Enamine Catalysis: Fifty Years in the Making ! Stork's landmark 1954 publication outlines benefits of enamines vs enolates O

O

Acylation

Ph

O Me

N

Alkylation

O Ph

Michael Addition

O CN

Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.

Enamine Catalysis: Fifty Years in the Making ! Stork's landmark 1954 publication outlines benefits of enamines vs enolates O

O

Acylation

Ph

O Me

N

Alkylation

O Ph

Michael Addition

O CN

Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.

Enamine Catalysis: Inspiration from Biology ! Mechanism of class I aldolases is proposed to involve enamine intermediates

OH

OH

2–O PO 3

O O

OH

OPO3

2–

NH2

OH

OH

OPO32–

OH H

2–O PO 3

HO OH

N

OPO3

2–

NH OPO32–

O OPO32–

H

Fructose bisphosphate aldolase

OH

Lysine reside is required for catalytic activity

Rutter, W. J. Fed. Proc. Am. Soc. Exp. Biol. 1964, 23, 1248

Enamine Catalysis: Early Adoption in Total Synthesis ! Woodward-Wieland-Miescher enamine cyclization for steroid synthesis

Me Me

Me

OH

H

Me

H5IO6

OH

H O

O

Me CHO

O

O

Me

N H

HOAc benzene

H

O

Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223

O

O Me

O Me

OH O O H

Me O O

N H

NaOH

Me O

OH

HO O

O

OH

O

H

Wieland, P.; Miescher, K. Helv. Chim. Acta 1950, 33, 2215

Hajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough ! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasion

Me O

proline (3 mol%)

O

O Me

proline (200 mol%)

Me O

Me O

DMF OH

98% ee

O

MeCN, HClO4 80 ºC

O

67% ee

J. Org. Chem. 1974, 39, 1615.

Angew. Chem. Int. Ed. 1971, 10, 496.

German Patent DE2102623 (July 29, 1971)

German Patent DE2014757 (Oct 7, 1971)

Hajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough ! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasion

Me O

proline (3 mol%)

O

O Me

proline (200 mol%)

Me O

Me O

DMF OH

98% ee ee 97%

O

MeCN, HClO4 80 ºC

O

67% ee

J. Org. Chem. 1974, 39, 1615.

Angew. Chem. Int. Ed. 1971, 10, 496.

German Patent DE2102623 (July 29, 1971)

German Patent DE2014757 (Oct 7, 1971)

Hajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough ! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasion

Me O

proline (3 mol%)

O

O Me

proline (200 mol%)

Me O

Me O

DMF OH

98% ee ee 97%

O

MeCN, HClO4 80 ºC

O

67% ee

J. Org. Chem. 1974, 39, 1615.

Angew. Chem. Int. Ed. 1971, 10, 496.

German Patent DE2102623 (July 29, 1971)

German Patent DE2014757 (Oct 7, 1971)

Hajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough ! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasion

Me O

proline (3 mol%)

O

O Me

proline (200 mol%)

Me O

Me O

DMF OH

98% ee ee 97%

O

MeCN, HClO4 80 ºC

O

67% ee

J. Org. Chem. 1974, 39, 1615.

Angew. Chem. Int. Ed. 1971, 10, 496.

German Patent DE2102623 (July 29, 1971)

German Patent DE2014757 (Oct 7, 1971)

3210

Bifunctional Enamine Catalysis: Generic Induction Platform ! Use of proline or proline-type activation a widely exploited mode of ketone activation Cbz N

N

O

NHCbz

Cbz

N

R'

O

Amination

Cbz

R

R'

Jørgensen JACS 2002, 124, 6254.

R

ketone

X

Y

H

NO2

Ph N

R X

Y

R' H

O

O

Ph NO2

R'

Nitro-olefin addition

O

Bifunctional activation

R

List Org Lett 2001, 13, 2423.

OH N H

O

O

proline

Me O

H

OH

Me

Me

Cross-Aldol

Me

Me

List Org Lett 2001, 3, 573.

Bifunctional Enamine Catalysis: Generic Induction Platform ! Use of proline or proline-type activation a widely exploited mode of ketone activation Cbz N

N

O

NHCbz

Cbz

N

R'

O

Amination

Cbz

R

R'

Jørgensen JACS 2002, 124, 6254.

R

ketone

X

Y

H

NO2

Ph N

R X

Y

R' H

O

O

Ph NO2

R'

Nitro-olefin addition

O

Bifunctional activation

R

List Org Lett 2001, 13, 2423.

OH N H

O

O

proline

Me O

H

OH

Me

Me

Cross-Aldol

Me

Me

List Org Lett 2001, 3, 573.

Bifunctional Enamine Catalysis: Generic Induction Platform ! Use of proline or proline-type activation a widely exploited mode of ketone activation Cbz N

N

O

NHCbz

Cbz

N

R'

O

Amination

Cbz

R

R'

Jørgensen JACS 2002, 124, 6254.

R

ketone

X

Y

H

NO2

Ph N

R X

Y

R' H

O

O

Ph NO2

R'

Nitro-olefin addition

O

Bifunctional activation

R

List Org Lett 2001, 13, 2423.

OH N H

O

O

proline

Me O

H

OH

Me

Me

Cross-Aldol

Me

Me

List Org Lett 2001, 3, 573.

Bifunctional Enamine Catalysis: Generic Induction Platform ! Use of proline or proline-type activation a widely exploited mode of ketone activation Cbz N

N

O

NHCbz

Cbz

N

R'

O

Amination

Cbz

R

R'

Jørgensen JACS 2002, 124, 6254.

R

ketone

X

Y

H

NO2

Ph N

R X

Y

R' H

O

O

Ph NO2

R'

Nitro-olefin addition

O

Bifunctional activation

R

List Org Lett 2001, 13, 2423.

OH N H

O

O

proline

Me O

H

OH

Me

Me

Cross-Aldol

Me

Me

List Org Lett 2001, 3, 573.

86%

5:1

Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 6722.

TFA

Me

Et2O Me

86%

Me

94%

5:1

97%

73%

64%

DMSO

97% –78 to –40 ºC

19:1 >19:1

95%

87% –20 to +4 ºC

>19:1

95%

79%

95%

–20 to +4 ºC

OAc

OH

OBn

OH

95%

95%

Predictable Stereochemistry for Aldol and Mannich ! Use of proline or proline-type catalysts leads to anti-aldol or syn-Mannich H R'

H

X

Y

H

H

OH

H

anti-selective

O

O

H

N

R

O

O

Aldol

N

R

R' R

O

O

Bifunctional activation

H PMP H

R

N

O

O

NHPMP

H

syn-selective

H

R'

O

Mannich

N

R' R

! Maruoka's binaphthyl catalyst is a significant advance to access opposite stereoisomers

NHTf O NTf

NH N

R'

O

R

H

OH

H

O NTf

R' R

H

Syn-aldol: ACIEE 2004, 43, 6722

N

H

N

R

H

NHPMP

H

R' R

R'

Anti-Mannich: JACS 2005, 127, 16408

Predictable Stereochemistry for Aldol and Mannich ! Use of proline or proline-type catalysts leads to anti-aldol or syn-Mannich H R'

H

X

Y

H

H

OH

H

anti-selective

O

O

H

N

R

O

O

Aldol

N

R

R' R

O

O

Bifunctional activation

H PMP H

R

N

O

O

NHPMP

H

syn-selective

H

R'

O

Mannich

N

R' R

! Maruoka's binaphthyl catalyst is a significant advance to access opposite stereoisomers

NHTf O NTf

NH N

R'

O

R

H

OH

H

O NTf

R' R

H

Syn-aldol: ACIEE 2004, 43, 6722

N

H

N

R

H

NHPMP

H

R' R

R'

Anti-Mannich: JACS 2005, 127, 16408

Monofunctional Enamine Catalysis ! Bifunctional activation is not absolutely required for selective catalysis

O

10 mol% catalyst

H

O

OMe OH

N

MeO

then, MeOH/CSA Me

Me

Me

Me

Bn

N H •TCA

4:1 (ant:syn) 94% ee

! Imidazolidinone and Jørgensen-type frameworks have been widely applied

O

Me

O

Me

N

Bn

N H

N

Bn

N H

Ar

Me Me

N H

Ar

OTMS

Ar N H

Ar

H

Enamine Chemistry with Jørgensen's Catalyst

O

Ar N

Ar N H

Ar

OTMS

H

Ar R R

E

O

HN

H

PMP

O

CO2Et

S

Ph

F

H

Et

O

H

O Me

Et

83%, 93% ee

HN N

H

H

NBn2 Et

Bn

83%, 96% ee

83%, 94% ee, 4:1 dr

O

O

H

Et

O

OTMS

74%, 93% ee

CO2Et CO2Et

Et

79%, 90% ee

84%, 90% ee

O

O Br

H i-Pr

74%, 94% ee

OH

H Bn

70%, 87% ee

Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804. Ibrahem, I.; Zhao, G.-L.; Sunden, H.; Córdova, A. Tettrahedron Lett. 2006, 47, 4659.

Enamine Chemistry with Jørgensen's Catalyst

O

Ar N

Ar N H

Ar

OTMS

H

Ar R R

E

O

HN

H

PMP

O

CO2Et

S

Ph

F

H

Et

O

H

O Me

Et

83%, 93% ee

HN N

H

H

NBn2 Et

Bn

85%, 96% ee

83%, 94% ee, 4:1 dr

O

O

H

Et

O

OTMS

74%, 93% ee

CO2Et CO2Et

Et

79%, 90% ee

84%, 90% ee

O

O Br

H i-Pr

74%, 94% ee

OH

H Bn

70%, 87% ee

Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804. Ibrahem, I.; Zhao, G.-L.; Sunden, H.; Córdova, A. Tettrahedron Lett. 2006, 47, 4659.

Enamine Chemistry with Jørgensen's Catalyst

O

Ar N

Ar N H

Ar

OTMS

H

Ar R R

E

O

HN

H

PMP

O

CO2Et

S

Ph

F

H

Et

O

H

O Me

Et

83%, 93% ee

HN N

H

H

NBn2 Et

Bn

85%, 96% ee

83%, 94% ee, 4:1 dr

O

O

H

Et

O

OTMS

74%, 93% ee

CO2Et CO2Et

Et

79%, 90% ee

84%, 90% ee

O

O Br

H i-Pr

74%, 94% ee

OH

H Bn

70%, 87% ee

Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804. Ibrahem, I.; Zhao, G.-L.; Sunden, H.; Córdova, A. Tettrahedron Lett. 2006, 47, 4659.

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

Ar N

OTMS

Ar

–H+

Ar N

OTMS

Ar

OTMS

R

E

R

10 mol %

O H EtO2C Me

N

N

R

Ar N H

Ar

O

OTMS

Ar = 3,5-(CF3)2C6H3

CO2Et H

HN

CO2Et

N

10 mol % PhCO2H

CO2Et

Me

toluene 56%, 89% ee

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

Ar N

OTMS

Ar

–H+

Ar N

OTMS

Ar

OTMS

R

E

R

10 mol %

O H EtO2C Me

N

N

R

Ar N H

Ar

O

OTMS

Ar = 3,5-(CF3)2C6H3

CO2Et H

HN

CO2Et

N

10 mol % PhCO2H

CO2Et

Me

toluene 56%, 89% ee

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

–H+

Ar N

OTMS

Ar

Ar N

OTMS

Ar

R

EtO2C R

N N

R CO2Et

Ar

20.9 kcal/mol

N Ar

13.0 kcal/mol

Ar N

OTMS EtO2C EtO2C

R

Ar

OTMS

NH N R

S-product (not observed)

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

OTMS

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

–H+

Ar N

OTMS

Ar

Ar N

OTMS

Ar

R

EtO2C R

N N

R CO2Et

Ar

20.9 kcal/mol

N Ar

13.0 kcal/mol

Ar N

OTMS EtO2C EtO2C

R

Ar

OTMS

NH N R

S-product (not observed)

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

OTMS

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

–H+

Ar N

OTMS

Ar

Ar N

OTMS

Ar

R

EtO2C R

N N

R CO2Et

Ar

20.9 kcal/mol

N Ar

13.0 kcal/mol

Ar N

OTMS EtO2C EtO2C

R

Ar

OTMS

NH N R

S-product (not observed)

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

OTMS

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

–H+

Ar N

OTMS

Ar

Ar N

OTMS

OTMS

Ar

R R

R

Ar Ar N Ar

OTMS

Ar N Ar

OTMS

6.7 kcal/mol

Ar N

OTMS NCO2Et

O

H2O

H

H

–cat

N N

NCO2Et R R

R

0 kcal/mol

7.5 kcal/mol

R

–23.5 kcal/mol

R–product

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

CO2Et CO2Et

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

–H+

Ar N

OTMS

Ar

Ar N

OTMS

OTMS

Ar

R R

R

Ar Ar N Ar

OTMS

Ar N Ar

OTMS

6.7 kcal/mol

Ar N

OTMS NCO2Et

O

H2O

H

H

–cat

N N

NCO2Et R R

R

0 kcal/mol

7.5 kcal/mol

R

–23.5 kcal/mol

R–product

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

CO2Et CO2Et

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

–H+

Ar N

OTMS

Ar

Ar N

OTMS

OTMS

Ar

R R

R

Ar Ar N Ar

OTMS

Ar N Ar

OTMS

6.7 kcal/mol

Ar N

OTMS NCO2Et

O

H2O

H

H

–cat

N N

NCO2Et R R

R

0 kcal/mol

7.5 kcal/mol

R

–23.5 kcal/mol

R–product

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

CO2Et CO2Et

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

–H+

Ar N

OTMS

Ar

Ar N

OTMS

OTMS

Ar

R R

R

Ar Ar N Ar

OTMS

Ar N Ar

OTMS

6.7 kcal/mol

Ar N

OTMS NCO2Et

O

H2O

H

H

–cat

N N

NCO2Et R R

R

0 kcal/mol

7.5 kcal/mol

R

–23.5 kcal/mol

R–product

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

CO2Et CO2Et

Dienamine Activation: !-Amination of Enals

O

–H2O

Ar N H

H

Ar

Ar N

OTMS

Ar

–H+

Ar N

OTMS

Ar

OTMS

R R

10 mol %

O H EtO2C Me

N

N

R

Ar N H

Ar

O

OTMS

Ar = 3,5-(CF3)2C6H3

CO2Et H

HN

CO2Et

N

10 mol % PhCO2H

CO2Et

Me

toluene 56%, 89% ee

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

HOMO-Raising Catalysis Beyond Enamine Activation ! Enamine activation is extremely powerful, but does not extend to esters, amides, etc. O

Me

O

N O

Me N

N H

Ph

H

O

N Ph

R

O Ph

X

O

N Ph X R

Me2N N Ph

Fe

Ph

OR

R1 N

Is there an alternative way to generate chiral ester enolate equivalents?

N H

N

R2

Me N

X = OR, NR2

OMe

X

O

No condensation

R R

Me N

Ph

Ph Ph

Chiral Ammonium Catalysis

Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596

HOMO-Raising Catalysis Beyond Enamine Activation ! Enamine activation is extremely powerful, but does not extend to esters, amides, etc. O

Me

O

N O

Me N

N H

Ph

H

O

N Ph

R

O Ph

X

O

N Ph X R

Me2N N Ph

Fe

Ph

OR

R1 N

Is there an alternative way to generate chiral ester enolate equivalents?

N H

N

R2

Me N

X = OR, NR2

OMe

X

O

No condensation

R R

Me N

Ph

Ph Ph

Chiral Ammonium Catalysis

Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596

Ketenes as Precursors for Ammonium Enolates ! Attack of nucleophilic tertiary amine on ketene leads directly to ammonium enolate

O

O

*NR3

• H

O Me

R3N*

Me

E+

O

HNuc

E

R3N*

H

E

Nuc

Me

Me

Enantioselective ester/amide !-functionalization

! First asymmetric example by Wynberg in 1982 (first racemic by Sauer in 1947) O

O H

•

catalyst (4 mol%)

O H

O

PhMe, –25 ºC

CCl3

OMe

Cl3C

H

N

"-Lactone formation: internal nucleophile

*NR3

OH N

O

O H

R3N*

H

O CCl3

Cl3C

NR3*

catalyst

O

H

Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166 Sauer, J. C. J. Am. Chem. Soc. 1947, 69, 2444

Ketenes as Precursors for Ammonium Enolates ! Attack of nucleophilic tertiary amine on ketene leads directly to ammonium enolate

O

O

*NR3

• H

O Me

R3N*

Me

E+

O

HNuc

E

R3N*

H

E

Nuc

Me

Me

Enantioselective ester/amide !-functionalization

! First asymmetric example by Wynberg in 1982 (first racemic by Sauer in 1947) O

O H

•

catalyst (4 mol%)

O H

O

PhMe, –25 ºC

CCl3

OMe

Cl3C

H

N

"-Lactone formation: internal nucleophile

*NR3

OH N

O

O H

R3N*

H

O CCl3

Cl3C

NR3*

catalyst

O

H

Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166 Sauer, J. C. J. Am. Chem. Soc. 1947, 69, 2444

Ammonium Enolates as Versatile Synthetic Intermediates Me2N

OMe

N

N

or O

Ph

N

Ph Ph

R X

R

O

"Cl+" X

O X

X

Cl Y

O

Cl

RO

Y

H

•

Y

O

Y

NTs O

TsN R

X R

Ph

OR

O

O

Fe

Ph

X

R3N*

Y

[4+2]

Y

O

O

N R

X Y

O O

•

O

O X R

R

MeOH

H

MeO X

Y

Gaunt, M. J. Johansson, C. C. C. Chem. Rev. 2007, 107, 5596 France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985

Y

Ammonium Enolates as Versatile Synthetic Intermediates Me2N

OMe

N

N

or O

Ph

N

Ph Ph

R X

R

O

"Cl+" X

O X

X

Cl Y

O

Cl

RO

Y

H

•

Y

O

Y

NTs O

TsN R

X R

Ph

OR

O

O

Fe

Ph

X

R3N*

Y

[4+2]

Y

O

O

N R

X Y

O O

•

O

O X R

R

MeOH

H

MeO X

Y

Gaunt, M. J. Johansson, C. C. C. Chem. Rev. 2007, 107, 5596 France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985

Y

Alternative Methods to Access Ammonium Enolates ! Alkylation of !-bromocarbonyls lead to chiral ammonium ylides

O

O

catalyst (10 mol%)

Ph

Et2N

CsCO3, MeCN, 80 ºC

Br

*NR3

Et2N

CsCO3

Ph O

Nucleophilic cyclopropanation

O

–*NR3

94% yield 97% ee

OMe N

O

O

O

OR

O N

Et2N

Ph

Et2N

NR3*

Ph NR3*

catalyst

! Also applicable to Baylis-Hillman type reactivity

Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 4641

Asymmetric Ylides Formed from Chalcogenides ! Combination with stronger bases/alkyl halides allows for asymmetric epoxide formation

O

O

BnBr

R2S

KOH, MeCN

H

OMe SMe

O Ar

Ar

Ph

Ph

OMe SMe

With 10 mol% sulfide: Ph

Ar

23% yield 31%ee

Furukawa, N.; Sugihara, Y.; Fujihara, H. J. Org. Chem. 1989, 54, 4222

! Vast array of structural types allows for epoxide, aziridine, cyclopropane formation, Baylis-Hillman

Me Et

S R

S

Ph

S

N O

R Et

Me

Se

Me

Et

Te

Et

S

McGarrigle, E. M.; Myers, E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. A. Chem. Rev. 2007, 107, 5841

"The Taxol Problem" An illustrative example ! Important ovarian, breast cancer treatment worldwide ! Originally available from Pacific Yew Taxus Brevifolia

O

AcO

OH

NHPh O Ph

(extraction killed the source) ! Global demands exceed a metric tonne annually

O OH HO

O AcO

BzO

! Wender, most expeditious, efficient chemical synthesis accomplished in 37 steps and 0.44% overall yield

Taxol

! Structural core available from European Yew

Taxus Baccata allows semi synthesis, production 11 Chemical steps

7 isolation steps

O

AcO

OH

HO HO

O BzO

AcO

10-deacetyl baccatin III (renewable source)

! Now produced via fermentation from Taxus Chinensis

! What if the European or Chinese Yew did not produce baccatin in the pine needles?

"The Taxol Problem" An illustrative example ! Important ovarian, breast cancer treatment worldwide ! Originally available from Pacific Yew Taxus Brevifolia

O

AcO

OH

NHPh O Ph

(extraction killed the source) ! Global demands exceed a metric tonne annually

O OH HO

O AcO

BzO

! Wender, most expeditious, efficient chemical synthesis accomplished in 37 steps and 0.44% overall yield

Taxol

! Structural core available from European Yew

Taxus Baccata allows semi synthesis, production 11 Chemical steps

7 isolation steps

O

AcO

OH

HO HO

O BzO

AcO

10-deacetyl baccatin III (renewable source)

! Now produced via fermentation from Taxus Chinensis

! What if the European or Chinese Yew did not produce baccatin in the pine needles?

"The Taxol Problem" An illustrative example ! Important ovarian, breast cancer treatment worldwide ! Originally available from Pacific Yew Taxus Brevifolia

O

AcO

OH

NHPh O Ph

(extraction killed the source) ! Global demands exceed a metric tonne annually

O OH HO

O AcO

BzO

! Wender, most expeditious, efficient chemical synthesis accomplished in 37 steps and 0.44% overall yield

Taxol

! Structural core available from European Yew

Taxus Baccata allows semi synthesis, production 11 Chemical steps

7 isolation steps

O

AcO

OH

HO HO

O BzO

AcO

10-deacetyl baccatin III (renewable source)

! Now produced via fermentation from Taxus Chinensis

! What if the European or Chinese Yew did not produce baccatin in the pine needles?

"The Taxol Problem" An illustrative example ! Important ovarian, breast cancer treatment worldwide ! Originally available from Pacific Yew Taxus Brevifolia

O

AcO

OH

NHPh O Ph

(extraction killed the source) ! Global demands exceed a metric tonne annually

O OH HO

O AcO

BzO

! Wender, most expeditious, efficient chemical synthesis accomplished in 37 steps and 0.44% overall yield

Taxol

! Structural core available from European Yew

Taxus Baccata allows semi synthesis, production 11 Chemical steps

7 isolation steps

O

AcO

OH

HO HO

O BzO

AcO

10-deacetyl baccatin III (renewable source)

! Now produced via fermentation from Taxus Chinensis

! What if the European or Chinese Yew did not produce baccatin in the pine needles?

"The Taxol Problem" An illustrative example ! Important ovarian, breast cancer treatment worldwide ! Originally available from Pacific Yew Taxus Brevifolia

O

AcO

OH

NHPh O Ph

(extraction killed the source) ! Global demands exceed a metric tonne annually

O OH HO

O AcO

BzO

! Wender, most expeditious, efficient chemical synthesis accomplished in 37 steps and 0.44% overall yield

Taxol

! Structural core available from European Yew

Taxus Baccata allows semi synthesis, production 11 Chemical steps

7 isolation steps

O

AcO

OH

HO HO

O BzO

AcO

10-deacetyl baccatin III (renewable source)

! Now produced via fermentation from Taxus Chinensis

! What if the European or Chinese Yew did not produce baccatin in the pine needles?

The problem with a 40 step synthesis: Step Economy and Losses ! Why is chemical synthesis able to produce complexity on small scale but not large ! For every step (operation) involved = exponential decrease in efficiency

50 % yield

40 steps

! Problems with taxol production arose from "stop and go" synthesis O

AcO

NHPh O

11 Chemical steps Ph

HO HO

O BzO

AcO

10-deacetyl baccatin III

O

AcO

OH

7 isolation steps

OH

O OH HO

O BzO

AcO

Taxol

! "Stop and Go" isolation can greatly diminsh the overall efficiency of processes with high yielding steps

The problem with a 40 step synthesis: Step Economy and Losses ! Why is chemical synthesis able to produce complexity on small scale but not large ! For every step (operation) involved = exponential decrease in efficiency

50 % yield

40 steps

! Problems with taxol production arose from "stop and go" synthesis O

AcO

NHPh O

11 Chemical steps Ph

HO HO

O BzO

AcO

10-deacetyl baccatin III

O

AcO

OH

7 isolation steps

OH

O OH HO

O BzO

AcO

Taxol

! "Stop and Go" isolation can greatly diminsh the overall efficiency of processes with high yielding steps

The problem with a 40 step synthesis: Step Economy and Losses ! Why is chemical synthesis able to produce complexity on small scale but not large ! For every step (operation) involved = exponential decrease in efficiency

50 % yield

40 steps

! Problems with taxol production arose from "stop and go" synthesis O

AcO

NHPh O

11 Chemical steps Ph

HO HO

O BzO

AcO

10-deacetyl baccatin III

O

AcO

OH

7 isolation steps

OH

O OH HO

O BzO

AcO

Taxol

! "Stop and Go" isolation can greatly diminsh the overall efficiency of processes with high yielding steps

Benchtop Synthesis vs. Biosynthesis : Why is Nature Winning? ! Nicolaou Synthesis of Taxol: Tour de force O

AcO O

55 Chemical steps Ph

H OTIPS

OH

NHBz O O OH

55 isolation steps

HO

BzO

O

H AcO

Taxol

! Biology employs enzymatic cascade catalysis: Continuous process assembly lines

taxadiene synthase

O

AcO

3 x enzyme benzoyl functionalizn transferase

NHBz O Ph

O OH HO

O6P2O

geranylgeranyl diphosphate

5 catalytic transformations in one cascade process

OH

Taxol

BzO

H AcO

O

Benchtop Synthesis vs. Biosynthesis : Why is Nature Winning? ! Nicolaou Synthesis of Taxol: Tour de force O

AcO O

55 Chemical steps Ph

H OTIPS

OH

NHBz O O OH

55 isolation steps

HO

BzO

O

H AcO

Taxol

! Biology employs enzymatic cascade catalysis: Continuous process assembly lines

taxadiene synthase

O

AcO

3 x enzyme benzoyl functionalizn transferase

NHBz O Ph

O OH HO

O6P2O

geranylgeranyl diphosphate

5 catalytic transformations in one cascade process

OH

Taxol

BzO

H AcO

O

Benchtop Synthesis vs. Biosynthesis : Why is Nature Winning? ! Nicolaou Synthesis of Taxol: Tour de force O

AcO O

55 Chemical steps Ph

H OTIPS

OH

NHBz O O OH

55 isolation steps

HO

BzO

O

H AcO

Taxol

! Biology employs enzymatic cascade catalysis: Continuous process assembly lines

taxadiene synthase

O

AcO

3 x enzyme benzoyl functionalizn transferase

NHBz O Ph

O OH HO

O6P2O

geranylgeranyl diphosphate

5 catalytic transformations in one cascade process

OH

Taxol

BzO

H AcO

O

Benchtop Synthesis vs. Biosynthesis : Why is Nature Winning? ! Nicolaou Synthesis of Taxol: Tour de force O

AcO O

55 Chemical steps Ph

H OTIPS

OH

NHBz O O OH

55 isolation steps

HO

BzO

O

H AcO

Taxol

! Biology employs enzymatic cascade catalysis: Continuous process assembly lines

taxadiene synthase

O

AcO

3 x enzyme benzoyl functionalizn transferase

NHBz O Ph

O OH HO

O6P2O

geranylgeranyl diphosphate

5 catalytic transformations in one cascade process

OH

BzO

H AcO

Taxol

! Why doesn't the field of chemical synthesis build complexity using cascade catalysis (biomimetic)

O

Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst

substrate

catalyst

LUMO–activation

O

Me N

O

O

+

+

substrate

Lewis acid (LA)

R

R

N H •HCl

catalyst

O

N

Me

LA

N H

+ R

+

R

HOMO–activation

Ph

Me

imidazolidinone generation 1

O

Me N

O

O

+

+

Lewis acid (LA)

R

R N H •HCl

O

N R

Me

LA

R

Ph

N H

Me

imidazolidinone generation 1

Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst

substrate

catalyst

LUMO–activation

O

Me N

O

O

+

+

substrate

Lewis acid (LA)

R

R

N H •HCl

catalyst

O

N

Me

LA

N H

+ R

+

R

HOMO–activation

Ph

Me

imidazolidinone generation 1

O

Me N

O

O

+

+

Lewis acid (LA)

R

R N H •HCl

O

N R

Me

LA

R

Ph

N H

Me

imidazolidinone generation 1

Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst

substrate

catalyst

LUMO–activation

O

Me N

O

O

+

+

substrate

Lewis acid (LA)

R

R

N H •HCl

catalyst

O

N

Me

LA

N H

+ R

+

R

HOMO–activation

Ph

Me

imidazolidinone generation 1

O

Me N

O

O

+

+

Lewis acid (LA)

R

R N H •HCl

O

N R

Me

LA

R

Ph

N H

Me

imidazolidinone generation 1

Enamine activation strategy is useful for a variety of organocatalytic reactions Aldehyde aldol

Two step sugars

!-Fluorination

JACS 2002, 124, 6798

Science 2004, 305, 1752

JACS 2005, 127, ASAP

O

OH Me

H Me

TIPSO

NBOC

!-Chlorination

Angew Chemie 2004, 43, 2152

JACS 2004, 126, 4108

OH

OBn

98% ee

Imidazolidinone aldol Angew Chemie 2004, 43, 6722

H

99% ee

O

98% ee

Aziridination

!-Oxyamination JACS 2003, 125, 10808

O Me

Me

F

Epoxidation

94% ee

Cl

OMe OH MeO

95% ee

O

H OBn

Ph

OH

!-Oxy Aldol

O

O

OH H

99% ee

Me

O

TIPSO

94% ee

H

BnN

Ph ONHPh

99% ee

98% ee

Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst

substrate

catalyst

LUMO–activation

O

Me N

O

O

+

+

substrate

Lewis acid (LA)

R

R

N H •HCl

catalyst

O

N

Me

LA

N H

+ R

+

R

HOMO–activation

Ph

Me

imidazolidinone generation 1

O

Me N

O

O

+

+

Lewis acid (LA)

R

R N H •HCl

O

N R

Me

LA

R

Ph

N H

Me

imidazolidinone generation 1

Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst

substrate

catalyst

LUMO–activation

O

Me N

O

O

+

+

substrate

Lewis acid (LA)

R

R

N H •HCl

catalyst

O

N

Me

LA

N H

+ R

+

R

HOMO–activation

Ph

Me

imidazolidinone generation 1

O

Me N

O

O

+

+

Lewis acid (LA)

R

R N H •HCl

O

N R

Me

LA

R

Ph

N H

Me

imidazolidinone generation 1

! Can we merge LUMO-lowering and HOMO-raising catalysis using the same catalyst

Merging LUMO-lowering and HOMO-raising with one catalyst O

! First step:

Me N

Iminium catalysis ! Second step:

Me HX

Enamine catalysis O

R

Ph N H

Me

Me

R

Nu

O

E

imidazolidinone

Me

O

Me

N

N

Ph

Me N

HX +

Nu–

Me

Nu O

Ph

Me

HX +

R O

Me

N Ph

Me

X–

First Cycle (Im)

Me

+ Ph

Nu O

Me Me

Me

R

X–

R O

+

Me

Ph

Nu

Me

Me

Second Cycle (En)

R

N

Ph

+ Me

E

Me

R

N Me

Nu

Me

N

Me

R

Me

– Ph X

Nu

Me R

Me N

O

Me

E+

Me

N

Me

N H

Me

N

N

R

O

O

N Me

Me

Nu

Me

+

Me N

N X–

O

O Ph

N H

Me

R

Me Nu

O E

Merging LUMO-lowering and HOMO-raising with one catalyst O

! First step:

Me N

Iminium catalysis ! Second step:

Me HX

Enamine catalysis O

R

Ph N H

Me

Me

R

Nu

O

E

imidazolidinone

Me

O

Me

N

N

Ph

Me N

HX +

Nu–

Me

Nu O

Ph

Me

HX +

R O

Me

N Ph

Me

X–

First Cycle (Im)

Me

+ Ph

Nu O

Me Me

Me

R

X–

R O

+

Me

Ph

Nu

Me

Me

Second Cycle (En)

R

N

Ph

+ Me

E

Me

R

N Me

Nu

Me

N

Me

R

Me

– Ph X

Nu

Me R

Me N

O

Me

E+

Me

N

Me

N H

Me

N

N

R

O

O

N Me

Me

Nu

Me

+

Me N

N X–

O

O Ph

N H

Me

R

Me Nu

O E

Merging LUMO-lowering and HOMO-raising with one catalyst O

! First step:

Me N

Iminium catalysis ! Second step:

Me HX

Enamine catalysis O

R

Ph N H

Me

Me

R

Nu

O

E

imidazolidinone

Me

O

Me

N

N

Ph

Me N

HX +

Nu–

Me

Nu O

Ph

Me

HX +

R O

Me

N Ph

Me

X–

First Cycle (Im)

Me

+ Ph

Nu O

Me Me

Me

R

X–

R O

+

Me

Ph

Nu

Me

Me

Second Cycle (En)

R

N

Ph

+ Me

E

Me

R

N Me

Nu

Me

N

Me

R

Me

– Ph X

Nu

Me R

Me N

O

Me

E+

Me

N

Me

N H

Me

N

N

R

O

O

N Me

Me

Nu

Me

+

Me N

N X–

O

O Ph

N H

Me

R

Me Nu

O E

Merging LUMO-lowering and HOMO-raising with one catalyst O

! First step:

Me N

Iminium catalysis ! Second step:

Me HX

Enamine catalysis O

R

Ph N H

Me

Me

R

Nu

O

E

imidazolidinone

Me

O

Me

N

N

Ph

Me N

HX +

Nu–

Me

Nu O

Ph

Me

HX +

R O

Me

N Ph

Me

X–

First Cycle (Im)

Me

+ Ph

Nu O

Me Me

Me

R

X–

R O

+

Me

Ph

Nu

Me

Me

Second Cycle (En)

R

N

Ph

+ Me

E

Me

R

N Me

Nu

Me

N

Me

R

Me

– Ph X

Nu

Me R

Me N

O

Me

E+

Me

N

Me

N H

Me

N

N

R

O

O

N Me

Me

Nu

Me

+

Me N

N X–

O

O Ph

N H

Me

R

Me Nu

O E

Merging LUMO-lowering and HOMO-raising with one catalyst O

! First step:

Me N

Iminium catalysis ! Second step:

Me HX

Enamine catalysis O

R

Ph N H

Me

Me

R

Nu

O

E

imidazolidinone

Me

O

Me

N

N

Ph

Me N

HX +

Nu–

Me

Nu O

Ph

Me

HX +

R O

Me

N Ph

Me

X–

First Cycle (Im)

Me

+ Ph

Nu O

Me Me

Me

R

X–

R O

+

Me

Ph

Nu

Me

Me

Second Cycle (En)

R

N

Ph

+ Me

E

Me

R

N Me

Nu

Me

N

Me

R

Me

– Ph X

Nu

Me R

Me N

O

Me

E+

Me

N

Me

N H

Me

N

N

R

O

O

N Me

Me

Nu

Me

+

Me N

N X–

O

O Ph

N H

Me

R

Me Nu

O E

Merging LUMO-lowering and HOMO-raising with one catalyst O

! First step:

Me N

Iminium catalysis ! Second step:

Me HX

Enamine catalysis O

R

Ph N H

Me

Me

R

Nu

O

E

imidazolidinone

Me

O

Me

N

N

Ph

Me N

HX +

Nu–

Me

Nu O

Ph

Me

HX +

R O

Me

N Ph

Me

X–

First Cycle (Im)

Me

+ Ph

Nu O

Me Me

Me

R

X–

R O

+

Me

Ph

Nu

Me

Me

Second Cycle (En)

R

N

Ph

+ Me

E

Me

R

N Me

Nu

Me

N

Me

R

Me

– Ph X

Nu

Me R

Me N

O

Me

E+

Me

N

Me

N H

Me

N

N

R

O

O

N Me

Me

Nu

Me

+

Me N

N X–

O

O Ph

N H

Me

R

Me Nu

O E

Cascade catalysis with imidazolidinones: preliminary results Me N

Cl

Cl

O

Cl

O

substrate

Cl

Cl Me

O

nucleophile

Cl

Me Me

Me

O

Me

N H

O BnIndole

Me

O Me

Cl

10 mol%

electrophile

–50 °C, EtOAc

86% yield

14:1 dr 99% ee

Cascade catalysis with imidazolidinones: preliminary results Me Cl

Cl

O

Cl

O

substrate

Cl

Cl Me

O

nucleophile

Cl

Me Me

Me

O N

Me

N H

O BnIndole

Me

O Me

Cl

10 mol%

electrophile

–50 °C, EtOAc

86% yield

14:1 dr 99% ee

Cascade catalysis with imidazolidinones: preliminary results Me Cl

Cl

O

Cl

O

substrate

Cl

Cl Me

O

nucleophile

R

Cl

Me Me

R

O N

Me

N H

O BnIndole

O R

Cl

10 mol%

electrophile

–50 °C, EtOAc

Temp °C

Me

Yield

syn:anti

ee%

Me

–50

86%

14:1

syn 99% ee

Pr

–50

74%

13:1

syn 99% ee

CO2Et

–40

80%

22:1

syn 99% ee

CH2OAc

–40

82%

11:1

syn 99% ee

! Cascade-catalsysis appears general for a range of enal substrates ! Diastereoselectivity suggests that catalyst control is dominant in second cycle

Enantioselective Organo–Cascade Catalysis

Me N

Rapid development of molecular complexity from simple materials

But

Cl TESO

Cl

Me

71% yield

O Me Cl Im

Cl

Bnindole

N H

O

O

Me

O

•TFA

10 mol% catalyst

! With a range of nucleophiles

Cl

O

syn:anti 25:1

O

En

Cl Me

Cl

O

99% ee

H

Me N

Cl Cl

TIPSO

O

Cl

O

Im Cl

Me

97% yield

Me

O En

O N

Cl

O

Me

Me

Im Cl

Cl Cl

O

75% yield

O

N Me

Me

Cl

Cl

Me

99% ee

Cl

Ph

Cl

Cl

syn:anti 9:1

O

En

NaBH4; NaOH

O N Me

Me

! Processes are highly selective also using thiophenes, nitroalkanes

syn:anti 12:1 99% ee

Enantioselective Organo–Cascade Catalysis

Me N

Rapid development of molecular complexity from simple materials

But

Cl TESO

Cl

Me

71% yield

O Me Cl Im

Cl

Bnindole

N H

O

O

Me

O

•TFA

10 mol% catalyst

! With a range of nucleophiles

Cl

O

syn:anti 25:1

O

En

Cl Me

Cl

O

99% ee

H

Me N

Cl Cl

TIPSO

O

Cl

O

Im Cl

Me

97% yield

Me

O En

O N

Cl

O

Me

Me

Im Cl

Cl Cl

O

75% yield

O

N Me

Me

Cl

Cl

Me

99% ee

Cl

Ph

Cl

Cl

syn:anti 9:1

O

En

NaBH4; NaOH

O N Me

Me

! Processes are highly selective also using thiophenes, nitroalkanes

syn:anti 12:1 99% ee

Enantioselective Organo–Cascade Catalysis

Me N

Rapid development of molecular complexity from simple materials

But

Cl TESO

Cl

Me

71% yield

O Me Cl Im

Cl

Bnindole

N H

O

O

Me

O

•TFA

10 mol% catalyst

! With a range of nucleophiles

Cl

O

syn:anti 25:1

O

En

Cl Me

Cl

O

99% ee

H

Me N

Cl Cl

TIPSO

O

Cl

O

Im Cl

Me

97% yield

Me

O En

O N

Cl

O

Me

Me

Im Cl

Cl Cl

O

75% yield

O

N Me

Me

Cl

Cl

Me

99% ee

Cl

Ph

Cl

Cl

syn:anti 9:1

O

En

NaBH4; NaOH

O N Me

Me

! Processes are highly selective also using thiophenes, nitroalkanes

syn:anti 12:1 99% ee

Cascade Catalysis Towards the Development of Modular Stereocontrol catalyst combination A

catalyst combination B

enamine catalyst and E

enamine catalyst and E

added after consumption of Nu

added after consumption of Nu

O

O

Me

Me N

N Me N H

Me

Me

(5S)-iminium

Ph

N H

O

Me N H

Me

(7.5 mol%)

(30 mol%)

Me

Me

N H

Ph

(5S)-iminium

(2R)-enamine catalyst

Me N

N

Me

catalyst

O

Me

Me Me

(2S)-enamine

catalyst

catalyst

(7.5 mol%)

(30 mol%)

Ph Me

O OO

O Ph

S

N

catalyst combination A

H Im

81% yield H

En

O S

Me O

F

anti:syn 16:1 99% ee

Ph

F H

H

RO2C

CO2R

catalyst combination B

H Im

Me O

62% yield H

En

syn:anti 9:1

F Me

N H

Me

With Huang, Walji, Larsen. J. Am. Chem. Soc. 2005, 127, 15051

99% ee

Cascade Catalysis Towards the Development of Modular Stereocontrol catalyst combination A

catalyst combination B

enamine catalyst and E

enamine catalyst and E

added after consumption of Nu

added after consumption of Nu

O

O

Me

Me N

N Me N H

Me

Me

(5S)-iminium

Ph

N H

O

Me N H

Me

(7.5 mol%)

(30 mol%)

Me

Me

N H

Ph

(5S)-iminium

(2R)-enamine catalyst

Me N

N

Me

catalyst

O

Me

Me Me

(2S)-enamine

catalyst

catalyst

(7.5 mol%)

(30 mol%)

Ph Me

O OO

O Ph

S

N

catalyst combination A

H Im

81% yield H

En

O S

Me O

F

anti:syn 16:1 99% ee

Ph

F H

H

RO2C

CO2R

catalyst combination B

H Im

Me O

62% yield H

En

syn:anti 9:1

F Me

N H

Me

With Huang, Walji, Larsen. J. Am. Chem. Soc. 2005, 127, 15051

99% ee

Cascade Catalysis Towards the Development of Modular Stereocontrol catalyst combination A

catalyst combination B

enamine catalyst and E

enamine catalyst and E

added after consumption of Nu

added after consumption of Nu

O

O

Me

Me N

N Me N H

Me

Me

(5S)-iminium

Ph

N H

O

Me N H

Me

(7.5 mol%)

(30 mol%)

Me

Me

N H

Ph

(5S)-iminium

(2R)-enamine catalyst

Me N

N

Me

catalyst

O

Me

Me Me

(2S)-enamine

catalyst

catalyst

(7.5 mol%)

(30 mol%)

Ph Me

O OO

O Ph

S

N

catalyst combination A

H Im

81% yield H

En

O S

Me O

F

anti:syn 16:1 99% ee

Ph

F H

H

RO2C

CO2R

catalyst combination B

H Im

Me O

62% yield H

En

syn:anti 9:1

F Me

N H

Me

With Huang, Walji, Larsen. J. Am. Chem. Soc. 2005, 127, 15051

99% ee

Cascade Catalysis Towards the Development of Modular Stereocontrol ! Olefin hydroamination H

Ph Me

Im O

En

Ph

Me

O NH2

Cascade Catalysis Towards the Development of Modular Stereocontrol ! Olefin hydroamination H

H

EtO2C

CO2Et BOC

Me

N H Im

N

N

BOC Me

Me

H

Ph Im

En

Ph

Me

O

Cbz BOC En

O N

N H

BOC Cbz

6:1 99% ee anti:syn 17:1

Cascade Catalysis Towards the Development of Modular Stereocontrol ! Olefin hydroamination Ph Ph Im

Me

En

Me

O

O

Cbz COB

N

N H

BOC Cbz

anti:syn 17:1 6:1 99% ee

! Olefin hydrolysis hydrooxidation H

Ph Im Me

O

En

Ph

Me

O OH

Cascade Catalysis Towards the Development of Modular Stereocontrol ! Olefin hydroamination Ph Ph Im

Me

En

Me

O

O

Cbz COB

N

N H

BOC Cbz

anti:syn 17:1 6:1 99% ee

! Olefin hydrolysis hydrooxidation H

H

EtO2C

CO2Et O

Me

N H Im

Me

H

Ph N

Im Me

O

En

Ph

Me

O O

N H

Ph

En

anti:syn 11:1 25:1 99% ee

Cascade Catalysis Towards the Development of Modular Stereocontrol ! Olefin hydroamination Ph Ph Im

Me

En

Me

O

O

Cbz COB

N

N H

BOC Cbz

anti:syn 17:1 6:1 99% ee

! Olefin hydrolysis hydrooxidation Ph Ph Im Me

En

Me

O

O O

N H

Ph

anti:syn 25:1 11:1 99% ee

! Olefin aminohydroxylation NH2 Me

O

Im

En

Me

O OH

Cascade Catalysis Towards the Development of Modular Stereocontrol ! Olefin hydroamination Ph Ph Im

Me

En

Me

O

O

Cbz COB

N

BOC Cbz

N H

anti:syn 17:1 6:1 99% ee

! Olefin hydrolysis hydrooxidation Ph Ph Im Me

En

Me

O

O

O

N H

Ph

anti:syn 25:1 11:1 99% ee

! Olefin aminohydroxylation BOC

N H

OSiR3

BOC O N

Me

O

Im

En

N

OSiR3

Me

O O

Im

En

N H

Ph

anti:syn 17:1 15:1 99% ee

Cascade Catalysis Towards the Development of Modular Stereocontrol

Ph

Ph Ph

Me

O

BOC

N

Im

En

BOC

N H

syn:anti 8:1

Im

Me

En

Me

O

O COB Cbz

99% ee

N

BOC Cbz

N H

anti:syn 17:1 6:1 99% ee

Ph

Ph Ph

Me

O O

N H

Im

En

Im Me

Ph

En

N

O

BOC O

O

N H

syn:anti 14:1 9:1

Ph

99% ee

N H

Ph

anti:syn 25:1 11:1 99% ee

OSiR3

Me

O

O

syn:anti 10:1 99% ee

BOC

Me

Im

En

Me

O

Im

En

N

OSiR3

Me

O O

N H

Ph

anti:syn 17:1 15:1 99% ee

Cascade Catalysis: Merging Organo and Organometallic Catalysis ! The structural core of aromadendranediol in one step

O

Me TMSO

O

O

Me

Ru

Im

OH

H

86% yield O H O

En

O

Me

8:1 dr 92% ee

Me

! 11 carbon framework ! 4 contiguous stereogenic centers

Me LxRu

retro [2+2]

Me

Merging Organocatalysis

[2+2] O Me

O

Me

H

Cross-Metathesis

[2+2]

Me N Me

retro [2+2]

Me LxRu

N H

Ph

Me

Me

HX O

O

O

H

Me

N Ph

Me

Me N

Iminium Cycle

Me

Me O

Me N

X

N

X

O Me

O

RuLx

Me O

and Organometallic Catalysis

O

Me

RuLx

Me

Cascade Catalysis:

O

Ph

Me

Me Me O

+ H2O O

Me

Me

N

Me

Me N

O Ph Me

O

Me Me O

OTMS H

Me

H

Me

O

O

CO2H

N H

Me

HX O

Me

CO2

OH

N

H Me

O

CO2

Enamine Cycle Me O H

Me

in one overall transformation

Me OH

H

+ H2O

O

rapid access to complex bicycle

H

O

N

Triple cascade catalysis should allow

Me

O

O

+ H2O

+ H2O

O

O

O

HO2C

N O

Me Me O H

O

Me LxRu

retro [2+2]

Me

Merging Organocatalysis

[2+2] O Me

O

Me

H

Cross-Metathesis

[2+2]

Me N Me

retro [2+2]

Me LxRu

N H

Ph

Me

Me

HX O

O

O

H

Me

N Ph

Me

Me N

Iminium Cycle

Me

Me O

Me N

X

N

X

O Me

O

RuLx

Me O

and Organometallic Catalysis

O

Me

RuLx

Me

Cascade Catalysis:

O

Ph

Me

Me Me O

+ H2O O

Me

Me

N

Me

Me N

O Ph Me

O

Me Me O

OTMS H

Me

H

Me

O

O

CO2H

N H

Me

HX O

Me

CO2

OH

N

H Me

O

CO2

Enamine Cycle Me O H

Me

in one overall transformation

Me OH

H

+ H2O

O

rapid access to complex bicycle

H

O

N

Triple cascade catalysis should allow

Me

O

O

+ H2O

+ H2O

O

O

O

HO2C

N O

Me Me O H

O

Me LxRu

retro [2+2]

Me

Merging Organocatalysis

[2+2] O Me

O

Me

H

Cross-Metathesis

[2+2]

Me N Me

retro [2+2]

Me LxRu

N H

Ph

Me

Me

HX O

O

O

H

Me

N Ph

Me

Me N

Iminium Cycle

Me

Me O

Me N

X

N

X

O Me

O

RuLx

Me O

and Organometallic Catalysis

O

Me

RuLx

Me

Cascade Catalysis:

O

Ph

Me

Me Me O

+ H2O O

Me

Me

N

Me

Me N

O Ph Me

O

Me Me O

OTMS H

Me

H

Me

O

O

CO2H

N H

Me

HX O

Me

CO2

OH

N

H Me

O

CO2

Enamine Cycle Me O H

Me

in one overall transformation

Me OH

H

+ H2O

O

rapid access to complex bicycle

H

O

N

Triple cascade catalysis should allow

Me

O

O

+ H2O

+ H2O

O

O

O

HO2C

N O

Me Me O H

O

Cascade Catalysis: Merging Organo and Organometallic Catalysis ! The structural core of aromadendranediol in one step

O

Me TMSO

O

O

Me

Ru

Im

OH

64% yield O H O

En Me

Me

H O

5:1 dr 95% ee

Cascade Catalysis: Merging Organo and Organometallic Catalysis ! The structural core of aromadendranediol in one step

O

Me TMSO

O

Me

O

Ru

Im

OH

H

64% yield O H O

En

O

95% ee

Me Me

! Aromadendranediol

HO

Me H

5 steps

! Analgesic in folk medicine H

! Previous synthesis 22 steps Me

Me

OH

Me

5:1 dr

Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine ! Strychnos alkaloid minfiensine and members of the akuammiline alkaloid family

OH

O

N

NBoc

N H

N

SMe

PMB Me

minfiensine

minfiensine core

NHBoc

Diels!Alder/amine cyclization cascade

O SMe N PMB

! Key strategy for minfiensine involving an organocatalytic Diels!Alder cyclization cascade Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606

Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine ! Strychnos alkaloid minfiensine and members of the akuammiline alkaloid family

OH

O

N

NBoc

N H

N

SMe

PMB Me

minfiensine

minfiensine core

NHBoc

Diels!Alder/amine cyclization cascade

O SMe N PMB

! Key strategy for minfiensine involving an organocatalytic Diels!Alder cyclization cascade Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606

Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine ! Strychnos alkaloid minfiensine and members of the akuammiline alkaloid family

OH

O

N

NBoc

N H

N

SMe

PMB Me

minfiensine

minfiensine core

NHBoc

Diels!Alder/amine cyclization cascade

O SMe N PMB

! Key strategy for minfiensine involving an organocatalytic Diels!Alder cyclization cascade Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606

Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine ! Organocascade catalysis provides rapid access to the core structure of minfiensine Me

O

O

N tBu

Me

S

Ar PMB

N

SMe

N

N

endo [4+2]

X– BocHN

X–

X– Me

O

Me Me

Me

X–

O

R

Iminium Cycle

Ar N

R N

N

SMe N

NHBoc

PMB

SMe N

NHBoc

PMB

H+ Cycle

O N

NHBoc

PMB

PMB

H N Boc X– SMe

R2NH •HX Me

O

Me

N Me O

Me

Ar Me

N H •HX

O N

Me

Me

O N

Me Ar

Me Me

Me

N H •HX

= R2NH •HX

Ar Me

N H •HX O NBoc N PMB

SMe

Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606

Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine ! Organocascade catalysis provides rapid access to the core structure of minfiensine Me

O

O

N tBu

Me

S

Ar PMB

N

SMe

N

N

endo [4+2]

X– BocHN

X–

X– Me

O

Me Me

Me

X–

O

R

Iminium Cycle

Ar N

R N

N

SMe N

NHBoc

PMB

SMe N

NHBoc

PMB

H+ Cycle

O N

NHBoc

PMB

PMB

H N Boc X– SMe

R2NH •HX Me

O

Me

N Me O

Me

Ar Me

N H •HX

O N

Me

Me

O N

Me Ar

Me Me

Me

N H •HX

= R2NH •HX

Ar Me

N H •HX O NBoc N PMB

SMe

Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606

Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine ! Diels!Alder/Bronsted acid cascade provides rapid access to the enantioenriched core of minfiensine

NHBoc

NHBoc

3 steps 63%

N H

SMe N

Diels!Alder cascade

OH NBoc N

87% yield

PMB

SMe

96% ee

PMB

commercially available 2 steps

OH OTES

N

2 steps

N H

radical cyclization

OTES

N Me

N

N

N

PMB

PMB

(+)-minfiensine 9 steps, 21% overall

Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606

SMe

StBu

Organocascade Catalysis Inspired by Nature NH2 N

N N H

Et

tryptamine N

MeO2C

CHO OGluc O

MeO2C

H Me CH2OH

preakuammicine Common Intermediate

N H

CO2Me

didehydrosecodine

secologanin N

N

N

H N

O

H

H H O

strychnine (Strychnos alkaloids)

N H

H Me CHO

norfluorocurarine

N H

Me

CO2Me

vincadifformine (Aspidosperma or Kopsia)

Natures employs transform specific enzymes in continous catalytic cascades to rapidly access common biosynthetic intermediates and natural products.

Organocascade Catalysis Inspired by Nature NH2 N

N N H

Et

tryptamine N

MeO2C

CHO OGluc O

MeO2C

H Me CH2OH

preakuammicine Common Intermediate

N H

CO2Me

didehydrosecodine

secologanin N

N

N

H N

O

H

H H O

strychnine (Strychnos alkaloids)

N H

H Me CHO

norfluorocurarine

N H

Me

CO2Me

vincadifformine (Aspidosperma or Kopsia)

Natures employs transform specific enzymes in continous catalytic cascades to rapidly access common biosynthetic intermediates and natural products.

Organocascade Catalysis Inspired by Nature NH2 N

N N H

Et

tryptamine N

MeO2C

CHO OGluc O

MeO2C

H Me CH2OH

preakuammicine Common Intermediate

N H

CO2Me

didehydrosecodine

secologanin N

N

N

H N

O

H

H H O

strychnine (Strychnos alkaloids)

N H

H Me CHO

norfluorocurarine

N H

Me

CO2Me

vincadifformine (Aspidosperma or Kopsia)

Natures employs transform specific enzymes in continous catalytic cascades to rapidly access common biosynthetic intermediates and natural products.

Proposed Diels-Alder/Michael Catalytic Cycle ! Double cascade would enantioselectively construct a highly functionalized spirocycle Boc A NR2 N H

[4+2]

X

Second Cycle

(Im)

(Im)

Me

t-Bu

N

PG

PG Me

O

t-Bu NHBoc

Ar N H •HA

•HA

= HNR2

NBoc O

O

X PG

O N

Ar N H

A

N

N

O

NHBoc

Boc NR2 N

First Cycle

BocHN

N

PG

Boc NR2 NH

Ar PG N

N

N A

PG

N t-Bu

X

N

O

Me

Boc NR2 N

N A

PG

N PG

Proposed Diels-Alder/Michael Catalytic Cycle ! Double cascade would enantioselectively construct a highly functionalized spirocycle Boc A NR2 N H

[4+2]

X

Second Cycle

(Im)

(Im)

Me

t-Bu

N

PG

PG Me

O

t-Bu NHBoc

Ar N H •HA

•HA

= HNR2

NBoc O

O

X PG

O N

Ar N H

A

N

N

O

NHBoc

Boc NR2 N

First Cycle

BocHN

N

PG

Boc NR2 NH

Ar PG N

N

N A

PG

N t-Bu

X

N

O

Me

Boc NR2 N

N A

PG

N PG

Proposed Diels-Alder/Michael Catalytic Cycle ! Double cascade would enantioselectively construct a highly functionalized spirocycle Boc A NR2 N H

[4+2]

X

Second Cycle

(Im)

(Im)

Me

t-Bu

N

PG

PG Me

O

t-Bu NHBoc

Ar N H •HA

•HA

= HNR2

NBoc O

O

X PG

O N

Ar N H

A

N

N

O

NHBoc

Boc NR2 N

First Cycle

BocHN

N

PG

Boc NR2 NH

Ar PG N

N

N A

PG

N t-Bu

X

N

O

Me

Boc NR2 N

N A

PG

N PG

Proposed Diels-Alder/Michael Catalytic Cycle ! Double cascade would enantioselectively construct a highly functionalized spirocycle Boc A NR2 N H

[4+2]

X

Second Cycle

(Im)

(Im)

Me

t-Bu

N

PG

PG Me

O

t-Bu NHBoc

Ar N H •HA

•HA

= HNR2

NBoc O

O

X PG

O N

Ar N H

A

N

N

O

NHBoc

Boc NR2 N

First Cycle

BocHN

N

PG

Boc NR2 NH

Ar PG N

N

N A

PG

N t-Bu

X

N

O

Me

Boc NR2 N

N A

PG

N PG

Proposed Diels-Alder/Michael Catalytic Cycle ! Double cascade would enantioselectively construct a highly functionalized spirocycle Boc A NR2 N H

[4+2]

X

Second Cycle

(Im)

(Im)

Me

t-Bu

N

PG

PG Me

O

t-Bu NHBoc

Ar N H •HA

•HA

= HNR2

NBoc O

O

X PG

O N

Ar N H

A

N

N

O

NHBoc

Boc NR2 N

First Cycle

BocHN

N

PG

Boc NR2 NH

Ar PG N

N

N A

PG

N t-Bu

X

N

O

Me

Boc NR2 N

N A

PG

N PG

Proposed Diels-Alder/Michael Catalytic Cycle ! Double cascade would enantioselectively construct a highly functionalized spirocycle Boc A NR2 N H

[4+2]

X

Second Cycle

(Im)

(Im)

Me

t-Bu

N

PG

PG Me

O

t-Bu NHBoc

Ar N H •HA

•HA

= HNR2

NBoc O

O

X PG

O N

Ar N H

A

N

N

O

NHBoc

Boc NR2 N

First Cycle

BocHN

N

PG

Boc NR2 NH

Ar PG N

N

N A

PG

N t-Bu

X

N

O

Me

Boc NR2 N

N A

PG

N PG

Proposed Diels-Alder/Michael Catalytic Cycle ! Double cascade would enantioselectively construct a highly functionalized spirocycle Boc A NR2 N H

[4+2]

X

Second Cycle

(Im)

(Im)

Me

t-Bu

N

PG

PG Me

O

t-Bu NHBoc

Ar N H •HA

•HA

= HNR2

NBoc O

O

X PG

O N

Ar N H

A

N

N

O

NHBoc

Boc NR2 N

First Cycle

BocHN

N

PG

Boc NR2 NH

Ar PG N

N

N A

PG

N t-Bu

X

N

O

Me

Boc NR2 N

N A

PG

N PG

Proposed Diels-Alder/Michael Catalytic Cycle ! Double cascade would enantioselectively construct a highly functionalized spirocycle Boc A NR2 N H

[4+2]

X

Second Cycle

(Im)

(Im)

Me

t-Bu

N

PG

PG Me

O

t-Bu NHBoc

Ar N H •HA

•HA

= HNR2

NBoc O

O

X PG

O N

Ar N H

A

N

N

O

NHBoc

Boc NR2 N

First Cycle

BocHN

N

PG

Boc NR2 NH

Ar PG N

N

N A

PG

N t-Bu

X

N

O

Me

Boc NR2 N

N A

PG

N PG

Proposed Diels-Alder/Michael Catalytic Cycle ! Double cascade would enantioselectively construct a highly functionalized spirocycle Boc A NR2 N H

[4+2]

X

Second Cycle

(Im)

(Im)

Me

t-Bu

N

PG

PG Me

O

t-Bu NHBoc

Ar N H •HA

•HA

= HNR2

NBoc O

O

X PG

O N

Ar N H

A

N

N

O

NHBoc

Boc NR2 N

First Cycle

BocHN

N

PG

Boc NR2 NH

Ar PG N

N

N A

PG

N t-Bu

X

N

O

Me

Boc NR2 N

N A

PG

N PG

Bioinspired Cascade of a Common Intermediate for Indole Alkaloid Synthesis Me

NHBoc

O

O

NBoc

N

CHO

Me N

SeMe

Me

PMB

Me

N H

N

PhMe, –40 °C

1-nap

TBA

20 mol% cat.

82%, 97% ee

Aspidosperma

Strychnos

PMB

to rt

Kopsia

N

N

N

H N

O

H

H

N H H

H O

strychnine

Me

aspidospermidine

N

N H

CO2Me

kopsinine O

N

N

N H

H CO2Me

akuammicine

Me

N H

Me

CO2Me

vincadifformine

N H

kopsanone

Bioinspired Cascade of a Common Intermediate for Indole Alkaloid Synthesis Me

NHBoc

O

O

NBoc

N

CHO

Me N

SeMe

Me

PMB

Me

N H

N

PhMe, –40 °C

1-nap

TBA

20 mol% cat.

82%, 97% ee

Aspidosperma

Strychnos

PMB

to rt

Kopsia

N

N

N

H N

O

H

H

N H H

H O

strychnine

Me

aspidospermidine

N

N H

CO2Me

kopsinine O

N

N

N H

H CO2Me

akuammicine

Me

N H

Me

CO2Me

vincadifformine

N H

kopsanone

Synthesis of High Profile Alkaloids via Cascade Catalysis N

N

9 steps N H

12 steps

H N

Me O

CO2Me

kopsinine

10 steps

N PG

N H

O

N CHO

11 steps

N H

kopsanone

H CO2Me

akuammicine

O

N

9 steps N H H

H

NR1

N

H

strychnine

common intermediate

O

H

Im Im

organocatalyst

Me

N

11 steps N H

NHBoc

aspidospermidine

Me CO2Me

vincadifformine N PG

X

Me

Synthesis of High Profile Alkaloids via Cascade Catalysis N

N

9 steps N H

12 steps

H N

Me O

CO2Me

kopsinine

10 steps

N PG

N H

O

N CHO

11 steps

N H

kopsanone

H CO2Me

akuammicine

O

N

9 steps N H H

H

NR1

N

H

strychnine

common intermediate

O

H

Im Im

organocatalyst

Me

N

11 steps N H

NHBoc

aspidospermidine

Me CO2Me

vincadifformine N PG

X

Me

Synthesis of High Profile Alkaloids via Cascade Catalysis N

N

9 steps N H

12 steps

H N

Me O

CO2Me

kopsinine

10 steps

N PG

N H

O

N CHO

11 steps

N H

kopsanone

H CO2Me

akuammicine

O

N

9 steps N H H

H

NR1

N

H

strychnine

common intermediate

O

H

Im Im

organocatalyst

Me

N

11 steps N H

NHBoc

aspidospermidine

Me CO2Me

vincadifformine N PG

X

Me

Synthesis of High Profile Alkaloids via Cascade Catalysis N

N

9 steps N H

12 steps

H N

Me O

CO2Me

kopsinine

10 steps

N PG

N H

O

N CHO

11 steps

N H

kopsanone

H CO2Me

akuammicine

O

N

9 steps N H H

H

NR1

N

H

strychnine

common intermediate

O

H

Im Im

organocatalyst

Me

N

11 steps N H

NHBoc

aspidospermidine

Me CO2Me

vincadifformine N PG

X

Me

Synthesis of High Profile Alkaloids via Cascade Catalysis N

N

9 steps N H

12 steps

H N

Me O

CO2Me

kopsinine

10 steps

N PG

N H

O

N CHO

11 steps

N H

kopsanone

H CO2Me

akuammicine

O

N

9 steps N H H

H

NR1

N

H

strychnine

common intermediate

O

H

Im Im

organocatalyst

Me

N

11 steps N H

NHBoc

aspidospermidine

Me CO2Me

vincadifformine N PG

X

Me

Synthesis of High Profile Alkaloids via Cascade Catalysis N

N

9 steps N H

12 steps

H N

Me O

CO2Me

kopsinine

10 steps

N PG

N H

O

N CHO

11 steps

N H

kopsanone

H CO2Me

akuammicine

O

N

9 steps N H H

H

NR1

N

H

strychnine

common intermediate

O

H

Im Im

organocatalyst

Me

N

11 steps N H

NHBoc

aspidospermidine

Me CO2Me

vincadifformine N PG

X

Me

Synthesis of High Profile Alkaloids via Cascade Catalysis N

N

9 steps N H

12 steps

H N

Me O

CO2Me

kopsinine

10 steps

N PG

N H

O

N CHO

11 steps

N H

kopsanone

H CO2Me

akuammicine

O

N

9 steps N H H

H

NR1

N

H

strychnine

common intermediate

O

H

Im Im

organocatalyst

Me

N

11 steps N H

NHBoc

aspidospermidine

Me CO2Me

vincadifformine N PG

X

Me

Synthesis of High Profile Alkaloids via Cascade Catalysis N

N

9 steps N H

7700 other alkaloids

12 steps

H N

Me O

CO2Me

kopsinine

10 steps

N PG

N H

O

N CHO

11 steps

N H

kopsanone

H CO2Me

akuammicine

O

N

9 steps N H H

H

NR1

N

H

strychnine

common intermediate

O

H

Im Im

organocatalyst

Me

N

11 steps N H

NHBoc

aspidospermidine

Me CO2Me

vincadifformine N PG

X

Me

Synthesis of High Profile Alkaloids via Cascade Catalysis N

N

9 steps N H

7700 other alkaloids

12 steps

H N

Me O

CO2Me

kopsinine

10 steps

N PG

N H

O

N CHO

11 steps

N H

kopsanone

H CO2Me

akuammicine

O

N

9 steps N H H

H

NR1

N

H

strychnine

common intermediate

O

H

Im Im

organocatalyst

Me

N

11 steps N H

NHBoc

aspidospermidine

Me CO2Me

vincadifformine N PG

X

Me