Our research program centers on the development of new synthetic methodology and new synthetic strategies and their application to the total synthesis of biologically active and structurally novel natural products.
Three major areas are currently under investigation: intramolecular photocycloadditions, synthesis of and manipulation of spiroketals, and the combination of asymmetric aldol and alkylation reactions in combination with olefin metathesis reactions.
The first area of interest involves the application of intramolecular photocycloaddition reactions in the synthesis of a variety of polycyclic natural products. Included in these targets are the platelet activating factor antagonist, ginkgolide B, CP263-114, the alkaloids magellanine, paniculatine, and serratinine, the antitumor taxanes, lubiminol and the antitumor agent ceroplastol. The central approach to these complex molecules relies on a stereoselective intramolecular photocycloaddition in which preexisting stereogenic centers on the tether between the enone and olefin are utilized to control the stereochemistry of the rest of the molecule. Asymmetric photocycloadditions are also under investigation. Ancillary to these studies are the use of zinc-copper homoenolates and bis-homoenolates for the construction of photocycloaddition substrates. We are also interested in developing new free radical reactions and their application to synthesis. An unusual reaction which involves a tandem radical cleavage of a cyclobutane ring and a radical ring expansion is currently under investigation. This reaction is the cornerstone of a novel synthetic approach to the phytoalexin, lubiminol.
The studies in spiroketal chemistry center around the addition of metalated pyrones to beta-alkoxy aldehydes followed by acid catalyzed cyclization for the synthesis of 6,6 - spiroketals. These spiroketals can be further functionalized and used as stereochemical templates for the control of stereochemistry on the rigid spiroketal template. Once properly functionalized, the spiroketals can be used directly or selectively converted to 2,6-tetrahydropyrans by a regio and stereoselective reductive cleavage which has recently been developed. Current targets in the spiroketal area include the antitumor agents spongistatin 1, bryostatin 11, and leucasandrolide A.
Studies in asymmetric enolate technology are at the center of the third area of research. The use of titanium enolates of acyloxazolidinethiones and acylthiazolidinethiones allows the production of either enantiomer of beta-hydroxy acid derivative without changing the chirality of the chiral auxiliary. This can be accomplished by simply changing the reaction conditions rather than changing the chiral auxiliary. Incorporation of an alkene into both the aldehyde and the acyloxazolidinethione allows for the enantioselective construction of alpha-omega dienes which can undergo ring-closing metathesis in the presence of the Grubbs ruthenium catalyst. The efficient formation of medium ring ethers has been accomplished using this strategy. An asymmetric glycolate alkylation has also been developed for the rapid construction of alpha-alpha' disubstituted ethers which can be utilized in the preparation of medium ring cyclic ethers by ring-closing metathesis. Targets such as laurencin, prelaureatin, isolaurallene have already been prepared through this technology and others such as trehazolin, isolaurallene, cocaine, and brevetoxin A are under investigation.