Illuminating Total Synthesis: Strategic Applications of Photochemistry in Natural Product Construction
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis review by Capurro, Basso and their coworkers provides a timely overview of the strategic use of photochemical reactions, including cycloadditions, rearrangements, oxidations, and photoredox catalysis, in the total synthesis of natural products. The authors have compiled an impressive array of recent examples, organized systematically by reaction type, which will be of great value to researchers in this field. The manuscript is well-structured, clearly written, and supported by relevant schemes and references. The focus on both classical and emerging photochemical methodologies reflects a balanced and insightful perspective. This manuscript represents a valuable contribution to the field of synthetic photochemistry and natural product synthesis. With minor revisions to address the following points, it will be a strong and informative addition to the literature. I recommend acceptance after these improvements.
Minor Issues, including:
1) It is suggested that some relevant review articles in this field of photochemistry in natural product should also be cited to enable readers to have a more comprehensive understanding.
2) While the review excels in presenting successful applications of photochemistry, it would benefit from a brief discussion of the limitations or challenges associated with these methods (e.g., scalability, functional group tolerance, competing pathways). A short paragraph in the conclusion or within relevant sections could provide a more balanced view. Add a brief discussion on the practical challenges (e.g., reactor design, wavelength selectivity, sensitizer availability) to provide a more critical and realistic perspective.
3) Some scheme captions (e.g., Scheme 15) are mismatched with the content described in the text.
4) Page15, line 469, The term "1,6-hydrogen atom transfer (1,6-HAT)" is used in the manuscript. It appears this is a typographical error. Based on the chemical context described, the correct process should be the "1,5-hydrogen atom transfer (1,5-HAT)". The text should be carefully double checked and revised accordingly throughout to ensure accuracy.
5) To properly contextualize the field, please acknowledge seminal contributors to the excited-state Nazarov reaction. Prof. Shuanhu Gao's pioneering work, which greatly advanced the methodology and showcased its power in complex total synthesis, is highly recommended for inclusion.
Author Response
1) It is suggested that some relevant review articles in this field of photochemistry in natural product should also be cited to enable readers to have a more comprehensive understanding.
Thank you for pointing this out, we agree with this comment, therefore some recent reviews have been added, highlighting the novelty of our manuscript
2) While the review excels in presenting successful applications of photochemistry, it would benefit from a brief discussion of the limitations or challenges associated with these methods (e.g., scalability, functional group tolerance, competing pathways). A short paragraph in the conclusion or within relevant sections could provide a more balanced view. Add a brief discussion on the practical challenges (e.g., reactor design, wavelength selectivity, sensitizer availability) to provide a more critical and realistic perspective.
Thank you for pointing this out, we agree with this comment, therefore the conclusions have been re-written including a critical analysis of limitations and challenges
3) Some scheme captions (e.g., Scheme 15) are mismatched with the content described in the text.
Thank you for pointing this out, we have corrected it
4) Page15, line 469, The term "1,6-hydrogen atom transfer (1,6-HAT)" is used in the manuscript. It appears this is a typographical error. Based on the chemical context described, the correct process should be the "1,5-hydrogen atom transfer (1,5-HAT)". The text should be carefully double checked and revised accordingly throughout to ensure accuracy.
Thank you for pointing this out, we have corrected it
5) To properly contextualize the field, please acknowledge seminal contributors to the excited-state Nazarov reaction. Prof. Shuanhu Gao's pioneering work, which greatly advanced the methodology and showcased its power in complex total synthesis, is highly recommended for inclusion.
Thank you for pointing this out, we agree with this comment, therefore a sentence and two references have been added
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors describe in this review a (more or less arbitrary) selection of recent (2020-2025) total syntheses of natural products in which at least a synthetic key step features a photochemical reaction. The aim of this review, according to the authors, is "to offer a glimpse into the growing trend of using photo-driven transformations to address significant synthetic challenges", and as such it can be said that this objective has been achieved.
The authors claim moreover that the manuscript "is organized by different photochemical processes, each introduced with relevant background"; but in my opinion this is not exactly true, and constitutes a weak point of the manuscript.
The body of the review is organized in three sections.
-Ring construction by light-promoted cycloadditions: [2+2]-photocycloadditions, Paternò-Buchi reactions, [4+2]-cycloadditions with singlet oxygen, miscellaneous ring-forming reactions (PEDA, Norrish-Yang, Nazarov)
-Photochemical rearrangements (Wolff, photosantonin, E/Z isomerization) and oxidations (benzylic, oxygen-ene (Schenck), carboxyl group manipulations (mostly radical decarboxylations)
-Photoredox catalysis (Radical Giese additions, photocatalyzed HAT and XAT reactions)
-Nicewicz's total synthesis of stemoamide alkaloids
A Table of Contents according to this lines should be added after the Introduction section.
In the Introduction, the authors say that "each [photochemical mechanism is] introduced with fundamental principles. However, very few mechanistic information appear in the paper (only in part in Schemes 5, 6, 16, 36, 39, 42) and no photoredox cycle is depicted. Moreover, no references on recent reviews about photocatalysis (Chem Soc Rev 2018, 47, 7190; Chem. Comm. 2020, 56, 11166; Synlett 2022, 33, 129; Synthesis 2023, 164... to name a few) appear in the references Section. An introductory comment on the differences between non-sensitized (classic) photochemistry and sensitized (catalyzed) photochemistry should have been added, together with brief conceptual and mechanistic discussions on the different activation modes: sensitized energy transfer, photoinduced electron transfer (photoredox catalysis), photoinduced HAT/XAT processes, EDA photocatalysis, excited state transition metal catalysis...), since in a given section these reaction types are appearing, without any explanation. The synthetically-oriented reader without a current knowledge of photochemical methods would greatly benefit from this type of introductory information.
On the other hand,in the last section, purportedly focused in the incorporation of photochemistry in retrosynthetic logic, the retrosynthetic analysis of the target stemoamide alkaloids is conspicuously missing, and only the synthetic sequence in Scheme 43 is discussed.
Finally, several errors appear in the numerous chemical structures. In particular, chiral centers are missing in Scheme 1, Scheme 12, Scheme 23, Scheme 25, Scheme 28, and in Scheme 37. In Scheme 39, acronims HAA and HAD are not explained.
In summary, in my opinion substantial revision is necessary before this review can be published.
Author Response
1) The authors describe in this review a (more or less arbitrary) selection of recent (2020-2025) total syntheses of natural products in which at least a synthetic key step features a photochemical reaction. The aim of this review, according to the authors, is "to offer a glimpse into the growing trend of using photo-driven transformations to address significant synthetic challenges", and as such it can be said that this objective has been achieved.
The authors claim moreover that the manuscript "is organized by different photochemical processes, each introduced with relevant background"; but in my opinion this is not exactly true, and constitutes a weak point of the manuscript.
The body of the review is organized in three sections.
-Ring construction by light-promoted cycloadditions: [2+2]-photocycloadditions, Paternò-Buchi reactions, [4+2]-cycloadditions with singlet oxygen, miscellaneous ring-forming reactions (PEDA, Norrish-Yang, Nazarov)
-Photochemical rearrangements (Wolff, photosantonin, E/Z isomerization) and oxidations (benzylic, oxygen-ene (Schenck), carboxyl group manipulations (mostly radical decarboxylations)
-Photoredox catalysis (Radical Giese additions, photocatalyzed HAT and XAT reactions)
-Nicewicz's total synthesis of stemoamide alkaloids
A Table of Contents according to this lines should be added after the Introduction section.
Thank you for pointing this out, we agree with this comment, therefore a TOC has been added after the introduction
2) In the Introduction, the authors say that "each [photochemical mechanism is] introduced with fundamental principles. However, very few mechanistic information appear in the paper (only in part in Schemes 5, 6, 16, 36, 39, 42) and no photoredox cycle is depicted. Moreover, no references on recent reviews about photocatalysis (Chem Soc Rev 2018, 47, 7190; Chem. Comm. 2020, 56, 11166; Synlett 2022, 33, 129; Synthesis 2023, 164... to name a few) appear in the references Section. An introductory comment on the differences between non-sensitized (classic) photochemistry and sensitized (catalyzed) photochemistry should have been added, together with brief conceptual and mechanistic discussions on the different activation modes: sensitized energy transfer, photoinduced electron transfer (photoredox catalysis), photoinduced HAT/XAT processes, EDA photocatalysis, excited state transition metal catalysis...), since in a given section these reaction types are appearing, without any explanation. The synthetically-oriented reader without a current knowledge of photochemical methods would greatly benefit from this type of introductory information.
Thank you for pointing this out, we agree with this comment, therefore the introduction has been implemented with Figure 1 and the corresponding text, offering a comprehensive taxonomy of the photochemical activation modes described in the review.
3) On the other hand,in the last section, purportedly focused in the incorporation of photochemistry in retrosynthetic logic, the retrosynthetic analysis of the target stemoamide alkaloids is conspicuously missing, and only the synthetic sequence in Scheme 43 is discussed.
Thank you for pointing this out, we agree with this comment, therefore a retrosynthetic analysis and an additional figure have been added
4) Finally, several errors appear in the numerous chemical structures. In particular, chiral centers are missing in Scheme 1, Scheme 12, Scheme 23, Scheme 25, Scheme 28, and in Scheme 37. In Scheme 39, acronims HAA and HAD are not explained.
Thank you for pointing this out. Chiral centres have been added in schemes 1, 12, 23, 25 and 28. We have added chiral centres also in scheme 9, 17 and 24, and in figure 2 (a double bond has been added to the structure of himalensine A), but scheme 37 seems ok to us.
HAA and HAD have been added in the abbreviation list.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors have provided adequate answers to the issues raised in my first review, and the manuscript has been correspondigly revised.
in my opinion, after these modifications, the original aim of the authors has been now fulfilled. In its present state, this review provides the interested reader with an excellent overview of the contribution of photochemistry to contemporary organic syntheses of natural products
