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 2 1) Jana,R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,  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

C(sp 3 )-C(sp 3 ) Cross-Couplings in Total Synthesis 3 1) Raghavan, S.; Babu, V. S. Chem. Eur. J. 2011, 17, ) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124, ) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756.

Examples of asymmetric Cross-Coupling with Alkylzinc Reagents 4 1) Fisher, C; Fu, G. C. J. Am. Chem. Soc. 2005, 127, ) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, First Asymmetric Negishi Cross-Coupling

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

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

Optimization of the Reaction 7 entryvariation from the “Standard” conditionsee (%)yield (%) 1(S)-4 instead of (S) none9591 3no NiBr 2. glyme-<2 4no (S)-1-9 5no CsI9369 6r.t % NiBr 2. glyme, 6.5% (S) (S,S)-pybox instead of (S)-1-<2 9(S,S)-5 instead of (S) ) 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, ) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756.

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

Scope of the Reaction 9 1) 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 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, First time that a branched product is formed from a linear alkylmetal compound. 2

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,  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)

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

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.

EntryAralkylalkyl 1 ee (%)yield (%) 1 ph Me ph n-Bu8264 5Me 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.

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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C(sp 3 )-C(sp 3 ) Cross-Couplings in Total Synthesis 18 1) Raghavan, S.; Babu, V. S. Chem. Eur. J. 2011, 17, ) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124, 14983