Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem . Soc. 2012 , ASAP

18
Catalytic Enantioselective Cross- Couplings of Secondary Alkyl Electrophiles with Secondary Alkylmetal Nucleophiles Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP Lea Constantineau November 21, 2012 R 1 Br R n IZn racemic R 1 R O N t-Bu N ( S )- 1 n 10% NiBr 2 . glyme 13% ( S )- 1 1.2 C sIorM gI 2 CH 2 Cl 2 /dioxane -30 °C

description

Catalytic Enantioselective Cross-Couplings of Secondary Alkyl Electrophiles with Secondary Alkylmetal Nucleophiles. Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem . Soc. 2012 , ASAP. « CRAZY » COUPLINgS !!. Lea Constantineau November 21, 2012. - PowerPoint PPT Presentation

Transcript of Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem . Soc. 2012 , ASAP

Page 1: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Catalytic Enantioselective Cross-Couplings of Secondary Alkyl Electrophiles with Secondary

Alkylmetal Nucleophiles

Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP

Lea ConstantineauNovember 21, 2012

R1

Br

R n

IZnracemic

R1

R

O

N

t-Bu

N

(S)-1

n

10% NiBr2.glyme

13% (S)-1

1.2 CsI or MgI2CH2Cl2 / dioxane

-30 °C

Page 2: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

R2 Mn+2D

MnLn

R2

D

M2YX-M2-Y

R2

D

R1 R1

homocoupling

hydrideelimination

R2

LnMn+2

D

X

R2

D

M2Y

R2

D

D

proto-demetalation

LnMn+2

X

R1

XR1

hydrideelimination

R1

R1

R1

oxidativeaddition

transmetalation

reductive elimination

n is oxidation state

The Challenges of C(sp3)-C(sp3) Cross-Coupling

21) Jana,R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417.

Slow oxidative addition: Homocoupling or β-elimination of the electrophile Spontaneous decomposition of alkyl organometallics via β-elimination or proto-demetalation Slow transmetalation: needs of additives

Slow oxidative addition: Homocoupling or β-elimination of the electrophile Spontaneous decomposition of alkyl organometallics via β-elimination or proto-demetalation Slow transmetalation: needs of additives

Page 3: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

C(sp3)-C(sp3) Cross-Couplings in Total Synthesis

3

O

OHHO

Zoapatanol1O

B-alkyl Suzuki-Miyaura Coupling

1) Raghavan, S.; Babu, V. S. Chem. Eur. J. 2011, 17, 8487. 2) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124, 14983. 3) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756.

Gambierol2

B-alkyl Suzuki-Miyaura Coupling

OHO

O

O

O

H

OH

H H H O

O

O

O HHH

HHHMeMe

H MeMe

HMe

OH

Fluvirucininie A13

Me

OH

MeEt

NH

O

First Negishi Coupling

Second Negishi coupling

Page 4: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Examples of asymmetric Cross-Coupling with Alkylzinc Reagents

41) Fisher, C; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594. 2) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756.

RBrZn

racemic

10% NiCl2.glyme

13% (S,S)-Pybox

DMI/THF (7:1)

0 °C

R1, R = alkyl 51-90% yield77-96% ee

R1

Br 1.3 equiv

NBn

O

Ph

R1

R

NBn

O

Ph

NN

O

DMI

(S,S)-pybox

N

N

OO

N

iPr iPr

RBrZn

racemic

5% NiCl2.glyme

5.5% (S,S)-BnCH2-pybox

4.0 equiv NaCl

DMA/DMF (1:1), -10 °C

R1= alkyl, COR, CONR2

R2 ,R = alkyl

54-95% yield69-98% ee

R2

Br

R1

1,2 equiv

R2

R

R1

(S,S)-BnCH2-pybox

N

N

OO

N

BnBn

First Asymmetric Negishi Cross-Coupling

Page 5: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

MeN

O

Ph

PhMe

O

O

85% ee63% yield

MeN

O

Ph

Ph

90% ee54% yield

EtN

O

Ph

Ph

91% ee74% yield

OTBS4

EtN

O

Ph

Ph

90% ee63% yield

N6

EtN

O

Ph

Ph

84% ee70% yield

EtN

O

Ph

Ph

69% ee51% yield

CN4

n-BuN

O

Ph

Ph

90% ee64% yield

2

FN

O

Ph

Ph

OMe

88% ee83% yield

Ph

2

Only one Example of a Secondary-Secondary Cross-Coupling

5Zultanski, S. L.; Fu, G.C. J. Am. Chem. Soc. 2011, 133, 15362.

(9-BBN)

10% Ni.glyme

12%

KOtBu(1.4 equiv)

n-hexanol (1.8 equiv)

Et2O/hexanes (1:1)

r.t.

RR1

Cl

N

O

R1

R

N

OMeHN

Ph Ph

NHMePh

Ph

Ph

Ph

Page 6: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Cross-Couplings of Secondary Alkyl Electrophiles with Primary Alkylzinc Nucleophiles

61) Arp, F.O.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 10482. 2) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890.

RR1BrZn

racemic

R

(S,S)-pybox

10% NiBr2.glyme

13% (S,S)-pybox

N,N-dimethylacetamide

0 °C

Br

N

N

OO

N

i-Pr i-Pr

R1

R1 = primary alkyl47-89% yield

90% ee

1.6 equiv

R1

Br

R n

IZnracemic

R1R

nSame condition

<5% yield<80% ee

Alkylzinc reagents synthesis by Knochel’s method

Page 7: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Optimization of the Reaction

7

R1

Br

Rn

IZnracemic

R1R

n

10% NiBr2.glyme

13% (S)-1

1.2 CsI or MgI2CH2Cl2 / dioxane

-30 °C1.8 equiv

entry variation from the “Standard” conditions ee (%) yield (%)

1 (S)-4 instead of (S)-1 78 84

2 none 95 91

3 no NiBr2.glyme - <2

4 no (S)-1 - 9

5 no CsI 93 69

6 r.t. 72 20

7 5% NiBr2.glyme, 6.5% (S)-1 93 64

8 (S,S)-pybox instead of (S)-1 - <2

9 (S,S)-5 instead of (S)-1 55 9

O

N

t-Bu

N

(S)-1

O

N

t-Bu

N

(S)-4

N

OO

N

i-Pr i-Pr(S,S)-5

(S,S)-pybox

N

N

OO

N

i-Pr i-Pr

1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP. 2) Choi, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 9102. 3) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756.

Page 8: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Cross-Couplings of Secondary Alkyl Electrophiles with Secondary Alkylzinc Nucleophiles

8Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP

R1

Br

R n

IZn

racemic

R1R

O

N

t-Bu

N

(S)-1

n

10% NiBr2.glyme

13% (S)-1

1.2 CsI or MgI2CH2Cl2 / dioxane

-30 °C

1.8 equiv

Page 9: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Scope of the Reaction

9

R1

Br

Rn

IZnracemic

R1R

n

10% NiBr2.glyme

13% (S)-1

1.2 CsI or MgI2CH2Cl2 / dioxane

-30 °C1.8 equiv

O

N

t-Bu

N

(S)-1

1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP.

95% ee91% yield

95% ee72% yield

93% ee75% yield

87% ee48% yield

F

95% ee86% yield

MeOEt

91% ee65% yield

BnO

96% ee74% yield

95% ee80% yield

Et

91% ee51% yield

F3C

Ph92% ee

74% yield

Cl

91% ee74% yield

I

Et

92% ee68% yield

Br98% ee

79% yield

95% ee54% yield

O

Et

87% ee60% yield

Et

84% ee52% yield

MeO

Page 10: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Cross-Couplings of Secondary Alkyl Electrophiles with Acyclic Secondary Alkylzinc Nucleophiles

101) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP. 2) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532.

BrMe Me

IZn

racemic

MeMe10% NiBr2

.glyme

13% (S)-1

1.2 CsI or MgI2CH2Cl2 / dioxane

-30 °C1.8 equiv

Bn Bn Bn

Me

76 : 24branched59% ee

linear9% ee

O

N

t-Bu

N

(S)-1

Br

IZn

racemic

MeMe10% NiBr2

.glyme

13% (S)-1

1.2 CsI or MgI2CH2Cl2 / dioxane

-30 °C1.8 equiv

Bn BnBn

Me

62 : 38 branched76% ee

linear9% ee

Me

First time that a branched product is formed from a linear alkylmetal compound.2

Page 11: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Possible Mechanism for Nickel-catalyzed Secondary-Secondary Cross-Couplings

11Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP 2) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532.

L*NiI-XRR1

oxidativeaddition

transmetalationreductive elimination

IZn R

L*NiI

MeL*NiI

Me

Me

R1 Br

L*NiIII R1

R

Br

R = i-Pr or n-Pr

O

N

t-Bu

N

L*

L*NiI

Me

HH

H

L*NiI

H

Me

L*NiI CH2

HMe

L*NiIMe

H

L*NiI

H

Me

HH

-hydride elimination

-hydride elimination

-migratory insertion

-migratory insertion

branchedlinear

Isomerisation: β-hydride elimination and β-migratory insertion

Use of a bidentate, rather than tridentate, ligand

Transmetalation occuring before oxidative addition (NiI catalyzed)

Isomerisation: β-hydride elimination and β-migratory insertion

Use of a bidentate, rather than tridentate, ligand

Transmetalation occuring before oxidative addition (NiI catalyzed)

Page 12: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Syn Selective mechanism

121) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP.

R1

Br

racemic

R1

10% NiBr2.glyme

13% L*

1.2 CsI or MgI2CH2Cl2 / dioxane

-30 °C

D

D ZnI

95% yield97% ee

Five isomersD and 1-phenylethyl: trans

L*NiI L*NiI

H

L*NiI

L*NiI

-hydride elimination

-hydride elimination

-migratory insertion

-migratory insertion

D

D

D

H L*NiIH L*NiIH L*NiIH L*NiIH

D D D D D

The β-hydride elimination and β-migratory insertion are Syn specific D always trans from the Nickel

Reaction with 0.5 equiv of cyclopentene did not give incorporation of unlabeled cyclopentane

The β-hydride elimination and β-migratory insertion are Syn specific D always trans from the Nickel

Reaction with 0.5 equiv of cyclopentene did not give incorporation of unlabeled cyclopentane

Page 13: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Conclusion

13

New enantioselective cross-coupling of secondary electrophiles with secondary alkylzinc reagents.

New class of ligand was used (Usually Negishi reactions are done with Pybox ligand).

Discovery of a unusual isomerization: formation of a branched product from a linear alkylzinc reagents.

O

N

t-Bu

N

(S)-1

Br

IZn

racemic

MeMe10% NiBr2

.glyme

13% (S)-1

1.2 CsI or MgI2CH2Cl2 / dioxane

-30 °C1.8 equiv

Bn BnBn

Me

62 : 38 branched76% ee

linear9% ee

Me

R1

Br

Rn

IZnracemic

R1

R

n

10% NiBr2.glyme

13% (S)-1

1.2 CsI or MgI2CH2Cl2 / dioxane

-30 °C1.8 equiv

Page 14: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

Entry Ar alkyl alkyl1 ee (%) yield (%)

1 ph Me 80 68

3 ph n-Bu 82 64

5 Me 66 62

6Et

85 74

First Asymmetric Suzuki-Miyaura Cross-Coupling of an Unactived Secondary Alkyl Halide

14

(9-BBN)

10% Ni(cod)2

12% (R,R)-1

KOtBu(1.2 equiv)iBuOH (2.0 equiv)

iPr2O, 5 °C

alkyl1Ar

alkyl

Br

Aralkyl

alkyl1

MeHN NHMe

F3C CF3

(R,R)-1

Ph

OTBS

OTBSO

O

O

OMe

OMe

Saito, B. Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694.

Page 15: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

β-hydride elimination and β-migratory insertion

15

L*NiI

Me

HH

H

L*NiI

H

Me

L*NiI

H

Me

L*NiI CH2

HMe

L*NiIMe

H

L*NiI

H

Me

HH

-hydride elimination

-hydrideelimination

-migratory insertion-migratory insertion

branched

linear

Use of a bidentate, rather than tridentate, ligand Transmetalation occuring before oxidative addition

Use of a bidentate, rather than tridentate, ligand Transmetalation occuring before oxidative addition

1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP. 2)

Page 16: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

16

Page 17: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

17

Page 18: Binder, J. T.; Cordier, C. J.; Fu, G. C.  J. Am.  Chem . Soc.  2012 , ASAP

C(sp3)-C(sp3) Cross-Couplings in Total Synthesis

18

O

OHHO

Zoapatanol1O

B-alkyl Suzuki-Miyaura Coupling

1) Raghavan, S.; Babu, V. S. Chem. Eur. J. 2011, 17, 8487. 2) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124, 14983

Gambierol2

B-alkyl Suzuki-Miyaura Coupling

OHO

O

O

O

H

OH

H H H O

O

O

O HHH

HHHMeMe

H MeMe

HMe

OH

alkyl1R

alkyl

Br

Ralkyl

Suzuki-MiyauraCross-Coupling

9-BBN alkyl1