LECTURE SIX

ganocatalysis
or
gareth j rowlands ©Meredith_Farmer@flickr
clean
chemistry ©Meredith_Farmer@flickr
avoid
waste

©triplej*@flickr
chemistry
improve
must

©j / f / photos@flickr
many
enzymes
metal-free
catalysts

©dullhunk@flickr
aldolases
can use enamine

chemistry
lysine

H
N O O
O
O P O P O
O
O OH OH

©www.biochemsoctrans.org
Biochem. Soc. Trans. (2004) 32, 259
 o rganic
chemistry
thesam
e

©David Reeves from Flickr

organocatalysis in the aldol reaction
O

H O OH
cat (10%)
H
O O
N
H H 88%
OH anti / syn 3 / 1
L-proline 97% ee
 O O
OH
H
H
H
O
N H
H
OH

O
O
N N
O O
OH H

N
O
mechanism of
OH proline-catalysed
aldo
organocatalyst
gold
rush

©bogenfreund@Flickr
enamine catalysis
O
Pr O
H cat. (1%) F
H
PhO2S SO2Ph
N Pr
F
NaBH4
F3C
OH
CF3
CF3 F

Pr
N 95%
H
OTMS CF3 96% ee
 enamine-catalysis
intermediates

SO2Ph Ar Ar
N Ar Ar
N N
PhO2S F
O F O
Si Si
Pr Pr
MacMillan’s imidazolidinone
catalysts
O
N

R1
N
H
Ph
 of
synthesis
MacMillan’s
catalysts

O O O O
O NH2 NH N

NH2 NH2 H N
HCl H
Ph Ph Ph
 O O
O
E
R1 N R1
R2 R2
N
H
Ph O
O
N N

N Bn N
Ph E
R1 R1
R2 R2
O O
N N

N N general
Ph
R1
Ph
R1 enamine
R2 R2
E mechanism
 O
O
H N
O
N Cl
H H
Ph •TFA
MOMO
O (5mol%)
Cl 94%
Cl 93%ee
Cl MOMO

Cl Cl enamine
Cl catalysis
(–)-brasoside
O
O
H

J. Am. Chem. Soc., 2005, 127, 3696

O
OH
Me H HO OH
O O OH

©aussiegall@flickr
enamine catalysis in O
O

total synthesis
H

O
OH
H HO OH
O O OH

O N CO2H
H N
OMes O2C
D-proline H N R
(0.4eq) O
PhN=O Ph

HO PhHN O
Wittig O
CO2Me reaction
OMes 56% OMes
(2 steps)
enamine catalysis in O
O

total synthesis
H

O
OH
O H
O
HO
O
OH
OH

H O OH
N CO2H
OBn H OBn
O 78% H
98%ee OBn
H
OBn

OBn
RO OBn
TMSO O OBn
 Sch50971 HN N
Tetrahedron: Asymmetry., 2000, 11, 3867

N
H HCl
enamine catalysis in HN N

total synthesis
N
H

H N TrN
H
NHSO2CF3 N
TrN N (20mol%) OHC NO2
78%
20:1dr
99%ee
NO2
enamine catalysis in
total synthesis
O
N
S N
F3C H
O O
H H
N
O O
H
Ar
LUMO-lowering
catalysis

LA
O nuc LA O nuc

R1 R2 R1 R2

slow fast
LUMO-lowering
catalysis

N
O nuc H
N nuc
R1 R2
R1 R2
slow fast
iminium
catalysis
iminium ion
catalysis

N
O
CO2Bn
Bn N CO2H
Ph H BnO2C

O O cat. (10%),
neat, rt, 165h Ph O
BnO OBn 86%
99% ee
iminium ion
catalysis

N N

N CO2H CO2H
N

BnO H
CO2Bn
H O
H CO Bn
2
CO2Bn
 OH Ph O

O O

(R)-warfarin
©Rosebud 23@flickr
Angew. Chem. Int. Ed., 2003, 42, 4955
OH Ph O

O O

(R)-warfarin
Angew. Chem. Int. Ed., 2003, 42, 4955
iminium catalysis
in total synthesis

O Ph H
N
CO2H
Ph OH Ph O
Ph N
H
OH
96%
82%ee
O O

O O
 iminium
catalysis
OMe in the Diels-Alder

cat. (20%) COEt

HClO4

96% ee
O endo / exo OMe
>200 : 1
Et O N

N O
Ph H
 iminium
catalysis
in the Diels-Alder

O
N O Ar
N
N
N OMe
O Et
Et
 hydrogen
bonding
©The University of Chicago Medical Center
 hydrogen
bonding catalysis
X
R 2 R 3
N N
LA H δ+ H
O O O

R1 H R1 H R1 H
unactivated Lewis acid H-bonding
H-bond
catalysis
O NC OTMS
(5mol%)
TMSCN
S S
87%
N 97%ee N

t-Bu S
H
N
N N
H H
O NHPr
 N
H
N
H H
H
MeO2C
OH

(+)-yohimbine
Org. Lett., 2008, 10, 745
 NH2
N

N
H N
H
OHC OTBS
OTBS t-Bu S
(iBu)2N
AcCl
N N cat. (10mol%)
H H 81%
O N Ph
94%ee

N Ac

H-bond N
H

catalysis in total synthesis OTBS

pictet-spengler
reaction
©1984 Columbia Pictures Industries
 t-Bu S
(iBu)2N
N N
N Ph
O H H
Cl
N Ac

N
H
H-bond OTBS
catalysis in total synthesis
 what is
smallest
catalyst ?

©djwudi@flickr
the
proton

H
 do you
how
make a
sphere
chiral ?

©limowreck666@flickr
chiral phosphoric
acids

O
O
P
O
O H
chiral proton in aza-ene

Bz
N

Ph Bz CO2Me
(10mol%) NH N
O
89%
95%ee Ph Ph
HN OMe

Ph O
O
P
O O H
chiral proton in Friedel-Crafts
Bz
N NHBz
Ar
Ar (10mol%)

89-99%
90-97%ee N
N Bn
Ph3Si
Bn O O
P
O
H O

Ph3Si
 reaction
chiral proton in hetero Diels-Alder
HO

N OH
O

(3mol%) N

Cl 90%
OTMS 97%ee OMe

MeO Cl

O
OMe O
O
P
O
N
H
photoredox
chemistry

©CiCCiO.it@flickr
 cat (0.2eq),
O Ru(bipy)3Cl2 (0.005eq), O
O fluorescent light
Ph
Br H H
Ph 85%
C6H13 96% ee C6H13 O

photoredox O
N

N t-Bu

chemistry
H
O O
N N

N t-Bu t-Bu N

C(O)Ph
C6H13 O C6H13
N
SET *Ru(bipy)32+
N t-Bu

PhC(O)
Ru(bipy)3+
C6H13 light
O

Ph
Ru(bipy)32+
O SET

Br
Ph