Permanganate mediated enantioselective oxidative cyclisation of 1,5- and 1,4-diene systems

Abstract

This thesis investigates the enantioselective oxidative cyclisation of 1,5-dienoates mediated by permanganate and catalysed by cinchona-derived quaternary ammonium salts as chiral phase- transfer catalysts (CPTCs), as illustrated in scheme 1. The reaction forms the cis-2,5- disubstituted tetrahydrofuran (THF)-diol core, a structural motif found in numerous natural and synthetic compounds, such as Annonaceous acetogenins and polyether ionophores. This process generates four stereocenters with controlled absolute stereochemistry. Additionally, 3,5-disubstituted and 2,3,5-trisubstituted THF-diols, which are prevalent in bioactive molecules like terpenoids and isofurans, were synthesized via permanganate-mediated oxidative cyclisation of 1,4-dienes, a relatively unexplored approach (Scheme 1). To optimize enantioselectivity and yield, various CPTCs were screened by systematically modifying the aromatic ring attached to the quinuclidine core of CPTC. This led to the identification of an optimised CPTC, which demonstrated excellent enantioselectivity (ee’s up to 92%) and yields (up to 81%) across a broad range of 1,5-dienoate substrates. By selecting the appropriate pseudo enantiomer of the optimized CPTC, the selectivity of the reaction was inversed to target the opposite enantiomer with high enantiomeric excess (ee’s up to 91%) and yields (up to 78%). The optimized CPTC and selected aromatic ester substrate of 1,5-diene was further applied in the formal synthesis of acetogenins, cis-solamin A and cis-solamin B, using permanganate-mediated enantioselective oxidative cyclisation. A key step of this formal synthesis was the permanganate mediated chiral phase transfer catalysed oxidative cyclisation (ee’s up to 92%, yields up to 22%) which also formed the unexpected diketoester. This thesis also describes the novel permanganate mediated racemic and enantioselective oxidative cyclisation of 1,4-dienoates (Scheme 1). During the enantioselective oxidative cyclisation, the optimised CPTC provided excellent ee’s (up to 86%) and yields (up to 50%). Notably, use of styrene derived 1,4-dienes, led to the unexpected formation of novel epoxy diols alongside regioisomers of the THF-diol, representing a unique addition to the synthetic outcomes in this system.

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Identifiers

ORCID for Richard Brown: orcid.org/0000-0003-0156-7087

ORCID for Lynda Brown: orcid.org/0000-0002-5678-0814

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