Development of X-H insertions on O-protected a-diazo-b-hydroxyesters– Application to the first diverted total synthesis of chaxalactins – CHAXATAC

The identification and the synthesis of new bioactive molecules are crucial to face societal challenges in the area of health, especially in the field of antibiotic resistance. For this purpose, natural products are an inexhaustible source of inspiration. Diverted total syntheses of structurally complex natural products allow a better understanding of their mode of action, and can lead to the development of new drugs. In this context, the development of new methods allowing the synthesis of a variety of natural products analogues from a common advanced precursor is of high value. The CHAXATAC project aims to develop new stereoselective X-H insertions (X = O, N, S, …) on highly functionalisable diazo compounds used as synthetic platforms, towards the formation of various a,ß-diheterofunctional esters incorporable into the skeleton of bioactive natural products, especially those containing 1,2-diol moiety. In this framework, the first objective is to develop stereoselective X-H insertions on a wide range of enantiopure O-protected a-diazo-ß-hydroxy-esters, synthesised by an asymmetric nucleophilic addition of diazoesters. No X-H insertion have been reported so far on such diazocarbonyl derivatives due to competitive 1,2-H and 1,2-R migrations. This project aims to tackle this challenge, investigating reaction conditions and parameters which could favour the X-H insertion (X = O, N and S). The methodology will then be extended to fluorination and trifluoromethylation. The usefulness of this new methodology for diverted total syntheses will be demonstrated in the first total synthesis of chaxalactins A, B and C and their analogues. Chaxalactins are 22-membered macrolactones isolated in the Atacama Desert in 2011. They are displaying antimicrobial and potential antitumoral activities. Thanks to the modular strategy and to the nucleophilic addition of diazoester/X-H insertion sequence developed in the first part of the project, the synthesis of chaxalactins and analogues will be achieved in an efficient way using a-diazo-ß-hydroxyesters as a synthetic platform. The ability to modify various positions on the natural products should lead to a wide range of derivatives and should allow the establishment of a complete structure-activity relationship study on such highly complex natural products. This project will be carried out at the Institut des Molécules et Matériaux du Mans (UMR6283).