Hydrogen-Bond Catalysis

For reviews see:

M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520-1543

A. G. Doyle, E. N. Jacobsen, Chem. Rev., 2007, 5713-5743

Nadia Fleary-Roberts03/02/10

• Lewis acids has dominated enantioselective catalysis• acceleration of Diels Alder reaction with AlCl3

•

A brief history…

• Wynberg reported asymmetric conjugate addition reactions with cinchona alkaloids bearing a free hydroxyl group.

Hiemstra H.; Wynberg H., J. Am. Chem. Soc. 1981, 103, 417-430

Yates P.; Eaton P., J.Am. Chem. Soc. 1960, 82, 4436

O

CH3

CH3

+

tBu

SH O

CH3

CH3ArS

75 % ee

cinchonidine (1 mol %)

benzene, 23 oC

N

OH

N

cinchonidine

•Jacobsen reported asymmetric hydrocyanation of aliphatic and aromatic aldehydes

R H

N+

2. TFAA

1.a (2 mol %)

toluene, -70 oCHCNR CN

NF3COC

R = Ph: 91 % eeR = tBu: 85 % ee

N

OCH3tBu

HO

NH

NH

StBu

N

O

Bn

H

a

Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901

Lewis acid catalysis• Highly tunable

• Can vary counter ion, chiral ligand

• Lewis base/acid interactions are stronger

• Interactions are more directional

H-bond catalysisModerately tunable

Active catalyst

Potentially recoverable

Strength can vary from 0.4 to 40 kcalmol-1.

What is a hydrogen bond?

“An XH···A interaction is called a ,hydrogen bond', if 1. it constitutes a local bond, and 2. XH acts as a proton donor to A.”

Steiner, Angew. Chem. Int. Ed. 2002, 41, 48

Most Hydrogen bonding in H-bond catalysis is of moderate strength

G.A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford University Press, New York, 1997

Role of H-bonds:DNA base pairingLigand/receptor binding

Specific acid catalysis

General acid catalysis

Brønsted acids can accelerate organic reactions by either of two fundamental mechanisms:

•protonation of the electrophile in a prior to nucleophilic attack

•proton transfer to the transition state in the rate-determining step

Modes of bonding

Double H-bond donors• Increased strength and directionality

e.g. Ureas, thioureas, Guanidinium and Amidinium ions

N

R3tBu

HO

NH

NH

XtBu

N

O

R1

R2

X = O, S

NR R

NNH

RRN

RNH

R

R

Guanidine Amidine

• Less strength than double H-bond donors

• Less directionality

Single H-bond donors

•e.g. Diols, biphenols, chiral phosphoric acids

O

O

OH

OH

Ar Ar

Ar Ar ArAr

ArAr

OH

OH

Ar

O

O

Ar

PO

OH

Bifunctional catalysis

•a single or dual H-bond donor site flanked by sites for secondary interaction with substrates.

e.g. Proline and proline analogs, cinchona alkaloids and derivatives

NH

CO2H

L- proline N

R

OH

N

Ureas and Thioureas

•Originally developed as ligands for lewis acidic metals.

•Most applicable class of chiral H-bond donors

•Can promote addition of a range of nucleophiles

•Imine activation

Double H-bond donors

N

R3tBu

HO

NH

NH

XtBu

N

O

R1

R2 b R1 = Bn, R2 = H, R3 = OCH3, X= S

c R1 = Bn, R2 = H, R3 = OCOtBu, X = O

d R1 = R2 = CH3, R3 = OCOtBu, X =S

e R1 = Bn, R2 = CH3, R3 = tBu, X = S

NH

NH

XtBuHN

O NR''R''

R'

X

Nu

LUMO activation

•Diels Alder reaction

•Aza Baylis-Hillman reaction

Double H-bond donors

CF3

F3C NH

NH

S

CF3

CF3

f

CF3

O

+solvent, 20 oC

catalyst f (10-100 mol%)

O

N

R3tBu

HO

NH

NH

XtBu

N

O

R1

R2

e R1 = Bn, R2 = CH3, R3 = tBu, X = S

N

Ph

NsDABCO

e (10 mol %)

xylenes, 4 oC

Ph OCH3

ONHNs

95 % ee40 % yield

N

N

+ OCH3

O

Wittkopp A.; Schreiner P. R., Chem. Eur. J. 2003, 9,

Raheem, I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005, 347, 1701

•Asymmetric Strecker reaction

Double H-bond donors

•Scaleable catalytic synthesis•Imines derived from alky, aryl, heteroaryl aldehydes•Aqueous cyanide salts•Robust catalyst•Access to the (R)-enantiomer of tert-leucine

Zuend S.J.; Coughlin M. P.; Lalonde M. P.; Jacobsen E. N., Nature, 2009, 461, 968

CF3

CF3NH

NH

StBu

N

O

Ph

Ph

g

R

NCHPh2 catalyst g, (0.5 mol %)

KCN, AcoH, H2O, tol, 0 oC, 4-8 hR

HNCHPh2

CN

H2SO4, HCl, 44-68 hNaOH, NaHCO3Boc2O, dioxane, 16 h

recrystallizeR

BocHNCHPh2

CO2H

98-99 % ee

•Asymmetric Pictet Spengler reaction

NH

N i-Bu

NH

AcCl2,6-lutidine

h (10 mol %)

Et2O, -60 oC

NAc

i-Bu

93 % ee75 % yield

i-BuN

NH

O

S

NH

t-Bui-Bu

N Ph

h

Double H-bond donors

Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558

Bifunctional Thiourea derivatives

Takemoto catalyst

•Aza-henry reaction-(addition of nitroalkanes to imines )

CF3

F3C NH

NH

S

N(CH3)2

y

PhNO2 H3CO2C CO2CH3+ Ph

NO2

CO2CH3H3CO2C

93 % ee86 % yield

y (10 mol%)

toluene, 23 oC

T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672 – 12673O O

SPh

PhSH+ 85 % ee97 % yield

y (10 mol%)

4 A M.S.

CH2Cl2, 0 oC

•1,4- additions

Ph

NP(O)Ph2

+ CH3NO2

Ph

NH

NO2

Ph2(O)Py (10 mol%)

toluene, 23 oC

67 % ee87 % yield

T. Okino, S. Nakamura, T. Furukawa, Y. Takemoto, Org. Lett. 2004, 6, 625

B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen, L.-S. Ding, Y. Wu, Synlett 2005, 4, 603

•1,2-additions

S

N

CH3

O

H3C

CH3

TMSCNy (5 mol%)

CF3CH2OH

CH2CL2, -78 oC

S

N

CH3

HO

H3C

CH3

CN i-Pr

NH

NH

SHN

O

t-Bu

y

D. E. Fuerst, E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127, 8964

F3C

F3C

CF3

CF3

HNNHHN

SNH

S

z

efficient catalyst for Baylis-Hillman reactions

•Other thiourea catalysts

•Capable of double H-bond interactions

•Are positively charged so result in increased H-bond donor abiltity.

Double H-bond donors

NR R

NNH

RRN

RNH

R

R

Guanidine Amidine

Guanidinium and Amidinium ions

Ph

NCH2Ph

HCN

i (10 mol %)

toluene, -40 oC

Ph CN

NHPhH2C

•Strecker reaction

NH

N

NPhPh

i

T. Steiner, Angew. Chem. 2002, 114, 50; Angew. Chem. Int. Ed. 2002, 41, 48 .

Double H-bond donors

•Diels Alder reaction

•Nitro-Mannich reaction

Schuster T.; Bauch M.; Durner G.; Gmbel M. W.; Org. Lett. 2000, 2, 179 – 181.

Cl

NBoc

+ H3C No2

j (10 mol%)

toluene, -20 oC

Cl

NHBoc

CH3

NO282 % ee17:1 d.r.59 % yield

H3CO+ O

O

Et k (25 mol%)

CH2Cl2, 4 oC

H3CO

H

Et

H

O

OH

-44 % ee

70 % combined yield3.1:1 regioisomer ratio

H3COO

OH

Et

H

H

40 % ee

+

N

HN HN

NH

OTf

j

kAr = 3,5-(CF3)2C6H3

Amidinium catalysed reactions

•Hetero Diels Alder reaction catalysed by chiral diols

Single H-bond donors

•Baylis-Hillman reaction -Binol derivatives

Diols and Biphenols

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

TBSO

N(CH3)2

+ O

O

H

1. 10 mol % l or m

toluene, -40 oC

2. AcCl

CH2Cl2/toluene, -78 oCO

OO

with l 92 & ee 67 % yieldwith m >99 % ee 96 %

O

O

OH

OH

Ar Ar

Ar Ar

Ar = 1-Np

ArAr

ArAr

OH

OH

Ar = 4-F-3,5-Et2C6H2

l m

Ph

NTs

H

O

+n (10 mol %)

toluene/c-C5H9OCH3

-15 oC

Ph

NH OTs

87 % ee93 % yield

OH

OH

NN

n

•Chiral phosphoric acids

Ar

O

O

Ar

PO

OH

p Ar = 3,5-dimesitylphenylq Ar = 4-NO2-C6H4

r Ar = 4-(2-Np)-C6H4

•Mannich reaction

OH3CO+

H

NBoc

Ph

OH3CO

HN

Ph

Boc

97 % ee95 % yield

p (2 mol%)

ClCH2CH2Cl

-35 oC

T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. 2004, 116, 1592 – 1594 Angew. Chem. Int. Ed. 2004, 43, 1566 –1568D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356 – 5357

HO

N

Ph

+

OTMS

OEt

CH3

toluene, -78 oC

q (10 mol%)

HO

HN

PhCH3

CO2Et

90 % ee; 19:1 d.r.91 % yield

Single H-bond donors

•Reductive amination

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

O NH2

OMe

+

t (10 mol %)

HEH,40-50 oC

5 A MS, 24-96 h benzene

X HNX

OMe

X = F, Cl, OMe, NO2

83 -96 % ee60 -82 % yield

TPS

O

OP

OH

O

TPS

t

HEH = ethyl Hantzsch ester

NH

CO2EtEtO2C

Bifunctional catalysis

NH

CO2H

L- proline

•enatioselective aldol cyclizations

Proline catalysed reactions

H3C

O

CH3

L-proline (30 mol%)

DMSO, 23 oC

O

i-Pr

OH

96 % ee97 % yield

Z. G. Hajos, D. R. Parrish, (Hoffman-La-Roche),German Patent DE 2102623, 1971 [Chem. Abstr. 1972, 76, 59072];

Proposed mechanism for proline catalysed transformations

A. G. Doyle, E. N. Jacobsen, Chem. Rev., 2007, 5713-5743

NH

NH

NO

HN

PhHO

Ph

H OTf

u v

NH

HN

O

SO

O i-Pr

i-Pri-Pr

w

NH HN N

NN

x

u higher yields and selectivity compared to proline

O+

H

O

NO2

OH

NO2

O

DMSO, 23 oC

L-Proline or w (10 mol%) L-proline: 73 % ee 42 % yield w: 97 % ee 96 % yield

O

+OH

H CF3

x (5 mol%)

CH3CN, 23 oC

O OH

CF3

94 % (syn), 92 % ee (anti) 97.5:2.5 syn/anti 65 % yield

Proline analogues

x increased solubilityTetrazole is a pharmacore for carboxylic acid

Cinchona alkaloidsBifunctional catalysis

•Enatioselective conjugate additions

•Baylis-Hillman reaction

Nakano A. et . al. 2006, 62, 381Iwabuchi Y. et. al. J. Am. Chem. Soc. 1999, 121, 10219Connon S.J., Chem. Comm., 2008, 2499

OSH

tBu

cinchonidine

benzene, 23 oC

O

S

tBu

75 % ee

Ph

NTsO

+CH3CN/DMF

-30 oC

-isocupreidine (10 mol %) ONH

Ph

Ts

97 % ee80 % yield

N

R

OH

N

R = OCH3: quinineR = H: cinchonidine

N

R

OH

N

R = OCH3: quinidineR = H: cinchonine

N

OH

O

N

CH2CH3

isocupreidine

Oligiopeptides

• Cyclo(l-phenylalanine-l-histidine) hydrocyanation of aldehydes

O

HH3CO

HCNcyclo-(L-Phe-L-His) (2 mol%)

toluene, -20 oC

H3CO

OH

CN

97 % ee83 % conv.

HN

NH

O

Ph

O

NHN

cyclo-(L-Phe-L-His)

S. Inoue, J.-I. Oku, J. Chem. Soc. Chem. Commun. 1981, 229 –230

Bifunctional catalysis

Uncertainty concerning mechanism

Summary

• A dynamic and large area of research which is continuing to be explored

• Applicable to a wide number of transformations

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