OrganocatalysisOrganocatalysis is the acceleration of chemical reactions with a substoichiometric amount of anorganic compound that does not contain a metal atom.Relatively simple organic molecules can be highly effective and remarkably enantioselective Catalysts for a variety of fundamentally important organic transformationsOrganocatalysts are robust, readily available, inexpensive, and non-toxicDemanding reaction conditions, inert atmosphere, absolute solvents, low temperatures,Are usually not required. Classic Organocatalysis: The Knoevenagle condensation

EtO

O O

OEt

+ RCHO

NH

cat.

EtO

O O

OEt

R

Nucleophilic Catalysis and Covalent Catalysis

3° amines and phosphines are good nucleophiles and often function as acylation catalysts:

R

O

X

R3N

R

O

NR3

X-

Nuc:

R

O

Nuc+ NR3

acyl ammonium ion - a superior electrophilewhen compared to the starting material!

Classic Example: DMAP catalysis of alcohol acylation by an anhydride

H3C

O

O

O

CH3

N

N

H3C

O

N

NMe3

acylpyridinium ionpowerful electrophile!

fast fast

ROH

H3C

O

OR+

N

N

+H3C

O

OH

R

O

X

R3P

R

O

PR3

X-

Nuc:

R

O

Nuc+ PR3

Fu’s Planar Chiral DMAP catalyst for Kinetic Resolution

N

Me2N

Fe

Ph Ph

Ph

PhPh

R

HO

R'

racemic

catalyst1% (-) 7

o-Tol

AcO

iPr

Ac2O +

R=Ph, R' =Me, yield 55%, ee=99%R=Ph, R'=Et, yield 54%, ee=99%R=Ph, R'=iPr, yield =52%, ee=97R=Ph, R'=tBu, yield=51%, ee=96%R=2-tolyl, R'=Me, yield=53%, ee=99%

NEt3

Acc. Chem. Res. 2000, 412

Hajos Parrish Reaction:Early Examples of Enantioselective Organocatalysis

JOC, 1974, 1615

N

O

OH

H

L-proline

Electrophilic or nucleophilic activation of a carbonyl by a secondary amine:

The L-proline-mediated enamine catalytic cycle:

N

O

OH

H

L-proline

N

R1

R2

O

OH

Y

X

electrophile(aldehyde, ketone,azodicarboxylate)

N

R1

R2

O

OY

X

H

N

R1

R2

O

O-Y

X

H

+H2O

R1

O

R2

X

YH

R1

O

R2

O N

R1 R2NH

R1 R2

+H+

N

R1 R2

-H+

ACIEE, 2004, 5138

JACS, 2002, 6798

ACIEE, 2005, 2186

Org. Lett, 2005, 1181

Examples of Proline-Catalyzed Aldol Reactions

O

H

Me

+

O

H

Me

Me

N

O

OH

H

10 mol%

DMF, 4°C

O

H

Me

OH Me

Me

88%, 97%ee

special conditions required to avoid self-condensation: slow addition, 4°C

O O

O

+

H

O

R

L-proline(20 mol%)

O O

O OH

R

R=CH2OAc; 60%; de>88%; ee=98%

R=iBu; 75%; de=82%; ee=98%

R=Ph; 80%; de=0%; ee=97%

Dynamic Kinetic Resolution:

S

O

+

S

O

OHC

OL-prolinewet DMSO

S

O

S

O OOH

56%, >98%ee

Examples of Proline derivatives in Aldol Catalysis

N

O

OH

H

10 mol%

H2O, 20°CR2 R3

O

R1CHO +

DPSO

R1

O

R3

OH

R2

R1=Ph, R2, R3=(CH2)3; 78%; de=86%; ee=99%

R1=Cy, R2, R3=(CH2)3; 76%; de>90%; ee>99%

R1=i-Pent, R2, R3=(CH2)3; 54%; de>90%; ee>99%

note: despite the variety of aldol acceptorspossible, the range of donors has remained narrow

ACIEE, 2006, 958

occurs in water.

Proline Amides:

N

O

NHH

2 mol%

neat, -25°R2

O

R1CHO +R1

O

R3

OH

R2

CO2Et

CO2Et

OH

R1=Ph, R2=H; 68%, ee=98%

R1=t-Bu, R2=H; 71%; ee>99%

R1=Cy, R2=H; 80%, ee=00%

JACS, 2005, 9285

See Also:

N

O

NHH

N

O

Bn

NH

N

O

NHH

SO2Me

Synlett, 2006, 2419 Org. Biomol. Chem, 2005, 84

NH

HN

O

O

NH

NH

BINAM

Tetrahedron Asym. 2006, 729

N

H

N N

N

HN

30 mol%

R3

O

+

O

X

R1 DMF, -35°CO

O

OH

R1

O

R2

X

R1=R2=X=H, 83%, 83%ee

R1=R2=H, X=NO2; 75%; ee=84%

R1, R2=(CH2)3, X=H 43%, 80%ee

TL, 2006, 3383

Non-Proline Catalysts of the Aldol

X X

O

R1 R2

+ R2CHO

amino acid(30 mol%)

X X

O

R1 R2

OH

R2

DMSO, H2O

20°C

L-Alanine

R1=H, R2=p-NO2C6H4, X=CH2; 95% de=88%, ee=99%

R1=Me, R2=CH2OBn, X=O; 41%; de>90%; ee=99%

L-valine:

R1=H, R2=p-ClC6H4, X=CH2; 98%; de=94%, ee>99%

L-isoleucine

R1=H, R2=pClC6H4, X=CH2; 82%, de=82%, ee>99%

L-serine

R1=H, R2=pClC6H4, X=CH2; 80%, de=72%, ee>99%

ACIEE, 2005, 7028TL, 2006, 6657

Dipeptides:

R1 R2

O

+ R3CHO

Catalyst(30 mol%)

R1 R2

O OH

R3

DMSO, H2O

20°C

L-ala-L-ala

R1, R2= (CH2)3, R3=p-NO2C6H4, 73%, de=78%, ee=91%

R1, R2 =OCH2O, R3=iPr, 50%, de=34%, ee=97%

L-ala-L-phe

R1, R2 =OCH2O, R3=p-NO2C6H4, 88%, de=66%, ee=99%

Chem, Eur. J, 2006, 5383

see also: Tetrahedron Asym. 2005, 1947; JOC, 2005, 7418tripeptides: Org. Lett, 2005, 1101

Morita-Baylis Hillman ReactionO

R1

Nu

O-

R1

Nu

R2CHOO

R1

Nu

O-

R2

H

O

R1

OH

R2 *

Asymmetric Morita Baylis Hillman:

O

+ RCHO

catalyst

(10mol%)

L-Proline

(10mol%)

CHCl3, 25°C

OOH

R

catalyst=

BocHN

O

N

N

NH

heptapeptideN

N

N

RHN

O

O

O

H

NR

O

bifunctional catalysis-rigidified substratethrough intramolecular hydrogen-bonding

O O

HH

proline (10 mol%)

imidazole (10 mol%)

CH3CN 25°C

O

H

OH

with L-proline: 73%ee (R)with D-Proline: 74% ee (S)

TL, 2005, 8899

Tetrahedron, 2006, 11450

Asymmetric Mannich Reactions

O

H

R

+

N

H CO2Et

PMPL-proline5mol%

dioxane, RT

O

H

R

NHPMP

CO2Et

d.r up to 19:1up to 99%ee

JACS, 2000, 9336JACS, 2002, 827

O

R2R1

+ ArNH2 + CH2O

L-proline

(10mol%)

H2O, DMSO

O

R2R1

NHAr

Ar=p-MeOC6H4, R1, R2=(CH2)3; 90%, ee>99%

Ar=Ph, R1, R2=(CH2)3; 92%, ee>99%

Tetrahedron 2006, 357TL 2005, 3363.

see also:

NH N

N

NN

H

Org. Biomol. Chem. 2005, 84

NBoc

H Ar

O

H

R

+

L-proline5mol%

DMF, 4°C

O

H

R

NHBoc

Ar

TL 2007, 421.

Ar=Ph, R=Me: 85%, de>90%; ee>99%Ar=Ph, R=allyl: 75%, de>90%, ee=98%

Imine formed in situ:

Syn vs. anti adducts in Asymmetric Mannich reactionsProline leads to syn adducts, but 3-pyrrolidine carboxylic acids give anti-adducts

N

CO2H

N CO2H

R1

R2

N

R1

R2

O

OH

N

PMP

CO2R3

H

O

R1 CO2R3

NHPMP

R2

syn

R2

An Alternate Amide rotamer favored in each case:

N

R2

O

O

H

N

CO2R3

PMP

O

H CO2R3

NHPMP

R2

anti

O

R1

R2

+

N

H CO2R3

PMPNH

R4

CO2H

(20 mol%)

O

R1 CO2R3

NHPMP

R2

R1=H, R2=iPr, R3=Et, R4=Me, 85%, de=96%, ee=99%

R1,=H, R2=n-pent, R3=iPr, R4=Me, 85%, de=92%, ee=>99%

R1, R2=(CH2)4, R3=allyl, R4=H, 95%, de>98%, ee=95%

DMSO, 20°C

see also:

NH

Ph

Ph

OTMS

Chem. Commun. 2006, 1760

anti -selective catalystdiphenyl prolinol

JACS, 2005, 18296TL, 2006, 7417JACS, 2006, 6804

Michael Additions - Asymmetric

Electrophilic catalysis-activation of the acceptor

O

R4

R1

R2 R3

+NH

R* R* H+

N

R4

R1

R2 R3

R* R*

+ H2O

Nu

N

R4

R1

R2 R3

R* R*

Nu

E+N

R4

R1

R2 R3

R* R*

Nu

EH2O

O

R4

R1

R2 R3

Nu

E

+NH

R* R*

NH

Ph

Ph

OTMS

O

HR1

+

O

R2(5 mol%)

4°C

OH

OH

CO2Et

O

R2

O

H

R1

R1, R2 Yield ee

Me, Me 82 97

Me, Et 70 99

iPr, Et 60 99

Bn, Et 87 >95

Org Lett, 2005, 4253

O

HR1

+

O

R2 (20 mol%)

O

R2

O

H

R1

R1, R2 R,R Yield ee

Me, Me (CH2)4 84 90

Et, Et (CH2)4 79 92

Et, Me Me, Me 85 81

JACS, 2005, 32JACS, 2005,11598

NH

NO

R

R

Bn

additive: 20mol%

OH

OH

CO2Et

nucelophilic enamines of iminium ion activation? Bronsted activation of carbonyl oxygen via hydrogen-bonding to phenol additive

A clear-cut case of iminium activation:

O

R1

H+ RO2C CO2R

NH

Ph

Ph

OTMS

10 mol%

EtOH

O

R1

H

CO2R

CO2R

R1=Ph, R2=Bn 91%ee

R1=Ph, R2=Me, 94%ee

R1=p-Tol, R2=Bn, 88%ee

ACIEE, 2003, 685ACIEE, 2006, 4305

see also:

NH N

H

N

NN Org.Lett, 2005, 3897

Chem. Commun, 2005, 5346Org. Biomol. Chem. 2006, 2039

Asymmetric Michael Additions

MacMillan Imidazolidinone - especially effective for Diels-alder and Michael additions

H3C O+

NH

NH

O

CMe3

Ph

H+

H2O N

NH

O

CMe3

Ph

H3C

Formation of iminium ion creates a much lower lying LUMO relative to that found in the starting enone

JACS, 124, 1172 (2002).

Nuc-

N

NH

O

CMe3

Ph

H3C Nuc

H+

H2ONH

NH

O

CMe3

Ph

O

H3C Nuc

H+

NH

NO

CMe3Ph

OX

Electron-rich nucleophiles

NR2

NH N

H

NO

Ph

O

HX

84-92%ee

NH

O

HX 87-93%ee

JACS, 2001, 4370JACS, 2002, 7894

R2N

Tl, 2005, 2437

CHO

+

HN

I

NH

NO

Ph

O

10-20 mol%

HN

ICHO

84%ee

JOC, 2005, 3473

Asymmetric Michael Additions

Asymmetric Michael Additions

NH

NO

CMe3Ph

TMSO

R1

+R2

CHO

30 mol%

tBuOH, iPrOH 0°C

OHC

R2 O

R1

R1=R2=Ph; 75%, 90% ee

R1-pTol, R2=Ph; 62%, 95%ee

R1=Ph, R2=p-CN-C6H4; 59%, 90%eeOrg Lett. 2005, 1637

O O

R1 R3

R2

+NBn

O

O

N

OMe

N

OH

(10-20 mol%)

CH2Cl2, -60°CNBn

O

OR2

O

R3

O

R1

R1, R2=(CH2)3, R3=OEt, de=74%, ee=98%

R1=Me, R2=Bn, R3=OEt, de=54%, ee=85%

R1, R2=O(CH2)2, R3=Me; de=96%, ee=93%

ACIEE, 2006, 4966see also: JACS, 2005, 8948.

cinchona alkaloid catalysts:

NH

Ar

Ar

OTMS

CHO

OH

R1

+ R2

CHO

10 mol%

CH2Cl2Ar=3,5-(CF3)2C6H3

O

CHO

R2

R1=H, R2=Ph; 60%ee

R1=OMe, R2=nPr, 90%ee

R1=H, R2=nPr, 69%ee

R1

Asymmetric Diels-AlderChiral secondary amines catalyze [4+2] cycloadditions through the revesible formation of iminium intermediatesfrom an unsaturated aldehyde and the catalyst

+

R1

O

R3

NH

NO

Ph

O

OR2

R1

endo:exo=6.5-21:161-92%ee

20 mol%

H2O, 0°C

JACS, 2002, 2458

intramolecular Diels-Alder Reactions:

X CHO

R2

R1 NH

NO

Ph

20 mol% X

R1

R2

CHO

H

R1=H, R2=Ph, X=CH2, de=>90%, ee=93%

R1=Me, R2=Ph, X=CH2, >90%de, 94%ee

R1=H, R2=OBn, X=CH2, 99%de, ee=72%

JACS, 2005, 11616

O

Et

+

R1

R2

NH

NO

Ph

O

20 mol%

EtOH, -30°C R2

CO2Et

R1100:1-200:1 endo:exo

79-82% yield85-98% ee

JACS, 2002, 2458

n n

Bronsted Acid Catalysis

R

O

H

+

O

10 mol% cat.

Et3P

O

R

OH

67-96% ee

OH

OHcatalyst:

JACS, 2003, 12094

NMe2

TBSO

+

O

H R

O

O

OH

OH

ArAr

Ar Ar

TBSO

NMe2

R CH3COCl O R

52-97% yield96:4-99:1 er

Nature, 2003, 146

10 mol%Ar-1-nap

Morita Baylis Hillman Reaction

Diels-Alder Reaction

Aza Henry:

Ar

N

Boc

+

R

NO2

10 mol% cat.

Ar

HN

Boc

R

NO2

N

N

HN

NH

Hcatalyst:

JACS, 2004,3148

OTf-

Lewis Basic Organocatalysis: Lewis Acid Activation

R1

R2

SiCl3 +Ar

O

H

Ar

OH

R1 R2

80-96%eesyn:anti = 1:99 - 99:1

P

ON

N NMe

NMe

H

H

P

O N

N

H

H

5 mol%

CH2Cl2, iPrNEt

-78°C 8-10h

57-92%

JACS, 2001, 9488

SiCl3+

R

O

H

NO-

OMe

5 mol%

1eq. iPr2NEt

R

OH

60-85%5-96%ee

ACIEE, 2003, 3674R=Ph, cinnamyl

2-furyl, 4 Cl-Ph,

4-NO2Ph

D

L

L

L

+ A

XX

X

D

L

L

L

A

X

X

X

ate-complex of acid

D

L

L

L

A

X

X

L-

Lewis base Lewis Acid

The Stetter Reaction uses thiazolium salts as acyl anion equivalents:

O

H +O

H

Et3N

N

S H

H3C

HO(H2C)2

Rcat. O

O

H

X-

An early example of enantioselective Stetter Reaction

Helv. Chim. Acta. 1996, 1899

Lewis Basic Carbene Catalysis

R1

O

H

+

X

N

R

X

N

R

OH

R1

O

X

CO2R

R1

20 mol%

2 eq. Et3N

toluene, 25°C

O

N

N

N

PFP

X

O

R1

CO2R

92-96% yield89-99% ee

JACS, 2004, 8876

R=H or Br

X=O, S, or CH2

R1=Et, Me

R2=Me, Et