Enamine Catalysis: Fifty Years in the Making! Stork's landmark 1954 publication outlines benefits of enamines vs enolatesNOOOMePhCNOPhOAlkylationAcylationMichaelAdditionStork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.Enamine Catalysis: Fifty Years in the Making! Stork's landmark 1954 publication outlines benefits of enamines vs enolatesNOOOMePhCNOPhOAlkylationAcylationMichaelAdditionStork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.Enamine Catalysis: Inspiration from Biology! Mechanism of class I aldolases is proposed to involve enamine intermediatesFructose bisphosphate aldolaseNH2NHOOPO32–OHHOHOPO32–NOHOHOHOPO32–OHOPO32–OH2–O3POOOHOHOHOPO32–2–O3PORutter, W. J. Fed. Proc. Am. Soc. Exp. Biol. 1964, 23, 1248Lysine reside is required for catalytic activityEnamine Catalysis: Early Adoption in Total Synthesis! Woodward-Wieland-Miescher enamine cyclization for steroid synthesisWieland, P.; Miescher, K. Helv. Chim. Acta 1950, 33, 2215OMeMeOHOHHH5IO6OMeMeOOHNHHOAcbenzeneOMeMeHCHOWoodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223O OMeOMeOOHOHHNHNaOHOOHOMeOHOOHOOOMeHajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasionOOMeOMeproline(200 mol%)MeCN, HClO480 ºCMeOOproline(3 mol%)DMFMeOOOH98% ee 67% eeJ. Org. Chem. 1974, 39, 1615. Angew. Chem. Int. Ed. 1971, 10, 496.German Patent DE2102623 (July 29, 1971)German Patent DE2014757 (Oct 7, 1971)Hajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasionOOMeOMeproline(200 mol%)MeCN, HClO480 ºCMeOOproline(3 mol%)DMFMeOOOH98% ee 67% eeJ. Org. Chem. 1974, 39, 1615. Angew. Chem. Int. Ed. 1971, 10, 496.German Patent DE2102623 (July 29, 1971)German Patent DE2014757 (Oct 7, 1971)97% eeHajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasionOOMeOMeproline(200 mol%)MeCN, HClO480 ºCMeOOproline(3 mol%)DMFMeOOOH98% ee 67% eeJ. Org. Chem. 1974, 39, 1615. Angew. Chem. Int. Ed. 1971, 10, 496.German Patent DE2102623 (July 29, 1971)German Patent DE2014757 (Oct 7, 1971)97% eeHajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasionOOMeOMeproline(200 mol%)MeCN, HClO480 ºCMeOOproline(3 mol%)DMFMeOOOH98% ee 67% eeJ. Org. Chem. 1974, 39, 1615. Angew. Chem. Int. Ed. 1971, 10, 496.German Patent DE2102623 (July 29, 1971)German Patent DE2014757 (Oct 7, 1971)97% ee3210Bifunctional Enamine Catalysis: Generic Induction Platform! Use of proline or proline-type activation a widely exploited mode of ketone activationR'ORNHOOHXYHNHROOketoneprolineBifunctionalactivationN NCbzCbzR'ORNNHCbzCbzJørgensen JACS 2002, 124, 6254.R'ORList Org Lett 2001, 13, 2423.OHMeMeMeO MeMeOHList Org Lett 2001, 3, 573.X YAminationCross-AldolR'PhNO2Nitro-olefinadditionNO2PhBifunctional Enamine Catalysis: Generic Induction Platform! Use of proline or proline-type activation a widely exploited mode of ketone activationR'ORNHOOHXYHNHROOketoneprolineBifunctionalactivationN NCbzCbzR'ORNNHCbzCbzJørgensen JACS 2002, 124, 6254.R'ORList Org Lett 2001, 13, 2423.OHMeMeMeO MeMeOHList Org Lett 2001, 3, 573.X YAminationCross-AldolR'PhNO2Nitro-olefinadditionNO2PhBifunctional Enamine Catalysis: Generic Induction Platform! Use of proline or proline-type activation a widely exploited mode of ketone activationR'ORNHOOHXYHNHROOketoneprolineBifunctionalactivationN NCbzCbzR'ORNNHCbzCbzJørgensen JACS 2002, 124, 6254.R'ORList Org Lett 2001, 13, 2423.OHMeMeMeO MeMeOHList Org Lett 2001, 3, 573.X YAminationCross-AldolR'PhNO2Nitro-olefinadditionNO2PhBifunctional Enamine Catalysis: Generic Induction Platform! Use of proline or proline-type activation a widely exploited mode of ketone activationR'ORNHOOHXYHNHROOketoneprolineBifunctionalactivationN NCbzCbzR'ORNNHCbzCbzJørgensen JACS 2002, 124, 6254.R'ORList Org Lett 2001, 13, 2423.OHMeMeMeO MeMeOHList Org Lett 2001, 3, 573.X YAminationCross-AldolR'PhNO2Nitro-olefinadditionNO2PhMangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 6722.86%5:1TFA86%94%Et2OMeMeMe5:197%DMSO73%64%97%19:195%–78 to –40 ºC–20 to +4 ºC87%95%>19:1>19:1–20 to +4 ºC79%95%OHOAcOHOBn95%95%Predictable Stereochemistry for Aldol and Mannich! Use of proline or proline-type catalysts leads to anti-aldol or syn-MannichXYHNHROOBifunctionalactivationOHNHROOHR'OH R'ROHAldolanti-selectiveNHNHROOR'HPMPOH R'RNHPMPMannichsyn-selective! Maruoka's binaphthyl catalyst is a significant advance to access opposite stereoisomersNHNHTfNNTfHROHR'NNTfHRNR'HOH R'ROHSyn-aldol: ACIEE 2004, 43, 6722OH R'RNHPMPAnti-Mannich: JACS 2005, 127, 16408Predictable Stereochemistry for Aldol and Mannich! Use of proline or proline-type catalysts leads to anti-aldol or syn-MannichXYHNHROOBifunctionalactivationOHNHROOHR'OH R'ROHAldolanti-selectiveNHNHROOR'HPMPOH R'RNHPMPMannichsyn-selective! Maruoka's binaphthyl catalyst is a significant advance to access opposite stereoisomersNHNHTfNNTfHROHR'NNTfHRNR'HOH R'ROHSyn-aldol: ACIEE 2004, 43, 6722OH R'RNHPMPAnti-Mannich: JACS 2005, 127, 16408Monofunctional Enamine Catalysis! Bifunctional activation is not absolutely required for selective catalysisHOMe10 mol% catalystthen, MeOH/CSAMeOOMeMeNNHMeOBn•TCAMeOH4:1 (ant:syn)94% ee! Imidazolidinone and Jørgensen-type frameworks have been widely appliedNNHMeOBnNNHMeOBnNHArArOTMSNHArArMeMeHEnamine Chemistry with Jørgensen's CatalystArArOTMSNHFranzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.OHROHBnFOHi-PrBrOHEtS PhOHEtNHNCO2EtCO2EtOHEtHNCO2EtPMPOHEtOMe74%, 94% ee74%, 93% ee83%, 93% ee83%, 94% ee, 4:1 dr79%, 90% ee83%, 96% eeArArOTMSNREOHEtNBn284%, 90% eeChi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.OHBnOH70%, 87% eeIbrahem, I.; Zhao, G.-L.; Sunden, H.; Córdova, A. Tettrahedron Lett. 2006, 47, 4659.Enamine Chemistry with Jørgensen's CatalystArArOTMSNHFranzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.OHROHBnFOHi-PrBrOHEtS PhOHEtNHNCO2EtCO2EtOHEtHNCO2EtPMPOHEtOMe74%, 94% ee74%, 93% ee83%, 93% ee83%, 94% ee, 4:1 dr79%, 90% ee85%, 96% eeArArOTMSNREOHEtNBn284%, 90% eeChi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128,