Editor's synthesis & decision
Major RevisionRevision requests
- Conduct a systematic investigation into the batch-to-batch variability of the domino reaction, identifying and controlling for variables such as moisture content, base quality, and temperature, to provide a more robust and reproducible protocol.
- Provide rigorous evidence for the stability of lappaceolides A and B by performing NMR analysis in non-acidic or buffered solvents (e.g., C6D6 or base-treated CDCl3) and clarify if silica gel chromatography was performed under base-neutralized conditions.
- Include a detailed transition state model or mechanistic rationale in the Supporting Information to explain the facial selectivity of the oxa-Michael addition and the observed diastereomeric outcomes.
- Clarify whether the reported 3:2 diastereomeric ratio is a kinetic product or a thermodynamic equilibrium, and provide evidence for the stability of this ratio over time under the reaction conditions.
Where this could be published
At its current quality
Specialist organic synthesis journals
- Journal of Organic Chemistry
- Tetrahedron Letters
- Synthesis
Then you could realistically aim for
Selective organic methodology journals
- Organic Letters
- Chemical Communications
The current manuscript is well-suited for specialist journals that prioritize synthetic strategy, but it requires significant improvement in reproducibility and experimental robustness to meet the standards of more selective venues. The most critical improvement is the stabilization of the key domino reaction and a more thorough characterization of the product stability. This guidance is based on the current state of the manuscript and does not guarantee acceptance; please verify the novelty of your findings against the most recent literature.
edited by model: gemini-flash-lite-latest
Reviewer comments — reproduced in full, unabridged
Reviewer 1
gemini-flash-lite-latestThis manuscript describes a concise, two-step total synthesis of the natural products lappaceolides A and B, starting from the monomer siphonodin. The key transformation is a base-mediated, biomimetic vinylogous-Michael–oxa-Michael domino reaction that effects the homodimerization of the monomer. While the authors successfully achieve the synthesis and provide evidence for the biosynthetic hypothesis, the reaction suffers from significant reproducibility issues and low isolated yields. The work is technically sound and fits the scope of a specialist organic synthesis journal, though the lack of stereocontrol in the dimerization step limits its broader synthetic utility. Overall, this is a solid, albeit incremental, contribution to the field of biomimetic total synthesis.
Strengths
- Concise and efficient two-step total synthesis of the target natural products.
- Successful validation of the proposed biosynthetic homodimerization hypothesis for lappaceolides A and B.
- Effective application of a domino reaction strategy to assemble complex tricyclic lactones from a simple monomer.
Weaknesses
- Poor reproducibility of the key domino reaction, with yields and diastereomeric ratios varying significantly between batches.
- Low isolated yield (30%) of the final products, which complicates their utility for further studies.
- Lack of stereocontrol in the vinylogous-Michael step, resulting in a mixture of diastereomers that are difficult to separate.
Detailed comments
The authors note that the "yields, conversions and diastereomeric ratios of 1 and 2 were however found to vary (8–30%, 75%–100%, dr 3:2–2:3) from batch to batch." This high level of variability is a significant concern for a total synthesis report. While the authors attribute this to the sensitivity of the domino reaction, it suggests that the reaction conditions are not sufficiently robust. To improve the manuscript, the authors should provide more detailed analysis of the factors contributing to this batch-to-batch variation, such as potential trace impurities in reagents or subtle variations in temperature control, and ideally, identify a more stable set of conditions or a purification protocol that mitigates these issues.
The authors state that "purification of lappaceolides A ( 1 ) and B ( 2 ) proved to be equally challenging," requiring a specific solvent system to separate the products from the unreacted monomer. Given that the products are also described as "acid labile" and decompose back to the monomer, the stability of these compounds is a major hurdle. The authors should provide more rigorous evidence for the stability of the isolated products, perhaps by performing the NMR analysis in a non-acidic solvent (e.g., C6D6 or base-treated CDCl3) to confirm that the observed decomposition is indeed due to trace acid and not an inherent instability of the dimeric structure itself.
Comments on figures
- Scheme 2: The proposed mechanism for the domino reaction is plausible, but the transition from intermediate 7 to the final products 1 and 2 is presented without clear evidence for the facial selectivity of the oxa-Michael addition. The text states that the stereochemistry at C3 is set with 'high fidelity,' but the figure does not illustrate the transition state or the specific orbital interactions that would dictate this selectivity. Providing a more detailed mechanistic rationale or a transition state model would significantly strengthen the argument for the biomimetic nature of this transformation.
Referee report rubric — reproduced exactly as submitted
Reviewer 2
gemini-3.1-flash-liteThis manuscript reports a concise two-step total synthesis of the natural products lappaceolides A and B, proceeding via a biomimetic vinylogous-Michael–oxa-Michael domino reaction of the monomer siphonodin. The synthesis is technically sound and successfully validates the biosynthetic hypothesis that these compounds are dimers of siphonodin. While the reaction optimization is clearly described, the reported variability in diastereomeric ratios and yields suggests that the transformation is highly sensitive to conditions, which is candidly acknowledged by the authors. The work represents a solid, incremental contribution to the field of natural product synthesis, fitting well within the scope of a specialist journal. I recommend acceptance following minor revisions to clarify the experimental limitations and ensure the reproducibility of the reported results.
Strengths
- Elegant and concise two-step total synthesis of lappaceolides A and B.
- Successful validation of the biosynthetic dimerization hypothesis of siphonodin.
- Scalable synthesis of the monomeric building block siphonodin.
- Candid discussion of reaction sensitivity and the challenges associated with the biomimetic approach.
Weaknesses
- Significant batch-to-batch variability in yields and diastereomeric ratios (8–30% yield, 3:2–2:3 dr).
- The manuscript lacks a detailed discussion on why the reaction is so sensitive to kinetic control, beyond a brief mention of decomposition.
- The purification process appears non-trivial and potentially low-yielding, which may limit the utility of this approach for larger-scale applications.
Detailed comments
The authors state that 'the yields, conversions and diastereomeric ratios of 1 and 2 were however found to vary (8–30%, 75%–100%, dr 3:2–2:3) from batch to batch.' This high level of variability is a significant concern for a total synthesis report. While the authors mention that 'careful kinetic control was therefore required,' they do not provide sufficient insight into what specific parameters (e.g., precise temperature control, moisture content, or base quality) might be driving this inconsistency. To improve the rigor of the manuscript, the authors should provide a more detailed analysis of these fluctuations in the Supporting Information, perhaps by correlating specific experimental observations with the observed outcomes, or by defining a more robust set of conditions that minimize this variance.
Regarding the stability of the products, the authors note that 'upon standing for overnight in CDCl3 a sample of lappaceolides A (1) and B (2) (dr = 3:2) started decomposing back to siphonodin (3).' This observation is critical, as it suggests that the products are inherently unstable under common experimental conditions. The authors attribute this to 'residual hydrochloric acid in the non-base treated deuterochloroforom.' It would be beneficial for the authors to demonstrate the stability of these compounds in more neutral or buffered environments, or to explicitly state if they have developed a protocol for long-term storage, as this would be highly relevant for future researchers working with these or similar labile natural products.
Comments on figures
- Scheme 2: The proposed mechanism involves a vinylogous Michael reaction followed by an intramolecular oxa-Michael reaction. The authors state that 'the stereogenic center at C3, however, is set in high fidelity by the intramolecular oxa-Michael-reac- tion 8 taking place from the bottom face of C3 center.' However, the scheme does not clearly depict the transition state or the geometric constraints that enforce this 'high fidelity.' Adding a brief description or a more detailed transition state model in the Supporting Information would help clarify how the cis-fused dioxabicyclo[3.3.0]octane ring is formed with such selectivity, especially given the lack of stereocontrol in the preceding step.
Referee report rubric — reproduced exactly as submitted
Reviewer 3
gemini-flash-lite-latestThis manuscript describes a two-step total synthesis of the natural products lappaceolide A and B, starting from the monomer siphonodin. The authors employ a biomimetic vinylogous-Michael–oxa-Michael domino reaction to achieve the dimerization, which they identify as a key step in the biosynthesis of these compounds. While the synthesis is concise and addresses a clear biosynthetic hypothesis, the reaction is plagued by significant reproducibility issues, with yields and diastereomeric ratios varying widely between batches. Given the target journal's focus on rapid, high-quality communication of synthetic methodology, the current lack of robust control over the key domino step is a substantial hurdle. The work provides a useful, albeit technically temperamental, proof-of-concept for the proposed biosynthesis.
Strengths
- Concise and elegant two-step total synthesis strategy.
- Successful application of a biomimetic domino reaction to assemble a complex dimeric natural product.
- Clear and well-articulated biosynthetic hypothesis regarding the dimerization of siphonodin.
Weaknesses
- Poor reproducibility of the key domino reaction, with yields and diastereomeric ratios fluctuating significantly between batches.
- High sensitivity of the final products to reaction conditions, leading to decomposition and difficult purification.
- Lack of detailed discussion on how to mitigate the batch-to-batch variation in the diastereomeric ratio.
Detailed comments
The authors state that 'The yields, conversions and diastereomeric ratios of 1 and 2 were however found to vary (8–30%, 75%–100%, dr 3:2–2:3) from batch to batch.' This is a significant concern for a methodology paper. In a journal focused on synthetic organic chemistry, providing a robust protocol is paramount. The authors should investigate the source of this variation—perhaps trace impurities in the starting material, moisture content in the solvent, or subtle temperature gradients—and provide a more optimized, reproducible procedure. Simply reporting the variation without a clear path toward stabilization undermines the utility of the method for the broader synthetic community.
Regarding the purification, the authors note: 'Ultimately, flash column chromatography using diethyl ether-acetonitrile-dichoromethane (1:1:3 v/v/v) allowed the separation of siphonodin (3) from lappaceolides (1 and 2).' This is a highly unusual and complex solvent system. It would be beneficial for the authors to explain why such a specific and non-standard mixture was necessary and whether this system is generally applicable or specific to this particular separation. Furthermore, given the reported acid-lability of the products, the authors should explicitly state if the silica gel used was pre-treated (e.g., with triethylamine) to prevent decomposition during chromatography.
Comments on figures
- Scheme 2: The proposed mechanism for the domino reaction is clear, but the text states that 'step 7 is not stereoselective' while the caption for Scheme 2 indicates '>95% conv. dr = 3:2'. It is unclear if the 3:2 ratio is a kinetic result or a thermodynamic equilibrium, given the subsequent mention of product decomposition. The authors should clarify if the 3:2 ratio is consistently observed at the 4-hour mark or if it shifts over time, as this is critical to understanding the 'careful kinetic control' mentioned in the text.
Referee report rubric — reproduced exactly as submitted
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