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.

1. LECTURE SIX
organocatalysis
gareth j rowlands ©Meredith_Farmer@flickr

2. clean
chemistry ©Meredith_Farmer@flickr

3. avoid
waste
©triplej*@flickr

4. chemistry
improve
must
©j / f / photos@flickr

5. many
enzymes
metal-free
catalysts
©dullhunk@flickr

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. o rganic
chemistry
thesam
e
©David Reeves from Flickr

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. 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. organocatalyst
gold
rush
©bogenfreund@Flickr

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. enamine-catalysis
intermediates
SO2Ph Ar Ar
N Ar Ar
N N
PhO2S F
O F O
Si Si
Pr Pr

13. MacMillan’s imidazolidinone
catalysts
O
N
R1
N
H
Ph

14. of
synthesis
MacMillan’s
catalysts
O O O O
O NH2 NH N
NH2 NH2 H N
HCl H
Ph Ph Ph

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. 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. (–)-brasoside
O
O
H
J. Am. Chem. Soc., 2005, 127, 3696
O
OH
Me H HO OH
O O OH
©aussiegall@flickr

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. 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. Sch50971 HN N
Tetrahedron: Asymmetry., 2000, 11, 3867
N
H HCl

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. enamine catalysis in
total synthesis
O
N
S N
F3C H
O O
H H
N
O O
H
Ar

23. LUMO-lowering
catalysis
LA
O nuc LA O nuc
R1 R2 R1 R2
slow fast

24. LUMO-lowering
catalysis
N
O nuc H
N nuc
R1 R2
R1 R2
slow fast
iminium
catalysis

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. iminium ion
catalysis
N N
N CO2H CO2H
N
BnO H
CO2Bn
H O
H CO Bn
2
CO2Bn

27. OH Ph O
O O
(R)-warfarin
©Rosebud 23@flickr
Angew. Chem. Int. Ed., 2003, 42, 4955

28. OH Ph O
O O
(R)-warfarin
Angew. Chem. Int. Ed., 2003, 42, 4955

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. 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. iminium
catalysis
in the Diels-Alder
O
N O Ar
N
N
N OMe
O Et
Et

32. hydrogen
bonding
©The University of Chicago Medical Center

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. 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. N
H
N
H H
H
MeO2C
OH
(+)-yohimbine
Org. Lett., 2008, 10, 745

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. pictet-spengler
reaction
©1984 Columbia Pictures Industries

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. what is
smallest
catalyst ?
©djwudi@flickr

40. the
proton
H

41. do you
how
make a
sphere
chiral ?
©limowreck666@flickr

42. chiral phosphoric
acids
O
O
P
O
O H

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. 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. 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. photoredox
chemistry
©CiCCiO.it@flickr

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