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.
Highlights
The 1,2-dicarbonyl motif is vital to biomolecules, especially natural products and pharmaceuticals
Since the dicarbonyl motif can bind to proteins in the body to increase their bioavailability, many well-known dicarbonyl-containing molecules have been turned into clinically used drugs, such as the anticancer drugs indibulin[7] and biricodar[8], the anti-HCV drug boceprevir[9], and the dermatologic agent fluocortin butyl, a synthetic corticosteroid with high topical to systemic activites (Fig. 1b)[10]
As a continuation of our investigations of the transformations of inorganic sulfur compounds to organic sulfur structures[23,24,25,26,27,28,29,30], we hypothesize that trisulfur radical anions can react at the α position of α-hydroxy ketones (Fig. 2c)
Summary
The 1,2-dicarbonyl motif is vital to biomolecules, especially natural products and pharmaceuticals. 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. 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. As a continuation of our investigations of the transformations of inorganic sulfur compounds to organic sulfur structures[23,24,25,26,27,28,29,30], we hypothesize that trisulfur radical anions can react at the α position of α-hydroxy ketones (Fig. 2c). The dicarbonylation of a broad range of amines and amino acids, and cross couplings with aryl borates to construct dicarbonyl-carbon bonds are realized by employing this stable and convenient αketothioester as a 1,2-dicarbonyl reagent
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