rearrangement of O-Acylation azlactone

NO

O

Ar

R

O

BnO2% (-)-6

Ar =4-MeO-C6H40C

FeN

N

Me

MeMe

Me

Me

NO

O

Ar

RBnO

O

(-)-6

Entry R %ee %Yield

123456

MeEt

CH2Phallyl

CH2CHMe2CH2CH2SMe

919090919288

949393939594

N

O

O

Ar

R

O

BnO

BnO cat

O

NO

O

R

Ar

N

O

O

Ar

O

BnOR

catalyst

Step1Fast

Step2Slow

Mechanism

1) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532-11533.2) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem, 1998, 63, 3154-3155.

N

N

O

O

CpFe

O

NOR

Ar

O

NO R

Ar

N

N

O

O

CpFe

Bn Bn

30

Rearrangement of O-Acylation azlactone

NO

O

Ar

R

O

BnO2% (-)-6

Ar =4-MeO-C6H40C

FeN

N

Me

MeMe

Me

Me

NO

O

Ar

RBnO

O

(-)-6

Entry R %ee %Yield

123456

MeEt

CH2Phallyl

CH2CHMe2CH2CH2SMe

919090919288

949393939594

N

O

O

Ar

R

O

BnO

BnO cat

O

NO

O

R

Ar

N

O

O

Ar

O

BnOR

catalyst

Step1Fast

Step2Slow

Mechanism

1) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532-11533.2) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem, 1998, 63, 3154-3155.

N

N

O

O

CpFe

O

NOR

Ar

O

NO R

Ar

N

N

O

O

CpFe

Bn Bn

31

Building quaternary centers: synthesis of oxindoles and benzofuranones

NBn

OOR

OPh

NBn

O

PhOR

O

OO

OROPh

OO

PhOR

O

FeN

N

Me

MeMe

Me

Me

(-)-6

XO

OROR

X =NPG, ON

O

O

Ar

R

BnO

O

I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.

32

Building quaternary centers: synthesis of oxindoles and benzofuranones

I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.

OO

OROR

N

N

OO

R

N

N

O

OR

OO

OR

OR

NR2O

OOR1

NR2O

R1O

O

5%catalyst (-)-6

OO

OR2OR1

OO

R1OR2

O

5%catalyst (-)-6

CH2Cl235C

CH2Cl235C

FeN

N

Me

MeMe

Me

Me

(-)-6

Entry R1 R2 R3 ee(%) Yield(%)

1 Ph Me H 99 912 2-thienyl Me H 95 813a benzyl Me H 94 824a Me Me H 93 725 Ph Me I 98 946 Ph Bn H 98 88

Entry R1 R2 ee(%) Yield(%)

1 Ph H 97 812 benzyl H 88 953a Mel Me 90 93

a Reaction was run at -12Cwith 10%catalyst.

CCl3 CCl3R3 R3

33

Building quaternary centers: synthesis of oxindoles and benzofuranones

I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.

34

Building quaternary centers: synthesis of -ketoesters

A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.

OTMS

Oi-PrAr

Et

5%catalystAc2O

t-AmylOH0C

O

Me Oi-Pr

O

EtAr

catalyst*O

R O

O

R

R

O

cat* O

O

R

OSiR3

OR3R1

R2

R

O

cat*

O

OR3R1

R2

R3SiO

O

R

O

OR3R1

R2

R

O

O

R

O

OR3

R2R1

cat*

- cat*

FeN

N

Me

MeMe

Me

Me

(-)-6

35

Building quaternary centers: synthesis of -ketoesters

A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.

OTMS

Oi-PrAr

Et

5%catalystAc2O

t-AmylOH0C

O

Me Oi-Pr

O

EtAr

catalyst*O

R O

O

R

R

O

cat* O

O

R

OSiR3

OR3R1

R2

R

O

cat*

O

OR3R1

R2

R3SiO

O

R

O

OR3R1

R2

R

O

O

R

O

OR3

R2R1

cat*

- cat*

FeN

N

Me

MeMe

Me

Me

(-)-6

36

Building quaternary centers: synthesis of -ketoesters

A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.

Mechanistic studies

OTMS

Oi-PrAr

Et

5% catalystAc2O

t-AmylOH0C

O

Me Oi-Pr

O

EtAr

FeN

N

MeMe

MeMe

Me

(-)-6

OTMS

ORAr

R

OTMS

ORR

Ar

+5% (-)-6

O

Me OR

O

RAr

O

Me OR

O

ArR

O

Ar

R

OR

O

Ar

R

OR

?

O

O

O

Me Me

37

Building quaternary centers: synthesis of -ketoesters

A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.

Mechanistic studies

OTMS

Oi-PrAr

Et

5%catalystAc2O

t-AmylOH0C

O

Me Oi-Pr

O

EtAr

FeN

N

MeMe

MeMe

Me

(-)-6

OTMS

ORAr

R

OTMS

ORR

Ar

+5%(-)-6

O

Me OR

O

RAr

O

Me OR

O

ArR

O

Ar

R

OR

O

R

Ar

OR

?

O

O

O

Me Me

38

Building quaternary centers: synthesis of -ketoesters

A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.

Mechanistic studies

OTMS

Oi-PrAr

Et

5%catalystAc2O

t-AmylOH0C

O

Me Oi-Pr

O

EtAr

FeN

N

Me

MeMe

Me

Me

(-)-6

OTMS

ORAr

R

OTMS

ORR

Ar

+5%(-)-6

O

Me OR

O

RAr

O

Me OR

O

ArR

O

Ar

R

OR

O

R

Ar

OR

O

O

O

Me Me

XOTMS

Ot-BuPh

Et

5%[Me4N]OAc

CD2Cl2, r.t. 60h

exp 1: 1.6/1 mixture of isomersexp 2: 2.6/1 mixture of isomers

no change inratio of isomers

39

Building quaternary centers: synthesis of -ketoesters

A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.

Mechanistic studies

OTMS

Oi-PrAr

Et

5%catalystAc2O

t-AmylOH0C

O

Me Oi-Pr

O

EtAr

FeN

N

Me

MeMe

Me

Me

(-)-6

OTMS

ORAr

R

OTMS

ORR

Ar

+5%(-)-6

O

Me OR

O

RAr

O

Me OR

O

ArR

O

Ar

R

OR

O

R

Ar

OR

O

O

O

Me Me

X

N

N

O

Me

CpFe

O

R

OR

Ar

N

N

O

Me

CpFe RAr

ORO

O

ORAr

R

O

ORR

Ar

N

N

O

Me

CpFe

N

N

O

Me

CpFe

40

Planar-chiral Brønsted Acid catalyst

B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.

FeN

N

Me

MeMe

Me

Me

(-)-1NH

NC OC R

Ar

2% (-)-1

toluene, r.t.

R

Ar

O

N

NC

NH

NC

N

NC

catalyst*

R1

O

N

NC

RH

R1

O

N

NC

R

H catalyst*

H catalyst*

OC

R

R1

41

Planar-chiral Brønsted Acid catalyst

B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.

FeN

N

Me

MeMe

Me

Me

(-)-1NH

NC OC R

Ar

2% (-)-1

toluene, r.t.

R

Ar

O

N

NC

NH

NC

N

NC

catalyst*

R1

O

N

NC

RH

R1

O

N

NC

R

H catalyst*

H catalyst*

OC

R

R1

42

Planar-chiral Brønsted Acid catalyst

FeN

N

Me

MeMe

Me

Me

(-)-1NH

NC OC R

Ar

2% (-)-1

toluene, r.t.

R

Ar

O

N

NC

entry Ar R ee(%) yield(%)

1 Ph Me 81 912 Ph Et 90 933 Ph i-Pr 95 964a Ph t-Bu 81 905 o-tol Et 98 956 o-anisyl Me 94 947 3-(N-Methylindolyl) Bn 86 89

a 5%catalyst

B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.

43

Planar-chiral Brønsted Acid catalyst

Support for a Brønsted-acid mechanism:

Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair.

The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes.

The ee of the product is inversely proportional to the concentration of the reaction.

Stereochemical outcome of the reaction can be explained by this pathway.

FeNH

N

Me

MeMe

Me

MeN

NC

G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.

44

Planar-chiral Brønsted Acid catalyst

Support for a Brønsted-acid mechanism:

Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair.

The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes.

The ee of the product is inversely proportional to the concentration of the reaction.

Stereochemical outcome of the reaction can be explained by this pathway.

N

NCFe

N

N

Me

MeMe

Me

Me FeND

N

Me

MeMe

Me

MeND

NC

G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.

45

Planar-chiral Brønsted Acid catalyst

Support for a Brønsted-acid mechanism:

Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair.

The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes.

The ee of the product is inversely proportional to the concentration of the reaction.

Stereochemical outcome of the reaction can be explained by this pathway.

NH

NC

R1

O

N

NC

RH

R1

O

N

NC

RH catalyst*

R1

O

N

NC

RH

racemic

G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.

46

Planar-chiral Brønsted Acid catalyst

Support for a Brønsted-acid mechanism:

Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair.

The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes.

The ee of the product is inversely proportional to the concentration of the reaction.

Stereochemical outcome of the reaction can be explained by this pathway.

G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.

47

Planar-chiral Brønsted Acid catalyst

S. L. Wiskur, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 6176-6177.

FeN

N

Me

MeMe

Me

Me

(-)-1

OC R

Ar

3% (-)-1

toluene, r.t.

R

Ar

O

Ot-Bu

OH

t-Bu

entry Ar R ee(%) yield(%)

1 Ph Me 79 872 Ph Et 91 893 Ph i-Bu 84 794 Ph cyclopentyl 87 885 Ph i-Pr 91 666 o-tol Et 92 847 o-anisyl Me 94 788 p-Cl i-Pr 89 979 3-thienyl i-Pr 79 94

FeN

N

Me

MeMe

Me

MePhOH FeNH

N

Me

MeMe

Me

MePhO

48

Planar-chiral Brønsted Acid catalyst

K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.

FeN

N

MeMe

MeMe

Me

(-)-1

OC R

Ar

3% (-)-1

toluene, r.t.

R

Ar

O

N3

FeN

N

Me

MeMe

Me

Me

N3H

N3H

pKa =5

O

XR1

R

H catalyst*

H X

O

XR1

R H

O

XR1

R H

enantioenriched

racemic

H catalyst*

reaction within the ion pair favoerd bylower concentrations and less-polar solvents

more abundant andmore acidic then

N3H Fe

NH

N

Me

MeMe

Me

MeN3

27%ee34%yield

49

Planar-chiral Brønsted Acid catalyst

K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.

FeN

N

MeMe

MeMe

Me

(-)-1

OC R

Ar

3% (-)-1

toluene, r.t.

R

Ar

O

N3

FeN

N

Me

MeMe

Me

Me

N3H

N3H

pKa =5

O

XR1

R

H catalyst*

H X

O

XR1

R H

O

XR1

R H

enantioenriched

racemic

H catalyst*

reaction within the ion pair favoerd bylower concentrations and less-polar solvents

more abundant andmore acidic then

N3H Fe

NH

N

Me

MeMe

Me

MeN3

27%ee34%yield

50

Planar-chiral Brønsted Acid catalyst

K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.

FeN

Me

Me

MeMe

Me

Me

(+)-2

OC R1

R

10%(+)-2

toluene/hexane-78C or -90C

HN R1

entry R R1 ee(%) yield(%)

1 Ph i-Pr 93 962 p-ClC6H4 i-Pr 90 923 p-(MeO)C6H4 i-Pr 94 974 3-thienyl i-Pr 92 945 Ph cyclohexyl 92 966 Ph cyclopentyl 93 967 Ph t-Bu 94 768 Ph Et 89 49 o-tol Et 93 9410 o-tol Me 90 8011 p-(MeO)C6H4 Et 92 5512 o-(MeO)C6H4 Me 90 70

N3H

1)

2) MeOH, 1.1 equiv

MeO

O R H

51

Planar-chiral ligands for transition metal-catalyzed reactions

H-L. Kwong, W-S. Lee, H-F. Ng, W-H. Chiu, W-T. Wong, J. Chem. Soc. Dalton Trans. 1998, 1043-1046.

N

Me

N

MeFe

FeMe

Me

Me

MeMe

Me

Me

Me

MeMe

• cyclopropanation

ArN2

O

OR

CH3Cl, 20h, r.t.

CuOTf 0,02 equiv

1,00 equiv4,00 equiv

Ar CO2R CO2RAr

N N

MeOHHMeO

trans:cis up to 90:10ee(%) trans isomer: 77-92

yield(%) trans isomer: 50-78

52

Planar-chiral ligands for transition metal-catalyzed reactions

N

Me

N

MeFe

FeMe

Me

Me

MeMe

Me

Me

Me

MeMe

N

Me

HO

POCl3 H2O2, AcOH

N

Me

Cl74% 88% N

Me

Cl

O

Ac2O

58% N

Me

ClOAc

N

Me

Cl

H2SO479%

i. BuLi, -78C

ii. CpFeCl58%

N

Me

FeMe

Me

Me

MeMe

Cl30 mol% NiBr2(PPh3)2

Zn, Et4NI58%

single diastereoisomer

N

Me

N

Me

Me

Me

Me

MeMe

Me

Me

Me

MeMe

N

Me

N

Me

Me

Me

Me

MeMe

Me

Me

Me

Me

Me

Fe

Fe Fe Fe

N

Me

N

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Fe Fe

R. Rios, J. Liang, M. M.-C. Lo, G. C. Fu, Chem. Commun. 2000, 377-378.

53

Planar-chiral ligands for transition metal-catalyzed reactions

N

Me

N

MeFe

FeMe

Me

Me

MeMe

Me

Me

Me

MeMe

N

Me

HO

POCl3 H2O2, AcOH

N

Me

Cl74% 88% N

Me

Cl

O

Ac2O

58% N

Me

ClOAc

N

Me

Cl

H2SO479%

i. BuLi, -78C

ii. CpFeCl58%

N

Me

FeMe

Me

Me

MeMe

Cl30 mol% NiBr2(PPh3)2

Zn, Et4NI58%

single diastereoisomer

1 2 3 4

5

(+)-6(-)-6

(S,S)-7

N

Me

N

Me

Me

Me

Me

MeMe

Me

Me

Me

MeMe

N

Me

N

Me

Me

Me

Me

MeMe

Me

Me

Me

Me

Me

Fe

Fe Fe Fe

N

Me

N

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Fe Fe

Not formed

Not formed

(R,R)-7 (R,S)-7

(S,R)-7

R. Rios, J. Liang, M. M.-C. Lo, G. C. Fu, Chem. Commun. 2000, 377-378.

54

Planar-chiral ligands for transition metal-catalyzed reactions

N

Me

N

MeFe

FeMe

Me

Me

MeMe

Me

Me

Me

MeMe

R N2

O

OtBu

tBu

(+)-(S,S)-1

1,0 mol%CuOTf1,2 mol% (+)-(S,S)-1

2,0 equiv

R

O

O

tBu

tBu

CH2Cl2 r.t.

Entry R trans:cis ee(%) (trans) Yield (%)

12345

Php-(MeO)C6H4p-(F3C)C6H4n-HexylEt3Si

97 : 395 : 594 : 694 : 696 : 4

8775947880

7871837860

• cyclopropanation

R

N2

CO2Ar 1% CuOTf1,2%(R,R)-1

CH2Cl2, r.t.Ar =BHT R

CO2Ar

entry R trans:cis %ee, trans yield (%)

1 Ph 96:4 94 792a p-(F3C)C6H4 94:6 96 813a p-(MeO)C6H4 94:6 87 904 PhCH2 94:6 91 785 n-Hex 93:7 90 806 Et3Si 99:1 95 64

a The yield refers to the isolated yield of a mixture ofcis ans trans isomers.

Fe

N

Me

Me

Me

Me

Me(R,R)-1

N

Me

Me

Me

Me

MeFe

1) R. Rios, J. Liang, M. M.-C. Lo, G. C. Fu, Chem. Commun. 2000, 377-378.2) M. M.-C. Lo, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 10270-10271.

55

Planar-chiral ligands for transition metal-catalyzed reactions

RO H Ar

N2

OMe

O2.0%Cu(OTf)2

3.8%(+)-14.0%H2O

ClCH2CH2Clr.t.

ArOMe

O

RO H

entry Ar yield (%) ee (%) entry Ar yield (%) ee (%)

1 Ph 94 90 9 (4-NHAc)C6H4 89 99a

2 (2-OMe)C6H4 90 96 10 (4-Ph)C6H4 91 863 (2-Me)C6H4 94 79 11 (4-Br)C6H4 95 794 (2-Cl)C6H4 96 96 12 (4-F)C6H4 92 895 (2-F)C6H4 98 98 13 (4-CF3)C6H4 90 216 (3-OMe)C6H4 96 89 14 2-naphthyl 93 847 (3-Cl)C6H4 92 658 (4-OMe)C6H4 85 86 15 88 89

16 3-thienyl 88 88

1.05 equiv

R=CH2CH2TMS

O

O

a After recrystallization.

Fe

N

Me

Me

Me

Me

Me(+)-1

N

Me

Me

Me

Me

MeFe

O

OMePh

O HTMS

BF3.OEt2

CH2Cl2r.t.98%

O

OMePh

HO H

T. C. Maier, G. C. Fu, J. Am. Chem. Soc. 2006, 128, 4594-4595.

• O-H insertion

56

Planar-chiral ligands for transition metal-catalyzed reactions

Boc NH2Ar

N2

Ot-Bu

O7.0%CuBr

6.0%AgSbF68.0%(-)-bpy*

ClCH2CH2Clr.t.

ArOt-Bu

O

BocHN H

entry Ar yield (%) ee (%)

1 Ph 75 942 (2-Me)C6H4 71 813 (3-Me)C6H4 75 884 (4-OMe)C6H4 61 955 (4-NHBoc)C6H4 77 916 (4-Br)C6H4 86 95a

7 (4-CF3)C6H4 89 858 2-naphthyl 73 91

9 74 90

10 3-thienyl 48 80

1.05 equiv

O

O

a After recrystallization.

N

Me

N

Me

Me

Me

Me

MeMe

Me

Me

Me

MeMe

Fe

Fe

(-)-bpy*

E. C. Lee, G. C. Fu, J. Am. Chem. Soc. ASAP

• N-H insertion

57

Planar-chiral ligands for transition metal-catalyzed reactions

N

Me

N

Me

Me

Me

Me

MeMe

Me

Me

Me

MeMe

Fe

Fe

(-)-bpy*

O

R R1N2

O

OAr1.0%CuOTf1.3% (-)-bpy*

CH2Cl2r.t.

OCO2Ar

R1R

~1.2 equiv

entry R R1 yield(%)a dr ee(%)

1 Ph Ph2 4-(F3C)C6H4 Ph3 4-ClC6H4 Ph4 4-(MeO)C6H4 Ph5 Ph 4-ClC6H46 Ph 4-(MeO)C6H47 N-Boc-2-pyrrolyl Ph8 Ph 3-furyl9 Ph CH=CHPh10 Ph n-Bu11 n-Hex Ph12 n-Hex Me

79 13:1 8559 19:1 7677 19:1 8884 20:1 9281 20:1 8884 9:1 9368 20:1 9363 6:1 8776 7:1 9392 20:1 7869 13:1 7580 20:1 71

a Isolated yield of the trans diastereomer.77%

over three steps

O

OTESR

OHO

OHR

OH

94%ee, 20:1 dr

BF3.OEt2

r.t.deoxy-C-nucleoside 86%

S. Son, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 1046-1047.

• Asymmetric [4+1] cycloaddition

58

Planar-chiral ligands for transition metal-catalyzed reactions

R HR2

NR1O

catalyticCuCl . 2

N

R R2

O R1

Fe

N

Me

Me

Me

Me

Me

N

Me

Me

Me

Me

MeFe

R =H: (+)-(R,R)-1R =Me: (+)-(R,R)-2

R R

R

CuLn

HR2

NR1O

[3+2] ON

LnCu

R

R2

R1

NR2

R1

LnCuO

R

CuLn H+-H+CuLn

base

M. M-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124,4572-4573.For mecanism, see: M. Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem. 1995, 60, 4999-5004.For -lactams trans-isomerization, see: M. Shimizu, K. Kume, T. Fujisawa, Chem. Lett. 1996, 545-546.

• -lactams synthesis, the Kinugasa reaction

59

Planar-chiral ligands for transition metal-catalyzed reactions

R HR2

NR1O

catalyticCuCl . 2

N

R R2

O R1

Fe

N

Me

Me

Me

Me

Me

N

Me

Me

Me

Me

MeFe

R =H: (+)-(R,R)-1R =Me: (+)-(R,R)-2

R R

R

CuLn

HR2

NR1O

[3+2] ON

LnCu

R

R2

R1

NR2

R1

LnCuO

R

CuLn H+-H+CuLn

base

M. M-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124,4572-4573.For mecanism, see: M. Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem. 1995, 60, 4999-5004.For -lactams trans-isomerization, see: M. Shimizu, K. Kume, T. Fujisawa, Chem. Lett. 1996, 545-546.

• -lactams synthesis, the Kinugasa reaction

60

Planar-chiral ligands for transition metal-catalyzed reactions

R HR1

NArO

1%CuCl1.1%(R,R)-2

N

R R1

O Ar

Fe

N

Me

Me

Me

Me

Me

N

Me

Me

Me

Me

MeFe

Me Me

Cy2NMe, -20CMeCN

(R,R)-2

entry nitrone R cis:trans %ee cis yield cis(%)

1 3 Ph 95:5 92 652 3 4-(F3C)C6H4 95:5 93 573 3 4-(MeO)C6H4 92:8 91 604 3 PhCH2 71:29 73 435a 4 Ph 90:10 90 566a 4 1-cyclhexenyl 90:10 91 45

HCy

NO

H

NPhO

OMe

Ph

O

3 4

a Run at -40C

M. M-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124,4572-4573.For mecanism, see: M. Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem. 1995, 60, 4999-5004.For b-lactams trans-isomerization, see: M. Shimizu, K. Kume, T. Fujisawa, Chem. Lett. 1996, 545-546.

• -lactams synthesis, the Kinugasa reaction

61

Planar-chiral ligands for transition metal-catalyzed reactions

• -lactams synthesis, the Kinugasa reaction

NArO

5%CuBr5.5%ligand

NO Ar

Fe

P

Me

Me

Me

Me

Me

N

O

R

Cy2NMe 0.5 equiv0C MeCN

H

N

O

N

O

iPriPr4 5a: R = iPr; 5b: R= tBu

Fe

P

Me

Me

Me

Me

Me

N

OiPr

6

Entry Ligand ee(%) Yield (%)

1 1 6 302 4 62a 393 5a 88 744 5b 90 475 6 58 52

aR,Renantiomer

Fe

N

Me

Me

Me

Me

Me

N

Me

Me

Me

Me

MeFe

Me Me

(R,R)-2

1

R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.

62

Planar-chiral ligands for transition metal-catalyzed reactions

• -lactams synthesis, the Kinugasa reaction

R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.

NAr

O

5%CuBr5.5%ligand

N

O

Ar

FeP

Me

Me

Me

MeMe

N

O

R

Cy2NMe 0.5 equiv0CMeCN

H

N

O

N

O

iPriPr4

5a: R= iPr; 5b: R= tBu

FeP

Me

Me

Me

Me

Me

N

OiPr

6

Entry Product Ligand ee(%) Yield (%) Entry Product Ligand ee(%) Yield (%)

1 1 88 74 4 5b 90 64

2 4 86 60 5 6 85 53

3 5a 90 46 6 5b 91 68

FeN

Me

Me

Me

MeMe

N

Me

Me

Me

MeMeFe

Me Me

(R,R)-2

1

N

O

Ar

N

O

ArOMe

N

O

Ar O

N

O

Ar S

N

O

ArO

N

O

ArO

63

Planar-chiral ligands for transition metal-catalyzed reactions

• -lactams synthesis, the Kinugasa reaction

R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.

NO

H

R R1

R2

H+

NLnCuO

R1

R2

R

NO

E

R R1

R2

E+

usualKinugasapathway

NArO

I

3.0 equiv

CuBr (5%)5a (5.5%)

OTMS

Ph2.0 equiv

KOAc (1.0 equiv)MeCN, r.t. N

O Ar

85%ee76%yield

S

NO

Ar

I

3.0 equiv

CuBr (5%)5a (5.5%)

OTMS

Ph2.0 equiv

KOAc (1.0 equiv)MeCN, r.t.

NO Ar

S

90%ee70%yield

Ar = p-carboethoxyphenyl

Ar = p-carboethoxyphenyl

Fe

P

Me

Me

Me

Me

Me

N

O

iPr

H

5a

64

Planar-chiral ligands for transition metal-catalyzed reactions

• -lactams synthesis, the Kinugasa reaction

R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.

NO

H

R R1

R2

H+

NLnCuO

R1

R2

R

NO

E

R R1

R2

E+

usualKinugasapathway

NArO

I

3.0 equiv

CuBr (5%)5a (5.5%)

OTMS

Ph2.0 equiv

KOAc (1.0 equiv)MeCN, r.t. N

O Ar

85%ee76%yield

S

NO

Ar

I

3.0 equiv

CuBr (5%)5a (5.5%)

OTMS

Ph2.0 equiv

KOAc (1.0 equiv)MeCN, r.t.

NO Ar

S

90%ee70%yield

Ar = p-carboethoxyphenyl

Ar = p-carboethoxyphenyl

Fe

P

Me

Me

Me

Me

Me

N

O

iPr

H

5a

65

Conclusion

MeOH

O

MeOMe

PhH

NTf

R1H

NTfO

Ar

R R1

NTsO

ArR1

R

NO

O

Ar

RBnO

O

NBn

O

PhOR

O

OO

PhOR

O

O

Me Oi-Pr

O

EtAr

NH

NC

R

Ar

O

N

NCO

C R

Ar

R

Ar

O

O

t-Bu

OHt-Bu

HN R1

N3H

MeO

O R H

R

CO2ArPh

OMe

O

RO H

ArOt-Bu

O

BocHN H

OCO2Ar

OTESR

N

R R1

O Ar

O

R

CO2CMeCy2O

R

CO2CMeCy2

NTs

R1H

• Nucleophilic catalysts

•Transition-metal ligands

• Building quaternary centers

•Brønsted acid catalyst