1. Total Synthesis of Rapamycin Isolation and Structure Determination: Vézina, C.; Kudelski, A.; Sehgal, S. N. J. Antibiotics 1975, 28, 721. Swindells, D. C. N.; White, P. S.; Findlay, J. A. Can. J. Chem. 1978, 56, 2491. Findlay, J. A.; Radics, L. Can. J. Chem. 1981, 59, 49. McAlpine, J. B.; Swanson, S. J.; Jackson, M.; Whittern, D. N. J. Antibiotics 1991, 44, C-3. Total Syntheses: Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. 1993, 115, 4419. Hayward, C. M.; Yohannes, D.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 9345. Romo, D.; Meyer, S. D.; Johnson, D. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 7906. Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1995, 117, 5407-5408.

2. Immunomodulators rapamycinFK-506 cyclosporin A

3. Rapamycin’s Mechanism of Action IL-2 Receptor ? p70 S6 Kinase The Cell Cycle G0 G1 G2 M S Restriction Point 40S Ribosomal Protein S6 Cdc2 Kinase Schreiber, S.L.; Albers, M. W.; Brown, E. J. Acc. Chem. Res. 1993, 26, 412. Chung, J.; Kuo, C. J.; Crabtree, G. R.; Blenis, J. Cell 1992, 69, 1227.

4. KCN's Retrosynthetic Analysis of Rapamycin rapamycin

5. Synthesis of Oxazolidone A

6. Synthesis of Oxazolidone A (continued)

7. KCN's Retrosynthetic Analysis of Rapamycin rapamycin

8. Synthesis of Subunit B Z-enolate

9. Synthesis of Subunit B (continued)

10. KCN's Retrosynthetic Analysis of Rapamycin rapamycin

11. Synthesis of Vinyliodide D

12. Synthesis of Vinyliodide D (continued)

13. KCN's Retrosynthetic Analysis of Rapamycin rapamycin

14. The Union of A + B + E

15. Elaboration of EAB

16. The Introduction of D EABD rapamycin

17. The End Game – Tricarbonyl Formation Note: the first HF step removes the TES groups and the second HF step removes the TIPS groups

18. The End Game – The “Stitching” Stille Reaction rapamycin

19. Summary Completed the first total synthesis of (-)-rapamycin. –The longest linear sequence from an article of commerce consists of thirty-seven steps. –The longest linear sequence from our five sub-targets is sixteen steps. –Total steps: 102 Instructional applications of the Stille reaction, oxidation chemistry, chiral auxiliaries, organosilicons, protective groups, etc.

20. Smith’s Retrosynthetic Analysis of Rapamycin and Demethoxyrapamycin

21. Synthesis of Iodide A

22. Synthesis of Dithiane B

23. Synthesis of Dithiane C

24. Retrosynthetic Analysis of Rapamycin

25. Synthesis of the Ortho Ester Exploitation of Alternate Ortho Ester Diastereomer Employed in Smith’s Latrunculin Synthetic Venture

26. Synthesis of the E and Z Eneynes

27. Mechanism of Olefin Isomerization

28. Stereochemistry of Eneyne Addition to Aldehyde

29. Synthesis of Dienylstannane D

30. Retrosynthetic Analysis of Rapamycin

31. Construction of a C27-C42 Aldehyde

32. Construction of the C22-C42 Subunit

33. Synthesis of Demethoxyrapamycin: Construction of Advanced ABC Intermediate

34. Retrosynthetic Analysis of Rapamycin and Demethoxyrapamycin: Introduction of the Tricarbonyl Segment

35. Tricarbonyl Formation I TBSO O O OMe TMS OHC TBSOOMe TMS O O OOH NCO 2 H O TBSOOMe TMS N OO OOH 1) 2) HOAc, H 2 O,THF (86%) 3) TBSCl, imid. (97%) 1) DIBAL (98%) 2) Swern [O] (80%) 2) Allylbromide, K 2 CO 3 DMF (98%) 2 equiv. LHMDS, THF -78 °C (80%) E 1) NaH, MeI, 15-crown-5 (80%) TMS

36. Tricarbonyl Formation II

37. Pipecolinyl Acylation

38. Proposed Endgame: Bis-Hydrostannylation

39. Attempted Macrocyclizations

40. Preparation of ABC vinylstannane & DE vinyl iodide

41. Proposed Endgame Strategy for the Total Synthesis of Rapamycin and Demethoxyrapamycin

42. Macrocyclization

43. Demethoxyrapamycin

44. Rapamycin

45. Summary Developed a highly convergent and efficient total synthesis of (-)-rapamycin. –The longest linear sequence from an article of commerce consists of thirty-three steps. –The longest linear sequence from our five sub-targets is fourteen steps. –After the coupling of the C(1)-C(20) fragment to the C(22)- C(42) fragment only three steps are required to complete the synthesis. Completed the first total synthesis of demethoxyrapamycin. –The synthesis serves as a structure proof. –The synthesis establishes our unified synthetic approach as being amenable to the preparation of analogs.