1. 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

2. The Challenges of C(sp 3 )-C(sp 3 ) Cross-Coupling 2 1) 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

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

4. Examples of asymmetric Cross-Coupling with Alkylzinc Reagents 4 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. First Asymmetric Negishi Cross-Coupling

5. Only one Example of a Secondary-Secondary Cross-Coupling 5 Zultanski, S. L.; Fu, G.C. J. Am. Chem. Soc. 2011, 133, 15362.

6. Cross-Couplings of Secondary Alkyl Electrophiles with Primary Alkylzinc Nucleophiles 6 1) Arp, F.O.; Fu, G.C. J. Am. Chem. Soc. 2005, 127, 10482. 2) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890. Alkylzinc reagents synthesis by Knochel’s method

7. Optimization of the Reaction 7 entryvariation from the “Standard” conditionsee (%)yield (%) 1(S)-4 instead of (S)-17884 2none9591 3no NiBr 2. glyme-<2 4no (S)-1-9 5no CsI9369 6r.t.7220 75% NiBr 2. glyme, 6.5% (S)-19364 8(S,S)-pybox instead of (S)-1-<2 9(S,S)-5 instead of (S)-1559 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.

8. Cross-Couplings of Secondary Alkyl Electrophiles with Secondary Alkylzinc Nucleophiles 8 Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP

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

10. Cross-Couplings of Secondary Alkyl Electrophiles with Acyclic Secondary Alkylzinc Nucleophiles 10 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. First time that a branched product is formed from a linear alkylmetal compound. 2

11. Possible Mechanism for Nickel-catalyzed Secondary-Secondary Cross-Couplings 11 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.  Isomerisation: β-hydride elimination and β- migratory insertion  Use of a bidentate, rather than tridentate, ligand  Transmetalation occuring before oxidative addition (Ni I catalyzed)  Isomerisation: β-hydride elimination and β- migratory insertion  Use of a bidentate, rather than tridentate, ligand  Transmetalation occuring before oxidative addition (Ni I catalyzed)

12. Syn Selective mechanism 12 1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP.  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

13. 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.

14. EntryAralkylalkyl 1 ee (%)yield (%) 1 ph Me8068 3 ph n-Bu8264 5Me6662 6 Et 8574 First Asymmetric Suzuki-Miyaura Cross-Coupling of an Unactived Secondary Alkyl Halide 14 Saito, B. Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694.

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

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