Synthesis of Lignan Lactones and Macrocyclic Natural Products Using Aryl Oxazolines

摘要

The goal of this research was to develop, refine, and extend aryl oxazoline methodology and to use it in the synthesis of naphthalene lignan lactones, macrocyclic natural products, and their analogs. The synthetic procedures were extended to include the preparation of a variety of substituted oxazolines (nitro, halogen, ether, and aryl). These compounds were used in metalation studies and as synthetic intermediates in the natural product synthesis. The disubstitution reaction of 2-(2,6-difluorophenyl)-4,4-dimethyl-2-oxazoline was investigated and found to depend on the nature of the organometallic used rather than the group size or the order of addition. The 5,5-dimethyl-2-oxazoline analogs were shown to undergo nucleophilic aromatic substitution in yields similar to that of the 4,4-dimethyl analogs. The aryl oxazoline methodology was extended to the naphthalene ring system. It was demonstrated that both nucleophilic displacement of an ortho methoxy group and ortho-metalation occur efficiently. This behavior formed the basis for the synthesis of Chinensin-type aryl naphthalene lignan lactones and a Justicidin A/F-type aryl naphthalene lignan lactone. Extension of this technique to the preparation of Taiwanic C was unsuccessful and it was shown that alkoxy substituents in the A ring of the naphthalene affects the regiochemistry of the metalations.