Synthetic Studies Toward Complex Polycyclic Natural Products

The first chapter of this dissertation describes the use of an intramolecular Staudinger/aza-Wittig reaction in the synthesis of 1,2,5,6-tetrahydro-1,2,4-triazines, a structural motif of the natural product noelaquinone. The DEF ring system of noelaquinone was prepared in 13 steps and 2% overall yield with key steps featuring a Cu(I)-catalyzed C-arylation and the controlled acidic hydrolysis of the PMB protective group. The second chapter describes the investigation of reactions between methyl 3-oxo-2-oxabicyclo[2.2.0]hexane-6-carboxylate and an indolo-indoline dimer in the presence of BF3·OEt2. Two tricyclic-fused heterocyclic products and a diene carboxylic acid have been obtained through a ring opening process, a retro-[2+2] cycloaddition, and a conjugate addition from the indole fragment. The third chapter describes progress toward the total synthesis of haouamine A. Several routes to the marine alkaloid have been attempted. The challenges associated with the late stage lactam reduction, epoxidation, and aromatization strategy to prepare the necessary tetrahydropyridine and aza-cyclophane moieties are discussed

Metagenomic Analysis of Apple Orchard Soil Reveals Antibiotic Resistance Genes Encoding Predicted Bifunctional Proteins▿

To gain insight into the diversity and origins of antibiotic resistance genes, we identified resistance genes in the soil in an apple orchard using functional metagenomics, which involves inserting large fragments of foreign DNA into Escherichia coli and assaying the resulting clones for expressed functions. Among 13 antibiotic-resistant clones, we found two genes that encode bifunctional proteins. One predicted bifunctional protein confers resistance to ceftazidime and contains a natural fusion between a predicted transcriptional regulator and a β-lactamase. Sequence analysis of the entire metagenomic clone encoding the predicted bifunctional β-lactamase revealed a gene potentially involved in chloramphenicol resistance as well as a predicted transposase. A second clone that encodes a predicted bifunctional protein confers resistance to kanamycin and contains an aminoglycoside acetyltransferase domain fused to a second acetyltransferase domain that, based on nucleotide sequence, was predicted not to be involved in antibiotic resistance. This is the first report of a transcriptional regulator fused to a β-lactamase and of an aminoglycoside acetyltransferase fused to an acetyltransferase not involved in antibiotic resistance