The Chiral Urea and Thiourea Scaffold: From Novel Catalyst to Privileged Motif David R. Stuart...

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


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


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!


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


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


2929.

.

H

N


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


3030.

.

H

N


CN

HN

O O

Bn(H)N

O

NH

tBu

NH

O

N

HO

t-Bu OPiv

(2 mol %)

Kinetic Analysis: ImineKinetic Analysis: Imine


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



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


][

]['2SKwhen

Ck

m

o


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


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


3838

H


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


3939

Pin-pointing the site of Catalyst Pin-pointing the site of Catalyst Binding: Effect of UreaBinding: Effect of Urea

H


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%


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


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


4242.

.

Ph

N

OMe Ph

N

MeOE : Z20 : 1

Which Isomer Interacts with Which Isomer Interacts with the Catalyst?the Catalyst?


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


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


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


4646

Making Sense of Old Results Making Sense of Old Results with New Informationwith New Information


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


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


4949


.

.

NH

NH

O

Bn(H)N

O

t-Bu

OPivt-Bu

HO

N

H

N+ HCN


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


5050


.

.

NH

NH

O

Bn(H)N

O

t-Bu

OPivt-Bu

HO

N

H

N+ HCN


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


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?


.

.

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


NH

NH

S

N

O

t-Bu

OPivt-Bu

HO

N

H

Ph





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


NH

NH

S

N

O

t-Bu

OPivt-Bu

HO

N

H

Ph


NH

NH

O

N

O

t-Bu

OPivt-Bu

HO

N

H

Ph





5656

What Effect does the Amino What Effect does the Amino Acid Moiety Have on Acid Moiety Have on


.

.

NH

NH

S

N

O

t-Bu

OPivt-Bu

HO

N

Me

Ph



5757



.

.

NH

NH

S

N

O

t-Bu

OPivt-Bu

HO

N

Me

Ph


NH

NH

S

N

O

i-Pr

OPivt-Bu

HO

N

H

Ph



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


NH

NH

S

N

O

i-Pr

OPivt-Bu

HO

N

H

Ph


NH

NH

S

N

O

Me

OPivt-Bu

HO

N

H

Ph





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?


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: 98% ee (S)

Catalyst A: 97% ee (R)




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 B: 27% ee (R)





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










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


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

The Chiral Urea and Thiourea Scaffold: From Novel Catalyst to Privileged Motif David R. Stuart...

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