Synthesis of Tetrahydroberberine N,N-Derived O-Acetamides
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe present manuscript by the Nechepurenko group describes a synthesis of the novel titled compounds 3a-g using the substitution reaction of berberine twitter ion 1 with seven bromoacetamides to provide alkylated intermediates 2a-g, followed by NaBH4 reduction to produce the target compounds 3a-g. This method seems to be a piece of the authors’ continuing studies of transformation of berberine derivatives (Refs. 27, 28). The presented new compounds 3a-g were synthesized via two accessible reaction sequences and structure determination was well-performed. Dese 1H NMR of newly produced “H (13a)” in the tetrahydrated berberine appeared as diastereomeric pattern? Please address and explain this issue concisely in the text.
There are several immature descriptions from the standpoint of organic syntheses manuscript. I recommend to consult with a professional editing person or team who is well-acquainted in this area.
Thus, the reviewer recommends the publication in the journal after revisions described below.
<General comments and suggestions>
1. isopropanol → isopropyl alcohol or 2-propanol (IUPAC nomenclature)
2. N,N-substituted O-acetamide → N,N-disubstituted O-acetamide (italic)
<Comments & suggestions>
1. P. 1, line 43; to obtain → to synthesize
2. P. 2, line 47; interaction → substitution (or coupling)
3. P. 2, line 47; bromoacetic acid amides → seven bromoacetamides
4. P. 2, line 48; by a base → by potassium carbonate
5. P. 2, line 48; was described by us in [27,28]. →as was performed by our group [27,28].
6. Scheme 1; The mark of cycle “C” should be embedded in formula 1.
7. P. 2, line 52; results in → resulted in
8. P. 2, line 53; occurs with the formation of → to produce
9. P. 2, line 57; the remaining compounds were 59-66%, → the remaining compounds 3a, 3d, 3e were 59-66%, ? The reviewer cannot understand the reason of result; Generally, higher solubility led to the higher yield due to the homogeneous conditions.
10. P. 2, line 64; were proved → were characterized
11. P. 3, lines 79-82; The 1H NMR and 13C NMR discussion should be moved and concisely combined to that of P. 2, line 70.
12. P. 3, line 80; Let’s consider these resonances → In order to analyze these resonances “Let’s” is not suitable for literature description.
13. P. 3, line 98; previously reported [27, 28] → previously reported procedure [27, 28]
14. P. 3, lines 121-122; were added to …… in portions → were added portion by portion to ……
15. P. 3, line 122; Stirred for 30 minutes while cooling → The mixture was stirred for 30 minutes while cooling
16. P. 3, line 123; divided by column chromatography → purified by column chromatography
17. P. 3, line 124; Concerning “silica gel”, is it aluminum oxide? as shown in experimental for 3a (P. 4, line 130)
18. P. 3, line 125; product 3 → products 3
Comments on the Quality of English LanguageSee the reviewer's report.
Author Response
We thank the reviewer 1 for the comments made and for the large number of language corrections. All your corrections have been made to the text of the work. We will focus on some of the comments that require comments separately.
> Dese 1H NMR of newly produced “H (13a)” in the tetrahydrated berberine appeared as diastereomeric pattern? Please address and explain this issue concisely in the text.
Added a phrase: "The reduction proceeds non-stereoselectively, the products are a mixture of diastereoisomers according to position 13a."
>Comments 9: The reviewer cannot understand the reason of result; Generally, higher solubility led to the higher yield due to the homogeneous conditions.
The preparative yield of the products was determined after the dissolution of chromatographically purified fractions in isopropyl alcohol, followed by their re-precipitation with hexane. Therefore, we consider the phrase "The yields of the remaining compounds 3a,d,e were 59-66%, which is probably due to their greater solubility in the hexane - isopropyl alcohol system." to be correct.
> Comments 11: P. 3, lines 79-82; The 1H NMR and 13C NMR discussion should be moved and concisely combined to that of P. 2, line 70.
These paragraphs have been rearranged.
> Comments 17. P. 3, line 124; Concerning “silica gel”, is it aluminum oxide? as shown in experimental for 3a (P. 4, line 130)
Silica gel was used for chromatographic purification of compounds 3b-g, and aluminum oxide was used for purification of compound 3a. The corresponding mark has been added to the text
Reviewer 2 Report
Comments and Suggestions for AuthorsManuscript presented me to review process showed a synthesis and spectral characteristic of tetrahydroberberine derivatives. The manuscript can be published, but a several corrections should be made beforehand. Detail below:
1. In the scheme 1 mark the tested reaction (main).
2. For each compound, please provide physical data (appearance, physical state, color, e.g. white crystal solid or yellow powder etc.).
3. Fill in the missing melting points.
4. Have other reaction conditions been tested? If so, please provide them in the table. The selection of appropriate synthesis conditions is important from the point of view of efficiency and the degree of reaction of the substrates.
5. On what basis was the selected time used during syntheses? Please describe in detail how you monitored the reaction (TLC, HPCL or other). Please provide the conditions, equipment specifications and composition of the eluents used.
6. Please also include the result of the MS analysis in the SI.
7. Due to the interesting structure of obtained compounds, consider performing IR analysis.
Author Response
We thank the reviewer 2 for his comments and we have made appropriate corrections to the text of the paper. Here are the answers to the comments.
>1. In the scheme 1 mark the tested reaction (main).
Unfortunately, we did not understand very well exactly how the reviewer suggests to mark the reaction. Are there standard notations for this if a chain of reactions is given?
>2. For each compound, please provide physical data (appearance, physical state, color, e.g. white crystal solid or yellow powder etc.).
Appropriate changes have been made.
>3. Fill in the missing melting points.
Appropriate changes have been made. For compounds 3b,f, it was not possible to determine the melting point, apparently it is slightly higher than room temperature. It is indicated that these compounds are a low-melting amorphous powder.
>4. Have other reaction conditions been tested? If so, please provide them in the table. The selection of appropriate synthesis conditions is important from the point of view of efficiency and the degree of reaction of the substrates.
In this case, an exhaustive selection of reaction conditions was not carried out. The conditions under which our group had previously carried out the recovery of some berberine derivatives were used and these conditions showed an acceptable result. The phrase was added to the work: "The reaction conditions used are similar to those in which our group previously carried out the reduction of compound 1 and some of its derivatives [32]."
>5. On what basis was the selected time used during syntheses? Please describe in detail how you monitored the reaction (TLC, HPCL or other). Please provide the conditions, equipment specifications and composition of the eluents used.
In general procedure was added: "The mixture was stirred for 30 minutes while cooling and then for 4 hours at room temperature until the starting substance disappeared (TLC, SiO2 plates, methylene chloride - methanol 10:1). "
>6. Please also include the result of the MS analysis in the SI.
Appropriate changes have been made.
>7. Due to the interesting structure of obtained compounds, consider performing IR analysis.
The characteristic oscillation frequencies in the IR spectra are given for all newly synthesized compounds.
