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

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

3. 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

4. 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

5. 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

6. 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.

7. 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

8. 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

9. Chem. Soc. Rev., 2011, 40, 1857–1869

10. 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

11. 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

13. 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

17. 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

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

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

20. Thank You For Listening
Any Questions?