The 23-step total synthesis of dolastatin 16, a cyclic depsipeptide of marine origin, is presented. Included are syntheses of nonnatural amino acids dolamethylleuine and dolaphenvaline. The biological activity of the synthetic product differed from naturally isolated dolastatin 16, which may indicate the initial screening identified an inactive compound and the active one was not detected initially, or may be a result of the conformational dynamics induced by the proline residues. Additionally, a family of structural analogues to the bacillistatins, another cyclic marine depsipeptide, were synthesized. These were deemed the silstatins. 8 modifications were produced. The alterations aimed to introduce a heteroatomic residue for further derivatization, such as producing an antibody-drug conjugate. This introduction did in general decrease the neoplastic activity of these agents, as expected, but by modulating the lipophilicity of the compound we were able to salvage much of the potency of the bacillistatins while potentially allowing prodrug development.

Background: Staphylococcus aureus and S. epidermidis biofilms differ in structure, growth and regulation, and thus the high-throughput method of evaluating biofilm susceptibility that has been published for S. epidermidis cannot be applied to S. aureus without first evaluating the assay's reproducibility and reliability with S. aureus biofilms.

Methods: Staphylococcus aureus biofilms were treated with eleven approved antibiotics, lysostaphin, or Conflikt®, exposed to the oxidation reduction indicator Alamar blue, and reduction relative to untreated controls was determined visually and spectrophotometrically. The minimum biofilm inhibitory concentration (MBIC) was defined as ≤ 50% Alamar blue reduction and a purple/blue well 60 min after the addition of Alamar blue. Because all of the approved antibiotics had MBICs >128 μg/ml (most >2048 μg/ml), lysostaphin and Conflikt®, with relatively low MBICs, were used to correlate Alamar blue reduction with 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction and viable counts (CFU/ml) for S. aureus ATCC 29213 and three clinical isolates. Alamar blue's stability and lack of toxicity allowed CFU/ml to be determined from the same wells as Alamar blue absorbances.

Results: Overall, Alamar blue reduction had excellent correlation with XTT reduction and with CFU/ml. For ATCC 29213 and two clinical isolates treated with lysostaphin or Conflikt®, Alamar blue reduction had excellent correlation with XTT reduction (r = 0.93-0.99) and with CFU/ml (r = 0.92-0.98). For one of the clinical isolates, the results were moderately correlated for Conflikt® (r = 0.76, Alamar blue vs. XTT; r = 0.81, Alamar blue vs. CFU/ml) and had excellent correlation for lysostaphin (r = 0.95, Alamar blue vs. XTT; r = 0.97, Alamar blue vs. CFU/ml).

Conclusion: A reliable, reproducible method for evaluating biofilm susceptibility was successfully applied to S. aureus biofilms. The described method provides researchers with a simple, nontoxic, relatively inexpensive, high throughput measure of viability after drug treatment. A standardized biofilm Alamar blue assay should greatly increase the rate of discovery of S. aureus biofilm specific agents.

The late first row transition metals, being inexpensive and environmentally benign, have become very attractive for sustainable catalyst development. However, to overcome the detrimental one electron redox processes exhibited by these metals, the employment of redox non-innocent chelates turned out to be very useful. The Trovitch group has designed a series of pentadentate bis(imino)pyridine ligands (pyridine diimine, PDI) that are capable of binding the metal center beyond their 3-N,N,N core and also possess coordination flexibility. My research is focused on developing PDI-supported manganese catalysts for organic transformations and renewable fuel production.

The thesis presents synthesis and characterization of a family of low valent (PDI)Mn complexes. Detailed electronic structure evaluation from spectroscopic and crystallographic data revealed electron transfer from the reduced metal center to the accessible ligand orbitals. One particular (PDI)Mn variant, (5-Ph2PPrPDI)Mn has been found to be the most efficient carbonyl hydrosilylation catalyst reported till date, achieving a maximum turnover frequency of up to 4950 min-1. This observation demanded a thorough investigation of the operative mechanism. A series of controlled stoichiometric reactions, detailed kinetic analysis, and relevant intermediate isolation suggest a mechanism that involves oxidative addition, carbonyl insertion, and reductive elimination. Noticing such remarkable efficiency of the (PDI)Mn system, it has been tested for application in renewable fuel generation. A modest efficiency for H2 production at an apparent pH of 8.4 have been achieved using a cationic Mn complex, [(Ph2PPrPDI)Mn(CO)]Br. Although, a detailed mechanistic investigation remained challenging due to complex instability, a set of relevant Mn(-I) intermediates have been isolated and characterized thoroughly.

The dissertation also includes synthesis, characterization, and electronic structure evaluation of a series of Triphos supported iron complexes. Using this pincer chelate and either 2,2’-bipyridine (bpy) or 1,3,5,7-cyclooctatetraene (COT), a set of electronically interesting complexes have been isolated. Detailed electronic structure investigation using spectroscopy, magnetometry, crystallography, and DFT calculations revealed redox non-innocent behavior in the Bpy and COT ligands. Additionally, CO binding to the (Triphos)Fe system followed by reaction with borohydride reagents allowed for the isolation of some catalytically relevant and reactive iron hydride complexes.

This dissertation assesses the impact of revenue diversification on state revenue growth and volatility and then, the economic, political and institutional factors that predict diversification. Previous studies, taking advice from modern portfolio theory, argue that diversifying a revenue portfolio can stabilize volatility and even lead to faster rates of growth over time. However, levels of diversification are not assigned randomly. Rather, differences among states in diversification might be a consequence of differences in states such as electoral cycles and the presence and strictness of tax limitations. Thus, the research question is: Whether or to what extent has diversification increased revenue growth and decreased volatility when the endogeneity of diversification is considered? Using two-stage least squares and fixed-effects regression models with the data of the 50 states from 1980 to 2011, I examined the impact of diversification, reflecting a state's own political and institutional characteristics (i.e., endogeneity), on growth and volatility. I found diversification was positively related to growth, but a diversified portfolio does not smooth volatility. Furthermore, I found that the level of revenue diversification increased in each year of legislators' terms and decreased in every year of governors' terms. These findings imply that legislators and governors have different preferences for diversification, perhaps due to different opportunities to enhance their reelection prospects. I then investigated the relationship between political leaders' year of the terms and changes in specific revenue sources, the biggest set of reelection opportunities. Selective sales and income taxes were negatively related to every year of legislators' terms. General sales taxes, corporate income taxes, and charges are positively related to every year of governors' terms. The results suggest that legislators focus on their districts or specific interest groups, closely associated with selective sales taxes. In contrast, governors' constituency-driven preferences lead them to be responsible for broader issues such as balancing the state budget, thereby using general sales taxes and charges as methods to do so. As a consequence of these political factors, levels of diversification will change, thereby influencing revenue growth and volatility.