Synthesis of (−)-Verbenone-Derived Triazolium Salts and Their Application in Enantioselective Intramolecular Stetter Reaction†
Round 1
Reviewer 1 Report
In this manuscript, the authors report the synthesis of (-)-verbenone-derived triazolium salts and its application in asymmetric intramolecular Stetter reaction. Although the intramolecular Stetter reaction is well studied, the development of new catalysts for enantioselective reactions is always well received by the chemical community.
In my opinion this article can be accepted in Catalysts after revision.
On page 1, line 39, the authors say:
“Triazolium salts 1 were synthesized from (1S)-(-)-verbenone as outlined in Scheme 1”
Also in the experimental part the authors expressly indicate the absolute configuration of the chiral carbons of the different compounds.
therefore it is understood that the starting material is enantiomerically pure (1S,5S)-(-)-verbenone.
However, on page 2, lines 42-44, the authors say:
“Due to the fact, that verbenone is not commercially available in enantiomerically pure form, attempts of enantiomeric enrichment through crystallization at the ketoxime stage failed”.
This point should be clarified by the authors in the new version of the manuscript. What is the starting material?.
On page 2, lines 51-52, the authors say:
“The NHC precatalyst 1b could be easily and cleanly isolated as tetraphenyl borate salt. For the salt 1a, preparation does not require chromatographic purification”
However in the experimental part, in the purification of both catalysts, chromatographic methods were used. Also, this point should be clarified by the authors.
The authors should indicate how they have established the absolute configuration of the chiral carbon of the compounds 10.
Some minor corrections:
The word “intramolecular” should be included in the title.
Throughout the manuscript the authors should always use 1A and 1B for the catalysts (always with capital letters).
In table 1, line 73, Diisopropylethylamine must be replaced by trimethylamine.
Table 3, entry 1, the results do not match those indicated in table 4.
Table 4, in all cases it is necessary to indicate % ee.
Page 10, line 347, the authors say:
“In conclusion, we have developed a series of novel chiral terpene triazolium salts”
It should be changed to: “In conclusion, we have developed two novel chiral terpene triazolium salts”.
In my opinion the manuscript may be accepted for publication in Catalysts when all these corrections and clarifications have been made.
Author Response
I would like to take this opportunity to express my sincere thanks to the Reviewer who identified areas of my manuscript that needed corrections or modification.
Commercially available (1S)-(-)-verbenone is most probably obtained from the (-)-alfa-pinene with an optical purity of about 60%, hence our (1S0-(-)verbenone had an optical purity of 58%. Therefore, it was necessary to enantiomeric enrichment at one of the steps of the synthesis of the triazolium salt. I put the information about optical purity of the starting material in the General Information.
All other comments have been applied in the text.
Reviewer 2 Report
Rafinski and Krzeminski described the synthesis of (-)-verbonone-derived triazolium salts and its application in asymmetric intramolecular Stetter reaction. The intramolecular Stetter reaction is well studied and several reports have been described. However, this referee thinks that is very interesting for the chemistry community the development of new catalysts for enantioselective reactions, and this article can be accepted in Catalysts after major revision.
The authors only tried the intramolecular Stetter reaction, therefore in the title the word intramolecular should be added.
The enantioselective intramolecular Stetter reaction is well studied, and several examples have been described in the literature. The authors should add all these references:
ACS Catal. 2017, 7, 6365-6375; Org. Lett. 2016, 18, 5764; Tetrahedron 2012, 68, 10188-10193; Org. Biomol. Chem. 2011, 9, 2072-2074; J. Org. Chem. 2008, 73, 2031-2040; J. Am. Chem. Soc. 2002, 124, 10298-10299; Helv. Chim. Act. 1996, 79, 1899-1902 (THE FIRST EXAMPLE); Tetrahedron Asymm. 2014, 25, 1401; Org. Lett. 2011, 13, 1742-1745.
In the Scheme of Table 1, the base is Et3N, however in the table footnotes the base is DIPEA. The authors should check which is the base used.
In Table 2, the authors should add a footnote with the description of the bases (such as TBD, P2-Et, DCyEA).
The authors should add more examples for study the scope of the reaction, such as examples with S, NR or CH2 between the aromatic ring and the Michael acceptor part. Also, the authors should try other electron-withdrawing groups in the Michael acceptor part, such as amides, ketones or nitriles. Also, could be very interesting if the authors show one example for the synthesis of a chromanone with a tetrasubstituted stereogenic center.
In materials and methods, the authors should add the mols of the products in the part of the synthesis of the catalysts. On the characterization of the chiral chromanones 10, the authors should add the mg and the mmols of all of them.
Author Response
I would like to take this opportunity to express my sincere thanks to the Reviewer who identified areas of my manuscript that needed corrections or modyfication.
Extending the research with systems containing nitrogen, sulfur and the CH2 group (Aza-chromanones, tiochromanones, and tetralones), additionally modified on the Michael acceptor side, would be undoubtedly interesting. Nevertheless, such material is a good basis for the next publication due to the time needed to perform all syntheses.
Other comments by the reviewer have been included in the main text.
Reviewer 3 Report
-I really appreciate the current authors for their work on developing new N-heterocyclic carbene catalysts from readily available natural chiral sources and their application to obtain high ee in the Stetter reaction.
-This method was studied in detail using variety of substrates, bases and solvents to obtain high yields and ee.
-Typo correction in line 58: Please use "together" insted of "
- Typo correction in Line 77: Please use "tolerable" insted of "tolarable"
Author Response
I would like to take this opportunity to express my sincere thanks to the Reviewer who identified areas of my manuscript that needed corrections or modification.
All comments from the Reviewer have been included in the text.
Round 2
Reviewer 1 Report
In this manuscript, the authors report the synthesis of (-)-verbenone-derived triazolium salts and its application in asymmetric intramolecular Stetter reaction. Although the intramolecular Stetter reaction is well studied, the development of new catalysts for enantioselective reactions is always well received by the chemical community.
In my opinion the revised version of this manuscript can be accepted in Catalysts.
Minor correction:
In the Abstract the authors say:
“A series of novel chiral verbenone-derived triazolium salts………”
As in the Conclusions it should be changed to:
“Two novel chiral verbenone-derived triazolium salts………”
Author Response
The changes have been included in the text.
Reviewer 2 Report
Rafinski and Krzeminski have corrected some of the issues that I point out. However there are still some issues to correct.
-Reference 29 is missing the journal, volume, year and pages: Helv. Chim. Act. 1996, 79, 1899-1902.
-How the authors determine the enantiomeric excess (99) of compound 5. Please explain, and put in the experimental and in the supporting the chiral HPLC trace.
-In the manuscript the authors claim: “The (1S)-(−)-verbenone that was purchased from Sigma-Aldrich 143 was of 94% chemical purity, and an optical purity of 58% was determined by polarimetry”. Please nowadays this is not the correct form to determine the enantiomeric excess. Please do it by chiral HPLC.
-The last thing, is that this is an article, not a communication. The reaction described in this article is well developed, therefore this referee thinks that the authors could do more compounds in order to improve the current methodologies.
Author Response
The reference has been corrected.
The enantiomeric excess for the verbenone and verbanone was determined by GC using chiral stationary phase - we added the chromatograms, (supporting information)
Trying to enrich enantiomerically ketoxime, we obtained a number of fractions with different enanctiomeric excesses. After reduction the low ee (ca 10% ee) fraction with NaBH4, we separated the enantiomers using HPLC. The chromatograms from the hydroxyoxime (5) separation were placed in Supporitng, and in the experimental section, the separation conditions were placed.
The main goal of this work is the synthesis of new NHC precursors derived from natural chiral sources. Then using them as chiral catalysts in the Stetter reaction as a known reaction model to get the information and have a comparison about catalytic activity and asymmetric induction. In our opinion, such an amount of examples provides sufficient information on the comparative matter to the NHC precursors known in the literature.
Round 3
Reviewer 2 Report
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