Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst
Design
New Reactions –
Enabling Valuable
Bond Disconnections
Activation
Modes
Priviledged
Achitecture
This Lecture – Broadened Activation Themes
Previous Lecture
 Enamine
Chiral
Pool
 Iminium
Me
O
Me
N
Me
N
N
H
R
Proline-derived
N
H
S
R
R
R
Me
n Nucleophile Activation
n Electrophile Activation
t-Bu
Imidazolidinone
N
H
N
H
R
RO
RO
O
NR4
P
OH
N
DMAP
Carbene
Acids and Phase Transfers
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst
Design
New Reactions –
Enabling Valuable
Bond Disconnections
Activation
Modes
Priviledged
Achitecture
This Lecture – Broadened Activation Themes
Previous Lecture
 Enamine
Chiral
Pool
 Iminium
Me
O
Me
N
Me
N
N
H
R
Proline-derived
N
H
S
R
R
R
Me
n Nucleophile Activation
n Electrophile Activation
t-Bu
Imidazolidinone
N
H
N
H
R
RO
RO
O
NR4
P
OH
N
DMAP
Carbene
Acids and Phase Transfers
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst
Design
New Reactions –
Enabling Valuable
Bond Disconnections
Activation
Modes
Priviledged
Achitecture
This Lecture – Broadened Activation Themes
Previous Lecture
 Enamine
Chiral
Pool
 Iminium
Me
O
Me
N
Me
N
N
H
R
Proline-derived
N
H
S
R
R
R
Me
n Nucleophile Activation
n Electrophile Activation
t-Bu
Imidazolidinone
N
H
N
H
R
RO
RO
O
NR4
P
OH
N
DMAP
Carbene
Acids and Phase Transfers
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst
Design
New Reactions –
Enabling Valuable
Bond Disconnections
Activation
Modes
Priviledged
Achitecture
This Lecture – Broadened Activation Themes
Previous Lecture
 Enamine
Chiral
Pool
 Iminium
Me
O
Me
N
Me
N
N
H
R
Proline-derived
N
H
S
R
R
R
Me
n Nucleophile Activation
n Electrophile Activation
t-Bu
Imidazolidinone
N
H
N
H
R
RO
RO
O
NR4
P
OH
N
DMAP
Carbene
Acids and Phase Transfers
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst
Design
New Reactions –
Enabling Valuable
Bond Disconnections
Activation
Modes
Priviledged
Achitecture
This Lecture – Broadened Activation Themes
Previous Lecture
 Enamine
Chiral
Pool
 Iminium
Me
O
Me
N
Me
N
N
H
R
Proline-derived
N
H
S
R
R
R
Me
n Nucleophile Activation
n Electrophile Activation
t-Bu
Imidazolidinone
N
H
N
H
R
RO
RO
O
NR4
P
OH
N
DMAP
Carbene
Acids and Phase Transfers
Phase Transfer Catalysis (PTC)
H2O, 105 °C
hex
Cl
hex
CN
No Reaction
NaCN
 Begining with Makosza and Brandstrom, Stark coined the term phase transfer catalysis
Starks, R. M. J. Am. Chem. Soc. 1971, 93, 195.
Phase Transfer Catalysis (PTC)
H2O, 105 °C
hex
Cl
hex
CN
High Yield
NaCN
Organic Phase
Bu3P(CH2)15CH3 CN
Aqueous Phase
NaCl
NaCN
(Interface)
Bu3P(CH2)15CH3 Cl
"The phenomenon of rate enhancement of a reaction between chemical species located in different
phases by addition of a small quantity of an agent (called the 'phase-transfer catalyst') that extracts
one of the reactants, most commonly an anion, across the interface into the other phase so that
reaction can proceed..." – IUPAC Gold book
Pioneering Studies at Merck
 In 1984 researchers at Merck published their work towards asymmetric alkylations
Cl
MeCl
O
Cl
10 mol % cat
Cl
Cl
50% aq NaOH
MeO
O
Ph
Me
MeO
toluene
95% yield
20 °C, 18 h
92% ee
H-bond / ion pair
Br
OH
O
H
N
N
N
H
N
Cl
O
Cl

CF3
phase transfer catalyst
MeO
-stack
Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446.
CF3
Pioneering Studies at Merck
 In 1984 researchers at Merck published their work towards asymmetric alkylations
Cl
MeCl
O
Cl
10 mol % cat
Cl
Cl
50% aq NaOH
MeO
O
Ph
Me
MeO
toluene
95% yield
20 °C, 18 h
92% ee
H-bond / ion pair
Br
OH
O
H
N
N
N
H
N
Cl
O
Cl

CF3
phase transfer catalyst
MeO
-stack
Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446.
CF3
Pioneering Studies at Merck
 In 1984 researchers at Merck published their work towards asymmetric alkylations
Cl
MeCl
O
Cl
10 mol % cat
Cl
Cl
50% aq NaOH
MeO
Ph
Me
MeO
toluene
95% yield
20 °C, 18 h
Cl
Cl
MeO
O
92% ee
Cl
O
60% overall
Ph
Me
O
Cl
HO
Ph
Me
O
O
(+)-indacrinone
MK-0197
Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446.
Pioneering Studies at Merck
 In 1984 researchers at Merck published their work towards asymmetric alkylations
Cl
MeCl
O
Cl
10 mol % cat
Cl
Cl
50% aq NaOH
MeO
O
Ph
Me
MeO
toluene
95% yield
20 °C, 18 h
92% ee
H-bond / ion pair
Br
OH
O
H
N
N
N
H
N
Cl
O
Cl

CF3
phase transfer catalyst
MeO
-stack
Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446.
CF3
Asymmetric Phase Transfer Catalysis
 The catalyst controls the orientation of the enolate alkylation
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
O
Ph
N
Ot-Bu
Ph
Glycine Imine Ester
Organic
Aqueous
OH
N
N
H
Br
Asymmetric Phase Transfer Catalysis
 The catalyst controls the orientation of the enolate alkylation
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
O
Ph
N
Ot-Bu
Ph
Glycine Imine Ester
Organic
Aqueous
NaOH
OH
N
O
Na
Ph
N
Ph
Ot-Bu
N
H
Br
Asymmetric Phase Transfer Catalysis
 The catalyst controls the orientation of the enolate alkylation
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
O
Ph
N
Si face sheilded
Ot-Bu
ion
OH
Ph
pairing
N
Glycine Imine Ester
HO
N
Ph
Ot-Bu
Ph
Re face open
Cl
Br
Organic
Aqueous
–NaBr
NaOH
OH
N
O
Na
Ph
N
Ph
Ot-Bu
N
H
Br
Asymmetric Phase Transfer Catalysis
 The catalyst controls the orientation of the enolate alkylation
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
O
Ph
N
O
Si face sheilded
Ph
Ot-Bu
ion
OH
Ph
Ot-Bu
Ph
pairing
N
Glycine Imine Ester
N
Cl
HO
N
Ph
Chlorophenylalanine
Ot-Bu
Ph
Re face open
Cl
Br
Organic
Aqueous
–NaBr
NaOH
OH
N
O
Na
Ph
N
Ph
Ot-Bu
N
H
Br
Asymmetric Phase Transfer Catalysis
 The catalyst controls the orientation of the enolate alkylation
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
O
Ph
N
O
Q uickTim e™ and a
decom pr essor
ar e needed t o see t his pict ur e.
Ph
Ot-Bu
Ph
N
Ot-Bu
Ph
Glycine Imine Ester
Cl
Chlorophenylalanine
Cl
Br
Organic
Aqueous
–NaBr
NaOH
OH
N
O
Na
Ph
N
Ph
Ot-Bu
N
H
Br
Switching Enantioselectivity Using Pseudoenantiomers
 Catalyst diastereomers give rise to the opposite product configuration
PhCH2Br
O
N
Ph
10 mol % cat
O
Ph
N
50% aq KOH
Ph
Ot-Bu
Ot-Bu
Ph
O
Ph
N
Ot-Bu
Ph
toluene
20 °C, 18 h
cat A
77% yield
86% ee
Et
Et
Br
OBn
Br
H
N
N
cat B
85% yield
94% ee
N
H
OBn
N
A From cinchonine
B From cinchonidine
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
Advances in Catalyst Design
 Catalysts have been benchmarked using the benzylation of glycine imine:
PhCH2Br
O
Ph
N
O
10 mol % cat
Ph
N
Ot-Bu
Ot-Bu
Ph
50% aq KOH
Ph
toluene
20 °C, 18 h
OH
H
Br
N
Ph
Maruoka 1999
1 mol %
91% yield, 98% ee
Ar
Br
H
N
OR
N
Ph
Ar
Ar = Ph
O'Donnell 1989
10 mol %
75% yield, 66% ee
N
N
Ar =
Br
R = allyl
Lygo, Corey 1997
10 mol %
87% yield, 94% ee
Cocatalyst:
18-crown-6
O
O
O
O
O
Maruoka 2005
0.05 mol %
0.05 mol % 18-crown-6
90% yield, 98% ee
O
Shirakawa, S.; Marouka, K. Catalytic Asymmetric Synthesis. Hoboken: Wiley, 2010.
Advances in Catalyst Design
 Catalysts have been benchmarked using the benzylation of glycine imine:
PhCH2Br
O
Ph
N
O
10 mol % cat
Ph
N
Ot-Bu
Ot-Bu
Ph
50% aq KOH
Ph
toluene
20 °C, 18 h
OH
H
Br
N
Ph
Maruoka 1999
1 mol %
91% yield, 98% ee
Ar
Br
H
N
OR
N
Ph
Ar
Ar = Ph
O'Donnell 1989
10 mol %
75% yield, 66% ee
N
N
Ar =
Br
R = allyl
Lygo, Corey 1997
10 mol %
87% yield, 94% ee
Cocatalyst:
18-crown-6
O
O
O
O
O
Maruoka 2005
0.05 mol %
0.05 mol % 18-crown-6
90% yield, 98% ee
O
Shirakawa, S.; Marouka, K. Catalytic Asymmetric Synthesis. Hoboken: Wiley, 2010.
Advances in Catalyst Design
 Catalysts have been benchmarked using the benzylation of glycine imine:
PhCH2Br
O
Ph
N
O
10 mol % cat
Ph
N
Ot-Bu
Ot-Bu
Ph
50% aq KOH
Ph
toluene
20 °C, 18 h
OH
H
Br
N
Ph
Maruoka 1999
1 mol %
91% yield, 98% ee
Ar
Br
H
N
OR
N
Ph
Ar
Ar = Ph
O'Donnell 1989
10 mol %
75% yield, 66% ee
N
N
Ar =
Br
R = allyl
Lygo, Corey 1997
10 mol %
87% yield, 94% ee
Cocatalyst:
18-crown-6
O
O
O
O
O
Maruoka 2005
0.05 mol %
0.05 mol % 18-crown-6
90% yield, 98% ee
O
Shirakawa, S.; Marouka, K. Catalytic Asymmetric Synthesis. Hoboken: Wiley, 2010.
Advances in Catalyst Design
 Catalysts have been benchmarked using the benzylation of glycine imine:
PhCH2Br
O
Ph
N
O
10 mol % cat
Ph
N
Ot-Bu
Ot-Bu
Ph
50% aq KOH
Ph
toluene
20 °C, 18 h
OH
H
Br
N
Ph
Maruoka 1999
1 mol %
91% yield, 98% ee
Ar
Br
H
N
OR
N
Ph
Ar
Ar = Ph
O'Donnell 1989
10 mol %
75% yield, 66% ee
N
N
Ar =
Br
R = allyl
Lygo, Corey 1997
10 mol %
87% yield, 94% ee
Cocatalyst:
18-crown-6
O
O
O
O
O
Maruoka 2005
0.05 mol %
0.05 mol % 18-crown-6
90% yield, 98% ee
O
Shirakawa, S.; Marouka, K. Catalytic Asymmetric Synthesis. Hoboken: Wiley, 2010.
The PTC Activation Mode Beyond Alkylation Reactions
 PTC activation of carbonyls has enabled the developement of many different asymmetric reactions
O
Ph
N
O
Ot-Bu
p-Cl-Ph
N
O
Ot-Bu
Ph
N
Me
Ph
Ot-Bu
Ph
CN
90%, 98% ee
85%, 98% ee
85%, 91% ee
glycine–alkylation
glycine alkylation–allylation
glycine–Michael
Angew. Chem. Int. Ed. 2005, 44 , 625.
J. Am. Chem. Soc. 2000, 122, 5228.
Org. Lett. 2000, 2, 1097.
OH
Boc
O
c-hex
Ot-Bu
NH2
NH
O
O
PMB
CO2Et
Ot-Bu
NH2
O2N
NO2
83% 96:4 anti, 98% ee
95%, 9:1 syn 82% ee
78%, 85% ee
glycine–aldol
glycine–Mannich
-ketoester SNAr
Angew. Chem. Int. Ed. 2005, 44, 4564.
J. Org. Chem. 2006, 71, 4980.
J. Am. Chem. Soc. 2004, 126, 9685.
Recent review: Ooi, T.; Maruoka, K. Angew. Chem. Int. Ed. 2007, 46, 4222.
The PTC Activation Mode Beyond Alkylation Reactions
 PTC activation of carbonyls has enabled the developement of many different asymmetric reactions
SO2Mes
HN
O
O
Me
t-Bu
Ph
CN
O
Ph
SO2Ph
Ph
H
94%, 94% ee
99%, 96% ee
70%, 81% ee
Strecker
enone epoxidation
Darzens epoxidation
J. Am. Chem. Soc. 2006, 128, 2548.
J. Am. Chem. Soc. 2004, 126, 6844.
Tetrahedron 2002, 58, 1407.
MeO
O
F
Cl
O
F3C
N
H
Boc
CO2Et
N
O
N
Boc
O
NH
t-BuO
Boc
N
Ph
94%, 84% ee
99%, 92% ee
79%, 84% ee
-ketoester fluorination
-ketoester amination
aziridation
J. Org. Chem. 2003, 68, 2494.
Angew. Chem. Int. Ed. 2008, 47, 9466.
Synthesis 2005, 2022.
Recent review: Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656.
Phase Transfer Catalysis
 Since the original reports the area continues to be a strong sector of organocatalysis research
 ISI web of knowledge references containing the key phrase "phase transfer catalysis" total 3698
60
Dolling’s
(+)-indacrinone
40
synthesis
30
20
10
0
2009
2004
1999
1994
1989
1984
Year
Publications
50
Carbenes as Organocatalysts
 Carbenes were long suspected as catalytic intermediates
Carbenes as Organocatalysts
 Carbenes were long suspected as catalytic intermediates
Breslow, R. J. Am. Chem. Soc. 1958, 14, 3719.
Carbenes as Organocatalysts
 Carbenes were long suspected as catalytic intermediates
Me
Me
H2N
H2N
HO
HO
N
N
N
N
S
S
N
H
N
Me
Thiazolium Salt of Thiamine Coenzyme (vitamin B1)
Me
Nature's Carbene Organocatalyst
 For many years a carbene catalyst for the enantioselective benzoin condensation was elusive
O
H
S
N
R
S
N
Ph
O
R
Ph
N
S
base
S
N
R
H
OH
Ph
O
Ph
S
OH
Ph
Benzoin Product
R
N
R
O
Ph
Ph
OH
O
H
Ph
Breslow-type
Intermediate
Carbenes as Organocatalysts
 Carbenes were long suspected as catalytic intermediates
Me
Me
H2N
H2N
HO
HO
N
N
N
N
S
S
N
H
N
Me
Thiazolium Salt of Thiamine Coenzyme (vitamin B1)
Me
Nature's Carbene Organocatalyst
 For many years a carbene catalyst for the enantioselective benzoin condensation was elusive
O
H
S
N
R
S
N
Ph
O
R
Ph
N
S
base
S
N
R
H
OH
Ph
O
Ph
S
OH
Ph
Benzoin Product
R
N
R
O
Ph
Ph
OH
O
H
Ph
Breslow-type
Intermediate
Carbenes as Organocatalysts
 Carbenes were long suspected as catalytic intermediates
Me
Me
H2N
H2N
HO
HO
N
N
N
N
S
S
H
N
Me
N
Me
Thiazolium Salt of Thiamine Coenzyme (vitamin B1)
Nature's Carbene Organocatalyst
 For many years a carbene catalyst for the enantioselective benzoin condensation was elusive
n The newly proposed intermediate exhibits umpolung reactivity
O
H
cat
S
N
O
R
Ph
Ph
Ph
electrophilic
OH
Breslow-type
Intermediate
Before we can get new reactions
we need better catalysts
acyl anion synthon
novel reactivty patterns
Carbenes as Organocatalysts
 Carbenes were long suspected as catalytic intermediates
Me
Me
H2N
H2N
HO
HO
N
N
N
N
S
S
H
N
Me
N
Me
Thiazolium Salt of Thiamine Coenzyme (vitamin B1)
Nature's Carbene Organocatalyst
 For many years a carbene catalyst for the enantioselective benzoin condensation was elusive
n The newly proposed intermediate exhibits umpolung reactivity
O
H
cat
S
N
O
R
Ph
Ph
Ph
electrophilic
OH
Breslow-type
Intermediate
Before we can get new reactions
we need better catalysts
acyl anion synthon
novel reactivty patterns
Carbenes as Organocatalysts
 Carbenes were long suspected as catalytic intermediates
Me
Me
H2N
H2N
HO
HO
N
N
N
N
S
S
H
N
Me
N
Me
Thiazolium Salt of Thiamine Coenzyme (vitamin B1)
Nature's Carbene Organocatalyst
 For many years a carbene catalyst for the enantioselective benzoin condensation was elusive
n The newly proposed intermediate exhibits umpolung reactivity
O
H
cat
S
N
O
R
Ph
Ph
Ph
electrophilic
OH
Breslow-type
Intermediate
Before we can get new reactions
we need better catalysts
acyl anion synthon
novel reactivty patterns
Carbenes as Organocatalysts
 Isolated in 1991 by Arduengo while working at DuPont
Mes
N
N
KOtBu
Mes
Mes
N
N
Mes
Bulky groups
prevent dimerization
Cl
H
Arduengo III, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361.
 In 1995 Enders and Teles develop stable triazole-based carbenes
Ph
N
Ph
N
Ph
NaOCH3
N
Ph
CH3OH
70 °C
N
Ph
N
Ph
N
80 °C
N
Ph
0.1 mbar
OCH3
Angew. Chem. Int. Ed. 1995, 34, 1021.
Ph
N
N
Ph
Asymmetric Carbene Catalysts
10 mol %
O
H
Ph
KOt-Bu
O
OH
Ph
Ph
THF
 The genesis of a new platform for asymmetric catalysis
1966 Sheehan Hunneman
Ph
S
N
1997 Leeper
O
2002 Enders
O
O
N
N
O
c-hex
Ph
N
N
Cl
22% ee
N
Ph
t-Bu
t-Bu
80% ee
N
BF4
83% 90% ee
 2002 Chiral triazole are made and are efficient and selective for the benzoin condensation
Sheehan, J.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666.
Knight, R. L.; Leeper, F. J. Tetrahedron Lett. 1997, 38, 3611.
Enders, D.; Kallfass, U. Angew. Chem. Int. Ed. 2002, 41, 1743.
Carbenes: Generic Activation Platform
 It was soon realized that carbenes activate carbonyls for a number of useful reactions
O
H
O
base
N
Ph
N
N
O
triazolium salt
N
N
electrophile
N
Ph
t-Bu
Ph
O
N
Ph
N
N
t-Bu
t-Bu
Ph
carbene
O
Breslow-type Nucleophile
O
N
Ph
N
N
t-Bu
Ph
OH
electrophile
n Alkene geometry controlled by bulky group
n Re face shielded by t-Bu
 Generically activated towards electrophiles
Recent Advance in Carbene Catalysis
 After the initial disclosures in the 1990's the Stetter reaction has been championed by Rovis
O
N
N
O
BF4
N
CO2Et
O
CO2Et
Rovis 2002
OMe
94% yield
20 mol %
O
94% ee
O
KHMDS
xylenes
Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am Chem. Soc. 2002, 124, 10298.
 The Rovis catalyst design has been have been proven to be excellent for many more reactions
O
N
N
N
Ph
O
BF4
H
Et
O
20 mol %
KOt-Bu
THF
Enders, D.; Niemeier, O.; Raabe, G. Synlett 2006, 2431.
O
Et
OH
Enders 2006
88% yield
94% ee
Recent Advance in Carbene Catalysis
 After the initial disclosures in the 1990's the Stetter reaction has been championed by Rovis
O
N
N
O
BF4
N
CO2Et
O
CO2Et
Rovis 2002
OMe
94% yield
20 mol %
O
94% ee
O
KHMDS
xylenes
Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am Chem. Soc. 2002, 124, 10298.
 The Rovis catalyst design has been have been proven to be excellent for many more reactions
O
N
N
N
Ph
O
BF4
H
Et
O
20 mol %
KOt-Bu
THF
Enders, D.; Niemeier, O.; Raabe, G. Synlett 2006, 2431.
O
Et
OH
Enders 2006
88% yield
94% ee
Beyond the Stetter and Bezoin Reactions
 Azadiene Diels–Alder
O
N
N
O
O
S
N
BF4
O
N
Ph
O
10 mol %
OEt
H
MeO
Mes
O
PMBO2S
OEt
N
DIPEA
Ph
O
toluene/THF
90%, 50:1 dr 99% ee
Bode 2006
O
Mes
N
Mes
N
N
Mes
N
N
O
OH
O
O
OEt
N
N
N
OH
O
O
O
N
OEt
O
OEt
N
Ph
He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418.
O
S
OMe
Beyond the Stetter and Bezoin Reactions
 Azadiene Diels–Alder
O
N
N
O
O
S
N
BF4
O
N
Ph
O
10 mol %
OEt
H
MeO
Mes
O
PMBO2S
OEt
N
DIPEA
Ph
O
toluene/THF
90%, 50:1 dr 99% ee
Bode 2006
O
Mes
N
Mes
N
N
Mes
N
N
O
OH
O
O
OEt
N
N
N
OH
O
O
O
N
OEt
O
OEt
N
Ph
He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418.
O
S
OMe
Beyond the Stetter and Bezoin Reactions
 Azadiene Diels–Alder
O
N
N
O
O
S
N
BF4
O
N
Ph
O
10 mol %
OEt
H
MeO
Mes
O
PMBO2S
OEt
N
DIPEA
Ph
O
toluene/THF
90%, 50:1 dr 99% ee
Bode 2006
O
Mes
N
Mes
N
N
Mes
N
N
O
OH
O
O
OEt
N
N
N
OH
O
O
O
N
OEt
O
OEt
N
Ph
He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418.
O
S
OMe
Substrate Activation Towards New Reactivity
 -chloroaldehydes provide access to alternate manifolds for e.g. esterification
N
10 mol %
O
H
HO
Ph
Ph
Ph
N
O
N
Cl
Ph
O
Ph
Cl
-chloroaldehyde
NEt3
alcohol
ester
Cl
Cl
N
Ph
N
N
N
Cl
N
N
Ph
N
OH
Ph
OH
Ph
Ph
N
N
O
Ph
n Oxy Diels–Alder reaction
O
O
O
N
O
H
Ph
Cl
Mes
Me
CO2Me
N
N
Cl
0.5 mol %
EtOAc, NEt3
O
Ph
CO2Me
88%, >20:1 dr, 99% ee
Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518. He, M.; Uc, G. J.; Bode, J. W. J Am. Chem. Soc. 2006, 128, 15088.
Substrate Activation Towards New Reactivity
 -chloroaldehydes provide access to alternate manifolds for e.g. esterification
N
10 mol %
O
H
HO
Ph
Ph
Ph
N
O
N
Cl
Ph
O
Ph
Cl
-chloroaldehyde
NEt3
alcohol
ester
Cl
Cl
N
Ph
N
N
N
Cl
N
N
Ph
N
OH
Ph
OH
Ph
Ph
N
N
O
Ph
n Oxy Diels–Alder reaction
O
O
O
N
O
H
Ph
Cl
Mes
Me
CO2Me
N
N
Cl
0.5 mol %
EtOAc, NEt3
O
Ph
CO2Me
88%, >20:1 dr, 99% ee
Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518. He, M.; Uc, G. J.; Bode, J. W. J Am. Chem. Soc. 2006, 128, 15088.
Substrate Activation Towards New Reactivity
 -chloroaldehydes provide access to alternate manifolds for e.g. esterification
N
10 mol %
O
H
HO
Ph
Ph
Ph
N
O
N
Cl
Ph
O
Ph
Cl
-chloroaldehyde
NEt3
alcohol
ester
Cl
Cl
N
Ph
N
N
N
Cl
N
N
Ph
N
OH
Ph
OH
Ph
Ph
N
N
O
Ph
n Oxy Diels–Alder reaction
O
O
O
N
O
H
Ph
Cl
Mes
Me
CO2Me
N
N
Cl
0.5 mol %
EtOAc, NEt3
O
Ph
CO2Me
88%, >20:1 dr, 99% ee
Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518. He, M.; Uc, G. J.; Bode, J. W. J Am. Chem. Soc. 2006, 128, 15088.
Hydrogen-Bonding Catalysis
10 mol %
H-bond catalysis
O
N
N
H
H
R
F3C
N
H
Me
O
R
CF3
S
S
R
CF3
N
H
CF3
krel 8.8 times faster with catalyst
Me
H
O
n Typically a 2-20 kcal/mol interaction
n Activates electrophiles
~30 new reactions
Jacobsen–Akiyama
Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407.
 Early examples using cinchonia alkaloidsas H-bonding catalysts
SH
O
cinchonidine
1 mol %
H
O
N
H
O
Me
Me
t-Bu
N
-
S
t-Bu
H
Me
Me
ArS
H O
Me
Me
75% ee
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
Hydrogen-Bonding Catalysis
10 mol %
H-bond catalysis
O
N
N
H
H
R
F3C
N
H
Me
O
R
CF3
S
S
R
CF3
N
H
CF3
krel 8.8 times faster with catalyst
Me
H
O
n Typically a 2-20 kcal/mol interaction
n Activates electrophiles
~30 new reactions
Jacobsen–Akiyama
Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407.
 Early examples using cinchonia alkaloidsas H-bonding catalysts
SH
O
cinchonidine
1 mol %
H
O
N
H
O
Me
Me
t-Bu
N
-
S
t-Bu
H
Me
Me
ArS
H O
Me
Me
75% ee
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
Hydrogen-Bonding Catalysis
10 mol %
H-bond catalysis
O
N
N
H
H
R
F3C
N
H
Me
O
R
CF3
S
S
R
CF3
N
H
CF3
krel 8.8 times faster with catalyst
Me
H
O
n Typically a 2-20 kcal/mol interaction
n Activates electrophiles
~30 new reactions
Jacobsen–Akiyama
Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407.
 Early examples using cinchonia alkaloidsas H-bonding catalysts
SH
O
cinchonidine
1 mol %
H
O
N
H
O
Me
Me
t-Bu
N
-
S
t-Bu
H
Me
Me
ArS
H O
Me
Me
75% ee
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
Hydrogen-Bonding Catalysis
10 mol %
H-bond catalysis
O
N
N
H
H
R
F3C
N
H
Me
O
R
CF3
S
S
R
CF3
N
H
CF3
krel 8.8 times faster with catalyst
Me
H
O
n Typically a 2-20 kcal/mol interaction
n Activates electrophiles
~30 new reactions
Jacobsen–Akiyama
Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407.
 Early examples using cinchonia alkaloidsas H-bonding catalysts
SH
O
cinchonidine
1 mol %
H
O
N
H
O
Me
Me
t-Bu
N
-
S
t-Bu
H
Me
Me
ArS
H O
Me
Me
75% ee
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
Early Examples of Hydrogen Bonding Catalysis
 A small dipeptide was designed by Inoue to mimic oxynitrilase
O
O
H
H
N
HN
NH
N
O
HN
Ph
Ph
CN
H
O
N
C
O
HCN
97%, 97% ee
2 mol %, toluene, –20 °C
NH
OH
H
Ph
Ph
Ph
H
H
N
H
O
 Asymmetric Strecker reaction using Corey's guanidine H-bonding catalyst
Ph
N
HCN
Ph
Ph
toluene, –40 °C
N
Ph
N
Ph
HN
Ph
N
H
Ph
Ph
CN
10 mol %
Ph
N
N
Ph
N
Ph
N
R
H
H
CN
Ph
N
N
H
H
N
CN
Ph
Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181. Grogan, M. J.; Corey, E. J. Org. Lett. 1999, 1, 157.
N
Early Examples of Hydrogen Bonding Catalysis
 A small dipeptide was designed by Inoue to mimic oxynitrilase
O
O
H
H
N
HN
NH
N
O
HN
Ph
Ph
CN
H
O
N
C
O
HCN
97%, 97% ee
2 mol %, toluene, –20 °C
NH
OH
H
Ph
Ph
Ph
H
H
N
H
O
 Asymmetric Strecker reaction using Corey's guanidine H-bonding catalyst
Ph
N
HCN
Ph
Ph
toluene, –40 °C
N
Ph
N
Ph
HN
Ph
N
H
Ph
Ph
CN
10 mol %
Ph
N
N
Ph
N
Ph
N
R
H
H
CN
Ph
N
N
H
H
N
CN
Ph
Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181. Grogan, M. J.; Corey, E. J. Org. Lett. 1999, 1, 157.
N
Early Examples of Hydrogen Bonding Catalysis
 A small dipeptide was designed by Inoue to mimic oxynitrilase
O
O
H
H
N
HN
NH
N
O
HN
Ph
Ph
CN
H
O
N
C
O
HCN
97%, 97% ee
2 mol %, toluene, –20 °C
NH
OH
H
Ph
Ph
Ph
H
H
N
H
O
 Asymmetric Strecker reaction using Corey's guanidine H-bonding catalyst
Ph
N
HCN
Ph
Ph
toluene, –40 °C
N
Ph
N
Ph
HN
Ph
N
H
Ph
Ph
CN
10 mol %
Ph
N
N
Ph
N
Ph
N
R
H
H
CN
Ph
N
N
H
H
N
CN
Ph
Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181. Grogan, M. J.; Corey, E. J. Org. Lett. 1999, 1, 157.
N
Discovery of Acid Mediated Strecker Reactions – Jacobsen Thioureas
 Parallel synthetic ligand libraries were evaluated with various metals
O
N
F3C
ligand library / metal
N
TBSCN
H
CN
TFA
 Modifed Schiff bases were prepared in a combinatorial fashion on a solid support
R
O
R1
O
R
N
H
N
M
H
N
5
N
H
Target Catalyst Architecture
Ru
R2
N
H
O
O
R
R2
O
69% conv 13% ee
N
HO
No Metal
12 Metals
R3
R4
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
59% conv 19% ee
Discovery of Acid Mediated Strecker Reactions – Jacobsen Thioureas
 Parallel synthetic ligand libraries were evaluated with various metals
O
N
F3C
ligand library / metal
N
TBSCN
H
CN
TFA
 Modifed Schiff bases were prepared in a combinatorial fashion on a solid support
R
O
R1
O
R
N
H
N
M
H
N
5
N
H
Target Catalyst Architecture
Ru
R2
N
H
O
O
R
R2
O
69% conv 13% ee
N
HO
No Metal
12 Metals
R3
R4
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
59% conv 19% ee
Discovery of Acid Mediated Strecker Reactions – Jacobsen Thioureas
 Parallel synthetic ligand libraries were evaluated with various metals
O
N
F3C
ligand library / metal
N
TBSCN
H
CN
TFA
 Modifed Schiff bases were prepared in a combinatorial fashion on a solid support
R
O
R1
O
R
N
H
N
M
H
N
5
N
H
Target Catalyst Architecture
Ru
R2
N
H
O
O
R
R2
O
69% conv 13% ee
N
HO
No Metal
12 Metals
R3
R4
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
59% conv 19% ee
Discovery of Acid Mediated Strecker Reactions – Jacobsen Thioureas
 The structure was quickly optimized to provide an efficient Strecker catalyst
R1
O
N
H
H
N
5
R2
O
N
H
t-Bu
Systematic
R2
N
H
O
Ph
H
N
N
H
optimization
N
O
N
H
O
N
HO
HO
Catalyst Lead
New Catalyst
R3
R4
t-Bu
O
2 mol % cat
N
toluene, –78 °C
F3C
N
TBSCN
H
CN
TFA
78% conv 91% ee
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
OMe
Discovery of Acid Mediated Strecker Reactions – Jacobsen Thioureas
 The structure was quickly optimized to provide an efficient Strecker catalyst
R1
O
N
H
H
N
5
R2
O
N
H
t-Bu
Systematic
R2
N
H
O
Ph
H
N
N
H
optimization
N
O
N
H
O
N
HO
HO
Catalyst Lead
New Catalyst
R3
R4
t-Bu
O
2 mol % cat
N
toluene, –78 °C
F3C
N
TBSCN
H
CN
TFA
78% conv 91% ee
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
OMe
How Do These New Catalysts Function?
t-Bu
Ph
H
N
O
N
H
 Knock-out studies show that the urea functional group is essential
N
H
O
N
 Hydrogen bonding established as the activation mode
HO
n Weaker product binding enables turnover
OBz
t-Bu
DFT and NMR Studies:
X
X
Me
N
H
Me
Me
N
H
Me
Me
X
N
N
H
Me
H
Me
HCN
Me
N
Me
N
N
N
H
H
Me
Me
Me
NH
CN
X=O
–8.5 kcal/mol
–5.0 kcal/mol
X=S
–10 kcal/mol
–6.3 kcal/mol
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 120, 10012.
How Do These New Catalysts Function?
t-Bu
Ph
H
N
O
N
H
 Knock-out studies show that the urea functional group is essential
N
H
O
N
 Hydrogen bonding established as the activation mode
HO
n Weaker product binding enables turnover
OBz
t-Bu
DFT and NMR Studies:
X
X
Me
N
H
Me
Me
N
H
Me
Me
X
N
N
H
Me
H
Me
HCN
Me
N
Me
N
N
N
H
H
Me
Me
Me
NH
CN
X=O
–8.5 kcal/mol
–5.0 kcal/mol
X=S
–10 kcal/mol
–6.3 kcal/mol
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 120, 10012.
Urea Stereochemical Model
Me
t-Bu
CN
S
Q uickTim e™ and a
decom pr essor
ar e needed t o see t his pict ur e.
N
Ph
N
N
H
N
H
P
O
h
M
e
N
HO
OBz
t-Bu
 With a better understanding of how these catalysts work new reaction methods can be developed
Strecker reaction with aldimine or ketoimine
1 mol % cat
N
Ph
HCN
toluene, –78 °C
O
F3C
N
Ph
R
t-Bu
R
TFA
t-Bu
CN
R =H
99% ee
R = Me
86% ee
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 120, 10012.
Urea Stereochemical Model
Me
t-Bu
CN
S
Q uickTim e™ and a
decom pr essor
ar e needed t o see t his pict ur e.
N
Ph
N
N
H
N
H
P
O
h
M
e
N
HO
OBz
t-Bu
 With a better understanding of how these catalysts work new reaction methods can be developed
Strecker reaction with aldimine or ketoimine
1 mol % cat
N
Ph
HCN
toluene, –78 °C
O
F3C
N
Ph
R
t-Bu
R
TFA
t-Bu
CN
R =H
99% ee
R = Me
86% ee
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 120, 10012.
Urea Catalyzed Reactions
 Enantioselective Mannich Reaction
Boc
H
OTBS
N
Oi-Pr
Ph
t-Bu
5 mol % cat
–40 °C
toluene, 48 h
TFA
O
NHBoc
i-PrO
H
N
Ph
S
N
H
N
H
O
Ph
N
HO
90% conv, 91% ee
OCOt-Bu
t-Bu
Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
 Enantioselective Acyl Pictet–Spengler Reaction
N
N
H
Et
Et
10 mol % cat
Ac-Cl
lutidine
–78 °C
NAc
N
H
N
N
H
i-Bu
Et
Et
81% conv, 93% ee
Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558.
S
t-Bu
i-Bu
O
N
H
Me
N
Ph
Urea Catalyzed Reactions
 Enantioselective Mannich Reaction
Boc
H
OTBS
N
Oi-Pr
Ph
t-Bu
5 mol % cat
–40 °C
toluene, 48 h
TFA
O
NHBoc
i-PrO
H
N
Ph
S
N
H
N
H
O
Ph
N
HO
90% conv, 91% ee
OCOt-Bu
t-Bu
Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
 Enantioselective Acyl Pictet–Spengler Reaction
N
N
H
Et
Et
10 mol % cat
Ac-Cl
lutidine
–78 °C
NAc
N
H
N
N
H
i-Bu
Et
Et
81% conv, 93% ee
Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558.
S
t-Bu
i-Bu
O
N
H
Me
N
Ph
Urea Catalyzed Reactions
 Enantioselective Aza-Henry Reaction
Boc
10 mol % cat
4 °C
toluene, i-Pr2NEt
N
H
EtNO2
Ph
Boc
NH
t-Bu
NO2
Ph
4 Å MS
Me2N
Me
S
N
H
N
H
O
NHAc
>95% conv, 91% ee
15:1 syn
Yoon, T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 124, 466.
 Enantioselective Hydrophosphorylation
O
O
Ar
O
P
O
Ar
N
H
Ph
10 mol % cat
Ar
Ar = 2-nitrophenyl
P
Ph
Me2N
HN
4 °C
Et2O
S
N
H
O
Ar
Ph
O
t-Bu
N
H
O
Ph
N
HO
87% yield, 98% ee
t-Bu
Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4108.
OCOt-Bu
Urea Catalyzed Reactions
 Enantioselective Aza-Henry Reaction
Boc
10 mol % cat
4 °C
toluene, i-Pr2NEt
N
H
EtNO2
Ph
Boc
NH
t-Bu
NO2
Ph
4 Å MS
Me2N
Me
S
N
H
N
H
O
NHAc
>95% conv, 91% ee
15:1 syn
Yoon, T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 124, 466.
 Enantioselective Hydrophosphorylation
O
O
Ar
O
P
O
Ar
N
H
Ph
10 mol % cat
Ar
Ar = 2-nitrophenyl
P
Ph
Me2N
HN
4 °C
Et2O
S
N
H
O
Ar
Ph
O
t-Bu
N
H
O
Ph
N
HO
87% yield, 98% ee
t-Bu
Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102.
OCOt-Bu
Bifunctional Urea Catalysts
 Enantioselective Michael Addition
O
O
EtO
O
10 mol % cat
Ph
OEt
NO2
O
EtO
toluene , 23 °C
OEt
NO2
Ph
 Both thiourea and tertiary amine are needed
S
CF3
CF3
R
S
AcHN
NMe2
F3C
N
H
S
N
H
F3C
N
H
N
N
H
H Me2N
O
O
H
N
H
NMe2
N
10 mol % NEt3
14%, 35% ee
57%, 0% ee
86%, 93% ee
Ph
Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 128, 12672.
Nu
Bifunctional Urea Catalysts
 Enantioselective Michael Addition
O
O
EtO
O
10 mol % cat
Ph
OEt
NO2
O
EtO
toluene , 23 °C
OEt
NO2
Ph
 Both thiourea and tertiary amine are needed
S
CF3
CF3
R
S
AcHN
NMe2
F3C
N
H
S
N
H
F3C
N
H
N
N
H
H Me2N
O
O
H
N
H
NMe2
N
10 mol % NEt3
14%, 35% ee
57%, 0% ee
86%, 93% ee
Ph
Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 128, 12672.
Nu
Urea Catalyzed Double Michael Cascade
 Enantioselective Double Michael Addition
O
O
O
Me
O
OEt
Ph
NO2
O
OEt
O
10 mol % cat
Me
Me
OEt
Ph
NO2
toluene , –20 °C
Ph
NO2
87% yield
>99% de
92% ee
CF3
S
catalyst =
F3C
N
H
N
H
NMe2
Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tettrahdron Lett. 2003, 45, 9185.
Rawal's Discovery of H-Bonding Catalyzed Diels–Alder
OMe
OMe
TBSO
H
solvent
O
Me
N
O
krel
solvent
1
THF
O
AcCl
Me
Benzene
1.3
t-BuOH
280
i-PrOH
630
Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662.
 Observed that the hetero Diels–Alder reaction is accelerated in alcohol solvent
 This observation was turned into an asymmetric reaction using a chiral H-donor catalyst
Ar
TBSO
H
Ph
O
Me
N
Me
20 mol % cat
AcCl
O
Ph
Me
OH
Me
OH
O
70% yield
99% ee
Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146.
Ar
Ar
Ar =
Ar
Rawal's Discovery of H-Bonding Catalyzed Diels–Alder
OMe
OMe
TBSO
H
solvent
O
Me
N
O
krel
solvent
1
THF
O
AcCl
Me
Benzene
1.3
t-BuOH
280
i-PrOH
630
Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662.
 Observed that the hetero Diels–Alder reaction is accelerated in alcohol solvent
 This observation was turned into an asymmetric reaction using a chiral H-donor catalyst
Ar
TBSO
H
Ph
O
Me
N
Me
20 mol % cat
AcCl
O
Ph
Me
OH
Me
OH
O
70% yield
99% ee
Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146.
Ar
Ar
Ar =
Ar
Mechanism of Rawal's H-Bonding Diels–Alder Reaction
 Is single or double point activation in operation?
P
Carbonyl
h
P
h
O
Activation
O
O
O
H
O
O
O
H
H
H
H
H
O
H
R
O
P
P
h
h
H
R
H
R
Single or Double–point activation
Q uickTim e™ and a
decom pr essor
ar e needed t o see t his pict ur e.
Re–Face
Open
R
P
h
P
h
O
H
H
O
H
O
P
P
h
h
Single–Point Activation
Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336.
Mechanism of Rawal's H-Bonding Diels–Alder Reaction
 Is single or double point activation in operation?
P
Carbonyl
h
P
h
O
Activation
O
O
O
H
O
O
O
H
H
H
H
H
O
H
R
O
P
P
h
h
H
R
H
R
Single or Double–point activation
Q uickTim e™ and a
decom pr essor
ar e needed t o see t his pict ur e.
Re–Face
Open
R
P
h
P
h
O
H
H
O
H
O
P
P
h
h
Single–Point Activation
Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336.
Chiral Phosphoric Acids
 Long used for chiral resolutions
R
O
 Used as a ligand for Lewis acid catalysis
O
P
O
OH
n 2004 Terada and Akiyama use as Brønsted acid catalyst
R
N
Ph
R=
n Size of R group very important for enantioselectivity
Boc
H
O
Me
O
Ac
2 mol % cat
Me
Boc
CH2Cl2
H
N
Ac
Ph
R=
R=
R=
92% yield
95% yield
88% yield
99% yield
12% ee
56% ee
90% ee
95% ee
H
Akiyama, T.; Itoh, K.; Yokota, K.; Fuchibe, K. Angew Chem. Int. Ed. 2004, 43, 1566.
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
Chiral Phosphoric Acids
 Long used for chiral resolutions
R
O
 Used as a ligand for Lewis acid catalysis
O
P
O
OH
n 2004 Terada and Akiyama use as Brønsted acid catalyst
R
N
Ph
R=
n Size of R group very important for enantioselectivity
Boc
H
O
Me
O
Ac
2 mol % cat
Me
Boc
CH2Cl2
H
N
Ac
Ph
R=
R=
R=
92% yield
95% yield
88% yield
99% yield
12% ee
56% ee
90% ee
95% ee
H
Akiyama, T.; Itoh, K.; Yokota, K.; Fuchibe, K. Angew Chem. Int. Ed. 2004, 43, 1566.
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
Chiral Phosphoric Acids
 Long used for chiral resolutions
R
O
 Used as a ligand for Lewis acid catalysis
O
P
O
OH
n 2004 Terada and Akiyama use as Brønsted acid catalyst
R
N
Ph
R=
n Size of R group very important for enantioselectivity
Boc
H
O
Me
O
Ac
2 mol % cat
Me
Boc
CH2Cl2
H
N
Ac
Ph
R=
R=
R=
92% yield
95% yield
88% yield
99% yield
12% ee
56% ee
90% ee
95% ee
H
Akiyama, T.; Itoh, K.; Yokota, K.; Fuchibe, K. Angew Chem. Int. Ed. 2004, 43, 1566.
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
Chiral Phosphoric Acids
 Long used for chiral resolutions
R
O
 Used as a ligand for Lewis acid catalysis
O
P
O
OH
n 2004 Terada and Akiyama use as Brønsted acid catalyst
R
N
Ph
R=
n Size of R group very important for enantioselectivity
Boc
H
O
Me
O
Ac
2 mol % cat
Me
Boc
CH2Cl2
H
N
Ac
Ph
R=
R=
R=
92% yield
95% yield
88% yield
99% yield
12% ee
56% ee
90% ee
95% ee
H
Akiyama, T.; Itoh, K.; Yokota, K.; Fuchibe, K. Angew Chem. Int. Ed. 2004, 43, 1566.
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
Chiral Phosphoric Acids
 Long used for chiral resolutions
R
O
 Used as a ligand for Lewis acid catalysis
O
P
O
OH
n 2004 Terada and Akiyama use as Brønsted acid catalyst
R
N
Ph
R=
n Size of R group very important for enantioselectivity
Boc
H
O
Me
O
Ac
2 mol % cat
Me
Boc
CH2Cl2
H
N
Ac
Ph
R=
R=
R=
92% yield
95% yield
88% yield
99% yield
12% ee
56% ee
90% ee
95% ee
H
Akiyama, T.; Itoh, K.; Yokota, K.; Fuchibe, K. Angew Chem. Int. Ed. 2004, 43, 1566.
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
New Reactivity – Imine Amination
No known reaction
metal or
N
Boc
organocatalytic
H2N
Ts
Ph
Boc
H
N
H
N
SO2Me
Ph
Boc-imine
tosyl-amine
enantioenriched aminal
(differentially protected)
5 mol % cat
Ph
O
Ph
O
O
Et2O, 1 h, 21 °C
P
OH
86% yield
93% ee
(S)-VAPOL
Rowlan, G. B.; Zang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696.
New Reactivity – Imine Amination
No known reaction
metal or
N
Boc
organocatalytic
H2N
Ts
Ph
Boc
H
N
H
N
SO2Me
Ph
Boc-imine
tosyl-amine
enantioenriched aminal
(differentially protected)
5 mol % cat
Ph
O
Ph
O
O
Et2O, 1 h, 21 °C
P
OH
86% yield
93% ee
(S)-VAPOL
Rowlan, G. B.; Zang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696.
Consideration of priviledged architecture and stereogenicity
Transfer Hydrogenation
Friedel–Crafts
Me2N
OMe
H
O
O
CO2Et
A
H
Me
H
X
B
important
important
chiral synthon
chiral synthon
 Perhaps the most important stereogenicity for biomedical applications
Amine conjugate addition
NH2
biomedically
relevant center
NR2
93–97% ee
X
Y
O
There are vast technologies for the construction of amine stereogenicity
 Favourite: Ellman imine, most general–dogma breaking
Me
Me
SR
Me
S
O
N
DIBAL
Me
Me
tert-butanesulfinamide
Me
Me
SR
Me
S
O
H
N
Me
Me
20:1 dr, 86% yield
There are vast technologies for the construction of amine stereogenicity
 Favourite: Ellman imine, most general–dogma breaking
Me
SR
Me
Me
S
O
N
DIBAL
Me
Me
Me
SR
Me
S
H
N
O
Me
tert-butanesulfinamide
Me
Me
20:1 dr, 86% yield
 Reductive Amination: Simultaneous fragment coupling and C–N bond formation
O
F
NaBH4
Me
NH2
Me
N
–H2O
F
Me
N
NH
O
Me
O
fragment 1
fragment 2
no enantioselective catalytic
reductive amination-coupling
Organic Catalyzed Reductions in Biological Systems
 NADH: Natures Reduction (Hydrogenation) Reagent (Coenzyme)
H
O
NH2
CONH2
OH
Me
alanine transferase
H
NH3
O
N
methyl
pyruvate
O
enzyme
R
catalyst
NADH
OH
Me
alanine
Q uickTim e™ and a
TI FF ( Uncom pr essed) decom pr essor
ar e needed t o see t his pict ur e.
H2N
H +
N
N H
H
R
N
Me
H
His
O
O
active site
NADH reduction
R
HN
O
H
H
NH
HN
Arg
NHR
Selective reduction of pyruvate imines to create amino acids
Could this organocatalytic sequence be utilized in the redution of carbon–carbon double bonds
Organic Catalyzed Reductions in Laboratory Systems
 Hantzsch ester as a useful surrogate for NADH reductions in the lab
H
O
H
MeO2C
NH2R
Me
Me
N
Me
acetophenone
MeO
Me
NADH analog
O
H
N
phenylethyl amine
catalyst
O
H +
H
N
Me
catalyst
H
R
NHR
CO2Me
R
Me
Me
H-bonded or Bronsted acid
organic iminium reduction
Can we translate a biochemical concept to a laboratory reaction
Can we develop a useful transformation on the basis of established Bronsted acid catalysts
Organic Catalyzed Reductions in Laboratory Systems
 Hantzsch ester as a useful surrogate for NADH reductions in the lab
H
O
H
MeO2C
NHR
CO2Me
NH2R
Me
Me
N
Me
catalyst
H
acetophenone
Me
NADH analog
phenylethyl amine
catalyst
MeO
Me
O
H
R
N
H
catalyst
O
H +
N
R
O
X
OH
Me
Me
H-bonded or Bronsted acid
organic iminium reduction
X
Y
Y
O
O
P
O
OH
simple carboxylic
or phosphonic acids
Can we translate a biochemical concept to a laboratory reaction
Can we develop a useful transformation on the basis of established Bronsted acid catalysts
Organocatalysis and the advent of Bronsted Acid/H-bonded catalysis
 Pioneers
CF3
Ph
Me2N
O
O
S
N
N
H
H
CF3
Ph
OH
Yamamoto
R
OH
OH
O
Ph
OH
Ph
Rawal
Jacobsen
Akiyama, Terada
OH
OH
Schaus
O
O
P
O
OH
Organocatalysis and the advent of Bronsted Acid/H-bonded catalysis
H
O
H
MeO2C
NH2PMP
CO2Me
NHPMP
Me
Me
N
Me
80°C, toluene
20 mol% catalyst
Me
H
acetophenone
 Pioneers
CF3
Ph
Me2N
O
O
S
N
N
H
H
CF3
Ph
OH
Yamamoto
R
OH
OH
O
Ph
OH
Ph
Rawal
Jacobsen
Akiyama, Terada
OH
OH
Schaus
O
O
P
O
OH
Organocatalysis and the advent of Bronsted Acid/H-bonded catalysis
H
O
H
MeO2C
NH2PMP
CO2Me
NHPMP
Me
Me
N
Me
80°C, toluene
20 mol% catalyst
Me
H
acetophenone
 Pioneers
CF3
Ph
Me2N
O
O
S
N
N
H
H
CF3
Ph
OH
Yamamoto
R
OH
OH
O
Ph
OH
Ph
Jacobsen
Rawal
No reaction
No reaction
No reaction
Akiyama, Terada
OH
OH
Schaus
O
No reaction
O
P
O
OH
43% yield
7%ee
Attempts to develop a Bronsted Acid Catalyst for Reductive Amination
H
O
H
MeO2C
CO2Me
NH2PMP
NHPMP
Me
Me
N
Me
H
acetophenone
H
O
O
H
OH
P
O
Me
O
N
O
80°C, toluene
20 mol% catalyst
Me
7% ee
Attempts to develop a Bronsted Acid Catalyst for Reductive Amination
H
O
H
MeO2C
CO2Me
NH2PMP
NHPMP
Me
Me
N
Me
H
Me
80°C, toluene
20 mol% catalyst
7% ee
acetophenone
R
O
O
OH
P
O
R
R
H
O
O
H
OH
P
O
Me
O
N
O
Yield
%ee
Attempts to develop a Bronsted Acid Catalyst for Reductive Amination
H
O
H
MeO2C
CO2Me
NH2PMP
NHPMP
Me
Me
N
Me
H
Me
80°C, toluene
20 mol% catalyst
7% ee
acetophenone
R
O
O
OH
P
O
R
R
H
O
O
H
OH
P
O
Yield
%ee
H
43
7
Me
O
Ph(NO2)2
45
16
N
O
Ph(CF3)2
39
65
2-Nap
56
40
Attempts to develop a Bronsted Acid Catalyst for Reductive Amination
H
O
H
MeO2C
CO2Me
NH2PMP
NHPMP
Me
Me
N
Me
H
Me
80°C, toluene
20 mol% catalyst
7% ee
acetophenone
R
O
O
OH
P
O
R
R
H
O
O
H
OH
P
O
Yield
%ee
H
43
7
Me
O
Ph(NO2)2
45
16
N
O
Ph(CF3)2
39
65
2-Nap
56
40
Ph3Si
90
85
The impact of additives and temperature on the reductive amination
H
O
TPS
H
MeO2C
CO2Me
80°C, toluene
20 mol% cat
Me
Me
N
NH2PMP
Me
H
NHPMP
Me
O
O
OH
P
TPS
catalyst
 What is the impact of the water biproduct
additive
Time
Yield
%ee
--
28 h
90
85
H2O (1eq)
72 h
35
77
H2O (2eq)
72 h
<10
72
MgSO4
20 h
79
83
Na2SO4
36 h
83
85
 What is the scope of this transformation with respect to ketones?
O
The impact of additives and temperature on the reductive amination
H
O
TPS
H
MeO2C
CO2Me
N
Me
H
O
Me
80°C, toluene
20 mol% cat
Me
Me
NH2PMP
NHPMP
O
OH
P
O
TPS
catalyst
 What is the impact of the water biproduct
additive
Time
Yield
%ee
--
28 h
90
85
H2O (1eq)
72 h
35
77
H2O (2eq)
72 h
<10
72
MgSO4
20 h
79
83
Na2SO4
36 h
83
6h
85
5A mol sieves
Temp
Time
Yield
%ee
80°
6h
85
90
85
60°
22 h
90
93
90
40°
36 h
86
95
 What is the scope of this transformation with respect to ketones?
The scope of the reductive amination with respect to aryl ketones
H
O
TPS
H
MeO2C
CO2Me
Me
Me
N
Me
H
X
NH2PMP
NHPMP
O
O
TPS
O
(m) 95% ee
(p) 94% ee
F
O
catalyst
(o) 83% ee
Me
OH
P
X
5A mol sieves
 Scope of the ketone component
O
Me
90% ee
85% ee
77% yield
75% yield
MeO
60-85% yield
O
O
Me
Me
95% ee
75% yield
Cl
O
Me
40°C, toluene
10 mol% cat
95% ee
O
71% yield
O2N
 Are there other systems that are successful in this transformation?
96% ee
Me
73% yield
The scope of the reductive amination
R
O
N
H
H
MeO2C
O
Me
CO2Me
N
H
Me
40°C, toluene
10 mol% cat
 Scope of the ketone-ketimine component
O
N
O
97% ee
82% yield
R
O
HN
O
NH2PMP
5A mol sieves
Me
TPS
O
O
OH
P
TPS
catalyst
O
The scope of the reductive amination
R
O
N
H
H
MeO2C
O
Me
CO2Me
N
Me
H
40°C, toluene
10 mol% cat
 Scope of the ketone-ketimine component
O
N
O
97% ee
82% yield
Et
O
N
O
79% ee
27% yield
R
O
HN
O
NH2PMP
5A mol sieves
Me
TPS
O
O
OH
P
TPS
catalyst
O
MM3-Calculations Provide Good Prediction of Asymmetric Environment
Si-face
MM3-structure
MM3-Calculations Provide Good Prediction of Asymmetric Environment
OMe
OMe
HEH,
N
HN
10 mol% cat
Me
5Å MS, 50 °C
benzene
Me
71% yield
95% ee
O2N
O2N
Si-face
Si-face
MM3-structure
X-ray structure
Crystal grown in toluene at –20 ÞC in glove box
The scope of the reductive amination: alkyl ketones
H
R
Me
Me
O
H
MeO2C
O
NH2PMP
CO2Me
N
Me
H
40°C, toluene
10 mol% cat
5A mol sieves
 Scope of the alkyl ketone component
O
Et
91% ee
Me
TPS
71% yield
NHPMP
R
Me
O
OH
P
TPS
catalyst
O
The scope of the reductive amination: alkyl ketones
H
R
Me
O
H
MeO2C
O
NH2PMP
CO2Me
Me
N
TPS
Me
H
O
NHPMP
40°C, toluene
10 mol% cat
R
Me
OH
P
O
TPS
catalyst
5A mol sieves
 Scope of the alkyl ketone component
O
O
Et
91% ee
71% yield
Me
NHPMP
86% ee
Me
BzO
49% yield
91% ee
Me
72% yield
50% yield
Me
O
O
O
86% ee
Me
94% ee
75% yield
92% ee
Cl
 This reductive amination process appears to be general for methyl ketones
68% yield
The scope of the reductive amination: aryl amines
H
MeO2C
O
R
H
Me
Me
CO2Me
N
Me
H
TPS
O
RNH2
O
NHR
40°C, toluene
10 mol% cat
5A mol sieves
R
Me
OH
P
O
TPS
catalyst
 Scope of the amine component
O
CF3
HN
HN
HN
Me
Me
93% ee
Ts
N
S
93% ee
90% yield
Me
91% ee
70% yield
90% ee
92% yield
Ts
N
N
HN
Me
Me
55% yield
73% yield
HN
95% ee
HN
Me
90% ee
75% yield
With Storer, Carrera, Ni. J. Am. Chem. Soc. 2006, 128, 84
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst Design
S
R
Activation
Modes
N
H
N
H
R
RO
O
P
RO
OH
H-Bonding, Brønsted Acids
R
R
Novel Reactivity
NR4
Carbene, Phase Transfer
Priviledged
Achitecture
Chiral
Pool
MacMiIlan, D. W. C. Nature 2008, 455, 304.
Valuable New Bond
Disconnections
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst Design
S
R
Activation
Modes
N
H
N
H
R
RO
O
P
RO
OH
H-Bonding, Brønsted Acids
R
R
Novel Reactivity
NR4
Carbene, Phase Transfer
Priviledged
Achitecture
Chiral
Pool
MacMiIlan, D. W. C. Nature 2008, 455, 304.
Valuable New Bond
Disconnections
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst Design
S
R
Activation
Modes
N
H
N
H
R
RO
O
P
RO
OH
H-Bonding, Brønsted Acids
R
R
Novel Reactivity
NR4
Carbene, Phase Transfer
Priviledged
Achitecture
Chiral
Pool
MacMiIlan, D. W. C. Nature 2008, 455, 304.
Valuable New Bond
Disconnections
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst Design
S
R
Activation
Modes
N
H
N
H
R
RO
O
P
RO
OH
H-Bonding, Brønsted Acids
R
R
Novel Reactivity
NR4
Carbene, Phase Transfer
Priviledged
Achitecture
Chiral
Pool
MacMiIlan, D. W. C. Nature 2008, 455, 304.
Valuable New Bond
Disconnections
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst Design
S
R
Activation
Modes
N
H
N
H
R
RO
O
P
RO
OH
H-Bonding, Brønsted Acids
R
R
Novel Reactivity
NR4
Carbene, Phase Transfer
Priviledged
Achitecture
Chiral
Pool
MacMiIlan, D. W. C. Nature 2008, 455, 304.
Valuable New Bond
Disconnections
Activation Modes Are Enabled by Priviledged Catalyst Achitectures
Catalysis Platform / Concept
Chemical Methodology
Catalyst Design
S
R
Activation
Modes
N
H
N
H
R
RO
O
P
RO
OH
H-Bonding, Brønsted Acids
R
R
Novel Reactivity
NR4
Carbene, Phase Transfer
Priviledged
Achitecture
Chiral
Pool
MacMiIlan, D. W. C. Nature 2008, 455, 304.
Valuable New Bond
Disconnections