The chemistry of disorazoles and structure-activity relationships: An update

The disorazoles are a family of 26- to 32-membered macrodiolides of mixed non-ribosomal peptide and polyketide origin that show exceptional cytotoxic activity. Of the 39 different disorazoles that have been isolated so far, total syntheses have been described for three family members, namely the non-symmetrical disorazole A1 and the symmetrical disorazoles B1 and C1. With the exception of the first total synthesis of disorazole C1, these syntheses were all reported within the last decade. Different approaches have been followed to meet the challenge of establishing the 30-membered macrodiolide ring in these natural products, including single-step macrolactonization or cyclodimerization via sequential inter-/intramolecular Suzuki coupling, ACM/RCAM, or inter-/intramolecular Sonogashira coupling. In this report, we review the total syntheses of disorazoles that have been developed over the last decade. In addition, we also summarize the synthetic and SAR work that has been performed on non-natural disorazole congeners, which built on the chemistry developed in the course of the total synthesis work.