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 Transformations that employ organic catalysts manuscripts on >150 discrete reaction types sporadically documented over last 100 years Used for enantioselective construction of C–C, Organocatalysis google page hits = 137,000 C–N, C–O, C–S, C–P, C–halogen bonds Olefin metathesis google page hits = 253,000 Gold catalysis google page hits = 28,600 Now 3rd major branch of catalysis 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 Transformations that employ organic catalysts manuscripts on >150 discrete reaction types sporadically documented over last 100 years Used for enantioselective construction of C–C, Organocatalysis google page hits = 137,000 C–N, C–O, C–S, C–P, C–halogen bonds Olefin metathesis google page hits = 253,000 Gold catalysis google page hits = 28,600 Now 3rd major branch of catalysis 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 Transformations that employ organic catalysts manuscripts on >150 discrete reaction types sporadically documented over last 100 years Used for enantioselective construction of C–C, Organocatalysis google page hits = 137,000 C–N, C–O, C–S, C–P, C–halogen bonds Olefin metathesis google page hits = 253,000 Gold catalysis google page hits = 28,600 Now 3rd major branch of catalysis 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 Transformations that employ organic catalysts manuscripts on >150 discrete reaction types sporadically documented over last 100 years Used for enantioselective construction of C–C, Organocatalysis google page hits = 137,000 C–N, C–O, C–S, C–P, C–halogen bonds Olefin metathesis google page hits = 253,000 Gold catalysis google page hits = 28,600 Now 3rd major branch of catalysis 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 ! Transformations that employ organic catalysts manuscripts on >150 discrete reaction types sporadically documented over last 100 years ! Used for enantioselective construction of C–C, ! Organocatalysis google page hits = 137,000 C–N, C–O, C–S, C–P, C–halogen bonds Olefin metathesis google page hits = 253,000 Gold catalysis google page hits = 28,600 ! Now 3rd major branch of catalysis ! 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 Transformations that employ organic catalysts manuscripts on >150 discrete reaction types sporadically documented over last 100 years Used for enantioselective construction of C–C, Organocatalysis google page hits = 137,000 C–N, C–O, C–S, C–P, C–halogen bonds Olefin metathesis google page hits = 253,000 Gold catalysis google page hits = 28,600 Now 3rd major branch of catalysis 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 ! Transformations that employ organic catalysts manuscripts on >150 discrete reaction types sporadically documented over last 100 years ! Used for enantioselective construction of C–C, ! Organocatalysis google page hits = 137,000 C–N, C–O, C–S, C–P, C–halogen bonds Olefin metathesis google page hits = 253,000 Gold catalysis google page hits = 28,600 ! Now 3rd major branch of catalysis ! 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 O 3 mol% Me N CO2H catalyst H Me Me O catalyst DMF OH O (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 O 3 mol% Me N CO2H catalyst H Me Me O catalyst DMF OH O (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 O 3 mol% Me N CO2H catalyst H Me Me O catalyst DMF OH O (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 O 3 mol% Me N CO2H catalyst H Me Me O catalyst DMF OH O (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 O 3 mol% Me N CO2H catalyst H Me Me O catalyst DMF OH O (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 O 3 mol% Me N CO2H catalyst H Me Me O catalyst DMF OH O (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) Salen (Jacobsen)

Ph Ph O X P M M N N O X P Ph M Ph Me3C O O CMe3

Diels-Alder Hydrogenation CMe3 Me3C Hydrosilylation Aldol Hetero-Diels-Alder Ene Allylation Epoxidation, Epoxide opening M = Ti, Al M = Rh, Ru M = Mn, Cr, Co

Bisoxazoline (Evans–Pfaltz–Corey)

Me Me Cyclopropanation O O Aziridination Diels-Alder N N Aldol M R X X R 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) Salen (Jacobsen)

Ph Ph O X P M M N N O X P Ph M Ph Me3C O O CMe3

Diels-Alder Hydrogenation CMe3 Me3C Hydrosilylation Aldol Hetero-Diels-Alder Ene Allylation Epoxidation, Epoxide opening M = Ti, Al M = Rh, Ru M = Mn, Cr, Co

Bisoxazoline (Evans–Pfaltz–Corey)

Me Me Cyclopropanation O O Aziridination Diels-Alder N N Aldol M R X X R 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

O OTMS O Me OTMS 10 mol% catalyst Et Et t tBuS Me BuS Me O Me O

Regioselection (2 options): >95 : 5

Diastereoselection (2 options): >98 : 2 Enantioselection (2 options): 99 : 1

O O N N Sn N TfO OTf Ph 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

O OTMS O Me OTMS 10 mol% catalyst Et Et t tBuS Me BuS Me O Me O

Regioselection (2 options): >95 : 5

Diastereoselection (2 options): >98 : 2 Enantioselection (2 options): 99 : 1 Nu

O O N N Sn N TfO OTf Ph 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

O OTMS O Me OTMS 10 mol% catalyst Et Et t tBuS Me BuS Me O Me O

Regioselection (2 options): >95 : 5

Diastereoselection (2 options): >98 : 2 Enantioselection (2 options): 99 : 1

O O N N Sn N TfO OTf Ph 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

O OTMS O Me OTMS 10 mol% catalyst Et Et t tBuS Me BuS Me O Me O

Regioselection (2 options): >95 : 5

Diastereoselection (2 options): >98 : 2 Enantioselection (2 options): 99 : 1

O O Glovebox N N Sn N Ligand synthesis TfO OTf Ph 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% O catalyst

Oxone

47–95% ee

O + O N O O O O O O O F O O O

Yang catalyst Shi catalyst Denmark catalyst JACS 1996, 118, 491 JACS 1996, 118, 9806 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% O catalyst

Oxone

47–95% ee

O + O N O O O O O O O F O O O

Yang catalyst Shi catalyst Denmark catalyst JACS 1996, 118, 491 JACS 1996, 118, 9806 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% O catalyst

Oxone

47–95% ee

O + O N O O O O O O O F O O O

Yang catalyst Shi catalyst Denmark catalyst JACS 1996, 118, 491 JACS 1996, 118, 9806 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% O catalyst

Oxone

47–95% ee

O + O N O O O O O O O F O O O

Yang catalyst Shi catalyst Denmark catalyst JACS 1996, 118, 491 JACS 1996, 118, 9806 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 LA LA O O O O X LA 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 catalyst LUMO–activation

LA O + Lewis acid (LA) O +

R R R + N N O H •HCl + 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 R N H HCl Ph Ph O catalyst CHO

! Amine Catalyzed [3 + 2] Cycloadditions

R R N + H HCl O Me Ph N Ph N Ph Me O O catalyst – Ph CHO

! Amine Catalyzed Mukaiyama Michael

R R OTMS N O Me H HCl EtS Me O EtS O catalyst Me Me

! Many other transforms should be possible: Conjugate Additions, Epoxidations, Cyclopropanations Organocatalyzed Diels–Alder Reaction: ReactIR Studies

Time Ph Ph O (hours) Abs Time Abs (hours) H O

15.0

B 10.0 A 5.0 A B

wavenumbers wavenumbers

•HCl

Ph N CO2Me Ph 10% H MeOH MeOH Ph O B H O Ph O A H O 81% yield 48% ee

! Amine Catalyzed Diels–Alder Reaction is facile at room temperature Organocatalyzed Diels–Alder Reaction: ReactIR Studies

Time Ph Ph O (hours) Abs Time Abs (hours) H O

15.0

B 10.0 A 5.0 A B

wavenumbers wavenumbers

•HCl

Ph N CO2Me Ph 10% H MeOH MeOH Ph O B H O Ph O A 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 + N Me O NHMe N Me trans N H CHO H •HCl or Me Me 20 mol% CO2R exo (2R)

+ N Me 65% ee N Me H cis

Si–face Re–face

CHO CHO Me Me exo (2S) exo (2R)

trans–iminium cis–iminium 232.44 kJmol–1 229.53 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 + N Me O NHMe N Me trans N H CHO H •HCl or Me Me 20 mol% CO2R exo (2R)

+ N Me 65% ee N Me H cis

Si–face Re–face

CHO CHO Me Me exo (2S) exo (2R)

trans–iminium cis–iminium 232.44 kJmol–1 229.53 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 Me O Me N Me CO2Me NHMe; N Me O Ph Me N Ph + Me NH2 acetone, HCl N Me Ph HCl H (S)-Phenyl alanine 4–imidazolidinone Me methyl ester favored geometry

CHO

CHO + Me Me

exo (S) 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 Me O Me N Me CO2Me NHMe; N Me O Ph Me N Ph + Me NH2 acetone, HCl N Me Ph HCl H (S)-Phenyl alanine 4–imidazolidinone Me methyl ester favored geometry

CHO

CHO + Me Me

exo (S) 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 Me O Me N Me CO2Me NHMe; N Me O Ph Me N Ph + Me NH2 acetone, HCl N Me Ph HCl H (S)-Phenyl alanine 4–imidazolidinone Me methyl ester favored geometry

CHO

CHO + Me Me

exo (S) 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 N Me H TfOH ! With Ahrendt, K. A.; Borths, C. J catalyst

OAc OAc 72% yield CHO endo:exo 11:1 H O 10 mol% cat endo (S) 85% ee

CHO Ph 75% yield Me O 90% ee 10 mol% cat Ph Me

Me Me 75% yield CHO endo:exo 5:1 H O endo (S) 90% ee 20 mol% Me Me

NHCBz NHCBz endo:exo 90:10 to 96:4 5 mol% cat CHO R O endo (S) 93–99% ee R = H, CH2OBz, Me, CO2Me R 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

! 3 Introduced for the first time, the terminology organocatalysis, organic catalysis and organocatalytic J. Am. Chem. Soc. 2000, 3122, 4243 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 generic activation mode? enantioselective bond formation

substrate catalyst activation mode

O Me Several O Me N Me N + enantioselective + Me N R O Me catalytic reactions? N Me Ph H Ph Nu: (we hoped for 3) R

! 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 generic activation mode? enantioselective bond formation

substrate catalyst activation mode

O Me Several O Me N Me N + enantioselective + Me N R O Me catalytic reactions? N Me Ph H Ph Nu: (we hoped for 3) R

! 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

CH OBz 2 CbzNH O

O CHO Et 90% ee 96% ee Me 98% ee N Me

Nitrone Cycloaddition Aniline Addition Enal hydrogenation JACS 2000, 122, 9874 JACS 2001, 124, 7894 JACS 2005, 127, 32

Bn Me2N N O Ph 94% ee O Ph Me 96% ee Et O 94% ee CHO CO2Me

Pyrrole Friedel–Crafts Vinylogous Michael Enone hydrogenation JACS 2001, 123, 4370 JACS 2003, 125, 1192 JACS 2006, 128, 12662

O O

O O 96% ee N Me 92% ee Me O Ph 93% ee Bu H i-Pr Iminium activation is useful for a variety of transformations

Intramolecular Diels–Alder Cyclopropanation Nitroalkane Addition JACS 2001, 124, 7894 JACS 2005, 127, 3240

O H Me n-Pr COPh H 95% ee O2N Ph O

CHO Me 93% ee 95% ee H

Addition–Cyclization Epoxidation Tertiary Amino Acid PNAS 2004, 101, 5482 Tetrahedron YI Award 2006, 1472 O O Me

O O O 92% ee N Me 90% ee Ph O 99% ee N N Ph H Bn BOC

Amine Conjugate Addition Aziridination Aryl or Vinyl BF3K Addition JACS 2006, 128, 9328 JACS 2007, 127, 15438

Boc OTES Ns N N O MeO2C O N n-Pr O 95% ee 93% ee BOC Me 91% ee Consideration of privileged architecture and stereogenicity

! Most common substituent found in asymmetric carbon stereogenicity

Hydrogenation H most common H X chiral substituent Y O H Traditional Methods for Asymmetric Hydrogenation

! Organometallic hydrogenation (Noyori)

Ph Ph X OH P H OH M H2 P Y Y O Ph O Ph X H

olefin M = Pd, Rh, Ru Enantioenriched olefin

! Organic systems: Enzymatic reduction (hydrogenation) is mediated by NADH

HO OH HO OH O H H O – NH2 O O N O O O NH H N N O P P O N 2 2 NH – H O O N N H O R nicotinamide-adenine-dinucleotide-H (NADH) NADH

Can a coenzyme analog be utilized in the reducion of carbon-carbon bonds Traditional Methods for Asymmetric Hydrogenation

! Organometallic hydrogenation (Noyori)

Ph Ph X OH P H OH M H2 P Y Y O Ph O Ph X H

olefin M = Pd, Rh, Ru Enantioenriched olefin

! Organic systems: Enzymatic reduction (hydrogenation) is mediated by NADH

HO OH HO OH O H H O – NH2 O O N O O O NH H N N O P P O N 2 2 NH – H O O N N H O R nicotinamide-adenine-dinucleotide-H (NADH) NADH

Can a coenzyme analog be utilized in the reducion of carbon-carbon bonds Traditional Methods for Asymmetric Hydrogenation

! Organometallic hydrogenation (Noyori)

Ph Ph X OH P H OH M H2 P Y Y O Ph O Ph X H

olefin M = Pd, Rh, Ru Enantioenriched olefin

! Organic systems: Enzymatic reduction (hydrogenation) is mediated by NADH

HO OH HO OH O H H O – NH2 O O N O O O NH H N N O P P O N 2 2 NH – H O O N N H O R nicotinamide-adenine-dinucleotide-H (NADH) 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)

alanine transferase O H H CONH NH2 OH 2 Me NH OH 3 Me O N O R enzyme methyl NADH catalyst alanine pyruvate

R H2N HN O H + N H N H R N Me His H O O H H NH active site HN Arg NADH reduction 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)

alanine transferase O H H CONH NH2 OH 2 Me NH OH 3 Me O N O R enzyme methyl NADH catalyst alanine pyruvate

R H2N HN O H + N H N H R N Me His H O O H H NH active site HN Arg NADH reduction 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 H

X MeO2C CO2Me H X Y O Y O Me N Me olefin R catalyst hydrogenation NADH analog

MeO Me O O N H X R N Me + N H Me H Y N Me 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 H

X MeO2C CO2Me H X Y O Y O Me N Me olefin R catalyst hydrogenation NADH analog

MeO Me O O N H X R N Me + N H Me H Y N Me 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 H Me MeO C CO Me N X 2 2 Me H H Me X Y O Y O Me N Me 10 mol% olefin H –40 °C, < 24 h "-chiral aldehyde 1.2 eqs

Me Et Me 93% ee 94% ee 96% ee O 91% yield O 74% yield O 91% yield

Me Me 91% ee 90% ee 97% ee TIPSO MeO C 83% yield Me O 95% yield O 74% yield 2 O

with Oulette and Tuttle, J. Am. Chem. Soc. 2005, 127, 32.

The Direct and Enantioselective Reduction of !,"-Unsaturated Enones

O Me O H H O N MeO2C CO2Me

N Bn R H Me N Me O R Me H 23 °C, < 10 h 10 mol% 120 mol% enantioenriched

O O O 96% ee 95% ee 96% ee 81% yield 72% yield 85% yield Me Me Me Me

O O O 88% ee 91% ee Me 98% ee 71% yield Me 66% yield 73% yield Me

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 NHBoc O

N N N H R R Boc Prochirality is found on nucleophile rather than aldehyde

O O Me O R Ph S Me Ph R CHO

Zwitterionic nucleophiles are unreactive towards typical iminium ions

O O

O H H

R R OH

Reversible nucleophile addition leads to racemic products Reliable Catalyst Framework Solves Basic Nucleophile Addition ! Iminium technology addresses problems of increasing complexity

O NHBoc O

N N N H R R Boc Prochirality is found on nucleophile rather than aldehyde

O O Me O R Ph S Me Ph R CHO

Zwitterionic nucleophiles are unreactive towards typical iminium ions

O O

O H H

R R OH

Reversible nucleophile addition leads to racemic products Reliable Catalyst Framework Solves Basic Nucleophile Addition ! Iminium technology addresses problems of increasing complexity

O NHBoc O

N N N H R R Boc Prochirality is found on nucleophile rather than aldehyde

O O Me O R Ph S Me Ph R CHO

Zwitterionic nucleophiles are unreactive towards typical iminium ions

O O

O H H

R R OH

Reversible nucleophile addition leads to racemic products Organocatalytic Synthesis of Pyrroloindoline Natural Products

O O H H H H N O N N N Br N N H N H N H H Me H O H O

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 B H H A C Urochordamine N N N N

A N O N N N H H Me N N H H Br N N Me (1) Quaternary sterocenter(s) H H Me (–) Chimonanthine (2) Vicinal sterocenter control (3) Pyrroloindoline ring system isolation Overman (4) Enantioselective Catalysis Tetrahedron Lett. 1993, 4819 JACS 1999, 121, 7702

! Can we perform enantioselective catalytic construction of pyrroleindoline core in one step? Organocatalyzed Pyrroloindoline Construction: Catalytic Cycle

! Organocatalytic Indole Alkylation ! Organocatalytic Pyrroloindoline Construction

H Me O NHR Me O N X– N X–

t N t R R O Bu N N Bu N O Ph R R Ph

R R Me O Me O Me O Me O N N N N tBu N tBu N tBu N H tBu N Ph Ph Ph H Me O Ph H NHR N R R Me O NR N R tBu N N X– X– Ph t Bu N NR HX Ph R HX NR R R R N R CHO CHO

N N N R H R R Organocatalyzed Pyrroloindoline Construction: Catalytic Cycle

! Organocatalytic Indole Alkylation ! Organocatalytic Pyrroloindoline Construction

H Me O NHR Me O N X– N X–

t N t R R O Bu N N Bu N O Ph R R Ph

R R Me O Me O Me O Me O N N N N tBu N tBu N tBu N H tBu N Ph Ph Ph H Me O Ph H NHR N R R Me O NR N R tBu N N X– X– Ph t Bu N NR HX Ph R HX NR R R R N R CHO CHO

N N N R H R R O Me Organocatalytic pyrroloindoline strategy is amenable to N

the synthesis of biomedically relevant molecules N H •pTSA N H ! Enantioselective construction of pyrroloindoline core

CHO

NHBoc 10 mol % catalyst 89% ee N O CH2Cl2/H2O N N 85% yield H Boc

! Enantioselective construction of (+)-pseudophyrnamine

O Me Me Me O O

3 steps 3 steps

46% yield N N 75% yield N N N N H H H H H Me H Me Me

This strategy is now being applied to many different natural product targets O Me Organocatalytic pyrroloindoline strategy is amenable to N

the synthesis of biomedically relevant molecules N H •pTSA N H ! Enantioselective construction of pyrroloindoline core

CHO

NHBoc 10 mol % catalyst 89% ee N O CH2Cl2/H2O N N 85% yield H Boc

! Enantioselective construction of (+)-pseudophyrnamine

O Me Me Me O O

3 steps 3 steps

46% yield N N 75% yield N N N N H H H H H Me H Me Me

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 Ph N Me H Me •pTSA

! Enantioselective construction of pyrroloindoline core

CHO

NHBoc 10 mol % catalyst 69% ee N O MeOH N N 64% yield H Boc

! Change in reaction medium influences sense of induction

CHO

NHBoc 10 mol % catalyst 84% ee N O toluene N N 50% yield H Boc

What is the effect of solvent dielectric constant on reaction selectivity + 90 + 69

+ 60 + 21 – 45 – 84 Cyclopropanation with Ammonium and Sulfonium Ylides

! Enantioenriched cyclopropane motif widespread in nature and medicine

>4000 natural isolates >100 medicinal agents

Lebel, H.; Macoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977.

! A variety of metal-carbenoid methodologies exist

Et Et Charette Me Me Evans O O O O JACS 123, 12168 N N JACS 113, 726 Ph Ph Cu Ph Ph OTf O O Up to 92% ee Up to 99% ee Ti i-PrO Oi-Pr

RO2C N Zn(CH2I)2 2 CO2R Ph OH Ph OH Ph Ph

Many other important contributions (Kobayashi, Denmark, Davies, Nishiyama) Cyclopropanation with Ammonium and Sulfonium Ylides

! Gaunt's ammonium ylide organocatalytic cyclopropanation example

O O Br OMe OtBu CsCO3 (1.3 equiv.) Me 63% yield N Ph Me 93% ee O MeCN, 80 ºC 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 CHO acetone 50% yield S CO Et 2 4:1 d.r. Me Me 60 ºC CO2Et

Payne, G. B. J. Org. Chem. 1967, 32, 3351 Enantioselective Organocatalytic Cyclopropanation

! Surprisingly, imidazolidinone amine were ineffective

O Me •TFA N Me O Me O N Me H n-Pr Ph Ph Me O S Me Ph 0% conversion CHCl3, 23 ºC CHO

O Me N •TFA O N Me O H n-Pr Ph Ph Me O S 0% conversion Me Ph CHCl3, 23 ºC CHO

! An initial success using proline as a catalyst

O Me O N CO2H n-Pr 46% ee H Ph Me O S 2:1 d.r. Me Ph CHCl3, 23 ºC 72% conversion CHO Enantioselective Organocatalytic Cyclopropanation

! Surprisingly, imidazolidinone amine were ineffective

O Me •TFA N Me O Me O N Me H n-Pr Ph Ph Me O S Me Ph 0% conversion CHCl3, 23 ºC CHO

O Me N •TFA O N Me O H n-Pr Ph Ph Me O S 0% conversion Me Ph CHCl3, 23 ºC CHO

! An initial success using proline as a catalyst

O Me O N CO2H n-Pr 46% ee H Ph Me O S 2:1 d.r. Me Ph CHCl3, 23 ºC 72% conversion CHO

Enantioselective Organocatalytic Cyclopropanations

O Me O N CO2H R H S Ph R O Me Ph (20 mol%) CHO CHCl3, –10 °C

O O O Me AllO Ph Ph Ph 3 CHO CHO CHO

95% ee 96% ee 91% ee 30:1 d.r. 24:1 d.r. 21:1 d.r. 85% yield 74% yield 77% yield

O O O Me Me Ph Ph Ph Me CHO CHO CHO 96% ee 90%ee 89% ee 43:1 d.r. >19:1 d.r. 33:1 d.r. 63% yield 67% yield 73% yield 95% ee 30:1 d.r. 85% yield Studies To Investigate the Mechanistic Postulate

Determing the essential features for catalytic activity N CO2

! Both a secondary aniline amine and carboxylic acid are essential R

iminium ion & electrostatic activation cannot form iminium ion no electrostatic activation

N CO2H N CO2H N CO2Me H H Me · TCA

78% conversion 0% conversion 0% conversion

! Michael electrophiles are unsuccessful cyclopropanation substrates cannot form iminium ion cannot form iminium ion cannot form iminium ion poor iminium substrate

CO2Me Me CN Ph NO2 Me CO2Me CHO

0% conversion 0% conversion 0% conversion low %ee Studies To Investigate the Mechanistic Postulate

Determing the essential features for catalytic activity N CO2

! Both a secondary aniline amine and carboxylic acid are essential R

iminium ion & electrostatic activation cannot form iminium ion no electrostatic activation

N CO2H N CO2H N CO2Me H H Me · TCA

78% conversion 0% conversion 0% conversion

! Michael electrophiles are unsuccessful cyclopropanation substrates cannot form iminium ion cannot form iminium ion cannot form iminium ion poor iminium substrate

CO2Me Me CN Ph NO2 Me CO2Me CHO

0% conversion 0% conversion 0% conversion low %ee Studies To Investigate the Mechanistic Postulate

Determing the essential features for catalytic activity N CO2

! Both a secondary aniline amine and carboxylic acid are essential R

iminium ion & electrostatic activation cannot form iminium ion no electrostatic activation

N CO2H N CO2H N CO2Me H H Me · TCA

78% conversion 0% conversion 0% conversion

! Michael electrophiles are unsuccessful cyclopropanation substrates cannot form iminium ion cannot form iminium ion cannot form iminium ion poor iminium substrate

CO2Me Me CN Ph NO2 Me CO2Me CHO

0% conversion 0% conversion 0% conversion low %ee Studies To Investigate the Mechanistic Postulate

Determing the essential features for catalytic activity N CO2

! Both a secondary aniline amine and carboxylic acid are essential R

iminium ion & electrostatic activation cannot form iminium ion no electrostatic activation

N CO2H N CO2H N CO2Me H H Me · TCA

78% conversion 0% conversion 0% conversion

! Michael electrophiles are unsuccessful cyclopropanation substrates cannot form iminium ion cannot form iminium ion cannot form iminium ion poor iminium substrate

CO2Me Me CN Ph NO2 Me CO2Me CHO

0% conversion 0% conversion 0% conversion low %ee Studies To Investigate the Mechanistic Postulate

Determing the essential features for catalytic activity N CO2

! Both a secondary aniline amine and carboxylic acid are essential R

iminium ion & electrostatic activation cannot form iminium ion no electrostatic activation

N CO2H N CO2H N CO2Me H H Me · TCA

78% conversion 0% conversion 0% conversion

! Michael electrophiles are unsuccessful cyclopropanation substrates cannot form iminium ion cannot form iminium ion cannot form iminium ion poor iminium substrate

CO2Me Me CN Ph NO2 Me CO2Me CHO

0% conversion 0% conversion 0% conversion low %ee Studies To Investigate the Mechanistic Postulate

Determing the essential features for catalytic activity N CO2

! Both a secondary aniline amine and carboxylic acid are essential R

iminium ion & electrostatic activation cannot form iminium ion no electrostatic activation

N CO2H N CO2H N CO2Me H H Me · TCA

78% conversion 0% conversion 0% conversion

! Michael electrophiles are unsuccessful cyclopropanation substrates cannot form iminium ion cannot form iminium ion cannot form iminium ion poor iminium substrate

CO2Me Me CN Ph NO2 Me CO2Me CHO

0% conversion 0% conversion 0% conversion low %ee 95 85 25 Heteroatom Nucleophile Addition to Iminium Ions

! Heteroatom containing stereocenters are ubiquitous in high-value molecules

O H OR NR2 HO R N R R

Me

Heteroatom nucleophile conjugate addition

! Iminium-catalyzed conjugate addition of water discovered by Langenbeck in 1937

O Me N N OH H Me O H2O Me O N N H H HOAc Ph Simple chiral substitution Langenbeck, W.; Sauerbier, R. Ber. Dtsch. Chem. Ges. 1937, 70, 1540.

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 Me N N Ph

N R OH Ph O O

R OH

R OH R OH Reversible Addition/Elimination Leads to Racemic Products

! Stereoselective addition is balanced by stereoselective elimination (microscopic reverse)

!G‡ difference leads to !!G‡ enantioenrichment in addition step

E O Me N

N Ph O Me N

R O Me N N Ph

N R OH Ph O O

R OH

R 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 N is identical by definition (enantiomers) N Ph O Me N

R O Me N N Ph

N R OH Ph O O

R OH

R 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 N is identical by definition (enantiomers) N Ph O Me N

R If process is reversible, O Me N enantiomer that is formed in excess N Ph will be consumed more rapidly

N R OH Ph O O

R OH

R OH R OH Heteroatom Nucleophile Addition to Iminium Ions

! Developing electronically tuned nucleophiles that do not add reversibly is crucial discovery

O Me N

Cbz OTBS N N O H Ph OTBS •pTSA Me O BnO N Me O H CHCl , –20 ºC 3 95% ee

Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328

Ar 1. Ph HO N Ar N O N H OTMS Me O H Me OH 2. NaBH4 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

Cbz OTBS N N O H Ph OTBS •pTSA Me O BnO N Me O H CHCl , –20 ºC 3 95% ee

Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328

Ar 1. Ph HO N Ar N O N H OTMS Me O H Me OH 2. NaBH4 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

O Ar Ar Large aryl and Si Group N H N CF3 OTMS H OTMS ! control iminium geometry R ! shield the top face R F3C CF3

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

–9.80 –8.20 –7.20 O Me N Me N N Bn N Me OTMS

Ph Ph Ph

Lakhdar S.; Tokuyasu, T.; Mayr, H. Angew. Chem. Int. Ed. 2008, 47, 8723. The Jørgensen Diarylprolinolether Class Catalysts

CF3

O Ar Ar Large aryl and Si Group N H N CF3 OTMS H OTMS ! control iminium geometry R ! shield the top face R F3C CF3

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

–9.80 –8.20 –7.20 O Me N Me N N Bn N Me OTMS

Ph Ph Ph

Lakhdar S.; Tokuyasu, T.; Mayr, H. Angew. Chem. Int. Ed. 2008, 47, 8723. Hydrophosphination of Enals with the Jørgensen Catalyst

O Ph 10 mol % catalyst O Ph H PPh2

H H PPh2

! Reactivity is typically orthogonal to the imidizolidinone class of catalysts

O Me CF3 N PhCO2H Me toluene, 21 °C Bn N Me H 95%, 75%ee N CF3 ·TFA H OTMS

p-NO2-PhCO2H toluene, 21 °C ether, –10 °C 76%, 0%ee F3C CF3 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 O Ph N O H OTMS Ph Me H Me H H NO2 Ph toluene, 0 °C to 21 °C 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 O H OTMS OMe Ar HO H H2O2 OMe

CH2Cl2; C H C7H15 OH 7 15 NaOMe/MeOH 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 Ph O CO2H O N O O Ph H BnO Me 93% yield BnO OBn Ph Me Neat, rt 99% ee BnO O

Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2003, 42, 661.

F3C O

Bn N Bn H 94% yield N H N 92% ee CH2Cl2, –20 ºC; O TFAA; NaBH4 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 Im Enamine catalysis En H-bond catalysis H+

O Me Me S Me N HO C + Me 2 N X N N Y N Me H H Ph Me Me O R R R H ~20 new reactions ~50 new reactions Hajos-Parrish ~30 new reactions with Jorgensen, K. A. Barbas-List 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 Im Enamine catalysis En H-bond catalysis H+

O Me Me S Me N HO C + Me 2 N X N N Y N Me H H Ph Me Me O R R R H ~20 new reactions ~50 new reactions Hajos-Parrish ~30 new reactions with Jorgensen, K. A. Barbas-List 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 Im Enamine catalysis En H-bond catalysis H+

O Me Me S Me N HO C + Me 2 N X N N Y N Me H H Ph Me Me O R R R H ~20 new reactions ~50 new reactions Hajos-Parrish ~30 new reactions with Jorgensen, K. A. Barbas-List 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 Im Enamine catalysis En H-bond catalysis H+

O Me Me S Me N HO C + Me 2 N X N N Y N Me H H Ph Me Me O R R R H ~20 new reactions ~50 new reactions Hajos-Parrish ~30 new reactions with Jorgensen, K. A. Barbas-List 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 Im Enamine catalysis En H-bond catalysis H+

O Me Me S Me N HO C + Me 2 N X N N Y N Me H H Ph Me Me O R R R H ~20 new reactions ~50 new reactions Hajos-Parrish ~30 new reactions with Jorgensen, K. A. Barbas-List 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 Im Enamine catalysis En H-bond catalysis H+

O Me Me S Me N HO C + Me 2 N X N N Y N Me H H Ph Me Me O R R R H ~20 new reactions ~50 new reactions Hajos-Parrish ~30 new reactions with Jorgensen, K. A. Barbas-List 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 Many Powerful Reactions

!-bond insertion !-bond insertion "-bond insertion C–C bond coupling C–N, S, O coupling Noyori Buchwald " Suzuki ! ! Toste Hartwig Negishi Heck Stille Hiyashi Kumada Krische Fu

Lewis acid catalysis Olefin metathesis Atom transfer catalysis

Yates La Grubbs Ru Sharpless At Corey Schrock Jacobsen Evans Hoveyda Shi Shibasaki Furstner Doyle Mukaiyama

! Relatively few activation modes have resulted in literally thousands of new chemical reactions Organocatalytic Activation Modes

Established Reaction Modes O Me N O HO2C N N * Me S Me Ph R3N Me R R R R Iminium Enamine Ammonium Ylide

F F

F F R OMe Me S Me N N F O O P N N R X N N Y O OH OH H H

N O R

Phase Transfer Carbene Hydrogen Bonding

! These systems have been developed widely during the previous decade 2000-2009