Enantioselective synthesis of 1,6-dihydropyridines with application to natural product synthesis; Racemic total synthesis of the non-nitrogenous opioid collybolide
Type of DegreePhD Dissertation
Chemistry and Biochemistry
Restriction TypeAuburn University Users
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Azaheterocycles, a common feature of many bioactive natural products, are still challenging motifs to construct in an asymmetric fashion. Dihydropyridines are advantageous intermediates in the synthesis of such heterocycles, but previous methods to synthesize such compounds usually required specialized starting materials generated in a linear synthesis. Dihydropyridines can be converted to the corresponding tetrahydropyridines and piperidines through functionalization reactions, or they can be rearomatized to form the corresponding pyridine. We investigated the use of boronic acid nucleophiles with rhodium catalysis to create 1,6-dihydropyridines for use as strategic intermediates in natural product synthesis. We have reported the formation of 1,6-dihydropyridines, which contain fully substituted stereogenic centers, using aryl and alkenyl boronic acids. Our dearomatization methodology has demonstrated a range of functional group tolerance that includes alkenes, free alcohols, ethers, amides, esters, halides, and other heterocycles. Next, we applied our methodology to the synthesis of the indoloquinolizine structural scaffold, a motif found in many polycyclic alkaloids. By employing our rhodium-catalysis in a formal synthesis of deplancheine, we introduce a new strategy for synthesizing azaheterocyclic natural product scaffolds. Digressing from azaheterocycle methodologies, we developed a 10-step racemic total synthesis of collybolide, as well as an asymmetric formal synthesis, to facilitate the potential creation of unnatural derivatives. Although collybolide has been touted as a potent nonnitrogenous κ-opioid in recent years, independent analysis of our synthetic racemate unfortunately indicates that the compound has no appreciable κOR activity.