Design of Novel Carbon-Carbon Bond Forming Processes


Our research program centers on the design, development and discovery of novel transition metal- and Lewis acid-promoted carbon-carbon bond forming processes for the enantio- and stereocontrolled synthesis of architecturally complex carbocycles and heterocycles with wide-ranging biological activities.


sp3-Geminal Organodimetallic Pd(II)/Main Group Metal Complexes: A major focus of our research program has centered on studying sp3-geminal organodimetallic palladium(II)/main group metal alkane complexes in synthesis. We have made significant advancements in the preparation of these reactive species and in establishing their distinct reactivity. Two approaches generating sp3-gem-dimetallic Pd(II)/main group metal alkane intermediates under catalytic conditions have been developed in our laboratories. We reported a catalytic entry into sp3-gem-organodimetallic iodopalladio-trialkylstannylalkane complexes by oxidative insertion of Pd(0) into the carbon-iodine bond of iodomethyltrialkylstannanes and established that these species exhibit carbenoid behavior. These results settled a long-standing debate on the cine substitution mechanism in the Stille coupling (Fillion, E.; Taylor, N. J. J. Am. Chem. Soc. 2003, 125, 12700-12701).



A second entry into sp3-geminal organodimetallic Pd(II)/main group metal complexes is via regioselective intramolecular carbopalladation of alkenyl metals. In the course of our studies on the carbopalladation of alkenyldimethyl alane derivatives, we discovered that (E)-2,2-disubstituted-1-alkenyldimethylalanes participate in 1,2-alkyl migration from aluminum to carbon with concomitant arylation at the 2-position when reacted intramolecularly with aryl iodides and triflates in the presence of a Pd(0) catalyst to furnish ethyl methyl substituted benzylic quaternary carbon centers (Fillion, E.; Carson, R. J.; Trépanier, V. E.; Goll, J. M.; Remorova, A. A. J. Am. Chem. Soc. 2004, 126, 15354-15355).



     Cataytic Friedel-Crafts Acylation and Alkylation Methods: We are also involved in the development of highly electrophilic acylating and alkylating agents with the objective of developing truly mild, catalytic and operationally simple Friedel-Crafts protocols. We have demonstrated that Meldrum’s acid derivatives are effective acylating agents in Friedel-Crafts reactions. 1-Benzocyclic ketones and their 2-alkyl analogs are conveniently fashioned from the metal triflate-catalyzed intramolecular Friedel-Crafts acylation of aromatics with 5-benzyl Meldrum’s acids. The protocol accommodates a wide variety of functional groups and has been applied to the synthesis of donepezil, a potent anti-Alzheimer drug [(a) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll J. M. J. Org. Chem. 2005, 70, 1316-1327. (b) Fillion E.; Fishlock, D. Org. Lett. 2003, 5, 4653-4656].



     The Yb(OTf)3-catalyzed annulation reactions of phenols with 5-alkylidene Meldrum’s acids enabled the synthesis of structurally diverse heterocycles in high isolated yields. A series of 4-substituted 3,4-dihydrocoumarins, 2,2-disubstituted 4-chromanones, coumarins, and 2-substituted chromones were readily and efficiently assembled, including the naturally occurring coumarins citropten, scoparone, and ayapin (Fillion, E.; Dumas, A. M.; Kuropatwa, B. A.; Malhotra, N. R.; Sitler, T. C. J. Org. Chem. In press).



     As part of our studies on Friedel-Crafts reactions, the Lewis acid-promoted fragmentation of oxabicyclo [3.1.0] hexanones for the enantio- and stereocontrolled synthesis of 8-membered carbo- and heterocycles was investigated (Fillion, E; Beingessner, R. L. J. Org. Chem. 2003, 68, 9485-9488).



     In addition to methodology development, our group has also been involved in the total synthesis of biologically relevant natural products. Taiwaniaquinol B, a diterpenoid exhibiting the uncommon fused 6-5-6 tricyclic carbon skeleton, has recently been prepared. Members of this family of natural products display aromatase inhibitory activity, which could lead to the development of valuable therapeutic agents in the treatment of estrogen-dependant cancers. A Lewis acid-promoted tandem intramolecular Friedel-Crafts/carbonyl a-tert-alkylation reaction has been exploited as the core strategy for the synthesis of the sterically congested 1-indanone-containing tricyclic structure (Fillion E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127, 13144-13145).



Our research plans are to fully develop the synthetic potential of organodimetallic species and electrophilic Meldrum’s acids in catalytic carbon-carbon bond forming transformations. The scope of these transformations is under investigation and the synthesis of a variety of bioactive natural products in progress.