the chiral urea and thiourea scaffold: from novel catalyst to privileged motif david r. stuart...
TRANSCRIPT
The Chiral Urea and The Chiral Urea and Thiourea Scaffold: From Thiourea Scaffold: From
Novel Catalyst to Privileged Novel Catalyst to Privileged MotifMotif
David R. StuartUniversity of Ottawa
Center for Catalysis Research and Innovation
Nov. 23, 2006
22
What Are Hydrogen Bonds?What Are Hydrogen Bonds?
“An X-H---A interaction is called a “hydrogen bond”, if 1. it constitutes a local bond, and 2. X-H acts as a proton donor to A.”
T. Steiner, Angew. Chem. Int. Ed. 2002, 41, 48 – 76.
.
.
X H A
33
How Strong Are Hydrogen How Strong Are Hydrogen Bonds?Bonds?
N NMeMe
MeMeH
Mostly Covalent: proton sponge
H-bond energy: 14 - 40 kcal/mol
Mostly Electrostatic: Peptides
RNH O CR2
H-bond energy: 4 -15 kcal/mol
Electrostatic
H-bond energy: <4 kcal/mol
.
.
HR OH
H
Covalent Bond Energies
C-H: 99 kcal/mol
N-H: 93 kcal/mol
O-H: 111 kcal/mol
G.A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford University Press, New York, 1997
44
OH
H3C
O
H HO
O
OPO32-
Type II aldolase
OH
H3C
OOH
OH
OPO32-
+
H CH3
OO
OH
H
Tyr-113
OH
Tyr-209
O
OGlu-73
H
O
O Zn+H
OPO32-
.
.
Hydrogen Bonding In Bio-Hydrogen Bonding In Bio-CatalysisCatalysis
Angew. Chem. Int. Ed. 2006, 45, 1520 – 1543.
55
Hydrogen Bonding in Small Hydrogen Bonding in Small Molecule Catalysis: Phase-Molecule Catalysis: Phase-
Transfer CatalysisTransfer Catalysis
.
.
t-Bu
O
t-Bu
OO
1 (3 mol%), 13% NaOCl
toluene, 0°C
N Br
Ar
Ar
O
Ar Ar
O
Ar Ar
1: Ar = 3,5-Ph2C6H3
H
H
T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc. 2004, 126, 6844 - 6845
66
TBSO
NMe2
+ H
O
O
1) 10 mol% 1toluene, -40°C
2) AcCl,DCM/toluene, -78°C
O
OO
67% yield92% ee
OH
OH
Ar Ar
Ar Ar
O
O
Me
Me
1: Ar = 1-naphthyl
OO
Ar
Ar
ArAr
O
OMeMe
H
H
H
O
O
.
.
Hydrogen Bonding in Small Hydrogen Bonding in Small Molecule Catalysis: Single H-Molecule Catalysis: Single H-
Bond DonationBond Donation
Y. Huang, A.K. Unni, A.N. Thandani, V.H. Rawal, Nature 2003, 424, 146
77.
.
+
1. Catalyst (5 mol %), -40°C, 48 h.
2. TFA, 2 minH Ph
NBoc
Oi-Pr
OTBS
i-PrO
O
Ph
NHBoc
2 equiv.
NH
NH
S
N
O
t-BuMe
Ph
Catalyst
100% yield; 94% ee
NN
S
N
O
t-BuMe
Ph
H Ph
NBoc
H H
Hydrogen Bonding in Small Hydrogen Bonding in Small Molecule Catalysis: Double H-Molecule Catalysis: Double H-
Bond DonationBond Donation
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
88
OutlineOutline
Discovery of Jacobsen’s novel catalyst for the Asymmetric Strecker Reaction
Analysis of the Strecker Reaction and Substrate-Catalyst interactions
Optimization of Jacobsen’s Catalyst to a general catalyst for an array of Carbon-Carbon bond forming reaction.
99
The Strecker Reaction The Strecker Reaction DiscoveredDiscovered
.
.
Strecker (1850):
OH
CO2H
O
H
lactic acid acetaldehyde
1010
The Strecker Reaction The Strecker Reaction DiscoveredDiscovered
H
O 1. NH3/H2O
2. HCN (dry)
NH2
HNC
1. HCl/H2O
2. Pb(OH)2 CO2H
NH2
Strecker (1850):
OH
CO2H
O
H
lactic acid acetaldehyde
acetaldehyde -amino nitrile +/- alanine
.
.
1111
The Modern Strecker ReactionThe Modern Strecker Reaction
.
.
R1 R2
NR3
+ HCNR1
HNR3
R2CN
1212
.
.
R1 R2
NR3
+ HCNR1
HNR3Chiral Catalyst
CNR2 R1
HNR3
R2
CNOR
A ent-A
The Modern Asymmetric The Modern Asymmetric Strecker ReactionStrecker Reaction
1313
The Modern Asymmetric The Modern Asymmetric Strecker ReactionStrecker Reaction
.
.
R1 R2
NR3
+ HCNR1
HNR3Chiral Catalyst
CNR2 R1
HNR3
R2
CNOR
A ent-A
R1
NH2
CO2HR2 R1
NH2
R2
CO2HOR
B ent-B
1414
.
.
Ph
NCHPh2
+ HCNPh
10 mol% 1
toluene, -40°C
N
NNH
Corey's Guandine Catalyst
(% ee = 50 - 86%)
1
CN
HNCHPh2
The Modern Asymmetric The Modern Asymmetric Strecker Reaction: Corey’s Strecker Reaction: Corey’s
ContributionContribution
E.J. Corey, M.J. Grogan, Org. Lett. 1999, 1, 157 - 160
1515
The Modern Asymmetric The Modern Asymmetric Strecker Reaction: Corey’s Strecker Reaction: Corey’s
ContributionContribution
.
.
Ph
NCHPh2
+ HCNPh
10 mol% 1
toluene, -40°C
N
NNH
Corey's Guandine Catalyst
(% ee = 50 - 86%)
1
CN
HNCHPh2
N
NN
H H
Ph
NPh2HC
CN
E.J. Corey, M.J. Grogan, Org. Lett. 1999, 1, 157 - 160
1616
O
NO
R'R
M R''linker-1 amino
acid linker-2
O
NN
R'R
M R''
.
.
Jacobsen’s Approach to the Jacobsen’s Approach to the Asymmetric Strecker ReactionAsymmetric Strecker Reaction
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901 - 4902
1717
O
NO
R'R
M R''linker-1 amino
acid linker-2
O
NN
R'R
M R''
.
.
NH
OHN
O
NH
N
Oi-Pr
N
O
t-Bu t-Bu
R
R
M
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901 - 4902
Jacobsen’s Approach to the Jacobsen’s Approach to the Asymmetric Strecker ReactionAsymmetric Strecker Reaction
1818
H
N
+ TMSCN1. Chiral Lewis Acid Catalyst
2. TFAA CN
NF3C
O
*
NH
OHN
O
NH
N
Oi-Pr
N
O
t-Bu
R
R
M
Metal ee (%) Conv (%)
Co 0 68
Zn 1 91
Ti 4 30
.
.
Fe
Ru
10 69
13 63
Gd
Yb
2 95
0 94
t-Bu
Catalyst Screening By Parallel Catalyst Screening By Parallel Library SynthesisLibrary Synthesis
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901 - 4902
1919
Catalyst Screening By Parallel Catalyst Screening By Parallel Library SynthesisLibrary Synthesis
H
N
+ TMSCN1. Chiral Lewis Acid Catalyst
2. TFAA CN
NF3C
O
*
NH
OHN
O
NH
NH
Oi-Pr
N
HO
t-Bu t-Bu
R
R
Metal ee (%) Conv (%)
Co 0 68
Zn 1 91
Ti 4 30
.
.
Fe
Ru
10 69
13 63
Gd
Yb
2 95
0 94
None 19 59Ligand alone catalyzes the reaction
with the highest level of % ee!
M.S. Sigman, E.N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901 - 4902
2020
Optimization by Parellel Library Optimization by Parellel Library SynthesisSynthesis
.
.
NH
NH
OHN
O
t-Bu
OPivt-Bu
HO
N
Catalyst 1
(Catalyst 1 was obtained from librariestotaling over 250 compounds)
M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed. 2000, 39, 1279 - 1281
2121
A Novel Organo-Catalyst A Novel Organo-Catalyst RealizedRealized
R1 H
NR
+ HCN
1. Catalyst 1 (2 mol %), toluene, -78°C, 24 h.
2. TFAA R1 CN
NR
F3C
O
.
..
.
CN
N
O
F3C
Br
88% yield95% ee
CN
N
O
F3C
88% yield96% ee
CN
N
O
F3C
69% yield78% ee
NH
NH
OHN
O
t-Bu
OPivt-Bu
HO
N
Catalyst 1
M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed. 2000, 39, 1279 - 1281
2222
Application to the Application to the Hydrocyanation of KetoiminesHydrocyanation of Ketoimines
R CH3
N+ HCN
Catalyst 1 (2 mol %)
toluene, -78°C
Ph
R
.
.
HN
CH3CN
Ph
.
.
HN
CNCH3
Ph
97% yield90% ee
HN
CNCH3
Ph
F3C
HN
CNCH3
Ph
99% yield95% ee
98% yield70% ee
NH
NH
OHN
O
t-Bu
OPivt-Bu
HO
N
Catalyst 1
P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867 - 870
2323
Synthesis of Enantiomerically Synthesis of Enantiomerically Enriched Amino-acids: D-Enriched Amino-acids: D-terttert--
leucineleucine
OH
O
NH2
D-tert-leucine (> $100/g)
H
N Ph
.
.
P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867 - 870
2424
Synthesis of Enantiomerically Synthesis of Enantiomerically Enriched Amino-acids: D-Enriched Amino-acids: D-terttert--
leucineleucine
.
.
OH
O
NH2
D-tert-leucine (> $100/g)
H
N
H
N1. HCN, Catalyst 1 (2 mol %),
toluene, -70°C, 20 h.
2. Ac2O, formic acid CN
NH
O65% (w/v) H2SO4,
45°C, 20h
CO2H
NH
O
HCl (conc), 70°C, 12h
CO2H
HN
Ph
PhPh Ph
PhHCl . H2, Pd/C
MeOH CO2H
NH2 HCl. 99% ee,84% yieldfrom imine
2.0 gramsP. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867 - 870
2525
O
HONHBoc
tBu
NH2Ph
+HBTU, DIPEA
CH2Cl2, r.t.Bn(H)N
O
NHBoc
tBuTFA/CH2Cl2, r.t.
Bn(H)N
O
NH2
tBu
Cl O
ONO2
pyridine/CH2Cl2, r.t.
1)
H2N NH2
DIPEA/CH2Cl2, r.t.
2)
Bn(H)N
O
NH
tBu
NH
O
NH2
O
HO
OPivt-Bu
MeOH, r.t. Catalyst 1
.
.
99% yield(over 2 steps)
82% yield(over 2 steps)
Bn(H)N
O
NH
tBu
NH
O
N
HO
t-Bu OPiv
98% yield(80% overall
yield)
10.55 g isolated
Optimized Synthesis of Urea Optimized Synthesis of Urea CatalystCatalyst
J.T. Su, P. Vachal, E.N. Jacobsen, Adv. Syn. Catal. 2001, 343, 197 - 200
2626
A Closer Look at the A Closer Look at the CatalystCatalyst
How does the catalyst activate the substrate and what are the major factors for enantioselective induction?
HNPh
O
NH
t-Bu
NH
O
N
HO
t-Bu OPiv
Acidic Protons
Acidic Proton
.
.
2727.
.
H
N
+ HCNtoluene, -78°C, 24 h.
CN
HN
O O
Bn(H)N
O
NH
tBu
NH
O
N
HO
t-Bu OPiv
(2 mol %)
Kinetic AnalysisKinetic Analysis
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
2828.
.
H
N
+ HCNtoluene, -78°C, 24 h.
CN
HN
O O
Bn(H)N
O
NH
tBu
NH
O
N
HO
t-Bu OPiv
(2 mol %)
Kinetic Analysis: HCNKinetic Analysis: HCN
The reaction displays 1st-orderdependance on HCN
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
2929.
.
H
N
+ HCNtoluene, -78°C, 24 h.
CN
HN
O O
Bn(H)N
O
NH
tBu
NH
O
N
HO
t-Bu OPiv
(x mol %)
Kinetic Analysis: CatalystKinetic Analysis: Catalyst
The reaction displays 1st-orderdependance on the catalyst
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
3030.
.
H
N
+ HCNtoluene, -78°C, 24 h.
CN
HN
O O
Bn(H)N
O
NH
tBu
NH
O
N
HO
t-Bu OPiv
(2 mol %)
Kinetic Analysis: ImineKinetic Analysis: Imine
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
The reaction displays saturationkinetics on the imine
3131
k2
H
N
Bn(H)NNH
O
NH
Ot-Bu
N
HO
t-BuOPiv
O
k1
k-1
.
.
H
N
Bn(H)NNH
ONH
Ot-Bu
N
HO
t-Bu OPivO
+
CN
HN
O
+ Catalyst
H
N
Bn(H)NNH
O
NH
Ot-Bu
N
HO
t-BuOPiv
O
HCN
A Mechanistic ProposalA Mechanistic Proposal
K.J. Laidler, Chemical Kinetics 3rd ed., HarperCollins Publishers, New York, 1987
3232
k2'
k1
k-1
.
.
H
N
Bn(H)NNH
ONH
Ot-Bu
N
HO
t-Bu OPivO
+
CN
HN
O
+ Catalyst
large excess
H
N
Bn(H)NNH
O
NH
Ot-Bu
N
HO
t-BuOPiv
O
H
N
Bn(H)NNH
O
NH
Ot-Bu
N
HO
t-BuOPiv
O
HCN
A Mechanistic ProposalA Mechanistic Proposal
K.J. Laidler, Chemical Kinetics 3rd ed., HarperCollins Publishers, New York, 1987
3333
k2
k1
k-1
.
.
H
N
Bn(H)NNH
ONH
Ot-Bu
N
HO
t-Bu OPivO
+
CN
HN
O
+ Catalyst
large excess
H
N
Bn(H)NNH
O
NH
Ot-Bu
N
HO
t-BuOPiv
O
H
N
Bn(H)NNH
O
NH
Ot-Bu
N
HO
t-BuOPiv
O
HCN
A Mechanistic ProposalA Mechanistic Proposal
][
]['2SKwhen
Ck
m
o
K.J. Laidler, Chemical Kinetics 3rd ed., HarperCollins Publishers, New York, 1987
3434
Experimental Distances Experimental Distances Obtained From a Obtained From a ROESYROESY
ExperimentExperiment
3535.
.
2.2 (2.4)
Catalyst 2
NH
Bn(H)N
O
NH
O
N
HO
t-Bu OPiv
t-Bu
2.8 (2.9)2.3 (2.3)
2.3 (2.3)
2.2 (2.2)
2.1 (2.3)
Experimental Distances Experimental Distances Obtained From a Obtained From a ROESYROESY
ExperimentExperiment
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
3636
NN
O
N
O
t-Bu
OPivt-Bu
O
N
H
H H
H
.
.
Another Look at the CatalystAnother Look at the Catalyst
Catalyst 1 adopts a well-defined secondary structure in solution.The transformation obeys Michaelis-Menten kinetics and this implies the reversible formation of an imine-catalyst complex. What role do the four acidic hydrogens play in substrate activation?
3737
H
N Ph 1. 1 mol% catalystHCN, toluene, -78°C
2. TFAA CN
N Ph
O
F3C
NN
O
N
O
t-Bu
OPivt-Bu
O
N
H
H H
H
NN
O
N
O
t-Bu
OPivt-Bu
O
N
Me
H H
HConv: 99%% ee: 95.6%
Conv: 99%% ee: 96.4%
.
.
Pin-pointing the site of Catalyst Pin-pointing the site of Catalyst Binding: Effect of AmideBinding: Effect of Amide
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
3838
H
N Ph 1. 1 mol% catalystHCN, toluene, -78°C
2. TFAA CN
N Ph
O
F3C
NN
OHN
O
t-Bu
OPivt-Bu
O
NH H
Conv: 99%% ee: 88%
.
.
NN
OHN
O
t-Bu
OPivt-Bu
O
NH H
HConv: 99%% ee: 95.6%
Pin-pointing the site of Catalyst Pin-pointing the site of Catalyst Binding: Effect of PhenolBinding: Effect of Phenol
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
3939
Pin-pointing the site of Catalyst Pin-pointing the site of Catalyst Binding: Effect of UreaBinding: Effect of Urea
H
N Ph 1. 1 mol% catalystHCN, toluene, -78°C
2. TFAA CN
N Ph
O
F3C
NN
OHN
O
t-Bu
OPivt-Bu
HO
NMe H
Conv: 46%% ee: 27%
.
.
NN
OHN
O
t-Bu
OPivt-Bu
HO
NH Me
Conv: 83%% ee: 13%
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
4040.
.
Catalyst
+
H
NBn
Catalyst
+
H
15NBn
1H NMR
NN
O
N
O
t-Bu
Bn
OPivt-Bu
HO
NH H
Catalyst
Bn
Isotope (Isotope (1515N) shift experiments N) shift experiments as further proofas further proof
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
4141
N
NHCN (2 eq.)
1. Catalyst 1, toluene, -78°C, 24 h.
2. TFAA+
N
O
F3C
NC
88% yield91% ee
HCN (2 eq.)
1. Catalyst 1, toluene, -78°C, 24 h.
2. TFAA+ No Product Observed
Z-imine
E-imine
.
.
H
An Interesting Observation An Interesting Observation Regarding Imine Regarding Imine StereochemistryStereochemistry
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
4242.
.
Ph
N
OMe Ph
N
MeOE : Z20 : 1
Which Isomer Interacts with Which Isomer Interacts with the Catalyst?the Catalyst?
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
4343.
.
Ph
N
OMe Ph
N
MeOE : Z20 : 1
Observed downfield shiftof imine-methyl resonance
+
Catalyst
+
Catalyst
No observed shift in anyproton resonances
11H NMR Spectroscopic Proof of H NMR Spectroscopic Proof of Imine StereochemistryImine Stereochemistry
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
4444.
.
NH
NH
O
HN O
Ph
OPiv
t-Bu
HO
N
O
N
H
H H
HH
NOENOE
What Is the 3-D Structure of What Is the 3-D Structure of the Catalyst-Imine Complexthe Catalyst-Imine Complex
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
4545.
.
NH
NH
O
HN O
Ph
OPiv
t-Bu
HO
N
O
N
H
H H
HH
3-D Structure of a Catalyst-Imine Complex;consistent with high level calculations
What Is the 3-D Structure of What Is the 3-D Structure of the Catalyst-Imine Complexthe Catalyst-Imine Complex
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
4646
Making Sense of Old Results Making Sense of Old Results with New Informationwith New Information
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
large substituent of imine
H (aldimine) or Me (ketoimine) of the imine
N-substituent of the imine
4747.
.
H
N
Si-face attack
NH
CNH
Making Sense of Old Results Making Sense of Old Results with New Informationwith New Information
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
4848.
.
NH
NH
O
Bn(H)N
O
t-Bu
OPivt-Bu
HO
N
H
N+ HCN
1. Catalyst (1 mol %), toluene, -78°C, 24 h.
2. TFAA
NF3C
O
Ph Ph
CN
% ee = 80%
Re-optimization of the CatalystRe-optimization of the Catalyst
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
4949
Re-optimization of the CatalystRe-optimization of the Catalyst
.
.
NH
NH
O
Bn(H)N
O
t-Bu
OPivt-Bu
HO
N
H
N+ HCN
1. Catalyst (1 mol %), toluene, -78°C, 24 h.
2. TFAA
NF3C
O
Ph Ph
CN
% ee = 80%
NH
NH
O
N
O
t-Bu
OPivt-Bu
HO
N
% ee = 95.8%
Me
Me
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
5050
Re-optimization of the CatalystRe-optimization of the Catalyst
.
.
NH
NH
O
Bn(H)N
O
t-Bu
OPivt-Bu
HO
N
H
N+ HCN
1. Catalyst (1 mol %), toluene, -78°C, 24 h.
2. TFAA
NF3C
O
Ph Ph
CN
% ee = 80%
NH
NH
O
N
O
t-Bu
OPivt-Bu
HO
N
% ee = 95.8%
Me
Me
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
% ee = 97%
Me
Me
P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014
5151
Extention of the Methodology: Extention of the Methodology: Asymmetric Mannich ReactionAsymmetric Mannich Reaction
.
.
HO
O
R1
NH2
R2O
O
R1
HNR3
R2O
OTBS
R1
NR3
5252
Extention of the Methodology: Extention of the Methodology: Asymmetric Mannich ReactionAsymmetric Mannich Reaction
.
.
+
1. Catalyst (5 mol %), toluene, 48 h.
2. TFA, 2 minH R
NBoc
Oi-Pr
OTBS
i-PrO
O
R
NHBoc
2 equiv.
i-PrO
O NHBoc
i-PrO
O NHBoc
Br
i-PrO
O NHBoc
N
95% yield97% ee
93% yield94% ee
99% yield98% ee
NH
NH
S
N
O
t-Bu
Bn
t-But-Bu
HO
N
Me
Catalyst
A.G. Wenzel, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 12964 - 12965
5353
What Effect do the Amide and What Effect do the Amide and Urea Moieties Have on Urea Moieties Have on
Stereoinduction?Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Ph
Strecker: 98 % eeMannich: 97% ee
5454
.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Ph
Strecker: 98 % eeMannich: 97% ee
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
H
Ph
Strecker: 98 % eeMannich: 91% ee
What Effect do the Amide and What Effect do the Amide and Urea Moieties Have on Urea Moieties Have on
Stereoinduction?Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
5555
.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Mannich Reaction is more sensitive to changes in Amide and Urea moieties
Ph
Strecker: 98 % eeMannich: 97% ee
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
H
Ph
Strecker: 98 % eeMannich: 91% ee
NH
NH
O
N
O
t-Bu
OPivt-Bu
HO
N
H
Ph
Strecker: 97 % eeMannich: 81% ee
What Effect do the Amide and What Effect do the Amide and Urea Moieties Have on Urea Moieties Have on
Stereoinduction?Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
5656
What Effect does the Amino What Effect does the Amino Acid Moiety Have on Acid Moiety Have on
Stereoinduction?Stereoinduction?
.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Ph
Strecker: 98 % eeMannich: 97% ee
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
5757
What Effect does the Amino What Effect does the Amino Acid Moiety Have on Acid Moiety Have on
Stereoinduction?Stereoinduction?
.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Ph
Strecker: 98 % eeMannich: 97% ee
NH
NH
S
N
O
i-Pr
OPivt-Bu
HO
N
H
Ph
Strecker: 96 % eeMannich: 51% ee
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
5858
.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Mannich Reaction is very sensitive to changes in amino acid moiety!
Ph
Strecker: 98 % eeMannich: 97% ee
NH
NH
S
N
O
i-Pr
OPivt-Bu
HO
N
H
Ph
Strecker: 96 % eeMannich: 51% ee
NH
NH
S
N
O
Me
OPivt-Bu
HO
N
H
Ph
Strecker: 91 % eeMannich: 22% ee
What Effect does the Amino What Effect does the Amino Acid Moiety Have on Acid Moiety Have on
Stereoinduction?Stereoinduction?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
5959.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
PhNH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Ph
Ph H
N+ HCN
1. Catalyst
2. TFAA Ph CN
N
O
Ph H
NBoc
+1. Catalyst
2. TFA Ph
NHBoc
OiPr
O
OiPr
OTBS
Catalyst A(L-amino acid;(R,R)-diamine)
Catalyst B(L-amino acid;(S,S)-diamine)
What Effect Does the Diamine What Effect Does the Diamine Moiety Have on Moiety Have on
Stereochemistry?Stereochemistry?
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
6060.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
PhNH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Ph
Ph H
N+ HCN
1. Catalyst
2. TFAA Ph CN
N
O
Ph H
NBoc
+1. Catalyst
2. TFA Ph
NHBoc
OiPr
O
OiPr
OTBS
Catalyst A(L-amino acid;(R,R)-diamine)
Catalyst B(L-amino acid;(S,S)-diamine)
Catalyst A: 98% ee (S)
Catalyst A: 97% ee (R)
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
What Effect Does the Diamine What Effect Does the Diamine Moiety Have on Moiety Have on
Stereochemistry?Stereochemistry?
6161.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
PhNH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Ph
Ph H
N+ HCN
1. Catalyst
2. TFAA Ph CN
N
O
Ph H
NBoc
+1. Catalyst
2. TFA Ph
NHBoc
OiPr
O
OiPr
OTBS
Catalyst A(L-amino acid;(R,R)-diamine)
Catalyst B(L-amino acid;(S,S)-diamine)
Catalyst A: 98% ee (S)
Catalyst B: 27% ee (R)
Catalyst A: 97% ee (R)
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
What Effect Does the Diamine What Effect Does the Diamine Moiety Have on Moiety Have on
Stereochemistry?Stereochemistry?
6262.
.
NH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
PhNH
NH
S
N
O
t-Bu
OPivt-Bu
HO
N
Me
Ph
Ph H
N+ HCN
1. Catalyst
2. TFAA Ph CN
N
O
Ph H
NBoc
+1. Catalyst
2. TFA Ph
NHBoc
OiPr
O
OiPr
OTBS
Catalyst A(L-amino acid;(R,R)-diamine)
Catalyst B(L-amino acid;(S,S)-diamine)
Catalyst A: 98% ee (S)
Catalyst B: 27% ee (R)
Catalyst A: 97% ee (R)
Catalyst B: 90% ee (R)
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
What Effect Does the Diamine What Effect Does the Diamine Moiety Have on Moiety Have on
Stereochemistry?Stereochemistry?
6363
A New Catalyst for the A New Catalyst for the Asymmetric Mannich ReactionAsymmetric Mannich Reaction
.
.
+
1. Catalyst (5 mol %), -40°C, 48 h.
2. TFA, 2 minH Ph
NBoc
OiPr
OTBS
i-PrO
O
Ph
NHBoc
2 equiv.
NH
NH
S
N
O
t-BuMe
PhNH
NH
S
N
O
t-BuMe
Ph
Original Catalyst Optimized Catalyst
Orig. Cat.: 95%; 97% ee
Optimized Cat: 100%; 94% ee
N
HO
t-Bu t-Bu
A.G. Wenzel, M.P. Lalonde, E.N. Jacobsen, Synlett.. 2003, 1919 - 1922
6464
Application of the Chiral Application of the Chiral Thiourea Scaffold to DateThiourea Scaffold to Date
.
.
NH
NH
S
N
O N
R1
R2
R4R3
R
N
CN
R'
O
F3C
R
NH
OiPr
OBoc
R''P
HNR'
O
RORO
NH
N
O
R
RNO2
NHBoc
R' R''
R R'
TMSO CN
O2NR'
OR
Strecker
Mannich
Nitro-Mannich
Hydrophosphonylation
Acyl-Pictet-Spengler
Cyanosilylation
Conjugate Addition to Nitro-Alkenes
6565
ConclusionConclusion
A novel Organo-Catalyst was discovered for the asymmetric Strecker reaction.
Analysis of the reaction and catalyst structure led to the optimization of the catalyst.
The catalyst is amenable to derivatization and the general thiourea/amino-acid scaffold was found to be applicable in numerous enantioselective reactions.
6666
AcknowledgmentsAcknowledgments
Prof. Keith Fagnou
Marc LafranceL.C. CampeauJ.P. LeclercMegan ApSimonKayode AkinnusiNicole Blaquiere
Derek SchipperDavid LapointeElisia VillemureSophie RousseauxDaniel ShoreCatherine CrawfordBenoit Liegault