Part I. Applications of inverse electron demand Diels-Alder reactions of heterocyclic azadienes: Two syntheses of Amaryllidaceae alkaloids. Part II. In situ activation of a DNA alkylating agent: Evaluation of simplified and reversed CPyI analogues of CC-1065 and the duocarmycins. Part III. Progress toward the total synthesis of cytostatin.

摘要

Two convergent total syntheses of anhydrolycorinone, hippadine, and anhydrolycorinium chloride are detailed. The first enlists sequential inverse electron demand Diels-Alder reactions of an unsymmetrical N-acyl-6-amino-1,2,4,5-tetrazine and is an application of a well precedented tetrazine → diazine → benzene strategy. The second utilizes sequential intramolecular Diels-Alder reactions of a suitably substituted 2-amino-1,3,4-oxadiazole defining a novel oxadiazole → furan → benzene strategy which was developed as part of broad investigation of the cycloaddition reactivity of oxadiazoles.; The examination of a novel class of reversed CPyl analogues of CC-1065 and the duocarmycins are described. Capable of a unique metal cation activation of DNA alkylation, these agents allowed the effects of the DNA binding domain (104-fold increase in DNA alkylation rate and efficiency) to be partitioned into two components: that derived from enhanced DNA binding affinity and selectivity (10–80-fold) and that derived from a contribution to catalysis (250–5000-fold). In addition, the reversed enantiomeric selectivity of these sequence selective DNA alkylating agents provides further strong support for a previously disclosed model where it is the noncovalent binding selectivity of the compounds, and not the alkylation subunit or the source of catalysis, that controls the DNA alkylation selectivity.; Efforts toward a total synthesis and stereochemistry determination for cytostatin are described. Three diasteromers of the lactone portion were prepared and comparisons with data available for the natural product are described. Initial attempts at elaboration of the central portion of cytostatin utilizing a copper-mediated epoxide opening are detailed.