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.

1. LECTURE FIVE
chiral catalysis
gareth j rowlands ©ystenes@flickr

2. chiral catalysis
is the goal
©velo_city@flickr

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. ©CarbonNYC@flickr

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

6. activation
in chiral
environment ©Cayusa@flickr

7. then
reaction
©darkmatter@flickr

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. Lewis acid
catalysis
O δ–
nuc
δ+
R R
slow

10. Lewis acid catalysis
F
F B
F
electron
acceptor

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

12. bis(oxazoline) ligands
O O
N N
R R
ligands
Box

13. ligands
Box
NC CN HO2C CO2H
OH HO
H
O O
N H2N
H
R R
fromamino acids

14. ligands
Box
M
C-2 symmetric

15. C-2 symmetric
M
O of
side
approach
R
unimportant

16. C-2 symmetric
R
O
M
of
side
approach
unimportant

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. chiral catalysis in the aldol reaction
O O
N N
Cu
t-Bu O O t-Bu

19. bottom
O O face
blocked
N N
Cu
t-Bu O O t-Bu

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

21. cartoon
form
O
t-BuS OSiMe3

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. 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. 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. 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. 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. 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. 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. chiral catalysis in hetero-Diels-Alder
reactions
O O
N 2+ N
Cu
O O
EtO H

30. chiral catalysis in hetero-Diels-Alder
reactions
O O H O O H
EtO H EtO H
H H

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

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

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

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

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. catalytic
enantioselective
reduction
PPh2
PPh2

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

44. proposed
transition state
Cl
O
P Ru P
OH
H

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

46. CF3
O
N•HCl
(R)-fluoxetine
22, 6510
©Calamity Meg@flickr J. Am. Ch em. Soc., 2000, 1

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. Sharpless
oxidations

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

51. Sharpless asymmetric epoxidation
OH
allylic alcohol

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. good
substrates
R 2 OH
R2 OH
R 1
high
and ee
yields

54. ok
substrates
R3 R 3
OH R 2 OH
R1 R 1
high limited
ee examples

55. poor
substrates
R 3
OH

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. 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. CF3
O
(R)-fluoxetine
N•HCl 81 &
J. Org. Che m., 1988, 53, 40 , 5165
, 109
©Jackal1@flickr J. Am. Chem. Soc., 1987

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

60. OH
H
venustatriol
O
O
H
O OH OH
Tetrahedron Le
tt., 1988, 29, 3171 O
H H
Br ©Nils Geylen@flickr

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

70. Et
exo-brevicomin O
Tetrahedron Lett., 1993, 34
, 5031 O
©Jack Scott, Department of Biological Sciences, University of Alberta

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. 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. 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