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