The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
! Between 2000 and 2008, more than 2000
manuscripts on >150 discrete reaction types
! Used for enantioselective construction of C–C,
C–N, C–O, C–S, C–P, C–halogen bonds
! Now 3rd major branch of catalysis
! Transformations that employ organic catalysts
sporadically documented over last 100 years
! Organocatalysis google page hits = 137,000
Olefin metathesis google page hits = 253,000
Gold catalysis google page hits = 28,600
! The field of organocatalysis was born 1998-2000
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
! Between 2000 and 2008, more than 2000
manuscripts on >150 discrete reaction types
! Used for enantioselective construction of C–C,
C–N, C–O, C–S, C–P, C–halogen bonds
! Now 3rd major branch of catalysis
! Transformations that employ organic catalysts
sporadically documented over last 100 years
! Organocatalysis google page hits = 137,000
Olefin metathesis google page hits = 253,000
Gold catalysis google page hits = 28,600
! The field of organocatalysis was born 1998-2000
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
! Between 2000 and 2008, more than 2000
manuscripts on >150 discrete reaction types
! Used for enantioselective construction of C–C,
C–N, C–O, C–S, C–P, C–halogen bonds
! Now 3rd major branch of catalysis
! Transformations that employ organic catalysts
sporadically documented over last 100 years
! Organocatalysis google page hits = 137,000
Olefin metathesis google page hits = 253,000
Gold catalysis google page hits = 28,600
! The field of organocatalysis was born 1998-2000
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
! Between 2000 and 2008, more than 2000
manuscripts on >150 discrete reaction types
! Used for enantioselective construction of C–C,
C–N, C–O, C–S, C–P, C–halogen bonds
! Now 3rd major branch of catalysis
! Transformations that employ organic catalysts
sporadically documented over last 100 years
! Organocatalysis google page hits = 137,000
Olefin metathesis google page hits = 253,000
Gold catalysis google page hits = 28,600
! The field of organocatalysis was born 1998-2000
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
! Between 2000 and 2008, more than 2000
manuscripts on >150 discrete reaction types
! Used for enantioselective construction of C–C,
C–N, C–O, C–S, C–P, C–halogen bonds
! Now 3rd major branch of catalysis
! Transformations that employ organic catalysts
sporadically documented over last 100 years
! Organocatalysis google page hits = 137,000
Olefin metathesis google page hits = 253,000
Gold catalysis google page hits = 28,600
! The field of organocatalysis was born 1998-2000
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
! Between 2000 and 2008, more than 2000
manuscripts on >150 discrete reaction types
! Used for enantioselective construction of C–C,
C–N, C–O, C–S, C–P, C–halogen bonds
! Now 3rd major branch of catalysis
! Transformations that employ organic catalysts
sporadically documented over last 100 years
! Organocatalysis google page hits = 137,000
Olefin metathesis google page hits = 253,000
Gold catalysis google page hits = 28,600
! The field of organocatalysis was born 1998-2000
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
! Between 2000 and 2008, more than 2000
manuscripts on >150 discrete reaction types
! Used for enantioselective construction of C–C,
C–N, C–O, C–S, C–P, C–halogen bonds
! Now 3rd major branch of catalysis
! Transformations that employ organic catalysts
sporadically documented over last 100 years
! Organocatalysis google page hits = 137,000
Olefin metathesis google page hits = 253,000
Gold catalysis google page hits = 28,600
! The field of organocatalysis was born 1998-2000
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
! Why did the field of chemical synthesis overlook the use of organic catalysts
for more than eighty years?
! Why did the field of organocatalysis initiate so rapidly at the beginning of the 21st century
The Advent and Development of the Field of Enantioselective Organocatalysis
Organocatalysis
! Organocatalysis: the use of small organic molecules
to catalyze organic transformations
! Why did the field of chemical synthesis overlook the use of organic catalysts
for more than eighty years?
! Why did the field of organocatalysis initiate so rapidly at the beginning of the 21st century
The Advent and Development of the Field of Enantioselective Organocatalysis
! Why did the field of chemical synthesis overlook the use of organic catalysts
until the beginning of the 21st century?
Dieter Seebach: A 1990 essay on the future of organic synthesis:
Angew. Chem. Int. Ed. 1990, 29, 1320.
“New synthetic methods are most likely to be encountered
in the fields of biological and organometallic chemistry.”
Why did Seebach omit organocatalysis from his vision of the future of organic synthesis?
One perspective: It is impossible to overlook a field that does not yet exist
(in much the same way that you cannot work on a problem that has not yet been defined)
The Advent and Development of the Field of Enantioselective Organocatalysis
! Why did the field of chemical synthesis overlook the use of organic catalysts
until the beginning of the 21st century?
Dieter Seebach: A 1990 essay on the future of organic synthesis:
Angew. Chem. Int. Ed. 1990, 29, 1320.
“New synthetic methods are most likely to be encountered
in the fields of biological and organometallic chemistry.”
Why did Seebach omit organocatalysis from his vision of the future of organic synthesis?
One perspective: It is impossible to overlook a field that does not yet exist
(in much the same way that you cannot work on a problem that has not yet been defined)
The Advent and Development of the Field of Enantioselective Organocatalysis
! Why did the field of chemical synthesis overlook the use of organic catalysts
until the beginning of the 21st century?
Dieter Seebach: A 1990 essay on the future of organic synthesis:
Angew. Chem. Int. Ed. 1990, 29, 1320.
“New synthetic methods are most likely to be encountered
in the fields of biological and organometallic chemistry.”
Why did Seebach omit organocatalysis from his vision of the future of organic synthesis?
One perspective: It is impossible to overlook a field that does not yet exist
(in much the same way that you cannot work on a problem that has not yet been defined)
The Advent and Development of the Field of Enantioselective Organocatalysis
! Why did the field of chemical synthesis overlook the use of organic catalysts
until the beginning of the 21st century?
Dieter Seebach: A 1990 essay on the future of organic synthesis:
Angew. Chem. Int. Ed. 1990, 29, 1320.
“New synthetic methods are most likely to be encountered
in the fields of biological and organometallic chemistry.”
Why did Seebach omit organocatalysis from his vision of the future of organic synthesis?
One perspective: It is impossible to overlook a field that does not yet exist
(in much the same way that you cannot work on a problem that has not yet been defined)
The Early Use of Organic Catalysts in Enantioselective Synthesis: Hajos-Parrish
! Intramolecular Aldol: Hajos–Parrish J. Org. Chem. 1974, 39, 1615
O
O
Me
Me
O
Me O
3 mol%
catalyst
DMF
N
H
O
OH
CO2H
catalyst
(S)-proline
97% ee
! Extraordinary result that was well received by the chemical synthesis community
! Viewed as a unique chemical reaction, not part of a larger interconnected field
! Manuscript emphasis never placed on the benefits of organocatalysts or
new catalysis concepts
! General lessons were never extrapolated thereby stalling potential application
over multiple reaction types (Agami mechanistic red herring)
! The value of a general over-arching field that used organic catalysts was never recognized
! Between 1960 and 2001, no review articles on the collective use of organic catalysts
The Early Use of Organic Catalysts in Enantioselective Synthesis: Hajos-Parrish
! Intramolecular Aldol: Hajos–Parrish J. Org. Chem. 1974, 39, 1615
O
O
Me
Me
O
Me O
3 mol%
catalyst
DMF
N
H
O
OH
CO2H
catalyst
(S)-proline
97% ee
! Extraordinary result that was well received by the chemical synthesis community
! Viewed as a unique chemical reaction, not part of a larger interconnected field
! Manuscript emphasis never placed on the benefits of organocatalysts or
new catalysis concepts
! General lessons were never extrapolated thereby stalling potential application
over multiple reaction types (Agami mechanistic red herring)
! The value of a general over-arching field that used organic catalysts was never recognized
! Between 1960 and 2001, no review articles on the collective use of organic catalysts
The Early Use of Organic Catalysts in Enantioselective Synthesis: Hajos-Parrish
! Intramolecular Aldol: Hajos–Parrish J. Org. Chem. 1974, 39, 1615
O
O
Me
Me
O
Me O
3 mol%
catalyst
DMF
N
H
O
OH
CO2H
catalyst
(S)-proline
97% ee
! Extraordinary result that was well received by the chemical synthesis community
! Viewed as a unique chemical reaction, not part of a larger interconnected field
! Manuscript emphasis never placed on the benefits of organocatalysts or
new catalysis concepts
! General lessons were never extrapolated thereby stalling potential application
over multiple reaction types (Agami mechanistic red herring)
! The value of a general over-arching field that used organic catalysts was never recognized
! Between 1960 and 2001, no review articles on the collective use of organic catalysts
The Early Use of Organic Catalysts in Enantioselective Synthesis: Hajos-Parrish
! Intramolecular Aldol: Hajos–Parrish J. Org. Chem. 1974, 39, 1615
O
O
Me
Me
O
Me O
3 mol%
catalyst
DMF
N
H
O
OH
CO2H
catalyst
(S)-proline
97% ee
! Extraordinary result that was well received by the chemical synthesis community
! Viewed as a unique chemical reaction, not part of a larger interconnected field
! Manuscript emphasis never placed on the benefits of organocatalysts or
new catalysis concepts
! General lessons were never extrapolated thereby stalling potential application
over multiple reaction types (Agami mechanistic red herring)
! The value of a general over-arching field that used organic catalysts was never recognized
! Between 1960 and 2001, no review articles on the collective use of organic catalysts
The Early Use of Organic Catalysts in Enantioselective Synthesis: Hajos-Parrish
! Intramolecular Aldol: Hajos–Parrish J. Org. Chem. 1974, 39, 1615
O
O
Me
Me
O
Me O
3 mol%
catalyst
DMF
N
H
O
OH
CO2H
catalyst
(S)-proline
97% ee
! Extraordinary result that was well received by the chemical synthesis community
! Viewed as a unique chemical reaction, not part of a larger interconnected field
! Manuscript emphasis never placed on the benefits of organocatalysts or
new catalysis concepts
! General lessons were never extrapolated thereby stalling potential application
over multiple reaction types (Agami mechanistic red herring)
! The value of a general over-arching field that used organic catalysts was never recognized
! Between 1960 and 2001, no review articles on the collective use of organic catalysts
The Early Use of Organic Catalysts in Enantioselective Synthesis: Hajos-Parrish
! Intramolecular Aldol: Hajos–Parrish J. Org. Chem. 1974, 39, 1615
O
O
Me
Me
O
Me O
3 mol%
catalyst
DMF
N
H
O
OH
CO2H
catalyst
(S)-proline
97% ee
! Extraordinary result that was well received by the chemical synthesis community
! Viewed as a unique chemical reaction, not part of a larger interconnected field
! Manuscript emphasis never placed on the benefits of organocatalysts or
new catalysis concepts
! General lessons were never extrapolated thereby stalling potential application
over multiple reaction types (Agami mechanistic red herring)
! The value of a general over-arching field that used organic catalysts was never recognized
! Between 1960 and 2001, no review articles on the collective use of organic catalysts
Enantioselective Metal Catalyzed Processes: State of the Art 1996
BINOL
BINAP (Noyori)
Ph
O
O
X
P
X
P
M
Ph
Diels-Alder
Aldol
Ene
Hydrogenation
Hydrosilylation
Allylation
M = Ti, Al
M = Rh, Ru
Salen (Jacobsen)
Ph
M
N
N
M
Ph
Me3C
O
CMe3
O
CMe3
Me3C
Hetero-Diels-Alder
Epoxidation, Epoxide opening
M = Mn, Cr, Co
Bisoxazoline (Evans–Pfaltz–Corey)
Me
Me
O
O
N
R
N
M
X
X
R
Cyclopropanation
Aziridination
Diels-Alder
Aldol
Michael
M = Cu, Mg, Sn
! Chiral transition metal complexes dominate the enantioselective catalysis landscape
Enantioselective Metal Catalyzed Processes: State of the Art 1996
BINOL
BINAP (Noyori)
Ph
O
O
X
P
X
P
M
Ph
Diels-Alder
Aldol
Ene
Hydrogenation
Hydrosilylation
Allylation
M = Ti, Al
M = Rh, Ru
Salen (Jacobsen)
Ph
M
N
N
M
Ph
Me3C
O
CMe3
O
CMe3
Me3C
Hetero-Diels-Alder
Epoxidation, Epoxide opening
M = Mn, Cr, Co
Bisoxazoline (Evans–Pfaltz–Corey)
Me
Me
O
O
N
R
N
M
X
X
R
Cyclopropanation
Aziridination
Diels-Alder
Aldol
Michael
M = Cu, Mg, Sn
Dave Evans, Harvard
! Chiral transition metal complexes dominate the enantioselective catalysis landscape
Chiral Sn(II) Lewis Acids: Enantioselective Mukaiyama Aldol
OTMS
O
O
tBuS
Et
Me
Me
O
10 mol% catalyst
Me
OTMS
Et
Me
O
tBuS
Regioselection (2 options): >95 : 5
Diastereoselection (2 options): >98 : 2
Enantioselection (2 options): 99 : 1
O
N
Ph
O
N
N
Sn
TfO
OTf
Ph
Sn(II)Pybox catalyst
Evans, D.A. MacMillan D.W.C. J. Am. Chem. Soc. 1997, 119, 10859
Chiral Sn(II) Lewis Acids: Enantioselective Mukaiyama Aldol
OTMS
O
O
tBuS
Et
Me
Me
O
10 mol% catalyst
Me
OTMS
Et
Me
O
tBuS
Regioselection (2 options): >95 : 5
Diastereoselection (2 options): >98 : 2
Enantioselection (2 options): 99 : 1
Nu
O
N
Ph
O
N
N
Sn
TfO
OTf
Ph
Sn(II)Pybox catalyst
Evans, D.A. MacMillan D.W.C. J. Am. Chem. Soc. 1997, 119, 10859
Chiral Sn(II) Lewis Acids: Enantioselective Mukaiyama Aldol
OTMS
O
O
tBuS
Et
Me
Me
O
10 mol% catalyst
Me
OTMS
Et
Me
O
tBuS
Regioselection (2 options): >95 : 5
Diastereoselection (2 options): >98 : 2
Enantioselection (2 options): 99 : 1
O
N
Ph
O
N
N
Sn
TfO
OTf
Ph
Sn(II)Pybox catalyst
Evans, D.A. MacMillan D.W.C. J. Am. Chem. Soc. 1997, 119, 10859
Chiral Sn(II) Lewis Acids: Enantioselective Mukaiyama Aldol
OTMS
O
O
tBuS
Et
Me
Me
O
10 mol% catalyst
Me
OTMS
Et
Me
O
tBuS
Regioselection (2 options): >95 : 5
Diastereoselection (2 options): >98 : 2
Enantioselection (2 options): 99 : 1
O
N
Ph
O
N
N
Sn
TfO
OTf
! Glovebox
! Ligand synthesis
Ph
! Reproducibility
Sn(II)Pybox catalyst
Evans, D.A. MacMillan D.W.C. J. Am. Chem. Soc. 1997, 119, 10859
Enantioselective Catalysis using Small Organic Molecules: Epoxidation
! Enantioselective Catalytic Expoxidations: Yian Shi, Scott Denmark, Dan Yang
10 mol%
catalyst
O
Oxone
47–95% ee
+
O
O
O
O
N
O
O
O
O
O
O
O
O
Yang catalyst
JACS 1996, 118, 491
Shi catalyst
JACS 1996, 118, 9806
F
Denmark catalyst
JOC 1997, 62, 8288
! Employed ketones as enantioselective catalysts
! Demonstrated that organic catalysts could be employed to solve major chemical problems
! Did not conceptualize the field or define the benefits of organocatalysis
! Involved the invention of a single catalyst for a single reaction type
Enantioselective Catalysis using Small Organic Molecules: Epoxidation
! Enantioselective Catalytic Expoxidations: Yian Shi, Scott Denmark, Dan Yang
10 mol%
catalyst
O
Oxone
47–95% ee
+
O
O
O
O
N
O
O
O
O
O
O
O
O
Yang catalyst
JACS 1996, 118, 491
Shi catalyst
JACS 1996, 118, 9806
F
Denmark catalyst
JOC 1997, 62, 8288
! Employed ketones as enantioselective catalysts
! Demonstrated that organic catalysts could be employed to solve major chemical problems
! Did not conceptualize the field or define the benefits of organocatalysis
! Involved the invention of a single catalyst for a single reaction type
Enantioselective Catalysis using Small Organic Molecules: Epoxidation
! Enantioselective Catalytic Expoxidations: Yian Shi, Scott Denmark, Dan Yang
10 mol%
catalyst
O
Oxone
47–95% ee
+
O
O
O
O
N
O
O
O
O
O
O
O
O
Yang catalyst
JACS 1996, 118, 491
Shi catalyst
JACS 1996, 118, 9806
F
Denmark catalyst
JOC 1997, 62, 8288
! Employed ketones as enantioselective catalysts
! Demonstrated that organic catalysts could be employed to solve major chemical problems
! Did not conceptualize the field or define the benefits of organocatalysis
! Involved the invention of a single catalyst for a single reaction type
Enantioselective Catalysis using Small Organic Molecules: Epoxidation
! Enantioselective Catalytic Expoxidations: Yian Shi, Scott Denmark, Dan Yang
10 mol%
catalyst
O
Oxone
47–95% ee
+
O
O
O
O
N
O
O
O
O
O
O
O
O
Yang catalyst
JACS 1996, 118, 491
Shi catalyst
JACS 1996, 118, 9806
F
Denmark catalyst
JOC 1997, 62, 8288
! Employed ketones as enantioselective catalysts
! Demonstrated that organic catalysts could be employed to solve major chemical problems
! Did not conceptualize the field or define the benefits of organocatalysis
! Involved the invention of a single catalyst for a single reaction type
April 1998: Shortly before undertaking an Asst Professorship at Berkeley
A visit to Caltech and some invaluable advice along the way
April 1998: Shortly before undertaking an Asst Professorship at Berkeley
A visit to Caltech and some invaluable advice along the way
! Erick Carreira
"At Berkeley you will be able to work with some of the smartest students
in the world. You have to make the assumption that any problem you
undertake, you will eventually solve. As such, you should always take
on the problem that will have the biggest impact, regardless of whether
you have devised a solution to this problem or not"
April 1998: Shortly before undertaking an Asst Professorship at Berkeley
A visit to Caltech and some invaluable advice along the way
! Erick Carreira
"At Berkeley you will be able to work with some of the smartest students
in the world. You have to make the assumption that any problem you
undertake, you will eventually solve. As such, you should always take
on the problem that will have the biggest impact, regardless of whether
you have devised a solution to this problem or not"
My own career
Organic Catalysis
My Independant Career = Organic Catalysis: Why?
Impact: I was convinced that the use of organic molecules as catalysts could become a (major) field
Why? Because of the inherent benefits of using organic molecules as catalysts
Insensitive to mositure and air
Operationally easy to handle
Inexpensive
Non-toxic, easily removed from waste streams
Readily available from bio-matter
Rich, new avenue for academic thought
Problem: In 1998, no general concepts associated with using organic catalysts
If organic catalysis were to become widely adopted, utilized (i.e. a field)
Instead of devising a singular catalyst for a single transformation
We would have to devise a general mode of organocatalytic activation that could be
applied across many useful reaction classes in organic synthesis
Problem: I had aboslutely no idea of how to do this
My Independant Career = Organic Catalysis: Why?
Impact: I was convinced that the use of organic molecules as catalysts could become a (major) field
Why? Because of the inherent benefits of using organic molecules as catalysts
Insensitive to mositure and air
Operationally easy to handle
Inexpensive
Non-toxic, easily removed from waste streams
Readily available from bio-matter
Rich, new avenue for academic thought
Problem: In 1998, no general concepts associated with using organic catalysts
If organic catalysis were to become widely adopted, utilized (i.e. a field)
Instead of devising a singular catalyst for a single transformation
We would have to devise a general mode of organocatalytic activation that could be
applied across many useful reaction classes in organic synthesis
Problem: I had aboslutely no idea of how to do this
My Independant Career = Organic Catalysis: Why?
Impact: I was convinced that the use of organic molecules as catalysts could become a (major) field
Why? Because of the inherent benefits of using organic molecules as catalysts
Insensitive to mositure and air
Operationally easy to handle
Inexpensive
Non-toxic, easily removed from waste streams
Readily available from bio-matter
Rich, new avenue for academic thought
Problem: In 1998, no general concepts associated with using organic catalysts
If organic catalysis were to become widely adopted, utilized (i.e. a field)
Instead of devising a singular catalyst for a single transformation
We would have to devise a general mode of organocatalytic activation that could be
applied across many useful reaction classes in organic synthesis
Problem: I had aboslutely no idea of how to do this
My Independant Career = Organic Catalysis: Why?
Impact: I was convinced that the use of organic molecules as catalysts could become a (major) field
Why? Because of the inherent benefits of using organic molecules as catalysts
Insensitive to mositure and air
Operationally easy to handle
Inexpensive
Non-toxic, easily removed from waste streams
Readily available from bio-matter
Rich, new avenue for academic thought
Problem: In 1998, no general concepts associated with using organic catalysts
If organic catalysis were to become widely adopted, utilized (i.e. a field)
Instead of devising a singular catalyst for a single transformation
We would have to devise a general mode of organocatalytic activation that could be
applied across many useful reaction classes in organic synthesis
Problem: I had aboslutely no idea of how to do this
My Independant Career = Organic Catalysis: Why?
Impact: I was convinced that the use of organic molecules as catalysts could become a (major) field
Why? Because of the inherent benefits of using organic molecules as catalysts
Insensitive to mositure and air
Operationally easy to handle
Inexpensive
Non-toxic, easily removed from waste streams
Readily available from bio-matter
Rich, new avenue for academic thought
Problem: In 1998, no general concepts associated with using organic catalysts
If organic catalysis were to become widely adopted, utilized (i.e. a field)
Instead of devising a singular catalyst for a single transformation
We would have to devise a general mode of organocatalytic activation that could be
applied across many useful reaction classes in organic synthesis
Problem: I had aboslutely no idea of how to do this
My Independant Career = Organic Catalysis: Why?
Impact: I was convinced that the use of organic molecules as catalysts could become a (major) field
Why? Because of the inherent benefits of using organic molecules as catalysts
Insensitive to mositure and air
Operationally easy to handle
Inexpensive
Non-toxic, easily removed from waste streams
Readily available from bio-matter
Rich, new avenue for academic thought
Problem: In 1998, no general concepts associated with using organic catalysts
If organic catalysis were to become widely adopted, utilized (i.e. a field)
Instead of devising a singular catalyst for a single transformation
We would have to devise a general mode of organocatalytic activation that could be
applied across many useful reaction classes in organic synthesis
Problem: I had absolutely no idea of how to do this
April 1998: Shortly before undertaking an Asst Professorship at Berkeley
A visit to Caltech and some invaluable advice along the way
! Erick Carreira
"At Berkeley you will be able to work with some of the smartest students
in the world. You have to make the assumption that any problem you
undertake, you will eventually solve. As such, you should always take
on the problem that will have the biggest impact, regardless of whether
you have devised a solution to this problem or not"
My own career
Organic Catalysis
A Fortunate Realization Based on a Simple
Mechanistic Discussion
Tristan Lambert: 1st year grad student (Now Asst Prof, Columbia)
Question: What is the mechanism of reductive amination?
A Fortunate Realization Based on a Simple
Mechanistic Discussion
Tristan Lambert: 1st year grad student (Now Asst Prof, Columbia)
Question: What is the mechanism of reductive amination?
A Fortunate Realization Based on a Simple
Mechanistic Discussion
Tristan Lambert: 1st year grad student (Now Asst Prof, Columbia)
Question: What is the mechanism of reductive amination?
A Fortunate Realization Based on a Simple
Mechanistic Discussion
Tristan Lambert: 1st year grad student (Now Asst Prof, Columbia)
Question: What is the mechanism of reductive amination?
Quintiessential AHA moment!
A Fortunate Realization Based on a Simple
Mechanistic Discussion
Tristan Lambert: 1st year grad student (Now Asst Prof, Columbia)
Question: What is the mechanism of reductive amination?
A Fortunate Realization Based on a Simple
Mechanistic Discussion
Tristan Lambert: 1st year grad student (Now Asst Prof, Columbia)
Question: What is the mechanism of reductive amination?
Design of General Organocatalytic Strategy: LUMO–Lowering
! Lewis acid catalysis typically involves activation of a substrate to !-facial addition by lowering
the LUMO component of one reactant with respect to the HOMO of the reacting partner
! Diels-Alder
O
LA
LA
O
X
O
LA
O
X
X
X
LA
! This activation–catalyst turnover mechanism should hold for any carbogenic system that exists
as an equilibrium between an electron–deficient and a relatively electron–rich state
substrate
O
O
catalyst
+
+
Lewis acid (LA)
R
R
N
H •HCl
LUMO–activation
O
N
LA
+
R
+
R
! Can amines function as catalysts for transformations that traditionally employ Lewis acids?
Design of General Organocatalytic Activation Strategy: Iminium Catalysis
! Amine Catalyzed Diels-Alder
R
Ph
N
H
R
HCl
Ph
O
catalyst
CHO
! Amine Catalyzed [3 + 2] Cycloadditions
R
+
Ph
N
Ph
Me
O–
O
N
H
R
HCl
O
Ph
catalyst
N
Ph
Me
CHO
! Amine Catalyzed Mukaiyama Michael
R
OTMS
EtS
Me
Me
O
N
H
R
O
HCl
catalyst
Me
EtS
O
Me
! Many other transforms should be possible: Conjugate Additions, Epoxidations, Cyclopropanations
Organocatalyzed Diels–Alder Reaction: ReactIR Studies
Ph
Time
(hours)
O
Ph
Time
(hours)
Abs
Abs
H
O
15.0
10.0
B
A
A
5.0
B
wavenumbers
wavenumbers
•HCl
Ph
10%
MeOH
Ph
O
B
H
O
Ph
O
A
N
H
Ph
CO2Me
MeOH
H
O
81% yield 48% ee
! Amine Catalyzed Diels–Alder Reaction is facile at room temperature
Organocatalyzed Diels–Alder Reaction: ReactIR Studies
Ph
Time
(hours)
O
Ph
Time
(hours)
Abs
Abs
H
O
15.0
10.0
B
A
A
5.0
B
wavenumbers
wavenumbers
•HCl
Ph
10%
MeOH
Ph
O
B
H
O
Ph
O
A
N
H
Ph
CO2Me
MeOH
H
O
81% yield 48% ee
! Amine Catalyzed Diels–Alder Reaction is facile at room temperature
MM3 Calculations Predict the Correct Sense of Enantioinduction
! Two possible iminium ion intermediates
CO2R
CO2R
Me
O
N
H
N
H
NHMe
•HCl
+ N
Me
CHO
or
Me
Me
20 mol%
CO2R
N
H
Si–face
trans
+ N
Me
exo (2R)
Me
65% ee
cis
Re–face
CHO
Me
exo (2S)
trans–iminium
232.44 kJmol–1
CHO
exo (2R)
Me
cis–iminium
229.53 kJmol–1
Is the reaction enantioselectivity compromised by participation of both cis and trans iminium ions
MM3 Calculations Predict the Correct Sense of Enantioinduction
! Two possible iminium ion intermediates
CO2R
CO2R
Me
O
N
H
N
H
NHMe
•HCl
+ N
Me
CHO
or
Me
Me
20 mol%
CO2R
N
H
Si–face
trans
+ N
Me
exo (2R)
Me
65% ee
cis
Re–face
CHO
Me
exo (2S)
trans–iminium
232.44 kJmol–1
CHO
exo (2R)
Me
cis–iminium
229.53 kJmol–1
Is the reaction enantioselectivity compromised by participation of both cis and trans iminium ions
Imidazolidinone Catalyst should also provide Iminum Ion Geometry Control
! Readily available from chiral pool
O
O
Ph
CO2Me
N
NHMe;
Me
Ph
NH2
(S)-Phenyl alanine
methyl ester
acetone, HCl
N
HCl H
Me
N
Me
Me
Me
O
+
N
Me
Ph
Me
4–imidazolidinone
Me
favored geometry
CHO
+
Me
exo (S)
CHO
Me
predict exo (R)
Re–face
(exposed)
Calculations suggest strong bias for addition to exposed Re–face
Highly Organizationed TS
Imidazolidinone Catalyst should also provide Iminum Ion Geometry Control
! Readily available from chiral pool
O
O
Ph
CO2Me
N
NHMe;
Me
Ph
NH2
(S)-Phenyl alanine
methyl ester
acetone, HCl
N
HCl H
Me
N
Me
Me
Me
O
+
N
Me
Ph
Me
4–imidazolidinone
Me
favored geometry
CHO
+
Me
exo (S)
CHO
Me
predict exo (R)
Re–face
(exposed)
Calculations suggest strong bias for addition to exposed Re–face
Highly Organizationed TS
Imidazolidinone Catalyst should also provide Iminum Ion Geometry Control
! Readily available from chiral pool
O
O
Ph
CO2Me
N
NHMe;
Me
Ph
NH2
(S)-Phenyl alanine
methyl ester
acetone, HCl
N
HCl H
Me
N
Me
Me
Me
O
+
N
Me
Ph
Me
4–imidazolidinone
Me
favored geometry
CHO
+
Me
exo (S)
CHO
Me
predict exo (R)
Re–face
(exposed)
Calculations suggest strong bias for addition to exposed Re–face
Highly Organizationed TS
Imidazolidinone Catalyst provides High Levels of Enantiocontrol
O
Me
N
First highly enantioselective organocatalytic Diels–Alder reaction
Me
Ph
TfOH
! With Ahrendt, K. A.; Borths, C. J
N
H
Me
catalyst
OAc
OAc
72% yield
H
CHO
O
endo (S) 85% ee
10 mol% cat
CHO
75% yield
Ph
Me
endo:exo 11:1
90% ee
O
10 mol% cat
Ph
Me
Me
Me
CHO
75% yield
H
O
20 mol%
Me
endo (S) 90% ee
Me
NHCBz
NHCBz
5 mol% cat
R
endo:exo 5:1
CHO
endo:exo 90:10 to 96:4
endo (S)
O
R = H, CH2OBz, Me, CO2Me
R
93–99% ee
93% yield
MacMillan: The Advent of Iminium Catalysis and the Field of Organocatalysis
! This manuscript conceptualized the field of organocatalysis for the first time in 3 important ways
!
J. Am. Chem. Soc. 2000, 3122, 4243
MacMillan: The Advent of Iminium Catalysis and the Field of Organocatalysis
! This manuscript conceptualized the field of organocatalysis for the first time in 3 important ways
1
Outlined the potential benefits of using
organic molecules as asymmetric
catalysts for industry or academia based
on cost, availability, ease of use
!
J. Am. Chem. Soc. 2000, 3122, 4243
MacMillan: The Advent of Iminium Catalysis and the Field of Organocatalysis
! This manuscript conceptualized the field of organocatalysis for the first time in 3 important ways
1
Outlined the potential benefits of using
organic molecules as asymmetric
catalysts for industry or academia based
on cost, availability, ease of use
2
Introduced the concept of a generic mode
of activation for organic catalysis that
could be used over many reaction types
!
J. Am. Chem. Soc. 2000, 3122, 4243
MacMillan: The Advent of Iminium Catalysis and the Field of Organocatalysis
! This manuscript conceptualized the field of organocatalysis for the first time in 3 important ways
1
Outlined the potential benefits of using
organic molecules as asymmetric
catalysts for industry or academia based
on cost, availability, ease of use
2
Introduced the concept of a generic mode
of activation for organic catalysis that
could be used over many reaction types
!
J. Am. Chem. Soc. 2000, 3122, 4243
3
Introduced for the first time, the
terminology organocatalysis, organic
catalysis and organocatalytic
What's in a name?
Two Opinions that I gave to my lab in April 1999 (one I still believe)
"The world does not care about another asymmetric catalytic Diels–Alder reaction"
(one of the most silly statements I have made as a prof)
Two Opinions that I gave to my lab in April 1999 (one I still believe)
"The world does not care about another asymmetric catalytic Diels–Alder reaction"
(one of the most silly statements I have made as a prof)
The most important part of asymmetric catalysis is developing new
generic modes of activation and induction
A generic mode of activation and induction?
! A generic activation mode describes a reactive species
that can participate in many different reaction types
with generically high levels of enantioselectivity
! Would the combination of iminium catalysis and
imidazolidinone catalyst provide a new
Re–face generically open to
enantioselective bond formation
generic activation mode?
catalyst
substrate
activation mode
O
O
R
O
N
+
Ph
Me
N
Me
N
H
+
Me
Me
N
Several
enantioselective
catalytic reactions?
Me
Me
Ph
R
Nu:
(we hoped for 3)
! Our goal was to avoid the development of a singular catalyst for a singular reaction!
A generic mode of activation and induction?
! A generic activation mode describes a reactive species
that can participate in many different reaction types
with generically high levels of enantioselectivity
! Would the combination of iminium catalysis and
imidazolidinone catalyst provide a new
Re–face generically open to
enantioselective bond formation
generic activation mode?
catalyst
substrate
activation mode
O
O
R
O
N
+
Ph
Me
N
Me
N
H
+
Me
Me
N
Several
enantioselective
catalytic reactions?
Me
Me
Ph
R
Nu:
(we hoped for 3)
! Our goal was to avoid the development of a singular catalyst for a singular reaction!
Iminium activation strategy is useful for a variety of organocatalytic reactions
Diels–Alder
Indole Addition
Ketone Diels–Alder
JACS 2000, 122, 4243
JACS 2002, 124, 1172
JACS 2002, 124, 2458
CH2OBz
CHO
Me
CbzNH
O
O
90% ee
Et
96% ee
98% ee
N
Me
Nitrone Cycloaddition
Aniline Addition
Enal hydrogenation
JACS 2000, 122, 9874
JACS 2001, 124, 7894
JACS 2005, 127, 32
Bn
N
Me2N
O
Ph
Ph
94% ee
Me
O
96% ee
Pyrrole Friedel–Crafts
Vinylogous Michael
JACS 2001, 123, 4370
94% ee
Enone hydrogenation
JACS 2003, 125, 1192
JACS 2006, 128, 12662
O
O
O
Ph
O
CO2Me
CHO
N
Me
Et
O
96% ee
Me
92% ee
O
93% ee
Bu
H
i-Pr
Iminium activation is useful for a variety of transformations
Intramolecular Diels–Alder
H
n-Pr
Me
COPh
H
Ph
Nitroalkane Addition
JACS 2005, 127, 3240
JACS 2001, 124, 7894
O
Cyclopropanation
95% ee
O2N
Me
CHO
93% ee
O
95% ee
H
Addition–Cyclization
Epoxidation
PNAS 2004, 101, 5482
Tetrahedron YI Award
2006, 1472
O
Tertiary Amino Acid
O
O
O
N
Bn
H
90% ee
N
Ph
O
92% ee
n-Pr
N
Ph
99% ee
Aryl or Vinyl BF3K Addition
Aziridination
JACS 2007, 127, 15438
JACS 2006, 128, 9328
N
O
Me
BOC
Amine Conjugate Addition
Boc
Me
Ns
OTES
N
O
95% ee
MeO2C
O
O
93% ee
N
BOC Me
91% ee
Consideration of privileged architecture and stereogenicity
! Most common substituent found in asymmetric carbon stereogenicity
Hydrogenation
H
most common
chiral substituent
H
X
O
Y
H
Traditional Methods for Asymmetric Hydrogenation
! Organometallic hydrogenation (Noyori)
Ph
X
Y
P
OH
P
O
Ph
Ph
H
H2
M
Y
Ph
O
X
H
M = Pd, Rh, Ru
olefin
OH
Enantioenriched
olefin
! Organic systems: Enzymatic reduction (hydrogenation) is mediated by NADH
HO
OH
HO
O
H2N
N
H
O
O
O–
P
O
H
O
O
P
O–
OH
NH2
N
O
O
N
H
H
O
NH2
NH
N
N
O
nicotinamide-adenine-dinucleotide-H (NADH)
R
NADH
Can a coenzyme analog be utilized in the reducion of carbon-carbon bonds
Traditional Methods for Asymmetric Hydrogenation
! Organometallic hydrogenation (Noyori)
Ph
X
Y
P
OH
P
O
Ph
Ph
H
H2
M
Y
Ph
O
X
H
M = Pd, Rh, Ru
olefin
OH
Enantioenriched
olefin
! Organic systems: Enzymatic reduction (hydrogenation) is mediated by NADH
HO
OH
HO
O
H2N
N
H
O
O
O–
P
O
H
O
O
P
O–
OH
NH2
N
O
O
N
H
H
O
NH2
NH
N
N
O
nicotinamide-adenine-dinucleotide-H (NADH)
R
NADH
Can a coenzyme analog be utilized in the reducion of carbon-carbon bonds
Traditional Methods for Asymmetric Hydrogenation
! Organometallic hydrogenation (Noyori)
Ph
X
Y
P
OH
P
O
Ph
Ph
H
H2
M
Y
Ph
O
X
H
M = Pd, Rh, Ru
olefin
OH
Enantioenriched
olefin
! Organic systems: Enzymatic reduction (hydrogenation) is mediated by NADH
HO
OH
HO
O
H2N
N
H
O
O
O–
P
O
H
O
O
P
O–
OH
NH2
N
O
O
N
H
H
O
NH2
NH
N
N
O
nicotinamide-adenine-dinucleotide-H (NADH)
R
NADH
Can a coenzyme analog be utilized in the reducion of carbon-carbon bonds
Organic Catalyzed Reductions in Biological Systems
! NADH: Natures Reduction (Hydrogenation) Reagent (Coenzyme)
H
O
NH3
O
N
methyl
pyruvate
H2N
R
enzyme
NADH
catalyst
N
H +
N
N H
Me
H
O
alanine
His
O
O
active site
NADH reduction
OH
Me
R
HN
O
H
R
NH2
CONH2
OH
Me
alanine transferase
H
H
H
NH
HN
Arg
NHR
Selective reduction of pyruvate imines to create amino acids
Could this organocatalytic sequence be utilized in the redution of carbon–carbon double bonds
Organic Catalyzed Reductions in Biological Systems
! NADH: Natures Reduction (Hydrogenation) Reagent (Coenzyme)
H
O
NH3
O
N
methyl
pyruvate
H2N
R
enzyme
NADH
catalyst
N
H +
N
N H
Me
H
O
alanine
His
O
O
active site
NADH reduction
OH
Me
R
HN
O
H
R
NH2
CONH2
OH
Me
alanine transferase
H
H
H
NH
HN
Arg
NHR
Selective reduction of pyruvate imines to create amino acids
Could this organocatalytic sequence be utilized in the redution of carbon–carbon double bonds
Organic Catalyzed Reductions in Chemical Synthesis
! Hansch Esters: NADH analogs for organocatalytic hydride reductions
H
X
H
MeO2C
CO2Me
H
X
Y
O
Me
N
olefin
Y
Me
catalyst
R
O
hydrogenation
NADH
analog
MeO
O
H
R
N
H
Me
O
N
X
+
Y
N
Me
Me
Me
N
H
H
transition state
MW = 156
organic iminium reduction
Can the Hansch ester be used to enantioselectively deliver hydride
Could this organocatalytic sequence be utilized in the reduction of carbon–carbon double bonds
Organic Catalyzed Reductions in Chemical Synthesis
! Hansch Esters: NADH analogs for organocatalytic hydride reductions
H
X
H
MeO2C
CO2Me
H
X
Y
O
Me
N
olefin
Y
Me
catalyst
R
O
hydrogenation
NADH
analog
MeO
O
H
R
N
H
Me
O
N
X
+
Y
N
Me
Me
Me
N
H
H
transition state
MW = 156
organic iminium reduction
Can the Hansch ester be used to enantioselectively deliver hydride
Could this organocatalytic sequence be utilized in the reduction of carbon–carbon double bonds
The Direct and Enantioselective Reduction of !,"-Unsaturated Aldehydes
Me
O
N
H
MeO2C
X
Y
O
olefin
Me
O
H
Me
Me
CO2Me
N
Me
Me
10 mol%
–40 °C, < 24 h
H
1.2 eqs
Et
93% ee
91% yield
O
Me
O
H
X
O
Y
"-chiral aldehyde
Me
94% ee
74% yield
O
Me
Me
97% ee
95% yield
Me
N
H
TIPSO
O
90% ee
74% yield
MeO2C
with Oulette and Tuttle, J. Am. Chem. Soc. 2005, 127, 32.
O
96% ee
91% yield
91% ee
83% yield
The Direct and Enantioselective Reduction of !,"-Unsaturated Enones
O
Me
H
O
N
O
H
MeO2C
N
H
O
CO2Me
R
Bn
Me
N
Me
H
Me
10 mol%
120 mol%
O
enantioenriched
O
O
Me
Me
R
23 °C, < 10 h
96% ee
81% yield
96% ee
85% yield
95% ee
72% yield
Me
Me
O
O
91% ee
73% yield
O
Me
Me
Me
98% ee
66% yield
88% ee
71% yield
also possible with larger rings: J. Am. Chem. Soc. 2006, 128, 12662.
MacH-(R)
Reliable Catalyst Framework Solves Basic Nucleophile Addition
! Iminium technology addresses problems of increasing complexity
O
O
NHBoc
N
N
R
R
N
H
Boc
Prochirality is found on nucleophile rather than aldehyde
O
O
Me
Me
O
S
R
Ph
Ph
R
CHO
Zwitterionic nucleophiles are unreactive towards typical iminium ions
O
O
H
O
H
R
R
Reversible nucleophile addition leads to racemic products
OH
Reliable Catalyst Framework Solves Basic Nucleophile Addition
! Iminium technology addresses problems of increasing complexity
O
O
NHBoc
N
N
R
R
N
H
Boc
Prochirality is found on nucleophile rather than aldehyde
O
O
Me
Me
O
S
R
Ph
Ph
R
CHO
Zwitterionic nucleophiles are unreactive towards typical iminium ions
O
O
H
O
H
R
R
Reversible nucleophile addition leads to racemic products
OH
Reliable Catalyst Framework Solves Basic Nucleophile Addition
! Iminium technology addresses problems of increasing complexity
O
O
NHBoc
N
N
R
R
N
H
Boc
Prochirality is found on nucleophile rather than aldehyde
O
O
Me
Me
O
S
R
Ph
Ph
R
CHO
Zwitterionic nucleophiles are unreactive towards typical iminium ions
O
O
H
O
H
R
R
Reversible nucleophile addition leads to racemic products
OH
Organocatalytic Synthesis of Pyrroloindoline Natural Products
H
O
H
O
N
O
Br
N
H
N
N
N
H
N
H
Me
H
N
H
O
N
H
H
O
H
Fructigenine C
Amouromine
Flustramine B
isolation
Takase Tetrahedron Lett. 1985, 847
J. Org. Chem 1980, 49, 1586
J. Nat Prod 1998, 61, 804
Danishefsky JACS 1999, 121, 11954
N
Me
Urochordamine
A
N
H H
N
N
N
N
B
C
O
N
Br
A
N
N
H H
Me
isolation
Tetrahedron Lett. 1993, 4819
N
N
H H
Me
N
N
H H
Me
(–) Chimonanthine
Overman
JACS 1999, 121, 7702
(1) Quaternary sterocenter(s)
(2) Vicinal sterocenter control
(3) Pyrroloindoline ring system
(4) Enantioselective Catalysis
! Can we perform enantioselective catalytic construction of pyrroleindoline core in one step?
Organocatalyzed Pyrroloindoline Construction: Catalytic Cycle
! Organocatalytic Indole Alkylation
Me
tBu
O
H
O
N
R
! Organocatalytic Pyrroloindoline Construction
Me
NHR
O
N
X–
N
N
R
Ph
tBu
N
X–
R
Ph
R
R
Me
O
Me
N
tBu
O
Me
N
N
H
tBu
O
Me
N
tBu
N
Ph
N
O
N
tBu
tBu
Ph
H
R
NHR
NR
R
N
X–
R
X–
Me
O
N
tBu
N
Ph
N
NR
Ph
HX
HX
R
NR
R
R
N
R
R
CHO
N
R
O
N
Ph
Me
R
O
N
N
N
R H R
CHO
N
H
Ph
Organocatalyzed Pyrroloindoline Construction: Catalytic Cycle
! Organocatalytic Indole Alkylation
Me
tBu
O
H
O
N
R
! Organocatalytic Pyrroloindoline Construction
Me
NHR
O
N
X–
N
N
R
Ph
tBu
N
X–
R
Ph
R
R
Me
O
Me
N
tBu
O
Me
N
N
H
tBu
O
Me
N
tBu
N
Ph
N
O
N
tBu
tBu
Ph
H
R
NHR
NR
R
N
X–
R
X–
Me
O
N
tBu
N
Ph
N
NR
Ph
HX
HX
R
NR
R
R
N
R
R
CHO
N
R
O
N
Ph
Me
R
O
N
N
N
R H R
CHO
N
H
Ph
O
Organocatalytic pyrroloindoline strategy is amenable to
Me
N
the synthesis of biomedically relevant molecules
N
H
•pTSA
N
H
! Enantioselective construction of pyrroloindoline core
CHO
10 mol %
catalyst
NHBoc
N
O
89% ee
CH2Cl2/H2O
N
H
85% yield
N
Boc
! Enantioselective construction of (+)-pseudophyrnamine
O
Me
Me
O
3 steps
46% yield
Me
O
3 steps
N
H
H
N
Me
75% yield
N
H
H
N
N
Me
Me
N
H H
This strategy is now being applied to many different natural product targets
O
Organocatalytic pyrroloindoline strategy is amenable to
Me
N
the synthesis of biomedically relevant molecules
N
H
•pTSA
N
H
! Enantioselective construction of pyrroloindoline core
CHO
10 mol %
catalyst
NHBoc
N
O
89% ee
CH2Cl2/H2O
N
H
85% yield
N
Boc
! Enantioselective construction of (+)-pseudophyrnamine
O
Me
Me
O
3 steps
46% yield
Me
O
3 steps
N
H
H
N
Me
75% yield
N
H
H
N
N
Me
Me
N
H H
This strategy is now being applied to many different natural product targets
Organocatalytic strategy is amenable to
Me
O
N
enantioselective synthesis of pyrroloindole structures
Me
Me
Ph
Me
N
H
•pTSA
! Enantioselective construction of pyrroloindoline core
CHO
10 mol %
catalyst
NHBoc
N
O
MeOH
69% ee
N
H
N
64% yield
Boc
! Change in reaction medium influences sense of induction
CHO
10 mol %
catalyst
NHBoc
N
O
toluene
84% ee
N
H
N
Boc
What is the effect of solvent dielectric constant on reaction selectivity
50% yield
+ 90
+ 69
+ 60
+ 21
– 45
– 84
Cyclopropanation with Ammonium and Sulfonium Ylides
! Enantioenriched cyclopropane motif widespread in nature and medicine
>100 medicinal agents
>4000 natural isolates
Lebel, H.; Macoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977.
! A variety of metal-carbenoid methodologies exist
Et
Et
O
Me
Charette
O
O
Ph
Ph
Ph
JACS 123, 12168
Ti
Cu
JACS 113, 726
N
OTf
Up to 92% ee
O
Evans
O
N
Ph
O
Me
Up to 99% ee
i-PrO Oi-Pr
Ph
OH
Zn(CH2I)2
RO2C
Ph
OH
Ph
N2
Ph
Many other important contributions (Kobayashi, Denmark, Davies, Nishiyama)
CO2R
Cyclopropanation with Ammonium and Sulfonium Ylides
! Gaunt's ammonium ylide organocatalytic cyclopropanation example
O
Br
O
OMe
OtBu
CsCO3 (1.3 equiv.)
N
O
Me
Me
MeCN, 80 ºC
Ph
63% yield
93% ee
OMe
Ph
N
20 mol%
Me
O
R3N *
OtBu
O
Ph
Me
Papageorgiu, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. 2003, 43, 4641
! Stabilized sulfonium ylides are compatible with aldehydes
CHO
Me
Me
Me
S
acetone
Me
CHO
50% yield
4:1 d.r.
CO2Et
60 ºC
Payne, G. B. J. Org. Chem. 1967, 32, 3351
CO2Et
Enantioselective Organocatalytic Cyclopropanation
! Surprisingly, imidazolidinone amine were ineffective
O
Me
N
Me
Me
O
Me
O
Ph
S
Ph
Me
N
H
O
Me
O
Ph
S
Ph
n-Pr
Ph
0% conversion
CHO
Me
N
Me
O
CHCl3, 23 ºC
O
Me
•TFA
Me
•TFA
O
N
H
n-Pr
Ph
0% conversion
CHCl3, 23 ºC
CHO
! An initial success using proline as a catalyst
O
Me
Me
O
Me
S
O
N
H
Ph
CO2H
n-Pr
Ph
CHCl3, 23 ºC
CHO
46% ee
2:1 d.r.
72% conversion
Enantioselective Organocatalytic Cyclopropanation
! Surprisingly, imidazolidinone amine were ineffective
O
Me
N
Me
Me
O
Me
O
Ph
S
Ph
Me
N
H
O
Me
O
Ph
S
Ph
n-Pr
Ph
0% conversion
CHO
Me
N
Me
O
CHCl3, 23 ºC
O
Me
•TFA
Me
•TFA
O
N
H
n-Pr
Ph
0% conversion
CHCl3, 23 ºC
CHO
! An initial success using proline as a catalyst
O
Me
Me
O
Me
S
O
N
H
Ph
CO2H
n-Pr
Ph
CHCl3, 23 ºC
CHO
46% ee
2:1 d.r.
72% conversion
Enantioselective Organocatalytic Cyclopropanations
O
Me
R
O
Me
S
O
N
H
Ph
(20 mol%)
CHCl3, –10 °C
Ph
Ph
CHO
O
Ph
3
CHO
CHO
95% ee
30:1 d.r.
85% yield
96% ee
24:1 d.r.
74% yield
Ph
AllO
CHO
91% ee
21:1 d.r.
77% yield
O
O
Me
Me
R
O
O
Me
CO2H
O
Ph
Ph
Ph
Me
CHO
CHO
96% ee
43:1 d.r.
63% yield
90%ee
>19:1 d.r.
67% yield
CHO
89% ee
33:1 d.r.
73% yield
95% ee
30:1 d.r.
85% yield
Studies To Investigate the Mechanistic Postulate
Determing the essential features for catalytic activity
N
! Both a secondary aniline amine and carboxylic acid are essential
N
H
CO2H
CO2H
N
N
H
Me
78% conversion
R
no electrostatic activation
cannot form iminium ion
iminium ion & electrostatic activation
CO2
0% conversion
CO2Me
· TCA
0% conversion
! Michael electrophiles are unsuccessful cyclopropanation substrates
cannot form iminium ion
CN
0% conversion
cannot form iminium ion
Ph
cannot form iminium ion
CO2Me
NO2
0% conversion
Me
CO2Me
0% conversion
poor iminium substrate
Me
CHO
low %ee
Studies To Investigate the Mechanistic Postulate
Determing the essential features for catalytic activity
N
! Both a secondary aniline amine and carboxylic acid are essential
N
H
CO2H
CO2H
N
N
H
Me
78% conversion
R
no electrostatic activation
cannot form iminium ion
iminium ion & electrostatic activation
CO2
0% conversion
CO2Me
· TCA
0% conversion
! Michael electrophiles are unsuccessful cyclopropanation substrates
cannot form iminium ion
CN
0% conversion
cannot form iminium ion
Ph
cannot form iminium ion
CO2Me
NO2
0% conversion
Me
CO2Me
0% conversion
poor iminium substrate
Me
CHO
low %ee
Studies To Investigate the Mechanistic Postulate
Determing the essential features for catalytic activity
N
! Both a secondary aniline amine and carboxylic acid are essential
N
H
CO2H
CO2H
N
N
H
Me
78% conversion
R
no electrostatic activation
cannot form iminium ion
iminium ion & electrostatic activation
CO2
0% conversion
CO2Me
· TCA
0% conversion
! Michael electrophiles are unsuccessful cyclopropanation substrates
cannot form iminium ion
CN
0% conversion
cannot form iminium ion
Ph
cannot form iminium ion
CO2Me
NO2
0% conversion
Me
CO2Me
0% conversion
poor iminium substrate
Me
CHO
low %ee
Studies To Investigate the Mechanistic Postulate
Determing the essential features for catalytic activity
N
! Both a secondary aniline amine and carboxylic acid are essential
N
H
CO2H
CO2H
N
N
H
Me
78% conversion
R
no electrostatic activation
cannot form iminium ion
iminium ion & electrostatic activation
CO2
0% conversion
CO2Me
· TCA
0% conversion
! Michael electrophiles are unsuccessful cyclopropanation substrates
cannot form iminium ion
CN
0% conversion
cannot form iminium ion
Ph
cannot form iminium ion
CO2Me
NO2
0% conversion
Me
CO2Me
0% conversion
poor iminium substrate
Me
CHO
low %ee
Studies To Investigate the Mechanistic Postulate
Determing the essential features for catalytic activity
N
! Both a secondary aniline amine and carboxylic acid are essential
N
H
CO2H
CO2H
N
N
H
Me
78% conversion
R
no electrostatic activation
cannot form iminium ion
iminium ion & electrostatic activation
CO2
0% conversion
CO2Me
· TCA
0% conversion
! Michael electrophiles are unsuccessful cyclopropanation substrates
cannot form iminium ion
CN
0% conversion
cannot form iminium ion
Ph
cannot form iminium ion
CO2Me
NO2
0% conversion
Me
CO2Me
0% conversion
poor iminium substrate
Me
CHO
low %ee
Studies To Investigate the Mechanistic Postulate
Determing the essential features for catalytic activity
N
! Both a secondary aniline amine and carboxylic acid are essential
N
H
CO2H
CO2H
N
N
H
Me
78% conversion
R
no electrostatic activation
cannot form iminium ion
iminium ion & electrostatic activation
CO2
0% conversion
CO2Me
· TCA
0% conversion
! Michael electrophiles are unsuccessful cyclopropanation substrates
cannot form iminium ion
CN
0% conversion
cannot form iminium ion
Ph
cannot form iminium ion
CO2Me
NO2
0% conversion
Me
CO2Me
0% conversion
poor iminium substrate
Me
CHO
low %ee
95
85
25
Heteroatom Nucleophile Addition to Iminium Ions
! Heteroatom containing stereocenters are ubiquitous in high-value molecules
O
NR2
OR
HO
R
R
H
N
R
Me
Heteroatom nucleophile conjugate addition
! Iminium-catalyzed conjugate addition of water discovered by Langenbeck in 1937
O
Me
O
H2O
OH
N
H
HOAc
Me
N
Me
O
Langenbeck, W.; Sauerbier, R. Ber. Dtsch. Chem. Ges. 1937, 70, 1540.
N
H
Ph
N
H
Simple chiral substitution
Enal hydration with water and chiral catalysts yields only racemic products
Reversible Addition/Elimination Leads to Racemic Products
! Stereoselective addition is balanced by stereoselective elimination (microscopic reverse)
E
O
Me
N
N
Ph
O
Me
N
R
O
N
N
O
Ph
R
R
OH
N
Me
Ph
R
OH
O
OH
R
OH
Reversible Addition/Elimination Leads to Racemic Products
! Stereoselective addition is balanced by stereoselective elimination (microscopic reverse)
!G‡ difference leads to
enantioenrichment in
addition step
!!G‡
E
O
Me
N
N
Ph
O
Me
N
R
O
N
N
O
Ph
R
R
OH
N
Me
Ph
R
OH
O
OH
R
OH
Reversible Addition/Elimination Leads to Racemic Products
! Stereoselective addition is balanced by stereoselective elimination (microscopic reverse)
!G‡ difference leads to
enantioenrichment in
addition step
E
O
Me
Free energy of the products
is identical by definition
(enantiomers)
N
N
Ph
O
Me
N
R
O
N
N
O
Ph
R
R
OH
N
Me
Ph
R
OH
O
OH
R
OH
Reversible Addition/Elimination Leads to Racemic Products
! Stereoselective addition is balanced by stereoselective elimination (microscopic reverse)
!G‡ difference leads to
enantioenrichment in
addition step
E
O
Me
Free energy of the products
is identical by definition
(enantiomers)
N
N
Ph
O
Me
N
R
O
N
N
O
Ph
R
R
OH
If process is reversible,
enantiomer that is formed in excess
will be consumed more rapidly
N
Me
Ph
R
OH
O
OH
R
OH
Heteroatom Nucleophile Addition to Iminium Ions
! Developing electronically tuned nucleophiles that do not add reversibly is crucial discovery
O
Me
N
O
Me
O
BnO
N
H
OTBS
Ph
Cbz
N
H
•pTSA
N
OTBS
Me
O
CHCl3, –20 ºC
95% ee
Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328
HO
Me
O
H
1.
N
N
H
Ar
Ar
Ph
O
OTMS
Me
2. NaBH4
N
OH
Ar = 3,5-CF3, 95% ee
Bertelsen, S.; Diner, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536
Heteroatom Nucleophile Addition to Iminium Ions
! Developing electronically tuned nucleophiles that do not add reversibly is crucial discovery
O
Me
N
O
Me
O
BnO
N
H
OTBS
Ph
Cbz
N
H
•pTSA
N
OTBS
Me
O
CHCl3, –20 ºC
95% ee
Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328
HO
Me
O
H
1.
N
N
H
Ar
Ar
Ph
O
OTMS
Me
2. NaBH4
N
OH
Ar = 3,5-CF3, 95% ee
Bertelsen, S.; Diner, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536
The Jørgensen Diarylprolinolether Class Catalysts
CF3
Ar
O
N
H
OTMS
CF3
N
H
OTMS
R
F3C
Ar
R
CF3
Large aryl and Si Group
! control iminium geometry
! shield the top face
Re face exposed
! In 2002 the Jørgensen group disclosed their very useful catalyst for enamine and iminium catalysis
! Reactivity is typically orthogonal to the imidizolidinone class of catalysts
Electrophilicity
E
–8.20
–9.80
–7.20
O
Me
N
N
Ph
N
Ph
OTMS
Bn
Ph
Lakhdar S.; Tokuyasu, T.; Mayr, H. Angew. Chem. Int. Ed. 2008, 47, 8723.
N
Me
Me
The Jørgensen Diarylprolinolether Class Catalysts
CF3
Ar
O
N
H
OTMS
CF3
N
H
OTMS
R
F3C
Ar
R
CF3
Large aryl and Si Group
! control iminium geometry
! shield the top face
Re face exposed
! In 2002 the Jørgensen group disclosed their very useful catalyst for enamine and iminium catalysis
! Reactivity is typically orthogonal to the imidizolidinone class of catalysts
Electrophilicity
E
–8.20
–9.80
–7.20
O
Me
N
N
Ph
N
Ph
OTMS
Bn
Ph
Lakhdar S.; Tokuyasu, T.; Mayr, H. Angew. Chem. Int. Ed. 2008, 47, 8723.
N
Me
Me
Hydrophosphination of Enals with the Jørgensen Catalyst
O
10 mol % catalyst
Ph
H
O
PPh2
H
Ph
H
PPh2
! Reactivity is typically orthogonal to the imidizolidinone class of catalysts
O
Me
CF3
N
Bn
N
H
·TFA
Me
Me
N
H
OTMS
toluene, 21 °C
76%, 0%ee
F3C
CF3
CF3
PhCO2H
toluene, 21 °C
95%, 75%ee
p-NO2-PhCO2H
ether, –10 °C
95%, 94%ee
Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P. Angew. Chem. Int. Ed. 2007, 46, 4504.
Scope of the Jørgensen Catalyst
Ph
O
Me
Ph
O
N
H
H
H
NO2
Ph
H
Me
toluene, 0 °C to 21 °C
Ph
O
OTMS
Ph
Ph
NO2
40%, 4:1 dr, 99% ee
Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861
Ar
N
H
O
H
C7H15
Ar
OMe
OTMS
H2O2
CH2Cl2;
NaOMe/MeOH
HO
C7H15
OMe
OH
65%, 98% ee
Albrecht, L.; Jiang, H.; Dickmeiss, G.; Gschwend, B.; Hansen, S. G.; Jørgensen, K. A. J. Am. Chem. Soc. ASAP
Scope of the Jørgensen Catalyst
! Involved in the development of other highly useful, though less well-known organocatalysts
Me
N
O
BnO
O
O
Ph
OBn
Ph
Me
N
H
O
CO2H
Ph
O
BnO
Neat, rt
Me
BnO
93% yield
99% ee
O
Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2003, 42, 661.
F3C
Bn
N
N
H
Bn
H
O
O
CH2Cl2, –20 ºC;
TFAA; NaBH4
N
94% yield
92% ee
HO
Frisch, K.; Landa, A.; Saaby, S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 6058.
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
N
+
Me
N
Ph
Me
Me
HO2C
N
X
S
N
~50 new reactions
with Jorgensen, K. A.
~20 new reactions
Hajos-Parrish
Barbas-List
Y
H
O
R
R
Me
N
H
Me
H+
R
H
~30 new reactions
Jacobsen–Akiyama
! Last 10 years, organocatalysis has delivered many new asymmetric transforms (~150-200)
! These 3 activation modes cover a large portion of the organocatalysis landscape
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
N
+
Me
N
Ph
Me
Me
HO2C
N
X
S
N
~50 new reactions
with Jorgensen, K. A.
~20 new reactions
Hajos-Parrish
Barbas-List
Y
H
O
R
R
Me
N
H
Me
H+
R
H
~30 new reactions
Jacobsen–Akiyama
! Last 10 years, organocatalysis has delivered many new asymmetric transforms (~150-200)
! These 3 activation modes cover a large portion of the organocatalysis landscape
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
N
+
Me
N
Ph
Me
Me
HO2C
N
X
S
N
~50 new reactions
with Jorgensen, K. A.
~20 new reactions
Hajos-Parrish
Barbas-List
Y
H
O
R
R
Me
N
H
Me
H+
R
H
~30 new reactions
Jacobsen–Akiyama
! Last 10 years, organocatalysis has delivered many new asymmetric transforms (~150-200)
! These 3 activation modes cover a large portion of the organocatalysis landscape
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
N
+
Me
N
Ph
Me
Me
HO2C
N
X
S
N
~50 new reactions
with Jorgensen, K. A.
~20 new reactions
Hajos-Parrish
Barbas-List
Y
H
O
R
R
Me
N
H
Me
H+
R
H
~30 new reactions
Jacobsen–Akiyama
! Last 10 years, organocatalysis has delivered many new asymmetric transforms (~150-200)
! These 3 activation modes cover a large portion of the organocatalysis landscape
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
N
+
Me
N
Ph
Me
Me
HO2C
N
X
S
N
~50 new reactions
with Jorgensen, K. A.
~20 new reactions
Hajos-Parrish
Barbas-List
Y
H
O
R
R
Me
N
H
Me
H+
R
H
~30 new reactions
Jacobsen–Akiyama
! Last 10 years, organocatalysis has delivered many new asymmetric transforms (~150-200)
! These 3 activation modes cover a large portion of the organocatalysis landscape
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
N
+
Me
N
Ph
Me
Me
HO2C
N
X
S
N
~50 new reactions
with Jorgensen, K. A.
~20 new reactions
Hajos-Parrish
Barbas-List
Y
H
O
R
R
Me
N
H
Me
H+
R
H
~30 new reactions
Jacobsen–Akiyama
! Last 10 years, organocatalysis has delivered many new asymmetric transforms (~150-200)
! These 3 activation modes cover a large portion of the organocatalysis landscape
Organometallic Catalysis: Few Activation Concepts
!-bond insertion
!-bond insertion
C–C bond coupling
C–N, 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
Hiyashi
Krische
"
Atom transfer catalysis
Sharpless
Jacobsen
Shi
Doyle
At
! Relatively few activation modes have resulted in literally thousands of new chemical reactions
Organocatalytic Activation Modes
Established Reaction Modes
O
Me
N
HO2C
N
Ph
O
N
Me
*
R3N
Me
R
R
R
Me
S
R
Iminium
Enamine
F
Ammonium
F
F
OMe
N
OH R
N
Phase Transfer
R
F
N
N
Ylide
N
Me
F
S
Me
P
X
N
H
N
H
Y
O
Carbene
O
O
O
R
Hydrogen Bonding
! These systems have been developed widely during the previous decade 2000-2009
OH