Synthesis of Substituted Pyrrole Derivatives Based on 8-Azaspiro[5.6]dodec-10-ene Scaffold

Round 1

Reviewer 1 Report

This manuscript presents a method of preparation of a series of (1H-pyrrol-2-yl)(8-azaspiro[5.6]dodec-10-en-8-yl)methanone derivatives via the acylation of 8-azaspiro[5.6]dodec-10-enes. This methodology is an approach via the known procedure and is quite straight forward, allowing to prepare quite a few potential molecules for pharmaceutical application. This contribution provides information for the synthetic use in pharmaceuticals. The subject matter is appropriate and meets the criteria for publication in this journal.

Several points prior to publication.

1.      Abstract : ‘This work describes the synthesis and X-ray diffraction properties of spirocyclic ……...’  Delete “and X-ray diffraction properties”.

2.      Page 2, line 50, ‘Therefore, a new synthetic approach was developed for the production of poxide 1 from commercially available reagents.” A new approach? Authors should describe the procedure more detail.

3.      Page 2, in scheme 1, some chemical formula are in improper presentation

4.      In Figure 2, please arrnge the molecular structure plot for better view to tell the relative configuration of chiral carbons, if possible.

5.      Line 94, authors should provide references for each acid used.

6.      Page 4, line 80 and so on, dH  H should be subscript

7.    Line 115, 10.17 (br. s., 1 H). à 10.17 (br. s, 1 H).

Author Response

Dear

Thank you for reviewing the manuscript ‘Synthesis of substituted pyrrole derivatives based on 8-azaspiro[5.6]dodec-10-ene scaffold’ by Ildar R. Iusupov et al.

We are grateful to each referee for helpful remarks. Below please find our step-by-step replies to the comments (italicized).

Referee 1:

Several points prior to publication. 

1. Abstract : ‘This work describes the synthesis and X-ray diffraction properties of spirocyclic ……...’ Delete “and X-ray diffraction properties”.

Corrected

2. Page 2, line 50, ‘Therefore, a new synthetic approach was developed for the production of epoxide 1 from commercially available reagents.” A new approach? Authors should describe the procedure more detail.

That part was edited, we added the modified synthetic scheme of epoxide 1 from commercially available reagents in SI. This epoxide was obtained from N-(((1RS,2RS,6SR)-2-allyl-7-oxabicyclo[4.1.0]heptan-2-yl)methyl)prop-2-en-1-amine, which in turn was obtained in seven steps from Ethyl 2-oxocyclohexanecarboxylate (CAS#1655-07-8, https://www.sigmaaldrich.com/RU/en/product/aldrich/e20004). The method for obtaining epoxide 1 is a new approach, despite the presence in the synthetic sequence of similar stages used in the synthesis of (1RS,2RS,6SR)-4',7'-dihydro-2'H-7-oxaspiro[bicyclo[4.1.0]heptane-2,3'-oxepine], which we described in 18 (Iusupov, I.R.; Lukyanenko, E.R.; Altieri, A.; Kurkin, A.V. Design and Synthesis of Fsp3‐Enriched Spirocyclic‐Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling. ChemMedChem 2022, 17, e202200394, doi:10.1002/cmdc.202200394).

3. Page 2, in scheme 1, some chemical formula are in improper presentation

Corrected 

4. In Figure 2, please arrnge the molecular structure plot for better view to tell the relative configuration of chiral carbons, if possible.

Corrected 

5. Line 94, authors should provide references for each acid used.

Corrected and one more reference was added 

6. Page 4, line 80 and so on, dH H should be subscript

Corrected 

7. Line 115, 10.17 (br. s., 1 H). à 10.17 (br. s, 1 H).

Corrected

We corrected each point indicated by the reviewer.

We are grateful to the reviewer for the encouraging comments.

The text was edited thoroughly. New additions are given in red.

We submit the revised text and Supplementary data.

Thank you for your consideration.

Sincerely,

            Alexander V. Kurkin, PhD

on behalf of all authors

Reviewer 2 Report

The manuscript of Short Note: “Synthesis of substituted pyrrole derivatives based on 8-azaspiro[5.6]dodec-10-ene scaffold” may be of interest to readers Molbank. The synthesis of substituted pyrrole derivatives of 8-azaspiro[5.6]dodec-10-enes has been properly  described and the product has been partially characterized by 1H, 13C NMR, HRMS and X-ray molecular structure of compound 8 with atom labeling. The characterization of the newly prepared compounds must be complete by IR spectroscopy. The present manuscript should be acceptable for publication in the Molbank after minor revisions.

Author Response

Dear 

Thank you for reviewing the manuscript ‘Synthesis of substituted pyrrole derivatives based on 8-azaspiro[5.6]dodec-10-ene scaffold’ by Ildar R. Iusupov et al.

We are grateful to each referee for helpful remarks. Below please find our step-by-step replies to the comments (italicized).

Referee 2:

The manuscript of Short Note: “Synthesis of substituted pyrrole derivatives based on 8-azaspiro[5.6]dodec-10-ene scaffold” may be of interest to readers Molbank. The synthesis of substituted pyrrole derivatives of 8-azaspiro[5.6]dodec-10-enes has been properly  described and the product has been partially characterized by 1H, 13C NMR, HRMS and X-ray molecular structure of compound 8 with atom labeling. The characterization of the newly prepared compounds must be complete by IR spectroscopy. The present manuscript should be acceptable for publication in the Molbank after minor revisions.

We added data of IR spectroscopy for the newly prepared compounds

We are grateful to the reviewer for the encouraging comments.

The text was edited thoroughly. New additions are given in red.

We submit the revised text and Supplementary data.

Thank you for your consideration.

Sincerely,

            Alexander V. Kurkin, PhD

on behalf of all authors