Expanding the uses of the NCAL and finding the spectrum of substrates best suited for such a transformation has been the main effort of my research. Previous studies had focused on aldedydes as the requisite functionality that would provide the needed electrophilicity in order to complete the aldol; however, recent advancements have introduced ketones as a viable carbonyl. With an established protocol in hand, I set out to explore various substrates that could yield Beta-lactones in good to moderate yields such as amino acid derivatives, diones, and large cyclic formations as well as simple, straight chain acids with varying groups Alpha to the ketone. In general, I was able to establish a basic framework of substrates that are highly and/or moderately susceptible towards the NCAL and current studies continue to further expand the scope. In addition to making Beta-lactones, I investigated alkyl cuprates as soft nucleophiles to afford addition at the Beta carbon yielding a variety of acids. Substrates for cuprate additions have been expanded to bulkier and multi-cyclic Beta-lactones and applied to the synthesis of a Merck IND intermediate. Additions to bi- and tri-chloro Beta-lactones due to the presence of the resulting moity in natural products are currently being studied.

The recently isolated bacterial metabolites, belactosins A-C from a fermentation broth of Streptomyces sp. UCK14, uniquely contain a β-lactone dipeptide motif and exhibit anticancer activities. The enantioselective synthesis of (-)-belactosin C and derivatives was accomplished in a concise manner employing the tandem, Mukaiyama aldol-lactonizaton (TMAL) process and test their bioactivities. . One approach involved a distal double diastereoselective TMAL reaction with a dipeptide glyoxamide, whereas a second approach involved amide coupling of a dipeptide with a β-lactone carboxylic acid, obtained via the TMAL process employing a chiral silyl ketene acetal. Enzymatic assays showed that the belactosins act as the dual inhibitors of the proteasome and the thioesterase domain of fatty acid synthase. Spongiolactone which uniquely contains a cyclopentyl-fused β-lactone was isolated in 1986 from Spongi-onellagracilis No biological activity have been reported for this compound; however, the acylating potential of the resident β-lactone warrants screening for potential activity. After many setbacks in the synthesis of spongiolactone, significant progress has been made. Importantly, NCAL process also enabled a concise construction of [3.2.0]-bicyclo β-lactone, which is the key structure in the spongiolactone synthesis and only a few steps remained to complete the synthesis.

Natural products are essential tools for basic cellular studies leading to the identification of medically relevant protein targets and the discovery of potential therapeutic agents. We have developed a set of second generation diazo reagents with small steric footprints, namely an alpha-trifluoroethyl (HTFB) diazo reagent, for simultaneous arming and SAR studies of bioactive natural products. The Rh(II)-catalyzed O-H insertions of several alcohol-containing natural products, including the potent translation inhibitor lactimidomycin, are investigated and useful reactivity and both chemo- and site- (chemosite) selectivities are observed. The alpha-trifluoroethyl diazo reagents (HTFB) shows clear differences in the IL-2 reporter assay with FK506 derivatives and provides greater retention of biological activity in a hMetAP2 proliferation assay of fumagillol derivatives compared to the first generation pbromophenyl diazo reagent (HBPA). The synthetic utilities of the new alpha-trifluoroethyl diazo reagent (HTFB) provide a great new tool for basic cellular studies facilitating the discovery of new drug candidates for human disease. Furthermore, we are interested in methodologies for beta-lactone synthesis and transformations. In this study, we demonstrated synthetic versatilities of beta-lactones for the synthesis of beta-lactam congeners of orlistat as fatty acid synthase inhibitors via SnCl4- promoted tandem Mukaiyama aldol-lactonization (TMAL) reaction and a one-pot, mild conversion of beta-lactones to beta-lactams. The inhibitory activities of the derived beta-lactam derivatives are determined in a biochemical fluorogenic assay using recombinant FASTE, and the micro-molar range FAS-TE inhibitory activities were observed. Additionally, we pursued synthetic studies toward the total synthesis of spongiolactone, which is a unique beta-lactone-containing marine diterpenoid, isolated from the marine sponge Spongionella gracilis. This natural product bears a unique tricyclic beta-lactone core possessing four contiguous stereogenic centers and an additional stereogenic quaternary carbon on a cyclohexyl appendage. We completed the total synthesis of 6,15-bis-epi-spongiolactone by employing an intramolecular nucleophilecatalyzed aldol-lactonization (NCAL) process as the key step to construct the fused tricyclic beta-lactone core. Importantly, we developed a double diastereoselective and, for the first time, a kinetic resolution via the NCAL process that enables an enantioselective strategy to the tricyclic beta-lactone core of (+)-spongiolactone.