Polysulfurating reagent design for unsymmetrical polysulfide construction

Polysulfurating reagent design for unsymmetrical polysulfide construction ARTICLE DOI: 10.1038/s41467-018-04306-5 OPEN Polysulfurating reagent design for unsymmetrical polysulfide construction 1 1 1,2,3 Xiao Xiao , Jiahui Xue & Xuefeng Jiang From life science to material science, to pharmaceutical industry, and to food chemistry, polysulfides are vital structural scaffolds. However, there are limited synthetic methods for unsymmetrical polysulfides. Conventional strategies entail two pre-sulfurated cross-coupling substrates, R–S, with higher chances of side reactions due to the characteristic of sulfur. Herein, a library of broad-spectrum polysulfurating reagents, R–S–S–OMe, are designed and scalably synthesized, to which the R–S–S source can be directly introduced for late-stage modifications of biomolecules, natural products, and pharmaceuticals. Based on the hard and soft acids and bases principle, selective activation of sulfur-oxygen bond has been accom- plished via utilizing proton and boride for efficient unsymmetrical polysulfuration. These polysulfurating reagents are highlighted with their outstanding multifunctional gram-scale transformations with various nucleophiles under mild conditions. A diversity of polysulfurated biomolecules, such as SS−(+)-δ-tocopherol, SS-sulfanilamide, SS-saccharides, SS-amino acids, and SSS-oligopeptides have been established for drug discovery and development. Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, 2 3 Shanghai 200062, China. State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. Correspondence and requests for materials should be addressed to X.J. (email: xfjiang@chem.ecnu.edu.cn) NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications 1 | | | 1234567890():,; ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 isulfide scaffolds, containing two covalently linked sulfur sulfide donor, mediating and regulating the release of hydrogen 1–6 23, 24 atoms, are important molecular motifs in life science , sulfide upon physiological activation (Fig. 1b) . From the 7–15 16–18 Dpharmaceutical science , and food chemistry by materials perspective, organotrisulfides, such as dimethyl tri- −1 virtue of their unique pharmacological and physiochemical sulfide (DMTS) with a theoretical capacity of 849 mAhg , hold properties (Fig. 1a). Disulfide bonds, for instance, in biomolecules promise as high-capacity cathode materials for high-energy take multifaceted roles in various biochemical redox processes to rechargeable lithium batteries . It should also be pointed out generate and regulate hormones, enzymes, growth factors, toxins, that trisulfides do exist in bioactive natural products from marine 7, 26–28 26 and immunoglobulins for very homeostasis and bio-signaling invertebrates , such as the antitumor varacins A and the (e.g., metal trafficking); secondary and tertiary structures of anti-fungus outovirin C . proteins are also well formed and stabilized via the disulfide Given the importance and predominance in pharmaceuticals 2–5 bridge . In recent decades, potent bioactive natural products and other bioactive compounds of polysulfurated structures, it is and pharmaceuticals possessing sulfur–sulfur bonds have been always sought-after to develop general polysulfuration protocols discovered, such as the antifungal polycarpamine family , the for synthetic purposes. Although typical methods for symmetrical 8, 9 29 anti-poliovirus epidithiodiketopiperazine (ETPs) family , disulfide preparation have been well developed , the construc- 10 11 romidepsin , gliotoxin , and some new histone deacetylase/ tion of unsymmetrical disulfides is still a challenging transfor- 12 30–40 methyltransferase inhibitors , which, mechanism-wise, either mation due to the high reactivity of S–S bond . In general, the sequester enzyme-cofactor zinc or generate highly reactive elec- synthesis of unsymmetrical disulfides can be achieved via an S 2 trophiles to induce DNA strand scission. When it comes to process between a thiol and a prefunctionalized thiol with leaving 32–38 antibody-drug conjugates (ADC), the disulfide bond has also group . Alternatively, one can employ either two different been extensively utilized as a linker to deliver the active drug into kinds of thiols with unavoidable formation of homocoupling 19–22 39 the targeted cell after cleavage upon internalization of ADC . byproducts or two distinct symmetrical disulfides with the use Due to the higher intracellular concentration of free thiols (glu- of rhodium(I) by Yamaguchi group . Based on our continuous 41–48 tathione) than in the bloodstream, the sulfur–sulfur bonds can be research in organic sulfur chemistry , comproportionation selectively cleaved in the cytoplasm of cancer cell, thereby between two distinct inorganic sulfur sources was utilized for achieving the specified release of cytotoxic molecules. Notably, unsymmetrical disulfides syntheses . However, the strategy of disulfide compounds in allium species plants can not only aforementioned methods introduces disulfide bonds from two demonstrate vasorelaxation activity, but also inhibit ADP- different kinds of sulfur-containing substrates, requiring more 16–18 induced platelet aggregation . synthetic steps and leading to side-reactions due to both reactive 30–40, 49 Tri-sulfides have recently received considerable attention. To thio-derivatives (Fig. 2a) . We intend to develop metho- cite the allium-derived diallyl trisulfide (DATS) as an example, it dology which can introduce the RSS source with one disulfurating serves as a gasotransmitter precursor and an excellent hydrogen reagent at a later stage so as to provide great compatibility and a b Disulfide: Trisulfide: Me Me NMe 2 Me N MeO S O O NH S S S S O Me S Me MeO NH Me S R NH S S Polycarpamine B S Me Me R = O DATS Protein structure Polycarpamine C DMTS Istodax (gasotransmitter R = S (electrode material) (romidepsin) H S donors) (anti-fungus) Life Science Natural Products Pharmaceuticals Life Science Materials Science Cytotoxic OMe O MeO OMe molecule MeO Allicin S HO OH (hypolipidemic, O S Linker hypotensive) S N S Attachment site S S NMe OH NH OH O Z-ajoene Outovirin C Varacins A (anti-thrombotic) (anti-fungus) (antitumor) Antibody Antibody Drug Conjugates (ADC) Food Chemistry Natural Products Fig. 1 Significant polysulfides. a The importance of disulfide scaffolds in life science, natural products, pharmaceuticals, antibody drug conjugates, and food chemistry. b Functional trisulfide molecules 2 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications | | | NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 ARTICLE several possibilities of polysulfuration. Hydropersulfide (RSSH) acetyl masked disulfurating nucleophiles and organometallic seems to be a prime disulfurating reagent, though it is unstable reagents (Fig. 2b) . 50, 51 owing to its high reactivity . Two sulfur atoms were suc- Nevertheless, there is a large demand for a universal dis- cessfully introduced in one step via oxidative cross-couplings of ulfurating reagent, which is compatible with diverse coupling Disulfuration via two sulfur sources: Two functionalized "sulfur" 1 S R (1) R S 1 + R S Direct disulfuration via masked strategy: 1 Oxidative cross-coupling Nucleophilic reagent: S Mask (2) R S Metal cat. (Mask = Ac) Nu δ S R S Umpolung Electrophilic reagent: S Mask 1 (3) R S (Mask = ?) Metal free This work: electrophilic disulfuration Nu BR / H Cat. S S OMe S Nu H 1 1 1 + + Nu S R R R S Nu = C, N, S Challenge: Solution: The same main group, similar electronic effec t HSAB Electronic effect i) Umpolung Mask ii) Selective S-O cleavage Lewis base Fig. 2 Strategies for polysulfide construction. a Traditional methodologies for unsymmetrical disulfide syntheses. b Masked strategy for disulfuration. c Electropilic disulfurating reagent for polysulfuration a,b Table 1 Optimization of polysulfide reagents Entry CuSO (mol%) Ligand (mol%) PhI(OPiv) (equiv) Temp (°C) Time (h) Yields (%) 4 2 1 10 bpy (10) 2.5 25 11 31 2 10 bpy (10) 2.5 25 11 ND 3 10 bpy/ phen (10) 2.5 25 11 50/53 4 10 L1 (10) 2.5 25 11 77 5 10 L2/L3/L4 (10) 2.5 25 11 70/63/68 6 10 L1 (10) 2.5 20 13 86 7 5 L1 (10) 2.5 20 13 86 8 2.5 L1 (10) 2.5 20 13 79 9 5 L1 (5) 2.5 20 13 76 10 5 L1 (10) 2.2 20 13 88 11 5 L1 (10) 1.9 20 13 65 Conditions: 1d (0.2 mmol, 1 equiv), CuSO ·5H O, Ligand, Li CO and PhI(OPiv) were added to MeOH (2 mL) at 20 °C for 13 h 4 2 2 3 2 Isolated yields PhI(OAc) was instead of PhI(OPiv) 2 2 PhI(OTFA) was instead of PhI(OPiv) 2 2 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications 3 | | | ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 a,b Table 2 The scope of polysulfurating reagents 1 (5 mmol, 1 equiv), CuSO ·5H O (0.0125 mol, 0.125 mol%), L1 (0.025 mol, 0.25 mol%), Li CO (5 mmol, 1 equiv) and PhI(OPiv) (11 mmol, 2.2 equiv) were added to MeOH (10 mL) at 20 °C for 15 h 4 2 2 3 2 Isolated yields 1 (10 mmol, 1 equiv) and MeOH (10 mL) were used partners without transition-metal catalysis. The umpolung strat- PhI(OAc) as oxidant (Table 1, entry 1). The bulky iodonium salt − + egy, replacement of acetyl (RSS ) with methoxyl (RSS ) group, PhI(OPiv) was the oxidant of choice in this conversion (Table 1, will afford the precursor of persulfide cation (Fig. 2c). Originating entries 1–3). Systematic investigations of ligands showed that 4,7- from the same main group, sulfur and oxygen possess similar diphenyl-1,10-phenanthroline helped to increase the yield of 2d electronic effect, which imposes a great challenge for selective to 77% (Table 1, entries 3–5). Further study demonstrated that cleavage of S–O bond with S–S bond untouched. Based on the slightly lower temperature was important for keeping product 2d hard and soft acids and bases (HSAB) principle , we hypothesize stable in this system (Table 1, entry 6). Catalyst loading was that boride/proton can help to make the difference between S–S lowered with the same efficiency of the transformation (Table 1, and S–O, in which the hard acid boride/proton prefers oxygen entries 7–9). The optimal conditions were found to involve coordination. Herein, we disclose a polysulfurating reagent which treatment of 1d with 5 mol% of catalyst, 10 mol% of ligand L1, 2.2 can construct unsymmetrical disulfide and trisulfide products by equivalents of bis(tert-butylcarbonyloxy)iodobenzene, and 1.0 utilizing a RSS source only on one substrate, which renders the equivalent of lithium carbonate in 0.1 M methanol at 20 °C, late-stage functionalization feasible. Different nucleophilic which afforded electrophilic polysulfurating reagent 2d in the regents, such as 1,3-dicarbonyl derivatives, electron-rich arenes, yield of 88% (Table 1, entry 10). When the oxidant bis(tert- heteroarenes, amines, and thiols, had been smoothly coupled with butylcarbonyloxy)iodobenzene was reduced to 1.9 equivalents, disulfurating reagents under mild, transition-metal-free, and the yield of 2d was dropped sharply to 65% (Table 1, entry 11). base-free conditions, especially suitable for the late-stage mod- With the optimized conditions in hand, the syntheses of ification of natural products and pharmaceuticals. electrophilic polysulfurating reagents were comprehensively investigated. A scale of 5 mmol operation was practicably performed, decreasing catalyst loading to 0.25 mol% (for details Results see the Supplementary Table 2). Various acetyl substituted Optimization and synthesis of polysulfurating reagents. Initial disulfides were readily transformed to methoxyl substituted studies commenced with the construction of designed electro- disulfides (Table. 2). Initially, the reagents bearing both philic polysulfurating reagents. It was hypothesized that the electron-donating and electron-withdrawing groups on aromatic electrophilic reagent could be obtained through hydropersulfide rings were successfully obtained (Table 2, 2a–2f). Notably, 1.84 g anion and methanol via oxidative cross-coupling. The poly- of 2d was achieved in a yield of 87% with 10 mmol scale sulfurating reagent 2d was obtained in 31% yield under the operation (Table 2, 2d). The arene substituted with conditions of copper(II) as catalyst, 2,2′-bipyridine as ligand, and 4 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications | | | NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 ARTICLE a,b Table 3 Disulfuration with carbon nucleophiles Standard conditions A: NuH (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv), B(C F ) (0.01 mmol, 5 mol%) and 4-MeOPy (0.01 mmol, 5 mol%) were added to DCE (0.25 mL) at r.t. for 22 h. Standard 6 5 3 conditions B: NuH (0.3 mmol, 1.5 equiv), 2 (0.2 mmol, 1 equiv) and B(C F ) (0.01 mmol, 5 mol%) were added to PhMe (0.5 mL) at 0 °C for 24 h. Standard conditions C: NuH (0.3 mmol, 1.5 equiv), 2 6 5 3 (0.2 mmol, 1 equiv) and MeSO H (0.02 mmol, 10 mol%) were added to AmylOH (0.5 mL) at 0 °C for 5–24 h Isolated yields r.t. was instead of 0 °C B(C F ) (0.002 mmol, 1 mol%) was used 6 5 3 B(C F ) (0.01 mmol, 0.2 mol%) was used 6 5 3 B(C F ) (0.004 mmol, 2 mol%) were added to PhMe (0.25 mL) at r.t. for 24 h 6 5 3 NuH (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv) and B(C F ) (0.004 mmol, 2 mol%) were added to PhMe (0.25 mL) at 0 °C for 24 h. Ar = 4-CNC H 6 5 3 6 4 chloromethylene group was compatible under the standard reagents are fairly stable without deterioration when stored in a conditions (Table 2, 2e–2f). Reactions involving secondary benzyl refrigerator (−18 °C) for half a year. Around 20% of these and propargyl derivatives were carried out smoothly (Table 2, 2g– reagents will decompose at room temperature (+25 °C) after 2h). When aliphatic substrates were evaluated, the corresponding 1 week. products were formed efficiently (Table 2, 2i–2m). The scope was further demonstrated through the successful syntheses of bis- disulfurating reagents (Table 2, 2n–2o). Notably, the modification Polysulfuration with designed reagents. With the class of dis- of saccharides and amino acids were also converted into ulfurating reagents in hand, the construction of unsymmetrical corresponding disulfurating reagents (Table 2, 2p–2t). These disulfides and trisulfides was consequently explored. We initiated NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications 5 | | | ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 a,b Table 4 Disulfuration with heteroatomic nucleophiles Standard conditions D: NuH (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv) and B(C F ) (0.005 mmol, 2.5 mol%) were added to PhMe (0.5 mL) at r.t. for 24 h. Standard conditions E: NuH (0.22 mmol, 6 5 3 1.1 equiv) and 2 (0.2 mmol, 1 equiv) were added to DCM (2.0 mL) at r.t. for 8 h Isolated yields B(C F ) (0.0125 mmol, 0.25 mol%) was used 6 5 3 CH CN was used as solvent NuH (0.2 mmol, 1 equiv), 2 (0.3 mmol, 1.5 equiv) and B(C F ) (0.005 mmol, 2.5 mol%) were added to DMF at r.t. for 24 h 6 5 3 B(C F ) (2.5 mol%) was added at r.t. for 5 h 6 5 3 B(C F ) (2.5 mol%) and DCM (0.5 mL) was added 6 5 3 B(C F ) (2.5 mol%) and DMF (0.5 mL) was added 6 5 3 24 h. Ar = 4-CNC H ,R = (CH ) Me 6 4 2 9 our efforts with 1,3-dicarbonyl compounds due to their excellent dicarbonyl structures effectively afford disulfuration catalyzed nucleophilic property. Based on the HSAB principle, the coupling with the combination of tris(perfluorophenyl)borane and 4- between acetylacetone and reagent 2d has been explored under methoxypyridine (Table 3). Acyclic and cyclic 1,3-dicarbonyl the assistance of the hard acid Tris(perfluorophenyl)borane as a substrates were smoothly converted to the desired disulfides catalyst (for details see the Supplementary Table 3). Various 1,3- (Table 3, 3a–3d). The configuration of 3a was further confirmed 6 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications | | | NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 ARTICLE through X-ray crystallographic analysis. Aliphatic and propargyl Discussion derivatives were compatible in this process (Table 3, 3e–3h). In summary, a class of stable and broad-spectrum polysulfurating Significantly, disulfurating reagents bearing both saccharide and reagents with masked strategy has been designed and a general amino acid groups accomplished this transformation efficiently polysulfurating methodology has been established under mild with two parts connected via the disulfur linkage (Table 3, 3i–3l). conditions, which can directly introduce two sulfur atoms into Following the activation mode, electron-rich aromatics were functional molecules. The designed reagents were compatible readily accommodated under standard conditions (Table 3, 4a– with a considerable range of significant biomolecules, such as 4d). (+)-δ-Tocopherol, a significant bioactive molecule, could be saccharides, amino acids, peptides and variety of heterocycles. disulfurated directly despite the presence of free hydroxyl group This protocol showcases the wide utility of both carbon and (Table 3, 4c–4d). Indole and pyrrole, ubiquitous in natural nitrogen nucleophiles resulting in the functional disulfides. Fur- products and pharmaceuticals, are excellent coupling partners as thermore, the trisulfuration provides a convenient and efficient well. Indoles bearing both electron-rich and -deficient functional method for sulfur-containing drug discovery. Further studies on groups proceeded smoothly with disulfurating reagents to afford modification of biomolecules and pharmaceuticals with these the corresponding indolyl-disulfides on 3-position (Table 3, 5a- disulfurating reagents are still ongoing. 5p). A bis-disulfurating electrophile also afforded the correspond- ing twofold disulfur-containing molecule efficiently (Table 3, 5q). Methods Saccharide and amino acid structures were directly installed with General methods. See Supplementary Methods for further details. indoles via the disulfide linker (Table 3, 5r-5u). A gram-scale operation was performed with 5 mmol of 2d under the catalysis of General procedure for syntheses of disulfurating reagents 2. To a Schlenk tube 1 mol% of B(C F ) affording 5o in 93% yield (1.38 g), which 6 5 3 were added RSSAc 1 (5 mmol, 1 equivalent), CuSO ·5H O (0.0125 mmol, 0.25 mol 4 2 structure was further confirmed through X-ray analysis. In %, 3.2 mg), L1 (0.025 mmol, 0.5 mol%, 8.1 mg), Li CO (5 mmol, 1 equivalent, 370 2 3 particular, iodo- and formyl-substituted indoles were also mg), PhI(OPiv) (11 mmol, 2.2 equivalents, 4.47 g) and undried MeOH (10 mL), compatible in this transformation (Table 3, 5m-5n). Pyrroles the mixture was stirred at 20 °C under normal conditions for 15 h. Then the mixture was quenched by saturated NaHCO and extracted by DCM before the substituted on different positions were treated to the disulfuration 3 organic phase was concentrated under vacuum without adding silica gel. Pur- conditions, successfully providing desired products as well ification by column chromatography afforded the desired product. (Table 3, 5v-5y). Subsequently, amine partners were systematically varied General procedure for syntheses of disulfides 3. To a Schlenk tube were added providing access to a wide range of functional aza-disulfide in 1,3-dicarbonyl compound (0.22 mmol, 1.1 equivalents), B(C F ) (0.01 mmol, 5 6 5 3 the presence of 2.5 mol% of tris(perfluorophenyl)borane. The mol%, 5.2 mg), 4-MeO-pyridine (0.01 mmol, 5 mol%, 1.1 mg), RSSOMe 2 (0.2 anilines substituted with electron-withdrawing and electron- mmol, 1 equivalent), and 1,2-dichloroethane (0.25 mL), the mixture was stirred at donating functional groups afforded the desired aza-disulfides r.t. for 22 h before it was concentrated under vacuum. Purification by column in moderate to excellent yields (Table 4, 6a-6f). The secondary chromatography afforded the desired product. amines proceeded in this transformation, affording correspond- ing products in favorable yields (Table 4, 6g-6h). Notably, allyl, General procedure for syntheses of disulfides 4. To a Schlenk tube were added propargyl and heteroaromatic amines were all efficiently arene (0.3 mmol, 1.5 equivalents), B(C F ) (0.01 mmol, 5 mol%, 5.2 mg), RSSOMe 6 5 3 transformed to the corresponding products (Table 4, 6i-6k). 2 (0.2 mmol, 1 equivalent), and toluene (0.5 mL), the mixture was stirred at 0 °C or r.t. for 24–60 h before it was concentrated under vacuum. Purification by column Sulfanilamides, as a significant type of antibiotic, could be chromatography afforded the desired product. modified with the designed persulfurating reagent in good to excellent yields (Table 4, 6m-6s). Lenalidomide, a myeloma drug, was installed with the disulfide under mild reaction conditions General procedure for syntheses of disulfides 5. Method A: To a Schlenk tube were added indole (0.3 mmol, 1.5 equivalents), MeSO H (0.02 mmol, 10 mol%, 2 (Table 4, 6t). Furthermore, functional disulfurating electrophiles, 3 mg), RSSOMe 2 (0.2 mmol, 1 equivalent), and t-AmylOH (0.5 mL), the mixture modified with saccharide and amino acid groups, were furnished was stirred at r.t. for 24 h before it was concentrated under vacuum. Purification by with the substituted disulfur amine linker (Table 4, 6u-6y). The column chromatography afforded the desired product. Method B: To a Schlenk structure of 6a was further confirmed by X-ray analysis. In order tube were added indole (0.22 mmol, 1.1 equivalents), B(C F ) (0.004 mmol, 2 mol 6 5 3 %, 2.1 mg), RSSOMe (0.2 mmol, 1 equivalent), and toluene (0.25 mL), the mixture to validate the efficiency and practicability of this aza-disulfura- was stirred at 0 °C or r.t. for 24 h before it was concentrated under vacuum. tion, 0.25 mol% catalyst loading was launched on a gram-scale Purification by column chromatography afforded the desired product. reaction to afford 6a in 81% yield (1.1 g). Trisulfuration was readily achieved with thiols as a nucleophile (Table 4, 7a-7q). Even sterically bulky aliphatic thiols, tert- General procedure for syntheses of aza-disulfides 6. To a Schlenk tube were added amine (0.22 mmol, 1.1 equivalents), B(C F ) (0.01 mmol, 2.5 mol%, 2.6 6 5 3 butylthiol and 1-adamantanethiol, displayed excellent trisulfura- mg), RSSOMe 2 (0.2 mmol, 1 equivalent), and toluene (0.5 mL), the mixture was tions (Table 4, 7d, and 7l). The structure of 7d was further stirred at 0 °C or r.t. for 24 h before it was concentrated under vacuum. Purification confirmed via X-ray analysis. A gram-scale production for 7g by column chromatography afforded the desired product. could be performed in 92% yield practically. Thiols substituted with vinyl, polyfluoroalkyl, silyl, and hydroxyl groups, and General procedure for syntheses of trisulfides 7. To a Schlenk tube were added heterocycles were all tolerated in this transformation, being thiol (0.22 mmol, 1.1 equivalents), B(C F ) , RSSOMe 2 (0.2 mmol, 1 equivalent), 6 5 3 converted to the unsymmetrical trisulfides, respectively (Table 4, and DCM (0.5 mL), the mixture was stirred at r.t. under N atmosphere for 5–8h 7h-7k, and 7o). Even dithiols efficiently formed the correspond- before it was concentrated under vacuum. Purification by column chromatography afforded the desired product. ing twofold trisulfur-containing products in good yields (Table 4, 7s-7t). Aliphatic trisulfurations could be achieved in high yields (Table 4, 7u-7v). It should be noted that trisulfides containing Data availability. The X-ray crystallographic coordinates for structures reported in saccharide and cysteine fragments were readily formed through this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 1565934 (3a), 1565935(5o), 1565936 these reagents (Table 4, 7r, 7w-7ac). Cysteine was successfully (6a) and 1565937 (7d). These data can be obtained free of charge from The utilized for constructing trisulfur-containing amino acids and Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. oligopeptides, which might provide another access for peptide The authors declare that all other data supporting the findings of this study are drug discovery (Table 4, 7aa-7ac). available within the article and Supplementary Information files, and also are available from the corresponding author on reasonable request. NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications 7 | | | ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 Received: 26 January 2018 Accepted: 19 April 2018 27. Oku, N., Matsunaga, S. & Fusetani, N. Shishijimicins A-C, novel enediyne antitumor antibiotics from the ascidian didemnum proliferum. J. Am. Chem. Soc. 125, 2044–2045 (2003). 28. Kajula, M. et al. Bridged epipolythiodiketopiperazines from penicillium raciborskii, an endophytic fungus of rhododendron tomentosum harmaja. J. Nat. Prod. 79, 685–690 (2016). 29. Witt, D. Recent developments in disulfide bond formation. Synthesis 16, References 2491–2509 (2008). 1. Narayan, M., Welker, E., Wedemeyer, W. J. & Scheraga, H. D. Oxidative 30. Musiejuka, M. & Witt, D. Recent developments in the synthesis of folding of proteins. Acc. Chem. Res. 33, 805–812 (2000). unsymmetrical disulfanes (disulfides). Org. Prep. Proced. Int. 47,95–131 2. A.-Cebollada, J., Kosuri, P., R.-Pardo, J. A. & Fernández, J. M. Direct (2015). observation of disulfide isomerization in a single protein. Nat. Chem. 3, 31. Feng, M., Tang, B., Liang, S. & Jiang, X. Sulfur containing scaffolds in drugs: 882–887 (2011). synthesis and application in medicinal chemistry. Curr. Top. Med. Chem. 16, 3. Wommack, A. J. et al. Discovery and characterization of a disulfide- 1200–1216 (2016). locked C -symmetric defensin peptide. J. Am. Chem. Soc. 136, 13494–13497 32. Swan, J. M. Thiols, disulphides and thiosulphates: some new reactions and (2014). possibilities in peptide and protein chemistry. Nature 180, 643–645 (1957). 4. Góngora-Benítez, M., Tulla-Puche, J. & Albericio, F. Multifaceted roles 33. Bao, M. & Shimizu, M. N-Trifluoroacetyl arenesulfenamides, effective of disulfide bonds. Peptides as therapeutics. Chem. Rev. 114, 901–926 precursors for synthesis of unsymmetrical disulfides and sulfenamides. (2014). Tetrahedron 59, 9655–9659 (2003). 5. Lu, S. et al. Mapping native disulfide bonds at a proteome scale. Nat. Methods 34. Sivaramakrishnan, S., Keerthi, K. & Gates, K. S. A chemical model for redox 12, 329–331 (2015). regulation of protein tyrosine phosphatase 1B (PTP1B) activity. J. Am. Chem. 6. Landeta, C. et al. Compounds targeting disulfide bond forming enzyme DsbB Soc. 127, 10830–10831 (2005). of gram-negative bacteria. Nat. Chem. Biol. 11, 292–298 (2015). 35. Hunter, R., Caira, M. & Stellenboom, N. Inexpensive, one-pot synthesis of 7. Jiang, C.-S., Müller, W. E. G., Schröder, H. C. & Guo, Y.-W. Disulfide- and unsymmetrical disulfides using 1-chlorobenzotriazole. J. Org. Chem. 71, multisulfide-containing metabolites from marine organisms. Chem. Rev. 112, 8268–8271 (2006). 2179–2207 (2012). 36. Antoniow, S. & Witt, D. A novel and eficient synthesis of unsymmetrical 8. Nicolaou, K. C. et al. Synthesis and biological evaluation of epidithio-, disulfides. Synthesis 22, 363–366 (2007). epitetrathio-, and bis-(methylthio)diketopiperazines: synthetic methodology, ’ 37. Szymelfejnik, M., Demkowicz, S., Rachon, J. & Witt, D. Functionalization of enantioselective total synthesis of epicoccin G, 8,8 -epi-ent-rostratin B, cysteine derivatives by unsymmetrical disulfide bond formation. Synthesis 22, gliotoxin, gliotoxin G, emethallicin E, and haematocin and discovery 3528–3534 (2007). of new antiviral and antimalarial agents. J. Am. Chem. Soc. 134, 17320–17332 38. Taniguchi, N. Unsymmetrical disulfide and sulfenamide synthesis via (2012). reactions of thiosulfonates with thiols or amines. Tetrahedron 73, 2030–2035 9. Chankhamjon, P. et al. Biosynthesis of the halogenated mycotoxin (2017). aspirochlorine in koji mold involves a cryptic amino acid conversion. Angew. 39. Vandavasi, J. K., Hu, W. P., Chen, C. Y. & Wang, J. J. Efficient synthesis of Chem. Int. Ed. 53, 13409–13413 (2014). unsymmetrical disulfides. Tetrahedron 67, 8895–8901 (2011). 10. Nielsen, D. S. et al. Orally absorbed cyclic peptides. Chem. Rev. 117, 40. Arisawa, M. & Yamaguchi, M. Rhodium-catalyzed disulfide exchange 8094–8128 (2017). reaction. J. Am. Chem. Soc. 125, 6624–6625 (2003). 11. Scharf, D. H. et al. A dedicated glutathione S-transferase mediates carbon- 41. Liu, H. & Jiang, X. Transfer of sulfur: from simple to diverse. Chem. Asian J. 8, sulfur bond formation in gliotoxin biosynthesis. J. Am. Chem. Soc. 133, 2546–2563 (2013). 12322–12325 (2011). 42. Qiao, Z. et al. Efficient access to 1, 4-benzothiazine: palladium-catalyzed 12. Liu, Y. et al. Development of the first generation of disulfide-based subtype- double C-S bond formation using Na S O as sulfurating reagent. Org. Lett. 2 2 3 selective and potent covalent pyruvate dehydrogenase kinase 1 (PDK1) 15, 2594–2597 (2013). inhibitors. J. Med. Chem. 60, 2227–2244 (2017). 43. Wei, J., Li, Y. & Jiang, X. Aqueous compatible protocol to both alkyl and aryl 13. Zorzi, A., Deyle, K. & Heinis, C. Cyclic peptide therapeutics: past, present and thioamide synthesis. Org. Lett. 18, 340–343 (2016). future. Curr. Opin. Chem. Biol. 38,24–29 (2017). 44. Qiao, Z. & Jiang, X. Recent development in sulfur-carbon bond Formation 14. Brocchini, S. et al. PEGylation of native disulfide bonds in proteins. Nat. reaction involving thiosulfate. Org. Biomol. Chem. 15, 1942–1946 (2017). Protoc. 1, 2241–2252 (2006). 45. Wang, M., Wei, J., Fan, Q. & Jiang, X. Cu(II)-catalyzed sulfide construction: 15. Stephanopoulos, N. & Francis, M. B. Choosing an effective protein both aryl groups utilization of intermolecular and intramolecular bioconjugation strategy. Nat. Chem. Biol. 7, 876–884 (2011). diaryliodonium salt. Chem. Commun. 53, 2918–2921 (2017). 16. Block, E., Ahmad, S., Catalfamo, J. L., Jain, M. K. & Apitz-Castro, R. T. 46. Tan, W., Wei, J. & Jiang, X. Thiocarbonyl surrogate via combination of sulfur Antithrombotic organosulfur compounds from garlic: structural, mechanistic, and chloroform for thiocarbamide and oxazolidinethione constructions. Org. and synthetic studies. J. Am. Chem. Soc. 108, 7045–7055 (1986). Lett. 19, 2166–2169 (2017). 17. Block, E., Bayer, T., Naganathan, S. & Zhao, S.-H. Allium chemistry: synthesis 47. Wang, M., Chen, S. & Jiang, X. Construction of functionalized annulated and sigmatropic rearrangements of alk(en)yl 1-propenyl disulfide S-oxides sulfone via SO /I exchange of cyclic diaryliodonium salts. Org. Lett. 19, from cut onion and garlic. J. Am. Chem. Soc. 118, 2799–2810 (1996). 4916–4919 (2017). 18. Hanschen, F. S., Lamy, E., Schreiner, M. & Rohn, S. Reactivity and stability of 48. Li, Y., Wang, M. & Jiang, X. Controllable sulfoxidationand sulfenylation with glucosinolates and their breakdown products in foods. Angew. Chem. Int. Ed. organic thiosulfate salts via dual electron- and energy-transfer photocatalysis. 53, 11430–11450 (2014). ACS Catalysis 7, 7587–7592 (2017). 19. Senter, P. D. Potent antibody drug conjugates for cancer therapy. Curr. Opin. 49. Xiao, X., Feng, M. & Jiang, X. Transition-metal-free persulfuration to Chem. Biol. 13, 235–244 (2009). construct unsymmetrical disulfides and mechanistic study of sulfur redox 20. Chari, R. V. J., Miller, M. L. & Widdison, W. C. Antibody–drug conjugates: an process. Chem. Commun. 51, 4208–4211 (2015). emerging concept in cancer therapy. Angew. Chem. Int. Ed. 53, 3796–3827 50. Bailey, T. S., Zakharov, L. N. & Pluth, M. D. Understanding hydrogen sulfide (2014). storage: probing conditions for sulfide release from hydrodisulfides. J. Am. 21. Staben, L. R. et al. Targeted drug delivery through the traceless release of Chem. Soc. 136, 10573–10576 (2014). tertiary and heteroaryl amines from antibody-drug conjugates. Nat. Chem. 8, 51. Chauvin, J.-P. R., Griesser, M. & Pratt, D. A. Hydropersulfides: H-atom 1112–1119 (2016). transfer agents par excellence. J. Am. Chem. Soc. 139, 6484–6493 (2017). 22. Beck, A., Goetsch, L., Dumontet, C. & Corvaïa, N. Strategies and challenges 52. Xiao, X., Feng, M. & Jiang, X. New design of disulfurating reagent: facile and for the next generation of antibody-drug conjugates. Nat. Rev. Drug Discov. straightforward pathway to unsymmetrical disulfanes via Cu-catalyzed 16, 315–337 (2017). oxidative cross coupling. Angew. Chem. Int. Ed. 55, 14121–14121 (2016). 23. Cerda, M. M., Hammers, M. D., Earp, M. S., Zakharov, L. N. & Pluth, M. D. 53. Pearson, R. G. Hard and soft acids and bases. J. Am. Chem. Soc. 85, 3533–3539 Applications of synthetic organic tetrasulfides as H S donors. Org. Lett. 19, (1963). 2314–2317 (2017). 24. Benavides, G. A. et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc. Natl Acad. Sci. USA 104, 17977–17982 (2007). 25. Wu, M. et al. Organotrisulfide: a high capacity cathode material for Acknowledgements rechargeable lithium batteries. Angew. Chem. Int. Ed. 55, 10027–10031 (2016). The authors are grateful for financial support provided by The National Key Research 26. Makarieva, T. N. et al. Varacin and three new marine antimicrobial and Development Program of China (2017YFD0200500), NSFC (21722202, 21672069, polysulfides from the far-eastern ascidian polycitorsp. J. Nat. Prod. 58, 21472050), Fok Ying Tung Education Foundation (141011), DFMEC (20130076110023), 254–258 (1995). the program for Shanghai Rising Star (15QA1401800), Professor of Special Appointment 8 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications | | | NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 ARTICLE (Eastern Scholar) at Shanghai Institutions of Higher Learning, and National Program for Open Access This article is licensed under a Creative Commons Support of Top-Notch Young Professionals. Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Author contributions Commons license, and indicate if changes were made. The images or other third party X.J. conceived the idea and supervised the whole project. 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Polysulfurating reagent design for unsymmetrical polysulfide construction

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ARTICLE DOI: 10.1038/s41467-018-04306-5 OPEN Polysulfurating reagent design for unsymmetrical polysulfide construction 1 1 1,2,3 Xiao Xiao , Jiahui Xue & Xuefeng Jiang From life science to material science, to pharmaceutical industry, and to food chemistry, polysulfides are vital structural scaffolds. However, there are limited synthetic methods for unsymmetrical polysulfides. Conventional strategies entail two pre-sulfurated cross-coupling substrates, R–S, with higher chances of side reactions due to the characteristic of sulfur. Herein, a library of broad-spectrum polysulfurating reagents, R–S–S–OMe, are designed and scalably synthesized, to which the R–S–S source can be directly introduced for late-stage modifications of biomolecules, natural products, and pharmaceuticals. Based on the hard and soft acids and bases principle, selective activation of sulfur-oxygen bond has been accom- plished via utilizing proton and boride for efficient unsymmetrical polysulfuration. These polysulfurating reagents are highlighted with their outstanding multifunctional gram-scale transformations with various nucleophiles under mild conditions. A diversity of polysulfurated biomolecules, such as SS−(+)-δ-tocopherol, SS-sulfanilamide, SS-saccharides, SS-amino acids, and SSS-oligopeptides have been established for drug discovery and development. Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, 2 3 Shanghai 200062, China. State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. Correspondence and requests for materials should be addressed to X.J. (email: xfjiang@chem.ecnu.edu.cn) NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications 1 | | | 1234567890():,; ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 isulfide scaffolds, containing two covalently linked sulfur sulfide donor, mediating and regulating the release of hydrogen 1–6 23, 24 atoms, are important molecular motifs in life science , sulfide upon physiological activation (Fig. 1b) . From the 7–15 16–18 Dpharmaceutical science , and food chemistry by materials perspective, organotrisulfides, such as dimethyl tri- −1 virtue of their unique pharmacological and physiochemical sulfide (DMTS) with a theoretical capacity of 849 mAhg , hold properties (Fig. 1a). Disulfide bonds, for instance, in biomolecules promise as high-capacity cathode materials for high-energy take multifaceted roles in various biochemical redox processes to rechargeable lithium batteries . It should also be pointed out generate and regulate hormones, enzymes, growth factors, toxins, that trisulfides do exist in bioactive natural products from marine 7, 26–28 26 and immunoglobulins for very homeostasis and bio-signaling invertebrates , such as the antitumor varacins A and the (e.g., metal trafficking); secondary and tertiary structures of anti-fungus outovirin C . proteins are also well formed and stabilized via the disulfide Given the importance and predominance in pharmaceuticals 2–5 bridge . In recent decades, potent bioactive natural products and other bioactive compounds of polysulfurated structures, it is and pharmaceuticals possessing sulfur–sulfur bonds have been always sought-after to develop general polysulfuration protocols discovered, such as the antifungal polycarpamine family , the for synthetic purposes. Although typical methods for symmetrical 8, 9 29 anti-poliovirus epidithiodiketopiperazine (ETPs) family , disulfide preparation have been well developed , the construc- 10 11 romidepsin , gliotoxin , and some new histone deacetylase/ tion of unsymmetrical disulfides is still a challenging transfor- 12 30–40 methyltransferase inhibitors , which, mechanism-wise, either mation due to the high reactivity of S–S bond . In general, the sequester enzyme-cofactor zinc or generate highly reactive elec- synthesis of unsymmetrical disulfides can be achieved via an S 2 trophiles to induce DNA strand scission. When it comes to process between a thiol and a prefunctionalized thiol with leaving 32–38 antibody-drug conjugates (ADC), the disulfide bond has also group . Alternatively, one can employ either two different been extensively utilized as a linker to deliver the active drug into kinds of thiols with unavoidable formation of homocoupling 19–22 39 the targeted cell after cleavage upon internalization of ADC . byproducts or two distinct symmetrical disulfides with the use Due to the higher intracellular concentration of free thiols (glu- of rhodium(I) by Yamaguchi group . Based on our continuous 41–48 tathione) than in the bloodstream, the sulfur–sulfur bonds can be research in organic sulfur chemistry , comproportionation selectively cleaved in the cytoplasm of cancer cell, thereby between two distinct inorganic sulfur sources was utilized for achieving the specified release of cytotoxic molecules. Notably, unsymmetrical disulfides syntheses . However, the strategy of disulfide compounds in allium species plants can not only aforementioned methods introduces disulfide bonds from two demonstrate vasorelaxation activity, but also inhibit ADP- different kinds of sulfur-containing substrates, requiring more 16–18 induced platelet aggregation . synthetic steps and leading to side-reactions due to both reactive 30–40, 49 Tri-sulfides have recently received considerable attention. To thio-derivatives (Fig. 2a) . We intend to develop metho- cite the allium-derived diallyl trisulfide (DATS) as an example, it dology which can introduce the RSS source with one disulfurating serves as a gasotransmitter precursor and an excellent hydrogen reagent at a later stage so as to provide great compatibility and a b Disulfide: Trisulfide: Me Me NMe 2 Me N MeO S O O NH S S S S O Me S Me MeO NH Me S R NH S S Polycarpamine B S Me Me R = O DATS Protein structure Polycarpamine C DMTS Istodax (gasotransmitter R = S (electrode material) (romidepsin) H S donors) (anti-fungus) Life Science Natural Products Pharmaceuticals Life Science Materials Science Cytotoxic OMe O MeO OMe molecule MeO Allicin S HO OH (hypolipidemic, O S Linker hypotensive) S N S Attachment site S S NMe OH NH OH O Z-ajoene Outovirin C Varacins A (anti-thrombotic) (anti-fungus) (antitumor) Antibody Antibody Drug Conjugates (ADC) Food Chemistry Natural Products Fig. 1 Significant polysulfides. a The importance of disulfide scaffolds in life science, natural products, pharmaceuticals, antibody drug conjugates, and food chemistry. b Functional trisulfide molecules 2 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications | | | NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 ARTICLE several possibilities of polysulfuration. Hydropersulfide (RSSH) acetyl masked disulfurating nucleophiles and organometallic seems to be a prime disulfurating reagent, though it is unstable reagents (Fig. 2b) . 50, 51 owing to its high reactivity . Two sulfur atoms were suc- Nevertheless, there is a large demand for a universal dis- cessfully introduced in one step via oxidative cross-couplings of ulfurating reagent, which is compatible with diverse coupling Disulfuration via two sulfur sources: Two functionalized "sulfur" 1 S R (1) R S 1 + R S Direct disulfuration via masked strategy: 1 Oxidative cross-coupling Nucleophilic reagent: S Mask (2) R S Metal cat. (Mask = Ac) Nu δ S R S Umpolung Electrophilic reagent: S Mask 1 (3) R S (Mask = ?) Metal free This work: electrophilic disulfuration Nu BR / H Cat. S S OMe S Nu H 1 1 1 + + Nu S R R R S Nu = C, N, S Challenge: Solution: The same main group, similar electronic effec t HSAB Electronic effect i) Umpolung Mask ii) Selective S-O cleavage Lewis base Fig. 2 Strategies for polysulfide construction. a Traditional methodologies for unsymmetrical disulfide syntheses. b Masked strategy for disulfuration. c Electropilic disulfurating reagent for polysulfuration a,b Table 1 Optimization of polysulfide reagents Entry CuSO (mol%) Ligand (mol%) PhI(OPiv) (equiv) Temp (°C) Time (h) Yields (%) 4 2 1 10 bpy (10) 2.5 25 11 31 2 10 bpy (10) 2.5 25 11 ND 3 10 bpy/ phen (10) 2.5 25 11 50/53 4 10 L1 (10) 2.5 25 11 77 5 10 L2/L3/L4 (10) 2.5 25 11 70/63/68 6 10 L1 (10) 2.5 20 13 86 7 5 L1 (10) 2.5 20 13 86 8 2.5 L1 (10) 2.5 20 13 79 9 5 L1 (5) 2.5 20 13 76 10 5 L1 (10) 2.2 20 13 88 11 5 L1 (10) 1.9 20 13 65 Conditions: 1d (0.2 mmol, 1 equiv), CuSO ·5H O, Ligand, Li CO and PhI(OPiv) were added to MeOH (2 mL) at 20 °C for 13 h 4 2 2 3 2 Isolated yields PhI(OAc) was instead of PhI(OPiv) 2 2 PhI(OTFA) was instead of PhI(OPiv) 2 2 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications 3 | | | ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 a,b Table 2 The scope of polysulfurating reagents 1 (5 mmol, 1 equiv), CuSO ·5H O (0.0125 mol, 0.125 mol%), L1 (0.025 mol, 0.25 mol%), Li CO (5 mmol, 1 equiv) and PhI(OPiv) (11 mmol, 2.2 equiv) were added to MeOH (10 mL) at 20 °C for 15 h 4 2 2 3 2 Isolated yields 1 (10 mmol, 1 equiv) and MeOH (10 mL) were used partners without transition-metal catalysis. The umpolung strat- PhI(OAc) as oxidant (Table 1, entry 1). The bulky iodonium salt − + egy, replacement of acetyl (RSS ) with methoxyl (RSS ) group, PhI(OPiv) was the oxidant of choice in this conversion (Table 1, will afford the precursor of persulfide cation (Fig. 2c). Originating entries 1–3). Systematic investigations of ligands showed that 4,7- from the same main group, sulfur and oxygen possess similar diphenyl-1,10-phenanthroline helped to increase the yield of 2d electronic effect, which imposes a great challenge for selective to 77% (Table 1, entries 3–5). Further study demonstrated that cleavage of S–O bond with S–S bond untouched. Based on the slightly lower temperature was important for keeping product 2d hard and soft acids and bases (HSAB) principle , we hypothesize stable in this system (Table 1, entry 6). Catalyst loading was that boride/proton can help to make the difference between S–S lowered with the same efficiency of the transformation (Table 1, and S–O, in which the hard acid boride/proton prefers oxygen entries 7–9). The optimal conditions were found to involve coordination. Herein, we disclose a polysulfurating reagent which treatment of 1d with 5 mol% of catalyst, 10 mol% of ligand L1, 2.2 can construct unsymmetrical disulfide and trisulfide products by equivalents of bis(tert-butylcarbonyloxy)iodobenzene, and 1.0 utilizing a RSS source only on one substrate, which renders the equivalent of lithium carbonate in 0.1 M methanol at 20 °C, late-stage functionalization feasible. Different nucleophilic which afforded electrophilic polysulfurating reagent 2d in the regents, such as 1,3-dicarbonyl derivatives, electron-rich arenes, yield of 88% (Table 1, entry 10). When the oxidant bis(tert- heteroarenes, amines, and thiols, had been smoothly coupled with butylcarbonyloxy)iodobenzene was reduced to 1.9 equivalents, disulfurating reagents under mild, transition-metal-free, and the yield of 2d was dropped sharply to 65% (Table 1, entry 11). base-free conditions, especially suitable for the late-stage mod- With the optimized conditions in hand, the syntheses of ification of natural products and pharmaceuticals. electrophilic polysulfurating reagents were comprehensively investigated. A scale of 5 mmol operation was practicably performed, decreasing catalyst loading to 0.25 mol% (for details Results see the Supplementary Table 2). Various acetyl substituted Optimization and synthesis of polysulfurating reagents. Initial disulfides were readily transformed to methoxyl substituted studies commenced with the construction of designed electro- disulfides (Table. 2). Initially, the reagents bearing both philic polysulfurating reagents. It was hypothesized that the electron-donating and electron-withdrawing groups on aromatic electrophilic reagent could be obtained through hydropersulfide rings were successfully obtained (Table 2, 2a–2f). Notably, 1.84 g anion and methanol via oxidative cross-coupling. The poly- of 2d was achieved in a yield of 87% with 10 mmol scale sulfurating reagent 2d was obtained in 31% yield under the operation (Table 2, 2d). The arene substituted with conditions of copper(II) as catalyst, 2,2′-bipyridine as ligand, and 4 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications | | | NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 ARTICLE a,b Table 3 Disulfuration with carbon nucleophiles Standard conditions A: NuH (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv), B(C F ) (0.01 mmol, 5 mol%) and 4-MeOPy (0.01 mmol, 5 mol%) were added to DCE (0.25 mL) at r.t. for 22 h. Standard 6 5 3 conditions B: NuH (0.3 mmol, 1.5 equiv), 2 (0.2 mmol, 1 equiv) and B(C F ) (0.01 mmol, 5 mol%) were added to PhMe (0.5 mL) at 0 °C for 24 h. Standard conditions C: NuH (0.3 mmol, 1.5 equiv), 2 6 5 3 (0.2 mmol, 1 equiv) and MeSO H (0.02 mmol, 10 mol%) were added to AmylOH (0.5 mL) at 0 °C for 5–24 h Isolated yields r.t. was instead of 0 °C B(C F ) (0.002 mmol, 1 mol%) was used 6 5 3 B(C F ) (0.01 mmol, 0.2 mol%) was used 6 5 3 B(C F ) (0.004 mmol, 2 mol%) were added to PhMe (0.25 mL) at r.t. for 24 h 6 5 3 NuH (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv) and B(C F ) (0.004 mmol, 2 mol%) were added to PhMe (0.25 mL) at 0 °C for 24 h. Ar = 4-CNC H 6 5 3 6 4 chloromethylene group was compatible under the standard reagents are fairly stable without deterioration when stored in a conditions (Table 2, 2e–2f). Reactions involving secondary benzyl refrigerator (−18 °C) for half a year. Around 20% of these and propargyl derivatives were carried out smoothly (Table 2, 2g– reagents will decompose at room temperature (+25 °C) after 2h). When aliphatic substrates were evaluated, the corresponding 1 week. products were formed efficiently (Table 2, 2i–2m). The scope was further demonstrated through the successful syntheses of bis- disulfurating reagents (Table 2, 2n–2o). Notably, the modification Polysulfuration with designed reagents. With the class of dis- of saccharides and amino acids were also converted into ulfurating reagents in hand, the construction of unsymmetrical corresponding disulfurating reagents (Table 2, 2p–2t). These disulfides and trisulfides was consequently explored. We initiated NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications 5 | | | ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 a,b Table 4 Disulfuration with heteroatomic nucleophiles Standard conditions D: NuH (0.22 mmol, 1.1 equiv), 2 (0.2 mmol, 1 equiv) and B(C F ) (0.005 mmol, 2.5 mol%) were added to PhMe (0.5 mL) at r.t. for 24 h. Standard conditions E: NuH (0.22 mmol, 6 5 3 1.1 equiv) and 2 (0.2 mmol, 1 equiv) were added to DCM (2.0 mL) at r.t. for 8 h Isolated yields B(C F ) (0.0125 mmol, 0.25 mol%) was used 6 5 3 CH CN was used as solvent NuH (0.2 mmol, 1 equiv), 2 (0.3 mmol, 1.5 equiv) and B(C F ) (0.005 mmol, 2.5 mol%) were added to DMF at r.t. for 24 h 6 5 3 B(C F ) (2.5 mol%) was added at r.t. for 5 h 6 5 3 B(C F ) (2.5 mol%) and DCM (0.5 mL) was added 6 5 3 B(C F ) (2.5 mol%) and DMF (0.5 mL) was added 6 5 3 24 h. Ar = 4-CNC H ,R = (CH ) Me 6 4 2 9 our efforts with 1,3-dicarbonyl compounds due to their excellent dicarbonyl structures effectively afford disulfuration catalyzed nucleophilic property. Based on the HSAB principle, the coupling with the combination of tris(perfluorophenyl)borane and 4- between acetylacetone and reagent 2d has been explored under methoxypyridine (Table 3). Acyclic and cyclic 1,3-dicarbonyl the assistance of the hard acid Tris(perfluorophenyl)borane as a substrates were smoothly converted to the desired disulfides catalyst (for details see the Supplementary Table 3). Various 1,3- (Table 3, 3a–3d). The configuration of 3a was further confirmed 6 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications | | | NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 ARTICLE through X-ray crystallographic analysis. Aliphatic and propargyl Discussion derivatives were compatible in this process (Table 3, 3e–3h). In summary, a class of stable and broad-spectrum polysulfurating Significantly, disulfurating reagents bearing both saccharide and reagents with masked strategy has been designed and a general amino acid groups accomplished this transformation efficiently polysulfurating methodology has been established under mild with two parts connected via the disulfur linkage (Table 3, 3i–3l). conditions, which can directly introduce two sulfur atoms into Following the activation mode, electron-rich aromatics were functional molecules. The designed reagents were compatible readily accommodated under standard conditions (Table 3, 4a– with a considerable range of significant biomolecules, such as 4d). (+)-δ-Tocopherol, a significant bioactive molecule, could be saccharides, amino acids, peptides and variety of heterocycles. disulfurated directly despite the presence of free hydroxyl group This protocol showcases the wide utility of both carbon and (Table 3, 4c–4d). Indole and pyrrole, ubiquitous in natural nitrogen nucleophiles resulting in the functional disulfides. Fur- products and pharmaceuticals, are excellent coupling partners as thermore, the trisulfuration provides a convenient and efficient well. Indoles bearing both electron-rich and -deficient functional method for sulfur-containing drug discovery. Further studies on groups proceeded smoothly with disulfurating reagents to afford modification of biomolecules and pharmaceuticals with these the corresponding indolyl-disulfides on 3-position (Table 3, 5a- disulfurating reagents are still ongoing. 5p). A bis-disulfurating electrophile also afforded the correspond- ing twofold disulfur-containing molecule efficiently (Table 3, 5q). Methods Saccharide and amino acid structures were directly installed with General methods. See Supplementary Methods for further details. indoles via the disulfide linker (Table 3, 5r-5u). A gram-scale operation was performed with 5 mmol of 2d under the catalysis of General procedure for syntheses of disulfurating reagents 2. To a Schlenk tube 1 mol% of B(C F ) affording 5o in 93% yield (1.38 g), which 6 5 3 were added RSSAc 1 (5 mmol, 1 equivalent), CuSO ·5H O (0.0125 mmol, 0.25 mol 4 2 structure was further confirmed through X-ray analysis. In %, 3.2 mg), L1 (0.025 mmol, 0.5 mol%, 8.1 mg), Li CO (5 mmol, 1 equivalent, 370 2 3 particular, iodo- and formyl-substituted indoles were also mg), PhI(OPiv) (11 mmol, 2.2 equivalents, 4.47 g) and undried MeOH (10 mL), compatible in this transformation (Table 3, 5m-5n). Pyrroles the mixture was stirred at 20 °C under normal conditions for 15 h. Then the mixture was quenched by saturated NaHCO and extracted by DCM before the substituted on different positions were treated to the disulfuration 3 organic phase was concentrated under vacuum without adding silica gel. Pur- conditions, successfully providing desired products as well ification by column chromatography afforded the desired product. (Table 3, 5v-5y). Subsequently, amine partners were systematically varied General procedure for syntheses of disulfides 3. To a Schlenk tube were added providing access to a wide range of functional aza-disulfide in 1,3-dicarbonyl compound (0.22 mmol, 1.1 equivalents), B(C F ) (0.01 mmol, 5 6 5 3 the presence of 2.5 mol% of tris(perfluorophenyl)borane. The mol%, 5.2 mg), 4-MeO-pyridine (0.01 mmol, 5 mol%, 1.1 mg), RSSOMe 2 (0.2 anilines substituted with electron-withdrawing and electron- mmol, 1 equivalent), and 1,2-dichloroethane (0.25 mL), the mixture was stirred at donating functional groups afforded the desired aza-disulfides r.t. for 22 h before it was concentrated under vacuum. Purification by column in moderate to excellent yields (Table 4, 6a-6f). The secondary chromatography afforded the desired product. amines proceeded in this transformation, affording correspond- ing products in favorable yields (Table 4, 6g-6h). Notably, allyl, General procedure for syntheses of disulfides 4. To a Schlenk tube were added propargyl and heteroaromatic amines were all efficiently arene (0.3 mmol, 1.5 equivalents), B(C F ) (0.01 mmol, 5 mol%, 5.2 mg), RSSOMe 6 5 3 transformed to the corresponding products (Table 4, 6i-6k). 2 (0.2 mmol, 1 equivalent), and toluene (0.5 mL), the mixture was stirred at 0 °C or r.t. for 24–60 h before it was concentrated under vacuum. Purification by column Sulfanilamides, as a significant type of antibiotic, could be chromatography afforded the desired product. modified with the designed persulfurating reagent in good to excellent yields (Table 4, 6m-6s). Lenalidomide, a myeloma drug, was installed with the disulfide under mild reaction conditions General procedure for syntheses of disulfides 5. Method A: To a Schlenk tube were added indole (0.3 mmol, 1.5 equivalents), MeSO H (0.02 mmol, 10 mol%, 2 (Table 4, 6t). Furthermore, functional disulfurating electrophiles, 3 mg), RSSOMe 2 (0.2 mmol, 1 equivalent), and t-AmylOH (0.5 mL), the mixture modified with saccharide and amino acid groups, were furnished was stirred at r.t. for 24 h before it was concentrated under vacuum. Purification by with the substituted disulfur amine linker (Table 4, 6u-6y). The column chromatography afforded the desired product. Method B: To a Schlenk structure of 6a was further confirmed by X-ray analysis. In order tube were added indole (0.22 mmol, 1.1 equivalents), B(C F ) (0.004 mmol, 2 mol 6 5 3 %, 2.1 mg), RSSOMe (0.2 mmol, 1 equivalent), and toluene (0.25 mL), the mixture to validate the efficiency and practicability of this aza-disulfura- was stirred at 0 °C or r.t. for 24 h before it was concentrated under vacuum. tion, 0.25 mol% catalyst loading was launched on a gram-scale Purification by column chromatography afforded the desired product. reaction to afford 6a in 81% yield (1.1 g). Trisulfuration was readily achieved with thiols as a nucleophile (Table 4, 7a-7q). Even sterically bulky aliphatic thiols, tert- General procedure for syntheses of aza-disulfides 6. To a Schlenk tube were added amine (0.22 mmol, 1.1 equivalents), B(C F ) (0.01 mmol, 2.5 mol%, 2.6 6 5 3 butylthiol and 1-adamantanethiol, displayed excellent trisulfura- mg), RSSOMe 2 (0.2 mmol, 1 equivalent), and toluene (0.5 mL), the mixture was tions (Table 4, 7d, and 7l). The structure of 7d was further stirred at 0 °C or r.t. for 24 h before it was concentrated under vacuum. Purification confirmed via X-ray analysis. A gram-scale production for 7g by column chromatography afforded the desired product. could be performed in 92% yield practically. Thiols substituted with vinyl, polyfluoroalkyl, silyl, and hydroxyl groups, and General procedure for syntheses of trisulfides 7. To a Schlenk tube were added heterocycles were all tolerated in this transformation, being thiol (0.22 mmol, 1.1 equivalents), B(C F ) , RSSOMe 2 (0.2 mmol, 1 equivalent), 6 5 3 converted to the unsymmetrical trisulfides, respectively (Table 4, and DCM (0.5 mL), the mixture was stirred at r.t. under N atmosphere for 5–8h 7h-7k, and 7o). Even dithiols efficiently formed the correspond- before it was concentrated under vacuum. Purification by column chromatography afforded the desired product. ing twofold trisulfur-containing products in good yields (Table 4, 7s-7t). Aliphatic trisulfurations could be achieved in high yields (Table 4, 7u-7v). It should be noted that trisulfides containing Data availability. The X-ray crystallographic coordinates for structures reported in saccharide and cysteine fragments were readily formed through this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 1565934 (3a), 1565935(5o), 1565936 these reagents (Table 4, 7r, 7w-7ac). Cysteine was successfully (6a) and 1565937 (7d). These data can be obtained free of charge from The utilized for constructing trisulfur-containing amino acids and Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. oligopeptides, which might provide another access for peptide The authors declare that all other data supporting the findings of this study are drug discovery (Table 4, 7aa-7ac). available within the article and Supplementary Information files, and also are available from the corresponding author on reasonable request. NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications 7 | | | ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 Received: 26 January 2018 Accepted: 19 April 2018 27. Oku, N., Matsunaga, S. & Fusetani, N. Shishijimicins A-C, novel enediyne antitumor antibiotics from the ascidian didemnum proliferum. J. Am. Chem. Soc. 125, 2044–2045 (2003). 28. Kajula, M. et al. Bridged epipolythiodiketopiperazines from penicillium raciborskii, an endophytic fungus of rhododendron tomentosum harmaja. J. Nat. Prod. 79, 685–690 (2016). 29. Witt, D. Recent developments in disulfide bond formation. Synthesis 16, References 2491–2509 (2008). 1. Narayan, M., Welker, E., Wedemeyer, W. J. & Scheraga, H. D. Oxidative 30. Musiejuka, M. & Witt, D. Recent developments in the synthesis of folding of proteins. Acc. Chem. Res. 33, 805–812 (2000). unsymmetrical disulfanes (disulfides). Org. Prep. Proced. Int. 47,95–131 2. A.-Cebollada, J., Kosuri, P., R.-Pardo, J. A. & Fernández, J. M. Direct (2015). observation of disulfide isomerization in a single protein. Nat. Chem. 3, 31. Feng, M., Tang, B., Liang, S. & Jiang, X. Sulfur containing scaffolds in drugs: 882–887 (2011). synthesis and application in medicinal chemistry. Curr. Top. Med. Chem. 16, 3. Wommack, A. J. et al. Discovery and characterization of a disulfide- 1200–1216 (2016). locked C -symmetric defensin peptide. J. Am. Chem. Soc. 136, 13494–13497 32. Swan, J. M. Thiols, disulphides and thiosulphates: some new reactions and (2014). possibilities in peptide and protein chemistry. Nature 180, 643–645 (1957). 4. Góngora-Benítez, M., Tulla-Puche, J. & Albericio, F. Multifaceted roles 33. Bao, M. & Shimizu, M. N-Trifluoroacetyl arenesulfenamides, effective of disulfide bonds. Peptides as therapeutics. Chem. Rev. 114, 901–926 precursors for synthesis of unsymmetrical disulfides and sulfenamides. (2014). Tetrahedron 59, 9655–9659 (2003). 5. Lu, S. et al. Mapping native disulfide bonds at a proteome scale. Nat. Methods 34. Sivaramakrishnan, S., Keerthi, K. & Gates, K. S. A chemical model for redox 12, 329–331 (2015). regulation of protein tyrosine phosphatase 1B (PTP1B) activity. J. Am. Chem. 6. Landeta, C. et al. Compounds targeting disulfide bond forming enzyme DsbB Soc. 127, 10830–10831 (2005). of gram-negative bacteria. Nat. Chem. Biol. 11, 292–298 (2015). 35. Hunter, R., Caira, M. & Stellenboom, N. Inexpensive, one-pot synthesis of 7. Jiang, C.-S., Müller, W. E. G., Schröder, H. C. & Guo, Y.-W. Disulfide- and unsymmetrical disulfides using 1-chlorobenzotriazole. J. Org. Chem. 71, multisulfide-containing metabolites from marine organisms. Chem. Rev. 112, 8268–8271 (2006). 2179–2207 (2012). 36. Antoniow, S. & Witt, D. A novel and eficient synthesis of unsymmetrical 8. Nicolaou, K. C. et al. Synthesis and biological evaluation of epidithio-, disulfides. Synthesis 22, 363–366 (2007). epitetrathio-, and bis-(methylthio)diketopiperazines: synthetic methodology, ’ 37. Szymelfejnik, M., Demkowicz, S., Rachon, J. & Witt, D. Functionalization of enantioselective total synthesis of epicoccin G, 8,8 -epi-ent-rostratin B, cysteine derivatives by unsymmetrical disulfide bond formation. Synthesis 22, gliotoxin, gliotoxin G, emethallicin E, and haematocin and discovery 3528–3534 (2007). of new antiviral and antimalarial agents. J. Am. Chem. Soc. 134, 17320–17332 38. Taniguchi, N. Unsymmetrical disulfide and sulfenamide synthesis via (2012). reactions of thiosulfonates with thiols or amines. Tetrahedron 73, 2030–2035 9. Chankhamjon, P. et al. Biosynthesis of the halogenated mycotoxin (2017). aspirochlorine in koji mold involves a cryptic amino acid conversion. Angew. 39. Vandavasi, J. K., Hu, W. P., Chen, C. Y. & Wang, J. J. Efficient synthesis of Chem. Int. Ed. 53, 13409–13413 (2014). unsymmetrical disulfides. Tetrahedron 67, 8895–8901 (2011). 10. Nielsen, D. S. et al. Orally absorbed cyclic peptides. Chem. Rev. 117, 40. Arisawa, M. & Yamaguchi, M. Rhodium-catalyzed disulfide exchange 8094–8128 (2017). reaction. J. Am. Chem. Soc. 125, 6624–6625 (2003). 11. Scharf, D. H. et al. A dedicated glutathione S-transferase mediates carbon- 41. Liu, H. & Jiang, X. Transfer of sulfur: from simple to diverse. Chem. Asian J. 8, sulfur bond formation in gliotoxin biosynthesis. J. Am. Chem. Soc. 133, 2546–2563 (2013). 12322–12325 (2011). 42. Qiao, Z. et al. Efficient access to 1, 4-benzothiazine: palladium-catalyzed 12. Liu, Y. et al. Development of the first generation of disulfide-based subtype- double C-S bond formation using Na S O as sulfurating reagent. Org. Lett. 2 2 3 selective and potent covalent pyruvate dehydrogenase kinase 1 (PDK1) 15, 2594–2597 (2013). inhibitors. J. Med. Chem. 60, 2227–2244 (2017). 43. Wei, J., Li, Y. & Jiang, X. Aqueous compatible protocol to both alkyl and aryl 13. Zorzi, A., Deyle, K. & Heinis, C. Cyclic peptide therapeutics: past, present and thioamide synthesis. Org. Lett. 18, 340–343 (2016). future. Curr. Opin. Chem. Biol. 38,24–29 (2017). 44. Qiao, Z. & Jiang, X. Recent development in sulfur-carbon bond Formation 14. Brocchini, S. et al. PEGylation of native disulfide bonds in proteins. Nat. reaction involving thiosulfate. Org. Biomol. Chem. 15, 1942–1946 (2017). Protoc. 1, 2241–2252 (2006). 45. Wang, M., Wei, J., Fan, Q. & Jiang, X. Cu(II)-catalyzed sulfide construction: 15. Stephanopoulos, N. & Francis, M. B. Choosing an effective protein both aryl groups utilization of intermolecular and intramolecular bioconjugation strategy. Nat. Chem. Biol. 7, 876–884 (2011). diaryliodonium salt. Chem. Commun. 53, 2918–2921 (2017). 16. Block, E., Ahmad, S., Catalfamo, J. L., Jain, M. K. & Apitz-Castro, R. T. 46. Tan, W., Wei, J. & Jiang, X. Thiocarbonyl surrogate via combination of sulfur Antithrombotic organosulfur compounds from garlic: structural, mechanistic, and chloroform for thiocarbamide and oxazolidinethione constructions. Org. and synthetic studies. J. Am. Chem. Soc. 108, 7045–7055 (1986). Lett. 19, 2166–2169 (2017). 17. Block, E., Bayer, T., Naganathan, S. & Zhao, S.-H. Allium chemistry: synthesis 47. Wang, M., Chen, S. & Jiang, X. Construction of functionalized annulated and sigmatropic rearrangements of alk(en)yl 1-propenyl disulfide S-oxides sulfone via SO /I exchange of cyclic diaryliodonium salts. Org. Lett. 19, from cut onion and garlic. J. Am. Chem. Soc. 118, 2799–2810 (1996). 4916–4919 (2017). 18. Hanschen, F. S., Lamy, E., Schreiner, M. & Rohn, S. Reactivity and stability of 48. Li, Y., Wang, M. & Jiang, X. Controllable sulfoxidationand sulfenylation with glucosinolates and their breakdown products in foods. Angew. Chem. Int. Ed. organic thiosulfate salts via dual electron- and energy-transfer photocatalysis. 53, 11430–11450 (2014). ACS Catalysis 7, 7587–7592 (2017). 19. Senter, P. D. Potent antibody drug conjugates for cancer therapy. Curr. Opin. 49. Xiao, X., Feng, M. & Jiang, X. Transition-metal-free persulfuration to Chem. Biol. 13, 235–244 (2009). construct unsymmetrical disulfides and mechanistic study of sulfur redox 20. Chari, R. V. J., Miller, M. L. & Widdison, W. C. Antibody–drug conjugates: an process. Chem. Commun. 51, 4208–4211 (2015). emerging concept in cancer therapy. Angew. Chem. Int. Ed. 53, 3796–3827 50. Bailey, T. S., Zakharov, L. N. & Pluth, M. D. Understanding hydrogen sulfide (2014). storage: probing conditions for sulfide release from hydrodisulfides. J. Am. 21. Staben, L. R. et al. Targeted drug delivery through the traceless release of Chem. Soc. 136, 10573–10576 (2014). tertiary and heteroaryl amines from antibody-drug conjugates. Nat. Chem. 8, 51. Chauvin, J.-P. R., Griesser, M. & Pratt, D. A. Hydropersulfides: H-atom 1112–1119 (2016). transfer agents par excellence. J. Am. Chem. Soc. 139, 6484–6493 (2017). 22. Beck, A., Goetsch, L., Dumontet, C. & Corvaïa, N. Strategies and challenges 52. Xiao, X., Feng, M. & Jiang, X. New design of disulfurating reagent: facile and for the next generation of antibody-drug conjugates. Nat. Rev. Drug Discov. straightforward pathway to unsymmetrical disulfanes via Cu-catalyzed 16, 315–337 (2017). oxidative cross coupling. Angew. Chem. Int. Ed. 55, 14121–14121 (2016). 23. Cerda, M. M., Hammers, M. D., Earp, M. S., Zakharov, L. N. & Pluth, M. D. 53. Pearson, R. G. Hard and soft acids and bases. J. Am. Chem. Soc. 85, 3533–3539 Applications of synthetic organic tetrasulfides as H S donors. Org. Lett. 19, (1963). 2314–2317 (2017). 24. Benavides, G. A. et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc. Natl Acad. Sci. USA 104, 17977–17982 (2007). 25. Wu, M. et al. Organotrisulfide: a high capacity cathode material for Acknowledgements rechargeable lithium batteries. Angew. Chem. Int. Ed. 55, 10027–10031 (2016). The authors are grateful for financial support provided by The National Key Research 26. Makarieva, T. N. et al. Varacin and three new marine antimicrobial and Development Program of China (2017YFD0200500), NSFC (21722202, 21672069, polysulfides from the far-eastern ascidian polycitorsp. J. Nat. Prod. 58, 21472050), Fok Ying Tung Education Foundation (141011), DFMEC (20130076110023), 254–258 (1995). the program for Shanghai Rising Star (15QA1401800), Professor of Special Appointment 8 NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications | | | NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-04306-5 ARTICLE (Eastern Scholar) at Shanghai Institutions of Higher Learning, and National Program for Open Access This article is licensed under a Creative Commons Support of Top-Notch Young Professionals. Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Author contributions Commons license, and indicate if changes were made. The images or other third party X.J. conceived the idea and supervised the whole project. X.X. designed and carried out material in this article are included in the article’s Creative Commons license, unless the experiments. J.X. contributed to part experiments. X.J. and X.X. discussed the results, indicated otherwise in a credit line to the material. If material is not included in the contributed to writing the manuscript, and commented on the manuscript. All authors article’s Creative Commons license and your intended use is not permitted by statutory approved the final version of the manuscript for submission. regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ Additional information licenses/by/4.0/. Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467- 018-04306-5. © The Author(s) 2018 Competing interests: The authors declare no competing interests. Reprints and permission information is available online at http://npg.nature.com/ reprintsandpermissions/ Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. NATURE COMMUNICATIONS (2018) 9:2191 DOI: 10.1038/s41467-018-04306-5 www.nature.com/naturecommunications 9 | | |

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