The Chiral Urea and The Chiral Urea and Thiourea Scaffold: From Thiourea Scaffold: From Novel Catalyst to Novel Catalyst to Privileged Motif Privileged Motif David R. Stuart University of Ottawa Center for Catalysis Research and Innovation Nov. 23, 2006
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The Chiral Urea and Thiourea Scaffold: From Novel Catalyst to Privileged Motif David R. Stuart University of Ottawa Center for Catalysis Research and Innovation.
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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.”
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
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