LECTURE TWO chiral catalysis ©ystenes@flickr 1
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LECTURE TWO
chiral catalysis©ystenes@flickr
1
chiralproduct
chira
l re
agen
t
substrate(achiral)
chiral catalyst
chiral reagent
substrate(achiral)
chiralproduct
chiralcatalysis
2
©mugley@flickr
HCO2H
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
productionL-DOPA
3
productionL-DOPA
P P
OMe
MeOO
MeNH
HO2C
Ar
RhL L
P P
OMe
MeO
Rh O
MeNH
HO2C
Ar
industrial
4
Ph
CO2Me
NHCOMe
PRhP
S S PhAr
ArPh+ kminor : kmajor 573 : 1
Rh
HN CO2Me
OPhPP
fast
major
Rh
HNMeO2C
OPh PP
fast
minor
Rh
HNMeO2C
OPh PH
H
P
Rh HP
O
P
SHN
Ph
MeO2C
Ph
HMeOCHNMeO2C
major
H2 slow RDS kminor
Rh
HN CO2Me
OPhPH
H
P
RhHP
O
P
S NH
Ph
CO2Me
Ph
H NHCOMeCO2Me
minor
H2 slow RDS kmajor
mechanismlock & keyanti
one of many mechanisms for hydrogenationapologies for old (>10 years) ChemDraw scheme
5
©AJC1@flickr
N
F
NOMeN
OCO2H
levofloxacin Proc. Natl. Acad. Sci. USA, 2004, 101, 5356
& Tetrahedron Lett., 1991, 32, 41636
OOH OH
H OH
Ph2PPPh2
RuCl2
H2
97%91%ee
in total synthesischiral catalysis
7
P PCl
H
RuOH
O
proposedtransition state
causehindrance
equatorial
8
©2004 by National Academy of Sciences
proposedtransition state
9
©Calamity Meg@flickr
O
N•HCl
CF3
(R)-fluoxetine J. Am. Chem. Soc., 2000, 122, 6510
10
Ph
O
Me2N
SM : catalyst10,000 : 1
H2
96%97.5%ee
Ph
Me2N
H OH
Ar2PPAr2
RuCl
Cl
NH2
H2N
iPrH
OMe
OMe
Ar = 3,5-Me2C6H3
in total synthesischiral catalysis
11
functionalised
HRu
NHO
CRSRLnon
ketone
12
OMeO
MeO
catalyst (10%)BH3•THF
MeO
MeO
OHH
93% eeNB O
HPhPh
Me catalyst
reductionenantioselectivecatalytic
reductionCBS
13
Ph
Ph
OBNB
HO
MeH
H
RL
RSPh
Ph
OBNB
HO
MeH
H
RL
RS
RL RS
H OH
NB O
HPhPh
MeH3B
RL RS
O
NB O
HPhPh
Me
BH3•THF
mechanism of
reductionCBS
14
mechanism of
reductionCBS
Ph
Ph
OBNB
HO
MeH
H
RL
RSPh
Ph
OBNB
HO
MeH
H
RL
RS
RL RS
H OH
NB O
HPhPh
MeH3B
RL RS
O
NB O
HPhPh
Me
BH3•THF
15
NO
F
OH
OH
F
ezetimibe J. Med. Chem., 2004, 47, 1
16
F
O
N
O
O Ph
catalyst (10%)BH3•THF
NB O
HPhPh
Me catalyst
F
N
O
O Ph
HHO
>95%>99:1 dr
in total synthesischiral catalysis
NO
F
OH
F
HO H
17
OH
(+)-DIPT, Ti(Oi-Pr)4,
TBHPOH
O
92% ee
OH
(–)-DET, Ti(Oi-Pr)4,
TBHP
OHO
>90% ee
epoxidationSharpless asymmetric
18
epoxidationSharpless asymmetric
OOH
TBHP
iPrO2CCO2iPr
OH
OH(+)-DIPT
EtO2CCO2Et
OH
OH(–)-DET
19
epoxidationSharpless asymmetric
OH
allylic alcohol20
E
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
iPr
iPr
EtOt-Bu
R
epoxidationSharpless asymmetric
21
R3
R1
R2
OH
D-(–)-DET unnatural isomer
“O”
“O”D-(+)-DET
natural isomer
R1
R2 R3
OHO
Ti(Oi-Pr)4TBHP
R1
R2 R3
OHO
Ti(Oi-Pr)4TBHP
mnemonicpredictive
22
left hand
R1
R2 R3
OH
R1
R2 R3
OHO
Ti(Oi-Pr)4TBHP
R1
R2 R3
OHO
Ti(Oi-Pr)4TBHP
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
©Jackal1@flickr
O
N•HCl
CF3
J. Org. Chem., 1988, 53, 4081 &
J. Am. Chem. Soc., 1987, 109, 5165
(R)-fluoxetine24
Ph OH
SAE(+)-DIPTTBHP
89%>98%ee
Ph OHO
Ph NHMe
O
CF3
in total synthesis
chiralcatalysis
25
dihydroxylationSharpless asymmetric
PhPh
PhPh
OH
OHPh
PhOH
OH98.8% ee >99.5% ee
K2OsO2(OH)4, K3Fe(CN)6, K2CO3,
MeSO2NH2, t-BuOH, H2O, 0°C,
(DHQD)2-PHAL (DHQ)2-PHAL
26
dihydroxylationSharpless asymmetric
ligands
N
HO
N
MeO
EtN
HO
N
OMe
EtNN
(DHQD)2-PHAL
N
HO
N
OMe
N
HO
N
MeO
N NEt Et
(DHQ)2-PHAL
27
SAD
H
MS
L
OsO4(DHQ)2PHAL
OsO4
(DHQD)2PHAL
mneumonic
attractive area - attracts aromatic substituents or
large, hydrophobic aliphatic groups
28
©Jack Scott, Department of Biological Sciences, University of Alberta
O
O
Et
exo-brevicominTetrahedron Lett., 1993, 34, 5031
29
OO
EtOsO4, K3Fe(CN)6,
K2CO3, MeSO2NH2, t-BuOH, H2O, 0°C,
(DHQD)2-PHAL
OO
Et
HO
OH
95% ee
TsOH
O
O
Etin total synthesisSAD
30
R R
OBF
FF
δ+++nuc
Lewis acid catalysis
fast31
ligandsbis(oxazoline)
Box ligands
N
O
N
O
R R
32
N
OH
H2N
HO
R R
O O
H
H
NC CN HO2C CO2H
amino acidsfrom
Box ligands
33
O
O
St-Bu
OSiMe3
N
O
N
O
t-Bu t-BuCu
TfO OTf
85%regioselectivity 98:2
97% ee86% de
OSt-Bu
OHO
in the aldol reactionchiral catalysis
34
in the aldol reactionchiral catalysis
N
O
N
O
t-Bu t-BuCu
O O
35
N
O
N
O
t-Bu t-BuCu
O O
St-BuMe3SiO
36
phoboxazole B Angew. Chem. Int. Ed., 2000, 39, 2536 & J. Am. Chem. Soc., 2000, 122, 10033
O
BrMeO
HO
HHO
OMe
O
N
O
N
O
O
O
OH O H H
H
OH
H
©rei-san@flickr37
Ph
O
N CHO
St-Bu
OSiMe3
N
O
N
O
Ph PhSn
TfO OTf
91%94% ee
Ph
O
N
OH
t-BuS O
in total synthesischiral catalysis
38
in Diels-Alder reactionschiral catalysis
NO
OO N
O
N
O
t-Bu t-BuCu
TfO OTf
cat 5-10mol%92%
97%ee
HO N
H
O
O
39
in Diels-Alder reactionschiral catalysis
Me Me
OOCu
N N
OO
O N MeMeMeMe
Me
2+
bidentatesubstrate
40
reactionsin hetero-Diels-Alderchiral catalysis
HOEt
O
Ocat 2-5mol%
72%97%ee
O
CO2Et
H
O
H
H
O
OH
i. KOHii. HCl
N
O
N
O
t-But-Bu
CuTfO OTf
*
*41
CuN N
OO
2+
O O
HEtO
reactionsin hetero-Diels-Alderchiral catalysis
42
©CDC
OCO2H
OHOH
O Et(+)-ambruticin
J. Am. Chem. Soc., 2001, 123, 10772
43
coccidioidomycosis
OCO2H
OHOH
O Et
©Dr J.W. Rippon
44
in total synthesischiral catalysis
TBSO
OBn
TBDPSO
O
H
NCr
O
O Cl
neat, 25°C64%
97%ee
O
OBn
OTBDPSTBSO
OCO2H
OHOH
O Et
45
in total synthesischiral catalysis
OCO2H
OHOH
O Et
NCr
O
O
TBDPSO H
O
TBSO
OBn
46
OCO2H
OHOH
O Etin total synthesischiral catalysis
TESO
Et
OTBS
O
H
Me
ent-catneat, 25°C
64%97%ee
O
Et
OTBSTESO
Me
47
organocatalysis©Meredith_Farmer@flickr
48
reactionin the aldol
H
O
H
O
cat (10%)H
O OH
88%anti / syn 3 / 1
97% ee
NH
O
OHL-proline
organocatalysis
49
aldolproline-catalysed
mechanism of
NH
O
OH
NO
OH
NO
OH
NO
O
H
H
O
H
H
OHH
O
H
O
50
O HNO
H
H
H
O
transition state?51
O
H
MOMO
OCl
ClCl
Cl
ClCl
N
NH•TFA
O
Ph
(5mol%)94%93%ee
O
H
MOMO
Cl
enaminecatalysis
52
enaminegeneral
mechanism
N
N
R2
R1
O
R2N
NH
O
Ph
R1
O
Ph
N
N
R2R1
O
Ph
N
N
R2R1
O
Ph
E
N
N
R2R1
O
Bn
E
R1
O
R2
E
53
©aussiegall@flickr
(–)-brasosideJ. Am. Chem. Soc., 2005, 127, 3696
OH
H
Me O O OHOH
OHHO
OO
54
total synthesisenamine catalysis in
O
OMes
NH
CO2H
D-proline(0.4eq)PhN=O
O
OMes
OPhHN
OMes
HO
CO2MeWittig
reaction
56% (2 steps)
O2CO
NH
N
RPh
OH
H
O O OHOH
OHHO
OO
55
OH
H
O O OHOH
OHHO
OO
total synthesisenamine catalysis in
H
O
OBn
H
O
OBn
NH
CO2H
78%98%ee
H
O
OBn
OHOBn
O OBnOBnTMSO
ROOBn
56
R1
O
R2nuc
R1
O
R2nuc
LALA
LUMO-lowering catalysis
fastslow
57
R1
N
R2nuc
R1
O
R2nuc
NH
LUMO-lowering catalysis
fastslow
catalysisiminium
58
Ph
O
BnO OBn
O O
N
NH
CO2HBn
cat. (10%), neat, rt, 165h Ph
CO2BnBnO2C
O86%
99% ee
catalysisiminium ion
59
catalysisiminium ion
N
N CO2H
H
CO2Bn
BnOO
N
N CO2H
H
CO2Bn
CO2Bn
H
60
O
OH
O
Ph O
(R)-warfarinAngew. Chem. Int. Ed., 2003, 42, 4955©Rosebud 23@flickr
61
O
OH
O
Ph O
(R)-warfarinAngew. Chem. Int. Ed., 2003, 42, 4955
62
in total synthesis
O
OH
O
Ph O
O
OH
O
Ph
O
NH
HN
Ph
Ph
CO2H
96%82%ee
catalysisiminium
63
O
HR1
O
HR1
LAO
HR1
HNN
H
XR2 R3
δ+
unactivated Lewis acid H-bonding
hydrogenbonding catalysis
64
N
S
O (5mol%)TMSCN
87%97%ee N
S
OTMSNC
HN
NH
NH
NHPr
t-Bu S
O
catalysisH-bond
65
OO
PO
O H
phosphoricacids
chiral
66
proton in hetero Diels-Alder reactionchiral
N
Cl
HO
OTMS
MeO
OMe
(3mol%)
90%97%ee
N
O
OMe
OH
Cl
OOPO
O NH
67
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