Stereocontrol of intramolecular Diels-Alder reactions : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry at Massey University

Abstract

The use of the intramolecular Diels-Alder (IMDA) reaction in target synthesis has prompted investigation into methods of controlling the stereochemistry of this versatile cycloaddition. Linking the diene and dienophile via an ester-tether is a synthetically facile method of generating a range of precursors for the IMDA reaction and allows rapid access to the hydroisobenzofuranone skeleton. This bicyclic[4.3.0]nonane ring system is common to many natural products, including spongians and several novel steroids. Many of the previous examples of ester-tethered IMDA reactions exhibited a lack of stereoselectivity or were performed on racemic mixtures of starting materials. This thesis describes the synthesis of chiral dienols and tetraenols in enantiomerically pure form from monosaccharides. The esters derived from these alcohols possessed a sterically demanding substituent in the ester tether, and the influence of this bulky dioxolane substituent upon the stereochemical outcome of the IMDA reaction was the subject of this study. The purpose of these investigations was to gain information on stereocontrol in the ester-tethered IMDA reaction and, thus, provide a foundation for the tandem IMDA (TIMDA) reaction. A chiral dienol was synthesised in an enantiomerically pure form from D-glucose and used to prepare Z-methyl, E-methyl and propynoate esters with a dioxolane substituent on the ester tether. The IMDA reactions of these substrates were studied and found to exhibit high levels of diastereoselectivity. In particular, the IMDA reaction of the Z-methyl ester had both extremely high exo/endo selectivity (86:14) and complete π-diastereofacial selectivity. The IMDA reaction of the E-methyl ester was less selective. The diastereoselectivities of the IMDA reactions were explained by the minimised A1.3-strain in the favoured transition state. It has been long contended in the literature that the IMDA reactions of maleate half-esters (carboxylic acids) produced endo adducts whereas the corresponding Z-methyl esters (of the maleate half-esters) produced exo adducts. Comparison of the IMDA reaction of the Z-methyl ester described above with that of its maleate half-ester, disputed this theory. The IMDA reactions of the acid and of the methyl ester exhibited the same diastereoselectivity, with the same ratio of exo:endo adduct in each case. This result prompted an investigation into previous research in this area. It was discovered that the previously made assumptions as to the mechanism of reaction between dienols and maleic anhydride (MA) were suspect. With the purpose of studying the differences in diastereoselectivity and relative rate caused by altering one of two adjacent stereocentres, the results of the model study on the chiral dienol were extended to two diastereomeric tetraenol systems. Both diastereomeric tetraene substrates were synthesised from monosaccharide starting materials; D-glucose and D-galactose. The D-glucose-derived esters were found to undergo IMDA reactions with higher levels of diastereoselectivity than those of the D-galactose-derived esters. In the case of the IMDA reactions of the D-galactose-derived esters, all four of the possible diastereoisomers were produced. In addition to the decreased diastereoselectivity, an increase in the rate of IMDA reaction of the D-galactose-derived substrates was observed when compared to the D-glucose-derived esters. Notably, as with the dienol series, the D-glucose-derived Z-methyl ester exhibited extremely high levels of diastereoselectivity. A disconnection analysis of the cyclopentano perhydroanthrene skeleton of the steroids reveals that a TEMDA reaction would be an elegant method of synthesis. Towards this end, and utilising the information garnered from the model studies on dienol and tetraenol-derived substrates, the ester-tethered TIMDA reaction was investigated. A range of TIMDA precursors, in which a bis-diene (tetraene moiety) and bis-dienophile were linked via an ester tether, were assembled and TIMDA reactions of these substrates were attempted. The most promising area of investigation proved to be a diketone intermediate and future work remains to be performed in this area.