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Enamine Catalysis: Fifty Years in the Making
! Stork's landmark 1954 publication outlines benefits of enamines vs enolates
N
O
O
O
Me
Ph
CN
O
Ph
O
Alkylation
Acylation
Michael
Addition
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
N
O
O
O
Me
Ph
CN
O
Ph
O
Alkylation
Acylation
Michael
Addition
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
Fructose bisphosphate aldolase
NH2
NH
O
OPO32–OH
HO
H
OPO32–
N
OH
OH
OH
OPO32–
O
HOPO3
2–
OH
2–O3PO
O
OH
OH
OH
OPO32–
2–O3PO
Rutter, W. J. Fed. Proc. Am. Soc. Exp. Biol. 1964, 23, 1248Lysine reside is required for catalytic activity
Enamine Catalysis: Early Adoption in Total Synthesis
! Woodward-Wieland-Miescher enamine cyclization for steroid synthesis
Wieland, P.; Miescher, K. Helv. Chim. Acta 1950, 33, 2215
O
Me
MeOH
OH
HH5IO6
O
Me
MeO
O
H NH
HOAcbenzene O
Me
Me
H
CHO
Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223
O O
Me
O
Me
O
OH
O
HH
NH
NaOH OOH
OMe
O
HOOH
O
O
OMe
Hajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough
! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasion
O
O
Me
OMe
proline
(200 mol%)
MeCN, HClO4
80 ºC
Me O
O
proline
(3 mol%)
DMF
Me O
OOH
98% ee 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
O
O
Me
OMe
proline
(200 mol%)
MeCN, HClO4
80 ºC
Me O
O
proline
(3 mol%)
DMF
Me O
OOH
98% ee 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)
97% ee
Hajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough
! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasion
O
O
Me
OMe
proline
(200 mol%)
MeCN, HClO4
80 ºC
Me O
O
proline
(3 mol%)
DMF
Me O
OOH
98% ee 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)
97% ee
Hajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough
! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasion
O
O
Me
OMe
proline
(200 mol%)
MeCN, HClO4
80 ºC
Me O
O
proline
(3 mol%)
DMF
Me O
OOH
98% ee 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)
97% ee
3210
Bifunctional Enamine Catalysis: Generic Induction Platform
! Use of proline or proline-type activation a widely exploited mode of ketone activation
R'
O
R
NH
O
OH
XY
H
N
H
R
O O
ketone
proline
Bifunctional
activation
N N
Cbz
Cbz
R'
O
R
N
NHCbz
Cbz
Jørgensen JACS 2002, 124, 6254.
R'
O
R
List Org Lett 2001, 13, 2423.
O
H
Me
Me
Me
O Me
Me
OH
List Org Lett 2001, 3, 573.
X Y
Amination
Cross-Aldol
R'
PhNO2
Nitro-olefin
addition
NO2
Ph
Bifunctional Enamine Catalysis: Generic Induction Platform
! Use of proline or proline-type activation a widely exploited mode of ketone activation
R'
O
R
NH
O
OH
XY
H
N
H
R
O O
ketone
proline
Bifunctional
activation
N N
Cbz
Cbz
R'
O
R
N
NHCbz
Cbz
Jørgensen JACS 2002, 124, 6254.
R'
O
R
List Org Lett 2001, 13, 2423.
O
H
Me
Me
Me
O Me
Me
OH
List Org Lett 2001, 3, 573.
X Y
Amination
Cross-Aldol
R'
PhNO2
Nitro-olefin
addition
NO2
Ph
Bifunctional Enamine Catalysis: Generic Induction Platform
! Use of proline or proline-type activation a widely exploited mode of ketone activation
R'
O
R
NH
O
OH
XY
H
N
H
R
O O
ketone
proline
Bifunctional
activation
N N
Cbz
Cbz
R'
O
R
N
NHCbz
Cbz
Jørgensen JACS 2002, 124, 6254.
R'
O
R
List Org Lett 2001, 13, 2423.
O
H
Me
Me
Me
O Me
Me
OH
List Org Lett 2001, 3, 573.
X Y
Amination
Cross-Aldol
R'
PhNO2
Nitro-olefin
addition
NO2
Ph
Bifunctional Enamine Catalysis: Generic Induction Platform
! Use of proline or proline-type activation a widely exploited mode of ketone activation
R'
O
R
NH
O
OH
XY
H
N
H
R
O O
ketone
proline
Bifunctional
activation
N N
Cbz
Cbz
R'
O
R
N
NHCbz
Cbz
Jørgensen JACS 2002, 124, 6254.
R'
O
R
List Org Lett 2001, 13, 2423.
O
H
Me
Me
Me
O Me
Me
OH
List Org Lett 2001, 3, 573.
X Y
Amination
Cross-Aldol
R'
PhNO2
Nitro-olefin
addition
NO2
Ph
Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 6722.
86%
5:1
TFA
86% 94%
Et2OMe
Me Me
5:1
97%
DMSO
73%
64%
97%
19:1 95%–78 to –40 ºC
–20 to +4 ºC
87%
95%
>19:1
>19:1
–20 to +4 ºC
79%
95%
OH
OAc
OH
OBn
95%
95%
Predictable Stereochemistry for Aldol and Mannich
! Use of proline or proline-type catalysts leads to anti-aldol or syn-Mannich
XY
H
N
H
R
O O
Bifunctional
activation
OH
N
H
R
O OH
R'
O
H R'
R
OHAldol
anti-selective
NH
N
H
R
O OR'
H
PMP O
H R'
R
NHPMPMannich
syn-selective
! Maruoka's binaphthyl catalyst is a significant advance to access opposite stereoisomers
NH
NHTf
N
NTf
H
R
O
HR'
N
NTf
H
R
N
R'H
O
H R'
R
OH
Syn-aldol: ACIEE 2004, 43, 6722
O
H R'
R
NHPMP
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
XY
H
N
H
R
O O
Bifunctional
activation
OH
N
H
R
O OH
R'
O
H R'
R
OHAldol
anti-selective
NH
N
H
R
O OR'
H
PMP O
H R'
R
NHPMPMannich
syn-selective
! Maruoka's binaphthyl catalyst is a significant advance to access opposite stereoisomers
NH
NHTf
N
NTf
H
R
O
HR'
N
NTf
H
R
N
R'H
O
H R'
R
OH
Syn-aldol: ACIEE 2004, 43, 6722
O
H R'
R
NHPMP
Anti-Mannich: JACS 2005, 127, 16408
Monofunctional Enamine Catalysis
! Bifunctional activation is not absolutely required for selective catalysis
H
O
Me
10 mol% catalyst
then, MeOH/CSAMeO
OMe
Me
N
NH
MeO
Bn •TCAMe
OH
4:1 (ant:syn)
94% ee
! Imidazolidinone and Jørgensen-type frameworks have been widely applied
N
NH
MeO
Bn
N
NH
MeO
Bn
NH
Ar
Ar
OTMSNH
Ar
ArMe
Me H
Enamine Chemistry with Jørgensen's Catalyst
Ar
ArOTMS
NH
Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.
O
H
R
O
H
Bn
F
O
H
i-Pr
Br
O
H
Et
S Ph
O
H
Et
N
HN
CO2Et
CO2Et
O
H
Et
HN
CO2Et
PMP
O
H
Et
O
Me
74%, 94% ee
74%, 93% ee
83%, 93% ee
83%, 94% ee, 4:1 dr
79%, 90% ee
83%, 96% ee
Ar
ArOTMS
N
RE
O
H
Et
NBn2
84%, 90% ee
Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.
O
H
Bn
OH
70%, 87% ee
Ibrahem, I.; Zhao, G.-L.; Sunden, H.; Córdova, A. Tettrahedron Lett. 2006, 47, 4659.
Enamine Chemistry with Jørgensen's Catalyst
Ar
ArOTMS
NH
Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.
O
H
R
O
H
Bn
F
O
H
i-Pr
Br
O
H
Et
S Ph
O
H
Et
N
HN
CO2Et
CO2Et
O
H
Et
HN
CO2Et
PMP
O
H
Et
O
Me
74%, 94% ee
74%, 93% ee
83%, 93% ee
83%, 94% ee, 4:1 dr
79%, 90% ee
85%, 96% ee
Ar
ArOTMS
N
RE
O
H
Et
NBn2
84%, 90% ee
Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.
O
H
Bn
OH
70%, 87% ee
Ibrahem, I.; Zhao, G.-L.; Sunden, H.; Córdova, A. Tettrahedron Lett. 2006, 47, 4659.
Enamine Chemistry with Jørgensen's Catalyst
Ar
ArOTMS
NH
Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.
O
H
R
O
H
Bn
F
O
H
i-Pr
Br
O
H
Et
S Ph
O
H
Et
N
HN
CO2Et
CO2Et
O
H
Et
HN
CO2Et
PMP
O
H
Et
O
Me
74%, 94% ee
74%, 93% ee
83%, 93% ee
83%, 94% ee, 4:1 dr
79%, 90% ee
85%, 96% ee
Ar
ArOTMS
N
RE
O
H
Et
NBn2
84%, 90% ee
Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.
O
H
Bn
OH
70%, 87% ee
Ibrahem, I.; Zhao, G.-L.; Sunden, H.; Córdova, A. Tettrahedron Lett. 2006, 47, 4659.
Dienamine Activation: !-Amination of Enals
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
E
Ar
ArOTMS
NH
Ar = 3,5-(CF3)2C6H3
10 mol % PhCO2H
toluene
NN CO2Et
EtO2C
O
H
Me
O
H
Me
N
HN
CO2Et
CO2Et
10 mol %
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
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
E
Ar
ArOTMS
NH
Ar = 3,5-(CF3)2C6H3
10 mol % PhCO2H
toluene
NN CO2Et
EtO2C
O
H
Me
O
H
Me
N
HN
CO2Et
CO2Et
10 mol %
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
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
Ar
ArOTMS
N
R
20.9 kcal/mol
13.0 kcal/mol
N
NEtO2C
CO2Et
Ar
ArOTMS
N
R
N
NH
EtO2C
EtO2C
S-product
(not observed)
Dienamine Activation: !-Amination of Enals
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
Ar
ArOTMS
N
R
20.9 kcal/mol
13.0 kcal/mol
N
NEtO2C
CO2Et
Ar
ArOTMS
N
R
N
NH
EtO2C
EtO2C
S-product
(not observed)
Dienamine Activation: !-Amination of Enals
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
Ar
ArOTMS
N
R
20.9 kcal/mol
13.0 kcal/mol
N
NEtO2C
CO2Et
Ar
ArOTMS
N
R
N
NH
EtO2C
EtO2C
S-product
(not observed)
Dienamine Activation: !-Amination of Enals
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
Ar
ArOTMS
N
R
7.5 kcal/mol
Ar
ArOTMS
N
R
Ar
Ar
OTMSN
R
NCO2Et
NCO2Et
6.7 kcal/mol
–23.5 kcal/mol0 kcal/mol
H2O
–cat
O
R
N
H NH CO2Et
CO2Et
R–product
Dienamine Activation: !-Amination of Enals
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
Ar
ArOTMS
N
R
7.5 kcal/mol
Ar
ArOTMS
N
R
Ar
Ar
OTMSN
R
NCO2Et
NCO2Et
6.7 kcal/mol
–23.5 kcal/mol0 kcal/mol
H2O
–cat
O
R
N
H NH CO2Et
CO2Et
R–product
Dienamine Activation: !-Amination of Enals
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
Ar
ArOTMS
N
R
7.5 kcal/mol
Ar
ArOTMS
N
R
Ar
Ar
OTMSN
R
NCO2Et
NCO2Et
6.7 kcal/mol
–23.5 kcal/mol0 kcal/mol
H2O
–cat
O
R
N
H NH CO2Et
CO2Et
R–product
Dienamine Activation: !-Amination of Enals
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
Ar
ArOTMS
N
R
7.5 kcal/mol
Ar
ArOTMS
N
R
Ar
Ar
OTMSN
R
NCO2Et
NCO2Et
6.7 kcal/mol
–23.5 kcal/mol0 kcal/mol
H2O
–cat
O
R
N
H NH CO2Et
CO2Et
R–product
Dienamine Activation: !-Amination of Enals
Ar
ArOTMS
NH
O
H
Ar
ArOTMS
N
R
R
Ar
ArOTMS
N
R
–H2O –H+
Ar
ArOTMS
NH
Ar = 3,5-(CF3)2C6H3
10 mol % PhCO2H
toluene
NN CO2Et
EtO2C
O
H
Me
O
H
Me
N
HN
CO2Et
CO2Et
10 mol %
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
N
OR
N
OMe
Ph
Ph Ph
Ph PhFe
N
Me2N
! Enamine activation is extremely powerful, but does not extend to esters, amides, etc.
O
H
R
N
NH
O Me
Ph
N
N
O Me
Ph
R
O
X
R
X = OR, NR2
N
NH
O Me
Ph
N
N
O Me
Ph
R
X
O
X
R1
R2
Is there an alternative way to generatechiral ester enolate equivalents?
Chiral Ammonium Catalysis
Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596
No condensation
HOMO-Raising Catalysis Beyond Enamine Activation
N
OR
N
OMe
Ph
Ph Ph
Ph PhFe
N
Me2N
! Enamine activation is extremely powerful, but does not extend to esters, amides, etc.
O
H
R
N
NH
O Me
Ph
N
N
O Me
Ph
R
O
X
R
X = OR, NR2
N
NH
O Me
Ph
N
N
O Me
Ph
R
X
O
X
R1
R2
Is there an alternative way to generatechiral ester enolate equivalents?
Chiral Ammonium Catalysis
Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596
No condensation
Ketenes as Precursors for Ammonium Enolates
! Attack of nucleophilic tertiary amine on ketene leads directly to ammonium enolate
O
•
MeH
*NR3
O
Me
H
R3N*E+
O
R3N*
Me
E HNuc
O
Nuc
Me
E
Enantioselective ester/amide!-functionalization
! First asymmetric example by Wynberg in 1982 (first racemic by Sauer in 1947)
•O
H
H
H CCl3
O
N
N
OMe
OH
catalyst (4 mol%)
PhMe, –25 ºC
O
O
Cl3C
*NR3
O
H
H
R3N* H CCl3
O
Cl3C
O
O
NR3*
"-Lactone formation: internal nucleophile
catalyst
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
•
MeH
*NR3
O
Me
H
R3N*E+
O
R3N*
Me
E HNuc
O
Nuc
Me
E
Enantioselective ester/amide!-functionalization
! First asymmetric example by Wynberg in 1982 (first racemic by Sauer in 1947)
•O
H
H
H CCl3
O
N
N
OMe
OH
catalyst (4 mol%)
PhMe, –25 ºC
O
O
Cl3C
*NR3
O
H
H
R3N* H CCl3
O
Cl3C
O
O
NR3*
"-Lactone formation: internal nucleophile
catalyst
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
N
OR
N
OMe
Ph
Ph Ph
Ph PhFe
N
Me2N
Gaunt, M. J. Johansson, C. C. C. Chem. Rev. 2007, 107, 5596
or
•O
X
Y
O
Cl
Y
X
H
O
R3N*
Y
X
O
O
R
X
Y
O
R
TsN
O
R
X
Y
NTs
R
O
O
X
YR
O
•
R
"Cl+"
O
ROCl
X Y
[4+2]
NR
O O
X
Y
MeOH
O
MeOH
X Y
France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985
Ammonium Enolates as Versatile Synthetic Intermediates
N
OR
N
OMe
Ph
Ph Ph
Ph PhFe
N
Me2N
Gaunt, M. J. Johansson, C. C. C. Chem. Rev. 2007, 107, 5596
or
•O
X
Y
O
Cl
Y
X
H
O
R3N*
Y
X
O
O
R
X
Y
O
R
TsN
O
R
X
Y
NTs
R
O
O
X
YR
O
•
R
"Cl+"
O
ROCl
X Y
[4+2]
NR
O O
X
Y
MeOH
O
MeOH
X Y
France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985
Alternative Methods to Access Ammonium Enolates
N
OR
N
OMe
Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 4641
Et2N
O
Br
O
Phcatalyst (10 mol%)
CsCO3, MeCN, 80 ºC
! Alkylation of !-bromocarbonyls lead to chiral ammonium ylides
PhEt2N
O O
94% yield97% ee
catalyst
*NR3
Et2N
O
NR3*
CsCO3
O
Ph Et2N
O
NR3*
Ph
O
Nucleophilic cyclopropanation –*NR3
! Also applicable to Baylis-Hillman type reactivity
Asymmetric Ylides Formed from Chalcogenides
Furukawa, N.; Sugihara, Y.; Fujihara, H. J. Org. Chem. 1989, 54, 4222
! Combination with stronger bases/alkyl halides allows for asymmetric epoxide formation
! Vast array of structural types allows for epoxide, aziridine, cyclopropane formation, Baylis-Hillman
SMeOMe
BnBr
KOH, MeCN
SMeOMe
Ph
O
ArH
O
Ar
Ph
R2S
O
Ph Ar
With 10 mol% sulfide: 23% yield31%ee
S
S RR
S
N
Me Ph
Et
Et
S
O Se MeMe Te EtEt
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
(extraction killed the source)
! Structural core available from European Yew
Taxus Baccata allows semi synthesis, production
! Global demands exceed a metric tonne annually
! Now produced via fermentation
from Taxus Chinensis
! Wender, most expeditious, efficient chemical synthesis
! What if the European or Chinese Yew did not produce baccatin in the pine needles?
accomplished in 37 steps and 0.44% overall yield
OHO
BzO AcO
OHAcO
HO
O
11 Chemical steps 7 isolation steps
10-deacetyl baccatin III (renewable source)
OHO
BzO AcO
OHAcO
O
O
Ph
O
OH
NHPh
Taxol
"The Taxol Problem" An illustrative example
! Important ovarian, breast cancer treatment worldwide
! Originally available from Pacific Yew Taxus Brevifolia
(extraction killed the source)
! Structural core available from European Yew
Taxus Baccata allows semi synthesis, production
! Global demands exceed a metric tonne annually
! Now produced via fermentation
from Taxus Chinensis
! Wender, most expeditious, efficient chemical synthesis
! What if the European or Chinese Yew did not produce baccatin in the pine needles?
accomplished in 37 steps and 0.44% overall yield
OHO
BzO AcO
OHAcO
HO
O
11 Chemical steps 7 isolation steps
10-deacetyl baccatin III (renewable source)
OHO
BzO AcO
OHAcO
O
O
Ph
O
OH
NHPh
Taxol
"The Taxol Problem" An illustrative example
! Important ovarian, breast cancer treatment worldwide
! Originally available from Pacific Yew Taxus Brevifolia
(extraction killed the source)
! Structural core available from European Yew
Taxus Baccata allows semi synthesis, production
! Global demands exceed a metric tonne annually
! Now produced via fermentation
from Taxus Chinensis
! Wender, most expeditious, efficient chemical synthesis
! What if the European or Chinese Yew did not produce baccatin in the pine needles?
accomplished in 37 steps and 0.44% overall yield
OHO
BzO AcO
OHAcO
HO
O
11 Chemical steps 7 isolation steps
10-deacetyl baccatin III (renewable source)
OHO
BzO AcO
OHAcO
O
O
Ph
O
OH
NHPh
Taxol
"The Taxol Problem" An illustrative example
! Important ovarian, breast cancer treatment worldwide
! Originally available from Pacific Yew Taxus Brevifolia
(extraction killed the source)
! Structural core available from European Yew
Taxus Baccata allows semi synthesis, production
! Global demands exceed a metric tonne annually
! Now produced via fermentation
from Taxus Chinensis
! Wender, most expeditious, efficient chemical synthesis
! What if the European or Chinese Yew did not produce baccatin in the pine needles?
accomplished in 37 steps and 0.44% overall yield
OHO
BzO AcO
OHAcO
HO
O
11 Chemical steps 7 isolation steps
10-deacetyl baccatin III (renewable source)
OHO
BzO AcO
OHAcO
O
O
Ph
O
OH
NHPh
Taxol
"The Taxol Problem" An illustrative example
! Important ovarian, breast cancer treatment worldwide
! Originally available from Pacific Yew Taxus Brevifolia
(extraction killed the source)
! Structural core available from European Yew
Taxus Baccata allows semi synthesis, production
! Global demands exceed a metric tonne annually
! Now produced via fermentation
from Taxus Chinensis
! Wender, most expeditious, efficient chemical synthesis
! What if the European or Chinese Yew did not produce baccatin in the pine needles?
accomplished in 37 steps and 0.44% overall yield
OHO
BzO AcO
OHAcO
HO
O
11 Chemical steps 7 isolation steps
10-deacetyl baccatin III (renewable source)
OHO
BzO AcO
OHAcO
O
O
Ph
O
OH
NHPh
Taxol
The problem with a 40 step synthesis: Step Economy and Losses
! "Stop and Go" isolation can greatly diminsh the overall efficiency of processes with high yielding steps
50 % yield
! For every step (operation) involved = exponential decrease in efficiency
! Why is chemical synthesis able to produce complexity on small scale but not large
40 steps
! Problems with taxol production arose from "stop and go" synthesis
OHO
BzO AcO
OHAcO
HO
O
OHO
BzO AcO
OHAcO
O
O
Ph
O
OH
NHPh
10-deacetyl baccatin III Taxol
11 Chemical steps
7 isolation steps
The problem with a 40 step synthesis: Step Economy and Losses
! "Stop and Go" isolation can greatly diminsh the overall efficiency of processes with high yielding steps
50 % yield
! For every step (operation) involved = exponential decrease in efficiency
! Why is chemical synthesis able to produce complexity on small scale but not large
40 steps
! Problems with taxol production arose from "stop and go" synthesis
OHO
BzO AcO
OHAcO
HO
O
OHO
BzO AcO
OHAcO
O
O
Ph
O
OH
NHPh
10-deacetyl baccatin III Taxol
11 Chemical steps
7 isolation steps
The problem with a 40 step synthesis: Step Economy and Losses
! "Stop and Go" isolation can greatly diminsh the overall efficiency of processes with high yielding steps
50 % yield
! For every step (operation) involved = exponential decrease in efficiency
! Why is chemical synthesis able to produce complexity on small scale but not large
40 steps
! Problems with taxol production arose from "stop and go" synthesis
OHO
BzO AcO
OHAcO
HO
O
OHO
BzO AcO
OHAcO
O
O
Ph
O
OH
NHPh
10-deacetyl baccatin III Taxol
11 Chemical steps
7 isolation steps
Benchtop Synthesis vs. Biosynthesis : Why is Nature Winning?
! Nicolaou Synthesis of Taxol: Tour de force
OHO
BzO
HAcO
OHAcO
O
O
Ph
O
OH
NHBz
Taxol
55 Chemical steps
! Biology employs enzymatic cascade catalysis: Continuous process assembly lines
O6P2O
geranylgeranyl diphosphate
taxadiene
synthase
3 x enzyme benzoyl
transferasefunctionalizn
OHO
BzO
HAcO
OHAcO
O
O
Ph
O
OH
NHBz
Taxol
5 catalytic transformations
in one cascade process
H
OTIPS
O
55 isolation steps
Benchtop Synthesis vs. Biosynthesis : Why is Nature Winning?
! Nicolaou Synthesis of Taxol: Tour de force
OHO
BzO
HAcO
OHAcO
O
O
Ph
O
OH
NHBz
Taxol
55 Chemical steps
! Biology employs enzymatic cascade catalysis: Continuous process assembly lines
O6P2O
geranylgeranyl diphosphate
taxadiene
synthase
3 x enzyme benzoyl
transferasefunctionalizn
OHO
BzO
HAcO
OHAcO
O
O
Ph
O
OH
NHBz
Taxol
5 catalytic transformations
in one cascade process
H
OTIPS
O
55 isolation steps
Benchtop Synthesis vs. Biosynthesis : Why is Nature Winning?
! Nicolaou Synthesis of Taxol: Tour de force
OHO
BzO
HAcO
OHAcO
O
O
Ph
O
OH
NHBz
Taxol
55 Chemical steps
! Biology employs enzymatic cascade catalysis: Continuous process assembly lines
O6P2O
geranylgeranyl diphosphate
taxadiene
synthase
3 x enzyme benzoyl
transferasefunctionalizn
OHO
BzO
HAcO
OHAcO
O
O
Ph
O
OH
NHBz
Taxol
5 catalytic transformations
in one cascade process
H
OTIPS
O
55 isolation steps
! Why doesn't the field of chemical synthesis build complexity using cascade catalysis (biomimetic)
Benchtop Synthesis vs. Biosynthesis : Why is Nature Winning?
! Nicolaou Synthesis of Taxol: Tour de force
OHO
BzO
HAcO
OHAcO
O
O
Ph
O
OH
NHBz
Taxol
55 Chemical steps
! Biology employs enzymatic cascade catalysis: Continuous process assembly lines
O6P2O
geranylgeranyl diphosphate
taxadiene
synthase
3 x enzyme benzoyl
transferasefunctionalizn
OHO
BzO
HAcO
OHAcO
O
O
Ph
O
OH
NHBz
Taxol
5 catalytic transformations
in one cascade process
H
OTIPS
O
55 isolation steps
Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst
O
RNH
R+ N
R
R
+•HCl
substrate catalyst LUMO–activation
O
RNH
R+ N
R
R
•HCl
substrate catalyst HOMO–activation
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
O OLALewis acid (LA)+
+
O OLALewis acid (LA)+
Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst
O
RNH
R+ N
R
R
+•HCl
substrate catalyst LUMO–activation
O
RNH
R+ N
R
R
•HCl
substrate catalyst HOMO–activation
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
O OLALewis acid (LA)+
+
O OLALewis acid (LA)+
O OLALewis acid (LA)+
+
O OLALewis acid (LA)+
Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst
O
RNH
R+ N
R
R
+•HCl
substrate catalyst LUMO–activation
O
RNH
R+ N
R
R
•HCl
substrate catalyst HOMO–activation
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
Aldehyde aldol
!-Oxy Aldol
Imidazolidinone aldol !-Oxyamination
Epoxidation
98% ee94% ee
99% ee
98% ee
94% ee
99% ee
Enamine activation strategy is useful for a variety of organocatalytic reactions
!-Chlorination
Aziridination
98% ee
!-Fluorination
99% ee
Two step sugars
JACS 2002, 124, 6798
Angew Chemie 2004, 43, 2152
Angew Chemie 2004, 43, 6722
Science 2004, 305, 1752
JACS 2004, 126, 4108
JACS 2003, 125, 10808
JACS 2005, 127, ASAP
95% eeH
Me
OHO
Me
Me
H
OBn
OHO
OBn
MeO
Me
OHOMe
Me
O OHTIPSO
TIPSO
OH
NBOC
H
Cl
O
HPh
ONHPh
O
HPh
F
O
O
BnN
O OLALewis acid (LA)+
+
O OLALewis acid (LA)+
Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst
O
RNH
R+ N
R
R
+•HCl
substrate catalyst LUMO–activation
O
RNH
R+ N
R
R
•HCl
substrate catalyst HOMO–activation
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
O OLALewis acid (LA)+
+
O OLALewis acid (LA)+
Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst
O
RNH
R+ N
R
R
+•HCl
substrate catalyst LUMO–activation
O
RNH
R+ N
R
R
•HCl
substrate catalyst HOMO–activation
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
N
NH
O Me
Ph
Me
Me
imidazolidinone
generation 1
! Can we merge LUMO-lowering and HOMO-raising catalysis using the same catalyst
N
N
O Me
R
N
N
O Me
R
N
NH
Ph
O Me
X–+
HX
N
NH
Me
imidazolidinone
! First step:
Iminium catalysis
! Second step:
Enamine catalysis
Ph Me
Merging LUMO-lowering and HOMO-raising with one catalyst
E+
O
MeMe
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
MeR
N
N
O Me
R
N
N
Ph
O Me
R
HX +
N
NH
Ph
O Me
N
N
Ph
O Me
+X–
R
X–+
Nu–
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
MeMe
R
N
N
Ph
O Me
R
X–+
Nu
Me
MeMe
Ph
Ph
E
E
R O Nu O
R
E
First Cycle
(Im)
Second Cycle
(En)
Ph
O
R
HX +
N
N
O Me
R
N
N
O Me
R
N
NH
Ph
O Me
X–+
HX
N
NH
Me
imidazolidinone
! First step:
Iminium catalysis
! Second step:
Enamine catalysis
Ph Me
Merging LUMO-lowering and HOMO-raising with one catalyst
E+
O
MeMe
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
MeR
N
N
O Me
R
N
N
Ph
O Me
R
HX +
N
NH
Ph
O Me
N
N
Ph
O Me
+X–
R
X–+
Nu–
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
MeMe
R
N
N
Ph
O Me
R
X–+
Nu
Me
MeMe
Ph
Ph
E
E
R O Nu O
R
E
First Cycle
(Im)
Second Cycle
(En)
Ph
O
R
HX +
N
N
O Me
R
N
N
O Me
R
N
NH
Ph
O Me
X–+
HX
N
NH
Me
imidazolidinone
! First step:
Iminium catalysis
! Second step:
Enamine catalysis
Ph Me
Merging LUMO-lowering and HOMO-raising with one catalyst
E+
O
MeMe
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
MeR
N
N
O Me
R
N
N
Ph
O Me
R
HX +
N
NH
Ph
O Me
N
N
Ph
O Me
+X–
R
X–+
Nu–
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
MeMe
R
N
N
Ph
O Me
R
X–+
Nu
Me
MeMe
Ph
Ph
E
E
R O Nu O
R
E
First Cycle
(Im)
Second Cycle
(En)
Ph
O
R
HX +
N
N
O Me
R
N
N
O Me
R
N
NH
Ph
O Me
X–+
HX
N
NH
Me
imidazolidinone
! First step:
Iminium catalysis
! Second step:
Enamine catalysis
Ph Me
Merging LUMO-lowering and HOMO-raising with one catalyst
E+
O
MeMe
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
MeR
N
N
O Me
R
N
N
Ph
O Me
R
HX +
N
NH
Ph
O Me
N
N
Ph
O Me
+X–
R
X–+
Nu–
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
MeMe
R
N
N
Ph
O Me
R
X–+
Nu
Me
MeMe
Ph
Ph
E
E
R O Nu O
R
E
First Cycle
(Im)
Second Cycle
(En)
Ph
O
R
HX +
N
N
O Me
R
N
N
O Me
R
N
NH
Ph
O Me
X–+
HX
N
NH
Me
imidazolidinone
! First step:
Iminium catalysis
! Second step:
Enamine catalysis
Ph Me
Merging LUMO-lowering and HOMO-raising with one catalyst
E+
O
MeMe
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
MeR
N
N
O Me
R
N
N
Ph
O Me
R
HX +
N
NH
Ph
O Me
N
N
Ph
O Me
+X–
R
X–+
Nu–
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
MeMe
R
N
N
Ph
O Me
R
X–+
Nu
Me
MeMe
Ph
Ph
E
E
R O Nu O
R
E
First Cycle
(Im)
Second Cycle
(En)
Ph
O
R
HX +
N
N
O Me
R
N
N
O Me
R
N
NH
Ph
O Me
X–+
HX
N
NH
Me
imidazolidinone
! First step:
Iminium catalysis
! Second step:
Enamine catalysis
Ph Me
Merging LUMO-lowering and HOMO-raising with one catalyst
E+
O
MeMe
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
MeR
N
N
O Me
R
N
N
Ph
O Me
R
HX +
N
NH
Ph
O Me
N
N
Ph
O Me
+X–
R
X–+
Nu–
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
MeMe
R
N
N
Ph
O Me
R
X–+
Nu
Me
MeMe
Ph
Ph
E
E
R O Nu O
R
E
First Cycle
(Im)
Second Cycle
(En)
Ph
O
R
HX +
Cascade catalysis with imidazolidinones: preliminary results
Me OOMe
O
ClCl
Cl
Cl
Cl
Cl
10 mol%
–50 °C, EtOAc
N
NH
OMe
Me
MeMe
BnIndole OMeO
Cl
Me
substrate electrophilenucleophile 86% yield 14:1 dr 99% ee
Cascade catalysis with imidazolidinones: preliminary results
Me OOMe
O
ClCl
Cl
Cl
Cl
Cl
10 mol%
–50 °C, EtOAc
N
NH
OMe
Me
MeMe
BnIndole OMeO
Cl
Me
substrate electrophilenucleophile 86% yield 14:1 dr 99% ee
! Cascade-catalsysis appears general for a range of enal substrates
! Diastereoselectivity suggests that catalyst control is dominant in second cycle
Cascade catalysis with imidazolidinones: preliminary results
R OOMe
O
ClCl
Cl
Cl
Cl
Cl
10 mol%
–50 °C, EtOAc
N
NH
OMe
Me
MeMe
BnIndole OMeO
Cl
R
substrate electrophilenucleophile
R ee%Yield syn:antiTemp °C
Me
Pr
CO2Et
CH2OAc
syn 99% ee
syn 99% ee
syn 99% ee
syn 99% ee
14:1
13:1
22:1
11:1
–50
–50
–40
–40
86%
74%
80%
82%
Enantioselective Organo–Cascade Catalysis
Me O
Im En syn:anti 25:1
99% ee
71% yield
N
NH
OMe
But Bnindole
! With a range of nucleophiles
OTESO
Cl
Cl
Cl
Cl
O
Cl Cl
10 mol% catalyst
•TFA
O
Im EnN
Cl
Cl
Cl
Cl
O
Cl Cl
Me O
Im Ensyn:anti 9:1
99% ee
97% yieldN
OTIPSOCl
Cl
Cl
Cl
O
Cl Cl
NaBH4;
NaOH
Me
N
O
O
OMe
Ph
Me
Cl
N
O syn:anti 12:1
99% ee
75% yield
Rapid development of molecular complexity from simple materials
! Processes are highly selective also using thiophenes, nitroalkanes
Me Me
Me
Me
Me
Me
O
Me
Cl
O
H
Me
O
Me
Enantioselective Organo–Cascade Catalysis
Me O
Im En syn:anti 25:1
99% ee
71% yield
N
NH
OMe
But Bnindole
! With a range of nucleophiles
OTESO
Cl
Cl
Cl
Cl
O
Cl Cl
10 mol% catalyst
•TFA
O
Im EnN
Cl
Cl
Cl
Cl
O
Cl Cl
Me O
Im Ensyn:anti 9:1
99% ee
97% yieldN
OTIPSOCl
Cl
Cl
Cl
O
Cl Cl
NaBH4;
NaOH
Me
N
O
O
OMe
Ph
Me
Cl
N
O syn:anti 12:1
99% ee
75% yield
Rapid development of molecular complexity from simple materials
! Processes are highly selective also using thiophenes, nitroalkanes
Me Me
Me
Me
Me
Me
O
Me
Cl
O
H
Me
O
Me
Enantioselective Organo–Cascade Catalysis
Me O
Im En syn:anti 25:1
99% ee
71% yield
N
NH
OMe
But Bnindole
! With a range of nucleophiles
OTESO
Cl
Cl
Cl
Cl
O
Cl Cl
10 mol% catalyst
•TFA
O
Im EnN
Cl
Cl
Cl
Cl
O
Cl Cl
Me O
Im Ensyn:anti 9:1
99% ee
97% yieldN
OTIPSOCl
Cl
Cl
Cl
O
Cl Cl
NaBH4;
NaOH
Me
N
O
O
OMe
Ph
Me
Cl
N
O syn:anti 12:1
99% ee
75% yield
Rapid development of molecular complexity from simple materials
! Processes are highly selective also using thiophenes, nitroalkanes
Me Me
Me
Me
Me
Me
O
Me
Cl
O
H
Me
O
Me
Im En
Me O
Ph
anti:syn 16:1
99% ee
81% yield
NH
MeMe
RO2C CO2R
H H
O
H
F
PhS
NS
Ph
O O O O
F
syn:anti 9:1
99% ee
62% yieldO
H
F
catalyst
combination A
catalyst
combination B
Me
Me
Im En
H
H
Cascade Catalysis Towards the Development of Modular Stereocontrol
N
NH
MeO
Me
Me
Me
catalyst
N
NH
MeO
catalyst
Me
Me
Ph
(5S)-iminium (2R)-enamine
(7.5 mol%) (30 mol%)
N
NH
MeO
Me
Me
Me
catalyst
N
NH
MeO
catalyst
Me
Me
Ph
(5S)-iminium (2S)-enamine
(7.5 mol%) (30 mol%)
catalyst combination A catalyst combination B
enamine catalyst and E
added after consumption of Nu
enamine catalyst and E
added after consumption of Nu
With Huang, Walji, Larsen. J. Am. Chem. Soc. 2005, 127, 15051
Im En
Me O
Ph
anti:syn 16:1
99% ee
81% yield
NH
MeMe
RO2C CO2R
H H
O
H
F
PhS
NS
Ph
O O O O
F
syn:anti 9:1
99% ee
62% yieldO
H
F
catalyst
combination A
catalyst
combination B
Me
Me
Im En
H
H
Cascade Catalysis Towards the Development of Modular Stereocontrol
N
NH
MeO
Me
Me
Me
catalyst
N
NH
MeO
catalyst
Me
Me
Ph
(5S)-iminium (2R)-enamine
(7.5 mol%) (30 mol%)
N
NH
MeO
Me
Me
Me
catalyst
N
NH
MeO
catalyst
Me
Me
Ph
(5S)-iminium (2S)-enamine
(7.5 mol%) (30 mol%)
catalyst combination A catalyst combination B
enamine catalyst and E
added after consumption of Nu
enamine catalyst and E
added after consumption of Nu
With Huang, Walji, Larsen. J. Am. Chem. Soc. 2005, 127, 15051
Cascade Catalysis Towards the Development of Modular Stereocontrol
N
NH
MeO
Me
Me
Me
catalyst
N
NH
MeO
catalyst
Me
Me
Ph
(5S)-iminium (2R)-enamine
(7.5 mol%) (30 mol%)
N
NH
MeO
Me
Me
Me
catalyst
N
NH
MeO
catalyst
Me
Me
Ph
(5S)-iminium (2S)-enamine
(7.5 mol%) (30 mol%)
catalyst combination A catalyst combination B
enamine catalyst and E
added after consumption of Nu
enamine catalyst and E
added after consumption of Nu
With Huang, Walji, Larsen. J. Am. Chem. Soc. 2005, 127, 15051
Im En
Me O
Ph
anti:syn 16:1
99% ee
81% yield
NH
MeMe
RO2C CO2R
H H
O
H
F
PhS
NS
Ph
O O O O
F
syn:anti 9:1
99% ee
62% yieldO
H
F
catalyst
combination A
catalyst
combination B
Me
Me
Im En
H
H
Cascade Catalysis Towards the Development of Modular Stereocontrol
Im EnMe O
Ph
Me O
Ph
NH2
! Olefin hydroamination
H
Cascade Catalysis Towards the Development of Modular Stereocontrol
Im En
anti:syn 17:1 99% ee
Me O
Ph
Me O
Ph
NNH
BOCBOC
! Olefin hydroamination
NH
MeMe
EtO2C CO2Et
H H
BOCN
NBOC
Im En
H
6:1
CbzCbz
Cascade Catalysis Towards the Development of Modular Stereocontrol
Im En
anti:syn 17:1 99% ee
Me O
Ph
Me O
Ph
NNH
BOCCOB
Im En Me O
Ph
Me O
Ph
OH
! Olefin hydroamination
! Olefin hydrolysis
H
6:1
hydrooxidation
CbzCbz
Cascade Catalysis Towards the Development of Modular Stereocontrol
Im En
anti:syn 17:1 99% ee
Me O
Ph
Me O
Ph
NNH
BOCCOB
Im En
anti:syn 25:1 99% ee
Me O
Ph
Me O
Ph
ONH
Ph
! Olefin hydroamination
! Olefin hydrolysis
H
NH
MeMe
EtO2C CO2Et
H H
Im En
ON
6:1
hydrooxidation
11:1
CbzCbz
Cascade Catalysis Towards the Development of Modular Stereocontrol
Im En
anti:syn 17:1 99% ee
Me O
Ph
Me O
Ph
NNH
BOCCOB
Im En
anti:syn 25:1 99% ee
Me O
Ph
Me O
Ph
ONH
Im EnMe O
Ph
Me O
OH
NH2
! Olefin hydroamination
! Olefin hydrolysis
! Olefin aminohydroxylation
6:1
hydrooxidation
11:1
CbzCbz
Cascade Catalysis Towards the Development of Modular Stereocontrol
Im En
anti:syn 17:1 99% ee
Me O
Ph
Me O
Ph
NNH
BOCCOB
Im En
anti:syn 25:1 99% ee
Me O
Ph
Me O
Ph
ONH
Im En
anti:syn 15:1 99% ee
Me O
Ph
Me O
ONH
Ph
NBOC OSiR3
! Olefin hydroamination
! Olefin hydrolysis
! Olefin aminohydroxylation
Im En
ON
BOCNH
OSiR3
6:1
hydrooxidation
11:1
17:1
CbzCbz
Cascade Catalysis Towards the Development of Modular Stereocontrol
Im En
anti:syn 17:1 99% ee
Me O
Ph
Me O
Ph
NNH
BOCCOB
Im EnMe O
Ph
NNH
BOCBOC
syn:anti 8:1 99% ee
Im En
anti:syn 25:1 99% ee
Me O
Ph
Me O
Ph
ONH
Im EnMe O
Ph
O
syn:anti 10:1 99% ee
Im En
anti:syn 15:1 99% ee
Me OIm EnMe O
ONH
Ph
syn:anti 9:1 99% ee
NH
Ph Ph
NBOC OSiR3
Me O
ONH
Ph
NBOC OSiR3
6:1
11:1
17:114:1
CbzCbz
Cascade Catalysis: Merging Organo and Organometallic Catalysis
! The structural core of aromadendranediol in one step
Me
Ru Im En
O
86% yield
8:1 dr
92% ee
OTMSO Me
OO
HMeOH
Me
HO
O
! 4 contiguous
stereogenic centers
! 11 carbon
framework
N
N
Ph
O Me
X Iminium CycleMe
MeMeMe O
O
Me N
N
Ph
O Me
Me
MeMe
O
Me
Me
H
O
O
O
Me
Me
H
O
O
N
N
Ph
O Me
XMe
MeMe
N
NH
Ph
O Me
Me
MeMe
O
Me
Me
H
O
O
HX
HX
NCO2
Me
H
O
O
O Me
H
OHMe
Me O
O
H
OH
Me
Me
O
O
H
O
NH
CO2H
+ H2O+ H2O
NCO2
+ H2O+ H2O
Enamine Cycle
NHO2C
Cross-Metathesis
RuLxMe
LxRu
Me
Me
O
RuLx
Me
Me
O
LxRu
Me
Me
O
O
H
Me
O
O
H
OOTMSMe
Me
O
[2+2]retro[2+2]
[2+2]retro[2+2]
Cascade Catalysis:
Merging Organocatalysis
and Organometallic Catalysis
Triple cascade catalysis should allow
rapid access to complex bicycle
in one overall transformation
N
N
Ph
O Me
X Iminium CycleMe
MeMeMe O
O
Me N
N
Ph
O Me
Me
MeMe
O
Me
Me
H
O
O
O
Me
Me
H
O
O
N
N
Ph
O Me
XMe
MeMe
N
NH
Ph
O Me
Me
MeMe
O
Me
Me
H
O
O
HX
HX
NCO2
Me
H
O
O
O Me
H
OHMe
Me O
O
H
OH
Me
Me
O
O
H
O
NH
CO2H
+ H2O+ H2O
NCO2
+ H2O+ H2O
Enamine Cycle
NHO2C
Cross-Metathesis
RuLxMe
LxRu
Me
Me
O
RuLx
Me
Me
O
LxRu
Me
Me
O
O
H
Me
O
O
H
OOTMSMe
Me
O
[2+2]retro[2+2]
[2+2]retro[2+2]
Cascade Catalysis:
Merging Organocatalysis
and Organometallic Catalysis
Triple cascade catalysis should allow
rapid access to complex bicycle
in one overall transformation
N
N
Ph
O Me
X Iminium CycleMe
MeMeMe O
O
Me N
N
Ph
O Me
Me
MeMe
O
Me
Me
H
O
O
O
Me
Me
H
O
O
N
N
Ph
O Me
XMe
MeMe
N
NH
Ph
O Me
Me
MeMe
O
Me
Me
H
O
O
HX
HX
NCO2
Me
H
O
O
O Me
H
OHMe
Me O
O
H
OH
Me
Me
O
O
H
O
NH
CO2H
+ H2O+ H2O
NCO2
+ H2O+ H2O
Enamine Cycle
NHO2C
Cross-Metathesis
RuLxMe
LxRu
Me
Me
O
RuLx
Me
Me
O
LxRu
Me
Me
O
O
H
Me
O
O
H
OOTMSMe
Me
O
[2+2]retro[2+2]
[2+2]retro[2+2]
Cascade Catalysis:
Merging Organocatalysis
and Organometallic Catalysis
Triple cascade catalysis should allow
rapid access to complex bicycle
in one overall transformation
Cascade Catalysis: Merging Organo and Organometallic Catalysis
! The structural core of aromadendranediol in one step
Me
Ru Im En
O
64% yield
5:1 dr
95% ee
OTMSO Me
OO
HMeOH
Me
HO
O
Cascade Catalysis: Merging Organo and Organometallic Catalysis
! The structural core of aromadendranediol in one step
MeHO H
OHMe
H
Me Me
! Aromadendranediol
! Previous synthesis 22 steps
! Analgesic in folk medicine
5 steps
Me
Ru Im En
O
64% yield
5:1 dr
95% ee
OTMSO Me
OO
HMeOH
Me
HO
O
Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine
N
PMB
NHBoc
SMe
NNBoc
O
SMePMB
O
Diels!Alder/amine
cyclization cascade
NH
N
Me
OH
minfiensine
! Strychnos alkaloid minfiensine and members of the akuammiline alkaloid family
! 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
minfiensine core
Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine
N
PMB
NHBoc
SMe
NNBoc
O
SMePMB
O
Diels!Alder/amine
cyclization cascade
NH
N
Me
OH
minfiensine
! Strychnos alkaloid minfiensine and members of the akuammiline alkaloid family
! 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
minfiensine core
Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine
N
PMB
NHBoc
SMe
NNBoc
O
SMePMB
O
Diels!Alder/amine
cyclization cascade
NH
N
Me
OH
minfiensine
! Strychnos alkaloid minfiensine and members of the akuammiline alkaloid family
! 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
minfiensine core
Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine
! Organocascade catalysis provides rapid access to the core structure of minfiensine
Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606
N
PMB
BocHN
SMe
N
N
OMe
Me
Me
MeN
PMB
N
R
R
SMe
NHBoc
N
NH
OMe
Me
Me
Me
N
NH
OMe
Me
Me
Me
N
PMB
O
SMe
NHBoc
N
PMB
O
SMe
NHBoc
NNBoc
PMB
O
SMe
NNBoc
PMB
O
SMe
O
R2NH •HX
N
NH
OMe
Me
Me
Me
= R2NH •HX
Ar
Ar
Ar
Ar
N
N
OMe
tBuAr
H
•HX
X–
X–
X–
X–
X–
•HX
Iminium
Cycle Cycle
•HX
H+
[4+2]
endo
Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine
! Organocascade catalysis provides rapid access to the core structure of minfiensine
Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606
N
PMB
BocHN
SMe
N
N
OMe
Me
Me
MeN
PMB
N
R
R
SMe
NHBoc
N
NH
OMe
Me
Me
Me
N
NH
OMe
Me
Me
Me
N
PMB
O
SMe
NHBoc
N
PMB
O
SMe
NHBoc
NNBoc
PMB
O
SMe
NNBoc
PMB
O
SMe
O
R2NH •HX
N
NH
OMe
Me
Me
Me
= R2NH •HX
Ar
Ar
Ar
Ar
N
N
OMe
tBuAr
H
•HX
X–
X–
X–
X–
X–
•HX
Iminium
Cycle Cycle
•HX
H+
[4+2]
endo
Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine
Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606
NH
N
OH
Me
(+)-minfiensine
9 steps, 21% overall
N
PMB
NHBoc
SMe NNBoc
PMB
OH
SMe87% yield
96% ee
cascade3 steps
NH
NHBoc
commercially available
NN
OTES
PMB
radical
cyclization2 steps
NN
PMB
OTES
SMe
StBu
2 steps
Diels!Alder
63%
! Diels!Alder/Bronsted acid cascade provides rapid access to the enantioenriched core of minfiensine
Organocascade Catalysis Inspired by Nature
strychnine
N
N
O O
H
H
H
H
O
OGluc
CHO
MeO2C
secologanin
NH
NH2
tryptamineN
N
H Me
MeO2C CH2OH
preakuammicine
NH
N
H Me
CHO
norfluorocurarine
NH
CO2Me
N
Et
didehydrosecodine
(Strychnos alkaloids)
Common Intermediate
NH
N
Me
vincadifformine
CO2Me
(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
strychnine
N
N
O O
H
H
H
H
O
OGluc
CHO
MeO2C
secologanin
NH
NH2
tryptamineN
N
H Me
MeO2C CH2OH
preakuammicine
NH
N
H Me
CHO
norfluorocurarine
NH
CO2Me
N
Et
didehydrosecodine
(Strychnos alkaloids)
Common Intermediate
NH
N
Me
vincadifformine
CO2Me
(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
strychnine
N
N
O O
H
H
H
H
O
OGluc
CHO
MeO2C
secologanin
NH
NH2
tryptamineN
N
H Me
MeO2C CH2OH
preakuammicine
NH
N
H Me
CHO
norfluorocurarine
NH
CO2Me
N
Et
didehydrosecodine
(Strychnos alkaloids)
Common Intermediate
NH
N
Me
vincadifformine
CO2Me
(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
N
N
OMe
t-BuAr
N
NBoc
PG
O
N
NH
t-Bu
Me O
Ar
N
NH
t-Bu
Me O
Ar
PGN
BocHN
X First Cycle
(Im)
Second Cycle
(Im)
N
N
PG
Boc
NR2
N
N
PG
Boc
NR2
N
NH
PG
Boc
NR2
X
N
NH
PG
Boc
NR2
N
NHBoc
PG
•HA
A
A
A
N
PG
NHBoc
X
O
O
•HA
A
[4+2]
= HNR2
Proposed Diels-Alder/Michael Catalytic Cycle
! Double cascade would enantioselectively construct a highly functionalized spirocycle
N
N
OMe
t-BuAr
N
NBoc
PG
O
N
NH
t-Bu
Me O
Ar
N
NH
t-Bu
Me O
Ar
PGN
BocHN
X First Cycle
(Im)
Second Cycle
(Im)
N
N
PG
Boc
NR2
N
N
PG
Boc
NR2
N
NH
PG
Boc
NR2
X
N
NH
PG
Boc
NR2
N
NHBoc
PG
•HA
A
A
A
N
PG
NHBoc
X
O
O
•HA
A
[4+2]
= HNR2
Proposed Diels-Alder/Michael Catalytic Cycle
! Double cascade would enantioselectively construct a highly functionalized spirocycle
N
N
OMe
t-BuAr
N
NBoc
PG
O
N
NH
t-Bu
Me O
Ar
N
NH
t-Bu
Me O
Ar
PGN
BocHN
X First Cycle
(Im)
Second Cycle
(Im)
N
N
PG
Boc
NR2
N
N
PG
Boc
NR2
N
NH
PG
Boc
NR2
X
N
NH
PG
Boc
NR2
N
NHBoc
PG
•HA
A
A
A
N
PG
NHBoc
X
O
O
•HA
A
[4+2]
= HNR2
Proposed Diels-Alder/Michael Catalytic Cycle
! Double cascade would enantioselectively construct a highly functionalized spirocycle
N
N
OMe
t-BuAr
N
NBoc
PG
O
N
NH
t-Bu
Me O
Ar
N
NH
t-Bu
Me O
Ar
PGN
BocHN
X First Cycle
(Im)
Second Cycle
(Im)
N
N
PG
Boc
NR2
N
N
PG
Boc
NR2
N
NH
PG
Boc
NR2
X
N
NH
PG
Boc
NR2
N
NHBoc
PG
•HA
A
A
A
N
PG
NHBoc
X
O
O
•HA
A
[4+2]
= HNR2
Proposed Diels-Alder/Michael Catalytic Cycle
! Double cascade would enantioselectively construct a highly functionalized spirocycle
N
N
OMe
t-BuAr
N
NBoc
PG
O
N
NH
t-Bu
Me O
Ar
N
NH
t-Bu
Me O
Ar
PGN
BocHN
X First Cycle
(Im)
Second Cycle
(Im)
N
N
PG
Boc
NR2
N
N
PG
Boc
NR2
N
NH
PG
Boc
NR2
X
N
NH
PG
Boc
NR2
N
NHBoc
PG
•HA
A
A
A
N
PG
NHBoc
X
O
O
•HA
A
[4+2]
= HNR2
Proposed Diels-Alder/Michael Catalytic Cycle
! Double cascade would enantioselectively construct a highly functionalized spirocycle
N
N
OMe
t-BuAr
N
NBoc
PG
O
N
NH
t-Bu
Me O
Ar
N
NH
t-Bu
Me O
Ar
PGN
BocHN
X First Cycle
(Im)
Second Cycle
(Im)
N
N
PG
Boc
NR2
N
N
PG
Boc
NR2
N
NH
PG
Boc
NR2
X
N
NH
PG
Boc
NR2
N
NHBoc
PG
•HA
A
A
A
N
PG
NHBoc
X
O
O
•HA
A
[4+2]
= HNR2
Proposed Diels-Alder/Michael Catalytic Cycle
! Double cascade would enantioselectively construct a highly functionalized spirocycle
N
N
OMe
t-BuAr
N
NBoc
PG
O
N
NH
t-Bu
Me O
Ar
N
NH
t-Bu
Me O
Ar
PGN
BocHN
X First Cycle
(Im)
Second Cycle
(Im)
N
N
PG
Boc
NR2
N
N
PG
Boc
NR2
N
NH
PG
Boc
NR2
X
N
NH
PG
Boc
NR2
N
NHBoc
PG
•HA
A
A
A
N
PG
NHBoc
X
O
O
•HA
A
[4+2]
= HNR2
Proposed Diels-Alder/Michael Catalytic Cycle
! Double cascade would enantioselectively construct a highly functionalized spirocycle
N
N
OMe
t-BuAr
N
NBoc
PG
O
N
NH
t-Bu
Me O
Ar
N
NH
t-Bu
Me O
Ar
PGN
BocHN
X First Cycle
(Im)
Second Cycle
(Im)
N
N
PG
Boc
NR2
N
N
PG
Boc
NR2
N
NH
PG
Boc
NR2
X
N
NH
PG
Boc
NR2
N
NHBoc
PG
•HA
A
A
A
N
PG
NHBoc
X
O
O
•HA
A
[4+2]
= HNR2
Proposed Diels-Alder/Michael Catalytic Cycle
! Double cascade would enantioselectively construct a highly functionalized spirocycle
N
N
OMe
t-BuAr
N
NBoc
PG
O
N
NH
t-Bu
Me O
Ar
N
NH
t-Bu
Me O
Ar
PGN
BocHN
X First Cycle
(Im)
Second Cycle
(Im)
N
N
PG
Boc
NR2
N
N
PG
Boc
NR2
N
NH
PG
Boc
NR2
X
N
NH
PG
Boc
NR2
N
NHBoc
PG
•HA
A
A
A
N
PG
NHBoc
X
O
O
•HA
A
[4+2]
= HNR2
Bioinspired Cascade of a Common Intermediate for Indole Alkaloid Synthesis
N
NBoc
PMB
82%, 97% ee
N
PMB
NHBoc
SeMe
O
PhMe, –40 °C
to rt20 mol% cat.
N
NH
1-napMe
Me
Me
OMe
TBA
akuammicine
strychnine
NH
N
HMe
aspidospermidine
kopsanone
kopsinine
NH
N
NH
N
CO2Me
O
N
N
O O
H
H
H
NH
N
CO2Me
H
H Me NH
N
Me
vincadifformine
CO2Me
KopsiaAspidospermaStrychnos
CHO
Bioinspired Cascade of a Common Intermediate for Indole Alkaloid Synthesis
N
NBoc
PMB
82%, 97% ee
N
PMB
NHBoc
SeMe
O
PhMe, –40 °C
to rt20 mol% cat.
N
NH
1-napMe
Me
Me
OMe
TBA
akuammicine
strychnine
NH
N
HMe
aspidospermidine
kopsanone
kopsinine
NH
N
NH
N
CO2Me
O
N
N
O O
H
H
H
NH
N
CO2Me
H
H Me NH
N
Me
vincadifformine
CO2Me
KopsiaAspidospermaStrychnos
CHO
Synthesis of High Profile Alkaloids via Cascade Catalysis
akuammicine
strychnine
aspidospermidine
kopsanone
kopsinine
vincadifformine
organo-Im
Imcatalyst
common intermediate
NPG
X
NHBoc
NPG
CHO
NR1
NH
N
Me
CO2Me
NH
N
MeH
NH
N
Me
CO2Me
O
NH
N
O
NH
N
CO2Me
MeH
N
N
O O
HH
H
H
9 steps
11 steps
9 steps
12 steps
10 steps
11 steps
Synthesis of High Profile Alkaloids via Cascade Catalysis
akuammicine
strychnine
aspidospermidine
kopsanone
kopsinine
vincadifformine
organo-Im
Imcatalyst
common intermediate
NPG
X
NHBoc
NPG
CHO
NR1
NH
N
Me
CO2Me
NH
N
MeH
NH
N
Me
CO2Me
O
NH
N
O
NH
N
CO2Me
MeH
N
N
O O
HH
H
H
9 steps
11 steps
9 steps
12 steps
10 steps
11 steps
Synthesis of High Profile Alkaloids via Cascade Catalysis
akuammicine
strychnine
aspidospermidine
kopsanone
kopsinine
vincadifformine
organo-Im
Imcatalyst
common intermediate
NPG
X
NHBoc
NPG
CHO
NR1
NH
N
Me
CO2Me
NH
N
MeH
NH
N
Me
CO2Me
O
NH
N
O
NH
N
CO2Me
MeH
N
N
O O
HH
H
H
9 steps
11 steps
9 steps
12 steps
10 steps
11 steps
Synthesis of High Profile Alkaloids via Cascade Catalysis
akuammicine
strychnine
aspidospermidine
kopsanone
kopsinine
vincadifformine
organo-Im
Imcatalyst
common intermediate
NPG
X
NHBoc
NPG
CHO
NR1
NH
N
Me
CO2Me
NH
N
MeH
NH
N
Me
CO2Me
O
NH
N
O
NH
N
CO2Me
MeH
N
N
O O
HH
H
H
9 steps
11 steps
9 steps
12 steps
10 steps
11 steps
Synthesis of High Profile Alkaloids via Cascade Catalysis
akuammicine
strychnine
aspidospermidine
kopsanone
kopsinine
vincadifformine
organo-Im
Imcatalyst
common intermediate
NPG
X
NHBoc
NPG
CHO
NR1
NH
N
Me
CO2Me
NH
N
MeH
NH
N
Me
CO2Me
O
NH
N
O
NH
N
CO2Me
MeH
N
N
O O
HH
H
H
9 steps
11 steps
9 steps
12 steps
10 steps
11 steps
Synthesis of High Profile Alkaloids via Cascade Catalysis
akuammicine
strychnine
aspidospermidine
kopsanone
kopsinine
vincadifformine
organo-Im
Imcatalyst
common intermediate
NPG
X
NHBoc
NPG
CHO
NR1
NH
N
Me
CO2Me
NH
N
MeH
NH
N
Me
CO2Me
O
NH
N
O
NH
N
CO2Me
MeH
N
N
O O
HH
H
H
9 steps
11 steps
9 steps
12 steps
10 steps
11 steps
Synthesis of High Profile Alkaloids via Cascade Catalysis
akuammicine
strychnine
aspidospermidine
kopsanone
kopsinine
vincadifformine
organo-Im
Imcatalyst
common intermediate
NPG
X
NHBoc
NPG
CHO
NR1
NH
N
Me
CO2Me
NH
N
MeH
NH
N
Me
CO2Me
O
NH
N
O
NH
N
CO2Me
MeH
N
N
O O
HH
H
H
9 steps
11 steps
9 steps
12 steps
10 steps
11 steps
Synthesis of High Profile Alkaloids via Cascade Catalysis
akuammicine
strychnine
aspidospermidine
kopsanone
kopsinine
vincadifformine
organo-Im
Imcatalyst
common intermediate
NPG
X
NHBoc
NPG
CHO
NR1
NH
N
Me
CO2Me
NH
N
MeH
NH
N
Me
CO2Me
O
NH
N
O
NH
N
CO2Me
MeH
N
N
O O
HH
H
H
9 steps
11 steps
9 steps
12 steps
10 steps
11 steps
7700 other alkaloids
Synthesis of High Profile Alkaloids via Cascade Catalysis
akuammicine
strychnine
aspidospermidine
kopsanone
kopsinine
vincadifformine
organo-Im
Imcatalyst
common intermediate
NPG
X
NHBoc
NPG
CHO
NR1
NH
N
Me
CO2Me
NH
N
MeH
NH
N
Me
CO2Me
O
NH
N
O
NH
N
CO2Me
MeH
N
N
O O
HH
H
H
9 steps
11 steps
9 steps
12 steps
10 steps
11 steps
7700 other alkaloids
