Step Efficient Synthesis of 3,4-Dioxygenated Quinolones Enabled by Aryne Chemistry

Abstract

In the present thesis, the step efficient synthesis of 3,4-dioxygenated quinolinones is described. Initially, step efficient syntheses of other natural products were analyzed by using a color-coded flow chart presentation. Thus, particularly powerful strategies were identified. These included disconnection in equally sized and complex substructures, avoidance of non-strategic redox- and functional group interconversions, as well as the usage of functional group tolerant transformations capable of forging multiple bonds in a single step. By applying these principles to the natural product class of 3,4-dioxygenated quinolinones, an aryne insertion into an unsymmetric imide followed by a diastereoselective aldol reaction was recognized.The target was thus built up from two equally sized molecules whilst the aryne insertion yielded two new carbon – sigma-bonds in a single step. When performed in continuous flow, the reaction proceeded within minutes, while lower yields and longer reaction times were observed in batch. Furthermore, both aryne and imide could easily be varied so that a multitude of differently substituted 3,4-dioxygenated quinolinones were synthesized. In total, nine natural products, including (±)-peniprequinolone, (±)-aflaquinolones E and F, (±)-6-deoxyaflaquinolone E, (±)-quinolinones A and B, (±)-aniduquinolone C and yaequinolones J1 and J2, were synthesized in one to three steps.