Asymmetric Synthesis of trans-3-Alkoxyamino-4-Oxygenated-2-Piperidones Mediated by Transition-Metal-Free Dual C-H Oxidation and Its CAL-B-Assisted Enzymatic Resolution
, Marina A. Ortega-Rojas 2, Jonathan R. Valdéz-Camacho 2, Luis G. Hernández-Vázquez 2, Fernando Sartillo-Piscil 1,* and Jaime Escalante 2,*
Round 1
Reviewer 1 Report (New Reviewer)
Sartillo Piscil, Escalante and coworkers have reported a general chemo-enzymatic approach to synthesize both enantioenriched trans-3-Alkoxyamine-4-oxy-2-Piperidones, important scaffold for various naturally occurring alkaloids. A metal-free C−H oxidation of piperidines mediated by TEMPO oxoammonium cation (TEMPO+) followed by Candida antarctica lipase (CAL-B) enzymatic resolution was employed.
This reviewer thinks this article may be accepted for publication in Catalysts journal after major revisions.
1. Formating mistakes
a. The type of the paper should be chosen.
b. In references 9, 18, 32, 34 43 should be provided the end pages
2. The methodology is only applied for a specific substrate. Would it be possible to apply it in piperidine derivatives with different protecting groups such as Boc which is easier to remove or with the appropiate protecting groups which enable the obtaining of piplaroxide or another alkaloid? Please provide one more example.
Author Response
“The type of the paper should be chosen. In references 9, 18, 32, 34, 43 should be provided the end pages”.
Response= End pages are now available whenever possible.
“The methodology is only applied for a specific substrate. Would it be possible to apply it in piperidine derivates with different protecting groups such as Boc which is easier to remove or with the appropriate protecting groups which enable the obtaining of piplaroxide or another alkaloid? Please provide one more example.
Response= No, it would not. The success of the dual C-H oxidation of N-heterocycles mediated by NaClO, NaClO2, and TEMPO depends on the electronic nature of nitrogen atom, which must not be deactivated by a protecting group such as Boc. Therefore, we further demonstrated that the benzyl group acts like sort of a nitrogen protecting/directing group (this has been recently demonstrated in mechanistic studies Synthesis 2023, DOI: 10.1055/a-2053-9558). In this regard, we have employed the PMB group as protecting/directing group in the total synthesis of piplaroxide (J. Nat. Prod. 2016, 79, 1174).
Reviewer 2 Report (Previous Reviewer 4)
Jaime and co-workers have studied the Asymmetric Synthesis of trans-3-Alkoxyamine-4-Oxygenated-2-Piperidones which was mediated under dual C-H oxidation without any Transition-Metal and the enzymatic resolution was performed using CAL-B. The author also proposed the ionic mechanism as on scheme 2 which was advantageous to the readers. The reaction was also analyzed by the developed HPLC technique using the Chiral column, the separation was clean and the explanation was amazing. In addition to the HPLC technique, the author also analyzed the reaction sample by NMR techniques over a period of 24 and 72 h which was explained well. I strongly recommend to accept this journal after a few spell checks.
Author Response
“Jaime and co-workers have studied the Asymmetric Synthesis of trans-3-alkoxyamine-4-oxygenated-2-piperidones which was mediated under dual C-H oxidation without any Transition-Metal and the enzymatic resolution was performed using CAL-B. The author also proposed the ionic mechanism as on scheme 2 which was advantageous to the readers. The reaction was also analyzed by the developed HPLC technique using the Chiral column, the separation was clean and the explanation was amazing. In addition to the HPLC technique, the author also analyzed the reaction sample by NMR techniques over a period of 24 and 72 h which was explained well. I strongly recommend to accept this journal after a few spell checks”.
Response: Typo and grammatical errors were corrected.
Reviewer 3 Report (New Reviewer)
This manuscript describes an asymmetric synthesis of trans-3-Alkoxyamine-4-Oxygenated-2-Piperidones via TEMPO mediated C-H Oxidation and a lipase assisted enzymatic resolution. The two steps are both well known in the field since 1970s. And there is nothing new in this paper. All the data are well presented and well collected. But considering Catalysts is such a high-ranking journal, I recommend the authors transfer this manuscript to MDPI Organics or Chemistry.
There are some minor issues:
For Scheme 1, please put the yield underneath the structure.
In Scheme 1, change AcO2 to Ac2O
Line 78，change proposal mechanism to proposed mechanism.
In all the schemes, the bond for the racemic chiral center should not be predefined(wedged)
The authors should calculate the turnover numbers of the enzymatic resolution reactions, that’s more important than the yield.
Author Response
“This manuscript describes an asymmetric synthesis of trans-3-alkoxyamine-4-oxygenated-2-piperidones via TEMPO mediated C-H Oxidation and a lipase assisted enzymatic resolution. The two steps are both well known in the field since 1970s. And there is nothing new in this paper. All the data are well presented and well collected. But considering Catalysts is such a high-ranking journal, I recommend the authors transfer this manuscript to MDPI Organics or Chemistry”.
Response: I respectfully disagree the comments of this reviewer. Perhaps he/she is confusing about the chemistry of TEMPO salts with alcohols with the recent chemistry of selective C-H functionalization of cyclic amines mediated by TEMPO oxoammonium cation, in which our group have developed in since 2016 (e.g., JOC 2016, 81, 8625, JOC 2028, 83, 24, 15333, ACIE 2018, 58, 8867, CEJ 2020, 26, 4671, and other papers). We kindly invite to this reviewer to check recent review (Asian J. Org. Chem. 2023, 12, e202200547), account (Synlett 2021; 32, 1385), and book chapter (THS http://dx.medra.org/10.17374/targets.2023.26.100), to thus confirm that the current work invokes a new chemistry beyond the oxidation of alcohols.
“For Scheme 1, please put the yield underneath the structure. In scheme 1, change AcO2 to Ac2O. Line 78, change proposal mechanism to proposed mechanism. The authors should calculate the turnover numbers of the enzymatic resolution reactions, that’s more important than the yield”.
Response= Yield is now underneath structure. AcO2 to Ac2O is now corrected. Proposal mechanism to proposed mechanism is now corrected.
Since turnover number for enzyme calculation relays on kinetics parameters was not calculated because to our end as organic chemists, was more important to discover a methodology that would help us to solve a racemic mixture with good yields. Therefore, no kinetics data was collected but it is something we will have in mind for our future papers.
“In all schemes, the bond for the racemic chiral center should not be predefined (wedged).”
Response= All bonds for racemic centers are now not predefined.
Round 2
Reviewer 3 Report (New Reviewer)
The authors have addressed the previous comments appropriately and made relevant revisions.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
This work presents an asymmetric approach to achieve trans-3-alkoxyamine-4-oxy-2-piperidones from simple 4-hydroxypiperidine by using selective dual C−H oxidation and enzymatic resolution. It is an interesting piece of work. However, these are a few minor issues to be addressed before publication.
1. The introduction needs to provide more background knowledge and more relevant references, introduce transition-metal, transition-metal-free C-H oxidation reaction and enzymatic resolution.
2. Arabic numerals should be used for the numbering of references, such as 1. 2. 3.
Reviewer 2 Report
Reviewer’s Comments:
The manuscript “Assymetric Synthesis of trans-3-Alkoxyamine-4-Oxygenated-2-Piperidones Mediated by Transition-Metal-Free Dual C-H Oxidation and its CAL-B-Assisted Enzymatic Resolution” is very interesting work. This paper investigates a general approach for accessing to enantioenriched trans-3-Alkoxyamine-4-oxy-2-Piperidones, which are the important scaffold of various naturally occurring alkaloids, is reported. To this end, we combined the selective transition-metal-free dual C−H oxidation reaction of piperidines mediated by TEMPO oxoammonium cation (TEMPO+) followed by CAL-B enzymatic resolution of the (u)-trans-3-alkoxyamine-4-oxy-2-piperidone intermediates, to thus obtain the title compounds in high enantiomeric excess. However, the following issues should be carefully treated before publication.
1. In abstract, the author should add more scientific findings.
2. Keywords: the synthesized system is missing in the keywords. So, modify the keywords.
3. In the introduction part, the introduction part is not well organized and cited references should cite recently published articles such as 10.3389/fchem.2022.1023316, 10.3390/molecules27196457
4. Introduction part is not impressive and systematic. In the introduction part, the authors should elaborate the scientific issues in the Enzymatic Resolution research.
5. Enzymatic resolution…, The author should provide reason about this statement “Reaction was monitored by TLC however after 22 h it was observed no conversion (Scheme 2, left)”.
6. The authors should explain regarding the recent literature why “Retention times for both rac-trans-2 enantiomers were 13.36 min and 16.45 min, while a more retained behavior for rac-trans-3 was observed with 18.69 min and 25.71 min retention times (Figure 2)”.
7. Discussion. The author should explain the latest literature “The best conditions to promote de-acylation reaction were found to be those from entry 3 in which enzyme concentration, substrate concentration, water equivalents and temperature were increased”.
8. The author should provide reason about this statement, “To achieve chemical correlation was found a report where (S)-5 was prepared by Huang et al. from a natural chiral source: (S)-malic acid”.
9. Comparison of the present results with other similar findings in the literature should be discussed in more detail. This is necessary in order to place this work together with other work in the field and to give more credibility to the present results.
10. The conclusion part is very week. Improve by adding the results of your studies.
Reviewer 3 Report
Although the idea of the synthesis pathway seems correct (though not really cutting-egde), the article cannot be accepted for publication in the present form. First of all, English is poor. There are so many errors that I am not able to enumerate them all.
Other reservations:
1. Line 65: "One approximation" - probably the Authors mean "approach"
2. The use of 2-methyl-2-butanol (2M2B) as a solvent seems inappropriate in the enzyme-catalyzed acetylation of a hydroxy group-containing substrate since it can compete with it. Maybe this is the reason of the unsuccessful approach.
3. Scheme 1 uder the left arrow: the symbol of sodium chlorite is wrong; it should read NaClO2.
4. The ee value of the starting acetylated substrate (after the enzymatic hydrolysis) is not shown in Table 1. Since the conversion is only 39%, it must have been lower than that of the hydroxy product, while Fig. 6 seems to show its pure enantiomer. This should be discussed/explained.
5. References are written in the way which is different (inappropriate?) from those recommended by the Journal.
Reviewer 4 Report
I do not feel any novelty in the selective dual C-H oxidation using TEMPO oxoammonium cation. There are few reports published on this type of chemistry like: J. Org. Chem. 2016, 81, 8625−8632. Due to the lack of Novelty and lack of work I am rejecting this manuscript to not publish in catalysts.
