Enantioselective Organo-Cascade CatalysisHuang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.

JACS, 2005, ASAP

and

Catalytic Asymmetric Reductive Michael CyclizationYang, J. W.; Hechavarria Fonseca, M. T.; List, B.

JACS, 2005, ASAP

Erick B. Iezzi, PhDCurrent LiteratureOctober 15, 2005

Erick Iezzi @ Wipf Group 1 10/15/2005

Why are these articles significant?

• Use chiral amines as enantioselective catalysts (iminium and enamine intermediates) to rapidly assemble complex structures

• MacMillan and co-workers use amine catalysts to mimic an enzymatic ‘cascade catalysis’ that controls product stereochemistry via intermolecular reactions

• List and co-workers use a single amine catalyst to generate complexity via an intramolecular tandem sequence

• Both achieve products with high yields and selectivities (diastereo- and enantioselectivity) under user-friendly conditions with safe and simple starting materials

Erick Iezzi @ Wipf Group 2 10/15/2005

Asymmetic Aminocatalysis• Amines can activate carbonyl groups (i.e., acetone) as do Lewis or BrØnsted acids - Iminium ion enhances both electrophilicity and α-C-H-acidity

• Two aminocatalytic pathways: 1. Iminium catalysis - Knoevenagel-type condensations, cyclo- and nucleophilic additions 2. Enamine catalysis - Electrophilic addition and pericyclic reactions

• Aminocatalysis is a biomimetic strategy used by important enzymes such as class I aldolases (enamine catalysis) and ketoacid decarboxylases (iminium catalysis)

List, et al. Synlett. 2001, 11, 1675; Lerner, et al. Science 1997, 278, 2085

O

OPO3-2

OH

NH2-EnzN

OPO3-2

OH

EnzH

-2O3PO

OH

O

H

N

OPO3-2

OH

EnzHOH

OH

-2O3PO

O

OPO3-2

OH

OH

OH

-2O3PO

O OH

R

O

NH2-Enz

O O

R

NH Enz

-CO2

R

NH Enz

H2O

R

O

fructose 1,6-diphosphate (FDP)

Erick Iezzi @ Wipf Group 3 10/15/2005

Proline-Catalyzed Direct Asymmetric Aldol Reaction (List and co-workers)

List, et al. J. Am. Chem. Soc. 2000, 122, 2395-2396

O

NO2

68%, 94% ee

OH

30 mol%

DMSO

NH

CO2H

O

NO2

H

O

+

20 vol%

Erick Iezzi @ Wipf Group 4 10/15/2005

Direct Catalytic Asymmetric Three-Component Mannich Reaction (List and co-workers)

Direct Catalytic Asymmetric α-Amination of Aldehydes(List and co-workers)

List, et al. J. Am. Chem. Soc. 2000, 122, 9336-9337

List, et al. J. Am. Chem. Soc. 2002, 124, 5656-5657

O

CHO

NO2

NH2

OMe

+ +

L-Proline(35 mol%)

DMSO50%

HNO

NO2

OMe

94% ee

20 mol%

H

O

i-Pr

N

NCO2Bn

BnO2C

+

(S)-Proline

(10 mol%)

CH3CN, 0 oC

then NaBH4,

EtOH

95%

NN

Cbz

Cbz

i-Pr

HO

>95% ee

i. H2, Raney-Ni,

MeOH, AcOH

ii. Phosgene, Et3N,

CH2Cl2O

NH

O

Bn64%

Erick Iezzi @ Wipf Group 5 10/15/2005

New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic Diels-Alder Reaction (MacMillan and co-workers)

MacMillan, et al. J. Am. Chem. Soc. 2000, 122, 4243-4244

NH

CO2MeMeO2C

•HCl

5

NH

MeO2C

•HCl

CO2Me

Bn Bn6

7

NH

N

O Me

Me

MePh

•HCl

Catalysts

Erick Iezzi @ Wipf Group 6 10/15/2005

Enantioselective Organocatalytic Indole Alkylations. Design of a Newand Highly Effective Chiral Amine for Iminium Catalysis

(MacMillan and co-workers)

NH

N

O Me

Me

MePh

cocatalysts:

a = TFAb = p-TSAc = 2-NO2PhCO2H

Cat. 1

NH

N

O Me

Ph

Cat. 2

MeMe

Me

N

Me

Me O

20 mol% cat. 1a

CH2Cl2, -40 oCN

Me

O

Me

85%, 56% ee

N

Me

Me O

20 mol% cat. 2a

CH2Cl2-i-PrOH,

-83 oC, 19 hN

Me

O

Me

82%, 92% ee

MacMillan, et al. J. Am. Chem. Soc. 2002, 124, 1172-1173

Erick Iezzi @ Wipf Group 7 10/15/2005

Enantioselective Organocatalytic Indole Alkylations: Furanoindole Construction (MacMillan and co-workers)

-for construction of Diazonamide A core

MacMillan, et al. PNAS 2004, 101, 5482-5487

NH

N

O Me

Ph

2a

MeMe

Me

N

Bn

t-BuO2C O

20 mol% cat. 2a

N

Bn

80%, 93% ee, 12:1 dr

•HO2CCF3

HO

CH2Cl2-i-PrOH,

-60 oC, 40 h

OH

CO2t-BuH

O

N

Bn

O

20 mol% cat. 2a

N

Bn

90%, 82% ee

HO

CH2Cl2-i-PrOH,

-80 oC, 72 h

OH

O

Erick Iezzi @ Wipf Group 8 10/15/2005

Catalytic Asymmetric Reductive Michael Cyclization (ASAP Article, List and co-workers)

• Use an amine catalyst to carry out a tandem sequence of events, which is similar to the metal-mediated reductive enolate generation-electrophile trapping process

• Use reductively generated (via Hantzsch ester) enamine intermediate (5) to react with in situ electrophiles

List, et al. J. Am. Chem. Soc. 2005, ASAP

O

18 mol% [CuH(PPh3)]6

PhMe2SiH (1.5 equiv.)Toluene, rt, 4 h

OSiMe2Ph

BF3•OEt2, -78 oC, 1 h

O2N

CHO

O OH

NO2

68%

Lipshutz, et al. Tetrahedron 2000, 56, 2779-2788

Erick Iezzi @ Wipf Group 9 10/15/2005

Catalyst Screening for the Reductive Michael Cyclization

List, et al. J. Am. Chem. Soc. 2005, ASAP

Erick Iezzi @ Wipf Group 10 10/15/2005

Substrate Variation in the Reductive Michael Cyclization

List, et al. J. Am. Chem. Soc. 2005, ASAP

Erick Iezzi @ Wipf Group 11 10/15/2005

Enantioselective Organo-Cascade Catalysis (ASAP Article, MacMillan and co-workers)

• Use amine catalysts to perform a ‘cascade catalysis’ of discrete events that mimic a biocatalytic assembly line, as opposed to the traditional ‘stop and go’ sequences

- Specifically, polyketide natural products (i.e., erythromycin and actinomyces) are assembled by polyketide synthases, which perform a successive decarboxylative condensations of simple precursors

(Khosla, et al. Annu. Rev. Biochem. 1999, 68, 219)

MacMillan, et al. J. Am. Chem. Soc. 2005, ASAP

• Imidazolidinone-based catalytic cycles are used to generate complex structures without catalyst-catalyst interactions

NH

N

O Me

Ph MeMe

Me

R O

Nucleophile (Nu)+

Electrophile (E)+

catalyst

Im En

cascadecatalysis

Nu O

R

E

cascadeproduct

Cascade Catalysis: Merging Iminium (Im) and Enamine (En) Activation

Erick Iezzi @ Wipf Group 12 10/15/2005

Organo-Cascade Catalysis: Effect of Catalyst and Solvent

Erick Iezzi @ Wipf Group 13 10/15/2005

Organo-Cascade Catalysis: Scope of Enal Component and Representative Nucleophiles

Erick Iezzi @ Wipf Group 14 10/15/2005

Organo-Cascade Catalysis: Employment of Discrete Amine Catalysts to Enforce Cycle-Specific Selectivities

MacMillan, et al. J. Am. Chem. Soc. 2005, ASAP

NH

N

O Me

PhMe

Me

NH

N

O Me

Me

MeMe

(5R)-iminium (2S)-enamine

catalyst catalyst

(7.5 mol%) (30 mol%)

catalyst combination A

enamine catalyst and E

added after consumption of Nu

NH

N

O Me

PhMe

Me

NH

N

O Me

Me

MeMe

(5R)-iminium (2R)-enamine

catalyst catalyst

(7.5 mol%) (30 mol%)

catalyst combination B

enamine catalyst and E

added after consumption of Nu

Ph

O

H

Me

SN

SPhPh

F

OO O O

NH

OtButBuO

OO

MeMe

H H

catalystcombination A

CHCl3THF/i-PrOH

catalystcombination B

CHCl3THF/i-PrOH

H

O

F

H Me

H

O

F

H Me

16:1 anti:syn99% ee, 81% yield

9:1 syn:anti99% ee, 62% yield

Erick Iezzi @ Wipf Group 15 10/15/2005

Summary

List and co-workers:

- Developed a highly enantioselective organocatalytic reductive Michael cyclization of enal enones - Practical and user-friendly conditions - Potential application in the synthesis of natural products

MacMillan and co-workers:

- Developed a new strategy for organo-catalysis based on the biochemical blueprints of cascade catalysis - Rapid access to structural complexity while achieving exquisite levels of enantiocontrol (combining catalytic cycles leads to enantioenrichment) - Studies in the area of triple cascade catalysis are underway

Erick Iezzi @ Wipf Group 16 10/15/2005