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
gareth j rowlands©Meredith_Farmer@flickr
LECTURE SIX
organocatalysis
chemistryclean
©Meredith_Farmer@flickr
©triplej*@flickr
wasteavoid
©j / f / photos@flickr
chemistry
must improve
©dullhunk@flickr
many enzymesmetal-freecatalysts
N
OH
OPO
OO
H
lysine
O
OH
PO
OO
©www.biochemsoctrans.orgBiochem. Soc. Trans. (2004) 32, 259
aldolases can use enamine chemistry
samethe
©David Reeves from Flickr
organic
chemistry
reactionin the aldol
H
O
H
O
cat (10%)H
O OH
88%anti / syn 3 / 1
97% ee
NH
O
OHL-proline
organocatalysis
aldolproline-catalysed
mechanism of
NH
O
OH
NO
OH
NO
OH
NO
O
H
H
O
H
H
OHH
O
H
O
©bogenfreund@Flickr
organocatalystgold
rush
enamine catalysis
PrH
O
NSO2PhPhO2S
F
cat. (1%) FH
O
Pr
NaBH4
FOH
Pr95%
96% eeNH OTMS
F3C
CF3
CF3
CF3
enamine-catalysis
N
Pr
O
ArAr
Si
NSO2Ph
PhO2S F N
Pr
O
ArAr
SiF
intermediates
catalysts
N
NH
O
Ph
R1
MacMillan’s imidazolidinone
catalystsMacMillan’ssynthesis of
N
NH
O
Ph
NH
NH2
O
Ph
O
NH2HCl
O
Ph
NH2
O
H
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
O
H
MOMO
OCl
ClCl
Cl
ClCl
N
NH•TFA
O
Ph
(5mol%)94%93%ee
O
H
MOMO
Cl
enaminecatalysis
©aussiegall@flickr
(–)-brasosideJ. Am. Chem. Soc., 2005, 127, 3696
OH
H
Me O O OHOH
OHHO
OO
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
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
NH
NHN
HCl
Sch50971Tetrahedron: Asymmetry., 2000, 11, 3867
H
O
NO2
NTrN (20mol%)78%20:1dr99%ee
OHC NO2
NTrNN
H NHSO2CF3
total synthesisenamine catalysis in
NH
NHN
N
H
Ar
NO
OOH
H
NS H
O
OF3C
total synthesisenamine catalysis in
R1
O
R2nuc
R1
O
R2nuc
LALA
LUMO-lowering catalysis
fastslow
R1
N
R2nuc
R1
O
R2nuc
NH
LUMO-lowering catalysis
fastslow
catalysisiminium
Ph
O
BnO OBn
O O
N
NH
CO2HBn
cat. (10%), neat, rt, 165h Ph
CO2BnBnO2C
O86%
99% ee
catalysisiminium ion
catalysisiminium ion
N
N CO2H
H
CO2Bn
BnOO
N
N CO2H
H
CO2Bn
CO2Bn
H
O
OH
O
Ph O
(R)-warfarinAngew. Chem. Int. Ed., 2003, 42, 4955©Rosebud 23@flickr
O
OH
O
Ph O
(R)-warfarinAngew. Chem. Int. Ed., 2003, 42, 4955
in total synthesis
O
OH
O
Ph O
O
OH
O
Ph
O
NH
HN
Ph
Ph
CO2H
96%82%ee
catalysisiminium
96% eeendo / exo
>200 : 1
cat. (20%)HClO4
OMe
Et
O
COEt
OMe
NH
N
Ph
O
O
catalysisiminium
in the Diels-Alder
catalysisiminium
in the Diels-Alder
OMeN
NO
OEt
NN
Et
ArO
©The University of Chicago Medical Center
hydrogenbonding
O
HR1
O
HR1
LAO
HR1
HNN
H
XR2 R3
δ+
unactivated Lewis acid H-bonding
hydrogenbonding catalysis
N
S
O (5mol%)TMSCN
87%97%ee N
S
OTMSNC
HN
NH
NH
NHPr
t-Bu S
O
catalysisH-bond
NH
N
H
H
H
MeO2C OH
(+)-yohimbineOrg. Lett., 2008, 10, 745
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
pictet-spenglerreaction
©1984 Columbia Pictures Industries
(iBu)2N N NN
t-Bu S
OPh
H HCl
NH
N Ac
OTBScatalysis
H-bondin total synthesis
©djwudi@flickr
catalyst ?what is smallest
H
the proton
©limowreck666@flickr
how do you
make a
spherechiral?
OO
PO
O H
phosphoricacids
chiral
Ph
NBz
HN
Ph
OMe
O
Ph
NH
Ph
NCO2MeBz(10mol%)
89%95%ee
proton in aza-enechiral
OOPO
O H
proton in Friedel-Craftschiral
Ar
NBz
NBn
(10mol%)
89-99%90-97%ee N
Bn
ArNHBz
Ph3Si
Ph3Si
OOP
O
OH
proton in hetero Diels-Alder reactionchiral
N
Cl
HO
OTMS
MeO
OMe
(3mol%)
90%97%ee
N
O
OMe
OH
Cl
OOPO
O NH
©CiCCiO.it@flickr
photoredoxchemistry
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