(S)-(1-Pyrrolidin-2-ylmethyl)quinuclidin-1-ium Bromide

Round 1

Reviewer 1 Report

The Short Note submitted by Alonso and colleagues is well written and interesting. Although, some relevant improvements are needed before further considering the manuscript for publication. I report my comments below.

Major comments:

-       Scheme 1 is presented in a misleading fashion. In fact, at a first glance, it appears that preparation of final compound (molecules numbering is also confusing) may be achieved through 2 steps. Although, several different reactions are reported under the same arrow.

-       Quality of 1-H NMR spectrum for compound 5 is rather low when compared to other spectra. Was purity profile assessed? Can the quality of the spectrum be improved?

-       Mass spectra/HPLC profiles are not shown and should be added. There is a mass spectrum in the “Appendix” which may be moved to Supplementary. HPLC analysis should be reported.

Minor comments:

-       Plant names should be in italics

-       In some figures, the style of chemical structures is not consistent. For example, in Figure 4 and Scheme 1, quinuclidinium is oversized (compared to Figure 3).

Author Response

Dear Edior and reviewer.

Please, find attached the new version of the manuscript and SI which have been modify according to the valuable reviewer comments.

Best regards

Diego

Major comments:

Scheme 1 is presented in a misleading fashion. In fact, at a first glance, it appears that preparation of final compound (molecules numbering is also confusing) may be achieved through 2 steps. Although, several different reactions are reported under the same arrow.

Scheme 1 has been modified according to the reviewer comments.

Quality of 1-H NMR spectrum for compound 5 is rather low when compared to other spectra. Was purity profile assessed? Can the quality of the spectrum be improved?

Compound 5 has been obtained and used in the next step without usual purification methodologies. As described in the manuscript, the crude from the reaction to obtain this compound it was just washed to eliminate major impurities. Several purification attempts have been performed on compound 5 by column chromatography using different stationary phases (SiO2, deactivated SiO2, and alumina) and solvent mixtures (using MeOH and CH2Cl2) but the amount of solvent to be use and the yield and purity of 5 were never satisfactory. Also, attempts to purify 5 by precipitation/crystallization were unsuccessful.

Mass spectra/HPLC profiles are not shown and should be added. There is a mass spectrum in the “Appendix” which may be moved to Supplementary. HPLC analysis should be reported.

Mass spectrum has been moved to SI. HPLC analysis for compound 6 has been added to the SI as well.

Minor comments:

Plant names should be in italics.

Plant names are now in italics

In some figures, the style of chemical structures is not consistent. For example, in Figure 4 and Scheme 1, quinuclidinium is oversized (compared to Figure 3).

All chemical structures in Figures are now consistent.

Round 2

Reviewer 1 Report

The authors revised the papers following previous suggestions and answered all comments. In particular, schemes have been improved as well as quality of presentation data.