Lecture5: 123.702

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This is the biggy, the one everyone wants to achieve. Here we will be looking at metal-based chiral catalysis. We will concentrate on bisoxazoline-based Lewis acid catalysis and then look at reductions before finishing with the ubiquitous Sharpless epoxidation and dihydroxylation.

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Lecture5: 123.702

  1. 1. LECTURE FIVE chiral catalysis gareth j rowlands ©ystenes@flickr
  2. 2. chiral catalysis is the goal ©velo_city@flickr
  3. 3. industrial L-DOPA production H H2(g) H H [((S)-DIPAMP)RhL2] MeO CO2H L=solvent MeO CO2H NHAc H NHAc AcO AcO MeO 95% ee P P OMe (S,S)-DIPAMP ©mugley@flickr
  4. 4. ©CarbonNYC@flickr
  5. 5. substrate chiral (achiral) product chiral chiral catalyst catalysis reagent reagent chiral chiral substrate chiral (achiral) product
  6. 6. activation in chiral environment ©Cayusa@flickr
  7. 7. then reaction ©darkmatter@flickr
  8. 8. industrial L-DOPA production Ar O MeO MeO HO2C N Me H Ar P P P P Rh Rh O L L HO2C N Me OMe OMe H
  9. 9. Lewis acid catalysis O δ– nuc δ+ R R slow
  10. 10. Lewis acid catalysis F F B F electron acceptor
  11. 11. Lewis acid catalysis F F B O nuc F δ+++ R R fast
  12. 12. bis(oxazoline) ligands O O N N R R ligands Box
  13. 13. ligands Box NC CN HO2C CO2H OH HO H O O N H2N H R R fromamino acids
  14. 14. ligands Box M C-2 symmetric
  15. 15. C-2 symmetric M O of side approach R unimportant
  16. 16. C-2 symmetric R O M of side approach unimportant
  17. 17. chiral catalysis in the aldol reaction O O O N N Cu O t-Bu TfO OTf t-Bu HO O OSiMe3 St-Bu 85% regioselectivity 98:2 O St-Bu 97% ee 86% de
  18. 18. chiral catalysis in the aldol reaction O O N N Cu t-Bu O O t-Bu
  19. 19. bottom O O face blocked N N Cu t-Bu O O t-Bu
  20. 20. O O N N Cu t-Bu O O t-Bu Me3SiO St-Bu
  21. 21. cartoon form O t-BuS OSiMe3
  22. 22. phoboxazole B Angew. Chem. Int. Ed., 2000, 39, 253 J. Am. Chem. Soc., 2000, 122, 1003 OH O OMe N H O H HO O O H O H H H O N O HO O MeO Br ©rei-san@flickr
  23. 23. chiral catalysis in total synthesis O O Ph N CHO N N Sn OH Ph TfO OTf Ph O Ph N OSiMe3 91% 94% ee O t-BuS O St-Bu
  24. 24. chiral catalysis in radical chemistry O O O O i. Et3B, O2 O N Ph ii. MgX2 O N Ph O O 90% I 97%ee N N
  25. 25. chiral catalysis in Diels-Alder reactions O O O O N N Cu O N t-Bu TfO OTf t-Bu H O H cat 5-10mol% 92% O N O 97%ee
  26. 26. chiral catalysis in Diels-Alder reactions O O N 2+ N Cu O O Me Me Me Me O N Me Me Me bidentate substrate
  27. 27. chiral catalysis in hetero-Diels-Alder O reactions OEt H cat 2-5mol% O O H 72% 97%ee CO2Et i. KOH ii. HCl O H OH O N N Cu O t-Bu O TfO OTf t-Bu H
  28. 28. chiral catalysis in hetero-Diels-Alder O reactions OEt H cat 2-5mol% O O H 72% 97%ee * CO2Et i. KOH ii. HCl O H OH O N N O t-Bu Cu TfO OTf t-Bu *O H
  29. 29. chiral catalysis in hetero-Diels-Alder reactions O O N 2+ N Cu O O EtO H
  30. 30. chiral catalysis in hetero-Diels-Alder reactions O O H O O H EtO H EtO H H H
  31. 31. OH OH O (+)-ambruticin O Et 10772 CO2H J. Am. Chem. Soc., 2001, 123, ©CDC
  32. 32. OH OH O O Et CO2H coccidioidomycosis ©Dr J.W. Rippon
  33. 33. chiral catalysis OH OH in total synthesis O O Et CO2H OBn N O OBn Cr Cl O TBSO O O neat, 25°C 64% TBSO 97%ee H OTBDPS TBDPSO
  34. 34. chiral catalysis OH OH in total synthesis O O Et CO2H N O Cr OBn O O TBDPSO H TBSO
  35. 35. chiral catalysis OH OH in total synthesis O O Et CO2H Et Me Et ent-cat Me neat, 25°C O TESO O 64% 97%ee TESO OTBS H OTBS
  36. 36. catalytic enantioselective reduction MeO O catalyst (10%) MeO H OH BH3•THF MeO MeO H Ph N 93% ee Ph B O Me catalyst CBS reduction
  37. 37. H H Ph BH3•THF Ph N Ph N Ph B O H3B B O Me Me of H OH mechanism O RL RS CBS reduction RL RS Ph Ph O Me O Me N B N B Ph H Ph H H B O RS H B O RS H H RL RL
  38. 38. H H Ph BH3•THF Ph N Ph N Ph B O H3B B O Me Me of H OH mechanism O RL RS CBS reduction RL RS Ph Ph O Me O Me N B N B Ph H Ph H H B O RS H B O RS H H RL RL
  39. 39. OH OH F N O F ezetimibe J. Med. Chem., 2004, 47, 1
  40. 40. chiral catalysis OH HO H in total synthesis F O N F O catalyst (10%) HO H O BH3•THF O N Ph N Ph H F O Ph F O N Ph B O >95% Me >99:1 dr catalyst
  41. 41. catalytic enantioselective reduction PPh2 PPh2
  42. 42. O F CO2H N N MeN O levofloxacin Proc. Natl. Acad. Sci. USA, 2004, 101, 5356 & Tetrahedron Lett., 1991, 32, 4163 ©AJC1@flickr
  43. 43. chiral catalysis in total synthesis Ph2 P RuCl2 P Ph2 O H2 H OH OH OH 97% 91%ee
  44. 44. proposed transition state Cl O P Ru P OH H
  45. 45. proposed transition state ©2004 by National Academy of Sciences
  46. 46. CF3 O N•HCl (R)-fluoxetine 22, 6510 ©Calamity Meg@flickr J. Am. Ch em. Soc., 2000, 1
  47. 47. chiral catalysis in total synthesis SM : catalyst O 10,000 : 1 H OH H2 Ph Ph 96% Me2N 97.5%ee Me2N OMe H OMe Ar2 Cl 2 N P Ru P iPr Ar2 Cl N H2 H Ar = 3,5-Me2C6H3
  48. 48. Sharpless oxidations
  49. 49. Sharpless asymmetric epoxidation (+)-DIPT, Ti(Oi-Pr)4, TBHP O OH OH 92% ee (–)-DET, Ti(Oi-Pr)4, TBHP O OH OH >90% ee
  50. 50. Sharpless asymmetric epoxidation OH OH CO2iPr CO2Et iPrO2C EtO2C OH OH (+)-DIPT (–)-DET OH O TBHP
  51. 51. Sharpless asymmetric epoxidation OH allylic alcohol
  52. 52. Sharpless asymmetric epoxidation CO2Et iPr O O O O O iPr Ti CO2Et Ti E O O O O O R t-Bu EtO
  53. 53. good substrates R 2 OH R2 OH R 1 high and ee yields
  54. 54. ok substrates R3 R 3 OH R 2 OH R1 R 1 high limited ee examples
  55. 55. poor substrates R 3 OH
  56. 56. Ti(Oi-Pr)4 R2 R3 D-(–)-DET TBHP unnatural isomer O “O” R1 OH R2 R3 predictive R1 OH mnemonic Ti(Oi-Pr)4 R2 R3 “O” TBHP D-(+)-DET O natural isomer R1 OH
  57. 57. Ti(Oi-Pr)4 R2 R3 TBHP O OH R2 R3 R1 for “O” on top or on R1 OH your kNuckles you use Negative (–)-DET for “O” on bottom or on your Palm you use Positive (+)-DET Ti(Oi-Pr)4 R2 R3 TBHP O left hand R1 OH
  58. 58. CF3 O (R)-fluoxetine N•HCl 81 & J. Org. Che m., 1988, 53, 40 , 5165 , 109 ©Jackal1@flickr J. Am. Chem. Soc., 1987
  59. 59. SAE (+)-DIPT TBHP O Ph OH 89% Ph OH >98%ee chiral CF3 catalysis in total synthesis O Ph NHMe
  60. 60. OH H venustatriol O O H O OH OH Tetrahedron Le tt., 1988, 29, 3171 O H H Br ©Nils Geylen@flickr
  61. 61. D-(–)-DET Ti(OiPr)4 O OH TBHP OH 92% >90%ee SAE in total synthesis O CN OH HO H O O H O OH OH O H H Br
  62. 62. O CN D-(–)-DET O CN Ti(OiPr)4 O TrOOH HO HO 74% 100%de SAE in total synthesis OH H O O H O OH OH O H H Br
  63. 63. D-(–)-DET Ti(OiPr)4 TBHP O OH OH 95% 91%ee SAE in total synthesis OH H O O H O OH OH O H H Br
  64. 64. Sharpless asymmetric dihydroxylation K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, OH CO2Et H2O, 0°C, ligand CO2Et C5H11 C5H11 OH 99% ee
  65. 65. Sharpless asymmetric dihydroxylation Et Et Et Et N N N N N N N N O O O O H H H H MeO OMe MeO OMe N N N N (DHQD)2-PHAL (DHQ)2-PHAL ligands
  66. 66. Sharpless asymmetric dihydroxylation Et Et Et Et N N N N N N N N O O O O H H H H MeO OMe MeO OMe N N N N (DHQD)2-PHAL (DHQ)2-PHAL inverted stereocentre
  67. 67. Sharpless asymmetric dihydroxylation Et Et Et Et N N N N N N N N O O O O H H H H MeO OMe MeO OMe N N N N (DHQD)2-PHAL (DHQ)2-PHAL retention
  68. 68. Sharpless asymmetric dihydroxylation (DHQD)2-PHAL (DHQ)2-PHAL Ph Ph OH K2OsO2(OH)4, OH Ph K3Fe(CN)6, K2CO3, Ph Ph MeSO2NH2, t-BuOH, Ph H2O, 0°C, OH OH 98.8% ee >99.5% ee
  69. 69. SAD mneumonic (DHQD)2PHAL OsO4 S M attractive area - attracts aromatic substituents or L H large, hydrophobic aliphatic groups OsO4 (DHQ)2PHAL
  70. 70. Et exo-brevicomin O Tetrahedron Lett., 1993, 34 , 5031 O ©Jack Scott, Department of Biological Sciences, University of Alberta
  71. 71. OsO4, K3Fe(CN)6, Et OH Et K2CO3, MeSO2NH2, t-BuOH, H2O, 0°C, (DHQD)2-PHAL HO O O O O 95% ee TsOH SAD in total synthesis Et O O
  72. 72. taxol® Acta. Chem. Scand., 1996, 50, 649 AcO O OH AcO BzHN O Ph O H OH OH AcO O taxol OBz ©Wsiegmund@wikimedia commons
  73. 73. Sharpless asymmetric aminohydroxylation AcNHBr, LiOH, O K2OsO2(OH)4, AcNH O (DHQ)2-PHAL Ph OiPr Ph OiPr OH regioselectivity >20:1 O Ph AcO O 94% ee O OH Ph N H O OH HO H O OBz AcO

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