Tesfa Hunie, Kibur (2008) Novel applications of chiral non-recemic propargyl alcohols for asymmetric intramolecular Nicholas reaction - synthesis and screening of novel benzopyrans. (PhD thesis), Kingston University, .

Abstract

The aim of this research programme was to investigate the use of an asymmetric intramolecular Nicholas reaction in the synthesis of novel, optically pure and biologically active benzopyran derivatives from optically active precursors. The novel compounds were designed for medicinal and pharmaceutical applications. A series of benzopyran derivatives was synthesised and screened for biological activity. The synthetic route involved the preparation of enantiopure and enantioenriched propargyl alcohols as cyclisation precursors. These alcohols were then subjected to the Nicholas reaction characterised by complexation-cyclisation-decomplexation steps. This thesis is divided in to three main chapters. Chapter one covers three different but interrelated sections. The first section discusses the properties of organocobalt complexes and the Nicholas reaction while the second one examines the different approaches to asymmetric synthesis of propargyl alcohols. The third section elaborates on the synthetic route to cromakalim, the prototype of benzopyran derivatives. Chapter two, details the result achieved during our investigations into the synthesis of a new family of benzopyran derivatives via intramolecular Nicholas cyclisation reactions from enantiopure and enriched chiral propargyl alcohols. During the course of this investigation, a mild and inexpensive literature methodology was improved upon for the synthesis of enantiopure chiral propargyl alcohols, enhancing the yield of the reaction. Moreover, it was found that the enantioselectivity depended upon the substitution pattern on the aromatic ring. The C-2 substituent plays an important role in terms of enantioselectivity. Thus, the presence of electron-donating groups decreased the enantioselectivity while electron-withdrawing groups enhanced the enantiomeric excesses. The absolute configuration of the synthesised chiral propargyl alcohols was found to be dependent on the chiral ligand used. This was confirmed by single crystal X-ray diffraction analysis. The outcome of the cyclisation reaction using the enantiopure and enriched alcohols was rather surprising. Single isomers and optically active cyclised products were obtained regardless of the degree of enantiopurity of the cyclisation precursors, the propargyl alcohols. Furthermore, the main feature of this cyclisation was the rapidity of the reaction, providing clean and high yielding benzopyran derivatives that consistently displayed cis-relative stereochemistry at the two newly formed stereogenic centres. The stereochemistry was based on [sup]1H NMR spectroscopy, NOE experiments and the chemical shift of the [sup]13C NMR of the two chiral carbons centres (C*). Moreover, high quality [sup]1H and [sup]13C NMR spectra were obtained for the cobalt complexed compounds for the first time during this study. Interesting results were obtained from the biological screening. The testing was conducted on Mouse Thoracic Aorta (MTA) tissue using cromakalim as a benchmark. The novel benzopyran derivatives exerted vasorelaxant activity. Most importantly, these agents seem to relax the tissue via a different mechanism to cromakalim i.e. not involving K[sup]+ channel activation. Chapter three conclude these investigations by describing the experimental procedures for both chiral non-racemic propargyl alcohols based on salicylaldehydes and benzaldehydes as well as the racemic propargyl alcohols and the stepwise cyclisation reaction.

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