Sorensen’s Enantioselective Total Synthesis of FR182877

1. Sorensen’s Enantioselective Total Synthesis of FR182877 Presented by BriAnneBentivegna Vanderwal, C.D.; Vosburg, D.A.; Weiler, S.; Sorensen, E.J. J. Am. Chem. Soc. 2003, 125, 5393

2. Erik J. Sorensen • B.A. in Chemistry from Syracuse University (1989) • Researched under Roger Hahn • PhD from K. C. Nicolaou at the University of California, San Diego (1995) • Post Doctoral Fellow with Samuel Danishefsky at The Memorial Sloan-Kettering Cancer Center in New York (1995-1997) • Began his independent career at The Scripps Research Institute (1997) • Achieved Tenure (2001) • Moved to Princeton University (2003) • Arthur Allan Patchett Professor in Organic Chemistry • Awards: Arthur C. Cope Scholar Award from ACS, Pfizer Global Research Award for Excellence in Organic Chemistry, Woodward Scholar at Harvard University, Beckman Young Investigator Award and many more http://www.princeton.edu/~ejsgroup/ejs.html

3. FR182877 • Isolated from the fermentation broth of Streptomyces sp. No9885 in 1988 • Constitution and relative stereochemistry determined by NMR and X-ray crystallography • Absolute stereochemistry determined by advanced Mosher ester analysis • Initial absolute proposed was (+)-1; later changed to (-)-1 • Part of family of secondary metabolites that bind and stabilize cellular microtubules • Other Members: Taxol, Discodermolide, Epothilones • Shown to have similar activity to Taxol • Potential as chemotherapeutic agent • Has 12 stereocenters and strained bridgehead olefin that’s part of carbonate moiety • Synthesized because of its biological activity and reactivity of its strained olefin Taxol FR182877 Discodermolide Epothilone A Images Source: Wikipedia H. Muramatsu, M. Miyauchi, B. Sato, S. Yoshimura, 40th Symposium on the Chemistry of Natural Products (Fukuoka, Japan), 1998, Paper 83, p. 487

4. Retro Synthesis of FR182877

5. The Beginning Hϋnig’s Base

6. Synthesis of 19-Membered Macrocycle Hϋnig’s Base Canonica, L.; Rindone, B.; Santaniello, E.; Scolastico, C. Tetrahedron1972, 28, 4395

7. Tandem Transannular Diels-Alder Reactions 7 NEW STEREOCENTERS FORMED!!!

8. The Final Steps! 2.09% Yield 22 Linear Steps

9. Large Scale Synthesis of the 19-Membered Macrocycle Used opposite enantiomers of small scale synthesis since it was found that the initially assigned absolute stereochemistry was incorrect!

10. Large Scale Synthesis of (-)-FR182877 a (a) NaHMDS, PhSeBr, <1 min, 23 °C, 89%, 10:1 dr. (b) mCPBA, CH2Cl2, -78 °C. (c) NaHCO3, CHCl3, 45 °C, 4 h, 61-66% of ent-62 over two steps (8-15% each of 63 and 64 also isolated). (d) PPTS, MeOH, 0 f 23 °C, 100%. (e) TFA/CH2Cl2 (1:9), 0 f 23 °C, 96%. (f) N-methyl-2-chloropyridinium iodide, Et3N, CH2Cl2/MeCN (9:1), 23 °C, 60% + 21% recovered starting material.

11. Conclusion • Both (+)-FR182877 and (-)-FR182877were synthesized • (-)-FR182877, the natural enantiomer, was synthesized on a large scale yielding 100 mg • There are 22 linear steps with 2.09% yield (+)-FR182877 (-)-FR182877

12. Synthesis of “Known Aldehyde” Canonica, L.; Rindone, B.; Santaniello, E.; Scolastico, C. Tetrahedron1972, 28, 4395