Lecture8: 123.702

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MacMillan's synthesis, highlighting the use of organocatalysis.

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Lecture8: 123.702

  1. 1. LECTURE EIGHT callipeltoside C gareth j rowlands ©oxmox@flickr
  2. 2. OH MeO OH O O H O H OH callipeltoside C MeO O O Cl Angew. Chem. Int. Ed., 2008, 47, 3568 ©Islands in the Stream Expedition 2002. NOAA Office of Ocean Exploration
  3. 3. anti-tumor activity ©mararie@flickr
  4. 4. retrosynthesis OH MeO OH O O H glycosylation remove sensitive O sugar H OH MeO O O Cl simplification
  5. 5. retrosynthesis Yamaguchi OH lactonisation form macrocycle by esterification O H OH MeO O O Cl allows molecule to be split into fragments
  6. 6. retrosynthesis OH CO2H O H OH chelation controlled MeO OH alkylation Cl divide in ha lf
  7. 7. retrosynthesis OH CO2H O H OH chelation controlled MeO OH alkylation Cl divide in ha lf
  8. 8. 3 targets OH MeO OH OH MeO OH OH HO O H O O H O CO2H H OH O MeO H OH O O O X Cl OH Cl
  9. 9. synthesis may change order ©YaniG@flickr
  10. 10. Horner-Wadsworth- X Emmons OH Cl organocatalysis MeO I MeO P OH Cl O O I retrosynthesis bottom half O
  11. 11. Semmelhack cyclisation OH OH OH 5 1 PGO 7 5 7 3 CO2Me 3 O H OH O retrosynthesis middle section
  12. 12. difficult to see seeforward reaction ©bitterlysweet@flickr
  13. 13. OH OH PGO retrosynthesis middle section
  14. 14. OH OH PGO pattern retrosynthesis recognition middle section
  15. 15. OH O R1 R2 think aldol ©lecates@flickr
  16. 16. alkylkation substrate OH OH control OH O PGO PGO aldol organocatalysis O O retrosynthesis PGO middle section
  17. 17. retrosynthesis sugar section OH MeO OH HO O H
  18. 18. retrosynthesis sugar section OH MeO OH HO O H aldol
  19. 19. retrosynthesis sugar section OH MeO OH HO O H aldol
  20. 20. OH OH MeO OH FGI MeO OTIPS C–C HO O HO O H H OTIPS aldol chelation control O MeO OTIPS retrosynthesis TESO TIPSO sugar section OTIPS
  21. 21. O O OTIPS C–C OTIPS TIPSO O OTIPS OTIPS aldol organocatalysis retrosynthesis sugar section
  22. 22. the synthesis ©Time Inc
  23. 23. the synthesis ©euthman@flickr
  24. 24. synthesis I OH bottom half Cl 1. AlMe3, ....Cp2ZrCl2 then I2 2. (COCl)2, I OH ....DMSO, Et3N O
  25. 25. Negishi carbometallation- iodination mechanism complex! ©Toby Maloy@flickr
  26. 26. R H R H Cl Cl Me δ– Cl Al Me Zr Cp Zr Al Me δ+ Cl Me Me Me Cp R H R H I2 Me I Me AlMe2 possible mechanis m
  27. 27. OH organocatalysis MeO OH O O H O H OH MeO O O Cl
  28. 28. synthesis I OH bottom half Cl N CO2H I H I NHPh PhNO O O 99%ee O see lecture six
  29. 29. synthesis I OH bottom half Cl 1. NaBH4 2. Zn, AcOH 3. Bu2Sn(OMe)2, PMBCl I NHPh I O 4. TBSCl, imidazole OTBS O 62% OPMB Bu I Bu O Sn O PG
  30. 30. synthesis OH of middle section CO2Me O H OPG PGO PMBO O N CO2H PMBO OH O H O 99%ee 12:1 syn:anti see lecture six
  31. 31. synthesis OH of middle section CO2Me O H OPG PGO Br PMBO OH OH PMBO OH O Zn 98% 6:1 syn
  32. 32. PMBO OH OH Me O Me OH R R HH H H Zn Felkin-Ahn substrate control
  33. 33. synthesis OH O of middle section H O OMe OMe PMBO [PdCl2(MeCN)2] CO, MeOH OH PMBO OH OH O O O 75% O OMe 20:1dr H OMe PMBO
  34. 34. nightmare mechansim ©New Line Cinema
  35. 35. HO OH HO Pd2+ O O Pd0 HO Pd2+ O O OMe MeOH O Pd+ O O Pd+ C O Pd2+ O O O O OMe O OMe O OMe Pd2+ Pd+ OMe MeOH
  36. 36. synthesis OTBS of middle section CO2Me O H OMe O 1. TBSCl OH OTBS 2. DDQ 3. SO3•pyr, O ....DMSO, Et3N CO2Me O OMe 80% O H OMe H OMe PMBO O NC O Cl NC OMe Cl O
  37. 37. I OTBS OTBS OPMB CO2Me O H OMe BrMg OTBS O OPMB MgBr•Et2O OH 98% OH MeO 16:1dr O H O OTBS O H OH O O MeO Cl CO2Me O H OMe synthesis HO OTBS OPMB callipeltoside C
  38. 38. I OTBS OTBS OPMB CO2Me O H OMe BrMg OTBS O OPMB MgBr•Et2O OH 98% OH MeO 16:1dr O H O OTBS O H OH O O MeO Cl CO2Me O H OMe chelation HO OTBS OPMB control
  39. 39. synthesis MeO OH OH callipeltoside C O H O O H OH MeO O O Cl OTBS OTBS 1. MeOTf, base 2. DDQ 3. SO3•pyr, CO2Me ....DMSO, Et3N CO2Me O O H OMe 84% H OMe HO OTBS MeO OTBS OPMB O
  40. 40. synthesis MeO OH OH callipeltoside C O H O O H OH MeO O O OTBS Cl OTBS CO2Me O 1. HWE H OMe 2. TBAF CO2H 3. Ba(OH)2 O MeO OTBS H OMe O 84% MeO OH MeO Cl MeO P Cl O Org. Lett., 2001, 3, 503
  41. 41. synthesis aglycone OTBS OTBS CO2H 2,4,6-Cl3C6H2COCl, O iPr2NEt, DMAP O H OMe H MeO OH 83% MeO O O Cl Cl
  42. 42. synthesis aglycone OTBS OH 1. PPh3•HBr, H2O O 2. TFA O H H OH MeO O O 81% MeO O O Cl Cl
  43. 43. sugar OH MeO OH portion HO O H
  44. 44. disaster OH MeO OH O O H O H OH MeO O O Cl ©dawn m. armfield@flickr
  45. 45. real sugar portion OH MeO OH HO O
  46. 46. synthesis of sugar MeO OH OH HO O O N CO2H O OH OTIPS H O 75% 99%ee TIPSO OTIPS OTIPS see lecture six
  47. 47. synthesis of sugar MeO OH OH HO O OTES OH OMe MgBr2•OEt2 MeO OTIPS O OH 47% >20:1dr HO O TIPSO TIPSO OTIPS substrate control
  48. 48. synthesis of sugar MeO OH OH HO O OTES OH OMe MgBr2•OEt2 MeO OTIPS O OH 47% >20:1dr HO O TIPSO TIPSO OTIPS substrate control
  49. 49. TIPSO O OH TIPSO R R MeO MeO H HH H H TESO O ≡ OH O OH OH MeO OTIPS HO O OMe OTIPSOTIPS OTIPS
  50. 50. synthesis of sugar MeO OH OH HO O 1. AcCl, BnOH OH 2. PhOC(S)Cl 3. Bu3SnH, AIBN O MeO OTIPS 4. DMP MeO OTIPS HO O 47% BnO O TIPSO Ac A cO O Ac O I O O
  51. 51. synthesis of sugar 1. MeMgBr, ....MgBr2•OEt2 O OH 2. H2, Pd/C then MeO OTIPS ....Cl3CCN MeO OTIPS CCl3 86% BnO O HN O O
  52. 52. endgame synthesis callipeltoside C OH OH MeO OH MeO OTIPS CCl3 OH O O HN O O 1. TMSOTf 2. TASF O H OH 63% O H OH MeO O O MeO O O Cl Cl
  53. 53. 18-steps longest linear 12% sequence O PMBO H corrected stereochemistry

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