Asymmetric Organocatalytic TransformationsLewis Base Organocatalysis

Stoltz / Reisman Group MeetingJanuary 09, 2015

Seojung Han

H

O

R1

+N

NHPh

O

cat.

R2R2

H

O

R1

+

O O

O

(S)-Proline(3 mol%)

O

O

OH

p-TsOH

C6H6

O

O

Ph

O

H

CN

Ph

O

OH

Ph

Organocatalysis

Catalysis

Biocatalysis Metal catalysis Organocatalysis

Organocatalysis

Lewis bases

Lewis acids

Brønsted bases

Brønsted acids

· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.

iminium catalyst, enamine catalyst, NHC catalystchiral dialkylaminopyridine

phase transfer catalyst, ketone catalyzed epoxidations

small molecule H-bond catalyst

cinchona alkaloid catalyzed alcoholyses of anhydride

Organocatalysis

Catalysis

Biocatalysis Metal catalysis Organocatalysis

Organocatalysis

Lewis bases

Lewis acids

Brønsted bases

Brønsted acids

· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.

iminium catalyst, enamine catalyst, NHC catalystchiral dialkylaminopyridine

phase transfer catalyst, ketone catalyzed epoxidations

small molecule H-bond catalyst

cinchona alkaloid catalyzed alcoholyses of anhydride

Organocatalysis

Catalysis

Biocatalysis Metal catalysis Organocatalysis

Organocatalysis

Lewis bases

Lewis acids

Brønsted bases

Brønsted acids

· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.

iminium catalyst, enamine catalyst, NHC catalyst

chiral dialkylaminopyridine

phase transfer catalyst, ketone catalyzed epoxidations

small molecule H-bond catalyst

cinchona alkaloid catalyzed alcoholyses of anhydride

N

Lewis Base Catalysis: Iminium Catalysis

N

N

cycloaddition nucleophilic1,4-addition

N

Nu

O O

Nu

LUMO: empty p* orbital

N

LUMO: empty p* orbital

Nu

R1

N

R2

Nu

N

R2

H

NHR

R2

R1

N

R2

R1

N

R2

nucleophilic1,2-addition

(R1 = H)

trans-amination

enamineformation

(R1 = H)

s-bondcleavage

X

O

R2

N

LUMO: empty

p* orbital

Nu

N

LUMO: empty

s* orbital

Iminium Catalyzed cycloadditions

Diels–Alder Reactions Catalyzed by Primary Amines

· The limitation of secondary amine catalysts: The catalytically active nitrogen atom is located in a sterically hindered environment, imposing strict demands on the structure of the substrate aldehyde or ketone. (e.g., a-substituted a,b-unsaturated aldehydes and an isopropyl-substituted ketone as dienophiles)· Novel primary amine organocatalyst has overcome this problem

H

O

O O

R

+

NH2

NH

N

R3

R4R6

R5

R1

R2

R3

R4

R2R1

R6 R5

CHO

O2CRCatalyst 1 (2.5-20 mol%)

C6F5SO3H (6.9-55 mol%)THF or EtNO2, 0 or 23 °C

Catalyst 181-99% yield

79-92% eeexo:endo 6.7:1-99:1

Ishihara, K. Adv. Synth. Catal. 2006, 348, 2457.Ishihara, K. J. Am. Chem. Soc. 2005, 127 , 10504.

H

N

O O

R

H

N

Bn

R

N

H

R'

R''X

X

H

NH

N

Bn

R

N

H

R'

R''X

X vs

OO

R

favored disfavored

NH2

NH2

Iminium Catalyzed cycloadditions

R O

O

CHO

+

Catalyst 2 (5 mol%)Tf2NH (9.5 mol%)

EtCN, –75 °C

CHO

O

R

O

Catalyst 2

48-95% yieldexo/endo 91:9-94:6

86-94% ee

Ishihara, K. Org. Lett. 2006, 8, 2229.Ishihara, K. Adv. Synth. Catal. 2006, 348, 2457.

Organocatalysis

Catalysis

Biocatalysis Metal catalysis Organocatalysis

Organocatalysis

Lewis bases

Lewis acids

Brønsted bases

Brønsted acids

· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.

iminium catalyst, enamine catalyst, NHC catalyst

chiral dialkylaminopyridine

phase transfer catalyst, ketone catalyzed epoxidations

small molecule H-bond catalyst

cinchona alkaloid catalyzed alcoholyses of anhydride

Enolendo AldolizationsHajos-Parrish-Eder-Sauer-Wiechert Reactions

O O

O

(S)-Proline(3 mol%)

DMF, rt20 h

(100% yield)

O

O

OH

93% ee

p-TsOH

C6H6

O

O

O

O

O(S)-Proline(3 mol%)

DMF, rt72 h

(52% yield)

O

OOH

p-TsOH

C6H6

O

O

O O

O

(S)-Proline(47 mol%)1N HClO4

MeCN, 80 °C, 20 h(87% yield) O

O

O

O

O O

O

(S)-Proline(47 mol%)1N HClO4

MeCN, 80 °C, 25 h(83% yield)

Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623, 1971.Eder, U.; Sauer, G. R.; Wiechert, R. German Patent DE 2014757, 1971.Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.Houk, K. N. J. Am. Chem. Soc. 2001, 123 , 12911.

NH

CO2H

(S)-Proline

84% ee

74% eeO

ON O

O

H

TS

74% ee

N O O

O

(S)-Proline1N HClO4

MeCN, 80 °C, 10 d(67% yield)

O

O

N

27% ee

86% ee

(S)-Phenylalanine1N HClO4

MeCN, 80 °C, 40 h(82% yield)

O

O

O

(S)-Proline

DMSO, 65 °C, 5 d

(S)-Phenylalanine1N HClO4

MeCN, 80 °C, 40 h

O

O32% ee

95% ee

H2N CO2H

Ph

(S)-Phenylalanine

Danishefsky, S. J. J. Am. Chem. Soc. 1976, 98, 4975Agami, C. Tetrahedron 1984, 40, 1031.

Phenylalanine Catalyzed Intramolecular Aldolizations

O

CHO

1a(25 mol%)

CH3CN, rt, 23 h(68% yield) O OH

>99% de, 94% ee

HO O

98% de, 94% ee

1b(5 mol%)

CH3CN, rt, 3 h(77% yield)

NH

TBDPSO

CO2H

NH

TBDPSO

CO2

1a

1b

R2

O

OO

R1

R'

R

(S)-Proline(30 mol%)

DMF, rt or 5 °C20 h - 5 d

O

OHR2

O

R1

R'

R

74-96% yield73-99 % de, 76-87% ee

Iwabuchi, Y. Org. Lett. 2005, 7, 4185.Enders, D. Synlett 2006, 3399.

NBu4

Intramolecular Aldol Reactions

Direct Catalytic Asymmetric syn-Aldol Reactions

O

OHR'+

H Ar

Ocat. A or B(20 mol%)

NMP4 °C, 16-48 h

O

R'Ar

OH

OHORH3C

H2N CO2H

H

A: R = HB: R = t-Bu

O

OH

OH

NO2

O

OH

OH O

OH

OH

NO2

With cat. AWith cat. B

75%, 15:1 dr, 90% ee>95%, 18:1 dr, 98% ee

70%, 8:1 dr, 86% ee87%, 10:1 dr, 80% ee 78%, 12:1 dr, 94% ee

O

HR

N

HO

H

H

R'

O

OH

Barbas, C. F., III, J. Am. Chem. Soc. 2007, 129 , 288

Organocatalysis

Catalysis

Biocatalysis Metal catalysis Organocatalysis

Organocatalysis

Lewis bases

Lewis acids

Brønsted bases

Brønsted acids

· Organocatalysis: The catalysis with small organic molecules, where an inorganic element is not part of the active principle.

iminium catalyst, enamine catalyst, NHC catalystchiral dialkylaminopyridine

phase transfer catalyst, ketone catalyzed epoxidations

small molecule H-bond catalyst

cinchona alkaloid catalyzed alcoholyses of anhydride

Isolable NHCs

N

N

R

R

R1

R1

p-electrondonation

s-electronwithdrawal

*Electronic factors operating in both the p and s frameworks resultin a "push-pull" synergistic effect to stabilize the carbene.

*p donation into the carbene from the out-of-plane p orbital of heteroatoms stabilizes electrophilic reactivity of carbenes.

*The electronegative heteroatoms adjacent to C-2 provide additional stability through the framework of s bonds.

* The combined effect is to increase the singlet-triplet gap and stablize the singlet-state carbene over the more reactive triplet-state carbene.

Scheidt, K. A. Aldrichimica Act. 2009, 42, 55.Bertrand, G. Chem. Rev. 2000, 100 , 39.

Additive Effect

O+

H

O

R

(S)-Proline (30 mol%)(S)-BINOL (1 mol%)

acetone/DMSO (3:1)0 °C, 48 h

O OH

R

OH

OH

(S)-BINOL

O OH

Br

O OHO OH

Without BINOLWith BINOL

82%, 75% ee76%, 97% ee 43%, 72% ee

56%, 98% ee

10%, 92% ee23%, 87% ee

Shan, Z. J. Org. Chem. 2006, 71, 9510.