Carbonyl–Olefin Metathesis and Its Application in Natural Product Synthesis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript sets out to present comparisons: "...throughout the text, based primarily on robustness, enantioselectivity, methodology, experimental simplicity, and utilization in the synthesis of natural products." There are no examples of enantioselective carbonyl-olefin metathesis to the best of my knowledge. Further, this manuscript includes no figures with this information. There are few examples of using modern carbonyl-olefin metathesis in the synthesis of natural products. This review does include many of them, to the best of my knowledge, but it falls very short on reviewing the field. Schindler's and Lambert's review of the field includes 100% more references, and I've listed some of the examples of metathesis references that are absent. Frankly, there are too many missing that I didn't even try to be exhaustive. No reason is given for this limited set of examples. The schemes are filled with errors. Half of the references are written incorrectly. This manuscript isn't remotely ready for publication and requires major revisions. 

• most instances of "et al." are written incorrectly. "al." is an abbreviation. - All Schemes: please label the carbonyl carbon and the targeted olefin carbon the same way in every scheme. These labels disappear randomly between schemes and sometimes within schemes. Please make them all consistent for the reader.
• Scheme 1: add atom labels like Scheme 2 for reader clarity
• Scheme 7:
  • the radicals need to placed on the correct atoms. It's not clear to me how showing these intermediates helps with the explanation, since the scheme is not really discussed in the text.
  • label the scheme with the fragmentation options
• Page 4, line 106: "Harsh conditions make the reaction scope highly limited and thus almost not useful for the synthesis of natural products."
  • There are no examples of use in natural products synthesis cited. Reference 9, which is cited, cites no examples of pyroytic methods in natural product synthesis. Please, be more specific with your language here.  
• Page 5, lines 127-140: No examples of what is described here are shown or cited. I'm not sure why this paragraph is here.
• Scheme 10: Show what actually worked in the image in addition to what didn't work
• Scheme 11: add h nu to reaction arrow between c and d
• Scheme 13: Glorius, the corresponding author, calls this "hole catalysis". This is also the first example of cross metathesis described, and yet no mention is made that this is not a ring-closing/opening method.  
• Scheme 14: why is this example in this review? it's not carbonyl-olefin metathesis. It also has no resemblance to the work Glorius's lab reported in the previous paragraph. Cut this whole section.  
• Page 7, line 189: "Despite the trend of new photochemical COM reaction designs going into the direction of photoredox methods..."
  • One reaction from 7 years ago is not a trend of any kind. Delete this.
• Scheme 15: No redox happens in this reaction. It is not a photoredox method. Worse, the word "photoredox" doesn't appear in the reference cited.  
• Page 11, line 260: "While a lot of successful applications of the Tebbe reagent have been developed in various synthetic categories, the Lewis acidity of the Tebbe reagent can often lead to the decomposition of highly substituted targets or substrates having functionality sensitive to Lewis acid"
  • You've reported 2. 2 is not a lot.  
• Page 12, line 293: "...among others"
  • What others? What reference is this for? Or are you just referring to the 2 other title molecules of reference 31 and just not writing them?
• Scheme 23: This mechanism is incredibly confusing. There's a random "[41]". You show the intermediate that is necessary for product formation [d], but you don't show that it leads to product. Your mechanism doesn't resemble Lei and coworkers proposal in references 13 and 35. Lei and coworkers also report that [b] is never observed in both references, but your scheme implies that it forms. This scheme needs to completely revised to be consistent with Lei's reports.
• Scheme 24: I don't understand the R groups here. Grubbs II is always Mes-substituted.
• Scheme 25: structure [k] shows a bond to the ligand with X. This bond should be to Ru.
• Scheme 27: charges on [c] are incorrect
• Page 21, line 479-490: That's not what the authors of reference 49 said. You're skipping empirical results, for some reason.
• Scheme 34: [c] and [e] are missing a dashed bond and show 2 pentavalent carbons in each as drawn. [g] and [h] are missing charges.  
• Scheme 36: you have free FeCl3 converting to free FeCl3 in your cycle. What happens is that 1 FeCl3 of [e] becomes the iron in the cycle and the other FeCl3 goes to the middle of the ring.
• Scheme 37: filled with typos. Please proofread this entire scheme.
• Scheme 41: this is the same ring-opening reaction as Scheme 29. They should be discussed together.
• Scheme 42: the oxetane in [c] should be beneath the plane of the ring system. You've drawn the wrong diastereomer.  
• Scheme 43: you're missing the bond disconnection symbols for the Ar groups. There should be a wavy line across the bonds to the carbonyl carbon.
• Scheme 44: [f] and [g] are missing charges
• Scheme 46: one of the intermediates is missing a carbon. The intermediates aren't labeled for some reason in this mechanism.
• Page 34, line 702: this line ends mid-sentence.
• Scheme 48: The first intermediate on the right is missing a double bond and is in the wrong oxidation state.

Comments on the Quality of English Language

Words are missing throughout. There are typos everyone in the text and in figures. 

Author Response

This manuscript sets out to present comparisons: "...throughout the text, based primarily on robustness, enantioselectivity, methodology, experimental simplicity, and utilization in the synthesis of natural products." There are no examples of enantioselective carbonyl-olefin metathesis to the best of my knowledge. Further, this manuscript includes no figures with this information. There are few examples of using modern carbonyl-olefin metathesis in the synthesis of natural products. This review does include many of them, to the best of my knowledge, but it falls very short on reviewing the field. Schindler's and Lambert's review of the field includes 100% more references, and I've listed some of the examples of metathesis references that are absent. Frankly, there are too many missing that I didn't even try to be exhaustive. No reason is given for this limited set of examples. The schemes are filled with errors. Half of the references are written incorrectly. This manuscript isn't remotely ready for publication and requires major revisions. 

We appreciate reviewer’s careful reading of our manuscript. Thank you for the note regarding the term “enantioselectivity”. This was a clerical mistake. We meant selectivity in general. We have correct our oversight in the revised abstract. Regarding the choice of references, we note that as opposed to a comprehensive catalogue of all methods available, our review is intended as a critical assessment of the main (catalytic) strategies to promote COM reactions, underlining its synthetic utility to construct complex molecular structures such as the ones present in natural products. Thus, we believe the references selected provide a balanced and valuable perspective for those interested in the field of COM reactions.

 

Most instances of "et al." are written incorrectly. "al." is an abbreviation. - All Schemes: please label the carbonyl carbon and the targeted olefin carbon the same way in every scheme. These labels disappear randomly between schemes and sometimes within schemes. Please make them all consistent for the reader.

We have thoroughly revised our manuscript based on the suggestions provided. Schemes have been revised to include atom labelling where we perceived the additional clarity was added value to the manuscript (e.g., Scheme 46B).

 

Scheme 1: add atom labels like Scheme 2 for reader clarity

This scheme has been revised as suggested.

 

Scheme 7:

• the radicals need to placed on the correct atoms. It's not clear to me how showing these intermediates helps with the explanation, since the scheme is not really discussed in the text.
• label the scheme with the fragmentation options

This scheme has been revised as suggested. As we mentioned in the text, the reaction is well established, so further discussion is not needed. In addition, readers are referred to ref 10, which is a thorough review about the Paternò-Büchi reaction. The scheme has been revised as suggested.

 

Page 4, line 106: "Harsh conditions make the reaction scope highly limited and thus almost not useful for the synthesis of natural products."

• There are no examples of use in natural products synthesis cited. Reference 9, which is cited, cites no examples of pyroytic methods in natural product synthesis. Please, be more specific with your language here.  

We have removed the word “almost” to make it clearer that pyrolytic methods are not useful for natural product synthesis.

 

Page 5, lines 127-140: No examples of what is described here are shown or cited. I'm not sure why this paragraph is here.

Thank you for the attentive note. We have revised the paragraph to better reflect that photo-induced ring openings have been used previously, while the new approaches using photo-induced electron transfer are yet restricted to small molecule synthesis.

 

Scheme 10: Show what actually worked in the image in addition to what didn't work

This is done in Scheme 23. We have added a reference to this scheme in the text to clarify where in the text such details have been included.

 

Scheme 11: add h nu to reaction arrow between c and d

This scheme has been revised as suggested.

 

Scheme 13: Glorius, the corresponding author, calls this "hole catalysis". This is also the first example of cross metathesis described, and yet no mention is made that this is not a ring-closing/opening method.  

The text has been revised to include the notes pointed out by the reviewer.

 

Scheme 14: why is this example in this review? it's not carbonyl-olefin metathesis. It also has no resemblance to the work Glorius's lab reported in the previous paragraph. Cut this whole section.  

We agree with the reviewer that the reaction on Scheme 15 is not a carbonyl-olefin metathesis. However, it showcases how the mechanisms developed for COM reactions can be leveraged for developing other synthetic methodologies. Thus, we believe it is worth including it. To make our intention clearer, we have reorganized the order of schemes 13, 14 and 15. Now, the carbonyl-carbonyl metathesis is the last example, working as an outlook of the section. The text has also been revised to express this message explicitly.

 

Page 7, line 189: "Despite the trend of new photochemical COM reaction designs going into the direction of photoredox methods..."

• One reaction from 7 years ago is not a trend of any kind. Delete this.

We have removed the passage indicated by the reviewer.

 

Scheme 15: No redox happens in this reaction. It is not a photoredox method. Worse, the word "photoredox" doesn't appear in the reference cited.  

This scheme caption has been revised as suggested.

 

Page 11, line 260: "While a lot of successful applications of the Tebbe reagent have been developed in various synthetic categories, the Lewis acidity of the Tebbe reagent can often lead to the decomposition of highly substituted targets or substrates having functionality sensitive to Lewis acid"

• You've reported 2. 2 is not a lot.  

This passage has been revised and the expression “a lot” has been deleted as suggested.

 

Page 12, line 293: "...among others"

• What others? What reference is this for? Or are you just referring to the 2 other title molecules of reference 31 and just not writing them?

We have revised this passage to make clearer that we are referring to the work in reference 31 and 32.

 

Scheme 23: This mechanism is incredibly confusing. There's a random "[41]". You show the intermediate that is necessary for product formation [d], but you don't show that it leads to product. Your mechanism doesn't resemble Lei and coworkers proposal in references 13 and 35. Lei and coworkers also report that [b] is never observed in both references, but your scheme implies that it forms. This scheme needs to completely revised to be consistent with Lei's reports.

This scheme has been revised as suggested.

 

Scheme 24: I don't understand the R groups here. Grubbs II is always Mes-substituted.

This scheme has been revised as suggested.

 

Scheme 25: structure [k] shows a bond to the ligand with X. This bond should be to Ru.

This scheme has been revised as suggested.

 

Scheme 27: charges on [c] are incorrect

This scheme has been revised as suggested.

 

Page 21, line 479-490: That's not what the authors of reference 49 said. You're skipping empirical results, for some reason.

Thank you for drawing our attention to this point. We have revised our statements to more comprehensively explain the findings in the original article. In short, the paper indeed suggests that the oxetane ring formation forms through a concerted mechanism (computational calculation and carbocation trapping experiments). However, the fragmentation of the oxetane ring can go through concerted or stepwise mechanism depending on the nature of the olefin being formed. The text has been revised accordingly.

 

Scheme 34: [c] and [e] are missing a dashed bond and show 2 pentavalent carbons in each as drawn. [g] and [h] are missing charges.  

The scheme has been revised as suggested. We have also included labelling for key intermediates to make it more clear how the reactions proceeds. Regarding the missing charges, we have used the original notation by the authors of the study, which don’t observe a explicit negative charge due to the oxygen coordination with the metal catalyst. Thus, we believe the present notation is appropriate to showcase the mechanism proposed in the literature.  

 

Scheme 36: you have free FeCl3 converting to free FeCl3 in your cycle. What happens is that 1 FeCl3 of [e] becomes the iron in the cycle and the other FeCl3 goes to the middle of the ring.

This scheme has been revised as suggested.

 

Scheme 37: filled with typos. Please proofread this entire scheme.

This scheme has been revised as suggested.

 

Scheme 41: this is the same ring-opening reaction as Scheme 29. They should be discussed together.

Indeed, both schemes present similar transformations. However, we decided to keep the text in its original form because each scheme is mentioned for a different reason. To make it clearer that both schemes have similarities among them, we have added a sentence in the first paragraph of section 5, to mark that a related work has appeared after the pioneer report by Kripach and coworkers.

 

Scheme 42: the oxetane in [c] should be beneath the plane of the ring system. You've drawn the wrong diastereomer.  

This scheme has been revised as suggested.

 

Scheme 43: you're missing the bond disconnection symbols for the Ar groups. There should be a wavy line across the bonds to the carbonyl carbon.

This scheme has been revised as suggested.

 

Scheme 44: [f] and [g] are missing charges

Similar to our justification for scheme 34, we followed the original notation by the authors of the study, which assumes a negative charge in the oxygen is compensated by its coordination with the metal catalyst. Thus, we believe the present notation is appropriate to showcase the mechanism proposed in the literature. 

 

Scheme 46: one of the intermediates is missing a carbon. The intermediates aren't labeled for some reason in this mechanism.

This scheme has been revised as suggested.

 

Page 34, line 702: this line ends mid-sentence.

This incomplete sentence has been deleted. It unintentionally remained from a previous version of the manuscript. During our own editing, the relevant information about the self-assembly in this system was included in the paragraph above Figure 1. We apologize for the inconvenience.

 

Scheme 48: The first intermediate on the right is missing a double bond and is in the wrong oxidation state.

This scheme has been revised as suggested.

Reviewer 2 Report

Comments and Suggestions for Authors

The submitted manuscript catalysts-3680147, entitled “Carbonyl – Olefin Metathesis and Its Application in Natural Product Synthesis” by F. De Azambuja et al., presents an up-to-date literature review on carbonyl–olefin metathesis (COM) reactions, highlighting both their historical development and their applications in natural product synthesis. This review complements previous accounts on the topic, such as 10.1021/acs.chemrev.0c01096, 10.1039/C7QO01037K, and 10.3390/molecules29204861.

One of the manuscript’s strengths lies in its broad and updated scope. The authors systematically explore the principal strategies employed to promote COM reactions—including photochemical protocols, metal alkylidenes, organocatalysts, and Lewis/Brønsted acid catalysis. The inclusion of recent literature (2020–2024) reflects commendable effort to maintain bibliographic relevance.

Importantly, the review underscores the synthetic utility of COM in complex molecule construction. Noteworthy examples such as capnellene, brevenal, and angucycline derivatives illustrate how these transformations can be strategically integrated into total syntheses of structurally demanding targets.

What further elevates the manuscript is its critical approach. Rather than merely cataloging methods, the authors contextualize each strategy, offering comparative insights based on efficiency, substrate scope, and atom economy—providing valuable perspective for practitioners in the field.

Overall, this is a well-composed and informative review that contributes meaningfully to the current literature. Given its clarity, technical depth, and relevance to natural product synthesis. I therefore recommend it for publication in its current form.

 

Author Response

We thank the reviewer for their support to our review.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have presented a clear and well-organized review of carbonyl-olefin metathesis and the application of this reaction in natural product synthesis. The topic of carbonyl-olefin metathesis is the subject of numerous review papers. 
The manuscript lacks citations of relevant papers, e.g., Chem. Soc. Rev. 2018, 7867; Org. Chem. Front. 2018, 1381; Current Green Chem. 2020, 7, 5; Catalysts 2020, 1092. After careful completion of the citations, the manuscript merits publication in Catalysts.

Author Response

We thank the reviewer for their support to our review. We have included the suggested references in introduction section.