Total Synthesis of (-)-Anominine Ben Roembke Department of Chemistry and Biochemistry University of Maryland, College Park

Ben Bradshaw and Josep Bonjoch University of Barcelona School of Pharmacy Department of Pharmacology and Therapeutic Chemistry Much of their recent work has been with terpenoids but more generally they work on synthesis of a variety of natural products

What is Anominine? Anominine is a diterpenoid stored in the sclerotia of the Aspergillus flavus fungus What are all these words you say? Terpenoids are a large class of natural products that are assemblies of the 5 carbon unit isoprene  A diterpenoid contains 4 isoprene units (e.g. 20 carbons) “Sclerotia are reproductive bodies produced by certain fungi as a mechanism for survival and propagation of the species.” Gloer, J. Acc. Chem. Res. 1995, 28,

Sclerotia Scelrotia are much more rugid than other parts of the fungus thus they can survive in extreme conditions. Under favorable conditions sclerotia will germinate to produce mycelia (finger like protrusions that absorb nutrients), fruiting bodies (mushrooms, etc.) and spores Gloer, J. Acc. Chem. Res. 1995, 28,

Sclerotia In other words sclerotia is an important vestibule to store excess chemical energy to regrow fungus later on down the road. Sclerotia must also contain secondary metabolites to ward off potential predators Gloer, J. Acc. Chem. Res. 1995, 28,

Anominine Exhibits an activity against the crop pest Helicoverpa zea  Cited as the most important insect pest in terms of economic losses in the United States Such a compound could be useful as an insecticide if able to be produced Gloer, J. Acc. Chem. Res. 1995, 28,

Robinson Annulation Starts with a Michael addition No stereochemistry at this point Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Robinson Annulation Catalyst contains two elements of chirality  Axial chirality (hindered rotation)  Chiral center (L-Proline) Chiral catalyst results in an asymmetric catalysis Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, a )-binam-L- Proline N-Ts-(S a )-binam-L- Proline

Robinson Annulation Covalent catalysis Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Robinson Annulation Newly formed alkene can act as a nucleophile to close the ring Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Wieland-Miescher Ketone Gives correct enatiomer in 94% ee and 96% yield Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Dialkyl Cuprate Reaction of the Wieland-Miescher ketone with a dialkyl cuprate yielded the correct enantiomer of the second quaternary carbon in 94%ee Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Diasterioselective Reduction of Ketone Hydride attacks from less sterically hindered side creating this alcohol Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Grieco Elimination Treatment of alcohol with aryl selenocyanate and tributyl phosphine creates alkyl aryl selenide. Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132, Greico, P. J. Org. Chem. 1976, 41,

Oxidation of the Selenide mCPBA (meta chloro perbezoic acid) is used to oxidize the selenide This makes a chiral center at the selenium. Only one of the enatiomers will react to form the alcohol due to hindered rotation Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Considerations This reaction did not work in dry solvent. Why? Oxidation by mCPBA is not a stereoselective process but only one of the two chiral selenoxides will react Water was introduced into the system establishing this equilibrium: Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Epimerization at Selenium Selenoxide reacts with the endocyclic alkene to form the fourth cis-stereo center Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Coupling of Indole to Product A Lewis acid had to be used to activate the double bond for nucleophilic attack KF in ethanol was added which cleaved the acetate Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Oxidation of Alchol with TPAP TPAP (tetra-n-propylammonium perruthenate): Oxidizes carbon one electron at a time Bradshaw, B; Bonjoch, J. J. Am. Chem. Comm. 2010, 132,

Wittig Reaction The Wittig reaction reduces the two carbonyls in the compound

Selective Olefin Cross-Metathesis Alkene gains two methyl groups through this process

(-)-Anominine The TES group is cleaved by TBAF (tetra-n- butylammonium fluoride) to give the final product

Acknowledgements Sonja Dr. Davis