Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions
, Vanlalngaihawma Khiangte 1,2, Zathang Laldinpuii 1,2, Lal Nunnemi 1,2, Joute Malsawmsanga 1,2, Gospel Lallawmzuali 1,3, Thanhming Liana 1, Chhakchhuak Lalhriatpuia 1, Zodinpuia Pachuau 2 and Khiangte Vanlaldinpuia 1,*Round 1
Reviewer 1 Report
The manuscript is well-written, readily understandable and the results are clearly presented.
Organocatalysts are extensively studied compounds, a lot of research has been conducted on their development in the last two decades. It is well-known today, that organocatalyst containing a thiourea unit and a primary amino group are able to generate high enantioselectivity. It was also proven that a thiourea moiety connected to a chiral diamine results in an efficient organocatalyst. In light of the above, the presented work does not contain a remarkable novelty.
However, the research work carried out is valuable, but needs to be supplemented.
A catalyst should be prepared from compound 3 using an achiral diamine to demonstrate whether the carbohydrate unit has a crucial role in the enantiodifferentiation or not.
The results presented in the manuscript should be compared with those found in the literature, in which the catalyst has the same structure but contains a different carbohydrate unit (see e.g. Ref. 37). Differences and similarities should be explained.
Absolut configuration of the products should be given in every case if it is known. Neither the tables nor the text reveal which enantiomer is formed in excess in case of the new catalysts. Again, this can shed light on the role of carbohydrate if there is any.
Scheme above Table 4 is wrong, NO2 group should be replaced by an R group with variable attachment. The reason of both diastareoselectivity and enantioselectivity should be unfolded in case of this reaction.
In general, the results should not only be presented, but also explained as much as possible.
The results of the aldol reaction (Table S1) should be presented in the manuscript. A shorter version of Table S1 would be also sufficient.
All experimental part of compounds 3-6 should be in the manuscript, instead of the Supplementary file.
Rows from 216 to 225 are unnecessary, the proposed mechanism has already been presented and known. Figure 2 should also be deleted.
And finally, the novel organocatalyst generated not excellent enantiomeric excess, but good in general (it would be excellent if all results were above 90% ee).
English language is good, minor editing is needed.
Author Response
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Reviewer 2 Report
In this work Lalhmangaihzuala et al. have synthesized new bifunctional organocatalysts derived from D-fructose. This was encapped with acetal functions to block the hydroxyl groups and the C2 of the sugar was functionalized with an amine, which was than bound to a thiourea, condensed with a chiarl double-primary amine. Specifically, the two different structures dervied from D-fructose (which differ for the configurazion of the aminic carbon) were modified with cyclohexane-1,2-diamine and 1,2-diphenylethane-1,2-diamine. Lalhmangaihzuala et al. then tested these new catalysts with two different reactions: addition of a ketone enolate to a nitroolefin and aldol condensation between a ketone and a aldehyde. In the former case they are able to obtain a good enantiomeric excess and yield, although with a poor diastereomeric ration, while in the latter they obtain a worst enantiomeric excess and yield, always with low diastereocontrol. The authors conclude that the new catalysts are suitable for the addition of ketones to nitroolefins and that oher reactions will be investigated.I think that this article should be accepted, but with some major revisions.
Many of the products obtained are present as two distinct diastereoisomers, but there’s no characterization or proof that what is obtained is actually two diastereoisomers. Moreover, the chromatogram derived from the HPLC can not be interpreted correctly: how do you now who are the diastereoisomers and the enantiomers? The UV-VIS spectra presumebly are very similar, so if you distinguish between them you need to furnish such data and show that they are clearly two different compounds. I suggest to do one of the following experimental procedures: when present two diastereoisomers, they should be separated using column chromatography and characterized. Then, the enantiomeric excess must be meausured for both the obtained samples. In case the separation using a preparative column is not possible, the mixture of compounds should be injected into an achiral HPLC with a MS detector, to prove the presence of both diastereoisomers (the interpretation of the chiral HPLC chromatogram is still difficult in this case).
Moreover, for the addition of ketone to nitroolefins the d.r. must be indicated in the main paper results. And it should be stated to what peaks the e.e. is referred to: a single peak or an avarege value?
You should add a reference when you sketch the transition state (Org. Lett. 2007, 9, 5, 923–925), since a very similar structure has already been reported.
I think that some aspects of this work are not completely clear and it would be scientifically interesting to insert some dissertations, to answer, if possible, the following questions:
· Why did you choose D-fructose as base structure for these new catalysts? Are there any reasons?
· Both diastereoisomers of the amino sugar were combined with both the enantiomers of 1,2-diphenylethane-1,2-diamine, while only one diastereoisomer was combined with the two enantiomers of cyclohexane-1,2-diamine. Are there any reasons?
· Can you measure the reaction speed without the presence of the catalyst? There can be a background reaction and this would explain why lowering the amount of catalyst the e.e. drops.
· Why DCM is the best solvent for the reaction?
· There is no explanation why benzoic acid works better than other aromatic carboxylic acids and aliphatic acids. And it is not explained why the diastereomeric ratio is always low. Can you try do sketch a more complex TS or write a dissertation?
· It would be interesting to discuss the structural difference between your new catalysts and similar once and try to correlate it with the enantiomeric excess observed in similar reactions. Are the acetal functions influent (ring forced-contraction, different dipole moment, ecc…)? Is the conformation of the far-blocked -OH groups important for the enantioselectivity?
N/A
Author Response
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Round 2
Reviewer 1 Report
The authors have slightly improved the manuscript.
Regarding the proposed achiral diamine-containing compound I understand the situation of the authors. As shown in ref. 37, the chiral thiourea-primary amine unit alone can generate a large enantiomeric excess. With the proposed catalyst, it would have been possible to prove how significant the effect of the carbohydrate unit is.
It is not clear why only one of the catalysts with similar structures was compared to the new compounds. Galactose- and mannose-based thiourea organocatalysts were also described in reference 37.
Why were the absolute configurations not included in the tables? The references given are fine, but why is it not specifically stated in the table that the R or S enantiomer was in excess?
Experimental part for compounds 3-6 are not complete in the main text. These compounds would be the main novelty, why have their data been banished to the Supplementary file?
The reviewer still feels that the manuscript is incomplete. Not only because of the lack of the proposed catalyst, but -among others- after optimizing the conditions, the substituent effect is only superficially examined, there is absolutely no substitutuent with -I -M effect or in the meta position.
The quality of English language is adequate.
Author Response
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