1. Organic Pedagogical Electronic Network Applications of C–H Functionalization in Total Synthesis Sorensen Lab, Princeton University

2. Approaches to (–)-tetrodotoxin ■ Highly functionalized/oxidized architecture has inspired many synthetic approaches ■ The mild and chemoselective nature of C–H functionalization methods reduces or removes the need for protecting groups in synthetic planning Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219-9221. Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 9798-8805. Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511. Sato, K.-i.; Akai, S.; Shoji, H.; Sugita, N.; Yoshida, S.; Nagai, Y.; Suzuki, K.; Nakamura, Y.; Kajihara, Y.; Funabashi, M.; Yoshimura, J. J. Org. Chem. 2008, 73, 1234-1242.

3. Du Bois Synthesis of (–)-tetrodotoxin Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511 ■ Selection of D-isoascorbic acid introduced two stereocenters ■ Early incorporation of requisite oxidation obviated need to perform oxidations in subsequent steps ■ C-H functionalization establishes two key stereocenters utilizing pre-existing functional group handles

4. Approaches to (+)-lithospermic acid ■ C-H functionalization features prominently in both approaches ■ Yu chemistry offers potentially greater flexibility toward lithospermic acid framework ■ Yu synthesis does not require the installation and removal of unnecessary functional groups to direct C-H functionalization events Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767-5769. O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 13496-13497. Wang, H.; Li, G.; Engle, K. M.; Yu, J.-Q.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 6774-6777.

5. Yu Synthesis of (+)-lithospermic acid Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767-5769

6. Approaches to (–)-colombiasin A and (–)-elisapterosin B Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485-2490. Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Angew. Chem. Int. Ed. 2001, 40, 2482-2486. Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Chem. Eur. J. 2001, 7, 5359-5371. Kim, A. I.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2003, 42, 1267-1270. Harrowven, D. C.; Pascoe, D. D.; Demurtas, D.; Bourne, H. O. Angew. Chem. Int. Ed. 2005, 44, 1221-1222.

7. Davies Synthesis of (–)-colombiasin A and (–)-elisapterosin B Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485-2490 ■ Catalyst control of C-H insertion/Cope reaction process leads to a fortuitous resolution of racemic starting material! Enantiotopic C-H bonds lead to two very different products!

8. Questions 1. What potential advantages does the use of C-H functionalization provide a synthetic chemist? 2. Propose a full, arrow-pushing mechanism for the C-H insertion/Cope reaction utilized by the Davies lab in their syntheses of colombiasin and elisapterosin.