An investigation into a series of asymmetric intramolecular Nicholas cyclisation reactions

Mazloumi, Khatebeh (2013) An investigation into a series of asymmetric intramolecular Nicholas cyclisation reactions. (PhD thesis), Kingston University, .


The Nicholas reaction is the reaction of a cobalt-stabilised propargyl cation with a nucleophile and the aim of this project was to attempt this reaction with a chiral substrate in an effort to effect an asymmetric Nicholas reaction. A range of contemporary techniques were applied to reach this goal. Initially an attempt was made to reproduce an earlier successful racemic synthesis of a fused carbocyclic compound using a chiral precursor. It was envisaged that this would be approached using a 1,4-conjugate addition to an enone using a chiral ligand to install the C-3 alkenyl group selectively. Although the conjugate addition reactions were successful, using well tried and tested ligands, the enantiomeric excesses were very low and unfortunately a suitable chelating catalyst that prevent fulfil the requirements was not identified at this stage of the investigation. The next approach made use of an asymmetric alkynylation reaction to an aldehyde. This was successfully carried out using a Carreira asymmetric alkynylation reaction to afford optically active propargyl alcohols with good to excellent enantiomeric excess (50%-82% ees). The desired optical active propargyl alcohols were then complexed, with dicobalt octacarbonyl, to afford the corresponding dicobalt hexacarbonyl complexes. These then successfully underwent the corresponding Nicholas cyclisation reaction to afford, after oxidative decomplexation of the cobalt species, a range of optically active chromane and isochromanes with ees of (45%-81%). In a second study a series of optically active benzopyran derivatives were also successfully synthesised, using the same methodology, again with high levels of enantiomeric excess (87% - 94%). In the final phase of this investigations it was explored the use of chiral derivatives of the chiral pool molecule citronellal as well as an achiral analogue in an effort to afford novel chiral aldehydes for propargylation and cyclisation. The new chiral centres were successfully installed using chiral auxiliary technology however unexpectedly difficulties were encountered in the removal of the chiral auxiliary. A lack of time, in order to further explore the removal step, unfortunately meant that this was put on hold for further studies.

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