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.

Non‐Bonding 1,4‐Sulphur‐Oxygen Interaction Governs the Reactivity of α‐Ketothioesters in Triphenylphosphine‐Catalyzed Cyclization with Acetylenedicarboxylates

“…A perusal of the X‐ray crystallographic literature on α‐ketothioesters also revealed the existence of attractive non‐bonded electrostatic 1,4‐S⋅⋅⋅O contact between the S and O atoms. The S⋅⋅⋅O distances of 2.80 Å, 2.85 Å, 2.75 Å, and 2.76 Å observed in single crystal structures such as for Ph−CH=CH( E )−C(=O)−C(=O)−SMe ( 4 k ), [11c,13–14] 4−CN−C 6 H 4 −CH=CH( E )−C(=O)−C(=O)−SMe, [13] MeSO 2 −C 6 H 4 −C(=O)−C(−O)−SCH 2 Ph, [14–15] and Ph−C(=O)−C(=O)−S−C 6 H 4 − p −Me ( 4 p ) [16] respectively are significantly less than the sum of the van der Waals radii of S and O atoms with the substituents on the sulphur atom oriented away from the ketone O atom.…”

Recent Advances in Asymmetric Organomulticatalysis

“…Thus, it can recognize the non‐ionic nitroolefin 115 [66d–h] through the H‐bond interaction to control the enantioselectivity. The catalyst of 2,6‐lutidine as Brønsted base can deprotonate the acidic nucleophile of thiol 116 , and then leading to realizing the asymmetric sulfa‐Michael addition and affording the desired sufide 117 [66i–t] . The diverse derivatization finally transfers the sulfide 117 to the bioactive molecules of taurine derivative 118 and 4‐monosubstituted β ‐sultam 119 .…”

Recent Advances in the Synthesis and Applications of α‐Ketothioesters

“…Very recently, based on the methods used in the nature, a radical coupling between α‐hydroxyketones and elemental sulphur was performed with excellent control to provide useful α‐ketothioesters (Section 2.6.) [49] . The method for the synthesis of α‐ketothioesters bearing a chiral centre is rare [7,50] .…”

“…As discussed earlier, the C(O)−S bond in α‐ketothioesters possesses weaker bond energy and this can be easily cleaved under mild conditions in the presence of various nucleophiles (C, N, and O). The utility of α‐ketothioesters via the cleavage of the C(O)−S bond for affording diverse functionalized organic compounds will be discussed in the Section 3.2 [49,52,66–68] . By utilizing this concept, pharmaceutically relevant anticancer drug indibulin and natural product polyandrocarpamide C have recently been developed (Section 3.2.)…”

“…By utilizing this concept, pharmaceutically relevant anticancer drug indibulin and natural product polyandrocarpamide C have recently been developed (Section 3.2.) [49] …”