Synthetic routes to azasteroids and cyclic amidines using aza diels-alder reactions

Abstract

Azasteroids exhibit a wide range of biological activity and hence the search for successful synthetic routes and novel azasteroid structures is of considerable scientific interest. The first section of this thesis deals with the formation of azasteroids using total synthesis via aza Diels-Alder reactions or a complementary approach based on the degradation of lanosterol. The second is concerned with the aza Diels-Alder reactions of a variety of aminoheterocycles leading to novel cyclic amidines along with a number of related structures. The total synthesis approach involved cycloaddition reactions of aromatic iminium ions with electron rich alkenes. Generated from bicyclic amines, the iminium ions behaved as 2-azadiene equivalents in the reactions with methylcyclopentadiene and cyclohexadiene to yield a selection of monoazasteroids. Furthermore, cyclohexadine was found to act as both diene and dienophile to yield both azabicyclo compounds and azasteroids; we believe that the formation of two separate products in this case suggests a stepwise mechanism is in operation. Also, the results of biological testing of some of these novel azasteroids acting as antifungal agents is presented. The degradative route designed to give azasteroids was based on lanosterol since this steroid is rarely found in plants, but occurs in fungi. Nitrogen was successfully introduced into the molecule in the form of an oxime following a series of reactions and Beckmann rearrangements of the oximes gave a series of B-homo azasteroids. The aza Diels-Alder reactions of 2-aminopyridines, behaving as 1,3-diazadienes, with electron rich alkenes including indene and styrene gave rise to a variety of pyridol[1,2-a]pyrimidine derivatives. The structure of the cyclic amidine products is confirmed by single crystal X-ray analysis of a neutral amidine and of a trifluoroacetate salt. Consequently, these structural studies permit the regio- and stereochemical outcome of these additions to be defined and compared with related processes. Several aminoheterocycles were used to synthesise a variety of cyclic amidines and cyclic isothioureas in good yields, including the case of 1-aminoiosquinoline, diazasteroids. Finally, the relationship of the diverse series of skeletons synthesised to compounds of known biological activity is emphasised.

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