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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. « CRAZY » COUPLINgS !!. Lea Constantineau November 21, 2012.

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

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  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 « CRAZY » COUPLINgS!! Lea Constantineau November 21, 2012

  2. The Challenges of C(sp3)-C(sp3) 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.

  3. C(sp3)-C(sp3) 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.

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

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

  6. 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. Synthesis2006, 890.

  7. Optimization of the Reaction 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 Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP

  9. Scope of the Reaction 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 First time that a branchedproductisformedfrom a linearalkylmetal 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.

  11. 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 (NiI 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.

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

  13. Conclusion • New enantioselective cross-coupling of secondaryelectrophileswithsecondaryalkylzincreagents. • New class of ligand wasused (UsuallyNegishireactions are donewithPybox ligand). • Discovery of a unusualisomerization: formation of a branchedproductfrom a linearalkylzincreagents.

  14. First Asymmetric Suzuki-Miyaura Cross-Coupling of an Unactived Secondary Alkyl Halide Saito, B. Fu, G. C. J. Am. Chem. Soc.2008, 130, 6694.

  15. β-hydride elimination and β-migratory insertion • Use of a bidentate, rather than tridentate, ligand • Transmetalationoccuring before oxidative addition 1) Binder, J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, ASAP. 2)

  16. C(sp3)-C(sp3) 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

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