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Pitt CHEM 2320 - Enantioselective Organo Cascade Catalysis

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Enantioselective Organo-Cascade CatalysisHuang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. JACS, 2005, ASAP Erick B. Iezzi, PhDCurrent LiteratureOctober 15, 2005Why 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 materialsAsymmetric 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, 2085OOPO3-2OHNH2-EnzNOPO3-2OHEnzH-2O3POOHOHNOPO3-2OHEnzHOHOH-2O3POOOPO3-2OHOHOH-2O3POO OHRONH2-EnzO ORNH Enz-CO2RNHEnzH2OROfructose 1,6-diphosphate (FDP)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, 9336-9337List, et al. J. Am. Chem. Soc. 2002, 124, 5656-5657OCHONO2NH2OMe+ +L-Proline(35 mol%)DMSO50%HNONO2OMe94% ee20 mol%HOi-PrNNCO2BnBnO2C+(S)-Proline(10 mol%)CH3CN, 0 oCthen NaBH4,EtOH95%NNCbzCbzi-PrHO>95% eei. H2, Raney-Ni,MeOH, AcOHii. Phosgene, Et3N,CH2Cl2ONHOBn64%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, 4243-4244NHCO2MeMeO2C•HCl5NHMeO2C•HClCO2MeBnBn67NHNOMeMeMePh•HClCatalystsEnantioselective 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 interactionsNHNOMePhMeMeMeRONucleophile (Nu)+Electrophile (E)+catalystImEncascadecatalysisNuOREcascadeproductCascade Catalysis: Merging Iminium (Im) and Enamine (En) ActivationOrgano-Cascade Catalysis: Effect of Catalyst and SolventOrgano-Cascade Catalysis: Scope of Enal Component and Representative NucleophilesOrgano-Cascade Catalysis: Employment of Discrete Amine Catalysts to Enforce Cycle-Specific SelectivitiesMacMillan, et al. J. Am. Chem. Soc. 2005, ASAPNHNOMePhMeMeNHNOMeMeMeMe(5R)-iminium (2S)-enaminecatalystcatalyst(7.5 mol%)(30 mol%)catalyst combination Aenamine catalyst and Eadded after consumption of NuNHNOMePhMeMeNHNOMeMeMeMe(5R)-iminium (2R)-enaminecatalystcatalyst(7.5 mol%)(30 mol%)catalyst combination Benamine catalyst and Eadded after consumption of NuPhOHMeSNSPhPhFOO OONHOtButBuOOOMeMeH Hcatalystcombination ACHCl3THF/i-PrOHcatalystcombination BCHCl3THF/i-PrOHHOFH MeHOFH Me16:1 anti:syn99% ee, 81% yield9:1 syn:anti99% ee, 62% yieldSummaryMacMillan 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


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Pitt CHEM 2320 - Enantioselective Organo Cascade Catalysis

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