Lecture7: 123.702

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Gives an introduction to total synthesis and why we do it (which reminds me, I must add a picture of Everest, as I think the fact that 'it is there' is the main reason for most syntheses). Then to introduce the topic with a reasonably simple synthesis, we will look at an example of the synthesis of Tamiflu.

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Lecture7: 123.702

  1. 1. LECTURE SEVEN total synthesis gareth j rowlands ©Michael Budde@flickr
  2. 2. O HO OAc OMe O O O O AcO HO O O HO OH O O OH OH Cl OH (+)-spongistatin 1 altohyrtin A ©Saad.Akhtar@flickr
  3. 3. potent anti-carcinogen ©Exothermic@flickr
  4. 4. O HO 400kg OAc OMe O O O O AcO HO O O HO OH O O OH OH Cl OH 13mg ©Saad.Akhtar@flickr
  5. 5. O HO O OMe O O O O AcO HO O need O OH PPh3I total synthesis OH HO OH O O OH OH Cl OH
  6. 6. < 0.5%
  7. 7. how ©mag3737@flickr
  8. 8. chemistry as a creative ‘art’
  9. 9. retrosynthesis syn thinking backwards ©_Max-B@flickr
  10. 10. disconnections lead to... R1 R2
  11. 11. O IPh3P R1 R2 Wittig alkene O McMurry metathesis R1 R1 O R1 R2 R2 R2 reduction new R1 R2 targets
  12. 12. more reactions you know...
  13. 13. easier ...the retrosynthesis is ©spackletoe@flickr
  14. 14. O AcHN CO2Et H2N Tamiflu® oseltamivir ©ALTO CONTRASTE . Edgar AVG --BUSY--@flickr
  15. 15. retrosynthesis of Tamiflu® TMSO O CO2Et RO CO2Et aziridine AcHN CO2Me Asymmetric HN opening NH2 Diels-Alder MeO2C substrate aziridine control opening HO CO2H CO2Et PGN O HO Asymmetric O OH NHPG allylic shikimic acid alkylation
  16. 16. retrosynthesis of Tamiflu® TMSO O CO2Et RO CO2Et aziridine AcHN CO2Me Asymmetric HN opening NH2 Diels-Alder MeO2C substrate aziridine control opening HO CO2H CO2Et PGN O HO Asymmetric O OH NHPG allylic shikimic acid alkylation
  17. 17. right wrong ©Capt Kodak@flickr
  18. 18. O CO2Et aziridine RO CO2Et opening AcHN C–N formation HN NH2 C–N epoxide opening / formation aziridine formation selective reduction O CO2Et epoxide RO CO2Et formation O OMs O protection retrosynthesis of HO CO2H Tamiflu® HO OH shikimic acid J. Org. Chem., 1998, 63, 4550
  19. 19. O CO2Et aziridine RO CO2Et opening AcHN C–N formation HN NH2 C–N epoxide opening / formation aziridine formation selective reduction O CO2Et epoxide RO CO2Et formation O OMs O protection HO CO2H HO retrosynthesis of OH shikimic acid Tamiflu®
  20. 20. O CO2Et aziridine RO CO2Et opening AcHN C–N formation HN NH2 C–N epoxide opening / formation aziridine formation selective reduction O CO2Et epoxide RO CO2Et formation O OMs O protection HO CO2H HO retrosynthesis of OH shikimic acid Tamiflu®
  21. 21. protecting group manipulation 1. EtOH, SOCl2 2. 3-pentanone, HO CO2H ....TsOH O CO2Et 3. MsCl, Et3N HO O 80% OH OMs shikimic acid
  22. 22. H Et CO2Et Et O TMSOTf BH3•SMe2 CO2Et O O HO OMs OMs KHCO3 ~72% H Et Et Tamiflu® O CO2Et synthesis O
  23. 23. Et Et " H" O CO2Et O CO2Et O TMS O OMs TMS OMs H Et Et selective O CO2Et reduction HO OMs
  24. 24. Et Et Et Et Et Et O CO2Et O CO2Et O CO2Et NaN3 86% HO N3 O N3 OH Me3P 97% Et Et Tamiflu® O CO2Et synthesis HN
  25. 25. aziridine formation OH OH OH R1 R1 R2 R1 R2 R2 N N N N N Me3P N N :PMe3 N N Me3P N N H R1 R2 R1 R2 O R1 R2 R1 HN O HN O R2 N P P H N Me3 Me3 Me3P
  26. 26. Tamiflu® synthesis 1. NaN3 Et Et Et Et 2. Ac2O 3. Ra-Ni, H2 4. H3PO4 O CO2Et O CO2Et Ac N H HN NH2•H3PO4
  27. 27. Na N N N azide-free route developed ©SiamEye@flickr
  28. 28. limited supply of shikimic acid ©Whirling Phoenix@flickr
  29. 29. Et retrosynthesis of AcHN O Et Tamiflu® Angew. Chem. Int. Ed., 2008, aziridine 47, 3759 opening C–O H2N CO2Et PGN aziridine formation C–N PG2N CO2Et PG2N CO2Et functional group interconversion asymmetric C=C allylic amination O C–N PG2N CO2Et O
  30. 30. Et retrosynthesis of AcHN O Et Tamiflu® Angew. Chem. Int. Ed., 2008, aziridine 47, 3759 opening C–O H2N CO2Et PGN aziridine formation C–N PG2N CO2Et PG2N CO2Et functional group interconversion asymmetric C=C allylic amination O C–N PG2N CO2Et O
  31. 31. Et retrosynthesis of AcHN O Et Tamiflu® Angew. Chem. Int. Ed., 2008, aziridine 47, 3759 opening C–O H2N CO2Et PGN aziridine formation C–N PG2N CO2Et PG2N CO2Et functional group interconversion asymmetric C=C allylic amination O C–N PG2N CO2Et O
  32. 32. asymmetric allylic O Cl Pd Pd N SiMe3 amination Cl O 1. O O NH HN Ph Ph P P O Ph Ph N CO2Et O 2. EtOH, TsOH O 84% 98%ee O
  33. 33. L Pd L L Pd L H H H O O O O O N SiMe3 O asymmetric O allylic N CO2Et amination O
  34. 34. Tamiflu® synthesis 1. KHMDS ....then PhSSO2Ph O 2. mCPBA ....then DBU, heat N CO2Et 80% PhthN CO2Et O
  35. 35. Ph O S H H PhthN H EtO2C all diastereoisomers undergo syn-elimination
  36. 36. aziridine synthesis cat (2mol%), SESNH2, PhI(O2Ct-Bu)2, SESN MgO PhthN CO2Et 86% PhthN CO2Et O O O Rh O O Rh O O O nitrene chemistry
  37. 37. Tamiflu® synthesis 1. 3-pentanol, Et ....BF3•OEt2 SESN 2. Ac2O, DMAP, ....pyr Ac O Et SESN 55% PhthN CO2Et PhthN CO2Et
  38. 38. Tamiflu® synthesis Et O Et Me3Si S O O Et 1. TBAF N 2. NH2NH2 O Et Ac H O N 95% Ac N CO2Et H2N CO2Et O end-game
  39. 39. OTMS Et O O Et O NH NHAc CO2Me NHBoc EtO2C NH2 MeO2C Tamiflu® synthesis Angew. Chem. Int. Ed., 2009, 48, 1070

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