Abstract
The first chapter of this thesis describes the first total synthesis, in racemic form, of the natural product pygmaeocin C (3) utilizing a polyene cyclization reaction as the key step to construct the B ring. Starting with commercially available dimedone (72), highly functionalized cross congjugated β-keto ester 81 was achieved in 10 steps. The pivotal cyclization step was accomplished by treating enone (81) with trifluoroacetic acid to give tricyclic keto ester 86. This cyclization step was found to be highly chemo- and facial selective as well as highly reproducible and high yielding. Following this, the total synthesis endeavor was achieved from ketone 86 by 3 steps including decarboxylation, oxidation, and removal of the methyl protecting groups. In all, the total synthesis of naturally occurring pygmaeocin C (3) in racemic form was achieved from dimedone (72) in 14 steps via the longest sequential with an overall yield of 4.6%. Chapter 2 of this thesis details a novel methodological development towards structural motifs which are difficult to attain using precedent processes. This newly established protocol calls for the employment of a γ-cyano-α,β-unsaturated ketone (i.e. 138 and 140) as a starting point for the generation of a β,γ- unsaturated ketone in a reductive process. As such, model compound 138 and 140 were readily synthesized starting with a Diels-Alder cycloaddition reaction between diene 131 and acrylonitrile followed by hydrolysis and oxidation. The thus obtained enone 125 was then treated with a suitably functionalized Michael acceptor to furnish the desired bicyclic enones 138 and 140 in a Robinson annulation process. The central theme of this methodology was then accomplished by treatment of enone 140 with lithium naphthalenide as the reducing agent which furnished ketone 147 in a high yielding fashion. The ensuing enolate in the reduction process could, alternatively, be trapped with an alkylating agent (i.e. allyl bromide) to give reductive products alkylated in highly regioselective manner (i.e. 138à149). As well, by the use of excess lithium naphthalenide and excess alkylating agent, symmetrical gem-alkylations was achieved (i.e. 140à145 or 146). This newly developed methodology not only allows simple access to it also provides for a one-pot procedure to functionalized said motif. The third chapter of this thesis delineated a newly developed process towards highly functionalized methylene cyclopentanes. Starting with α-cyano ketones 173 and 174, readily obtained using established synthetic procedures, treatment with zinc iodide allowed for the formation of bicyclic products 191 and 197 respectively in a high yielding and stereoselective fashion. This exo-dig cyclization process was found to not be affected by steric congestion of the starting carbocycle as highly congested ketone 175 readily yielded compound 198. The details of the development of this and above mentioned methodology as well as the total synthesis of 3 constitutes the contents of this thesis.