Semester

Spring

Date of Graduation

2022

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Bjorn Soderberg

Committee Member

Gregory Dudley

Committee Member

Brian Popp

Committee Member

Carsten Milsmann

Committee Member

Mark McLaughlin

Abstract

A short and flexible synthesis of 2,3-disubstituted indoles employing a Barluenga-type palladium-catalyzed cross-coupling of p-tosylhydrazones with 2-nitroarylhalides followed by a palladium-catalyzed, carbon monoxide-mediated reductive cyclization was developed. Significantly better overall yields were obtained performing the two-step reaction sequence in a one-pot reaction. Secondly, in order to facilitate biological studies of ergotryptamine, a recently isolated ergot alkaloid, it was selected as a target for synthesis. In an attempt to synthesize ergotryptamine, a palladium catalyzed Kosugi-Migita-Stille cross coupling, a Mizoroki-Heck reaction, and a carbon monoxide-mediated palladium-catalyzed reductive cyclization were utilized as the key steps. Using a similar synthetic approach, synthesis of another indole norpsilocin, a component of magic mushroom, was accomplished in two additional steps. Additionally, a selection of β-acyl-β-alkyl substituted 2-nitrostyrenes were subjected to a palladium-catalyzed, carbon monoxide-mediated reductive cyclization. 2-Substituted 3-acylindoles with rearranged carbon skeleton were observed in all cases. In addition to indoles, small amounts of the corresponding quinolone-N-oxide and/or quinoline were isolated as side products in a number of cases. The cyclization precursors, β-acyl-β-alkyl substituted 2-nitrostyrenes, were synthesized via either a Wittig reaction or an aldol condensation. Finally, a short synthetic sequence leading to two marine diastereomeric azepino indole alkaloids hyrtioreticulins C and D was completed. A reductive amination via a trans-imination, a regioselective intramolecular Mizoroki-Heck reaction, and a palladium-catalyzed reductive cyclization were the major steps in the synthetic sequence.

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