Characterization of E and Z-α-methylene γ-butyrolactones OBJECTIVE  The purpose of this study is to develop a new method for construction of the aryltetralignan ring system of the antimitotic natural product podophyllotoxin PRELIMINARY FINDINGS  A palladium (II)-catalyzed enyne cyclization method 1 was employed to form an alpha-methylene gamma- butyrolactone with orthogonal bromides  Elaboration of this lactone has yielded advanced intermediates en route towards the aryltetralignan ring system FUTURE WORK  End-game completion of this ring system  Alternative synthetic strategies α. EXPERIMENTAL DESIGN  Engman, M.; Paptchikhine, A.; Bergquist, J.; Church, T. L.; Leung, A. W.-M.; Andersson, P. G. “Iridium-Catalyzed Asymmetric Hydrogenation Yielding Chiral Diarylmethines with Weakly Coordinating or Noncoordinating Substituents.” Journal of the American Chemical Society, 2009, 131, 8855–8860.  Stadler, D.; Bach, T. “Concise Stereoselective Synthesis of (-)-Podophyllotoxin by an Intermolecular Iron(III)- Catalyzed Friedel-Crafts Alkylation.” Angewandte Chemie, International Edition, 2008, 47,  Ma, S.; Lu, X. “Divalent Palladium Catalyzed Stereoselective Synthesis of α-(Z)-(Halomethy1ene)-γbutyrolactone Derivatives and Its Mechanism.” Journal of Organic Chemistry 1991, 56, SUMMARY BACKGROUND MATERIALS AND METHODS PRODUCT CHARACTERIZATION FUTURE WORK REFERENCES BIBLIOGRAPHY. 1.Ji, J.; Zhang, C.; Lu, X. Journal of Organic Chemistry 1995, 60, Podophyllotoxins: Current Status and Recent Developments. Damayanthi, Y.; Lown, J. Current Medicinal Chemistry 1998, 5, Gupta, S.; Das, L.; Datta, A. B.; Poddar, A.; Janik, M. E.; Bhattacharyya, B. Biochemistry 2006, 45, CONTACTS/ACKNOWLEDGEMENT Jason N. Abrams: Funding: Louisiana Cancer Research Consortium (LCRC)  Readily accessible model system (Enyne 7) was prepared as well as Target Enyne 4 ●Pd(II)-catalyzed enyne cyclization produced target E and Z-α- methylene γ-butyrolactones 1.5:1 Z:E ratio (isolated yields)  Small scale functionalization successful with both model and target E and Z-α-methylene γ-butyrolactones (a) Intramolecular Lewis Acid-Mediated Cyclization; asymmetric alkene reduction; oxidation/ reduction sequence (b) Suzuki Coupling/ conversion of bromide to aldehyde (c) Pd(II)-catalyzed enyne cyclization (d) Sonogashira Reaction/ alkyne deprotection/ coupling with allyl chloroformate 4. Stereochemistry of diastereomers of lactones 3 and 8 determined by Dr. Ion Ghiviriga; Department of Chemistry; University of Florida. 5. X-ray Crystal Structure of Z-3 Determined by Dr. Naijue Zhu, Xavier University After Benoit, et al Retrosynthetic Strategy Pd(II)-Catalyzed Cyclization of Enyne 4/ Functionalization of Lactone 3 Preparation of Enyne 7 and subsequent Pd(II)-Catalyzed Cyclization See ref. 3 See ref. 2 PLAN A End-Game Synthetic Strategy: Lewis Acid-Mediated Intramolecular Alkylation PLAN C Alternative End-Game Synthetic Strategy: Intramolecular Heck Reaction PLAN B Alternative End-Game Synthetic Strategy: Intramolecular Friedel-Crafts Alkylation Preparation of Enyne 4 Functionalization of Resulting Lactone 8 See Ref. 5 See Ref. 4 Crystal Structure of the Tubulin/ Podophyllotoxin Complex Pharmacaphore of Podophyllotoxin Synthetic Efforts towards Podophyllotoxin via a Palladium(II)-Catalyzed Enyne Cyclization Strategy Jasmine Holmes 1 ; Corinne Williams 1 ; Jason N. Abrams 1 ; Ion Ghiviriga 2 1. Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 2. Department of Chemistry, University of Florida, Gainesville, FL FUTURE WORK/ STRATEGIES 1 H NMR X-Ray Crystal Structure