MacMillan Lecture 4

Enantioselective Organocatalysis: A Valuable Strategy for Chemical Synthesis
The rapid growth of organocatalysis over the
Organocatalysis
last 10 years was fueled by the development

of a small number of generic activation modes
Iminium catalysis
O
Im
Enamine catalysis
En
H-bond catalysis
Me
Me
Me
N
Ph
Me
Me
HO2C
S
N
~50 new reactions

with Jorgensen, K. A.
~20 new reactions

Hajos-Wiechert
Barbas-List
H
O
R
R
Me
N
Me
H+
~30 new reactions

JacobsenAkiyama
! Last 10 years, organocatalysis has delivered many new asymmetric transforms (~150-200)
! These 3 activation modes cover a large portion of the organocatalysis landscape

Organocatalysis

Iminium catalysis
O
Im
Enamine catalysis
En
H-bond catalysis
Me
Me
Me
N
Ph
Me
Me
HO2C
S
N
~50 new reactions

~20 new reactions

Hajos-Wiechert
Barbas-List
H
O
R
R
Me
N
Me
H+
~30 new reactions

JacobsenAkiyama

Organocatalysis

Iminium catalysis
O
Im
Enamine catalysis
En
H-bond catalysis
Me
Me
Me
N
Ph
Me
Me
HO2C
S
N
~50 new reactions

~20 new reactions

Hajos-Wiechert
Barbas-List
H
O
R
R
Me
N
Me
H+
~30 new reactions

JacobsenAkiyama

Organocatalysis

Iminium catalysis
O
Im
Enamine catalysis
En
H-bond catalysis
Me
Me
Me
N
Ph
Me
Me
HO2C
S
N
~50 new reactions

~20 new reactions

Hajos-Wiechert
Barbas-List
H
O
R
R
Me
N
Me
H+
~30 new reactions

JacobsenAkiyama

Organocatalysis

Iminium catalysis
O
Im
Enamine catalysis
En
H-bond catalysis
Me
Me
Me
N
Ph
Me
Me
HO2C
S
N
~50 new reactions

~20 new reactions

Hajos-Wiechert
Barbas-List
H
O
R
R
Me
N
Me
H+
~30 new reactions

JacobsenAkiyama

Organocatalysis

Iminium catalysis
O
Im
Enamine catalysis
En
H-bond catalysis
Me
Me
Me
N
Ph
Me
Me
HO2C
S
N
~50 new reactions

~20 new reactions

Hajos-Wiechert
Barbas-List
H
O
R
R
Me
N
Me
H+
~30 new reactions

JacobsenAkiyama
Organometallic Catalysis: Few Activation Concepts
!-bond insertion
!-bond insertion
CC bond coupling
CN, S, O coupling
Suzuki
Negishi
Stille
Kumada
Fu
Lewis acid catalysis
Yates
La
Corey
Evans
Shibasaki
Mukaiyama
Buchwald
Hartwig
Olefin metathesis
Grubbs
Schrock
Hoveyda
Furstner
Ru
Many Powerful Reactions
"-bond insertion
Noyori
Toste
Heck
Feringa
Krische
"
Atom transfer catalysis
Sharpless
Jacobsen
Shi
Doyle
At
! Relatively few activation modes have resulted in literally thousands of new chemical reactions
Relatively Few Catalysis Activation Concepts
Instead of focusing completely on the invention of individual catalytic reactions

using long-established activation modes
Why don't we focus on the invention of new, useful catalytic activation modes?
Design of an entirely new catalyst activation mode is extremely challenging
So
OrganoSOMO catalysis
+ e
Photoredox organocatalysis
! Two new modes of catalyst activation using organocatalysts

So
+ e

So
+ e

So
+ e
So+ e
catalysis
OrganoSOMO
organocatalysis
Photoredox
!!AAnew
newmode
modeofoforganocatalytic
organocatalyticactivation
activation
Holy Grails in Asymmetric Catalysis: Asymmetric !-Carbonyl Alyklation
catalyst
Me
alkylBr
O
Me
alkyl
Holy Grails in Asymmetric Catalysis: Enolate Alyklation

! Chiral Auxiliary Controlled 1982, Evans, Meyers
O
O
O
N
Me
LDA;
O
BnBr
Ph
93% yield
Me
120:1 dr
Bn
Me
Ph
Me
! Catalytic Ketone Variant: Abby Doyle, Eric Jacobsen
OSnBu3
5 mol% cat
Me
Cr
Me
t-Bu
Br
t-Bu
84% yield
94% ee
N
Cl O
t-Bu
t-Bu
salen catalyst
! O'Donnell, Corey and Maruoka: glycine imine alkylation via PTC (seminal contributions )
! Fu has also introduced an elegant enantioselective alkyl-halide alkylation reaction

O
O
O
N
Me
LDA;
O
BnBr
Ph
93% yield
Me
120:1 dr
Bn
Me
Ph
Me
OSnBu3
5 mol% cat
Me
Cr
Me
t-Bu
Br
t-Bu
84% yield
94% ee
N
Cl O
t-Bu
t-Bu
salen catalyst

O
O
O
N
Me
LDA;
O
BnBr
Ph
93% yield
Me
120:1 dr
Bn
Me
Ph
Me
OSnBu3
5 mol% cat
Me
Cr
Me
t-Bu
Br
t-Bu
84% yield
94% ee
N
Cl O
t-Bu
t-Bu
salen catalyst
Can we use Enamine Catalysis to Solve Asymmetric Catalytic Carbonyl Alkylation

! Teresa Beeson: 3rd Year Graduate Student
! Initial idea: to perform asymmetric alkylation on aldehydes
N
H
aldehyde
enamine
catalyst
or
H
MeI or
BnBr
Me
no alkylation product
! Only products of aldehyde self dimerization were observed
Can we use Enamine Catalysis to Solve Asymmetric Catalytic Carbonyl Alkylation

! Teresa Beeson: 3rd Year Graduate Student
! Initial idea: to perform asymmetric alkylation on aldehydes
N
H
aldehyde
enamine
catalyst
or
H
MeI or
BnBr
Me
no alkylation product
! Only products of aldehyde self dimerization were observed
Inherent Problems for Enamine Catalysis and Asymmetric Catalytic Alkylation

! Potential Issues for Enantioselective Alkylation using Enamine Catalysis
H
O
MeI
R
N
H
insufficient e- density
to react with
enamine
catalyst
aldehyde
sp3-electrophile
in comparison to sp2-aldehyde
H
O
OH
H
R
O+
aldehyde-aldehyde
aldol dominates
sufficient e- density
to react with
sp2-aldehyde
! Intramolecular aldehyde alkylation can be accomplished (List and coworkers)
Designing a New Organocatalytic Catalysis Concept: SOMO Catalysis
O
N
not
H
R
H
R
Trying to force a reaction to work within the confines

of a known catalysis concept or activation mode
(square peg, round hole)
Reface
Reface
activated
activated
iminium catalysis
LUMOactivation
O
Me
N
+2
+
Me
R
Me
somo catalysis
SOMOactivation
Me
Me
N
Me
Me
N
Ph
enamine catalysis
HOMOactivation
N
Ph
Me
R
Me
Me
[oxid]
N
Ph
Me
Me
! Can we utilize the one electron species that lies between iminium and enamine catalysis
Reface
Reface
activated
activated
iminium catalysis
LUMOactivation
O
Me
N
+2
+
Me
R
Me
somo catalysis
SOMOactivation
Me
Me
N
Me
Me
N
Ph
enamine catalysis
HOMOactivation
N
Ph
Me
R
Me
Me
[oxid]
N
Ph
Me
Me
Reface
Reface
activated
activated
iminium catalysis
LUMOactivation
O
Me
N
+2
+
Me
R
Me
somo catalysis
SOMOactivation
Me
Me
N
Me
Me
N
Ph
enamine catalysis
HOMOactivation
N
Ph
Me
R
Me
Me
[oxid]
N
Ph
Me
Me
Reface
Reface
activated
activated
iminium catalysis
LUMOactivation
O
Me
N
+2
+
Me
R
Me
somo catalysis
SOMOactivation
Me
Me
N
Me
Me
N
Ph
enamine catalysis
HOMOactivation
N
Ph
Me
R
Me
Me
[oxid]
N
Ph
Me
Me
Reface
Reface
activated
activated
iminium catalysis
LUMOactivation
O
Me
N
+2
+
Me
R
Me
somo catalysis
SOMOactivation
Me
Me
N
Me
Me
N
Ph
enamine catalysis
HOMOactivation
N
Ph
Me
R
Me
Me
[oxid]
N
Ph
Me
Me
SOMO Catalysis: Potential Utility of New Catalysis Platform

O
Me
N
Me
Ph
N
H
Me
Me
catalyst
substrate
oxidant
CAN
Br
not electrophile
O
Me
N
Me
N
Ph
Me
Me
SOMO species
O
SiMe3
with SOMOphile
!-allyl aldehydes

O
Me
N
Me
Ph
N
H
Me
Me
catalyst
substrate
oxidant
CAN
Br
not electrophile
O
Me
N
Me
N
Ph
Me
Me
SOMO species
O
SiMe3
with SOMOphile
!-allyl aldehydes

O
Me
N
Me
Ph
N
H
Me
Me
catalyst
substrate
oxidant
CAN
Br
not electrophile
O
Me
N
Me
N
Ph
Me
Me
SOMO species
O
SiMe3
with SOMOphile
!-allyl aldehydes

O
Me
N
Me
Ph
N
H
Me
Me
catalyst
substrate
oxidant
CAN
Br
not electrophile
O
Me
N
Me
N
Ph
Me
Me
SOMO species
O
SiMe3
with SOMOphile
!-allyl aldehydes

O
Me
N
Me
Ph
N
H
Me
Me
catalyst
substrate
oxidant
CAN
Br
not electrophile
O
Me
N
Me
N
Ph
Me
Me
SOMO species
O
SiMe3
with SOMOphile
!-allyl aldehydes

O
Me
Me
Ph
Me
Me
catalyst
substrate
enantiopure
!-aryl aldehydes
N
H
oxidant
CAN
Ph
enantiopure
1,4-keto-aldehydes
O
O
Me
N
Me
N
Ph
Me
Me
enantiopure
ring formation
enantiopure
!"vinylation
SOMO species
O
O
H
H
OR
enantiopure
!-oxy aldehydes
!-allyl aldehydes

SOMO catalysis concept
substrate
catalyst
oxidant
R
N
H HCl
SOMOactivation
1 e
Why will there be selective oxidation: oxidation potentials
N
N
H
butanal
pyrrolidine
1-(but-1-enyl)pyrrolidine
IP = 9.84 eV
IP = 8.8 eV
IP = 7.24 eV
Oxidant should selectively reract with transient enamine to generate radical iminium cation

substrate
catalyst
oxidant
R
N
H HCl
SOMOactivation
1 e
Why will there be selective oxidation: oxidation potentials
N
N
H
butanal
pyrrolidine
1-(but-1-enyl)pyrrolidine
IP = 9.84 eV
IP = 8.8 eV
IP = 7.24 eV
Oxidant should selectively reract with transient enamine to generate radical iminium cation

substrate
catalyst
R
oxidant
R
N
H HCl
1 e
SOMOactivation
Requirements for enantioselectivity:

Iminium geometry control
!-carbon radical geometry control
Me
N
Me
+
Ph
substrate
N
H
Me
CAN
Me
organocatalyst
oxidant
Reface
activated to
SOMO nucleophiles
Could this be a third general platform of induction for the imidazolidinone catalyst family
Studies to determine the utility of SOMO catalysis for aldehyde alkylation

10 mol%
Bn
O
TMS
aldehyde
allyl silane
Me
N
N
H
tBu
DME
2 eq CAN
OH
aldehyde aldol (undesired)

10 mol%
Bn
O
TMS
aldehyde
allyl silane
Me
N
N
H
tBu
DME
2 eq CAN

10 mol%
Bn
O
TMS
aldehyde
allyl silane
Me
N
N
H
tBu
DME
2 eq CAN
OH
aldehyde aldol (undesired)

10 mol%
Bn
O
TMS
aldehyde
allyl silane
Me
N
N
H
tBu
DME
2 eq CAN

O
10 mol%
Bn
N
H
TMS
aldehyde
Me
N
O
tBu
81% yield
91% ee
DME
2 eq CAN
allyl silane
!-alkylated aldehyde
! Varying the allylsilane and the aldehyde component

O
81% yield
88% yield
H
Me
91% ee
O
H
Me
91% ee
CO2Et
58% yield
94% ee
81% yield
O
Ph
87% yield
Ph
90% ee
90% ee
NBoc
70% yield
93% ee
with Beeson, Masstrachio, Hong, Ashton, Science, 2007, 316, 582

O
10 mol%
Bn
N
H
TMS
aldehyde
Me
N
O
tBu
81% yield
91% ee
DME
2 eq CAN
allyl silane
! Varying the allylsilane and the aldehyde component

O
81% yield
88% yield
H
Me
91% ee
O
H
Me
91% ee
CO2Et
58% yield
94% ee
81% yield
O
Ph
87% yield
Ph
90% ee
90% ee
NBoc
70% yield
93% ee
with Beeson, Masstrachio, Hong, Ashton, Science, 2007, 316, 582
Enantioselective OrganoSOMO Catalysis: Possible Catalytic Cycle

! OrganoSOMO Aldehyde Alkylation
O
! Mechanistic Evidence for radical cation

O
1e
radical-clock substrate
used to detect
radical-cation ?
O
Me
N
Ph
Ph
SOMO catalysis versus

enamine catalysis
N
H
N
But
1e
N
1e
cat A
Ph
stable
! Enamine catalysis
O
H
Ph
Ph
unstable
! SOMO catalysis
O
O
2 eq NCS
Ph
Cl
SiMe3
10% catalyst A
Ph
Ph
82 %
Ph
10% catalyst A
2 eq CAN
O2NO
Ph
68 %
Ph
not
observed

O

O
1e
used to detect
radical-cation ?
O
Me
N
Ph
Ph

enamine catalysis
N
H
N
But
1e
N
1e
cat A
Ph
stable
! Enamine catalysis
O
H
Ph
Ph
unstable
! SOMO catalysis
O
O
2 eq NCS
Ph
Cl
SiMe3
10% catalyst A
Ph
Ph
82 %
Ph
10% catalyst A
2 eq CAN
O2NO
Ph
68 %
Ph
not
observed

O

O
1e
used to detect
radical-cation ?
O
Me
N
Ph
Ph

enamine catalysis
N
H
N
But
1e
N
1e
cat A
Ph
stable
! Enamine catalysis
O
H
Ph
Ph
unstable
! SOMO catalysis
O
O
2 eq NCS
Ph
Cl
SiMe3
10% catalyst A
Ph
Ph
82 %
Ph
10% catalyst A
2 eq CAN
O2NO
Ph
68 %
Ph
not
observed

O

O
1e
used to detect
radical-cation ?
O
Me
N
Ph
Ph

enamine catalysis
N
H
N
But
1e
N
1e
cat A
Ph
stable
! Enamine catalysis
O
H
Ph
Ph
unstable
! SOMO catalysis
O
O
2 eq NCS
Ph
Cl
SiMe3
10% catalyst A
Ph
Ph
82 %
Ph
10% catalyst A
2 eq CAN
O2NO
Ph
68 %
Ph
not
observed

O

O
1e
used to detect
radical-cation ?
O
Me
N
Ph
Ph

enamine catalysis
N
H
N
But
1e
N
1e
cat A
Ph
stable
! Enamine catalysis
O
H
Ph
Ph
unstable
! SOMO catalysis
O
O
2 eq NCS
Ph
Cl
SiMe3
10% catalyst A
Ph
Ph
82 %
Ph
10% catalyst A
2 eq CAN
O2NO
Ph
68 %
Ph
not
observed

O
1e
SiMe3
Me
Me
Ph
N
H
But
O
N
+
tBu
N
X-
Bn
R
cat A
SOMOphile addition?
SiMe3

O
1e
SiMe3
Me
Me
Ph
N
H
But
O
N
+
tBu
N
X-
Bn
R
cat A
SOMOphile addition?
SiMe3

! Test for SOMOphile

+
1e
SiMe3
MeO
Me
Me
Ph
OMe
But
tBu
N
X-
Bn
OMe
N
N
H
Ph
H
Ph
Ph
cat A
O
SiMe3
O
OMe
H
X
! Newcombe radical vs cation discrimination
B
MeO
Ph
Newcombe: to detect
2e !-addition pathway
versus
1e SOMOphile addition
Bu
10% catalyst A
2 eq CAN
Ph
olefin B
Ph
OMe
57%
O2NO
Ph


+
1e
SiMe3
MeO
Me
Me
Ph
OMe
But
tBu
N
X-
Bn
OMe
N
N
H
Ph
H
Ph
Ph
cat A
O
SiMe3
O
OMe
H
X
B
MeO
Ph
Newcombe: to detect
versus
Bu
10% catalyst A
2 eq CAN
Ph
olefin B
Ph
OMe
57%
O2NO
Ph


+
1e
SiMe3
MeO
Me
Me
Ph
OMe
But
tBu
N
X-
Bn
OMe
N
N
H
Ph
H
Ph
Ph
cat A
O
SiMe3
O
OMe
H
X
B
MeO
Ph
Newcombe: to detect
versus
Bu
10% catalyst A
2 eq CAN
Ph
olefin B
Ph
OMe
57%
O2NO
Ph


+
1e
SiMe3
MeO
Me
Me
Ph
OMe
But
tBu
N
X-
Bn
OMe
N
N
H
Ph
H
Ph
Ph
cat A
O
SiMe3
O
OMe
H
X
B
MeO
Ph
Newcombe: to detect
versus
Bu
10% catalyst A
2 eq CAN
Ph
olefin B
Ph
OMe
57%
O2NO
Ph

! Test for second oxidation

O
1e
SiMe3
Me
Me
N
H
N
X-
% Yield
Bn
1.0
37%
1.5
61%
2.0
88%
3.0
87%
cat A
SiMe3
Me
Bu
tBu
But
10% catalyst A
X eq CAN
X eq CAN
Ph
H
Bu
SiMe3
O
N
+
tBu
N
X-
! Second oxidation is
important ?
Bn
1e
! !-silyl radical readily oxidized

1e
SiMe3
! This catalytic cycle would require 2 oxidation events
SiMe3
SiMe3


O
1e
SiMe3
Me
Me
N
H
N
X-
% Yield
Bn
1.0
37%
1.5
61%
2.0
88%
3.0
87%
cat A
SiMe3
Me
Bu
tBu
But
10% catalyst A
X eq CAN
X eq CAN
Ph
H
Bu
SiMe3
O
N
+
tBu
N
X-
important ?
Bn
1e

1e
SiMe3
SiMe3
SiMe3


O
1e
OO
SiMe3
Me
Me
N
H
N
X-
Bn
R
cat A
SiMe3
Me
Bu
Bu
%%Yield
Yield
tBu
But
10%
10%catalyst
catalystAA
XXeq
eqCAN
CAN
XXeq
eqCAN
CAN
Ph
HH
HH
Bu
Bu
OO
SiMe
SiMe
33
1.0
1.0
1.5
1.5
37%
37%
61%
61%
2.0
2.0
3.0
3.0
88%
88%
87%
87%
O
N
+
tBu
N
X-
important ?
Bn
1e

1e
SiMe3
SiMe3
SiMe3


O
1e
OO
SiMe3
Me
Me
N
H
N
X-
Bn
R
cat A
SiMe3
Me
Bu
Bu
%%Yield
Yield
tBu
But
10%
10%catalyst
catalystAA
XXeq
eqCAN
CAN
XXeq
eqCAN
CAN
Ph
HH
HH
Bu
Bu
OO
SiMe
SiMe
33
1.0
1.0
1.5
1.5
37%
37%
61%
61%
2.0
2.0
3.0
3.0
88%
88%
87%
87%
O
N
+
tBu
N
X-
important ?
Bn
1e

1e
SiMe3
SiMe3
SiMe3

O
1e
SiMe3
O
N
Ph
N
H
Me
SOMO
cycle
Me
tBu
But
oxidant = 1e
cat A
O
N
N
X-
Bn
R
SiMe3
+ H 2O
SiMe3+
Me
+
tBu
N
X-
O
H
O
N
Bn
1e
SiMe3
R
important
!-allyl aldehyde
! Loss of TMS-cation
SOMO activation strategy is useful for a variety of organocatalytic reactions

Aldehyde !-allylation
Aldehyde !-enolation
"-Nitro-!-alkyl aldehyde
Science 2007, 316, 582

ACIE 2010, asap (Flowers)
JACS 2007,129, 7004
JACS 2009, 131, 11332
91% ee
O
Ph
hex
hex
90% ee
NO2
Me
91% ee
hex
Aldehyde !-vinylation
Olefin carbo-oxidation
!-Chlorination/epoxidation
JACS 2008, 130, 398
JACS 2008, 130, 16494
ACIE 2009, 48, 5121
O
Ph
94% ee
hex
JACS 2010, 132, asap
Bn
H
S
Intramolecular !-arylation
90% ee
94% ee
ONO2
Polyene cyclization
JACS 2009, 131, 11640

JACS 2009, 131, 2086 (Nicolaou)
JACS 2010, 132, 6001 (Houk)
Ph
96% ee
hex
Cascade Cycloaddition
Ph
JACS 2010, 132, 5027

Me
Me
CN
OMe
98% ee
92% ee
Multiple Radical Bond Formations

R
Me
O
N
R
R
N
H
R R
R
Ar
2 x 1e oxidant
R
O
Direct and enantioselective access to steroid-type scaffolds
amine catalyst
1e, H+
amine catalyst
H2O, 1e
Me
What substituent
pattern will favor
polycyclization?
N
N
N
Ar
Ar
R R
R
What oxidant favors

a long-lived radical
for polycyclization?
Me
R R
R
Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027.

R
Me
O
N
R
R
N
H
R R
R
Ar
2 x 1e oxidant
R
O
amine catalyst
1e, H+
amine catalyst
H2O, 1e
Me
Me
What substituents
N
N
favor polycyclization?
N
Ar
Ar
R R
R
R R
R
What oxidant favors

polycyclization?

R
Me
O
N
R
R
N
H
R R
R
Ar
2 x 1e oxidant
R
O
amine catalyst
1e, H+
amine catalyst
H2O, 1e
Me
Me
What substituents
N
N
favor polycyclization?
N
Ar
Ar
R R
R
R R
R
What oxidant favors

polycyclization?
Radical vs. Cation Propagating Species in Polycyclization

Me
Me
Me
Me
Me
TFA
HO
Me
Me
Me
Me
Me
Me
Me
Propagating species is carbocation: electron rich double bonds favor cyclization
Me
Me
Electron
donating
N
Ar
Me
Electron
withdrawing
N
Ar
Me CN
Me
Electrophillic
radical
O
N
N
Ar
Me CN
Me
Me CN
Me
Nucleophillic
radical
Propagating species is radical: alternating polarity favors cyclization

Johnson, W. S.; Semmelhack, M. F.; Sultanbawa, M. U. S.; Dolak, L. A. J. Am. Chem. Soc. 1968, 90, 2994.

Me
Me
Me
Me
Me
TFA
HO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Electron
donating
N
Ar
Me
Electron
withdrawing
N
Ar
Me CN
Me
Electrophillic
radical
O
N
N
Ar
Me CN
Me
Me CN
Me
Nucleophillic
radical


Me
Me
Me
Me
Me
TFA
HO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Electron
donating
N
Ar
Me
Electron
withdrawing
N
Ar
Me CN
Me
Electrophillic
radical
O
N
N
Ar
Me CN
Me
Me CN
Me
Nucleophillic
radical


Me
Me
Me
Me
Me
TFA
HO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Electron
donating
N
Ar
Me
Electron
withdrawing
N
Ar
Me CN
Me
Electrophillic
radical
O
N
N
Ar
Me CN
Me
Me CN
Me
Nucleophillic
radical


Me
Me
Me
Me
Me
TFA
HO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Electron
donating
N
Ar
Me
Electron
withdrawing
N
Ar
Me CN
Me
Electrophillic
radical
O
N
N
Ar
Me CN
Me
Me CN
Me
Nucleophillic
radical


Me
Me
Me
Me
Me
TFA
HO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Electron
donating
N
Ar
Me
Electron
withdrawing
N
Ar
Me CN
Me
Electrophillic
radical
O
N
N
Ar
Me CN
Me
Me CN
Me
Nucleophillic
radical

Competition with Premature Radical Oxidation

Me
O
N
Me
N
H
Bicyclization
Ar
CAN
or
Fe(phen)3(PF6)3
precursor
Me
N
Ar
Me
O
N
N
Ar
Monocylization
Me
N
N
product
Me
Ar
Me
Further oxidation
outcompetes cyclization

Me
O
N
Me
N
H
Bicyclization
Ar
CAN
or
Fe(phen)3(PF6)3
precursor
Me
N
Ar
Me
O
N
N
Ar
Monocylization
Me
N
N
product
Me
Ar
Me
Further oxidation

Me
O
N
Me
N
H
Bicyclization
Ar
CAN
or
Fe(phen)3(PF6)3
precursor
Me
N
Ar
Me
O
N
N
Ar
Monocylization
Me
N
N
product
Me
Ar
Me
Further oxidation

Me
O
N
Me
N
H
Bicyclization
Ar
CAN
or
Fe(phen)3(PF6)3
precursor
Me
N
Ar
Me
O
N
N
Ar
Monocylization
Me
N
N
product
Me
Ar
Me
Further oxidation
Copper Oxidant Allows for Efficient Bicyclization
Me
O
N
Me
N
H
Me
1-Np
Cu(OTf)2
i-PrCN/DME, 23 C
70% yield
87% ee
H
O
CN
F
CO2Me
MeO
Me
Me
Me
Me
65% yield
90% ee
75% yield
88% ee
74% yield
88% ee
77% yield
87% ee
Alternating Polarity of Olefins Allows for Multicyclization

CN
Me
O
N
Me
OMe
N
Me
Ar
Me CN
CN
H
Me
H
Will alternating polarity

enable multicyclization?
CN
H
OMe
H
61% yield
91% ee
CN
Me
Tricyclization
56% yield
92% ee
Tetracyclization
CN
Me
OMe
Me
CN
Me
6 new CC bonds
CN
11 contiguous stereocenters
Me
CN
H
H
O
Me
OMe
CN
H
63% yield
93% ee
62% yield
5 all-carbon quaternary
stereocenters
92% yield per bond formation
Pentacyclization
Hexacyclization

CN
Me
O
N
Me
OMe
N
Me
Ar
Me CN
CN
H
Me
H

CN
H
OMe
H
61% yield
91% ee
CN
Me
Tricyclization
56% yield
92% ee
Tetracyclization
CN
Me
OMe
Me
CN
Me
6 new CC bonds
CN
Me
CN
H
H
O
Me
OMe
CN
H
63% yield
93% ee
62% yield
stereocenters
Pentacyclization
Hexacyclization

CN
Me
O
N
Me
OMe
N
Me
Ar
Me CN
CN
H
Me
H

CN
H
OMe
H
61% yield
91% ee
CN
Me
Tricyclization
56% yield
92% ee
Tetracyclization
CN
Me
OMe
Me
CN
Me
6 new CC bonds
CN
Me
CN
H
H
O
Me
OMe
CN
H
63% yield
93% ee
62% yield
stereocenters
Pentacyclization
Hexacyclization

CN
Me
O
N
Me
OMe
N
Me
Ar
Me CN
CN
H
Me
H

CN
H
OMe
H
61% yield
91% ee
CN
Me
Tricyclization
56% yield
92% ee
Tetracyclization
CN
Me
OMe
Me
CN
Me
6 new CC bonds
CN
Me
CN
H
H
O
Me
OMe
CN
H
63% yield
93% ee
62% yield
stereocenters
Pentacyclization
Hexacyclization

CN
Me
O
N
Me
OMe
N
Me
Ar
Me CN
CN
H
Me
H

CN
H
OMe
H
61% yield
91% ee
CN
Me
Tricyclization
56% yield
92% ee
Tetracyclization
CN
Me
OMe
Me
CN
Me
6 new CC bonds
CN
Me
CN
H
H
O
Me
OMe
CN
H
63% yield
93% ee
62% yield
stereocenters
Pentacyclization
Hexacyclization
So+ e
catalysis
OrganoSOMO
organocatalysis
Photoredox
!!AAnew
newmode
modeofoforganocatalytic
organocatalyticactivation
activation
The Utility of Merging Different Catalysis Areas: New Catalytic Bond Constructions
Photoredox Catalysis
Representative
Utility
H2 Production
N
N
N
Ru2+
N
N
N
O2 Production
CH4 Production
Light
Energy Storage
Organocatalysis
Representative
Transformations
Representative
Utility
O
Aldol
Me
N
Friedel-Crafts
N
H
Vinylation
H2 Production
N
N
N
Ru2+
N
N
N
O2 Production
amine
Allylation
CH4 Production
Enolation
Enal Reduction
Diels-Alder
H2O
Light
Energy Storage
Organocatalysis
Representative
Transformations
Representative
Utility
O
Aldol
Me
N
Friedel-Crafts
N
H
Vinylation
H2 Production
N
N
N
Ru2+
N
N
N
O2 Production
amine
Allylation
CH4 Production
Enolation
Enal Reduction
Diels-Alder
H2O
Light
Energy Storage
Organocatalysis
Representative
Transformations
Representative
Utility
O
Aldol
Me
N
Friedel-Crafts
N
H
Vinylation
Enal Reduction
Diels-Alder
Ru2+
N
N
N
O2 Production
amine
Allylation
Enolation
H2 Production
N
N
H2O
CH4 Production
Light
Energy Storage
New Organic Transformations with Enantioselective Induction
How can we use Photoredox Catalysis to Enable Aldehyde !-Alkylation

! SOMO catalysis, activated species reacts with electron rich "-systems
Me
N
Ph
Me
Me
Ph
SOMO-phile
Me
Me
N
OSiMe3
Me
oxidant
Me
SiMe3
So
KF3B
! Can we electronically reverse the role of the catalyst
Me
N
Me
N
Ph
Me
Me
h#
photolytic
bond homolysis
enamine
SOMO-activated
(SOMO-phile)
(!-acyl radical)
Me
So
Me
SOMOactivated
SOMO-philes =
Br
h#
= photobox!
Ph

Me
N
Ph
Me
Me
Ph
SOMO-phile
Me
Me
N
OSiMe3
Me
oxidant
Me
SiMe3
So
KF3B
Me
N
Me
N
Ph
Me
Me
h#
photolytic
bond homolysis
enamine
SOMO-activated
(SOMO-phile)
(!-acyl radical)
Me
So
Me
SOMOactivated
SOMO-philes =
Br
h#
= photobox!
Ph

Me
N
Ph
Me
Me
Ph
SOMO-phile
Me
Me
N
OSiMe3
Me
oxidant
Me
SiMe3
So
KF3B
Me
N
Me
N
Ph
Me
Me
h#
photolytic
bond homolysis
enamine
SOMO-activated
(SOMO-phile)
(!-acyl radical)
Me
So
Me
SOMOactivated
SOMO-philes =
Br
h#
= photobox!
Ph

Me
N
Ph
Me
Me
Ph
SOMO-phile
Me
Me
N
OSiMe3
Me
oxidant
Me
SiMe3
So
KF3B
Me
N
Me
N
Ph
Me
Me
h#
photolytic
bond homolysis
enamine
SOMO-activated
(SOMO-phile)
(!-acyl radical)
Me
So
Me
SOMOactivated
SOMO-philes =
Br
h#
= photobox!
Ph

Me
N
Ph
Me
Me
Ph
SOMO-phile
Me
Me
N
OSiMe3
Me
oxidant
Me
SiMe3
So
KF3B
Me
N
Me
N
Ph
Me
Me
h#
photolytic
bond homolysis
enamine
SOMO-activated
(SOMO-phile)
(!-acyl radical)
Me
So
Me
SOMOactivated
SOMO-philes =
Br
h#
= photobox!
Ph
Ru(bpy)3: A Versatile and Extensively Utilized Photredox Catalyst
2+
N
N
N
Ru
N
N
N
Ru(bpy)3X2
Coord. Chem. Rev. 1982, 46, 159.
! Visible MLCT absorption at 452 nm (weak visible light)

! Long-lived excited state (~ 620ns)
! High quantum yield (~0.05 - H2O/298K)
! Effective excited state oxidant and reductant
! Used extensively as electron transfer catalyst
! Inexpensive ($38/g - Strem 2008)
Ru(bpy)3: Electronic Properties that Enable Photredox Catalysis

2+
2+
N
N
N
Ru
N
N
N
Ru
N
N
N
Strong Oxidant
E = 0.84V
Ru(bpy)31+
Photon
Excitation
with weak
visible light
Ru-centered
orbitals (t2g)
Ru(bpy)32+
Metal-Based Ground State
Ligand-centered
orbital (!*)
*Ru(bpy) 2+
3
E = 0.86V
Excited, Ligand-Based State
Strong Reductant
Ru(bpy)33+
Balzani, A. J. V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zewelsky, A. Coord. Chem. Rev. 1988, 84, 85.
How can we use Photoredox Catalysis to Enable Single Electron Pathways

2+
N
N
N
Ru
N
N
N
Ru(bpy)32+
15W
Fluorescent bulb

*
2+
2+
Br
N
N
N
Ru
N
absorbs
photon
Ru
N
15W
Fluorescent bulb
= single electron transfer
Br
Ru(bpy)32+ *
(excited state)
Ru(bpy)32+
SET
N
N
SET
SOMO-activated

*
2+
2+
Br
N
N
N
Ru
N
absorbs
photon
N
N
N
Ru
N
Br
N
N
SET
SOMO-activated
Ru(bpy)32+ *
(excited state)
*
Ru(bpy)32+
SET
Fluorescent bulb
Br
N
N
N
SET
1+
15W
Ru
N
Br

Ru(bpy)31+
SET
SOMO-activated

*
2+
2+
Br
N
N
N
Ru
N
absorbs
photon
N
N
N
Ru
N
Br
N
N
SET
SOMO-activated
Ru(bpy)32+ *
(excited state)
*
Ru(bpy)32+
SET
Fluorescent bulb
Br
N
N
N
SET
1+
15W
Ru
N
Br

Ru(bpy)31+
! Using a household 15W light bulb with Ru(bpy)
SET
SOMO-activated
highly reactive one-electron species
Merging Enantioselective Organocatalysis and Photoredox Catalysis
Photoredox Catalytic
Cycle
Ru(bpy)32+
photoredox catalyst 1
Cycle
Ru(bpy)32+
15W Fluorescent bulb
!Ru(bpy) 2+
3
oxidant
Cycle
Ru(bpy)32+
Ru(bpy)31+ 3
reductant
!Ru(bpy) 2+
3
oxidant
Cycle
Ru(bpy)32+
Ru(bpy)31+ 3
reductant
alkyl halide
alkyl halide
substrate
substrate
!Ru(bpy) 2+
3
oxidant
O
Ph
Br
Cycle
Ru(bpy)32+
Ru(bpy)31+ 3
reductant
oxidant
alkyl halide
alkyl halide
substrate
substrate
Ph
Br
SET
electron-deficient
radical A
!Ru(bpy) 2+
3
Cycle
Br
Ph
Ru(bpy)32+
aldehyde
substrate
H
R
O
N
Me
t-Bu
N
H
Organocatalytic
Cycle
catalyst
Ru(bpy)31+ 3
reductant
oxidant
alkyl halide
alkyl halide
substrate
substrate
Ph
Br
SET
electron-deficient
radical A
!Ru(bpy) 2+
3
Cycle
Br
Ph
Ru(bpy)32+

O
Me
N
aldehyde
substrate
Me
t-Bu
H
R
R
O
Me
N
Me
t-Bu
N
H
Organocatalytic
Cycle
catalyst
Ru(bpy)31+ 3
reductant
oxidant
alkyl halide
alkyl halide
substrate
substrate
Ph
Br
SET
electron-deficient
radical A
!Ru(bpy) 2+
3
Cycle
Br
Ph
Ru(bpy)32+

O
Me
N
aldehyde
substrate
Me
t-Bu
H
R
R
O
Me
N
Me
t-Bu
N
H
Organocatalytic
Cycle
catalyst
Ru(bpy)31+ 3
reductant
oxidant
alkyl halide
alkyl halide
substrate
substrate
Ph
Br
SET
electron-deficient
radical A
!Ru(bpy) 2+
3
Cycle
Br
Ph
Ru(bpy)32+

O
Me
N
aldehyde
substrate
Me
t-Bu
H
R
R
O
Me
N
Me
t-Bu
N
H
Organocatalytic
Ph
radical A
Cycle
catalyst
Ru(bpy)31+ 3
reductant
!Ru(bpy) 2+
3
oxidant
alkyl halide
alkyl halide
substrate
substrate
Ph
Br
SET
electron-deficient
radical A
Si-face
open
Cycle
Br
Ph
Ru(bpy)32+

O
Me
N
aldehyde
substrate
Me
t-Bu
H
R
R
O
Me
N
Me
t-Bu
N
H
Si-face
open
Organocatalytic
Ph
radical A
Cycle
catalyst
Me
O
N
t-Bu
Me
Ph
R
Ru(bpy)31+ 3
reductant
oxidant
alkyl halide
alkyl halide
substrate
substrate
Ph
Br
SET
electron-deficient
radical A
!Ru(bpy) 2+
3
Cycle
Br
Ph
Ru(bpy)32+

O
Me
N
aldehyde
substrate
Me
t-Bu
H
R
R
O
Me
N
Me
t-Bu
N
H
Si-face
open
Organocatalytic
radical A
Cycle
catalyst
Me
Me
O
+
t-Bu
O
N
t-Bu
Me
Me
Ph
Ph
SET
Ru(bpy)31+ 3
reductant
!Ru(bpy) 2+
3
oxidant
alkyl halide
alkyl halide
substrate
substrate
Ph
Br
SET
electron-deficient
radical A
Ph
Cycle
Br
Ph
Ru(bpy)32+

O
Me
N
aldehyde
substrate
Me
t-Bu
H
R
R
O
Me
N
Me
t-Bu
N
H
Si-face
open
Organocatalytic
Ph
radical A
Cycle
catalyst
O
Me
Ph
Me
O
N
t-Bu
enantioenriched
t-Bu
Me
Me
Ph
Ph
SET
Ru(bpy)31+ 3
reductant
"Ru(bpy) 2+
3
oxidant
alkyl halide
alkyl halide
substrate
substrate
Ph
Br
SET
electron-deficient
radical A
O
N
Cycle
Br
Ph
Ru(bpy)32+
Merging Photoredox and Enantioselective Organocatalysis: Initial Results
Catalyst Combination
O
Me
Me
HOTf
N
Me
N
H
Me
Photon Source
N
N
N
Ru
N
N
N
Me
organocatalyst A (20 mol%)
Ru(bpy)3Cl2 B (0.5 mol%)
15 W fluorescent light bulb
O
Me
HOTf
N
Me
Me
N
H
Me
O
Bu
Br
octanal
N
N
N
Ru
N
N
N
Me
Photon Source
!-bromoketone
fluorescent light
organocatalyst A
Ru(bpy)3Cl2 B
2,6-lutidine, DMF,
23 C
84% yield
H
96% ee
Hex
enantioenriched
preliminary experiments revealed that the asymmetric tandem catalysis mechanism was possible
Photoredox and Organocatalysis: Bromocarbonyl Scope
Me
HOTf
N
O
catalyst combination
15 W fluorescent light
Br
Hex
octanal
FG
2,6-lutidine, DMF, 23 C
alkylation product
!-bromocarbonyl
Hex
Hex
84% yield, 95% ee
80% yield, 92% ee
O Me
EtO2C
CO2Et
Me
H
H
Br
Hex
NO2
OR
H
Br
Br
O2N
alkylation product
87% yield, 96% ee
Me
0.5 mol% Ru(bpy)3Cl2
O
RO
Br
Me
20 mol% catalyst
!-bromocarbonyl
H
MeO
OMe
N
H
FG
enantioenriched
racemic
!-bromocarbonyl
Me
Me
CO2Et
CO2Et
Hex
80% yield, 88% ee
A variety of alkylation substrates can be used that are outside the realm of 2e pathways
O
Me
Photon Source
N
Me
HOTf
N
N
N
Me
N
H
Me
Ru
N
N
N
Me
CO2Et
H
Hex
octanal
Br
racemic
!-bromoketone
EtO2C
fluorescent light
organocatalyst A
Ru(bpy)3Cl2 B
2,6-lutidine, DMF,
23 C
70% yield,
5:1 dr, 99% ee
O
Hex
enantioenriched
with David Nicewicz, Science, 2008, 3, 77 (published online Thurs, Sept 4th)
Photoredox Organocatalysis: Potential Utility of New Catalysis Platform

O
Me
N
Me
N
H
Ph
substrate
Me
catalyst
Me
N
Me
N
Ph
Me
Me
FG
N
Br
FG
substrate
N
N
Ru
N
N
N
catalyst
Me

O
Me
N
Me
H
EtO2C
Me
CO2Et
N
H
Ph
substrate
enantiopure
!-malonyl aldehydes
Me
catalyst
Me
N
Me
N
Ph
Me
Me
R
O
FG
enantiopure
"-keto aldehydes
N
Br
FG
substrate
N
N
Ru
N
N
N
catalyst
Me

O
Me
N
Me
H
EtO2C
Me
CO2Et
N
H
Ph
substrate
Me
Me
catalyst
enantiopure
!-benzyl aldehydes
enantiopure
!-malonyl aldehydes
Me
N
Me
N
Ph
Me
Me
H
NR2
enantiopure
!"amino aldehydes
O
FG
enantiopure
#-keto aldehydes
O
O
N
H
Br
CN
enantioselective
!-alkylcyanation
FG
N
N
Ru
N
N
N
H
CF3
!-CF3-aldehydes
substrate
catalyst

O
Me
N
Me
H
EtO2C
Me
CO2Et
N
H
Ph
substrate
Me
Me
catalyst
enantiopure
!-benzyl aldehydes
enantiopure
!-malonyl aldehydes
Me
N
Me
N
Ph
Me
Me
H
NR2
enantiopure
!"amino aldehydes
O
FG
enantiopure
#-keto aldehydes
O
O
N
H
Br
CN
enantioselective
!-alkylcyanation
FG
N
N
Ru
N
N
N
H
CF3
!-CF3-aldehydes
substrate
catalyst
Merging Photoredox and Organocatalysis: !-Perfluoroalkylation

Versatile synthon for medicinal agent synthesis
O
CF3
H
R
Enhance potency, elevate lipophilicity

and/or improve metabolic stability
No known catalytic routes to !-formyl CF3
Me
F
Odanacatib (Merck)
N
O
O
S
O
NC
N
H
Me
F
H
OMe
Me
N
H CO2Me
H
N
CF3
Vinflunine
(BMS)
H
N
Me
H
OH
Me
Et
CO2Me
OAc
Enantioselective !-perfluoralkylation of formyl could provide new entry to pharmacaphores
Photoredox and Organocatalysis: Trifluoromethylation
Me
HOTf
aldehyde
CF3
2,6-lutidine, THF, 20 C
CF3
aldehyde
trifluoromethylation product
CF3
CF3
79% yield, 99% ee
70% yield, 98% ee
N
Boc
O
O
H
H
NBoc
( )5
Me
0.5 mol% Ir(ppy)2bpy
Me
20 mol% catalyst
enantioenriched
!-trifluoromethylation
N
H
Me
Me
trifluoromethyl iodide
aldehyde
OMe
OMe
H
CF3
73% yield, 90% ee
CF3
61% yield, 93% ee
with Nagib, Scott, JACS, 2009, 131, 10875
Photoredox and Organocatalysis: Trifluoromethylation
Me
HOTf
aldehyde
CF3
O
H
CF3
aldehyde
( )5
CF3
CF3
79% yield, 99% ee
70% yield, 98% ee
O
O
H
CF3
73% yield, 90% ee
OMe
NBoc
Me
Me
20 mol% catalyst
enantioenriched
!-trifluoromethylation
N
H
Me
Me
H
trifluoromethyl iodide
aldehyde
CF3
N
Boc
61% yield, 93% ee
Photoredox and Organocatalysis: perfluoroalkylation
Me
HOTf
n-hex
RF2
n-hex
fluoroalkylation product
CF2CF2
RFnI
F3C
n-hex
CO2Et
CF2CO2Et
F3C
F
CF3
n-hex
72% yield, 98% ee
Me
fluoroalkylation product
CF3
73% yield, 96% ee
Me
CF2CF3
N
H
20 mol% catalyst
O
I
Me
Me
enantioenriched
!-perfluoroalkylation
fluoroalkyl iodide
RFnI
F
R
aldehyde
n-hex
n-hex
89% yield, 99% ee
85% yield, 98% ee

O
Me
N
Me
H
EtO2C
Me
CO2Et
N
H
Ph
substrate
Me
Me
catalyst
enantiopure
!-benzyl aldehydes
enantiopure
!-malonyl aldehydes
Me
N
Me
N
Ph
Me
Me
H
NR2
enantiopure
!"amino aldehydes
O
FG
enantiopure
#-keto aldehydes
O
O
N
H
Br
CN
enantioselective
!-alkylcyanation
FG
N
N
Ru
N
N
N
H
CF3
!-CF3-aldehydes
substrate
catalyst

O
Me
N
Me
H
EtO2C
Me
CO2Et
N
H
Ph
substrate
Me
Me
catalyst
enantiopure
!-benzyl aldehydes
enantiopure
!-malonyl aldehydes
Me
N
Me
N
Ph
Me
Me
H
NR2
enantiopure
!"amino aldehydes
O
FG
enantiopure
#-keto aldehydes
O
O
N
H
Br
CN
enantioselective
!-alkylcyanation
FG
N
N
Ru
N
N
N
H
CF3
!-CF3-aldehydes
substrate
catalyst

O
Me
N
Me
H
EtO2C
Me
CO2Et
N
H
Ph
substrate
Me
Me
catalyst
enantiopure
!-benzyl aldehydes
enantiopure
!-malonyl aldehydes
Me
N
Me
N
Ph
Me
Me
H
NR2
enantiopure
!"amino aldehydes
O
FG
enantiopure
#-keto aldehydes
O
O
N
H
Br
CN
enantioselective
!-alkylcyanation
FG
N
N
Ru
N
N
N
H
CF3
!-CF3-aldehydes
substrate
catalyst

O
Me
N
Me
H
EtO2C
Me
CO2Et
N
H
Ph
substrate
Me
Me
catalyst
enantiopure
!-benzyl aldehydes
enantiopure
!-malonyl aldehydes
Me
N
Me
N
Ph
Me
Me
H
NR2
enantiopure
!"amino aldehydes
O
FG
enantiopure
#-keto aldehydes
O
O
N
H
Br
CN
enantioselective
!-alkylcyanation
FG
N
N
Ru
N
N
N
H
CF3
!-CF3-aldehydes
substrate
catalyst

O
Me
N
Me
H
EtO2C
Me
CO2Et
N
H
Ph
substrate
Me
Me
catalyst
enantiopure
!-benzyl aldehydes
enantiopure
!-malonyl aldehydes
Me
N
Me
N
Ph
Me
Me
H
NR2
enantiopure
!"amino aldehydes
O
FG
enantiopure
#-keto aldehydes
O
O
N
H
Br
CN
enantioselective
!-alkylcyanation
FG
N
N
Ru
N
N
N
H
CF3
!-CF3-aldehydes
substrate
catalyst

O
Me
N
aldehyde
substrate
Me
t-Bu
H
R
R
O
Me
N
Me
t-Bu
N
H
Si-face
open
Organocatalytic
Ph
radical A
Cycle
catalyst
O
Me
Ph
Me
O
N
t-Bu
enantioenriched
t-Bu
Me
Me
Ph
Ph
SET
Ru(bpy)31+ 3
reductant
"Ru(bpy) 2+
3
oxidant
alkyl halide
alkyl halide
substrate
substrate
Ph
Br
SET
electron-deficient
radical A
O
N
Cycle
Br
Ph
Ru(bpy)32+
Photoredox Catalysis: New Directions for Organic Synthesis

! Visible Light Photocatalysis of [2+2] Enone Cycloadditions
Ph
5 mol% Ru(bpy)3Cl2
Ph
i-Pr2NEt, LiBF4
O
Ph
Ph
MeCN
visible light
Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12866-12887.
89%
>10:1 d.r.
J. Am. Chem. Soc. 2009, 131, 14604-14605.
! Photoredox Catalysis: Hydro-dehalogenation of alkanes
Br
i-Pr2NEt, HCO2H
N
N
Boc
Boc
DMF
visible light
Stephenson, C. R. J. J. Am. Chem. Soc. 2008, 130, 12866-12887.
N
N
Boc
90%
Boc
Photoredox Catalysis: New Directions for Organic Synthesis

! Visible Light Photocatalysis of [2+2] Enone Cycloadditions
Ph
5 mol% Ru(bpy)3Cl2
Ph
i-Pr2NEt, LiBF4
O
Ph
Ph
MeCN
visible light
Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12866-12887.
89%
>10:1 d.r.
J. Am. Chem. Soc. 2009, 131, 14604-14605.
! Photoredox Catalysis: Hydro-dehalogenation of alkanes
Br
i-Pr2NEt, HCO2H
N
N
Boc
Boc
DMF
visible light
Stephenson, C. R. J. J. Am. Chem. Soc. 2008, 130, 12866-12887.
N
N
Boc
90%
Boc
Putting Science, Catalysis and Organocatalysis in Context

# of Hits for Google Keyword Search:
Overview of Chemistry Hot Topics Google Hits

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Organocatalytic
Activation Modes

600,000
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Emerging
Important Areas
Organocatalytic
Activation Modes
The early years: Berkeley
MacMillan Group (1st Year)

Kateri Ahrendt
Chris Borths
Tristan Lambert
Jake Wiener
Vy Dong
Tehshik Yoon
Wendy Jen
Dr. Jeongbob Seo
Naiomi Anchor (UG)
MacMillan Group Caltech 2002
Joel Austin
Chris Borths
Sean Brown
Craig Countryman
Vy Dong
James Falsey
Nikki Goodwin
Wendy Jen
Brian Kwan
Dr. Seongon Kim
Tristan Lambert
Catharine Larsen
Ian Mangion
Alan Northrup
Nick Paras
Julie Park
Dr. Claudia Roberson
Dr. Jeongbob Seo
Dr. Chris Sinz

Jake Wiener
Rebecca Wilson
Dr. Wenjing Xiao
Tehshik Yoon
MacMillan Group Present
Dr. Muriel Amatore

Dr. Kate Ashton
Teresa Beeson
Joe Carpenter
Diane Carrera
Dr. Jay Conrad
Dr. Tom Graham
Dr. Christoph Grondal
Dr. Pilar Garcia Garcia

Dr. J. B. Hong
Jeff Van Humbeck
Casey Jones
Spencer Jones
Nate Jui
Dr. Mark Kerr
Dr. Hahn Kim
Rob Knowles
Sandra Lee
Dr. Jon Martel
Tony Mastracchio
David Nagib
Dr. David Nicewicz
Atsushi Ohigashi
Phong Pham
Dr. Trevor Rainey

Dr.Maud Reiter
Katie Saliba
Bryon Simmons
Grace Wang
Dr. Abbas Walji
Alex Warkentin
Ben Zegarelli
MacMillan Group Present
Anna Allen
Anthony Casarez
Joe Carpenter
Diane Carrera
Dr. Giuseppe Cecera
Dr. Jay Conrad
Jae Won Lee
Dr. Andrew Dilger
Dr. Rebecca Grange

Benjamin Horning
Jeff Van Humbeck
Spencer Jones
Nate Jui
Dr. Hahn Kim
Dr. Chris Kokotos
Brian Laforteza
Dr. Esther Lee

Tony Mastracchio
Dr. Andrew McNally
David Nagib
Phong Pham
Dr. Mark Pickworth
Dr. Seb Rendler
Hui-Wen Shih
Bryon Simmons
Scott Simonovich
Dr. Feili Tang
Mark Vander Wal
Jeff Van Humbeck
Alex Warkentin
SiYi Wang
Dr. Alan Watson
Acknowledgments
Funding (non-profit)
NIH
(NIGMS)
UC AIDS
Research Fund
Petroleum Research
Foundation
Sloan Fellowship
NSF
Funding (pharmaceutical)
Research Corporation
Innovation Award
Cottrell Scholar

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Enantioselective Organocatalysis: A Valuable Strategy for Chemical Synthesis

The rapid growth of organocatalysis over the

last 10 years was fueled by the development

~50 new reactions

~20 new reactions

~30 new reactions

Enantioselective Organocatalysis: A Valuable Strategy for Chemical Synthesis

last 10 years was fueled by the development

~50 new reactions

~20 new reactions

~30 new reactions

Enantioselective Organocatalysis: A Valuable Strategy for Chemical Synthesis

last 10 years was fueled by the development

~50 new reactions

~20 new reactions

~30 new reactions

Enantioselective Organocatalysis: A Valuable Strategy for Chemical Synthesis

last 10 years was fueled by the development

~50 new reactions

~20 new reactions

~30 new reactions

Enantioselective Organocatalysis: A Valuable Strategy for Chemical Synthesis

last 10 years was fueled by the development

~50 new reactions

~20 new reactions

~30 new reactions

Enantioselective Organocatalysis: A Valuable Strategy for Chemical Synthesis

last 10 years was fueled by the development

~50 new reactions

~20 new reactions

~30 new reactions

Organometallic Catalysis: Few Activation Concepts

Lewis acid catalysis

Many Powerful Reactions

Atom transfer catalysis

Relatively Few Catalysis Activation Concepts

Many Powerful Reactions

Instead of focusing completely on the invention of individual catalytic reactions

Design of an entirely new catalyst activation mode is extremely challenging

! Two new modes of catalyst activation using organocatalysts

Relatively Few Catalysis Activation Concepts

Many Powerful Reactions

Instead of focusing completely on the invention of individual catalytic reactions

Design of an entirely new catalyst activation mode is extremely challenging

! Two new modes of catalyst activation using organocatalysts

Relatively Few Catalysis Activation Concepts

Many Powerful Reactions

Instead of focusing completely on the invention of individual catalytic reactions

Design of an entirely new catalyst activation mode is extremely challenging

! Two new modes of catalyst activation using organocatalysts

Relatively Few Catalysis Activation Concepts

Many Powerful Reactions

Instead of focusing completely on the invention of individual catalytic reactions

Design of an entirely new catalyst activation mode is extremely challenging

! Two new modes of catalyst activation using organocatalysts

Relatively Few Catalysis Activation Concepts

Many Powerful Reactions

Holy Grails in Asymmetric Catalysis: Asymmetric !-Carbonyl Alyklation

Holy Grails in Asymmetric Catalysis: Enolate Alyklation

! Catalytic Ketone Variant: Abby Doyle, Eric Jacobsen

Holy Grails in Asymmetric Catalysis: Enolate Alyklation

! Catalytic Ketone Variant: Abby Doyle, Eric Jacobsen

Holy Grails in Asymmetric Catalysis: Enolate Alyklation

! Catalytic Ketone Variant: Abby Doyle, Eric Jacobsen