Natural product synthesis via anodic cyclization reactions: Enantioselective synthesis of (-)-alliacol A

Since the inception of our group, we have used anodic oxidation to form radical cation intermediates from electron rich olefins. These intermediates are highly reactive and are used to initiate intramolecular cyclization reactions. Because anodic oxidation has the ability to reverse the polarity of functional groups, entirely new synthetic disconnections are created with this methodology. Past efforts have focused on coupling reactions between enol ethers and aromatic rings such as substituted phenyl rings or furan rings. The furan ring proved to be one of the most reactive systems studied in our lab.; In order to further study the synthetic utility of the furan/enol ether cyclization reaction we have used it to synthesize the natural product alliacol A. In this experiment, the anodic coupling reaction was used to rapidly assemble a highly functionalized bicyclic furan that was then submitted to a Friedel-Crafts alkylation reaction. The sequence quickly afforded the tricyclic core of the natural product in an efficient manner. The novel approach provided an entirely new synthetic disconnection for the molecule. Use of a copper catalyzed asymmetric Michael addition produced a chiral substrate for the anodic cyclization reaction and allowed for the first enantioselective synthesis of the natural product.; The approach we have developed to synthesize alliacol A may also be used to construct other natural products. Along these lines, the other anodic cyclizations which have been studied include 5-exocyclic trigonal reactions of bicyclic furans, 6-endocyclic trigonal reactions of bicyclic furans and 5-endocyclic trigonal cyclizations of bicyclic furans. The 5-exo reaction was found to be very efficient even when not fully optimized. Attempts to perform the same 5-exo ring closure using radical initiated methods failed. This observation provides evidence that the radical cation is much more reactive than an ordinary radical species. The unoptimized success of the 6-endo reaction suggests that this reaction may lead to an approach for the asymmetric synthesis of the arteanniun family of natural products.; For ordinary olefins, the 5-endo case is known to suffer from poor orbital and is not considered synthetically useful. We were very interested to learn if a highly reactive radical cation might be able to overcome this challenge. While we have met with some success in this effort, further work is needed and is currently underway by other members of our group.