Lecture8: 123.312

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Lecture 8: the aldol reaction and conjugate additions
Just what it says in the title.

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Lecture8: 123.312

  1. 1. FUNCTIONALGROUP 123.312 INTERCONVERSIONS LECTURE 8
  2. 2. issue eight the aldol reaction & conjugate additions
  3. 3. previously...
  4. 4. we have looked at the carbonyl as nucleophile... Li O O R X Li X R
  5. 5. we have looked at the carbonyl as electrophile... O HO Cnuc Cnuc 1 2 R1 R2 R R
  6. 6. combine the two... ©marvel/sony pictures
  7. 7. chapter one “the aldol reaction”
  8. 8. The aldol reaction O O NaOH OH O O
  9. 9. mechanism of the aldol reaction O O H H O HO H O O OH O H H O O
  10. 10. mechanism of the aldol reaction HO O enolisation OH O H HO elimination O
  11. 11. the problem with the aldol reaction
  12. 12. how do we control chemoselectivity? OH O O OH O O OH OH O O
  13. 13. correct choice of nucleophile O R enolate nucleophilicity O O O > > EtO C H
  14. 14. correct choice of electrophile O R1 R2 carbonyl electrophilicity O O O 1 > 1 2 > 1 C H C C C OEt
  15. 15. correct choice of reagents (no choice of reaction) O O H NaOH OH O
  16. 16. pre-form enolate... O Li LDA O R2 R2 R 1 R 1
  17. 17. ...then add Electrophile Li O O OH O R 1 R 2 R 1 R 3 R2 R3
  18. 18. Synthesize an enolate equivalent... Me3SiCl SiMe3 O Et3N O R 2 R 2 R 1 R 1
  19. 19. ...then add Electrophile SiMe3 O O OH O R1 R 2 R1 R3 R2 R3
  20. 20. Synthesize an enolate equivalent... Cy2BCl BCy2 O O Et3N R2 R1 R 1 R2
  21. 21. ...then add Electrophile BCy2 O O OH O R 1 R 1 R 3 R2 R3 R2
  22. 22. B Me Me Me Me H B Me O H Me O R Me Me allows us to control stereochemistry...
  23. 23. chapter two “aldol-like chemistry”
  24. 24. the claisen condensation O O NaOEt O O OEt OEt OEt
  25. 25. the dieckman cyclisation O O O EtO O NaOEt OEt OEt
  26. 26. Mannich
 many other examples... Darzens reaction reaction enamine reaction enamine Darzens reaction Mannich reaction
  27. 27. OH O H O Me OH O O H H O Me (–)-laulimalide (fijianolide B)
  28. 28. aldol reaction in total synthesis (+)-Ipc2BO Me CO2Me OTBS H H H O O O Me OH OPMB CO2Me H H OTBS O Me H H O 86% 62%de O OPMB Me
  29. 29. chapter three “michael Additions” (conjugate additions 1,4-additions)
  30. 30. conjugate addition also known as Michael Addition or 1,4-addition Nuc O Nuc O R1 R2 R1 R2 H Nuc O R1 R2
  31. 31. potential problem: 1,2-addition O Nuc OH R1 R2 R1 R2
  32. 32. ? why
  33. 33. ©Jill Greenseth@flickr not going to tell you!
  34. 34. all about the interplay of two factors depending on the nucleo- phile & the conditions: kinetic vs thermodynamic & Hard vs soft page 230 onwards
  35. 35. Solution: change nucleophile Cu Li 2 x H3C Li CuI H3C CH3
  36. 36. Solution: change nucleophile O O H Cu Li H3C CH3 CH3 O CH3
  37. 37. Can convert grignard reagents as well O O CuClcat H3C MgBr CH3
  38. 38. organocoppers are soft nucleophiles... δ– δ+ C Li δ– δ+ C Mg δ– δ+ C Cu
  39. 39. but imho its probably a radical reaction C•
  40. 40. Addition of 1,3-dicarbonyl compounds O O O OEt OEt NaOEt O O OEt EtO O
  41. 41. 1,3-dicarbonyls are soft nucleophiles... O O O O O O OEt OEt OEt O ≡ O OEt
  42. 42. the robinson annulation O O O NaOH O O
  43. 43. Mechanism of the robinson annulation O O H OH O O O O O H2O HO O O O O
  44. 44. Mechanism of the robinson annulation O O O O O O H2O O O OH O O OH
  45. 45. the next one is a bit of a tongue twister...
  46. 46. the Hajos-Parrish-Eder- Sauer-Wiechert reaction O O N CO2H H O O O OH 99% 93% ee
  47. 47. synthesis is about finding the hidden patterns ©moominsean@flickr
  48. 48. C-C at position O R 2 R 1 O R2 X R 1
  49. 49. 1,3-di-O relationship O OH R1 R 2 O O R 1 R 2
  50. 50. 1,3-di-O relationship O O R 1 R2 O O 1 EtO R 2 R
  51. 51. enone relationship O R 1 R2 O O R 1 R 2
  52. 52. 1,4-di-O relationship O R 2 R1 OH O O R 2 R 1
  53. 53. 1,5-di-O relationship O O R 1 R 2 O O R 1 R 2
  54. 54. ©woodleywonderworks@flickr learn to recognise patterns

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