A new route for the asymmetric total synthesis of 16-membered ring macrolide antibiotic aglycones tylonolide and carbonolide B is being developed. Attachment of an iron carbonyl moiety to a cycloheptadienyl cation ligand allows stereocontrolled successive introduction of two substituents to give, ultimately, 5,7-disubstituted cycloheptadienes which can be further elaborated to C(1) - C(11) sections of the macrolides. Detailed study and development of the phenomenon of chiral recognition during reactions of cycloheptadienyliron complexes with optically pure sulfoximinyl ester enolate nucleophiles will allow access to these subunits as the natural antipodes. Completion of the synthesis of the macrolide aglycones by attachment of C(12) - C(16) units will be studied. The approach described has considerable potential fexibility and allows planned variations in substitution around the macrolide ring, thereby making available compounds which can be used to study structure/activity relationships in the macrolide series. The chemistry of 2-alkoxy-substituted cycloheptadienyliron complexes will be studied in detail, leading to a flexible preparation of subunits for synthesis of the ionophore antibiotic ionomycin, in optically active form. Detailed studies into cyclofunctionalization of dienes and their iron complexes will be undertaken, as will studies into the asymmetric functionalization of cycloheptadiene and 5,7-dimethyl cycloheptadiene. These studies will culminate in asymmetric syntheses of the alkaloid luciduline and the Prelog-Djerassi lactone. Detailed studies into the chemistry and potential synthetic utility of cyclooctadienyliron complexes will be undertaken.
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