Asymmetric Organocatalysis

By Chiral Brønsted Acids :

Focus on Chiral Phosphoric Acids

Maryon Ginisty

Pr. A.B. CharetteLiterature Meeting - November 6th, 2007

Role in the formation of prebiotic key building blocks, such as sugars

Introduction and spread of homochirality in living organisms.

Enantiomerically enriched amino acids L-Alanine and L-Isovaline: Present up to 15 % ee in carbonaceous meteorites Catalysis of dimerization of glycal and aldol-type reaction between glycal and formaldehyde.

Term introduced in 1900 by Ostwald 1 to distinguish small organic molecules-mediated reactions from enzymatic or inorganic catalyzed reactions.

Organocatalysis: an Old Story…

« Acceleration of chemical reactions through the addition of a substoechiometric quantity of an organic compound which does not contain a metal atom »

OHO

OHOH

H

O

H

+ Sugar derivatives

1) Ostwald W. Z. Phys. Chem. 1900, 32, 509.

+

NMe

NH (7 mol%)

MeOH/ H2O

99 %

O

O

Bn

Ph

CHO +

CHO

Ph

exo

93 % ee

endo

93 % ee

1904-1908 First publications= Desymmetrization of prochiral substrates by alkaloids1,2

1932 Early treatise on « organic catalysis » : reaction mechanism, kinetics and catalyst optimization for amine-catalyzed decarboxylations3

2000-2006 Increase in publications containing the words « organocatalysis »,« organocatalytic » or « organocatalyst »

LIST - Cross-aldol reactions between acetone and different aldehydes catalyzed by the simple proline4

MacMILLAN- Diels-Alder reactions activated by chiral imidazolidinium salts5

Organocatalysis: Development and Fast Evolution

1) Marckwald W. Ber. Dtsch. Chem. Ges. 1904, 37, 349. 2) Bredig G.; Fajans K. Ber. Dtsch. Chem. Ges. 1908, 41, 752. 3) Langenbeck W. Angew. Chem. 1932, 45, 97. 4) List B.; Lerner A.; Barbas III C. F. J. Am. Chem. Soc. 2000, 122, 2395. 5) Ahrendt K. A.; Borths C. J.; MacMillan D. W. C. J. Am. Chem. Soc. 2000, 122, 4243.

+

O O NH

CO2H

(30 mol%)

DMSO/ acetone

97 %

O OH

96 % ee

0

50

100

150

200

250

300

350

2000 2001 2002 2003 2004 2005 2006

Year

Nu

mb

er o

f p

ub

licat

ion

s

Scope Typical transition metal-mediated coupling reactions: Suzuki, Sonogashira, Ullmann, Heck-type and Tsuji-Trost reactions

Organocatalysis Features Evolved essentially from the ligand chemistry of organometallic reactions

The most effective organocatalysts are ligands developed for metal-mediated enantioselective catalytic reactions.

More closely related to enzyme- or antibody-catalyzed reactions than to organometallic processes.

The organocatalysts often show some characteristic features of bioorganic reactions (e.g. Michaelis-Menten kinetics)

Organocatalysis: Reaction Characteristics

H

N

CN

NF3C

O

1/ Catalyst, toluene,TBSCN

2/ TFAA

O

M

N

R R'

O

R''

linker 1amino acid linker 2 N

R R'

N

M

O

R''

tridentate Schif f

base complexNH

OHN

O

NH

NH

O

R2

N

HO

tBu tBu

5

R2

Library Size : 12 Compounds

Metal (M)

M None Ti Mn Fe Ru Co Cu Zn Gd Nd Yb Eu

ee (%) 19 4 5 10 13 0 9 1 2 3 0 5

Conversion (%) 59 30 61 69 63 68 55 91 95 84 94 34

Organocatalysis: a New Orientation of Organometallic Processes

Sigman M. S.; Jacobsen E. N.; J. Am. Chem. Soc. 1998, 4901.

Organocatalysis: Evidence of Lewis Acid Efficiency

CCl3CO2H

Hexanes or Benzene

+

O

O

O

Wasserman A. J. Chem. Soc. 1942, 618.

Brønsted Acid Catalysis

Lewis Acid Catalysis

AlCl3

Benzene, 1 h 30

+ O

O

O

O

O

O

O

O+

HOH5C6

Yates P.; Eaton P. J. Am. Chem. Soc. 1960, 4436.

« Third order reaction »

≈ 3200 x increase

Metal Lewis Acid

Product InhibitionStrong bonding between LA and basic sites

Limited use in aqueous media

Stoichiometric amountdue to presence of a basic moietyon the product that binds the LA

High priceToxicity

Product contamination

Difficult to immobilize onpolymers or other stationary

phases for easier catalyst removaland flow processes without washout

Lewis Acids vs Brønsted Acids: Application to Asymmetric Catalysis

Metal-free catalysis through hydrogen bonding interactions offers attractive alternatives to metal-catalyzed reactions.

Lewis Acids vs Brønsted Acids: Application to Asymmetric Catalysis

M

Y

YY

Y

X

H

X

A L**L

X XMetal Lewis Acid Brønsted Acid

Y = O, P, N, S or Y4 = diene

Organizational role of the metal by translating chiral information and activating the reagents

Multiple coordination opportunities available

Catalytic activity relative to the formation of a donor-acceptor complex

Tunable electronic properties between electron-deficient metal sites and excess electron densities Tunable steric parameters

TS formed by passive interactions (hydrophobic, VDW, electrostatic…) or dynamic interactions (between cata--lysts and substrates at the reaction centers)

One valence orbital and spherical symmetry

Catalytic activity relative to the establishment of anionic hydrogen bond (1-6 kcal/ mol)

Supramolecular design required for steric control: formation of rigid three-dimensional structures

Contribution to affinity and selectivity of molecular recognition

Brønsted Acids : Powerful Catalysts for Addition Reactions to C=O, C=C and C=N Double Bonds

R1 H

XH Y

X = O, NR2R1 H

XH

Y

R1 H

XH

YH

Y

Brønsted acid catalysisSingle hydrogen bonding Double hydrogen bonding

Monofunctional and bifunctional thiourea catalysts

TADDOL derivatives

BINOL derivatives

Phosphoric acids

Diene Dienophile Temp. (°C)

Time % Product Formation Product(s)

Without BWith B

(mol. equiv. B)

r.t.10

min3 90 (0.4)

r.t.30

min10 76 (0.4)

55 2 h 16 97 (0.5)

55 45 h 21 95 (0.5)

55 48 h 5 60 (0.5)

55 120 h 7 10 (0.5)

Early Bidentate Catalysts

OHOH

X X

X= H, NO2

OHOH

NO2 NO2

A

B

Applications in Diels-Alder Reactions

CH3

O

H

O

H

O

H3C

H

O

H3C

H

O

H3C

CH3

O

COCH3

CHO

CH3

CHO

CHO

CH3

H3C

H3C CHO

CH3

H3C

H3C CO2CH3

Kelly T. R.; Meghani P.; Ekkundi V. S. Tetrahedron Lett. 1990, 31, 3381.

Entry Solvent Additive trans/ cis (yield, %)

1 benzene - 2.5/ 1 (60)

2 DCM - 5.5/ 1 (62)

3 EtOH - 4.9/ 1 (87)

4 AcOH - 6.7/ 1 (51)

5 CF3CH2OH - 8.1/ 1 (83)

6 benzene A (0.2 equiv) 3.7/ 1 (57)

7 benzene A (0.6 equiv) 5.8/ 1 (72)

8 benzene A (1.0 equiv) 7.0/ 1 (81)

Early Bidentate Catalysts

Applications in Allylation Reactions of Phenylseleno Sulfoxide

NO2NO2

O O

C3H7C3H7

H HO

OH H

O OHH

trans/ cis : 6 .6/ 1

SSePh

O

SnBu3 S

O

S

O

+

S

O

trans cis

NO2

N

H

O

N

H

NO2

C8H17O2C CO2C8H17

O

S

H

1 Severance D. L.; Jorgensen W. J. Am. Chem. Soc. 1992, 114, 10966. 2 Curran D. P.; Kuo L. H. J. Org. Chem. 1994, 59, 3259.

A :

Jorgensen’s hydration model

Bidentate Catalysts : a Short Lineage

R2R2

O O

R1R1

H HX

RR

R1

N

H

X

N

H

R1

R2 R2

X

RR

a : R1 = NO2, R2 = H, X = O

Etter urea catalyst

b : R1 = R2 = CF3, X = S

Schreiner thiourea catalyst

RN

O

N N

StBuMe

N

OCOtBu

HO

tBu

H HX

RR

1990

1994-2003

1998

T. R. KellyP. R. Scheiner

M. C. EtterD. P. Curran

E. N. Jacobsen

1 Etter M. C.; Reutzel S. M. J. Am. Chem. Soc. 1991, 113, 2586. 2 Schreiner P. R.; Wittkopp A. Org. Lett. 2002, 4, 217.

Catalysis by Hydrogen Bond

Monofunctional Thiourea and Urea Catalysts

Asymmetric hydrocyanation of N-allyl- or N-benzylaldimines (Strecker reaction)

HCN, toluene, -78°C

85-99 % (70-99 % ee)

R1 R2

N R3R1 = alkyl, arylR2 = H, MeR3 = aryl, alkyl, heteroatom

R1

R2

HN R3

CN

1c (1 mol%)

High degree of generalityHigh enantioselectivity

RN

O

NH

NH

YtBuMe

N

X

HO

tBu1a : R = Bn, X = OCOtBu, Y = O

1b : R = Bn, X = tBu, Y = O

1c : R = Me, X = OCOtBu, Y = S

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

Michaelis-Menten kinetics 1st order dependance on catalyst and HCN Saturation kinetics with respect to the imine

Reversible formation of an imine-catalyst complex

Synthesis of a series of analogues of the catalyst Only urea protons essential for catalytic activity

NMR studies of a model solution of a ketoimine derivative Downfield shift of the Z-imine methyl group exclusively Interaction between catalyst and Z-isomer

Me

N

PMB

E: Z = 20: 1

TBS > TMS

Better reactivity

and catalyst loading

Entry R imine Catalyst Temp. (°C) Yield (%) ee (%)

1 Ph 1a (10 mol%) r.t. 92 47

2 Ph 1b (5 mol%) r.t. 93 68

3 Ph 1b (5 mol%) -40 90 91

4 Ph 1c (5 mol%) -40 95 97

Catalysis by Hydrogen Bond

Asymmetric Mannich-type reaction of N-Boc aldimines with silylketene acetals

Goal Catalyst capable of activating imines toward nucleophilic attack, yet resistant to inhibition by the strongly Lewis-basic amine products

68-98 % ee

R H

NBoc

NH

+OR'

OTBS 1/ 1b (5 mol%), toluene

2/ TFA R

Boc

OR'

O

BnN

O

NH

NH

XtBuR1

N

R2

HO

tBu

1a : R1 = H, R2 = OCOtBu, X = O

1b : R1 = H, R2 = OCOtBu, X = S

1c : R1 = Me, R2 = tBu, X = S

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

R’ = Me → Et → iPr

reaction rate

R’ = tBu

ee (51 %)

Monofunctional Thiourea and Urea Catalysts

N N

S

F3C

CF3 CF3

CF3

H HO

HPh

N N

S

F3C

CF3 CF3

CF3

H HO

R3N

O

H H

NN

Ar

S

Ph

HOHHN

NS

Ar

R3N

N N

S

F3C

CF3 CF3

CF3

H HO

H

Ph

O

R3N

O

Ph

OH

R

R3N + 1b

ArAr

33-99%, 22-61 % ee

R H

O

OH

+(40 mol%) R

O

F3C

CF3

HN NH

S

HN

S

HN CF3

CF3

O

amine, neat, r.t., 72 h - 120 h

Catalysis by Hydrogen Bond

Monofunctional Thiourea Catalysts

Baylis-Hillman reaction

1a : X = O

1b : X = S

NH

NH

X

F3C

CF3 CF3

CF3

Sohtome Y.; Tanatami A.; Hashimoto Y.; Nagasawa K. Tetrahedron Lett. 2004, 45, 5589.

NMR studies

Interaction of the thiourea 1b

with both the enone and aldehyde

1b involved in 2 steps of the

BH reaction

Hetero-Michael reaction

Aldol reaction

Aldehyde Yield (%)ee (%)

88 33

38 30

88 19

99 33

63 60

72 90

Catalysis by Hydrogen Bond

Bifunctional Thiourea Catalysts

33 - 99 % (19 - 90 % ee)

R H

O

OH

+A (40 mol%) R

O O

DMAP , neat, -5 °C, 72 h

NH

NH

S

CF3

CF3NHS

NH

CF3

F3C

A

Sohtome Y.; Tanatami A.; Hashimoto Y.; Nagasawa K. Tetrahedron Lett. 2004, 45, 5589.

H

O

H

OCF3

H

O

F3C

H

O

CH3(CH2)5

H

O

H

O

F3C

O

H H

NN

Ar

S

Ph

HOH

HN

NS

Ar

R3N

O

R

OH

R

Baylis-Hillman Reaction

Nagasawa’s Catalyst

Catalysis by Hydrogen Bond

Bifunctional Thiourea Catalysts

Michael Reactions of Malonates to Nitroolefines

Ph+ R'O2C CO2R'

catalyst, toluene, r.t.

Ph

R'O2C

NO2

NO2

CO2R'

O

NH

NH

StBu

NMe2

F3C

CF3

Okino T.; Hoashi Y.; Furukawa T.; Xu X.; Takemoto Y. J. Am. Chem. Soc. 2005, 127, 119.McCooey S. H.; Connon S. J. Angew. Chem. Int. Ed. 2005, 44, 6367.Ye J.; Dixon D. J.; Hynes P. S. Chem. Commun. 2005, 4481.

X

O

N N

StBu

NH H

O ON

Ph

R2R1

HO

EtO OEt

O

Takemoto : R’ = Et72-99 % yield, 81-93 % ee

NH

NH

S N

Et

N

MeO

H

CF3

F3C

Connon : R’ = Me75-99 % ee

(10 mol%)

(2-5 mol%)

O

NH

NH

StBu

F3C

CF3

N

Et

N

MeO

H

Dixon : R’ = Me82-97 % ee

(10 mol%)

Takemoto’s Transition State

9

8

R Yield (%) ee (%)

Ph 92 47

4-MeOC6H4 93 68

4-MeC6H4 90 91

2-thienyl 95 97

Me 70 98

nBu 78 95

Catalysis by Hydrogen Bond

Bifunctional Thiourea Catalysts

Michael Reactions of Ketones to Nitroolefines

Huang H.; Jacobsen E. N. J. Am. Chem. Soc. 2006, 128, 7170.

R+

A (10 mo%), PhCO2H (10 mol%),

toluene, r. t.NO2

NO2

O

RO

BnN

O

NH

NH

StBuMe

NH2

A

R+ R2

Catalyst

toluene, r. t.NO2

O

R1

O2NR2

O

R1

R

O2NMe

O

Me

Ph

O2N(CH2)4CH3

O

Me

Ph

97 % ee, 2: 1 rr,15: 1 dr, 53 % y

(+ regioisomer: 95 % ee, 25 % y)

98 % ee, > 30: 1 rr,20: 1 dr, 50 % y

O2N

OPh

O2N

O

97 % ee, > 30: 1 rr,71 % y

(+ r% ee, 25 % y)

96 % ee, 4: 1 rr,50 % y

O2N

O

97 % ee, > 30: 1 rr,56 % y

BnN

O

N N

StBuMe

HNH HO2N

R

R2

R1

BnN

O

N N

StBuMe

HNH HO2N

R

R2

R1Disfavored E-enamine

Favored Z-enamine

= poor catalysts

⇒ hydrogen bond crucial for the catalysis

O

O

O

O

OMe

O

O

O

O

70 %, > 99 : 1 er 68 %, 97 : 3 er 69 %, > 99 : 1 er 97 %, 97 : 3 er

O

O

O

O

O

O

O

O Ph

68 %, 97 : 3 er 67 %, 96 : 4 er 64 %, 93 : 7 er 52 %, 97 : 3 er

CF3O

Catalysis by Hydrogen Bond

TADDOL Derived Catalysts

O

O

OH

Ar Ar

OH

Ar Ar

Ar = naphtylTMSO

NMe2

+ HR

O

A (20 mol%)

toluene, - 78 °C or - 40 °C

O

TMSO

NMe2

R

Ac-Cl,

DCM / toluene- 78 °C, 15 min

O

O R

Huang Y.; Unni A. K.; Thadini A. N.; Rawal V. H. Nature 2003, 424, 146.

Without A : no reaction

O

O

OMe

Ar Ar

OH

Ar Ar

O

O

OEt

Ar Ar

OEt

Ar Ar

A

Catalysis by Hydrogen Bond

TADDOL Derived Catalysts

Ar =

CH3

CH3

F

OH

OH

Ar Ar

ArAr

Unni A. K.; Takenaka N.; Yamamoto H.; Rawal V. H. J. Am. Chem. Soc. 2005, 127, 1336.

TBSO

NMe2

+ HR

O

BAMOL (20 mol%)

toluene, - 78 °C or - 40 °C

O

TBSO

NMe2

RAc-Cl,

DCM / toluene- 78 °C, 15 min

O

O R

BAMOL

Axial Chirality

Tweak of the chiral environment

O

O

O

O

70 %, > 98 % ee84 %, 98 % ee

69 %, > 98 % ee67 %, 97 % ee

O

O

O

O

O

67 %, > 92 % ee96 %, > 99 % ee

64 %, > 86 % ee99 %, 84 % ee

1 : 1 association between BAMOL and PhCHOPresence of an intramolecular H-bondPresence of an intermolecular H-bond to the carbonyl O of PhCHO

TADDOL Catalysis: C=O activation through a single-point H-bond

Ar = Ph

OH O

Ph

88 % (90 %ee)

OH O

72 % (96 %ee)

OH O

71 % (96 %ee)

OH O

82 % (95 %ee)

OH O

40 % (67 %ee)

OH O

O

O

70 % (92 %ee)

OH

OR

X

X

1: R = H, X = H2: R = H, X = Br3: R = H, X = Ph

7: R = CH3, X = H8: R = CH3, X = Br

4: R = H, X =

5: R = H, X =

6: R = H, X =

H3C

CH3

H3C

CH3

CH3

CF3

CF3

Catalysis by Hydrogen Bond

BINOL Derived Catalysts

Morita-Baylis-Hillman Reaction

69-84 % (32 - 88 % ee)

H

O

OH

+Cat (2 mol%)

O O

Et3P, THF, 0 °CPh

Ph

Catalyst Yield (%) ee (%)

- 5 -

(R) -BINOL 74 32

1 73 48

2 73 79

3 69 86

4 9 31

5 70 88

6 84 86

7 43 3

8 15 3

Bulky substituents on the 3,3’-positions essential for excellent ee

Mesityl group restricting rotation about the biaryl bond of the 3-substituent, prerequisite for catalysis

Removal of one BA equiv : no enantioselectivity and catalytic activity

Best results with 5 and 6

McDougal N. T.; Schaus S. E. J. Am. Chem. Soc. 2003, 125, 12094.

R

O

O

R

PO

OH

Chiral Phosphoric Acids: A New Class of Strong Brønsted Acids

Strong Brønsted Acid relied on one single proton(pKa (EtO)2PO3H = 1, 39)

Hydrogen bonding with the substrate without loose ion-pair formation

Tetradentate P(V)Formation of a rigid ring structure

Prevent free rotation at of the P center

Transfer of stereochemical information to the substrate

Lewis basic phosphoryl moiety

Bifunctional catalysis (electophilic and nucleophilic activations)

Connon S. J. Angew. Chem. Int. Ed. 2006, 45, 3909.

Catalyst t (h) Yield (%) ee (%)

1a 22 57 0

1b 20 100 27

1c 27 100 60

1d 46 99 52

1e 4 96 87

Phosphoric Acid Catalysis : Mannich-Type Reactions

Akiyama’s Work

1/ Ar-X, Pd0

2/ BBr3,

3/ POCl34/ HCl

B(OH)2

OCH3

OCH3

B(OH)2

Ar

O

O

Ar

PO

OH

1a: Ar = H1b: Ar = Ph1c: 2,4,6-Me3C6H41d: 4-MeOC6H41e: 4-NO2C6H4

HO

N

R1

+H

R2

OR3

OTMSCatalyst (10 mol%),

toluene, -78 °C

HO

HN

R1CO2R3

R2

+

HO

HN

R1CO2R3

R2

Akiyama T.; Itoh J.; Yokota K.; Fuchibe K. JACS 2007, 129, 6756. Akiyama T.; Itoh J.; Yokota K.; Fuchibe K. Angew. Chem. Int. Ed. 2004, 43, 1566.

R1 R2 R3 Yield (%) Syn/ anti ee (%)

Ph Me Et 100 87:13 96

p-MeOC6H4 Me Et 100 92:8 88

p-FC6H4 Me Et 100 91:9 84

p-ClC6H4 Me Et 100 86:14 83

p-MeC6H4 Me Et 100 94:6 81

PhCH=CH Me Et 91 95:5 90

Ph Bn Et 100 93:7 91

p-MeOC6H4 Bn Et 92 93:7 87

Ph Ph3SiO Me 79 100:0 91

X t (h) Y(%) ee (%)

2-OH 13 98 89

4-OH 33 28 20

2-OCH3 46 56 3

H 43 76 39

X

Phosphoric Acid Catalysis : Mannich-Type Reactions

Akiyama’s Work: Mechanism and Transition State

OP

O

O OH*O

O*

O

O

+

HO

N

Ph

O

N

Ph

H

H

O

O

PO

O*

O

N

Ph

H

H

OP

O

O

O

O

N

Ph

H

H

OP

O

O

O

O

N

Ph

HO

O

PO

O*

H

OH

NH

Ph OMe

O

OSiMe3

OMeMonocoordinationpathway

Dicoordinationpathway

O

N H

H

Me3SiO OMe

O

O

P *

1.555

1.0051.488

1.335

1.726

2.0771.490

O

N

Me3SiO OMe

H

HO P O

O

O*

2.122

1.630

0.989

1.763

1.020

MonocoordinationPathway

(TS: + 3.4 kcal/ mol)

DicoordinationPathway

(TS: 0.0 kcal/ mol)

More crowded concave structure for the attacking nucleophileLonger forming bond C-C

Nine membered-cyclic TS

FAVORED

TSd

TSm

Phosphoric Acid Catalysis : Mannich-Type Reactions

Akiyama’s Work : Origin of Selectivity

O

OP

O

O

NO2

NO2

H

H

N

OSiMe3

OMe

O

H O

OP

O

O

NO2

NO2

H

H

N

O3.862

H

3.821

re facial attack

- stacking interaction

repulsive interaction

Phosphoric Acid Catalysis : Mannich-Type Reactions

Terada’s Work

Terada and coll. Tetrahedron Lett. 2007, 48, 497.Terada and coll. J. Am. Chem. Soc. 2004, 126, 5356.

O

N

R1+

O

Catalyst (2 mol%),

DCM, r.t.

O

HN

R1Ac

Ac

O

OR2 OR2

92 - 99 % (90 - 98 % ee)R1 = 4-MeO-C6H4, 4-Me-C6H4, 1-Napht, 4-Br-C6H4, 4-F-C6H4, 2-Me-C6H4

R

O

O

R

PO

OH

1a: R = H1b: R = Ph1c: R = 4-biphenyl1d: R = 4-( -naphtyl)-C6H4

Catalyst Yield (%) ee (%)

1a 92 12

1b 95 56

1c 88 90

1d 99 98

O P

O

O H N O

OAc

Ac HN

OO

PhAc

Ac

HS

O

R2 Yield (%) ee (%)

tBu 88 90 (S)

Bn 76 26

Me 96 6

Formation of 1:1 adducts (catalyst: imine) sterically controlled by the bulky substituents of the phosphoric acid

One side of C=N shielded by one of the biphenyl substituents

Another side completely open for the approach of the nucleophile

re facial attack

Phosphoric Acid Catalysis : Mannich-Type Reactions

Akiyama: A New TADDOL-Based Catalyst

Adv. Synth. Catal. 2005, 347, 1523.

1a: Ar = Ph1b: Ar = p-C6H5-C6H41c: Ar = p-F-C6H41d: Ar = p-CF3-C6H4

O

P

O

ArAr

ArAr

O

O

O

OH

N

R1+

Catalyst (5 mol%),

toluene,-78 °C

81-100 % (85 - 92 % ee)R1 = Ph, 4-Cl-C6H4, 4-Me-C6H4, 4-F-C6H4, 4-MeO-C6H4

HO

OTMS

OMe

NH

R1

OH

O

OMe

O

P

O

ArAr

ArAr

O

O

O

OHCO2Et

CO2EtO

O

Ar-MgBr, THF

49 % OH

OH

ArAr

ArAr

O

O

1/ PCl3 (2.2 equiv), Et3N, THF, 0 °C, 1 h

2/ Et3N,H2O,

3/ I2 (3.2 equiv), Py-H2O, r. t., 20 min

79 %

O

OP

O

O

H

H

N

O

HO

O

F

F FF3C

F

FF

Nu

Catalyst Time (h) Yield (%) ee (%)

1a 24 0 -

1b 66 47 31

1c 26 63 34

1d 21 97 73

R1 = Ph

re facial attack

Phosphoric Acid Catalysis : Aza-Ene Reaction

Terada’s Work

Angew. Chem. Int. Ed. 2006, 45, 2254.J. Am. Chem. Soc. 2007, 129, 10336.

O

N

Ar+

HN R2

O

1/ A (2 - 0.05 mol%),toluene, r.t.

2/ H3O+

O

NH

Ar

R1 R2

53-97 % (93-98 % ee)1a: R1 = Ph, R2 = Me1b: R1 = Ph, R2 = OtBu

Ph

1c: R1 = Ph, R2 = OBn1d: R1 = Ph, R2 = OMe

Ph

O

R

O

O

R

PO

OH

A: R = 9-anthrylB: R = 4-Ph-C6H4

PhN

O

ArH

H

OP

O

O

O

H

NCOR

Ph

PhN

O

Ar

H

OP

O

O

O

H

NCOR

Ph

O

P

O

O

O

H

Ph

O

N H

Ar NCOR

Ph

Ar Yield (%) ee (%)

p-Me-C6H4 90 95

o-Me-C6H4 61 93

p-MeO-C6H4 82 92

p-F-C6H4 89 95

p-CN-C6H4 97 98

2-naphtyl 91 95

Phosphoric Acid Catalysis : Aza-Ene Reaction

Terada’s Work

Angew. Chem; Int. Ed. 2006, 45, 2254.J. Am. Chem. Soc. 2007, 129, 10336.

O

N

Ar+

HN R2

O

R1

1a: R1 = Ph, R2 = Me1b: R1 = Ph, R2 = OtBu

H

1c: R1 = Ph, R2 = OBn1d: R1 = Ph, R2 = OMe

N

HNCbz

Boc

Ar NHCbz

+ N

HNCbz

Boc

Ar NHCbz

1/ B (2 mol%),DCM, r.t., 30 min

2/ H3O+

R1 = OtBuR2 = OBn

> 99 % y, trans : cis = 95:5, > 99 % ee of trans, 40 % ee of cis

Ar Yield (%) trans:cisee (%)

of trans

ee (%)

of cis

p-Br-C6H4 > 99 94:6 99 23

pMe-C6H4 > 99 95:5 98 4

2-furyl 76 88:12 99 14

c-C6H11 68 94:6 97 40

R

O

O

R

PO

OH

A: R = 9-anthrylB: R = 4-Ph-C6H4

O

N

Ar+

HN R2

O

R1

H

N

HN

COR2

Ar NH

intermolecularaza-ene reaction

O

N R2

HAr

NHR1

O

2nd intermolecularaza-ene reaction

O

NH

R2

Ar

NHR1

O

H

N

O

R2

aza-ene cyclization

R1

O

O

R2

cascade transformation

O

OP

O

OH

CF3

CF3

CF3

CF3

A

Phosphoric Acid Catalysis : Addition on Activated Imine Derivatives

Hydrophosphonylation of Imines - Akiyama

+A (10 mol%),

m-Xylene, r.t.

72-97 % (52-90 % ee)

R

N

OMe

P

O

HO-iPr

O-iPr

R P(O-iPr)2

O

HN

OMe

O

OP

O

O

CF3

CF3

CF3

CF3

H O

H

POR

ORN

Ar

H

Ar

Org. Lett. 2005, 7, 2583.

R Time (h) Yield (%) ee (%)

C6H5 24 84 52

o-Me-C6H4 46 76 69

C6H5CH=CH 101 92 84

p-CH3C6H4CH=CH 170 88 86

p-Cl-C6H4CH=CH 145 97 83

o-CH3C6H4CH=CH 171 80 82

o-Cl-C6H4CH=CH 70 82 87

1-naphtyl-CH=CH 168 76 81

re facial attack

P

O

HO-iPr

O-iPrP

OH

O-iPr

O-iPr

Phosphonate form(unreactive)

Phosphite form(reactive)

Phosphoric Acid Catalysis : Addition on Activated Imine Derivatives

Strecker Reaction - Rueping

+ HCN

A (10 mol%),

toluene, -40 °C, 6 h

53-97 % (85-99 % ee)

Ar

NBn

Ar CN

HNBn

O

OP

O

OH

A

75 % (97 % ee)

CN

HNBn

F3C

53 % (96 % ee)

CN

HNBn

H3CO

59 % (98 % ee)

CN

HNBn

F

F

85 % (99 % ee)

CN

HNBn

84 % (89 % ee)

CN

HNBn

O

85 % (92 % ee)

CN

HNBn

O

87 % (89 % ee)

CN

HN

OCH3

re facial attack

si face efficiently shieldedby the large phenanthryl group of the catalyst

O

OP

O

OH N

MeO

H

Angew. Chem. Int. Ed. 2006,45, 2617.

Phosphoric Acid Catalysis : Addition on Activated Imine Derivatives

Imine Amidation - Antilla

J. Am. Chem. Soc. 2005, 127, 1596.

+ H2NR

Catalyst

ether, r.t.Ar

N

Ar NHR

HNBoc

O

OtBu

Catalyst A: Tf2NH Catalyst B : PO

HOH

Ar R mol% acid Time Yield (%)

C6H5 SO2Me 0.5 mol% A 20 min 99

C6H5 SO2–C6H4-Me 5 mol% B 20 h 91

4-BrC6H4 C(O)CH=CH2 10 mol% B 2.5 h 94

4-MeOC6H4 C(O)CH=CH2 5 mol% B 14 h 91

2-furyl C(O)CH=CH2 10 mol% B 11 h 99

Catalyst CR = H

Catalyst DR = 4-(-naph)-C6H4

Catalyst ER = 4-(-naph)-C6H4

R

O

O

R

PO

OH

O

OP

O

OHPhPh

Catalyst F

Ar R mol% acidTime (h)

Yield (ee) (%)

Ph Ts 5 mol% C 16 95 (<5)

Ph Ts 4 mol% D 20 96 (60)

Ph Ts 5 mol% E 24 99 (71)

Ph Ts 5 mol% F 1 95 (94)

Ph Ms 5 mol% F 1 86 (93)

Ph 5 mol% F 1 89 (91)

4-BrC6H4 Ts 10 mol% F 13 96 (92)

4-CF3C6H4 Ts 10 mol% F 20 99 (99)

S OMe

O

O

89-99 %(73-99 % ee)

Phosphoric Acid Catalysis : Hetero-Diels-Alder Reactions

Akiyama’s Work

N

Ar

+

Catalyst (5 mol%),

CH3CO2H (1.2 equiv),

toluene,-78 °C

72-100 % (76-91 % ee)

HO

OTMS N

Ar

OH

MeO

O

R

O

O

R

PO

OH

1a: R = Ph1b: R = C6H4(p-NO2)1c: R = C6H2[2,4,6-(i-Pr)3]

Catalyst Time (h) Yield (%) ee (%)

1a 23 67 3

1b 21 90 5

1c 20 32 42

Ar Time (h) Yield (%) ee (%)

C6H5 18 99 80

p-I-C6H4 24 86 84

p-Br-C6H4 13 100 84

p-Cl-C6H4 35 72 84

p-F-C6H4 13 77 78

p-CF3-C6H4 21 82 81

o-Br-C6H4 10 96 80

o-Cl-C6H4 12 100 76

1-naphtyl 12 100 91

Synlett 2006, 1, 141.

O

OP

O

O

iPr

iPr

H

H N

OiPr

iPr

iPr

iPr

si facial approach

Additive Yield (%) ee (%)

None 29 34

MeOH 97 46

CF3CH2OH 88 41

PhCO2H 85 63

CH3CO2H 78 67

PhSO3H 87 15

Ar = Ph

OMe

TMSO

Terada’s Work : FC Reactions on Furan

Phosphoric Acid Catalysis : Friedel-Crafts ReactionsR

O

O

R

PO

OH

R =

+A (2 mol%),

DCE, -35 °C, 24 h

80-95 % (86-97 % ee)

R

NBoc

H

O

OMe

O

OMeR

NHBoc

Temp (°C) Yield (%) ee (%)

0 86 92

-20 89 95

-35 87 97

R Yield (%) ee (%)

C6H5 95 97

p-MeO-C6H4 84 94

o-Br-C6H4 85 91

p-Br-C6H4 86 96

p-Cl-C6H4 88 97

p-F-C6H4 82 97

p-CF3-C6H4 82 81

2-furyl 94 86

1-naphtyl 100 91 NBS, NaHCO3, Et2O/ H2O,

0°C, 30 min

90 %

O

OMePh

NHBoc

Ph

NHBoc

OO OMe

CeCl3.7H2O, NaBH4, MeOH,

-78 °C to r.t., 5h

95 % (syn/ anti: 85/ 15)

Ph

NHBoc

O

O

Synthetic Utility of Furan-2-ylamine

Uraguchi D.; Sorimachi K.; Terada M. J. Am. Chem. Soc. 2004, 126, 11804.

+Catalyst (5 mol%), CHCl3

- 60 °C, 23-26 h

66-95 % (42-96 % ee)

N

HN

Ph

O

NHPh

O

R1

R2

R3

MeO MeON

R1

R2

R3

R1 = Me, CH2CH2Br, n-Pr, n-C6H13, allylR2 = H, n-BuR3 = H, Et

Antilla’s Work : FC Reactions on Indole and Pyrrole

Phosphoric Acid Catalysis : Friedel-Crafts Reactions SiPh3

O

O

SiPh3

PO

OH

O

OP

O

OHPh

Ph

A

B

+Catalyst (5 mol%), DCM,

- 30 °C, 4 A MA, 16 h

92-99 % (92-96 % ee)

N

HR1

NBn

Ph

O

R1

NHPh

O

NBn

R1 Temp. (°C) Catalyst Yield (%) ee (%)

H -60 B 89 86

H -60 A (10 mol%) 92 97

H -30 A (5 mol%) 99 94

R1 Yield (%) ee (%)

H 99 94

p-MeO 93 94

m-MeO 96 92

p-Br 92 96

p-Cl 97 96

p-F 97 95

p-NO2 99 94

1-naphtyl 99 95

Application to Pyrroles

Rowland G. B.; Rowland E. B.; Liang Y.; Perman J. A.; Antilla J. C. Org. Lett. 2007, 14, 2609.Li G.; Rowland G. B.; Rowland E. B.; Antilla J. C. Org. Lett. 2007, 20, 4065.

HR''O2C

N

PN

R R'

N

activator

NH

R''O2CN

R R'P

NH

O

PO N2

R''O2CR'

PHN R

NH

R''O2CR'

N R

N

P

N

P

HR''O2C

R'

R

O

H X

R R'

activatorO

HR'

XRaddition O

R'

HXRelimination

Phosphoric Acid Catalysis : Alkylation of -Diazoester

Friedel-Crafts adduct

Aziridine(usual fate)

« Friedel-Crafts type » adduct

+Catalyst (2 mol%),

toluene, r.t., 5 h

62-89 % (91-97 % ee)

HRO2C

N2

O N

R'

H Ar

OHN

R'

Ar

N2

RO2C

R = tBu, Et

R

O

O

R

PO

OH

R = 9-anthryl

Uraguchi D.; Sorimachi K.; Terada M. J. Am. Chem. Soc. 2005, 127, 9360.

Phosphoryl oxygen = intramolecular basic site

« slow »

« fast »

A

B

C

Ar, R’ CatalystYield (%)

ee (%)

Ph A 70 -

Ph B 59 90

R’ Yield (%) ee (%)

C6H5 59 90

o-Br-C6H4 80 90

o-Me-C6H4 84 90

o-MeO-C6H4 77 92

m-MeO-C6H4 76 91

1-naphtyl 82 90

p-Br-C6H4 68 86

p-Me-C6H4 72 91

p-MeO-C6H4 73 93

p-Me2N-C6H4 81 97

+Catalyst (2 mol%),

toluene, r.t., 5 h

62-89 % (91-97 % ee)

HRO2C

N2

O N

R'

H Ar

OHN

R'

Ar

N2

RO2C

R = tBu, iPr,Et

R

O

O

R

PO

OH

R = 9-anthryl

O

OP

O

OH

A

B

PtO2, H2, EtOAc/ AcOH,r.t.

79 %

R = p-Me2N-C6H4(97 % ee)

O NH

R

Ph

N2

CO2tBu

1/ Tf2O, 2,6-lutidine,DCM, -78 °C to 0 °C

then MeOH, 0 °C to rt 70 %

2/ Pd/C, MeOH, r.t.60 %

O NH

R

PhCO2tBu

NH2

PhCO2tBu

Oxone, NaHCO3,H2O/ acetone/ DCM,

0 °C to r.t.R = Ph

(> 99 % ee)

NaBH4, MeOH, - 78 °C, anti/ syn = > 99/ < 1

95 % (over two steps)

O NH

R

Ph

O

CO2tBu

NH

PhCO2tBu

O

R

97 % ee

> 99 % ee

OH

Synthetic Utility of -Amino--Diazoesters

Ar Yield (%) ee (%)

p-F-C6H4 74 97

p-Ph-C6H4 71 97

p-Me-C6H4 74 97

p-MeO-C6H4 62 97

o-F-C6H4 89 91

o-MeO-C6H4 85 91

p-F-C6H4 84 93

Phosphoric Acid Catalysis : Alkylation of -Diazoester

Uraguchi D.; Sorimachi K.; Terada M. J. Am. Chem. Soc. 2005, 127, 9360.

Phosphoric Acid Catalysis : Pictet-Spengler Reaction

40-96 % (62-96 % ee)

R2-CHO, catalyst (20 mol%),Na2SO4,

toluene, -30 °C, 3-5 dHN NH2

CO2Et

CO2Et

HN NH

R2

CO2Et

CO2Et

R1 R1

R

O

O

R

PO

OH

1a: R = H1b: R = p-NO2-C6H4

1c: 3,5-CF3-C6H3

1d: 2,4,6-Me-C6H2,

1e: 1-naphtyl1f: 2,4,6-( i-Pr)-C6H4

List’s Work

Et-CHO, TFA (1 equiv),DCM, r.t.

> 90 %HN NH2

H

H

HN

N

H

Et

Et-CHO, TFA (1 equiv),DCM, r.t.

> 90 %HN NH2

CO2Et

CO2Et

HN NH

Et

CO2Et

CO2Et

Aldol Condensation

Pictet-Spengler Reaction

R1 R2 Yield (%)

ee (%)

OMe Et 96 90

H Et 76 88

OMe n-Bu 90 87

H n-Bu 91 87

OMe Bn 85 72

H Bn 58 76

OMe p-NO2-C6H4 98 96

H p-NO2-C6H4 60 88

OMe p-CN-C6H4 60 80

H p-CN-C6H4 40 89

+ Toleration of aromatic aldehydes (especially electron-poor ones)

- Requirement of a geminal diester functionality (Thorpe-Ingold effect)

Seayad J.; Seayad A. M.; List B. J. Am. Chem. Soc. 2006, 128, 1086.

Phosphoric Acid Catalysis : Pictet-Spengler Reaction

R'-CHO, catalyst (5 mol%),MS 3A, BHT

toluene, 0 °C, 3-5 dHN HN HN NS

R

R'

S

1a: R = o-NO2-C6H41b: R = CPh3

77-90 % (30-87 % ee)

HCl, PhSH

HN NH

R'

R = CPh3

2a: R = o-NO2-C6H4

31 % ee

3 (from 1b)

R

R

O

O

R

PO

OH

1a: R = H1b: R = p-NO2-C6H4

1c: 3,5-CF3-C6H31d: biphenyl1e: SiPh3

1f: 2,4,6-(i-Pr)-C6H4

Hiemstra’s Work

R R’ Time (h)

Yield 3 (%)

ee 3 (%)

CPh3 n-hept 2 87 84

CPh3 i-Pr 24 77 78

CPh3 Me 1 88 30

CPh3 c-hex 24 81 72

CPh3 CH2Bn 0.5 88 76

CPh3 Bn 4 90 87

CPh3 Ph 24 77 82

CPh3 p-NO2-C6H4 24 78 82

+ Easy preparation of Pictet-Spengler precursors Stabilization of th iminium ion by the sulfenyl substituent Easy removal of the sulfenyl group Fast reactions

- Unstability of N-tritylsulfenyl tetrahydro--carboline ⇒ Use of BHT Slightly lower yields and ees

Wanner M. J.; Van der Haas R. N. S.; de Cuba K. R.; Van Maarseven J. H.; Hiemstra H. Angew. Chem. Int. Ed. 2007, 46, 7485.

Phosphoric Acid Catalysis : Asymmetric Transfer Hydrogenation with Hantzsch Esters

General Mechanism: Reduction of C=N Bonds

Ar

O

O

Ar

PO

OH

Ar

O

O

Ar

PO

O

N

R2R3

H R1 NH

H HRO2C CO2R

N

RO2C CO2R

Ar

O

O

Ar

PO

O

N

R2R3

H R1

HHN

R2R3

R1

N

R2R3

R1

I

II

III

You S.-L. Chem. Asian J. 2007, 2, 820.

Hantzsch method vs H2 or metal hydride process

1/ Mild Reaction Conditions (r.t. or slight heating in conventional solvents)

2/ Operational simplicity (no HP apparatus or air-free conditions)

3/ Availability of Hantzsch Esters

4/ Safe handling

5/ Compatiblity with Organocatalysts

1/ Poor atom economy

2/ Problematic removal of pyridine by-products

+

-

O

OP

O

OH N

CH3

OCH3

R R’ CatalystYield (%)

ee (%)

Napht PMP

1a 20 rac

1b 42 38

1c 37 44

1d 54 40

1e 59 48

1f 57 62

Phosphoric Acid Catalysis : Asymmetric Transfer Hydrogenation with Hantzsch Esters

Reduction of C=N Bonds: Rueping’s Work

Ar

O

O

Ar

PO

OH

1a: Ar = mesityl1b: Ar = 9-phenantryl1c: Ar = 1-naphtyl1d: Ar = 2-naphtyl1e: Ar = 4-biphenyl1f: Ar = 3,5-(CF3)-C6H3

Rueping M.; Sugiono E.; Azap C.; Theissmann T.; Bolte M. Org. Lett. 2005, 17, 3781.

amine Yield (%) ee (%)

82 70 (94)*

R = CF3: 71

R = Ph: 71

R = OMe: 76

72

74 (98)

72

76 74

82 84

46 82

91 78

R = PMPNHR

NHR

R NHR

NHR

F

NHR

CF3

NHR

si face selectivity

* In parenthesis, ee obtained after one recrystallization from MeOH

catalyst (20 mol%),benzene, 60 °C

46-86 % (70-98 % ee)

N

CH3R'

R

NH

EtO2C CO2EtHH

HN

CH3R'

R

R t (h) Yield (%)ee (%)

t (d) Yield (%) ee (%) t (h) Yield (%) ee (%)

Ph 45 96 88 3 76 74 19 93 96

42 85 84 3 82 94 - - -

45 95 85 3 82 84 - - -

71 91 93 3 74 78 22 98 96

71 88 92 3 91 78 - - -

- - - 3 71 72 21 98 96F3C

Catalyst (10 mol%), A (1.4 equiv),

toluene, 35 °C

PMPHN

R

NPMP

R

Phosphoric Acid Catalysis : Asymmetric Transfer Hydrogenation with Hantzsch Esters (A)

Ar

O

O

Ar

PO

OH

List's CatalystAr = 2,4,6-(i-Pr)-C6H2

Ar

O

O

Ar

PO

OH

Rueping's CatalystAr = 3,5-(CF3)-C6H3

Antilla's Catalyst

O

OP

O

OHPh

Ph

List B. and coll. Angew. Chem. Int. Ed. 2005, 44, 7424. Rueping M. and coll. Org. Lett. 2005, 17, 3781. Antilla J. C. and coll. JACS 2007, 129, 5830.

F

CH3

Catalyst (20 mol%), A (1.4 equiv),

benzene, 60 °C

PMPHN

R

NPMP

R

Catalyst (5 mol%), A (1.4 equiv),

toluene, 50 °C

PMPHN

R CO2Et

NPMP

CO2EtR

Phosphoric Acid Catalysis : Enantiomeric Reductive Amination with Hantzsch Esters (A)

Catalyst (10 mol%), A (1.4 equiv),

benzene, 24 h.Me

O

+

NH2

OMe

Me

HN

OMe

NMe2

NH

NH

S

CF3

CF3

O

OOH

OH

Ph Ph

Ph Ph

O

OP

O

OH

1, 0 % yield

Jacobsen, Takemoto

2, 0 % yield

Rawal

3a, 6 % yield, 37 % ee

Akiyama, Terada

R

R

Storer R. I.; Carrera D. E.; Ni Y.; MacMillan D. W. C. J. Am. Chem. Soc. 2006, 128, 84.

Catalyst R Additive Temp. (°C) Conv (%) ee (%)

3a 2-naphtyl - 80 6 37

3a 2-naphtyl 5 Ǻ MS 80 41 45

3b H 5 Ǻ MS 80 43 7

3c 3,5-NO2-Ph 5 Ǻ MS 80 45 16

3d 3,5-CF3-Ph 5 Ǻ MS 80 39 65

4 TBDPS 5 Ǻ MS 80 35 61

5 SiPh3 5 Ǻ MS 80 70 87

5 SiPh3 5 Ǻ MS 40 85 94

Me

HN

OMe

87 % yield94 % ee

Me

HN

OMe

81 % yield95 % ee

Me

HN

OMe

79 % yield91 % ee

Me

HN

OMe

60 % yield83 % ee

F

F

Me

HN

OMe

77 % yield90 % ee

Me

HN

OMe

73 % yield96 % ee

MeO

Me

HN

OMe

71 % yield95 % ee

HN

OMe

75 % yield85 % ee

O2N

Me

HN

OMe

75 % yield95 % ee

Cl

HN

OMe

70 % yield88 % ee

F

Me Et

87 % 27 %

Phosphoric Acid Catalysis : Enantiomeric Reductive Amination with Hantzsch Esters (A)

Storer R. I.; Carrera D. E.; Ni Y.; MacMillan D. W. C. J. Am. Chem. Soc. 2006, 128, 84.

Chemoselectivity StudySiPh3

O

O

SiPh3

PO

OH

Selectivity for the reduction of iminium ions derived from methyl ketones

Catalyst (10 mol%), A (1.4 equiv),

benzene, 24 h.

Me

O

+

NH2

OMe

Me

NHAr

Et

O

Et

O

18 : 1 Methyl vs Ethyl ketone selectivity 85 % yield, 96 % ee

Catalyst (10 mol%), A (1.4 equiv),

benzene, 40 °C, 72 h.Et Me

O

+

NH2

OMe

Et Me

NHAr

butanone71 % yield, 83 % ee

Viable conditions for substrates containing substituents of similar steric and electronic character

Me

HN

OMe

71 % yield83 % ee

Me

HN

OMe

72 % yield91 % ee

Me

HN

OMe

75 % yield94 % ee5

Ph

Catalyst anion R’ Conv (%) er (%)

CF3CO2 - 23 75:25

CF3CO2 - 66 77:23

CF3CO2 - 72 76:24

1a 25 87:13

1b 81a 97:3

Phosphoric Acid Catalysis : Enantiomeric Reduction of ,-Unsaturated Ketones with Hantzsch Esters (A)

Catalyst salt (20 mol%),

1,4-dioxane, 60 °C, 48 h+

NH

H HEtO2C CO2Et

O O

S

Development of Ammonium Phosphates

CO2tBu

NH3

iPr CO2tBu

NH3

tBu CO2tBu

NH3

iPr CO2tBu

NH3

R

O

O

R

PO

O

1a: R = Ph1b: R = 2,4,6-(i-Pr)3-C6H2

iPr CO2tBu

NH3

a in Bu2O

EnoneYield (%)

er (%)

R = Me 99 97:3

R = Et 98 98:2

R = CH2CH2Ph 99 98:2

R = Ph 99 92:8

R = Me 78 99:1

R = Et 71 98:2

R = CH2CH2Ph 68 98:2

R

O

O

R

EnoneYield (%)

er (%)

> 99 98:2

R = CO2Et 99 92:8

R = Ph 81 85:15

O

O

R

(E)

Martin N. J. A.; List B. J. Am. Chem. Soc. 2006, 128, 13368.

Conclusion

Difficulties previously thought to hinder Bronsted acid catalysis overcome in three ways: bidentate hydrogen bonding, supramolecular architecture and bifunctional hydrogen bonding

Large variety of Brønsted acid catalysts presented, but many not discussed (proline, Fu’s PPY, ammonium salts…) and more that I’ve missed (I’m sure…)

Strong Brønsted acid catalysts = easy to handle (stable toward water and oxygen), easy to prepare, non toxic, potentially recoverable and recyclable

Significant expansion of the scope of asymmetric nucleophilic additions to carbonyl and carbonyl derivatives

New applications and advances in terms of both catalyst design and the expansion of substrate scope for Brønsted acid catalysts and particularly for Phosphoric Acids