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Intramolecular deMayo photocyclization: The total synthesis of hippadine and pratosine

Type: Graduate
Author(s): Charles Ochoa Chemistry & Biochemistry
Advisor(s): David Minter Chemistry & Biochemistry

Various total syntheses of the Lycorine-type pharmacologically active alkaloids hippadine and pratosine have been developed. However, most of these synthetic routes require prohibitively expensive materials and/or achieve yields that are subpar, making these schemes unlikely to be used in an industrial setting. Current research involves developing better synthetic methods for these two alkaloids starting with a 6,7-disubstituted isoquinoline. These syntheses are appealing since they utilize readily available starting materials and avoid expensive catalysts. The key step in the synthetic scheme centers around an intramolecular de Mayo photocyclization which involves a reaction between an alkene moiety in the isocarbostyril system and a 1,3-diketone (a functionalized tether on nitrogen), which forms a third ring in the structure of the molecule. Research on a model system (an isocarbostyril without the substituents at positions 6 and 7) for these natural products has been done in order to elucidate the optimal conditions for each step on the synthetic strategy. Initial attempts were made in order to synthesize the 6,7-disubstituted isocarbostyril with the 1,3-diketone tether so that the deMayo photocyclization could be performed. However, the established synthetic strategy led to compounds along the synthetic route that had very undesirable solubility properties. To resolve this issue, the substituents were replaced with bulkier, more non-polar moieties in order to increase the solubility of the compound in ethyl ether.

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Mutated leucyl- tRNA synthetase for the incorporation of unnatural amino acids

Type: Undergraduate
Author(s): Courtney Wright Chemistry & Biochemistry
Advisor(s): Youngha Ryu Chemistry & Biochemistry

Traditionally the genetic code has utilized the canonical twenty amino acids in order to construct proteins and facilitate life. The process of translation involves an RNA template and codons that will be read and matched to corresponding tRNA molecules carrying charged amino acids. An aminoacyl tRNA synthetase specific to each amino acid is responsible for loading and charging the amino acid to the tRNA. In recent years, a few orthogonal pairs of the tRNA and aminoacyl tRNA synthetase have been utilized to expand the genetic code past the traditional 20 amino acids. Expanding the genetic code allows for new insight into protein function, structure, and interactions within the cell. The introduction of new amino acids could lead to proteins with new chemical or biological activity and even advantageously alter function leading to evolutionary events. In our research we attempt to incorporate unnatural amino acids using a leucyl-tRNA synthetase from Methanobacterium thermoautotrophicum and a tRNA which will suppress the amber stop codon (TAG). A mutant LeuRS lacking an editing domain (MLRS CP1) was generated. The best mutant was isolated and sequenced. The leucine binding site, determined from sequence homology, was randomized at five amino acids to create a library of mutants. The best mutant is selected through a positive selection process where only MLRS CP1 that add an amino acid to the tRNA will survive in the presence of chloramphenicol. Finally, in a negative selection step, those mutants which add natural amino acids to the tRNA will die in the presence of 5-fluorouracil. The library can then be used for further experiments to determine how effectively unnatural amino acids are incorporated.

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