Editor's synthesis & decision
Minor RevisionRevision requests
- Provide computational (e.g., DFT) or experimental (e.g., VT-NMR) evidence to support the mechanistic rationale for the observed atroposelectivity.
- Include a direct comparison of the synthetic ECD spectrum with the reported data for the natural product to confirm the absolute configuration.
- Clarify the reaction concentrations in Table 1 and provide additional details regarding the purification and batch-to-batch consistency of the gram-scale macrocyclization.
- Include a brief discussion on the observed solubility or purification challenges encountered during the optimization process.
Where this could be published
At its current quality
Solid specialist synthetic chemistry journals
- Journal of Organic Chemistry
- Organic Letters
- Tetrahedron
Then you could realistically aim for
Highly selective broad-interest chemistry journals
- Journal of the American Chemical Society
- Angewandte Chemie International Edition
- Chemical Science
The manuscript currently sits at a level appropriate for specialist organic synthesis journals; it can reach the target venue by providing the requested mechanistic and structural depth. The single most important improvement is the transition from speculative mechanistic claims to data-backed evidence. This guidance is not a guarantee of acceptance, and you must verify the novelty of your findings against the most current literature.
edited by model: gemini-flash-lite-latest
Reviewer comments — reproduced in full, unabridged
Reviewer 1
gemini-flash-lite-latestThis manuscript describes a scalable total synthesis of the natural product cihunamide B, featuring a decagram-scale SNAr reaction and an atroposelective Larock macrocyclization to construct the strained Trp-Trp cross-linkage. The authors demonstrate the utility of their route by producing several grams of a protected intermediate, which is a significant practical achievement for a complex natural product synthesis. While the chemistry is technically sound and well-executed, the manuscript is primarily a synthetic report. Given the target venue's high selectivity, the work would benefit from a more thorough discussion of the stereochemical model for the atroposelective cyclization and a clearer demonstration of the biological utility of the synthesized material. Overall, the work is a solid contribution to the field of natural product synthesis.
Strengths
- Development of a highly scalable synthetic route, highlighted by the decagram-scale SNAr reaction.
- Successful application of the Larock macrocyclization to construct a strained atropisomeric Trp-Trp linkage.
- Demonstration of gram-scale production of a protected intermediate, facilitating potential future SAR studies.
Weaknesses
- The stereochemical rationale for the atroposelectivity is largely speculative and lacks computational or experimental support beyond a brief mention of 'energetic disadvantage'.
- The biological evaluation is limited to citing literature values for the natural product rather than testing the synthetic material.
- The discussion of the Larock macrocyclization mechanism is brief and lacks detailed analysis of the transition state.
Detailed comments
The authors claim that the Larock macrocyclization proceeds with 'perfect atroposelectivity' and attribute this to the 'energetic disadvantage of the process via 13'. However, this assertion is made without any supporting evidence, such as DFT calculations or variable-temperature NMR studies to probe the rotational barriers or transition state energies. To justify this claim in a high-impact journal, the authors should provide a more rigorous analysis of why the undesired atropisomer is not formed, perhaps by calculating the relative transition state energies for the two possible pathways.
Regarding the biological activity, the authors state that 'the details of its mechanism involved in bioactivity study are still unclear' and that the synthetic material is 'expected to be a potential antibacterial agent'. Since the authors have successfully synthesized a significant quantity of the protected natural product, it is a missed opportunity not to report any preliminary biological data on the synthetic material itself. Even if the full natural product is not yet fully deprotected, demonstrating that the synthetic intermediate or the final product retains the reported antibacterial activity would significantly strengthen the impact of the paper.
Comments on figures
- In Table 1, the authors report the optimization of the Larock macrocyclization. While the yield improvement from 18% (entry 2) to 51% (entry 7) is clear, the table lacks information on the diastereomeric ratio or the atropisomeric purity of the product in the non-optimized entries. The text claims 'perfect atroposelectivity', but it is unclear if this was observed across all entries or only under the optimized conditions. The authors should clarify if the 'trace' or low-yield entries also produced only the desired atropisomer or if they were mixtures.
- In Scheme 1, the authors propose a mechanism involving intermediates 12 and 13. The transition from 11 to 14 is depicted as a single step, but the description of the migratory insertion is quite simplified. It would be helpful to include a more detailed scheme or a brief discussion in the text explaining why the migratory insertion is regioselective and why it favors the specific atropisomer, perhaps by referencing the steric bulk of the TES group relative to the macrocycle geometry.
Referee report rubric — reproduced exactly as submitted
Reviewer 2
gemini-3.1-flash-liteThis manuscript describes the first total synthesis of cihunamide B, a cyclic peptide featuring a strained atropisomeric Trp-Trp linkage. The authors utilize a scalable SNAr reaction and an atroposelective Larock macrocyclization as key steps to access the natural product and its protected derivatives on a multi-gram scale. The work is technically sound, well-executed, and provides a practical route to a compound that was previously limited by low natural isolation yields. While the methodology relies on established transformations, the successful application to this specific strained macrocycle is a significant contribution to the field of natural product synthesis. The manuscript meets the standards of a high-impact specialist journal.
Strengths
- Successful execution of a scalable synthesis for a complex, strained natural product.
- Effective application of Larock macrocyclization to construct a challenging atropisomeric Trp-Trp linkage.
- Clear demonstration of scalability, with multi-gram production of key intermediates.
Weaknesses
- The mechanistic rationale for the observed atroposelectivity is largely speculative and lacks computational or experimental evidence beyond the observed outcome.
- The manuscript lacks a detailed discussion of the stereochemical analysis (e.g., specific ECD data or NMR coupling constants) that confirms the atropisomeric configuration of the synthetic product matches the natural isolate.
- The discussion of the 'unprecedented' nature of the linkage could be better contextualized with more specific comparisons to existing atropisomeric peptide literature.
Detailed comments
The authors claim that the Larock macrocyclization proceeds with 'perfect atroposelectivity' and attribute this to the 'energetic disadvantage of the process via 13 in the transition state of the reaction.' However, this assertion is purely qualitative. To strengthen this claim, the authors should provide a more rigorous justification. For example, are there specific steric interactions in the transition state that destabilize the formation of 15? A brief discussion of the conformational constraints imposed by the peptide backbone would significantly improve the logical flow of the argument.
Regarding the structural confirmation, the authors note that 'The atropisomeric configurations of the cihunamides were determined by electronic circular dichroism (ECD) spectra and DFT calculations.' While this references the original isolation paper, it is essential for a total synthesis report to explicitly demonstrate that the synthetic material 1 matches the natural product. The authors should include a comparison of the synthetic ECD spectrum with the reported data for the natural product to confirm the absolute configuration of the atropisomer.
Comments on figures
- Table 1: The optimization table is clear, but the entries 11 and 12 ('Na2CO3 and K2CO3 showed little progress') should be supported by a brief mention of the observed solubility issues in the text. Additionally, the yield for entry 8 is reported as 68% at a larger scale (2.12 g); it would be helpful to clarify if this yield refers to the isolated product after chromatography, as the high yield at scale is a significant claim.
Referee report rubric — reproduced exactly as submitted
Reviewer 3
gemini-flash-lite-latestThis manuscript describes the first total synthesis of cihunamide B, a cyclic peptide featuring an atropisomeric Trp-Trp cross-linkage. The authors utilize a scalable SNAr reaction and a palladium-catalyzed Larock macrocyclization to construct the strained macrocycle. The work is technically sound and provides a practical route to a complex natural product, which is a valuable contribution to the field of total synthesis. The methodology is well-optimized, and the demonstration of gram-scale synthesis is a significant strength that facilitates future biological studies. Overall, the paper is a solid, well-executed piece of work that fits the scope of a specialist chemical journal.
Strengths
- Successful development of a scalable synthetic route to a complex, strained natural product.
- Demonstration of the Larock macrocyclization on a gram scale with high atroposelectivity.
- Clear and logical presentation of the synthetic strategy and optimization of key steps.
Weaknesses
- The discussion on the mechanism of atroposelectivity is speculative and lacks computational or experimental support beyond a qualitative transition state argument.
- The manuscript lacks detailed characterization data for the final natural product in the main text, relying heavily on the assumption of successful synthesis.
- The rationale for the specific choice of ligand/base combinations in Table 1 is somewhat descriptive rather than mechanistic.
Detailed comments
The authors state that 'the Larock macrocyclization of 11 proceeds with perfect atroposelectivity and regioselectivity.' While the experimental outcome is clear, the discussion of the mechanism in Scheme 1 remains purely qualitative. To strengthen this claim, the authors should provide more rigorous evidence, such as variable-temperature NMR studies or DFT calculations, to support the assertion that the 'undesired atrop-Trp-Trp linkage is not generated at all' due to the 'energetic disadvantage of the process via 13.' Simply stating that it is 'probably due to the energetic disadvantage' is insufficient for a high-impact journal.
Regarding the scalability, the authors emphasize that 'the reaction was also found to proceed well at the gram scale.' It would be beneficial to include a brief discussion on the purification challenges encountered at this scale, particularly for the highly strained macrocycle 14. Providing information on the robustness of the process, such as the consistency of the atroposelectivity across different batches, would significantly enhance the reproducibility and impact of the work.
Comments on figures
- Table 1: The optimization table is clear, but it would be helpful to include the reaction concentration for each entry, as macrocyclization efficiency is highly dependent on dilution. Additionally, the 'trace' entries (1, 11, 12, 13) lack quantitative context; were these analyzed by crude NMR or HPLC? Specifying the detection limit would clarify the efficacy of these conditions.
Referee report rubric — reproduced exactly as submitted
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