Author: Benjamin Henry Shupe

Publisher:

Published: 2015

Total Pages:

ISBN-13: 9781339544113

Herein I describe my research that was performed in the Franz Group while working toward the completion of a PhD at the University of California, Davis. My research has focused on developing new synthetic methods to access enantioenriched nitrogen-containing spirooxindoles. Chapter 1 contains an overview of the previous literature that provides a background for my research. This chapter includes an overview of biologically active spirooxindoles, Lewis acid-catalyzed allylsilane annulations, the Tamao-Fleming reaction, stereoselective methodology to access nitrogen containing spirooxindoles, enantioselective copper-catalyzed reactions and the use of Sodium Tetrakis[(3,5-trifluoromethyl)phenyl]borate (NaBArF) as a loosely coordinating counter ion to increase the Lewis acidity of metal complexes. Chapter 2 presents research resulting from collaborative efforts with Joseph Badillo and Abel Silva to develop a chiral binaphthyl phosphoric acid-catalyzed Pictet Spengler reaction between isatin and tryptamine to access enantioenriched spiroindolones with up to 99% yield and 98:2 er. We discovered that two different binaphthyl phosphoric acids with opposite axial chirality ((S)-2,4,6-triisopropylphenyl and (R)-9-anthracenyl) afford the same enantiomer of product. This chapter uses a stereochemical model to rationalize this phenomena. Ongoing research with this methodology will extend the scope of the reaction to isotryptamine scaffolds in order to access additional spirocycles. Chapter 3 discusses the synthesis of N-aryl and N-Boc iminooxindoles and the Lewis acid-catalyzed addition of pi-nucleophiles to these electrophiles. Initial studies showed that the addition of methallyltrimethylsilane to N-Boc iminooxindole was significantly more reactive than N-aryl iminooxindoles to access 3-amino-3-allyloxindoles. The Lewis acid-catalyzed addition of trimethylallylsilane to N-Boc iminooxindoles led to the discovery of novel silyl-containing spirocarbamate oxindoles via a [beta]-silyl trapping pathway (up to 91% yield and up to 80:20 dr). This reaction can be catalyzed by metal chloride complexes with NaBArF). Additional work in collaboration with Brittany Armstrong led to the development of the enantioselective synthesis of spirocarbamates (75% conv., up to 99:1 er and >95:5 dr) using CuCl2/BArF catalyst system with a phenyl-bisoxazoline ligand. We discovered that accessing these compounds with high stereoselectivity required increasing the quantity of 4Å molecular sieves. Spirocarbamate oxindoles were also screened in a molecular docking study with Mouse double minute 2 homolog (MDM2), which led to the design and synthesis of a series of compounds that are currently being evaluated for their biological activity. Chapter 4 continues the work presented in Chapter 3 by investigating the addition of enantioenriched crotylsilanes to N-Boc iminooxindoles. It was discovered that both CuCl2 and Montmorillonite K10 can catalyze crotylsilane addition to N-Boc iminooxindoles in the presence of NaBArF to provide enantioenriched spiropyrrolidine as a single isomer by a [3+2] annulation pathway. Spiropyrrolidine oxindoles were further functionalized to add additional hydrogen bond donating groups to be investigated as potential organocatalysts. I utilized these derivatized-spiropyrrolidine oxindoles to attempt forming carbon-carbon bonds but this scaffold has been unsuccessful at catalyzing any reaction. Chapter 5 presents investigation for the transformation of a carbon-silicon bond to a carbon-nitrogen bond in order to access chiral amines from silyl groups. The strategy that I investigated for this transformation was designed based on mechanistic analysis that parallels the Tamao-Fleming reaction utilizing amphiphilic amine reagents. While this work is ongoing, preliminary results show that the nitrogen-silicon bond is labile under these reaction conditions. Reactions were also investigated for the conversion of silicon-hydrogen bonds to silicon-carbon bonds.