Design and application of α-ketothioesters as 1,2-dicarbonyl-forming reagents

Abstract

The 1,2-dicarbonyl motif is vital to biomolecules, especially natural products and pharmaceuticals. Conventionally, 1,2-dicarbonyl compounds are prepared via an α-keto acyl chloride. Based on the methods used in nature, a transition-metal-free approach for the synthesis of an α-ketothioester reagent via the combination of an α-hydroxyl ketone, elemental sulfur and a benzyl halide is reported. Mechanistic studies demonstrate that the trisulfur radical anion and the α-carbon radical of the α-hydroxy ketone are involved in this transformation. The dicarbonylation of a broad range of amines and amino acids, and importantly, cross couplings with aryl borates to construct dicarbonyl-carbon bonds are realized under mild conditions by employing this stable and convenient α-ketothioester as a 1,2-dicarbonyl reagent. The dicarbonyl-containing drug indibulin and the natural product polyandrocarpamide C, which possess multiple heteroatoms and active hydrogen functional groups, can be efficiently prepared using the designed 1,2-dicarbonyl reagent.

Fig. 1

Significant dicarbonyl-containing molecules. a Dicarbonyl-containing natural products. b Dicarbonyl-containing drug molecules

Fig. 2

Strategies for the design of a 1,2-dicarbonyl-forming reagent and its applications. a The role of thioesters in life and biomimetic synthesis. b The strategy of α-ketothioester as dicarbonyl reagent. c Metal-free synthesis of an α-ketothioester reagent and its applications

Fig. 3

Mechanistic studies. a The control experiment of α-formyl ketones. b Radical-trapping experiments. c The control experiment in the absence of elemental sulphur. d The plausible reaction pathway

Fig. 4

Further transformations. Dicarbonylation of alcohols and water

Fig. 5

Synthesis of dicarbonyl-containing drugs and natural products. a The synthesis of indibulin. b The synthesis of polyandrocarpamide C. c The synthesis of a 9,10-phenanthrenequinone