Novel Photochemical Methodologies For Diversity Oriented Synthesis And Screening Of Combinatorial Libraries

The main goal of this project was to develop an efficient methodology allowing rapid access to structurally diverse scaffolds decorated with various functional groups. Initially, we discovered and subsequently developed an experimentally straightforward, high-yielding photoinduced conversion of readily accessible diverse starting materials into polycyclic aldehydes and their (hemi)acetals decorated by various pendants. The two step sequence, involving the Diels-Alder addition of heterocyclic chalcones and other benzoyl ethylenes to a variety of dienes, followed by the Paternò-Büchi reaction, was described as an alkene-carbonyl oxametathesis. This methodology offers a rapid increase in molecular complexity and diversity of the target scaffolds. To develop this novel methodology further and explore its generality, we directed our attention to the Diels-Alder adducts based on various chromones. We discovered that the Diels-Alder adducts of chromones are capable of photoinduced alkene-arene [2+2] cycloaddition producing different dienes, which can either dimerize or be introduced into a double-tandem [4π+2π]·[2π+2π]·[4π+2π]·[2π+2π] synthetic sequence, followed by an acid-catalyzed oxametathesis, leading to a rapid expansion of molecular complexity over a few experimentally simple steps. In view of the fact that oxametathesis previously was primarily observed in aromatic oxetanes, we decided to prepare model aliphatic oxetanes with a conformationally unconstrained or "flexible" methyl group based on the Diels-Alder adducts of cyclohexadiene or cyclopentadiene with methyl vinyl ketone. Upon addition of an acid, the expected oxametathesis occurred with results similar to those observed in the aromatic series proving the generality of this approach. Also we synthesized polycyclic oxetanes resulting from the Diels-Alder adducts of cyclic ketones. This not only gave us access to remarkably strained oxetane systems, but also the mechanism for their protolytic ring opening provided a great deal of insight to how the strain affects the reactivity. Additionally, we discovered that although the model Hetero-Diels-Alder adducts did not undergo [2+2] cycloaddition, both exo- and endo-Sulfa-Diels-Alder products, nonetheless, were photochemically active and various products with defined stereochemistry could be produced upon photolysis. In conclusion, we have developed an approach to the encoding and screening of solution phase libraries based on the photorelease of externally sensitized photolabile tags. The encoding tags can be released into solution only when a binding event occurs between the ligand and the receptor, equipped with an electron transfer sensitizer. The released tags are analyzed in solution revealing the identity of the lead ligand or narrowing the range of potential leads.

Photogenerated o-Azaxylylenes: Mechanistic Studies and Synthetic Applications

This research sets out to build upon excited state o-azaxylylene cycloaddition. The mechanism behind the excitation and cycloaddition process of photogenerated o-azaxylylenes was determined experimentally. Time-correlated single-photon counting, steady-state spectroscopy, triplet quenching experiments, and quantum yield studies provided evidence suggesting that excited state intramolecular proton transfer is followed by intersystem crossing and stepwise addition to the tethered unsaturated pendant. In keeping with the principles of diversity oriented synthesis, a modular approach was taken to gain access to a diverse array of N,O,S-Polyheterocycles which were modified postphotochemically via Suzuki coupling to yield fused biaryls. Cycloaddition products, outfitted with halogens in the aromatic ring of the o-azaxylylene, proved to be reactive with a variety of boronic acids resulting in a rapid growth in structural complexity. A novel procedure was developed that utilized multiple o-azaxylylene cores in a photochemical cascade transformation yielding complex scaffolds of unprecedented topology. The photoprecursors were produced in a one-pot two-step sequence from commercially available starting materials, and upon irradiation yield structures containing up to five fused hetrocyclic rings, and showed complete diastereoselectivity.

An Investigation of Ozone Related Data and Development of a Model to Evaluate Ozone Episodes for Exceptional Event Criteria

The EPA promulgated the Exceptional Events Rule codifying guidance regarding exclusion of monitoring data from compliance decisions due to uncontrollable natural or exceptional events. This capstone examines documentation systems utilized by agencies requesting data be excluded from compliance decisions due to exceptional events. A screening tool is developed to determine whether an event would meet exceptional event criteria. New data sources are available to enhance analysis but evaluation shows many are unusable in their current form. The EPA and States must collaborate to develop consistent evaluation methodologies documenting exceptional events to improve the efficiency and effectiveness of the new rule. To utilize newer sophisticated data, consistent, user-friendly translation systems must be developed.