Enantioselective Organo-Cascade Catalysis

Enantioselective Organo-Cascade Catalysis Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. JACS, 2005, ASAP and

Catalytic Asymmetric Reductive Michael Cyclization Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. JACS, 2005, ASAP

Erick B. Iezzi, PhD Current Literature October 15, 2005

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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

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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) O

H

NH2-Enz OH OPO3-2

N

Enz

-2

O3PO

OH OPO3-2 -2

O3PO

H Enz OH N

-2

O3PO

OH O OH OH OPO3-2

OH OH OPO3-2

fructose 1,6-diphosphate (FDP)

O H OH

H

O NH2-Enz

R

N

Enz H

-CO2

R

N

Enz

H2O

R O

OH

O

O R

O

List, et al. Synlett. 2001, 11, 1675; Lerner, et al. Science 1997, 278, 2085 Erick Iezzi @ Wipf Group

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

O

20 vol%

CO2H N H 30 mol%

O +

H

O

OH

DMSO

NO2

NO2 68%, 94% ee

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

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

+

OMe

NH2

L-Proline (35 mol%)

+

20 mol%

NO2

O

HN

DMSO 50%

OMe

NO2 94% ee

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

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

BnO2C +

H i-Pr

N N

(S)-Proline (10 mol%) CH3CN, 0 oC CO2Bn

then NaBH4, EtOH 95%

HO

Cbz N Cbz N i-Pr

i. H2, Raney-Ni, MeOH, AcOH ii. Phosgene, Et3N, CH2Cl2 64%

O O

NH Bn

>95% ee

List, et al. J. Am. Chem. Soc. 2002, 124, 5656-5657 Erick Iezzi @ Wipf Group

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

5

MeO2C

CO2Me

N H

•HCl

MeO2C 6

Bn

CO2Me N H

Bn •HCl

O N

7 Ph

N H

Me Me

Me •HCl

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

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Enantioselective Organocatalytic Indole Alkylations. Design of a New and Highly Effective Chiral Amine for Iminium Catalysis (MacMillan and co-workers)

O N Ph

Me

N H

Me Me

Cat. 1

O

cocatalysts:

N

a = TFA b = p-TSA c = 2-NO2PhCO2H

Ph

Me Me Me Me

N H Cat. 2

Me 20 mol% cat. 1a N Me

Me

O

O

o

CH2Cl2, -40 C

N Me 85%, 56% ee

Me 20 mol% cat. 2a N Me

Me

O

O

CH2Cl2-i-PrOH, -83 oC, 19 h

N Me 82%, 92% ee

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

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Enantioselective Organocatalytic Indole Alkylations: Furanoindole Construction (MacMillan and co-workers) O N 2a Ph

N H

Me Me Me Me

•HO2CCF3

H

O

HO

CO2t-Bu

20 mol% cat. 2a t-BuO2C

N

O

Bn

O N H Bn

CH2Cl2-i-PrOH, -60 oC, 40 h

80%, 93% ee, 12:1 dr

O HO

20 mol% cat. 2a O N Bn

O N H Bn

CH2Cl2-i-PrOH, -80 oC, 72 h

-for construction of Diazonamide A core

90%, 82% ee

MacMillan, et al. PNAS 2004, 101, 5482-5487 Erick Iezzi @ Wipf Group

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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 CHO OSiMe2Ph

O 18 mol% [CuH(PPh3)]6 PhMe2SiH (1.5 equiv.) Toluene, rt, 4 h

O

OH

O2N BF3•OEt2, -78 oC, 1 h

NO2 68%

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

• Use reductively generated (via Hantzsch ester)

enamine intermediate (5) to react with in situ electrophiles List, et al. J. Am. Chem. Soc. 2005, ASAP

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Catalyst Screening for the Reductive Michael Cyclization

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

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Substrate Variation in the Reductive Michael Cyclization

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

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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)

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

catalyst-catalyst interactions Cascade Catalysis: Merging Iminium (Im) and Enamine (En) Activation Nucleophile (Nu) + Electrophile (E) + R

O

O N Ph

R

Me

N H

Me Me Me

Im

En

cascade catalysis

catalyst

Nu

O E cascade product

MacMillan, et al. J. Am. Chem. Soc. 2005, ASAP Erick Iezzi @ Wipf Group

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Organo-Cascade Catalysis: Effect of Catalyst and Solvent

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

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Organo-Cascade Catalysis: Employment of Discrete Amine Catalysts to Enforce Cycle-Specific Selectivities catalyst combination A enamine catalyst and E added after consumption of Nu O

Me Ph

catalyst combination B

O

H H

tBuO

CHCl3 THF/i-PrOH

F 16:1 anti:syn 99% ee, 81% yield

Me

N H

Me

N

Me Me Me

N H

Ph

(5R)-iminium

(2S)-enamine

catalyst

catalyst

(7.5 mol%)

(30 mol%)

catalyst combination B

H

enamine catalyst and E

F

added after consumption of Nu

9:1 syn:anti 99% ee, 62% yield

O N N H

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

Erick Iezzi @ Wipf Group

O

H Me O

OtBu CHCl3 THF/i-PrOH

Me Me Me Me

N H

H

H

O OO O S S Ph N Ph F O

H Me O

catalyst combination A

O

N

15

Me

O N

Me Me Me

Ph

Me

N H

Me Me

(5R)-iminium

(2R)-enamine

catalyst

catalyst

(7.5 mol%)

(30 mol%)

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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

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