Lecture3: 123.702

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Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.

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Lecture3: 123.702

  1. 1. LECTURE THREE chiral auxiliaries gareth j rowlands
  2. 2. MeO OMe OR O O MeO NH O macbecin I J. Chem. Soc., Perkin Trans 1, 1989, 190 & 1990, 47 & J. Chem. Soc., Chem, Commun., 1989, 378 ©Lisa Pickard@Institute of Cancer Research
  3. 3. OMe OMe O O N N O OMe i. NaHMDS ii. O N PhO2S Ph OMe OMe O O MeO N N O OMe OR O OH MeO O NH OMe O
  4. 4. substrate control ? ©Oberazzi@flickr
  5. 5. auxiliary control overall product substrate reaction (chiral) (achiral) add remove auxiliary auxiliary substrate product substrate control (chiral) (achiral) chiral chiral auxiliary auxiliary
  6. 6. at worst substrate product substrate control (chiral) (achiral) chiral chiral auxiliary auxiliary chiral chiral product auxiliary in built resolution
  7. 7. O O (–)-frontalin not the right beetle! ©BugMan50@flickr
  8. 8. O O Ph OH O RMgBr O Ph O LiAlH4 O HO OH O3 O 100% ee
  9. 9. chiral auxiliary control O O O
  10. 10. oxazolidinones O R O N R2 common auxiliary
  11. 11. oxazolidinones H H H O N O R 2 made from amino acids
  12. 12. enolate Li chemistry O O O O N O LDA N O O 1. n-BuLi HN O 2. EtCOCl O O Li O N O LDA O N O
  13. 13. Li O O O O PhCH2I N O N O Ph good I diastereoselectivity Ph Li O Bn O O O O O N H N H H
  14. 14. most enolate chemistry works O Li O O O O O Br LDA N O N O N O H Ph Ph Ph 96% de
  15. 15. most enolate chemistry works O O O O i. NaHMDS N O N O ii. H O HO H N Ph Ph Ph SO2Ph >90% de
  16. 16. most enolate chemistry works O O O O i. KHMDS N O N O i-Pr ii. i-Pr N3 H Ph Ph >90% de SO2N3 i-Pr
  17. 17. auxiliary easily removed O O O O N O LiOBn Bn HN O O Ph Ph
  18. 18. auxiliary easily removed O O O N O LiOOH OH Ph Ph as but not as easy people claim!
  19. 19. auxiliary easily removed O O H H N O LiAlH4 OH Ph Ph
  20. 20. Bistramide A J. Am. Chem. Soc., 2006, 128, 4936 Me Me O O Me H N Me O N O H H H H O OH O Me Me H Me OH ©Nemo's great uncle@Flickr
  21. 21. chiral auxiliary Me Me O O Me H N Me O N O H H H H O control OH O Me Me H Me OH iPr NaHMDS, THF, –78°C H N O N O I BnO BnO 81% O O O O 96%de i. LiBH4 ii. DMSO, (COCl)2, Et3N H H BnO O
  22. 22. the aldol reaction
  23. 23. the aldol M O reaction M O OH O O R1 R2 R1 R3 R1 R3 O R2 R2 R3
  24. 24. O O OH OLi H R Me X R X Me cis-enolate enolate syn aldol geometry X X H M H M O O H O H O R R Me Me
  25. 25. O OLi O OH H R X X R Me Me trans-enolate enolate anti aldol geometry H H Me O Me O R O R O M M X X H H
  26. 26. chiral auxiliary in the aldol O O OH O O Bu2BOTf N O iPrNEt2 Ph N O O Ph H 500 : 1 dr (opposite syn isomer)
  27. 27. warning ©GraemeNicol@Flickr
  28. 28. Bu Bu O O B Bu2BOTf O O N O iPrNEt2 N O O chiral Ph H Ph Bu auxiliary Bu B in the aldol H O O N O O
  29. 29. favoured transition state Bu Bu O O O O B B Ph Ph H Bu Bu H H O N N H O O O disfavoured
  30. 30. Bu O O OH O O O O Bu2BOTf B Ph N O iPrNEt2 Ph N O H Bu O H O N Ph H O 500 : 1 dr (opposite syn isomer) chiral auxiliary in the aldol
  31. 31. cytovaricin J. Am. Chem. Soc., 1990, 112, 7001 ©http://www.icm.uu.se/micro/groupResearch.php?G=ProkaryoticDevelopment Me H O OH Me O OH H Me H O O H Me Me H OH Me O H HO OH H OH MeO Me O O Me OH OH H
  32. 32. Me chiral auxiliary Me H O O OH in the aldol OH H Me H O O H Me Me H OH Me O H HO OH H OH MeO Me O O Me OH OH H 1. Bu2BOTf, Et3N O O 2. O Me O OH O N Et N Et Ph Ph O Ph O O 92% 100%de O Bu HN B Bu Et O H O
  33. 33. Me chiral auxiliary Me H O O OH in the aldol OH H Me H O O H Me Me H OH Me O H HO OH H OH MeO Me O O Me OH OH H 1. Bu2BOTf, Et3N 2. O O O O OH OPMB O N N 87% Ph 100%de O O OPMB Ph
  34. 34. the Diels-Alder reaction ©Anchor Bay Entertainment
  35. 35. Diels-Alder reaction R 1 R1 R 3 R3 heat R 4 R4 R 2 R2
  36. 36. Diels-Alder reaction R1 R 1 R 3 R 3 heat 4 R 4 R R2 R 2 2 new bonds
  37. 37. Diels-Alder reaction R 1 R1 R3 R3 heat R 4 R4 R 2 R2 4 new stereocentres
  38. 38. Diels-Alder reaction R 1 R1 R 3 R3 heat R 4 R4 R 2 R2 control excellent
  39. 39. achiral example O O OBn OBn O OBn 0%ee
  40. 40. chiral auxiliary control O O R N O O R Et2AlCl O N O single enantiomer R = H 86% de R = Me 90% de >98% endo
  41. 41. chiral auxiliary control O O R N O O R Et2AlCl O N O single enantiomer R = H 86% de R = Me 90% de >98% endo
  42. 42. Et Et Et2AlCl2 Et2 O Al O O Al O H H N O N O Et2 O Al O H N O chiral auxiliary control
  43. 43. Et Et Et2AlCl2 Et2 O Al O O Al O H H N O N O Et2 O Al O H N O chiral auxiliary control
  44. 44. (–)-stenine Angew. Chem. Int. Ed., 1996, 35, 904 O Me H O H H Et N H ©Christian Puff
  45. 45. O chiral auxiliary Me H O H control H N Et H S S S S Me2AlCl H PMBO O H PMBO O Me N O NR2* Ph O
  46. 46. Bond: "Free radicals," sir? M: Yes. They're toxins that destroy the body and the brain, caused by eating too much red meat and white bread and too many dry martinis! Bond: Then I shall cut out the white bread, sir.
  47. 47. chiral auxiliary in conjugate addition O O O O R2 Yb(OTf)3, R2–X, O N R1 Bu3SnH, Et3B, O2 O N R1 81-94% Ph Ph 76-96%de Ph Ph Ln Yb O O R2 O N R1 Ph Ph
  48. 48. other chiral auxiliaries Me O Me H H O BnO Me BnO AlCl3 O Me Me OBn ≡ H ≡ Me O O Me CO2R Me O BnO Me
  49. 49. other chiral auxiliaries Me Me R O H TiCl4 N R R = H 99% de O N S O R = Me >97% de O >98% endo O2S Me Me Me Me R Me Me R N S O N SO2 O O O Ti Ln
  50. 50. other chiral auxiliaries H EtMgCl N N Et S O O S O O O O 90% de LiOH HO NH S O O Et O
  51. 51. other chiral auxiliaries O O O O ZnBr2 S S O O O MgBr H MeO MeO O Ar O O MeO O MeO H OMe O (–)-podorhizon O 95% ee
  52. 52. other many chiral auxiliaries ©Jared Zimmerman@flickr
  53. 53. other many chiral auxiliaries ©Gaetan Lee@flickr

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