An organometallic approach towards the total synthesis of phyllanthocin

The research detailed within this dissertation is concerned with the synthesis of a sesquiterpenoid aglycone called (+)-phyllanthocin. It is derived from a naturally occurring antineoplastic glycoside phyllanthoside. (+)-Phyllanthoside is presently under advanced clinical trials both the United States and Great Britain for the treatment of solid malignant tumours of the breast and colon.The introduction to this thesis reviews all the synthetic routes, to date, towards the aglycon phyllanthocin. Several new techniques have been developed during these synthetic undertakings, including Burke's hydroformylation methodology and Smith's metalated dihydropyran chemistry. Also reviewed are the syntheses of a structurally related hypercholesterolaemic agent called breynolide.Chapters five through eight discuss the progress to date of our research towards a new total synthesis of phyllanthocin. We have applied directed aldol chemistry in the construction of several β-keto-δ-lactones, a key reagent in our synthetic strategy. The most noteworthy step in our synthesis was the alkylation of an organomolybdenum complex by the sodium enolate of a homochiral β-keto-δ-lactone. Oxidative cyclofunctionalisation of the resultant η3-allyl molybdenum complex generated a tetrahydrobenzofuran which incorporates the cis-fused A and B rings of phyllanthocin.An unprecedented metal catalysed homo-Claisen rearrangement has been postulated to account for the diastereomeric mixture of products observed during the alkylation/cyclofunctionalisation step of the synthesis.Attempts to form the spiroacetal unit of phyllanthocin and thus complete the synthesis are described. Unfortunately all attempts at spiroacetalisation failed and further research possibilities have been proposed which may open the way to a successful organometallic based synthesis of phyllanthocin.(DX191,322)