lecture6: 123.702
DESCRIPTION
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.TRANSCRIPT
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gareth j rowlands©Meredith_Farmer@flickr
LECTURE SIX
organocatalysis
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chemistryclean
©Meredith_Farmer@flickr
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©triplej*@flickr
wasteavoid
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©j / f / photos@flickr
chemistry
must improve
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©dullhunk@flickr
many enzymesmetal-freecatalysts
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N
OH
OPO
OO
H
lysine
O
OH
PO
OO
©www.biochemsoctrans.orgBiochem. Soc. Trans. (2004) 32, 259
aldolases can use enamine chemistry
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samethe
©David Reeves from Flickr
organic
chemistry
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reactionin the aldol
H
O
H
O
cat (10%)H
O OH
88%anti / syn 3 / 1
97% ee
NH
O
OHL-proline
organocatalysis
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aldolproline-catalysed
mechanism of
NH
O
OH
NO
OH
NO
OH
NO
O
H
H
O
H
H
OHH
O
H
O
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©bogenfreund@Flickr
organocatalystgold
rush
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enamine catalysis
PrH
O
NSO2PhPhO2S
F
cat. (1%) FH
O
Pr
NaBH4
FOH
Pr95%
96% eeNH OTMS
F3C
CF3
CF3
CF3
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enamine-catalysis
N
Pr
O
ArAr
Si
NSO2Ph
PhO2S F N
Pr
O
ArAr
SiF
intermediates
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catalysts
N
NH
O
Ph
R1
MacMillan’s imidazolidinone
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catalystsMacMillan’ssynthesis of
N
NH
O
Ph
NH
NH2
O
Ph
O
NH2HCl
O
Ph
NH2
O
H
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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
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O
H
MOMO
OCl
ClCl
Cl
ClCl
N
NH•TFA
O
Ph
(5mol%)94%93%ee
O
H
MOMO
Cl
enaminecatalysis
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©aussiegall@flickr
(–)-brasosideJ. Am. Chem. Soc., 2005, 127, 3696
OH
H
Me O O OHOH
OHHO
OO
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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
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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
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NH
NHN
HCl
Sch50971Tetrahedron: Asymmetry., 2000, 11, 3867
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H
O
NO2
NTrN (20mol%)78%20:1dr99%ee
OHC NO2
NTrNN
H NHSO2CF3
total synthesisenamine catalysis in
NH
NHN
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N
H
Ar
NO
OOH
H
NS H
O
OF3C
total synthesisenamine catalysis in
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R1
O
R2nuc
R1
O
R2nuc
LALA
LUMO-lowering catalysis
fastslow
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R1
N
R2nuc
R1
O
R2nuc
NH
LUMO-lowering catalysis
fastslow
catalysisiminium
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Ph
O
BnO OBn
O O
N
NH
CO2HBn
cat. (10%), neat, rt, 165h Ph
CO2BnBnO2C
O86%
99% ee
catalysisiminium ion
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catalysisiminium ion
N
N CO2H
H
CO2Bn
BnOO
N
N CO2H
H
CO2Bn
CO2Bn
H
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O
OH
O
Ph O
(R)-warfarinAngew. Chem. Int. Ed., 2003, 42, 4955©Rosebud 23@flickr
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O
OH
O
Ph O
(R)-warfarinAngew. Chem. Int. Ed., 2003, 42, 4955
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in total synthesis
O
OH
O
Ph O
O
OH
O
Ph
O
NH
HN
Ph
Ph
CO2H
96%82%ee
catalysisiminium
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96% eeendo / exo
>200 : 1
cat. (20%)HClO4
OMe
Et
O
COEt
OMe
NH
N
Ph
O
O
catalysisiminium
in the Diels-Alder
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catalysisiminium
in the Diels-Alder
OMeN
NO
OEt
NN
Et
ArO
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©The University of Chicago Medical Center
hydrogenbonding
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O
HR1
O
HR1
LAO
HR1
HNN
H
XR2 R3
δ+
unactivated Lewis acid H-bonding
hydrogenbonding catalysis
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N
S
O (5mol%)TMSCN
87%97%ee N
S
OTMSNC
HN
NH
NH
NHPr
t-Bu S
O
catalysisH-bond
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NH
N
H
H
H
MeO2C OH
(+)-yohimbineOrg. Lett., 2008, 10, 745
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NH
NH2
OHCOTBS
NH
N
OTBSAcCl
cat. (10mol%)81%
94%ee
NH
N Ac
OTBScatalysisH-bond
in total synthesis
(iBu)2N NH
NH
N
t-Bu S
O Ph
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pictet-spenglerreaction
©1984 Columbia Pictures Industries
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(iBu)2N N NN
t-Bu S
OPh
H HCl
NH
N Ac
OTBScatalysis
H-bondin total synthesis
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catalyst ?what is smallest
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H
the proton
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how do you
make a
spherechiral?
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OO
PO
O H
phosphoricacids
chiral
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Ph
NBz
HN
Ph
OMe
O
Ph
NH
Ph
NCO2MeBz(10mol%)
89%95%ee
proton in aza-enechiral
OOPO
O H
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proton in Friedel-Craftschiral
Ar
NBz
NBn
(10mol%)
89-99%90-97%ee N
Bn
ArNHBz
Ph3Si
Ph3Si
OOP
O
OH
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proton in hetero Diels-Alder reactionchiral
N
Cl
HO
OTMS
MeO
OMe
(3mol%)
90%97%ee
N
O
OMe
OH
Cl
OOPO
O NH
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photoredoxchemistry
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N
NH
O
t-Bu
N
N
O
t-Bu
C6H13
N
N
O
t-Bu
C6H13
PhC(O)
N
N
O
t-Bu
C6H13
C(O)Ph
H
O
C6H13
H
O
C6H13
Ph
O
cat (0.2eq), Ru(bipy)3Cl2 (0.005eq),
fluorescent light
85%96% ee
Ph
OBr
Ru(bipy)3+
Ru(bipy)32+
*Ru(bipy)32+
light
SET
Ph
O
SET
Ph
OBr
photoredoxchemistry