Asymmetric Palladium-Catalyzed [3+2] Cycloadditions of Trimethylenemethane

Scott Krabbe University of North Carolina at Chapel Hill

January 27, 2012

5-Membered Rings in Natural Products

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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

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Cycloadditions of Pd-Trimethylenemethane

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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  

First Catalytic Asymmetric Variant

Hayashi, T. Tetrahedron Lett. 1989, 30, 375 7  

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  

Asymmetric [3+2] of Nitroalkenes

Trost, B. M. et. al. Org Lett. 2012, 14, 234 12  

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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Asymmetric [3+2] of Imines

Trost, B. M. et. al. J. Am. Chem. Soc. 2007, 129, 12398 14  

[3+2] of Substituted Pd-TMM

Trost, B. M. et. al. J. Am. Chem. Soc. 1993, 115, 6636 15  

Cycloaddition of Ketimines

Trost, B. M. et. al. J. Am. Chem. Soc. 2010, 132, 8238 16  

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 18  

Spirocyclic Oxindolic Cyclopentanes

Trost, B. M. et. al. J. Am. Chem. Soc. 2007, 129, 12396 19  

What about methylenetetrahydrofurans?

BINOL Derivatization

Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 7664 20  

Diverse Methylenetetrahydrofurans

Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 7664 21  

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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Acknowledgements

•  Professor Jeff Johnson •  Johnson Group •  NSF GRFP

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Regioselectivity with Substituted TMM Precursors

Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 19483 24  

Additional Ligand Optimization

Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 19483 25  

Ligand Development for Carbocycle Formation

Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 19483

Mechanistic Rationale

Trost, B. M. et. al. J. Am. Chem. Soc. 2007, 129, 12396 27  

Preliminary Investigations

Trost, B. M. et. al. J. Am. Chem. Soc. 2011, 133, 7664 28  

Synthesis of TMM precursors

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