Exploring the Synthetic Utility of Divinyl Ketones

Reference:

Silvanus, A., 2010. Exploring the Synthetic Utility of Divinyl Ketones. Thesis (Doctor of Philosophy (PhD)). University of Bath.

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Abstract

Divided into three distinct research areas, this thesis investigates the synthetic utility of divinyl ketones as versatile substrates in the construction of novel cyclic structures. The first volume of work (Chapter 2) examines the one-pot Brønsted acid-catalysed tandem double alkylation of indole with non-symmetrical divinyl ketones. The [6,5,7] tricyclic indole products are often furnished in excellent yield, with complete regioselectivity and high levels of syn-diastereoselectivity. Optimisation, a thorough substrate investigation and initial results are all discussed within. An in-depth mechanistic study is described in Chapter 3. Experimental and computational data is utilised to elucidate the reaction pathway and help explain the high levels of regioand diastereoselectivity observed during the tandem double alkylation of indoles developed in Chapter 2. The mechanism for the annulation step is shown to proceed via a 7-endo-mode C-2 Friedel-Crafts alkylation of the indole for which the rate-determining step is believed to be the loss of C-2 the proton to regain aromaticity. The final chapter concerns the phase transfer catalysed double Michael addition of activated methylene pronucleophiles to non-symmetrical divinyl ketones. The resultant substituted cyclohexanones are constructed in high yields with broad tolerance to substrate scope. In addition, proof-of-concept levels of enantioselectivity have been obtained with the use of N-alkylated Cinchona alkaloids as chiral phase transfer catalysts. With 36% enantiomeric excess, this tandem [5C+1C] annulation is shown to be an appropriate method of furnishing enantioenriched cyclohexanones.

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