Methyl 6-Benzyl-3-Hydroxy-3,6-Dimethyl-1,2-Dioxane-4-Carboxylate

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This paper reveals routine synthetic aproach leading to a particular new compound i.e. not previously described in the literature. The manuscript does not convincingly explain to the reader why this particular compound is significantly important. Although it is mentioned that compound 1 is a synthon in the series, but manuscript does event not show any examples of  other derivatives.

 1.       In the work, only one of the possible synthesis methods (under 3 different conditions) available in the literature was used. The authors are satisfied with obtaining the design compound with a moderate yield. Why was there no mention of testing the effectiveness of other known protocols with oxidants other than oxygen, or even considering their use?

2.       Instead of using the phrase " oxygen-enriched atmosphere" please use "oxygen atmosphere" in this case.

3.       Please change the CI₅₀ to IC₅₀ in Figure 2.

4.       Both in the abstract and in the main text, the yield of the reaction under optimized conditions decreased from 36% to 23% (as I understand the optimized conditions were taken from the literature for a different substrate?). The authors explain this result by the need to reduce the initial amount of substrate due to the volume of the solvent.  This is unconvincing, since the experiments were conducted on a scale of 1-3 g of substrate, which can be done in a 1 liter flask. In addition, a reduction in the amount of solvent could have been considered and applied.

5.       This paragraph in the Discussion section seems to be inconsistent with the scope of the article, which did not cover compound 1 methylation at C-3: „Prior to biological tests in vitro against Plasmodium falciparum, the hydroxyl group at C-3 must be methylated as previous studies reported 1,2-dioxane-3-ols to be inactive (IC₅₀ > 50 µM) against both chloroquine-sensitive and chloroquine-resistant strains [5]. An optimized methylation protocol using (1S)-(+)-10-camphorsulphonic acid in refluxing anhydrous methanol was previously reported, with strong influence of the amount of acid used on diastereoselectivity” 

6.       In the experimental part, the mass of the substrates used is missing, there are only millimoles. This should be corrected. The amount of reactants (g, mL) is also missing. The key difference in NMR spectra that allows the distinction of diastereoisomers is not addresed in the Discussion section.  Also missing is the numbering of atoms in a compound 1 or 1' to help the reader identify NMR signal assignments.

7.       The main weakness of the paper is that other compounds from this single reaction were not separated and characterized. Considering the yields of 7-36%, I assume that by-products with different types of structures known from the literature were obtained.  Although the possibility of a dihydrofuran by-product (LC-MS) was mentioned in the article, this topic was not explored. There are also no drawings of the structure of this impurity, which would have improved the manuscript.

 

Comments on the Quality of English Language

The manuscript needs to be polished/corrected by a native speaker, as some of sentences  are  confusing: „Starting with a methylallyl derivative, we have compared these last alkyl-oriented condi-tions, with and without an oxygen atmosphere, to manganese (II) and (III) acetate aryl-oriented conditions [9]” or „This protocol being studied for 1 mmol of alkene reactions, we increased the alkene quantity by only 10-fold, but not up to 20 mmol for a practical reason, the large amount of solvent required.”

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Benech et al. reported the synthesis of Methyl 6-benzyl-3-hydroxy-3,6-dimethyl-1,2-dioxane-4-carboxylate through a catalytic protocol based on the use of Manganese (II and III) acetate. The utilization of such a scaffold is well examined in the introduction of the paper and two different reported protocols are presented for both alkyl and aryl alkene derivatives. Applying both catalytical pathways to commercial available substrates, the authors underlined different outcomes for the synthesis of the desired products. Target products have been obtained in trace to meagre yield following the two different protocols using pure O2 or air, always in diastereomeric mixture.  Although a further optimization of catalytic protocol is required for methylallyl derivatives, as admitted by authors, products are new and fully characterized through ESI, m.p. 1D and 2D NMR spectroscopy. For this reason, the present paper indeed fits the requirements for publication on molbank provided that the reaction mechanism is better explained in the revision process even if already reported.

They explored the possibility to obtain Methyl 6-benzyl-3-hydroxy-3,6-dimethyl-1,2-dioxane-4-carboxylate with two different catalytic protocol using pure O2 or air. The best outcome of the reaction was obtained following the reaction pathway for alkyl derivatives in an open vessel (36%). The outcome clearly underlines the impossibility for the product to be embodied in a larger work (according to your checklist) without further optimization of reaction parameters. The molecule could be worthy of major study, but authors provided the full characterization of new compounds (according to your checklist).

They applied previous known protocol to other substrates to obtain an endoperoxide ringed compound new in literature. The structure of compounds and their synthesis might get lost (according to your checklist) if not published. In the optic of the increasing need for new drugs, this paper could represent a valid starting point for the synthesis of target molecule if found biologically relevant in future studies.

Practically a new example to ref 7 in which Lombardo et al. did not explore synthesis of 1,2-Dioxanes bearing a benzylic and methyl fragment.

The methodology should be studied again trying different reaction parameters for enhancing the yield of the products that anyway remains suitable for publication in molbank. XRD could be considered for analysis (they provided m.p.) beside NMR to enrich the paper.

Author Response

 

Open Review

(x) I would not like to sign my review report
( ) I would like to sign my review report

Quality of English Language

( ) I am not qualified to assess the quality of English in this paper
( ) English very difficult to understand/incomprehensible
(x) Extensive editing of English language required
( ) Moderate editing of English language required
( ) Minor editing of English language required
( ) English language fine. No issues detected

 

	Yes	Can be improved	Must be improved	Not applicable
Does the introduction provide sufficient background and include all relevant references?	( )	(x)	( )	( )
Are all the cited references relevant to the research?	(x)	( )	( )	( )
Is the research design appropriate?	( )	( )	(x)	( )
Are the methods adequately described?	( )	( )	(x)	( )
Are the results clearly presented?	( )	( )	(x)	( )
Are the conclusions supported by the results?	( )	( )	( )	(x)

Comments and Suggestions for Authors

This paper reveals routine synthetic aproach leading to a particular new compound i.e. not previously described in the literature. The manuscript does not convincingly explain to the reader why this particular compound is significantly important. Although it is mentioned that compound 1 is a synthon in the series, but manuscript does event not show any examples of other derivatives.

 

 

Thank you for reviewing our work, and especially for your comments which helped us improve our manuscript.

As a therapeutic chemistry laboratory, we develop antiparasitic compounds with here a focus on Plasmodium falciparum. Extensive literature proved that endoperoxide has high potential, with numerous simple derivatives already synthesized, and reaction condition optimized for different types of derivatives. These previous publications helped us to send a first group of derivatives for biological tests with satisfying results yet unpublished, so we unfortunately cannot disclose the structures here. The low yield with methylallyl benzene derivatives and absence of literature on these led us to compare the main optimized conditions for aryl and alkyl derivatives. Now, we would like to share our findings with the community in the current manuscript.

 

 

 

 

 

 

1. In the work, only one of the possible synthesis methods (under 3 different conditions) available in the literature was used. The authors are satisfied with obtaining the design compound with a moderate yield. Why was there no mention of testing the effectiveness of other known protocols with oxidants other than oxygen, or even considering their use?

 

In addition to the inadequacy of existing protocols, our yields are severely reduced by extensive purifications to achieve a biological grade, and here, also for isomers separation. Overall, these manganese-mediated free-radical cyclizations tend to provide a wide range of yields with each new condition or reagent. Other oxidants were indeed explored in few studies, so in the first time, we took advantage of your observation to improve our discussion with this:

 

“Among other methods to synthesize similar endoperoxides, we can mention cycloaddition of molecular oxygen, cyclic 1,3-diketone, and alkene by electrochemical oxidation. This reaction initiated by electrolysis was found to have a radical chain mechanism, prompting the authors to investigate using a radical initiator, the azobis(isobutyronitrile) (AIBN), in the same 1989 study [11]. Although both methods gave cyclic peroxides from styrene and α-methylstyrene in 11-90% yields, acyclic 1,3-diketones did not give similar products.

Another study used manganese(III) acetate to produce endoperoxide from 1,1-diphenylethene, N-(4-methylphenyl)acetoacetamide and molecular oxygen with 92% yield. Manganese(II) acetate was as effective as Mn(III), but other metal acetates gave lower yields: Co(II), 60% and Co(III), 66% [10].

The optimized conditions for aryl-oriented derivatives we chose are issued from a 1993 study. Both acyclic and cyclic β-ketoesters gave 1,2-dioxanes: most of the screening was based on ethyl 3-oxobutanoate, but the methyl derivative we used was included. Alkenes having no phenyl substituent did not give 1,2-dioxanes: 1,1-diphenylethene was the main candidate for catalyst and oxidant screening. As catalysts, copper(II), nickel(II), and thallium(III) acetates were not reactive. Chromium(VI) trioxide, cobalt(III) acetate, and iron(III) perchlorate did not yield 1,2-dioxane. Unsatisfactory yields were obtained from potassium permanganate (42%), and ammonium cerium nitrate in acetic acid (51%) and in acetonitrile (13%). From the metal salts tested, manganese(II) acetate (1 equivalent) gave good results: 72% (23°C, 96 hours) and 68% (60°C, 24 hours) yields. Manganese(III) acetate gave a comparable yield: 74% (1 equivalent, 23°C, 12 hours) and 65% (0.1 equivalent, 23°C, 24 hours) yields.

Then, reactions using a combination of manganese(II) acetate and various oxidizing reagents were investigated. In all cases, the reactions were carried out under a dry air steam, as molecular oxygen is required to form the endoperoxide. A 1:0.1 molar mixture of manganese(II) and manganese(III) acetates gave the maximum 95% yield for ethyl 3-oxobutanoate, and 90% yield for methyl 3-oxobutanoate after 12 hours. Other suitable oxidants were cobalt(III) acetate (93%), chromium(VI) trioxide (80%), potassium permanganate (79%), thallium(III) acetate (73%), and ammonium cerium nitrate (62%) [9]. Although less effective on 1,1-diaryl derivatives, these oxidants might be good candidates for a future screening on (methylallyl)benzene derivatives. ”

 

 

2. Instead of using the phrase " oxygen-enriched atmosphere" please use "oxygen atmosphere" in this case.
3. Please change the CI₅₀ to IC₅₀ in Figure 2.

We fixed these errors, thanks for noticing.

4. Both in the abstract and in the main text, the yield of the reaction under optimized conditions decreased from 36% to 23% (as I understand the optimized conditions were taken from the literature for a different substrate?). The authors explain this result by the need to reduce the initial amount of substrate due to the volume of the solvent. This is unconvincing, since the experiments were conducted on a scale of 1-3 g of substrate, which can be done in a 1 liter flask. In addition, a reduction in the amount of solvent could have been considered and applied.

 

Yes, these optimized conditions were inspired from literature, with one main team working on alkyl derivatives, and the other on aryl derivatives. Although very similar, the last one specified that their conditions do not work at all on alkyl derivatives. And our derivative is in the middle between these two types, resulting in mixed result.

Here as well, we implemented our answer to your question in our manuscript:

 

“The volume of 500 mL of solvent required for the 20 mmol-scale seemed substantial. We finally tried this scale to assess whether this volume allowed enough gaseous exchanges for the molecular oxygen from the air to be incorporated. The reaction time was also extended to 17.5 hours. Surprisingly, this 20-fold scale-up still gave us a decent 30% yield. This further extension of reaction duration may have contributed to an improvement in yield.

A reduction in the amount of solvent was considered, but we stuck to conditions already optimized in previous literature: reactions of 1,1-diphenylethene with N-(4-methylphenyl)acetoacetamide in the presence of manganese(III) acetate and molecular oxygen in AcOH gave 1,2-dioxanes with 92% yield in 25 mL/mmol, 89% yield in 60 mL/mmol and only 59% yield in 10 mL/mmol [10]. This volume was further used in later aryl-oriented studies.”

 

5. This paragraph in the Discussion section seems to be inconsistent with the scope of the article, which did not cover compound 1 methylation at C-3: „Prior to biological tests in vitro against Plasmodium falciparum, the hydroxyl group at C-3 must be methylated as previous studies reported 1,2-dioxane-3-ols to be inactive (IC₅₀ > 50 µM) against both chloroquine-sensitive and chloroquine-resistant strains [5]. An optimized methylation protocol using (1S)-(+)-10-camphorsulphonic acid in refluxing anhydrous methanol was previously reported, with strong influence of the amount of acid used on diastereoselectivity”

It was indeed premature to give this information here. We deleted this paragraph, as the knowledge is still available in literature.

 

 

6. In the experimental part, the mass of the substrates used is missing, there are only millimoles. This should be corrected. The amount of reactants (g, mL) is also missing. The key difference in NMR spectra that allows the distinction of diastereoisomers is not addresed in the Discussion section.  Also missing is the numbering of atoms in a compound 1 or 1' to help the reader identify NMR signal assignments.

            We filled the experimental part with the missing information. Regarding NMR spectra, there is no remarkable difference between the two isomers. It was more of a puzzle, and a lot of zooming on the COSY spectra. We developed about our methodology with an example here:

“NMR analysis of separated fractions with a 1/0.7 ratio enabled the discrimination of diastereoisomers, making one major and one minor, identifiable by their relative ratio.

Finally, COSY 2D NMR analysis enabled precise attribution within the multiplets. For example, in the doublet of triplets at 2.22 ppm integrating for 2 protons, the right side of this “multiplet” correlates with the doublet of doublets at 1.84 ppm, which integrates for 1 proton of the major diastereoisomer. This right side also correlates with the doublet of doublets at 3.10 ppm, integrating as well for 1 proton of the major diastereoisomer. This describes the expected situation of the 3 protons located directly in the endoperoxide of the major diastereoisomer.

On the other hand, the left side of the 2.22 ppm multiplet correlates with the doublet of doublet at 1.63 ppm and the doublet of doublet at 2.92 ppm, each integrating for 1 proton of the minor diastereoisomer. This describes the expected situation of the 3 protons located directly in the endoperoxide of the minor diastereoisomer.

Finaly, the slight superposition of the correlation signal indicates the overcrossing between the extreme pics of these two triplets, rather than a simple juxtaposition, which made them look like a multiplet before this 2D analysis.”

 

7. The main weakness of the paper is that other compounds from this single reaction were not separated and characterized. Considering the yields of 7-36%, I assume that by-products with different types of structures known from the literature were obtained. Although the possibility of a dihydrofuran by-product (LC-MS) was mentioned in the article, this topic was not explored. There are also no drawings of the structure of this impurity, which would have improved the manuscript.

            We also share this feeling. After few confirmations, we completed the manuscript:

 

“LC-MS analyses strongly suggested the formation of a dihydrofuran byproduct, indicating the presence of a mass corresponding to the β-ketoester fused with the alkene, without the addition of molecular oxygen, namely methyl 5-benzyl-2,5-dimethyl-4,5-dihydrofuran-3-carboxylate (Figure 3). This by-product has a predicted exact mass of 246.126 and appears on (ESI+) LC-MS as a 247.15 peak in all our crude batches, but we couldn’t isolate it for NMR confirmation.

Although highly visible on the TLC, the masses of the isolated impurities were negligible, apart from the excess methyl 3-oxobutanoate, which remained unchanged.”

 

 

 

Comments on the Quality of English Language

The manuscript needs to be polished/corrected by a native speaker, as some of sentences  are  confusing: „Starting with a methylallyl derivative, we have compared these last alkyl-oriented condi-tions, with and without an oxygen atmosphere, to manganese (II) and (III) acetate aryl-oriented conditions [9]” or „This protocol being studied for 1 mmol of alkene reactions, we increased the alkene quantity by only 10-fold, but not up to 20 mmol for a practical reason, the large amount of solvent required.”

            We reread the whole manuscript with a clear head and corrected most of it. For the two main flaws you pointed out, we came out with these alternatives:

“Using a methylallyl derivative, we conducted a comparative analysis between these alkyl-oriented conditions, both with and without an oxygen atmosphere, and the aryl-oriented conditions, utilizing manganese (II) and (III) acetate [9]. ”

“This protocol was initially designed for 1 mmol-scale reactions; however, we scaled up the alkene quantity by 10-fold, at first. […] The volume of 500 mL of solvent required for the 20 mmol-scale seemed substantial. We finally tried this scale […]”

 

Submission Date

25 March 2024

Date of this review

05 Apr 2024 13:48:15

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for rewriting the manuscript according to my suggestions. However, I am not convinced by the phrase "optimized method".  You are using literature methods at the level of discovery chemistry rather than an optimized method. I recommend changing the wording in the manuscript for literature method.  I am also not convinced by your choice of a particular method as necessary to obtain biological samples.

Comments on the Quality of English Language

Only the exemplary phrase mentioned in the previous review has been changed. It would be good to give the whole text to a qualified person to evaluate the language quality.

Author Response

Please see the attachment.

Author Response File: Author Response.docx