Novel Photochemical Methodologies for Diversity Oriented Synthesis and Screening of Combinatorial Libraries

<p>The main goal of this project was to develop an efficient methodology allowing rapid access to structurally diverse scaffolds decorated with various functional groups.</p> <p>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 <em>Diels-Alder</em> addition of heterocyclic chalcones and other benzoyl ethylenes to a variety of dienes, followed by the <em>Paternò-Büchi</em> reaction, was described as an alkene-carbonyl oxametathesis. This methodology offers a rapid increase in molecular complexity and diversity of the target scaffolds.</p> <p>To develop this novel methodology further and explore its generality, we directed our attention to the <em>Diels-Alder</em> adducts based on various chromones. We discovered that the <em>Diels-Alder</em> 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 [4_π+2_π]·[2_π+2_π]·[4_π+2_π]·[2_π+2_π] synthetic sequence, followed by an acid-catalyzed oxametathesis, leading to a rapid expansion of molecular complexity over a few experimentally simple steps.</p> <p>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 <em>Diels-Alder</em> 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 <em>Diels-Alder</em> 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.</p> <p>Additionally, we discovered that although the model <em>Hetero-Diels-Alder</em> adducts did not undergo [2+2] cycloaddition, both <em>exo-</em> and <em>endo-Sulfa-Diels-Alder</em> products, nonetheless, were photochemically active and various products with defined stereochemistry could be produced upon photolysis.</p> <p>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.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Year dc:date.available

2010

Author dc:creator

• Valiulin, Roman Askatovich

Contributors dc:contributor

• Andrei G. Kutateladze, Ph.D.
• Susan Sadler
• Joseph Hornback
• Sandra Eaton
• Donald Stedman
• Byron Purse

• Combinatorial
• Diversity
• Library
• Oriented
• Photochemistry
• Synthesis
• Organic Chemistry

Statement dc:rights

• <p>Copyright is held by the author. User is responsible for all copyright compliance.</p>

Language dc:language

en

Repository record dc:identifier

https://digitalcommons.du.edu/etd/943

OAI identifier oai:identifier

oai:digitalcommons.du.edu:etd-1942