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

ARTICLE https://doi.org/10.1038/s41467-019-10651-w OPEN Design and application of α-ketothioesters as 1,2-dicarbonyl-forming reagents 1234567890():,; Ming Wang 1, Zhihong Dai1 & Xuefeng Jiang 1,2 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. 1 Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. 2 State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. Correspondence and requests for materials should be addressed to X.J. (email: ) NATURE COMMUNICATIONS | (2019)10:2661 | https://doi.org/10.1038/s41467-019-10651-w | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-10651-w T he 1,2-dicarbonyl motif is an important life-related structure that is ubiquitous in natural products1-5 and modern pharmaceuticals6–10. Licoagrodione, isolated from a Chinese herb, was found to exhibit antimicrobial activity2. Tanshinone IIA is a transcription factor inhibitor and was isolated from Salvia miltiorrhiza BUNGE3. Mansonone C, isolated from Mansonia altissima, displays antifungal activity against P. parasitica4. Sophoradione was isolated from the roots of S. flavescens and is cytotoxic to KB tumour cells (Fig. 1a)5. 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 indibulin7 and biricodar8, the anti-HCV drug boceprevir9, and the dermatologic agent fluocortin butyl, a synthetic corticosteroid with high topical to systemic activites (Fig. 1b)10. Furthermore, dicarbonyl-containing compounds frequently serve as valuable synthetic intermediates and precursors in organic synthesis and materials science. For example, aromatic substituted quinoxalines, which possess broad applications as photoinitiators and fluorescence-based sensors, have been synthesized from dicarbonyl-containing compounds11–14. Conventionally, dicarbonyl compounds are prepared via Müller’s αketo acyl chloride, but the compatibility is imperfect and side reactions can occur15–18. Based on the methods used in nature, ester bonds can be formed through the transesterification of thioesters, such as acetyl coenzyme A19, and native chemical ligation via peptide chemistry20. Thioesters, as active but stable esters, have been widely used as synthetic intermediates for acyl transfer reactions such as Corey-Nicolaou macrolactonizations (Fig. 2a)21. Due to the C–S bond possessing both weaker bond energy and relative stability at ambient conditions, we assume that an α-ketothioester will be an excellent 1,2-dicarbonyl-forming reagent and be broadly applicable in chemistry (Fig. 2b). Previously, we found that α-hydroxy ketones were efficient acylating reagents, and that they easily initiated radical formation at the α position22. As a continuation of our investigations of the transformations of inorganic sulfur compounds to organic sulfur structures23–30, we hypothesize that trisulfur radical anions can a react at the α position of α-hydroxy ketones (Fig. 2c). Herein, a transition-metal-free approach for the synthesis of an αketothioester 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 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. Results Optimization and Synthesis of a 1,2-Dicarbonyl-forming Reagent. We commenced our studies by investigating the transformation of readily available 2-hydroxy-1-phenylethanone to the corresponding α-ketothioester in the presence of S8 and tetrabutylammonium bromide (TBAB) in cyclopentyl methyl ether (CPME) under an inert atmosphere. Unfortunately, desired α-ketothioester 2a was not obtained when the reaction was run with only base or water (Table 1, entries 1, 2). 2a could not be provided under the conditions of organic bases, regardless of whether water was added or not in the reaction (Table 1, entries 3–6). Encouragingly, dicarbonyl-forming reagent 2a was isolated in 71% yield when both potassium carbonate and water were added (Table 1, entry 7). When potassium hydrogen carbonate (KHCO3) was used instead of potassium carbonate (K2CO3), the yield increased to 86% (Table 1, entry 8). Decreasing the amount of water to 10 equivalents resulted in a lower yield (Table 1, entry 9). Increasing the equivalents of water did not improve the reaction outcome (Table 1, entry 10). TBAB was not necessary when DMF was used as the solvent, and the yield remained acceptable (Table 1, entry 11). When the reaction was carried out under air, the isolated yield of 2a decreased to 61%, which means that oxygen affects this type of radical (Table 1, entry 12). However, the efficiency of the reaction was dramatically lower in the absence of TBAB as a phase-transfer reagent (Table 1, entry 13). The effects of different solvents implied the unique importance of cyclopentyl methyl ether (CPME) (see the Supporting Information). Natural products O O O HO O Me H3C O OH CH3 Licoagrodione (antimicrobial) b H3C Me Me Tanshinone IIA (antioxidant) OH Me CH3 OH O OH Me HO O MeO OH OMe O O Me Mansonone C (antifungal) Sophoradione (anticancer) Drug molecules O O N H O N O MeO N N MeO CI Indibulin (anticancer, Baxter Oncology) O N H N O O OMe N H N H N N O HO Me NH2 Boceprevir (anti-HCV drug, Merk) OnBu H O F Fluocortin butyl (dermatologic agents) Fig. 1 Significant dicarbonyl-containing molecules. a Dicarbonyl-containing natural products. b Dicarbonyl-containing drug molecules 2 O Me H O O Biricodar (anticancer, Vertex) O O Me NATURE COMMUNICATIONS | (201 (...truncated)