Super-Armed Thiomannopyranosides in the Synthesis of a Mannose-Capped Trisaccharide of Mycobacterium tuberculosis Lipoarabinomannan
, Zinaida Vladimirovna Kuznetsova, Dmitry Sergeevich Novikov, Alexander Ivanovich Zinin, Natalya G. Georgievna Kolotyrkina and Leonid Olegovich Kononov *Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis manuscript describes the synthesis, conformational analysis, and glycosylation reactivity of polysilylated (“super-armed”) thiomannopyranosides, and their application in the preparation of a mannose-capped trisaccharide related to Mycobacterium tuberculosis ManLAM. This manuscript studied the low-temperature NMR and provides an interesting approach to stereoselective α-mannosylation without classical neighboring group participation. Overall this manuscript could be accepted before monor revision .
- The authors use polysilylated “super-armed” thiomannopyranosides as donors. It would be helpful to clarify their advantages over other established systems, such as 2-O-benzoyl-3,4,6-O-benzyl protected donors, particularly in terms of reactivity and stereoselectivity.
- The manuscript would benefit from a clearer statement of its conceptual advance relative to existing “armed/disarmed” and polysilylated glycosyl donor strategies.
- The correlation between conformational preference (1C4 vs 4C1) and α-selectivity is interesting, but currently discussed relatively briefly.
Author Response
Reviewer #1:
Comments and Suggestions for Authors
This manuscript describes the synthesis, conformational analysis, and glycosylation reactivity of polysilylated (“super-armed”) thiomannopyranosides, and their application in the preparation of a mannose-capped trisaccharide related to Mycobacterium tuberculosis ManLAM. This manuscript studied the low-temperature NMR and provides an interesting approach to stereoselective α-mannosylation without classical neighboring group participation. Overall this manuscript could be accepted before monor revision .
REPLY. We thank the Reviewer #1 for high evaluation of our manuscript.
- The authors use polysilylated “super-armed” thiomannopyranosides as donors. It would be helpful to clarify their advantages over other established systems, such as 2-O-benzoyl-3,4,6-O-benzyl protected donors, particularly in terms of reactivity and stereoselectivity.
REPLY:
Based on our research, we can conclude that glycosylation with polysilylated thiomannopyranosides led to the same a-stereoselectivity as in the case of mannopyranosyl donors with a 2-O-acyl participating group. Despite the formation of conformers in the course of glycosylation, the advantage of using silylated thioglycosides is the possibility of exploring one-pot methodology, which could significantly reduce the number of synthetic steps. Next, we plan to study the reactivity of silylated mannopyranosides towards various glycosyl acceptors and to compare the outcome of glycosylation with the use of 2-O-acyl-3,4,6-O-benzyl mannopyranosyl derivatives.
The text was modified.
The manuscript would benefit from a clearer statement of its conceptual advance relative to existing “armed/disarmed” and polysilylated glycosyl donor strategies.
REPLY:
The obtained data may be regarded as a continuation of known “super armed”–“armed-disarmed” concept based on the difference of the reactivity between glycosyl donors having silyl, benzyl and acyl protecting groups. The main goal of our research is the investigation of reactivity of polysilylated mannopyranosyl donors with “disarmed” (e.g. benzoylated) glycosyl acceptors. It allows us to implement a benzyl-free approach and to expand the library of terminal oligoarabinofuranosides (with 2-azidoethyl, 4-(2-azidoethoxy)phenyl (AEP) and 4-(3-azidopropoxy)phenyl (APP) aglycones) related to the fragments of M. tuberculosis LAM.
The text was modified.
- The correlation between conformational preference (1C4 vs 4C1) and α-selectivity is interesting, but currently discussed relatively briefly.
REPLY:
We can conclude that in all cases, regardless of conformational preference (1C4 or 4C1) of polysilylated thiomannopyranosides during glycosylation of 3,4,6-tri-O-benzoylated S- and O-mannopyranosides, exclusively alpha isomers were formed.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript entitled “Super-armed thiomannopyranosides in the synthesis of a mannose-capped trisaccharide of Mycobacterium tuberculosis lipoarabinomannan” by P. I. Abronina, Z. V. Kuznetsova, D. S. Novikov, A. I. Zinin, N. G. Kolotyrkina, and L. O. Kononov reports the selective synthesis of a bacterial trisaccharide.
Overall, the manuscript is well structured. The introduction provides sufficient scientific background and includes relevant references. The research design is sound: the authors clearly articulate their interest in this specific trisaccharide and convincingly demonstrate how selective synthesis is achieved through the use of super-armed thiomannopyranosides.
The methods, particularly the experimental procedures, are described in adequate detail. It is especially commendable that the authors provide and interpret the NMR spectra of all intermediates, which enhances the transparency and reproducibility of the work. The figures and tables are generally clear and well presented; Table 1, in particular, is informative and easy to follow. However, Table 2 may be overly detailed for inclusion in the main text, and the authors might consider relocating it to the Supporting Information.
The manuscript would benefit from a clearer presentation of the results. While the current version is technically sound, the addition of a concise overview figure or reaction scheme at the beginning of the Results and Discussion section would greatly improve readability. Such a scheme could summarize the key steps in the construction of the trisaccharide and outline the sequence of transformations (e.g., silylation of phenyl derivatives, comparison of silylation conditions, etc.). This addition would provide readers with a helpful roadmap and make it easier to follow the subsequent discussion.
In summary, this is a solid and carefully executed study, and with minor improvements in the presentation of the results, it would be further enhanced.
Therefore, I highly recommend publishing the article in the special issue: ‘30th Anniversary of Molecules—Recent Advances in Organic Chemistry’ pending minor revisions:
Page 1 (3rd to last line): M. bovis and M. leprae. Please change and to non-italic.
Page 3 (4th line): Recently, we successfully… Please add: ,
Page 5: First sentence in 2.4: Please add in brackets that 2, 10 are alpha and 13 is beta. This would make it more clearer.
Page 6: Last sentence of description of Scheme 4. Conditions b: I think here you mean 20 instead of 19? Right before: (according to NMR data).
Page 6: At the end of the second paragraph after scheme 4 (Right before . ‘It should be noted than in all cases we observed…’), you could consider to also mention that the use of the beta donor led to less side reactions and enabled simpler purification.
Page 12: In the general section you mention that you measured 19F spectra but I was not able to find any 19F spectra? Please remove.
Page 12: Nomenclature of compound 3: please use tris instead of tri.
All reactions from here on: Please add the moles of obtained product. For compound 2: 219 mg (xxx mmol, 63%).
Page 13: NMR data of compound 3: You have: 4.11 (dd ,2H…) This should be 1H. Same line: You have 0H at the 4.29 signal.
Page 15, first sentence: was added instead of were added.
Page 15, experimental of compound 10. The TIPS signal should add up to 168H and not 165H.
Author Response
Reviewer #2:
Comments and Suggestions for Authors
The manuscript entitled “Super-armed thiomannopyranosides in the synthesis of a mannose-capped trisaccharide of Mycobacterium tuberculosis lipoarabinomannan” by P. I. Abronina, Z. V. Kuznetsova, D. S. Novikov, A. I. Zinin, N. G. Kolotyrkina, and L. O. Kononov reports the selective synthesis of a bacterial trisaccharide.
Overall, the manuscript is well structured. The introduction provides sufficient scientific background and includes relevant references. The research design is sound: the authors clearly articulate their interest in this specific trisaccharide and convincingly demonstrate how selective synthesis is achieved through the use of super-armed thiomannopyranosides.
The methods, particularly the experimental procedures, are described in adequate detail. It is especially commendable that the authors provide and interpret the NMR spectra of all intermediates, which enhances the transparency and reproducibility of the work. The figures and tables are generally clear and well presented; Table 1, in particular, is informative and easy to follow.
REPLY. We thank the Reviewer #2 for high evaluation of our manuscript.
However, Table 2 may be overly detailed for inclusion in the main text, and the authors might consider relocating it to the Supporting Information.
REPLY.
We are very grateful to the Reviewer #2 for the recommendation to relocate Tables 2–5 in the Supporting Information. However, we would like to leave Tables 2–5 in the main text, since according to our opinion, it is important for discussing the NMR spectral properties of conformers.
The manuscript would benefit from a clearer presentation of the results. While the current version is technically sound, the addition of a concise overview figure or reaction scheme at the beginning of the Results and Discussion section would greatly improve readability. Such a scheme could summarize the key steps in the construction of the trisaccharide and outline the sequence of transformations (e.g., silylation of phenyl derivatives, comparison of silylation conditions, etc.). This addition would provide readers with a helpful roadmap and make it easier to follow the subsequent discussion. In summary, this is a solid and carefully executed study, and with minor improvements in the presentation of the results, it would be further enhanced.
REPLY.
We would like to thank the reviewer for the recommendation. We focused on the key retrosynthetic scheme to access the trisaccharide 22 bearing 2-chloroethyl aglycone, which illustrates the principal steps of its preparation. The new scheme was added in the Section 2.5. “Synthesis of mannose-capped trisaccharide of the M. tuberculosis ManLAM”.
Therefore, I highly recommend publishing the article in the special issue: ‘30th Anniversary of Molecules—Recent Advances in Organic Chemistry’ pending minor revisions:
REPLY.
We are very grateful to the reviewer.
Page 1 (3rd to last line): M. bovis and M. leprae. Please change and to non-italic.
REPLY: The text was modified. We changed “and” to non-italic.
Page 3 (4th line): Recently, we successfully… Please add: ,
REPLY: We added a comma.
Page 5: First sentence in 2.4: Please add in brackets that 2, 10 are alpha and 13 is beta. This would make it more clearer.
REPLY: The text was modified.
Page 6: Last sentence of description of Scheme 4. Conditions b: I think here you mean 20 instead of 19? Right before: (according to NMR data).
REPLY: The text was modified.
Page 6: At the end of the second paragraph after scheme 4 (Right before . ‘It should be noted than in all cases we observed…’), you could consider to also mention that the use of the beta donor led to less side reactions and enabled simpler purification.
REPLY: We thank the Reviewer and mentioned that the use of the beta donor led to less side reactions and enabled simpler purification.
Page 12: In the general section you mention that you measured 19F spectra but I was not able to find any 19F spectra? Please remove.
REPLY:
We thank the Reviewer and removed 19F from the general section
Page 12: Nomenclature of compound 3: please use tris instead of tri.
REPLY: We thank the Reviewer and corrected the name of compound 3.
All reactions from here on: Please add the moles of obtained product. For compound 2: 219 mg (xxx mmol, 63%).
REPLY:The moles of the obtained products were added.
Page 13: NMR data of compound 3: You have: 4.11 (dd ,2H…) This should be 1H. Same line: You have 0H at the 4.29 signal.
REPLY: We thank the Reviewer and changed NMR data.
Page 15, First sentence: was added instead of were added.
REPLY: The text was modified.
Page 15, experimental of compound 10. The TIPS signal should add up to 168H and not 165H.
REPLY:
The NMR data was modified.
