Lecture10: 123.702


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A look at epothilone A as it includes examples of many different forms of asymmetric synthesis. Also includes a little bit about ring-closing metathesis.

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Lecture10: 123.702

  1. 1. gareth j rowlands LECTURE TEN epothilone A
  2. 2. O S N HO O OH O O epothilone A Angew. Chem. Int. Ed. Engl., 1997, 36, 523 ©NASA
  3. 3. anti-cancer interacts with microtubules © Katja Röper@Department of Physiology, Development, and Neuroscience, University of Cambridge
  4. 4. epoxidation O S HO N O O OH O retrosynthesis of epothilone A S HO N O O OH O epothilone C!
  5. 5. ring-closing metathesis S HO N O O OH O retrosynthesis of epothilone C S HO N O O OH O
  6. 6. aldol C12 S C13 HO C15 C7 N C6 O esterification C1 O OH O S C12 C13 N C7 C15 C6 OHC OH C1 O O O retrosynthesis
  7. 7. of retrosynthesis C1-C6 fragment C–C FGI O O O OH OH carbonyl addition asymmetric C–C allylation R2B O OH
  8. 8. of retrosynthesis C7-C12 fragment C–C FGI O OHC aux* FGI auxiliary- controlled alkylation O O
  9. 9. of C retrosynthesis 13-C21 fragment S O S FGI EtO P N C=C EtO N PGO OH Horner- Wadsworth- O Emmons OH Sharpless FGI kinetic resolution PGO & PGO Grignard O OH
  10. 10. the synthesis ©Status Frustration@Flickr
  11. 11. of synthesis C1-C6 fragment 1. NaH, TBSCl 2. DMSO, (COCl)2 ....then Et3N 3. B(ipc)2 OH OH 36%; 95%ee OH OTBS see le cture four
  12. 12. Brown allylation H (ipc)2B H B O OTBS O OTBS see le cture four
  13. 13. of synthesis C1-C6 fragment 1. acetone, ....CuSO4, H+ 2. OsO4, NaIO4 O O O OH OTBS 62%
  14. 14. of synthesis C1-C6 fragment 1. EtMgBr C6 2. TPAP, NMO C1 O O O 69% O O O
  15. 15. of synthesis C7-C12 fragment 1. NaOH 2. TBSCl, imidazole 3. K2CO3, MeOH O O O 4. SOCl2 5. aux, n-BuLi O N O 46% OTBS
  16. 16. of synthesis C7-C12 fragment Na O O O O O N NaHMDS O N OTBS Me OTBS I MeI O 1. LiAlH4 O O 2. DMSO, (COCl)2 ....then Et3N O N 60% OTBS OTBS
  17. 17. missing alkene formation ©mugley@Flickr
  18. 18. of synthesis C13-C21 fragment TBSO MgBr 88% CHO OTBS OH see slide 11
  19. 19. of synthesis C13-C21 fragment TBSO (–)-DIPT, 4Å MS, TBSO Ti(OiPr)4, TBHP 46% OH 80%ee OH Sharpless kinetic resol ution
  20. 20. Sharpless kinetic resolution see lecture 5 R3 R R2 OH R1 slow fast "O" (–)-DIPT R2 R2 R3 R3 R H R1 R1 OH OH H R 0.6eq TBHP 0.45eq TBHP R3 R R3 R O R2 OH R2 OH R1 R1
  21. 21. of synthesis C13-C21 fragment 1. TBSCl, TBSO ....imdazole TBSO 2. O3, PPh3 69% O OH S OTBS c AcO OA c O OA I O MeO P N 75% MeO BuLi O 1. HF / glass 2. DMP S 3. Ph3P=CH2 OTBS S 4. TBAF N N 56% OH OTBS
  22. 22. now put the blocks together ©EJP Photo@Flickr
  23. 23. the coupling fragments C6 C1 C12 O O O HO LDA C7 O 70% C6 C1 C7 >98%de O O O C12
  24. 24. enolate formation R iPr O H Li O N H O Li iPr O
  25. 25. aldol C12 H H R R HO R Li R C7 O OH H H C6 O O C1 O O O substrate control
  26. 26. the coupling fragments 1. pPTS, MeOH 2. TBSOTf HO 3. CSA, MeOH 4. PDC TBSO 55% OH O O O O OTBS O
  27. 27. S TBSO N OH OH O OTBS O the coupling N N Cy N C N Cy fragments 80% C12 S C13 TBSO C15 C7 N C6 O C1 O OTBS O
  28. 28. alkene metathesis © Nobel Web AB © Nobel Foundation
  29. 29. © Nobel Foundation 2005
  30. 30. [M] R1 R2 R1 R2 [M] R2 [M] [M] R1 R1 H H [M] R2 R1 H H
  31. 31. [M] H H H H [M] ring-closing metathesis [M] RCM [M] H H [M] H H
  32. 32. PCy3 iPr iPr Cl Ru N Ph Cl PCy3 Ph (F3C)2MeCO Mo (F3C)2MeCO Schrock Grubbs's '1st generation' (but he had many before) N N Cl Ru catalysts Cl PCy3 Ph Grubbs's '2nd generation'
  33. 33. Ph Cl Ru NHC Cy3P Cl ©manu_le_manu@Flickr
  34. 34. MeO OMe MeO OMe PCy3 Cl Ru H H Cl N PCy3 Ph H H N O N 67% N O O O N N MeO OMe H O PCy3 H H Cl N OH Ru Cl H H OH H H OH PCy3 Ph N H N N HCl 26% N O H N synthesis of manzamine A
  35. 35. PCy3 Cl Si Si Ru O Cl O PCy3 Ph TsN TsN ROM-RCM cascade TBAF 78% 2 steps OH OH N N H H Ts H (–)-halosalin
  36. 36. OTBDPS OTBDPS PCy3 Cl Ru Cl PCy3 Ph [Ru] enyne metathesis OTBDPS OTBDPS repeat [Ru] 70%
  37. 37. synthesis of epothilone C C12 S C13 TBSO C15 C7 N C6 O C1 O OTBS O PCy3 Cl 1:1 Ru Cl 94% PCy3 Ph C12 S TBSO S C13 TBSO C15 O C7 N N C6 O O C1 O OTBS O OTBS O HF gives product
  38. 38. non-selective two stereoisomers ©Little Blue Penguin@Flickr
  39. 39. want pure stereoisomer ©Little Blue Penguin@Flickr
  40. 40. alkyne metathesis S TBSO N O O OTBS O N N Mo catalyst N 80% S TBSO N O O OTBS O Fürstner Chem. Commun., 2001, 1057
  41. 41. Fürstner’s S synthesis of TBSO epothilone C N O O OTBS O 1. H2, Lindlar cat. 2. HF 79% S HO N O O OH O
  42. 42. to back original synthesis ©gregoryjameswalsh@Flickr
  43. 43. of synthesis C12 S C13 epothilone A TBSO C15 C7 N C6 O C1 O OTBS O 1. HF O O 2. DMDO 31% C12 O S C13 HO C15 C7 N C6 O C1 O OH O
  44. 44. 2nd synthesisof epothilone A