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Asymmetric Palladium-Catalyzed [3+2] Cycloadditions of Trimethylenemethane
Scott Krabbe University of North Carolina at Chapel Hill
January 27, 2012
Pd-Catalyzed [3+2] Cycloaddition of Trimethylenemethane
Trost, B. M. et. al. J. Am. Chem. Soc. 1979, 101, 6429, 6432
• Formation of Pd-trimethylenemethane complex • Reacts with electron deficient olefins • Variety of methylenecyclopentanes accessed
3
Difficulty in Development of Asymmetric Version
• Nucleophilic addition – enantiodetermining step • Occurs distal to the ligand set
Trost, B. M. et. al. J. Am. Chem. Soc. 2006, 128, 13328 5
First Asymmetric Variant Utilizes Chiral Auxiliaries
Trost, B. M. et. al. J. Am. Chem. Soc. 1989, 111, 6482 Trost, B. M. Pure Appl. Chem. 1988, 60, 1615 6
Phosphoramidite Ligands
Arimoto, H. et. al. Angew. Chem. Int. Ed. 2007, 46, 5746 Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 19483
• Various phosphites and HMPA perform well as ligands in achiral [3+2]
• Phosphoramidite ligands provide axial and point chirality • Initial hit with Feringa ligand provides modest %ee • Ligand optimization necessary
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Ligand Development for Carbocycle Formation
Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 19483 9
Asymmetric [3+2] of α,β-Unsaturated Ketones
Trost, B. M. et. al. J. Am. Chem. Soc. 2006, 1328, 13328 10
Asymmetric [3+2] of Higher Oxidation Substrates
Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 19483 11
Formal Synthesis of (+)-Cephalotaxine
Trost, B. M. et. al. Org Lett. 2012, 14, 234 Ikeda, M. et. al. Chem. Pharm. Bull. 1993, 41, 276
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Cycloaddition with Substituted TMM Precursors
Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 19483 17
Spirocyclic Oxindolic Cyclopentanes
Trost, B. M. et. al. J. Am. Chem. Soc. 2007, 129, 12396 19
What about methylenetetrahydrofurans?
Conclusions
• Palladium-catalyzed [3+2] cycloadditions of trimethylenemethane provide a wide variety of 5-membered rings with good chemo-, regio-, and diastereoselectivity
• Ligand tuning proved essential in identifying the optimal conditions • Phosphoramidite ligands provide carbocycles and heterocycles in excellent
yield and enantioselectivity
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Regioselectivity with Substituted TMM Precursors
Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 19483 24