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Total Synthesis of Rapamycin

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.

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Total Synthesis of Rapamycin

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  1. Total Synthesis of Rapamycin Isolation and Structure Determination: Vézina, C.; Kudelski, A.; Sehgal, S. N. J. Antibiotics1975, 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 rapamycin FK-506 cyclosporin A

  3. Rapamycin’s Mechanism of Action The Cell Cycle IL-2 Receptor Restriction Point ? G1 p70 S6 Kinase S G0 Cdc2 Kinase M G2 40S Ribosomal Protein S6 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. Cell1992, 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 rapamycin EABD

  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 ofRapamycin 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 DiastereomerEmployed 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 Rapamycinand Demethoxyrapamycin:Introduction of the Tricarbonyl Segment

  35. CO H 2 1) DIBAL (98%) 2 equiv. LHMDS, THF 2) Swern [O] (80%) -78 °C (80%) Tricarbonyl Formation I O TBSO OMe 1) NaH, MeI, 15-crown-5 (80%) O O TBSO O O OH 2) HOAc, H O,THF (86%) 2 TMS 3) TBSCl, imid. (97%) TMS 1) N E O TBSO OMe OHC 2) Allylbromide, K2CO3 TMS DMF (98%) O O O OH TBSO OMe N 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 Rapamycinand 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.

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