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

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.

How Strong Are Hydrogen How Strong Are Hydrogen Bonds?Bonds?

N NMeMe

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

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

OPO32-

Type II aldolase

OPO32-

Tyr-113

Tyr-209

OGlu-73

O Zn+H

OPO32-

Hydrogen Bonding In Bio-Hydrogen Bonding In Bio-CatalysisCatalysis

Angew. Chem. Int. Ed. 2006, 45, 1520 – 1543.

Hydrogen Bonding in Small Hydrogen Bonding in Small Molecule Catalysis: Phase-Molecule Catalysis: Phase-

Transfer CatalysisTransfer Catalysis

1 (3 mol%), 13% NaOCl

toluene, 0°C

1: Ar = 3,5-Ph2C6H3

T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc. 2004, 126, 6844 - 6845

1) 10 mol% 1toluene, -40°C

2) AcCl,DCM/toluene, -78°C

67% yield92% ee

1: Ar = 1-naphthyl

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

1. Catalyst (5 mol %), -40°C, 48 h.

2. TFA, 2 minH Ph

2 equiv.

t-BuMe

Catalyst

100% yield; 94% ee

t-BuMe

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

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.

The Strecker Reaction The Strecker Reaction DiscoveredDiscovered

Strecker (1850):

lactic acid acetaldehyde

The Strecker Reaction The Strecker Reaction DiscoveredDiscovered

O 1. NH3/H2O

2. HCN (dry)

1. HCl/H2O

2. Pb(OH)2 CO2H

Strecker (1850):

lactic acid acetaldehyde

acetaldehyde -amino nitrile +/- alanine

The Modern Strecker ReactionThe Modern Strecker Reaction

+ HCNR1

HNR3Chiral Catalyst

CNR2 R1

A ent-A

The Modern Asymmetric The Modern Asymmetric Strecker ReactionStrecker Reaction

+ HCNR1

HNR3Chiral Catalyst

CNR2 R1

A ent-A

CO2HR2 R1

CO2HOR

B ent-B

NCHPh2

+ HCNPh

10 mol% 1

toluene, -40°C

Corey's Guandine Catalyst

(% ee = 50 - 86%)

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

The Modern Asymmetric The Modern Asymmetric Strecker Reaction: Corey’s Strecker Reaction: Corey’s

ContributionContribution

NCHPh2

+ HCNPh

10 mol% 1

toluene, -40°C

Corey's Guandine Catalyst

(% ee = 50 - 86%)

HNCHPh2

NPh2HC

E.J. Corey, M.J. Grogan, Org. Lett. 1999, 1, 157 - 160

M R''linker-1 amino

acid linker-2

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

M R''linker-1 amino

acid linker-2

t-Bu t-Bu

Jacobsen’s Approach to the Jacobsen’s Approach to the Asymmetric Strecker ReactionAsymmetric Strecker Reaction

+ TMSCN1. Chiral Lewis Acid Catalyst

2. TFAA CN

Metal ee (%) Conv (%)

Co 0 68

Zn 1 91

Ti 4 30

Catalyst Screening By Parallel Catalyst Screening By Parallel Library SynthesisLibrary Synthesis

+ TMSCN1. Chiral Lewis Acid Catalyst

2. TFAA CN

t-Bu t-Bu

Metal ee (%) Conv (%)

Co 0 68

Zn 1 91

Ti 4 30

None 19 59Ligand alone catalyzes the reaction

with the highest level of % ee!

Optimization by Parellel Library Optimization by Parellel Library SynthesisSynthesis

OPivt-Bu

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

A Novel Organo-Catalyst A Novel Organo-Catalyst RealizedRealized

1. Catalyst 1 (2 mol %), toluene, -78°C, 24 h.

2. TFAA R1 CN

88% yield95% ee

88% yield96% ee

69% yield78% ee

OPivt-Bu

Catalyst 1

M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed. 2000, 39, 1279 - 1281

Application to the Application to the Hydrocyanation of KetoiminesHydrocyanation of Ketoimines

N+ HCN

Catalyst 1 (2 mol %)

toluene, -78°C

97% yield90% ee

99% yield95% ee

98% yield70% ee

OPivt-Bu

Catalyst 1

P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867 - 870

Synthesis of Enantiomerically Synthesis of Enantiomerically Enriched Amino-acids: D-Enriched Amino-acids: D-terttert--

leucineleucine

D-tert-leucine (> $100/g)

P. Vachal, E.N. Jacobsen, Org. Lett. 2000, 2, 867 - 870

Synthesis of Enantiomerically Synthesis of Enantiomerically Enriched Amino-acids: D-Enriched Amino-acids: D-terttert--

leucineleucine

D-tert-leucine (> $100/g)

N1. HCN, Catalyst 1 (2 mol %),

toluene, -70°C, 20 h.

2. Ac2O, formic acid CN

O65% (w/v) H2SO4,

45°C, 20h

HCl (conc), 70°C, 12h

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

HONHBoc

+HBTU, DIPEA

CH2Cl2, r.t.Bn(H)N

tBuTFA/CH2Cl2, r.t.

Bn(H)N

pyridine/CH2Cl2, r.t.

H2N NH2

DIPEA/CH2Cl2, r.t.

Bn(H)N

OPivt-Bu

MeOH, r.t. Catalyst 1

99% yield(over 2 steps)

82% yield(over 2 steps)

Bn(H)N

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

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?

t-Bu OPiv

Acidic Protons

Acidic Proton

+ HCNtoluene, -78°C, 24 h.

Bn(H)N

t-Bu OPiv

(2 mol %)

Kinetic AnalysisKinetic Analysis

P. Vachal, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012 - 10014

Bn(H)N

t-Bu OPiv

(2 mol %)

Kinetic Analysis: HCNKinetic Analysis: HCN

The reaction displays 1st-orderdependance on HCN

Bn(H)N

t-Bu OPiv

(x mol %)

Kinetic Analysis: CatalystKinetic Analysis: Catalyst

The reaction displays 1st-orderdependance on the catalyst

Bn(H)N

t-Bu OPiv

(2 mol %)

Kinetic Analysis: ImineKinetic Analysis: Imine

The reaction displays saturationkinetics on the imine

Bn(H)NNH

t-BuOPiv

Bn(H)NNH

t-Bu OPivO

+ Catalyst

Bn(H)NNH

t-BuOPiv

A Mechanistic ProposalA Mechanistic Proposal

K.J. Laidler, Chemical Kinetics 3rd ed., HarperCollins Publishers, New York, 1987

Bn(H)NNH

t-Bu OPivO

+ Catalyst

large excess

Bn(H)NNH

t-BuOPiv

Bn(H)NNH

t-BuOPiv

Bn(H)NNH

t-Bu OPivO

+ Catalyst

large excess

Bn(H)NNH

t-BuOPiv

Bn(H)NNH

t-BuOPiv

]['2SKwhen

Experimental Distances Experimental Distances Obtained From a Obtained From a ROESYROESY

ExperimentExperiment

2.2 (2.4)

Catalyst 2

Bn(H)N

t-Bu OPiv

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

OPivt-Bu

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?

N Ph 1. 1 mol% catalystHCN, toluene, -78°C

2. TFAA CN

OPivt-Bu

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

2. TFAA CN

OPivt-Bu

Conv: 99%% ee: 88%

OPivt-Bu

HConv: 99%% ee: 95.6%

Pin-pointing the site of Catalyst Pin-pointing the site of Catalyst Binding: Effect of PhenolBinding: Effect of Phenol

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

2. TFAA CN

OPivt-Bu

Conv: 46%% ee: 27%

OPivt-Bu

Conv: 83%% ee: 13%

Catalyst

1H NMR

OPivt-Bu

Catalyst

Isotope (Isotope (1515N) shift experiments N) shift experiments as further proofas further proof

NHCN (2 eq.)

1. Catalyst 1, toluene, -78°C, 24 h.

2. TFAA+

88% yield91% ee

HCN (2 eq.)

1. Catalyst 1, toluene, -78°C, 24 h.

2. TFAA+ No Product Observed

Z-imine

E-imine

An Interesting Observation An Interesting Observation Regarding Imine Regarding Imine StereochemistryStereochemistry

OMe Ph

MeOE : Z20 : 1

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

OMe Ph

MeOE : Z20 : 1

Observed downfield shiftof imine-methyl resonance

Catalyst

No observed shift in anyproton resonances

11H NMR Spectroscopic Proof of H NMR Spectroscopic Proof of Imine StereochemistryImine Stereochemistry

NOENOE

What Is the 3-D Structure of What Is the 3-D Structure of the Catalyst-Imine Complexthe Catalyst-Imine Complex

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

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

Si-face attack

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

Bn(H)N

OPivt-Bu

N+ HCN

1. Catalyst (1 mol %), toluene, -78°C, 24 h.

2. TFAA

% ee = 80%

Re-optimization of the CatalystRe-optimization of the Catalyst

Bn(H)N

OPivt-Bu

N+ HCN

2. TFAA

% ee = 80%

OPivt-Bu

% ee = 95.8%

Bn(H)N

OPivt-Bu

N+ HCN

2. TFAA

% ee = 80%

OPivt-Bu

% ee = 95.8%

OPivt-Bu

% ee = 97%

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

2 equiv.

O NHBoc

95% yield97% ee

93% yield94% ee

99% yield98% ee

t-But-Bu

Catalyst

A.G. Wenzel, E.N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 12964 - 12965

What Effect do the Amide and What Effect do the Amide and Urea Moieties Have on Urea Moieties Have on

Stereoinduction?Stereoinduction?

OPivt-Bu

Strecker: 98 % eeMannich: 97% ee

OPivt-Bu

Mannich Reaction is more sensitive to changes in Amide and Urea moieties

OPivt-Bu

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

OPivt-Bu

Mannich Reaction is very sensitive to changes in amino acid moiety!

OPivt-Bu

N+ HCN

1. Catalyst

2. TFAA Ph CN

+1. Catalyst

2. TFA Ph

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?

OPivt-Bu

N+ HCN

1. Catalyst

2. TFAA Ph CN

+1. Catalyst

2. TFA Ph

Catalyst A: 98% ee (S)

Catalyst A: 97% ee (R)

OPivt-Bu

N+ HCN

1. Catalyst

2. TFAA Ph CN

+1. Catalyst

2. TFA Ph

Catalyst B: 27% ee (R)

OPivt-Bu

N+ HCN

1. Catalyst

2. TFAA Ph CN

+1. Catalyst

2. TFA Ph

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

2 equiv.

t-BuMe

Original Catalyst Optimized Catalyst

Orig. Cat.: 95%; 97% ee

Optimized Cat: 100%; 94% ee

t-Bu t-Bu

Application of the Chiral Application of the Chiral Thiourea Scaffold to DateThiourea Scaffold to Date

R' R''

TMSO CN

Strecker

Mannich

Nitro-Mannich

Hydrophosphonylation

Acyl-Pictet-Spengler

Cyanosilylation

Conjugate Addition to Nitro-Alkenes

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.

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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