LECTURE FIVE chiral catalysis ©ystenes@flickr gareth j rowlands
Lecture5: 123.702
May 11, 2015
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.
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LECTURE FIVE
chiral catalysis©ystenes@flickr
gareth j rowlands
is the goalchiral catalysis
©velo_city@flickr
©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
©CarbonNYC@flickr
chiralproduct
chira
l re
agen
t
substrate(achiral)
chiral catalyst
chiral reagent
substrate(achiral)
chiralproduct
chiralcatalysis
activation
environmentin chiral
©Cayusa@flickr
©darkmatter@flickr
then reaction
productionL-DOPA
P P
OMe
MeOO
MeNH
HO2C
Ar
RhL L
P P
OMe
MeO
Rh O
MeNH
HO2C
Ar
industrial
R R
Oδ+δ–
nuc
Lewis acidcatalysis
slow
Lewis acid catalysis
F BFF
electronacceptor
R R
OBF
FF
δ+++nuc
Lewis acid catalysis
fast
ligandsbis(oxazoline)
Box ligands
N
O
N
O
R R
N
OH
H2N
HO
R R
O O
H
H
NC CN HO2C CO2H
amino acidsfrom
Box ligands
M
Box ligands
C-2 symmetric
M
RO
C-2 symmetric
side of
approachunimportant
MO
RC-2 symmetric
side of
approachunimportant
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
in the aldol reactionchiral catalysis
N
O
N
O
t-Bu t-BuCu
O O
N
O
N
O
t-Bu t-BuCu
O O
bottomface
blocked
N
O
N
O
t-Bu t-BuCu
O O
St-BuMe3SiO
O
t-BuS OSiMe3
cartoonform
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@flickr
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
NO Ph
OO
I
i. Et3B, O2ii. MgX2
N
O
N
O
NO Ph
OO
90%97%ee
in radical chemistrychiral catalysis
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
in Diels-Alder reactionschiral catalysis
Me Me
OOCu
N N
OO
O N MeMeMeMe
Me
2+
bidentate
substrate
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
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
*
*
CuN N
OO
2+
O O
HEtO
reactionsin hetero-Diels-Alderchiral catalysis
reactionsin hetero-Diels-Alderchiral catalysis
H
O
EtO
O
H
H
H
O
EtO
O H
H
©CDC
OCO2H
OHOH
O Et(+)-ambruticin
J. Am. Chem. Soc., 2001, 123, 10772
coccidioidomycosis
OCO2H
OHOH
O Et
©Dr J.W. Rippon
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
in total synthesischiral catalysis
OCO2H
OHOH
O Et
NCr
O
O
TBDPSO H
O
TBSO
OBn
OCO2H
OHOH
O Etin total synthesischiral catalysis
TESO
Et
OTBS
O
H
Me
ent-catneat, 25°C
64%97%ee
O
Et
OTBSTESO
Me
OMeO
MeO
catalyst (10%)BH3•THF
MeO
MeO
OHH
93% eeNB O
HPhPh
Me catalyst
reductionenantioselectivecatalytic
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
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
mechanism of
reductionCBS
NO
F
OH
OH
F
ezetimibe J. Med. Chem., 2004, 47, 1
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
PPh2PPh2
reduction
enantioselectivecatalytic
©AJC1@flickr
N
F
NOMeN
OCO2H
levofloxacin Proc. Natl. Acad. Sci. USA, 2004, 101, 5356
& Tetrahedron Lett., 1991, 32, 4163
OOH OH
H OH
Ph2PPPh2
RuCl2
H2
97%91%ee
in total synthesischiral catalysis
P PCl
H
RuOH
O
proposedtransition state
©2004 by National Academy of Sciences
proposedtransition state
©Calamity Meg@flickr
O
N•HCl
CF3
(R)-fluoxetine J. Am. Chem. Soc., 2000, 122, 6510
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
Sharplessoxidations
OH
(+)-DIPT, Ti(Oi-Pr)4,
TBHPOH
O
92% ee
OH
(–)-DET, Ti(Oi-Pr)4,
TBHP
OHO
>90% ee
epoxidationSharpless asymmetric
epoxidationSharpless asymmetric
OOH
TBHP
iPrO2CCO2iPr
OH
OH(+)-DIPT
EtO2CCO2Et
OH
OH(–)-DET
epoxidationSharpless asymmetric
OH
allylic alcohol
E
OO
O
TiO
O O
O
O
TiO
O
CO2Et
CO2Et
iPr
iPr
EtOt-Bu
R
epoxidationSharpless asymmetric
R2 OHR2 OH
R1
substratesgood
high yields and ee
substratesok
high ee
OHR1
R3
R2 OHR1
R3
exampleslimited
substratespoor
OH
R3
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
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
©Jackal1@flickr
O
N•HCl
CF3
J. Org. Chem., 1988, 53, 4081 &
J. Am. Chem. Soc., 1987, 109, 5165
(R)-fluoxetine
Ph OH
SAE(+)-DIPTTBHP
89%>98%ee
Ph OHO
Ph NHMe
O
CF3
in total synthesis
chiralcatalysis
O
Br
O
O
OH
OHH
HH
O HOH
Tetrahedron Lett., 1988, 29, 3171
venustatriol©Nils Geylen@flickr
OHD-(–)-DETTi(OiPr)4TBHP
92%>90%ee
OHO
O
HO
CNin total synthesisSAE
O
Br
O
O
OH
OHH
HH
O HOH
in total synthesisSAE
O
Br
O
O
OH
OHH
HH
O HOH
O
HO
CND-(–)-DETTi(OiPr)4TrOOH
74%100%de
OO
HO
CN
in total synthesisSAE
O
Br
O
O
OH
OHH
HH
O HOH
OH
D-(–)-DETTi(OiPr)4TBHP
95%91%ee
OHO
C5H11CO2Et
K2OsO2(OH)4, K3Fe(CN)6, K2CO3,
MeSO2NH2, t-BuOH, H2O, 0°C, ligand
C5H11CO2Et
OH
OH99% ee
dihydroxylationSharpless asymmetric
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
dihydroxylationSharpless asymmetric
inverted stereocentre
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
dihydroxylationSharpless asymmetric
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
retention
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
SAD
H
MS
L
OsO4(DHQ)2PHAL
OsO4
(DHQD)2PHAL
mneumonic
attractive area - attracts aromatic substituents or
large, hydrophobic aliphatic groups
©Jack Scott, Department of Biological Sciences, University of Alberta
O
O
Et
exo-brevicominTetrahedron Lett., 1993, 34, 5031
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
©Wsiegmund@wikimedia commons
O
AcO
H
OH
OBzOHO
O
OHPh
BzHN
AcO O
AcOtaxol
taxol®Acta. Chem. Scand., 1996, 50, 649
Ph OiPr
O
Ph OiPr
OAcNH
OHregioselectivity
>20:194% ee
AcNHBr, LiOH, K2OsO2(OH)4, (DHQ)2-PHAL
aminohydroxylationSharpless asymmetric
ONH
Ph
O OPh
OH
OBz
AcOOH
H OAcO
O
HO
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