The document discusses chiral catalysis, detailing various reactions and mechanisms involved in the production of chiral compounds, such as L-DOPA and fluoxetine. It includes specific examples of reaction conditions, catalysts used, and efficiency metrics (e.g., enantiomeric excess). Additionally, it explores different methods and strategies for achieving selectivity in chiral synthesis.

1. LECTURE TWO
chiral catalysis
©ystenes@flickr
1

2. chiral
product
chiral
reagent
substrate
(achiral)
chiral
catalyst
chiral
reagent
substrate
(achiral)
chiral
product
chiral
catalysis
2

3. ©mugley@flickr
H
CO2H
NHAc
MeO
AcO
H2(g)
[((S)-DIPAMP)RhL2]
L=solvent MeO
AcO
CO2H
H NHAc
H H
95% ee
(S,S)-DIPAMP
P P
OMe
MeO
industrial
production
L-DOPA
3

4. productionL-DOPA
P P
OMe
MeO
O
MeN
H
HO2C
Ar
Rh
L L
P P
OMe
MeO
Rh O
MeN
H
HO2C
Ar
industrial
4

5. Ph
CO2Me
NHCOMe
P
Rh
P
S S
PhAr
ArPh
+ kminor : kmajor 573 : 1
Rh
H
N CO2Me
OPhP
P
fast
major
Rh
H
NMeO2C
OPh P
P
fast
minor
Rh
H
NMeO2C
OPh P
H
H
P
Rh
H
P
O
P
SHN
Ph
MeO2C
Ph
HMeOCHN
MeO2C
major
H2 slow
RDS
kminor
Rh
H
N CO2Me
OPhP
H
H
P
Rh
H
P
O
P
S NH
Ph
CO2Me
Ph
H NHCOMe
CO2Me
minor
H2 slow
RDS
kmajor
mechanismlock & keyanti
one of many mechanisms for hydrogenation
apologies for old (>10 years) ChemDraw scheme
5

6. ©AJC1@flickr
N
F
N
OMeN
O
CO2H
levofloxacin
Proc. Natl. Acad. Sci. USA, 2004, 101, 5356
& Tetrahedron Lett., 1991, 32, 4163
6

7. O
OH OH
H OH
Ph2
P
P
Ph2
RuCl2
H2
97%
91%ee
in
total synthesis
chiral catalysis
7

8. P P
Cl
H
Ru
OH
O
proposed
transition state
cause
hindrance
equatorial
8

9. ©2004 by National Academy of Sciences
proposed
transition state
9

10. ©Calamity Meg@flickr
O
N•HCl
CF3
(R)-fluoxetine
J. Am. Chem. Soc., 2000, 122, 6510
10

11. Ph
O
Me2N
SM : catalyst
10,000 : 1
H2
96%
97.5%ee
Ph
Me2N
H OH
Ar2
P
P
Ar2
Ru
Cl
Cl
N
H2
H2
N
iPr
H
OMe
OMe
Ar = 3,5-Me2C6H3
in
total synthesischiral catalysis
11

12. functionalised
H
Ru
N
H
O
C
RSRLnon
ketone
12

13. OMeO
MeO
catalyst (10%)
BH3•THF
MeO
MeO
OHH
93% eeN
B O
H
Ph
Ph
Me
catalyst
reductionenantioselectivecatalytic
reduction
CBS
13

14. Ph
Ph
O
BN
B
H
O
Me
H
H
RL
RS
Ph
Ph
O
BN
B
H
O
Me
H
H
RL
RS
RL RS
H OH
N
B O
H
Ph
Ph
Me
H3B
RL RS
O
N
B O
H
Ph
Ph
Me
BH3•THF
mechanismof
reductionCBS
14

15. mechanismof
reductionCBS
Ph
Ph
O
BN
B
H
O
Me
H
H
RL
RS
Ph
Ph
O
BN
B
H
O
Me
H
H
RL
RS
RL RS
H OH
N
B O
H
Ph
Ph
Me
H3B
RL RS
O
N
B O
H
Ph
Ph
Me
BH3•THF
15

16. N
O
F
OH
OH
F
ezetimibe
J. Med. Chem., 2004, 47, 1
16

17. F
O
N
O
O
Ph
catalyst (10%)
BH3•THF
N
B O
H
Ph
Ph
Me
catalyst
F
N
O
O
Ph
HHO
>95%
>99:1 dr
in
total synthesis
chiral catalysis
N
O
F
OH
F
HO H
17

18. OH
(+)-DIPT,
Ti(Oi-Pr)4,
TBHP
OH
O
92% ee
OH
(–)-DET,
Ti(Oi-Pr)4,
TBHP
OH
O
>90% ee
epoxidationSharpless asymmetric
18

19. epoxidationSharpless asymmetric
O
OH
TBHP
iPrO2C
CO2iPr
OH
OH
(+)-DIPT
EtO2C
CO2Et
OH
OH
(–)-DET
19

20. epoxidationSharpless asymmetric
OH
allylic alcohol
20

21. E
OO
O
Ti
O
O O
O
O
Ti
O
O
CO2Et
CO2Et
iPr
iPr
EtO
t-Bu
R
epoxidationSharpless asymmetric
21

22. R3
R1
R2
OH
D-(–)-DET
unnatural isomer
“O”
“O”
D-(+)-DET
natural isomer
R1
R2 R3
OH
O
Ti(Oi-Pr)4
TBHP
R1
R2 R3
OH
O
Ti(Oi-Pr)4
TBHP
mnemonic
predictive
22

23. left hand
R1
R2 R3
OH
R1
R2 R3
OH
O
Ti(Oi-Pr)4
TBHP
R1
R2 R3
OH
O
Ti(Oi-Pr)4
TBHP
for “O” on top or on
your kNuckles you
use Negative (–)-DET
for “O” on bottom or
on your Palm you
use Positive (+)-DET
23

24. ©Jackal1@flickr
O
N•HCl
CF3
J. Org. Chem., 1988, 53, 4081 &
J. Am. Chem. Soc., 1987, 109, 5165
(R)-fluoxetine
24

25. Ph OH
SAE
(+)-DIPT
TBHP
89%
>98%ee
Ph OH
O
Ph NHMe
O
CF3
in
total synthesis
chiral
catalysis
25

26. dihydroxylation
Sharpless asymmetric
Ph
Ph
Ph
Ph
OH
OH
Ph
Ph
OH
OH
98.8% ee >99.5% ee
K2OsO2(OH)4,
K3Fe(CN)6, K2CO3,
MeSO2NH2, t-BuOH,
H2O, 0°C,
(DHQD)2-PHAL (DHQ)2-PHAL
26

27. dihydroxylation
Sharpless asymmetric
ligands
N
H
O
N
MeO
Et
N
H
O
N
OMe
Et
NN
(DHQD)2-PHAL
N
H
O
N
OMe
N
H
O
N
MeO
N N
Et Et
(DHQ)2-PHAL
27

28. SAD
H
MS
L
OsO4
(DHQ)2PHAL
OsO4
(DHQD)2PHAL
mneumonic
attractive area - attracts
aromatic substituents or
large, hydrophobic
aliphatic groups
28

29. ©Jack Scott, Department of Biological Sciences, University of Alberta
O
O
Et
exo-brevicominTetrahedron Lett., 1993, 34, 5031
29

30. O
O
Et
OsO4, K3Fe(CN)6,
K2CO3, MeSO2NH2,
t-BuOH, H2O, 0°C,
(DHQD)2-PHAL
O
O
Et
HO
OH
95% ee
TsOH
O
O
Etin
total synthesis
SAD
30

31. R R
O
B
F
F
F
δ+++
nuc
Lewis acid catalysis
fast
31

32. ligandsbis(oxazoline)
Box ligands
N
O
N
O
R R
32

33. N
OH
H2N
HO
R R
O O
H
H
NC CN HO2C CO2H
amino acidsfrom
Box ligands
33

34. O
O
St-Bu
OSiMe3
N
O
N
O
t-Bu t-Bu
Cu
TfO OTf
85%
regioselectivity 98:2
97% ee
86% de
O
St-Bu
OHO
in the
aldol reaction
chiral catalysis
34

35. in the
aldol reactionchiral catalysis
N
O
N
O
t-Bu t-Bu
Cu
O O
35

36. N
O
N
O
t-Bu t-Bu
Cu
O O
St-Bu
Me3SiO
36

37. phoboxazole B
Angew. Chem. Int. Ed., 2000, 39, 253
J. Am. Chem. Soc., 2000, 122, 1003
O
BrMeO
HO
H
HO
OMe
O
N
O
N
O
O
O
O
H O H H
H
OH
H
©rei-san@flickr
37

38. Ph
O
N CHO
St-Bu
OSiMe3
N
O
N
O
Ph Ph
Sn
TfO OTf
91%
94% ee
Ph
O
N
OH
t-BuS O
in
total synthesis
chiral catalysis
38

39. in
Diels-Alder reactionschiral catalysis
NO
OO
N
O
N
O
t-Bu t-Bu
Cu
TfO OTf
cat 5-10mol%
92%
97%ee
H
O N
H
O
O
39

40. in
Diels-Alder reactionschiral catalysis
Me Me
OO
Cu
N N
OO
O N MeMe
Me
Me
Me
2+
bidentate
substrate
40

41. reactions
in
hetero-Diels-Alderchiral catalysis
H
OEt
O
O
cat 2-5mol%
72%
97%ee
O
CO2Et
H
O
H
H
O
OH
i. KOH
ii. HCl
N
O
N
O
t-Bu
t-Bu
Cu
TfO OTf
*
*
41

42. Cu
N N
OO
2+
O O
HEtO
reactions
in
hetero-Diels-Alderchiral catalysis
42

43. ©CDC
O
CO2H
OH
OH
O Et
(+)-ambruticin
J. Am. Chem. Soc., 2001, 123, 10772
43

44. coccidioidomycosis
O
CO2H
OH
OH
O Et
©Dr J.W. Rippon
44

45. in
total synthesis
chiral catalysis
TBSO
OBn
TBDPSO
O
H
N
Cr
O
O
Cl
neat, 25°C
64%
97%ee
O
OBn
OTBDPS
TBSO
O
CO2H
OH
OH
O Et
45

46. in
total synthesis
chiral catalysis
O
CO2H
OH
OH
O Et
N
Cr
O
O
TBDPSO H
O
TBSO
OBn
46

47. O
CO2H
OH
OH
O Et
in
total synthesis
chiral catalysis
TESO
Et
OTBS
O
H
Me
ent-cat
neat, 25°C
64%
97%ee
O
Et
OTBS
TESO
Me
47

48. organocatalysis
©Meredith_Farmer@flickr
48

49. reactionin the aldol
H
O
H
O
cat (10%)
H
O OH
88%
anti / syn 3 / 1
97% ee
N
H
O
OH
L-proline
organocatalysis
49

50. aldo
proline-catalysed
mechanism of
N
H
O
OH
N
O
OH
N
O
OH
N
O
O
H
H
O
H
H
OH
H
O
H
O
50

51. O H
N
O
H
H
H
O
transition state?
51

52. O
H
MOMO
O
Cl
Cl
Cl
Cl
Cl
Cl
N
N
H
•TFA
O
Ph
(5mol%)
94%
93%ee
O
H
MOMO
Cl
enamine
catalysis
52

53. enamine
general
mechanism
N
N
R2
R1
O
R2
N
N
H
O
Ph
R1
O
Ph
N
N
R2
R1
O
Ph
N
N
R2
R1
O
Ph
E
N
N
R2
R1
O
Bn
E
R1
O
R2
E
53

54. ©aussiegall@flickr
(–)-brasoside
J. Am. Chem. Soc., 2005, 127, 3696
O
H
H
Me O O OH
OH
OH
HO
O
O
54

55. total synthesis
enamine catalysis in
O
OMes
N
H
CO2H
D-proline
(0.4eq)
PhN=O
O
OMes
OPhHN
OMes
HO
CO2Me
Wittig
reaction
56%
(2 steps)
O2C
O
NH
N
R
Ph
O
H
H
O O OH
OH
OH
HO
O
O
55

56. O
H
H
O O OH
OH
OH
HO
O
O
total synthesis
enamine catalysis in
H
O
OBn
H
O
OBn
N
H
CO2H
78%
98%ee
H
O
OBn
OH
OBn
O OBn
OBn
TMSO
RO
OBn
56

57. R1
O
R2
nuc
R1
O
R2
nuc
LA
LA
LUMO-lowering
catalysis
fastslow
57

58. R1
N
R2
nuc
R1
O
R2
nuc
N
H
LUMO-lowering
catalysis
fastslow
catalysis
iminium
58

59. Ph
O
BnO OBn
O O
N
N
H
CO2HBn
cat. (10%),
neat, rt, 165h Ph
CO2Bn
BnO2C
O
86%
99% ee
catalysis
iminium ion
59

60. catalysis
iminium ion
N
N CO2H
H
CO2Bn
BnO
O
N
N CO2H
H
CO2Bn
CO2Bn
H
60

61. O
OH
O
Ph O
(R)-warfarin
Angew. Chem. Int. Ed., 2003, 42, 4955©Rosebud 23@flickr
61

62. O
OH
O
Ph O
(R)-warfarin
Angew. Chem. Int. Ed., 2003, 42, 4955
62

63. in total synthesis
O
OH
O
Ph O
O
OH
O
Ph
O
N
H
H
N
Ph
Ph
CO2H
96%
82%ee
catalysisiminium
63

64. O
HR1
O
HR1
LA
O
HR1
H
NN
H
X
R2 R3
δ+
unactivated Lewis acid H-bonding
hydrogen
bonding catalysis
64

65. N
S
O
(5mol%)
TMSCN
87%
97%ee N
S
OTMSNC
H
N
N
H
N
H
NHPr
t-Bu S
O
catalysis
H-bond
65

66. O
O
P
O
O H
phosphoric
acids
chiral
66

67. proton in heteroDiels-Alder reaction
chiral
N
Cl
HO
OTMS
MeO
OMe
(3mol%)
90%
97%ee
N
O
OMe
OH
Cl
O
O
P
O
O
N
H
67