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

The Challenges of C(sp 3 )-C(sp 3 ) Cross-Coupling    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 1) Jana,R.; Pathak, T. P.; Sigman, M. S.

Chem. Rev. 2011 ,

111

, 1417.

2

C(sp 3 )-C(sp 3 ) Cross-Couplings in Total Synthesis 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. 3

Examples of asymmetric Cross-Coupling with Alkylzinc Reagents First Asymmetric Negishi Cross-Coupling 1) 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.

4

Only one Example of a

Secondary

-

Secondary

Cross-Coupling Zultanski, S. L.; Fu, G.C. J. Am. Chem. Soc. 2011 ,

133

, 15362. 5

Cross-Couplings of

Secondary

Alkyl Electrophiles with

Primary

Alkylzinc Nucleophiles Alkylzinc reagents synthesis by Knochel ’s method 1) Arp, F.O.; Fu, G.C. J. Am. Chem. Soc. 2005 ,

127

, 10482. 2) Krasovskiy, A.; Knochel, P.

Synthesis 2006,

890

.

6

Optimization of the Reaction

entry

1 4 5

2

3 6 7 8 9

variation from the “Standard” conditions

(

S

)-

4

instead of (

S

)-

1 none

no NiBr 2

.

glyme no (

S

)-

1

no CsI r.t.

5% NiBr 2

.

glyme, 6.5% (

S

)-

1

(

S,S

)-

pybox

instead of (

S

)-

1

(

S,S

)-

5

instead of (

S

)-

1 ee (%)

78

95

93 72 93 55

yield (%)

84

91

<2 9 69 20 64 <2 9 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.

7

Cross-Couplings of

Secondary

Alkyl Electrophiles with

Secondary

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

Scope of the Reaction 1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012 , ASAP. 9

Cross-Couplings of

Secondary

Alkyl Electrophiles with Acyclic

Secondary

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

2 1) 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.

10

Possible Mechanism for Nickel-catalyzed

Secondary

-

Secondary

Cross-Couplings  Isomerisation: β-hydride elimination and β migratory insertion  Use of a bidentate, rather than tridentate, ligand  Transmetalation occuring before oxidative addition (Ni I catalyzed) 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.

11

Syn

Selective mechanism  The  β-hydride elimination and β-migratory insertion are D always

trans

from the Nickel

Syn

specific  Reaction with 0.5 equiv of cyclopentene did not give incorporation of unlabeled cyclopentane 1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012 , ASAP. 12

Conclusion  New enantioselective cross-coupling of

secondary secondary

alkylzinc reagents.

electrophiles with  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.

13

First Asymmetric Suzuki-Miyaura Cross-Coupling of an Unactived

Secondary

Alkyl Halide

Entry Ar alkyl

1 3 5 ph ph Me n-Bu Me 6 Et Saito, B. Fu, G. C. J. Am. Chem. Soc. 2008 ,

130

, 6694.

alkyl 1 ee (%)

80 82 66 85

yield (%)

68 64 62 74 14

β-hydride elimination and β-migratory insertion   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) 15

16

17

C(sp 3 )-C(sp 3 ) Cross-Couplings in Total Synthesis 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 18