LECTURE SIX

   organocatalysis
gareth j rowlands   ©Meredith_Farmer@flickr
clean
chemistry   ©Meredith_Farmer@flickr
avoid
waste




        ©triplej*@flickr
chemistry
        improve
must




                  ©j / f / photos@flickr
many
 enzymes
  metal-free
  catalysts




               ©dullhunk@flickr
aldolases
can use enamine

chemistry
             lysine



                          H
                      N        O  ...
o rganic
chemistry
 thesam
         e




©David Reeves from Flickr
organocatalysis    in the   aldol reaction
        O

    H                            O      OH
            cat (10%)
   ...
O                                                          O
                                                      OH
    ...
organocatalyst
     gold
       rush




                 ©bogenfreund@Flickr
enamine catalysis
               O
    Pr                                               O
                   H          ca...
enamine-catalysis
  intermediates

        SO2Ph                 Ar                      Ar
        N                     ...
MacMillan’s imidazolidinone
                          catalysts
         O
                   N

                        R...
of
synthesis
MacMillan’s
catalysts

 O                O         O    O
      O    NH2         NH                N

     NH...
O                                                                           O
                                     O
     ...
O
                    O
              H          N
                                      O
                        N      ...
(–)-brasoside
                                                  O
                                          O
            ...
enamine catalysis in                        O
                                                    O



total synthesis
   ...
enamine catalysis in                O
                                            O



total synthesis
                   ...
Sch50971                               HN   N
Tetrahedron: Asymmetry., 2000, 11, 3867



                                 ...
enamine catalysis in                           HN   N


total synthesis
                                                  ...
enamine catalysis in
total synthesis
           O
                   N
               S                   N
       F3C    ...
LUMO-lowering
  catalysis

                        LA
     O       nuc   LA        O           nuc

R1          R2        ...
LUMO-lowering
  catalysis

                   N
     O       nuc   H
                            N           nuc
R1       ...
iminium ion
     catalysis

                                 N
          O
                                               ...
iminium ion
     catalysis

           N                        N

       N       CO2H                     CO2H
          ...
OH   Ph   O




                O    O




                                       (R)-warfarin
©Rosebud 23@flickr
         ...
OH   Ph   O




O    O




                       (R)-warfarin
              Angew. Chem. Int. Ed., 2003, 42, 4955
iminium catalysis
 in total synthesis


         O       Ph    H
                       N
                              CO...
iminium
                              catalysis
OMe                    in the Diels-Alder

         cat. (20%)            ...
iminium
                        catalysis
                 in the Diels-Alder

O
        N              O      Ar
        ...
hydrogen
 bonding
©The University of Chicago Medical Center
hydrogen
 bonding catalysis
                                      X
                           R 2                R 3
    ...
H-bond
catalysis
       O                                 NC OTMS
                    (5mol%)
                     TMSCN
 ...
N
                            H
         N
         H    H
                    H
              MeO2C
                     ...
NH2
                                                    N

        N
        H                                    N
      ...
pictet-spengler
   reaction
                  ©1984 Columbia Pictures Industries
t-Bu S
     (iBu)2N
                     N      N
                                N   Ph
               O     H      H
   ...
what is
                          smallest
                     catalyst ?




©djwudi@flickr
the
      proton




               H
do you
how
 make a
sphere
 chiral ?




   ©limowreck666@flickr
chiral phosphoric
   acids

                            O
                    O
                        P
                ...
chiral proton       in aza-ene

           Bz
      N

 Ph                                Bz            CO2Me
            ...
chiral proton in Friedel-Crafts
          Bz
      N                               NHBz
                            Ar
 Ar...
reaction
chiral proton in hetero Diels-Alder
           HO


            N                          OH
                   ...
photoredox
 chemistry




      ©CiCCiO.it@flickr
cat (0.2eq),
                          O                  Ru(bipy)3Cl2 (0.005eq),                     O
           O      ...
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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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