Polysulfurating reagent design for unsymmetrical polysulfide construction

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 accomplished 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.

Reviewer #3 (Remarks to the Author): This article is described about copper-catalyzed synthesis of RSSOMe from RSSAc and its application. Authors have been recently reported that the preparation of RSSAc from TolSO2SNa and its reactivity in Angew. Chem. Int. Ed.. However, the paper reveals that RSSOMe can use to widespread substrates. The procedure can produce various unsymmetrical polysulfides such as disulfides or trisulfides by using nucleophilic reagents. These obtained products is very interesting. The research shows valuable results. I'm sure that the article is suitable for the journal. After minor revision, I would like to recommend for the publication.

Responds to the reviewers' comments:
Reviewer 1： Q1: While there is some very interesting and useful organosulfur chemistry presented in this manuscript, unfortunately it is very poorly presented and is unacceptable for publication in its present form.

A1:
Thanks for your suggestion. The presentation of the whole manuscript has been carefully polished in the revised version according to your recommendation.
Q2: In addition to numerous errors of grammar (e.g., frequent omission of articles "the" and "a") and style, the bombastic and overstated language is inappropriate for a scientific paper. For example, I have never seen words such as "triumphantly", "famous", "paramount", "preeminently," "prosperously," "excitingly", or "remarkably" used in typical chemistry journal articles. These are gross exaggerations. Even phrases such as "enormous challenges" and "burgeoning and urgent demand" are overblown. The use of slang expressions such as "Besides," "What's more" and "agreeably compatible" also makes the paper appear unprofessionally written. The authors would do well to follow the style and language used in typical mainstream organic chemistry journals and allow the interesting chemistry to sell itself rather than annoy the reader with ill-chosen and over-blown language. The others have been revised and the details are as follows: 1. The sentence of "Initial studies were commenced with the construction of designed electrophilic polysulfurating reagents." has been deleted the word of "were" and has been revised as "Initial studies commenced with the construction of designed electrophilic polysulfurating reagents." 2. The sentence of "It was hypothesized that the electrophilic reagent could be achieved through hydropersulfide anion and methanol under the oxidative cross-coupling." has been revised as "It was hypothesized that the electrophilic reagent could be obtained through hydropersulfide anion and methanol via oxidative cross-coupling." 3. The word of "Fortunately" has been deleted. 4. The sentence of "The bulky iodonium salt of PhI(OPiv) 2 was more efficient oxidant in this conversion (Table 1, entries 1-3)." has been revised as "The bulky iodonium salt of PhI(OPiv) 2 was the optimized oxidant in this conversion (Table 1, entries 1-3)." 5. The word of "enhance" has been corrected as "increase".
6. The word of "slightly lowering temperature" has been revised as "slightly lower temperature". 7. The words of "solution of methanol" have been revised as "methanol". 8. The sentence of "5 mmol scale operation was practicably performed, decreasing catalyst loading to 0.25 mol% (for details see the Supporting Information)." has been revised as "A scale of 5 mmol operation was practicably performed, decreasing catalyst loading to 0.25 mol% (for details see the Supporting Information)." 9. The phrase of "What's more" has been revised as "Notably".
10. The words of "agreeably compatible" have been revised as "compatible". 11. The word of "Besides" has been deleted.
12. The phrase of "What's more" has been deleted.
13. The word of "triumphantly" has been deleted.
14. The word of "Remarkably" has been deleted.
16. The word of "prosperously" has been deleted.
19. The word of "Remarkably" has been deleted. 20. The sentence of "What's more, cysteine, a significant intracellular life motif, was successfully utilized for constructing trisulfur-containing amino acids and oligopeptides, which may provide a new access for peptide drug discovery (Table 4, 7aa-7ac)." has been revised as "Cysteine, was successfully utilized for constructing trisulfur-containing amino acids and oligopeptides, which might provide a new access for peptide drug discovery (Table 4, 7aa-7ac).". 21. The sentence of "In summary, a novel class of stable and broadspectrum polysulfurating reagents with masked strategy has been practicably designed and universal persulfuration are consequently established under mild conditions." has been revised as "In summary, a novel class of stable and broad-spectrum polysulfurating reagents with masked strategy has been designed and a general polysulfurating methodology has been established under mild conditions, which can directly introduce two sulfur atoms into functional molecules." 22. The sentence of "This protocol serves as a fascinating protocol with toleration of both carbonic and nitrogenous nucleophiles resulting in the functional disulfides." has been revised as "This protocol showcases wide utility of both carbonic and nitrogenous nucleophiles resulting in the functional disulfides." 23. The sentence of " Furthermore, trisulfuration is an indispensable property of these unique reagents, providing a convenient and efficient method for sulfur-containing drug discovery." has been revised as "Furthermore, the trisulfuration provides a convenient and efficient method for sulfur-containing drug discovery."  This paper contains some nice chemistry, worthy of publication in Nature Communications. While the manuscript has been somewhat improved in this revision, it is still unacceptable due to poor English. The authors are advised to engage an editor expert in English to correct the remaining numerous problems, unless Nature Communications is willing to extensively copy-edit this paper. As a Reviewer my time is limited to suggest changes. Below I identify English language problems, and make a few suggestions for corrections; I also identify some but not all of the sentences which still do not make sense. I believe that it is the author's responsibility to submit a revised manuscript in excellent English for the paper to be acceptable for publication.
Line 49, "by virtue" not "in virtues" Line 52, meaning of "for very homeostasis and bio-signaling" is unclear; please revise Line 58, "romidepsin and gliotoxin" should not be capitalized.
Lines 58, 59, "sequester" and "generate" --subject is plural Line 66, allium species plants Line 70, the use of "on the other hand" seems out of place here because there is nothing to contrast -both disulfides and trisulfides are important and widely discussed Line 75, delete "do" Line 83, "a challenging" Line 84 "synthesis of the unsymmetrical disulfide" Line 86 "with unavoidable formation of homocoupling products" Line 95 "at a late-stage" Line 109 "a R-S-S source" or better, "a RSS source" [use m-dashes not hyphens for bonds] Line 126 "helped" Line 135 delete "of" Line 144 "a yield" not "the yield" Line 146 "Reactions involving secondary…" Line 147 "the corresponding" Line 152 "a refrigerator"; "these reagents will decompose…"