Stereoselective Synthesis of Spirocarbamate and Spiropyrrolidine Oxindoles Utilizing Lewis Acid and Montmorillonite Clay Catalysts and Synthesis of a Triazole Containing Oxindole Library PDF Download

Author: Jacob Parker MacDonald
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ISBN: 9780438289703
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Languages : en
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Book Description
The development of new synthetic strategies towards oxindoles and spirooxindoles is important due to the ubiquity of these structures found in natural and biologically active compounds. This dissertation describes several strategies to achieve the synthesis of a diverse array of oxindoles and spirocyclic oxindoles. The strategies applied include two mechanistically distinct allylsilane annulations, allylsilanes additions using either a catalytic Lewis acid or a novel montmorillonite K10/NaBArF catalytic system and strategy for the rapid functionalization of these scaffolds. Chapter 1 describes recent methods for the synthesis of the scaffolds. In addition, chapter one also provides a brief overview of histone deacetylase inhibitors, which are synthetic targets of interest, and montmorillonite clay as an active catalyst. Chapter two describes the development of a pilot scale library of 64 triazole-containing oxindoles and spirocyclic oxindoles. Starting with a common N-propargyl isatin core, we were able to synthesize three different scaffolds utilizing enantioselective Lewis and Brönsted acidic conditions. These scaffolds were then diversified further with a series of azides via copper catalyzed azide-alkyne cycloaddition chemistry. Analysis of several drug-like properties of these molecules was performed, including XLogP and molecular weight. Chapter three describes the enantioselective synthesis of 2,3’-pyridinyl-spirooxindoles. This transformation was achieved using a Lewis acid catalyst and enantiomerically enriched crotylsilane to perform an annulation with 3-iminooxinodoles. A Boc deprotection was performed with montmorillonite K10. Further, it was discovered that montmorillonite K10 and NaBArF are able to facilitate the annulation reaction. Mechanistic studies were performed on this species, and the data suggests a transient Brønsted acidic NaBArF species is being formed. Chapter four focuses on the optimization of an asymmetric spirocarbamate formation with an iminooxindoles and allylsilane. This transformation is mechanistically distinct from the annulation in chapter 3, and was initially optimized to be diastereoselective. Enantioselectivity was achieved by use of a Cu(II)-BOX complex. Mechanistic studies of the active catalyst species are on going. Chapter five describes the use of montmorillonite clay as a catalyst for allylsilane additions to isatins. It was found that a proton-exchanged montmorillonite clay facilitates the addition on a variety of electrophilic substrates such as electron rich and deficient oxindoles, iminooxindoles and coumarins. It was also demonstrated that the clay can be recycled. Chapter six is a brief introduction to a strategy and initial work to transform the oxindole structures described herein into compounds to be evaluated as histone deacetylase inhibitors.