Enantioselective Synthesis of (-)-Coniine
Jeffrey Cannon
Project Advisor: Donald Deardorff

     (-)-Coniine is a toxic six-membered ring alkaloid that is isolated from spotted hemlock. The molecule has been a popular synthetic target for showcasing new methods of enantioselective synthesis. Our own strategy for the synthesis of (-)-coniine blends the enantioselectivity of an enzyme with the rich organometallic chemistry of pi-allyl palladium and ring-closing metathesis.
     The enzyme, oxynitrilase, is an especially robust enzyme found in raw almonds. This enzyme is able to produce the corresponding unsaturated cyanohydrin of trans-2-hexenal in greater than 99% enantiomeric excess. The cyano moiety is then converted to the ethyl ester and the hydroxy function transformed to an acetate leaving group in preparation for a subsequent palladium-catalyzed allylic substitution step. Importantly, the stereochemistry is conserved throughout this process. Exposure to palladium(0) initiates a novel substitutive 1,3-chiral transfer where the crucial 3-butenylamino fragment is incorporated at the gamma-position of the alpha,beta-unsaturated ester with full enantiofidelity. The unsaturated amine then undergoes an intramolecular Grubbs-catalyzed metathesis to form an unsaturated piperidine ring system. Catalytic hydrogenation over Pd/C affords the desired natural product in high enantiomeric excess and yield.
     The successful synthesis of (-)-coniine provides proof-of-concept for our sequential enzymatic-organometallic strategy. This unique methodology has widespread applications in the synthesis of other biologically important piperidines.
 

Support provided by: Pfizer Summer Undergraduate Research Fellowship