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Lecture6: 123.702

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The big topic of the last few years, the use of small organic molecules to catalyse enantioselective transformations. This lecture will start with proline before moving on to some of MacMillan's contributions to this field and, finally, finish with hydrogen bond catalysts and Brønsted acids.

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Lecture6: 123.702

  1. 1. LECTURE SIX organocatalysis gareth j rowlands ©Meredith_Farmer@flickr
  2. 2. clean chemistry ©Meredith_Farmer@flickr
  3. 3. avoid waste ©triplej*@flickr
  4. 4. chemistry improve must ©j / f / photos@flickr
  5. 5. many enzymes metal-free catalysts ©dullhunk@flickr
  6. 6. aldolases can use enamine chemistry lysine H N O O O O P O P O O O OH OH ©www.biochemsoctrans.org Biochem. Soc. Trans. (2004) 32, 259
  7. 7. o rganic chemistry thesam e ©David Reeves from Flickr
  8. 8. organocatalysis in the aldol reaction O H O OH cat (10%) H O O N H H 88% OH anti / syn 3 / 1 L-proline 97% ee
  9. 9. O O OH H H H O N H H OH O O N N O O OH H H N O mechanism of OH proline-catalysed aldo
  10. 10. organocatalyst gold rush ©bogenfreund@Flickr
  11. 11. enamine catalysis O Pr O H cat. (1%) F H PhO2S SO2Ph N Pr F NaBH4 F3C OH CF3 CF3 F Pr N 95% H OTMS CF3 96% ee
  12. 12. enamine-catalysis intermediates SO2Ph Ar Ar N Ar Ar N N PhO2S F O F O Si Si Pr Pr
  13. 13. MacMillan’s imidazolidinone catalysts O N R1 N H Ph
  14. 14. of synthesis MacMillan’s catalysts O O O O O NH2 NH N NH2 NH2 H N HCl H Ph Ph Ph
  15. 15. O O O E R1 N R1 R2 R2 N H Ph O O N N N Bn N Ph E R1 R1 R2 R2 O O N N N N general Ph R1 Ph R1 enamine R2 R2 E mechanism
  16. 16. O O H N O N Cl H H Ph •TFA MOMO O (5mol%) Cl 94% Cl 93%ee Cl MOMO Cl Cl enamine Cl catalysis
  17. 17. (–)-brasoside O O H J. Am. Chem. Soc., 2005, 127, 3696 O OH Me H HO OH O O OH ©aussiegall@flickr
  18. 18. enamine catalysis in O O total synthesis H O OH H HO OH O O OH O N CO2H H N OMes O2C D-proline H N R (0.4eq) O PhN=O Ph HO PhHN O Wittig O CO2Me reaction OMes 56% OMes (2 steps)
  19. 19. enamine catalysis in O O total synthesis H O OH O H O HO O OH OH H O OH N CO2H OBn H OBn O 78% H 98%ee OBn H OBn OBn RO OBn TMSO O OBn
  20. 20. Sch50971 HN N Tetrahedron: Asymmetry., 2000, 11, 3867 N H HCl
  21. 21. enamine catalysis in HN N total synthesis N H O H N TrN H NHSO2CF3 N TrN N (20mol%) OHC NO2 78% 20:1dr 99%ee NO2
  22. 22. enamine catalysis in total synthesis O N S N F3C H O O H H N O O H Ar
  23. 23. LUMO-lowering catalysis LA O nuc LA O nuc R1 R2 R1 R2 slow fast
  24. 24. LUMO-lowering catalysis N O nuc H N nuc R1 R2 R1 R2 slow fast iminium catalysis
  25. 25. iminium ion catalysis N O CO2Bn Bn N CO2H Ph H BnO2C O O cat. (10%), neat, rt, 165h Ph O BnO OBn 86% 99% ee
  26. 26. iminium ion catalysis N N N CO2H CO2H N BnO H CO2Bn H O H CO Bn 2 CO2Bn
  27. 27. OH Ph O O O (R)-warfarin ©Rosebud 23@flickr Angew. Chem. Int. Ed., 2003, 42, 4955
  28. 28. OH Ph O O O (R)-warfarin Angew. Chem. Int. Ed., 2003, 42, 4955
  29. 29. iminium catalysis in total synthesis O Ph H N CO2H Ph OH Ph O Ph N H OH 96% 82%ee O O O O
  30. 30. iminium catalysis OMe in the Diels-Alder cat. (20%) COEt HClO4 96% ee O endo / exo OMe >200 : 1 Et O N N O Ph H
  31. 31. iminium catalysis in the Diels-Alder O N O Ar N N N OMe O Et Et
  32. 32. hydrogen bonding ©The University of Chicago Medical Center
  33. 33. hydrogen bonding catalysis X R 2 R 3 N N LA H δ+ H O O O R1 H R1 H R1 H unactivated Lewis acid H-bonding
  34. 34. H-bond catalysis O NC OTMS (5mol%) TMSCN S S 87% N 97%ee N t-Bu S H N N N H H O NHPr
  35. 35. N H N H H H MeO2C OH (+)-yohimbine Org. Lett., 2008, 10, 745
  36. 36. NH2 N N H N H OHC OTBS OTBS t-Bu S (iBu)2N AcCl N N cat. (10mol%) H H 81% O N Ph 94%ee N Ac H-bond N H catalysis in total synthesis OTBS
  37. 37. pictet-spengler reaction ©1984 Columbia Pictures Industries
  38. 38. t-Bu S (iBu)2N N N N Ph O H H Cl N Ac N H H-bond OTBS catalysis in total synthesis
  39. 39. what is smallest catalyst ? ©djwudi@flickr
  40. 40. the proton H
  41. 41. do you how make a sphere chiral ? ©limowreck666@flickr
  42. 42. chiral phosphoric acids O O P O O H
  43. 43. chiral proton in aza-ene Bz N Ph Bz CO2Me (10mol%) NH N O 89% 95%ee Ph Ph HN OMe Ph O O P O O H
  44. 44. chiral proton in Friedel-Crafts Bz N NHBz Ar Ar (10mol%) 89-99% 90-97%ee N N Bn Ph3Si Bn O O P O H O Ph3Si
  45. 45. reaction chiral proton in hetero Diels-Alder HO N OH O (3mol%) N Cl 90% OTMS 97%ee OMe MeO Cl O OMe O O P O N H
  46. 46. photoredox chemistry ©CiCCiO.it@flickr
  47. 47. cat (0.2eq), O Ru(bipy)3Cl2 (0.005eq), O O fluorescent light Ph Br H H Ph 85% C6H13 96% ee C6H13 O photoredox O N N t-Bu chemistry H O O N N N t-Bu t-Bu N C(O)Ph C6H13 O C6H13 N SET *Ru(bipy)32+ N t-Bu PhC(O) Ru(bipy)3+ C6H13 light O Ph Ru(bipy)32+ O SET Br Ph

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