Site–Selective and Stereoselective Functionalization of Unactivated C–H Bonds Presented by Arianne Hunter Sharma Lab Literature Meetings August 27th 2016

Mechanism of the Week Reference: J. Org. Chem., 44(25), 1979, (4742–4744)

C–H Activation Chem. Soc. Rev., 2011, 40, 1857–1869 The synthesis of complex organic molecules requires introduction and manipulation of various functional groups By providing the tools to functionalize C–H bonds selectively in the midst of a complex molecule, the synthetic chemists tool kit will become far more valuable Chem. Soc. Rev., 2011, 40, 1857–1869

What is Metal Carbene C–H Activation Catalytically generated metal carbenes are highly versatile for insertion into carbon–hydrogen and heteroatom–hydrogen bonds C–H bond insertions are mechanistically different from X–H bond insertions due to their low bond polarity

The character of the metal center greatly effects selectivity Mechanistic Insight MECHANISM: Metal carbene’s p orbital overlaps with the σ orbital of the reacting C–H bond. The character of the metal center greatly effects selectivity

Effects of Metal on Selectivity Increased electron withdrawal by the ligand from the metal increases the electrophilicity of the carbene and causes bond formation to take place at a greater distance from the reacting C–H bond resulting in lower selectivity.

Problems with C–H Activation A key challenge in C–H functionalization is achieving high selectivity Selectivity in intermolecular reactions is highly difficult unless donor/acceptor carbenes are used Donor group stabilizes electron deficient carbene and stabilizes its reactivity Also, control of C–H functionalization is challenging due to an organic substrate having many different C–H bonds Chem. Soc. Rev., 2011, 40, 1857–1869

Increasing Selectivity in C–H Activation Donor/acceptor rhodium carbenes are sensitive to both steric and electronic factors From the reacting substrate and the employed catalyst Sites that stabilize positive charge are very susceptible to C–H activation But due to the typical bulkiness of dirhodium catalysts sterics also play a hand in reactivity Chem. Soc. Rev., 2011, 40, 1857–1869

Chem. Soc. Rev., 2011, 40, 1857–1869

Recent Advances Nature, 2016, 533, 230–234 Recently Davies has pioneered advancements toward high selectivity in C–H activation through catalyst control Rh2(S-DOSP)4 prefers functionalization at secondary and tertiary C–H bonds Rh2(R-p-PhTPCP)2 prefers functionalization at primary C–H bonds Nature, 2016, 533, 230–234

TPCP Ligands and Selectivity Electronic and steric biases in the reacting substrate can be overcome through use of the sterically demanding triphenylcyclopropane carboxylate (TPCP) ligand. These bulky ligands favor functionalization at less crowded C–H bonds (Trichloroethyl [TCE] esters were used to limit intramolecular C-H activation of ester to form beta- lactone) J. Am. Chem. Soc. 2016, 138, 5761−5764

The Optimal TPCP Ligand for 2º Unactivated C–H Bond Functionalization The Davies Group synthesized a variety of TPCP ligands and found the optimal catalyst was Rh2[R-3,5-di(p-tBuC6H4)TPCP]4 Provided the highest selectivity for secondary C–H functionalization and gave the best d.r. and e.e. Gave prime selectivity in reactions with modifications at diazo ester, diazo aromatic, and alkyl group of the reacting substrate Nature, 2016, 533, 230–234

Application of Methodology The biggest complaint received when developing methodology, especially in the field of C–H activation, is the lack of applicability. Davies has shattered this perception by applying his methods in key steps toward the total synthesis of natural products In an unprecedented (in synthetic organic chemistry) multi-lab collaboration, Sorensen (Princeton), Davies (Emory), and Yu (Scripps) rapidly assembled the tricyclic core of indoxamycins using their respective specialties Angew. Chem. Int. Ed. 2016, 55, 8270 –8274

Angew. Chem. Int. Ed. 2016, 55, 8270 –8274

Angew. Chem. Int. Ed. 2016, 55, 8270 –8274

Thank You For Listening Any Questions?