rel-(2R,3S)-2-((Diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
The manuscript submitted by Tasheva et al. describes the racemic synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile (3) by Michael addition of 2-((diphenylmethylene)amino)acetonitrile (1) to (E)-1-phenyl-3-(thiophen-2-yl)prop-2-en-1-one (2) with a high diastereoselectivity of 95:5. Compound 3 is quite interesting as a precursor for non-proteinogenic alpha-amino acids. However, the asymmetric synthesis of compound 3 has already been reported in reference 20 as compound 3qa, although compound characterization of 3qa has not been included in the literature. In addition, the conditions for the synthesis of compound 3 and method for the stereochemical assignment were the same as in a previous report (reference 15), which implies that the manuscript is just an extension of their previous report. Therefore, it is very difficult to find the advantages of this manuscript in the current version, and I cannot agree with its publication in Molbank. If the authors address the following major remarks, I would like to reconsider.
1) In the Introduction, the authors should describe the importance of the 2-thiophenyl group because the 2-thiophenyl substituent is a new part and is not described in their previous synthesis (reference 15).
2) In the Introduction, the authors should mention that an asymmetric synthesis of compound 3 has been reported in reference 20, although compound characterization was not carried out.
3) L41,42: The authors determined the diastereomeric ratio of compound 3 as 95:5 (1H NMR), however, the details are not included. Therefore, the 1H NMR spectrum of crude compound 3 should be included in the Supporting Information to indicate the 95:5 dr.
4) L45,47: The authors determined the relative configuration of compound 3 by comparing the proton NMR spectrum of compound 3 and the proton NMR spectra of oxonitriles, previously reported by them, however, the details are not included. Therefore, the authors should explain the details of this proton NMR comparison. The use of figures or tables is preferable.
5) L70,71: Because compound 3 is purified by recrystallization, the X-ray crystallographic structure of compound 3 is quite interesting. Please consider the inclusion of X-ray crystallographic analysis of compound 3 if the crystal is suitable enough for X-ray analysis.
6) L73–L79: Assignment of the 2-thienyl motif in the IR and 1H NMR data should be included. For the assignment of the 2-thienyl group in 1H NMR, the measurement of COSY spectrum is highly recommended.
Other points:
7) L10: Insert a space between “0” and “°C”. Also, in L35, L67, L68, L70, L73, Scheme 1.
8) L21: Insert a hyphen between “non” and “proteinogenic”.
9) Scheme 1: Insert “racemic” below the structure of compound 3.
10) L46: “spectra” could be “spectrum”.
11) L52: Correct “chalcones” to “chalcone”.
12) L60: For the reference peak in 13C NMR, the use of the central peak of CDCl3 (77.0 ppm) is more suitable than the use of the tiny TMS peak.
13) L62 and L64: Correct “Thetmo” to “Thermo”.
14) L67: The phrase “Cooled to 0°C aqueous sodium hydroxide (33% NaOH, 0.75 mL) was added” should be modified such as “An aqueous solution of sodium hydroxide (33% NaOH, 0.75 mL) cooled at 0 °C was added”.
15) L67: Insert an amount of mmol for NaOH.
16) L72: Add a period at the end of the sentence.
17) L75: The two peaks of “3.76, 3.87 (2dd, 2H, 2J = 17.6 Hz, 3J = 8.9 Hz, 3J = 4.6 Hz, CH2CO)” should be described separatory. For example, “3.76 (dd, 1H, 2J = 17.6 Hz, 3J = 4.6 Hz, CH2CO)” and “3.87 (dd, 1H, 2J = 17.6 Hz, 3J = 8.9 Hz, CH2CO)”.
18) L99: The link URL is not correct, and should be https://doi.org/10.1021/ar0300625.
19) L102: Correct “Shirakava” to “Shirakawa”.
20) SI, Figure S6: The compound on the top center might have E-configuration rather than Z-configuration.
21) SI, Figure S6: The m/z value for the compound on the bottom left is missing.
Comments on the Quality of English Language
Described in the Comments and Suggestions.
Author Response
To the Editors in chief of Molbank
Professor Nicholas Leadbeater
Dear Prof. Dr. Nicholas Leadbeater,
We are pleased to submit the detailed responses and the corresponding corrections of our manuscript: Manuscript ID molbank-3189763
"rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile"
Sincerely,
Assoc. Prof. Donka N. Tasheva, PhD
Department of Organic Chemistry and Pharmacognosy, Faculty of Chemistry and Pharmacy, Sofia University “St. Kliment Ohridski”, 1 James Bourchier blvd. 1164, Sofia, Bulgaria
e-mail: ohdt@chem.uni-sofia.bg
tel: +35928161437; +359898204289
For research article
Molbank (ISSN 1422-8599)
Manuscript ID
molbank-3189763
Type
Short Note
Title
rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile
Authors
Donka Nikolova Tasheva * , Vesela Mihaylova Mihaylova
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Response to Reviewer X Comments
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1. Summary |
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Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.
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2. Questions for General Evaluation |
Reviewer’s Evaluation |
Response and Revisions |
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Does the introduction provide sufficient background and include all relevant references? |
Yes/Can be improved/Must be improved/Not applicable |
[We agree and a new text was included.] |
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Are all the cited references relevant to the research? |
Yes/Can be improved/Must be improved/Not applicable |
No comment from the reviewer. |
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Is the research design appropriate? |
Yes/Can be improved/Must be improved/Not applicable |
We included additional information in the results. |
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Are the methods adequately described? |
Yes/Can be improved/Must be improved/Not applicable |
We added COSY spectrum for the compound. |
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Are the results clearly presented? |
Yes/Can be improved/Must be improved/Not applicable |
We included additional information. |
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Are the conclusions supported by the results? |
Yes/Can be improved/Must be improved/Not applicable |
Conclusions have added. |
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3. Point-by-point response to Comments and Suggestions for Authors |
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Comments 1: [In the Introduction, the authors should describe the importance of the 2-thiophenyl group because the 2-thiophenyl substituent is a new part and is not described in their previous synthesis (reference 15).] |
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Response 1: [Thank you for pointing this out. We agree with this comment. Therefore, we have corrected the text – p.1, L28-L32 and have included a new text – p.1, L33-L41 and references [21-23] have added.] “[updated text in the manuscript: The aim of this work is to continue our research on the reaction of 2-((diphenylmethylene)amino)acetonitrile with enones, especially with chalcone containing a thiophene ring for synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile (3) as a precursor of the corresponding non-proteinogenic α-amino acid – a derivative of 3-(2-thienyl)alanine (Tia) that is modified in the side chain. It is described that Tia as a synthetic analogue of phenylalanine, activates the enzyme phenylalanine hydroxylase (PAR) and helps reduce serum L-Phe levels in individuals with phenylketonuria [21]. Synthetic peptides containing Tia in their structure have shown to be potent antagonists of bradykinin receptors [22]. The therapeutic potential of targeting bradykinin receptor antagonists are related to the possibility of their use in the treatment of Covid-19 and inflammatory diseases [23]. For these reasons compound 3 as a precursor of the corresponding amino acid has gained our attention due to the potential applications in the biochemistry and medicine.]” Comments 2: [In the Introduction, the authors should mention that an asymmetric synthesis of compound 3 has been reported in reference 20, although compound characterization was not carried out.] Response 2: [We agree with this comment. Therefore, we have included a new text – p.1, L42-L44] “[updated text in the manuscript: We should note that recently Lee et al. [20] reported an asymmetric synthesis of 5-phenyl-3-(thiophen-2-yl)-3,4-dihydro-2H-pyrrole-2-carbonitrile via the corresponding 5-oxonitrile, which was not isolated and characterized.]” |
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Comments 3: [L41,42: The authors determined the diastereomeric ratio of compound 3 as 95:5 (1H NMR), however, the details are not included. Therefore, the 1H NMR spectrum of crude compound 3 should be included in the Supporting Information to indicate the 95:5 dr.] Response 3: [We agree with this comment. Therefore, we have added 1H NMR spectrum of crude product in Supplementary Materials.] Comments 4: [L45,47: The authors determined the relative configuration of compound 3 by comparing the proton NMR spectrum of compound 3 and the proton NMR spectra of oxonitriles, previously reported by them, however, the details are not included. Therefore, the authors should explain the details of this proton NMR comparison. The use of figures or tables is preferable.] Response 4: [We agree with this comment. Therefore, we have added a new text – p.2, L60-L64, a new figure and a table – p.2, L60-L64, L68-L75] “[updated text in the manuscript: 1H-1H COSY and HRMS. In the 1H NMR spectrum, the two protons of the methylene group were nonequivalent with 55 Hz chemical shift difference and coupling constants of 2J = 17.6 Hz, 3J = 4.6 Hz (H4a) and 2J = 17.6 Hz, 3J = 8.9 Hz (H4b) calculated from the two observed doublets of doublets. Assignment of the protons from the 2-thienyl group was performed through analysis using 1H-1H COSY.]” “[updated text in the manuscript:
Figure 1. General formula of oxonitriles.
Table 1. Selected 1H NMR spectral data for compound 3 and substituted oxonitriles (CDCl3).
a Major diastereoisomer. b Minor diastereoisomer. c Oxonitriles, previously reported by us [15]. d 3J (H3-H4b) could not be measured in 1H NMR spectrum of crude product.]” Comments 5: [L70,71: Because compound 3 is purified by recrystallization, the X-ray crystallographic structure of compound 3 is quite interesting. Please consider the inclusion of X-ray crystallographic analysis of compound 3 if the crystal is suitable enough for X-ray analysis.] Response 5: [Unfortunately оur attempts to obtain crystals for X-ray failed.] Comments 6: [L73–L79: Assignment of the 2-thienyl motif in the IR and 1H NMR data should be included. For the assignment of the 2-thienyl group in 1H NMR, the measurement of COSY spectrum is highly recommended.] Response 6: [We agree with this comment. Therefore, we have assigned the 2-thienyl motif by the IR and COSY spectra. - p.3, L101-L108.] “[updated text in the manuscript: IR (KBr): 2235 (νCN), 1690 (νC=O), 1623 (νC=N), 1595, 1578, 1489, 1446 (νC=C), 764, 695 (γC-H), 642 (νC-S) сm-1. 1H NMR (500.13 MHz, CDCl3) δ (ppm): 3.76, (dd, 1H, 2J = 17.6 Hz, 3J = 4.6 Hz, CH2CO), 3.87 (dd, 1H, 2J = 17.6 Hz, 3J = 8.9 Hz, CH2CO), 4.32-4.35 (m, 1H, CН-C4H3S), 4.55 (d, 1H, 3J = 4.4 Hz, CНCN), 6.90 (dd, 1H, 3J = 5.0 Hz, 3J = 3.6 Hz, thiophene H-4’), 6.93-6.95 (m, 3H, thiophene H-3’ and aromatics), 7.14 (d, 1H, 3J = 5.0 Hz, thiophene H-5’), 7.36-7.39 (m, 2H, aromatics), 7.42-7.48 (m, 6H, aromatics), 7.55-7.59 (m, 1H, aromatic), 7.67-7.69 (m, 2H, aromatics), 7.96-7.98 (m, 2H, aromatics).]” Comments 7: [L10: Insert a space between “0” and “°C”. Also, in L35, L67, L68, L70, L73, Scheme 1.] Response 7: [We agree. We have made corrections– p.1, L10, p.2, L49, Scheme 1, p.3, L96, L96, L98, L101] Comments 8: [L21: Insert a hyphen between “non” and “proteinogenic”.] Response 8: [We agree. We have made correction– p.1, L21] Comments 9: [Scheme 1: Insert “racemic” below the structure of compound 3.] Response 9: [We agree. We have made correction– p.2, L54] Comments 10: [L46: “spectra” could be “spectrum”.] Response 10: [We agree. We have made correction– p.2, L66] Comments 11: [L52: Correct “chalcones” to “chalcone”.] Response 11: [We agree. We have made correction– p.3, L79] Comments 12: [L60: For the reference peak in 13C NMR, the use of the central peak of CDCl3 (77.0 ppm) is more suitable than the use of the tiny TMS peak.] Response 12: [We agree. We have made correction– p.3, L86-L89] “[updated text in the manuscript: Chemical shifts (δ) are reported in parts per million (ppm). 1H NMR spectra were referenced to the tetramethylsilane (TMS) as an internal standard and 13C NMR spectrum was calibrated according to the carbon atom signal of CDCl3 (δ = 77.0 ppm).]” Comments 13: [L62 and L64: Correct “Thetmo” to “Thermo”.] Response 13: [We agree. We have made correction– p.3, L91-L92] Comments 14: [L67: The phrase “Cooled to 0°C aqueous sodium hydroxide (33% NaOH, 0.75 mL) was added” should be modified such as “An aqueous solution of sodium hydroxide (33% NaOH, 0.75 mL) cooled at 0 °C was added”.] Response 14: [We agree. We have made correction– p.3, L95-L96] Comments 15: [L67: Insert an amount of mmol for NaOH.] Response 15: [We agree. We have added an amount of mmol for NaOH– p.3, L95] Comments 16: [L72: Add a period at the end of the sentence.] Response 16: [We agree. We have made correction– p.3, L100] Comments 17: [L75: The two peaks of “3.76, 3.87 (2dd, 2H, 2J = 17.6 Hz, 3J = 8.9 Hz, 3J = 4.6 Hz, CH2CO)” should be described separatory. For example, “3.76 (dd, 1H, 2J = 17.6 Hz, 3J = 4.6 Hz, CH2CO)” and “3.87 (dd, 1H, 2J = 17.6 Hz, 3J = 8.9 Hz, CH2CO)”.] Response 17: [We agree. We have made correction– p.3, L103-104] “[updated text in the manuscript: 3.76, (dd, 1H, 2J = 17.6 Hz, 3J = 4.6 Hz, CH2CO), 3.87 (dd, 1H, 2J = 17.6 Hz, 3J = 8.9 Hz, CH2CO)]” Comments 18: [L99: The link URL is not correct, and should be https://doi.org/10.1021/ar0300625] Response 18: [We agree. We have made correction– p.4, L133] Comments 19: [L102: Correct “Shirakava” to “Shirakawa”.] Response 19: [We agree. We have made correction– p.4, L136] Comments 20: [SI, Figure S6: The compound on the top center might have E-configuration rather than Z-configuration.] |
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Response 20: [We agree. We have made correction in the Supplementary Materials] “[updated text in the Supplementary Materials: Figure S8]” Comments 21: [SI, Figure S6: The m/z value for the compound on the bottom left is missing.] Response 21: [We agree. We have made correction] “[updated text in the Supplementary Materials: Figure S8]” |
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4. Response to Comments on the Quality of English Language |
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Point 1: |
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Response 1: (Minor editing of English language was made) |
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5. Additional clarifications |
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1)“[updated text in the manuscript: 1H-1H COSY p.1, L12]”. 2) Conclusions have added “[updated text in the manuscript: 5. Conclusions In conclusion, the procedure represented here is a simple and efficient route for the preparation of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile. The reaction proceeds with high yield and diastereoselectivity. p.3, L112-L115]”. 3) “[updated text in the manuscript: Supplementary Materials: Figure S1: FT-IR spectrum of compound 3; Figure S2: 1H NMR spectrum of crude product; Figure S3: 1H NMR spectrum of compound 3; Figure S4: 13C NMR spectrum of compound 3; Figure S5: 1H-1H COSY spectrum of compound 3; Figure S6: HRMS ESI spectrum of compound 3; Figure S7: HRMS ESI-MS/MS spectrum of compound 3; Figure S8: Proposed structure of the fragment ions of compound 3. p.3, L116-L120]”. 4) References [21-23] have added. The reference [21] have changed to [24]. “[updated text in the manuscript: 21. Stokka, A.J.; Flatmark, T. 3-(2-Thienyl)-L-Alanine as a Competitive Substrate Analogue and Activator of Human Phenylala-nine Hydroxylase. In Chemistry and Biology of Pteridines and Folates, 1st ed.; Milstien, S., Kapatos, G., Levine, R.A., Shane, B., Eds.; Springer: Boston, USA, 2002; pp. 109–113. https://doi.org/10.1007/978-1-4615-0945-5_18 22. Whalley, E.T.; Nwator, I.A.; Stewart, J.M.; Vavrek R.J. Analysis of the receptors mediating vascular actions of bradykinin. Naunyn-Schmiedeberg's Arch. Pharmacol. 1987, 336, 430–433. https://doi.org/10.1007/BF00164878 23. Rex, D.A.B.; Vaid, N.; Deepak, K.; Dagamajalu S.; Prasad T.S.K. A comprehensive review on current understanding of bradykinin in COVID-19 and inflammatory diseases. Mol. Biol. Rep. 2022, 49, 9915–9927. https://doi.org/10.1007/s11033-022-07539-2 24. Li, J.-T.; Yang, W.-Z.; Wang, S.-X.; Li, S.-H.; Li, T.-S. Improved synthesis of chalcones under ultrasound irradiation. Ultrason. Sonochem. 2002, 9, 237–239. https://doi.org/10.1016/s1350-4177(02)00079-2. p.3, L175-L183]”.
5) In Supplementary Materials have added: Figure S2: 1H NMR spectrum of crude product (CDCl3). Figure S5: 1H-1H COSY spectrum of compound 3 (CDCl3). The names of figures have changed: Figure S6: HRMS ESI spectrum of compound 3. Figure S7: HRMS ESI-MS/MS spectrum of compound 3. Figure S8: Proposed structure of the fragment ions of compound 3.
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Author Response File: 
Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for Authors
The revised manuscript by Tasheva et al. has been corrected appropriately. Notably, the aims of the research and compound assignments are presented with exceptional clarity and informativeness. Therefore, I would like to recommend that this manuscript be published in Molbank.
If possible, please consider the following points during proof-correction.
1) The word “3-(2-thienyl)alanine (Tia)” could be added to the keywords to attract much attention from readers.
2) Use small capital size for “L” of “L-Phe” (L34).
3) Insert a period at the end of the title of Scheme 1 (L54).
4) Compound numbers 4 (for entries 3 and 4), 5 (for entry 5),and 6 (for entry 6) could be used and added in Table 1.
