Towards the synthesis of steroids, salvinorin A and (+)-lepadiformine

In this thesis, written partially in “thesis by publication” and partially in traditional thesis format, several alternative strategies for the activation of established carbon-carbon bond forming reactions were assessed. In each of the following three chapters different methods for activation of these powerful reactions are explored. This thesis is divided into three chapters, namely towards a general modular de novo synthesis of steroids, towards the total synthesis of salvinorin A and towards the total synthesis of (+)-lepadiformine. Chapter one is written in “thesis by publication" format and explores a new general modular de novo synthesis of the steroid nucleus. Proof of principle work has shown that steroid-like structures can be accessed diastereoselectively and in excellent yields. One of the key steps required Diels-Alder addition with a 1,2-naphthoquinone. In a model study, it was shown that c/s-tetrahydrophenanthrenes could be conveniently accessed via this Diels-Alder reaction for the first time. While the Diels-Alder reaction of 1,2-naphthoquiones has been studied sporadically, there has been no published method to access the non-aromatised adduct prior to this work. Also, a microwave assisted method for preparing the required 1,2-naphthoquinone substrates was developed, which effectively reduced the reaction time for the selenium dioxide oxidation of 1-tetralones to 1,2-napthoquiones from hours to minutes. Chapter two investigates the activation of the Diels-Alder addition of two highly substituted reaction partners. While the Diels-Alder reaction is one of the most studied reactions, cycloaddition of substituted dienes and dienophiles remains a synthetic challenge. The key hypothesis of this research was that significant activation may be achieved for this proposed reaction via synthesis of an oxygenated diene and either Brödnsted or Lewis acid activation of the dienophile. This proposed reaction was designed to complete the key step in the total synthesis of salvinorin A. The eastern portion, the oxygenated semi-cyclic diene, was prepared enantioselectively in nine steps and 10 % overall yield (based on recovered starting material). Chapter three highlights an attempt to execute the first vinylsilane addition to a ketone derived acyl iminium ion, undertaken with Professor David Evans at Harvard University. Previously, vinylsilane additions to aldehyde-derived iminium or acyl iminium ions have been employed in a variety of syntheses of nitrogen containing ring systems. It was hypothesised that if the two reaction components, the vinylsilane and the acyl iminium ion, were constrained into a macrocyclic environment, the energy barrier for the reaction may be sufficiently decreased to allow for bond construction. To investigate this hypothesis a synthetically challenging macrocyclic substrate was prepared in 19 - i - steps overall (15 steps, longest linear sequence) in 15 % overall yield. If successful the product of this transannular reaction may be used to complete the total synthesis of (+)-lepadiformine.