Iterative synthesis of nitrogen-containing polyketide via oxime intermediates.

Abstract

Typical polyketides consist of C, H, and O atoms, whereas several types of N-containing polyketides are known to show intriguing properties. Because conventional synthetic approaches for such compounds focus on only specific structures, a more general method is desirable. Here, we have developed an iterative synthesis of nitrogen-containing polyketide. Chain elongation of carboxylic acid via decarboxylative Claisen condensation with malonic acid half thioester was iteratively performed to construct carbon frameworks. β-Keto groups formed by the chain elongation were appropriately converted to O-methyl oximes for incorporation of nitrogen atoms. Cyclization of the resulting oxime intermediates followed by reductive N–O cleavage afforded structurally diverse nitrogen-containing polyketides such as 2-pyridone, 4-aminopyrone, and 4-aminosalicylate. This method was finally applied to the synthesis of (R)-6-aminomellein, which is a nitrogen-substituted derivative of bioactive compound, (R)-6-methoxymellein. The versatility of the present method would enable the synthesis of diverse polyketides with nitrogen functional groups, which can be potentially utilized for the development of novel bioactive compounds.