Enantioselective Mannich Reaction Promoted by Chiral Phosphinoyl-Aziridines

Round 1

Reviewer 1 Report

In this paper, Rachwalski et al. reported the use of chiral phosphinoyl-aziridines as catalysts in the three component Mannich reaction of  hydroxyacetone. Although yields in product as well as enantio- and diastereoselectivities are fairly good, from a synthetic point of view, this method appears to be much lower than the original well-established procedure which use commercially available proline as catalyst and even much lower than the one reported by the authors themselves (ref 3 of the manuscript). In addition The paper is very concise and only 4 examples are reported.

However, the paper also has some merits which deserve to be noted: after all, the authors demonstrated that these phosphinoyl-aziridines act with a synergistic effort of the two basic functionalities ( the aminic nitrogen  and the P=O) suggesting their potential usefulness in other more challenging synthetic processes.

Overall, I recommend the publication of this manuscript on Catalysts provided that the following are addressed:

-In fig 1 the absolute configuration of (S)-9 is not correctly drawn.

-The tentative transition state models are depicted with poor quality drawings which fail to give an idea of the origin of the stereoselectivity. On the other hand, the text is so concise that it appears to make it even worse.

-The use of “SELECTED” HPLC data in the supporting info is quite unjustified, especially considering that only 4 examples have been reported in the work. HPLC chromatograms should be also tagged with the name or the structure of each compound.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Enantioselective Mannich reaction promoted by chiral phosphinoyl-aziridines

Aleksandra Buchcic, Anna Zawisza, Stanislaw Lesniak, Justyna Adamczyk, Adam Marek Pieczona and Michal Rachwalski

 

The authors described the application of a series of optically pure aziridines bearing phosphine oxide moiety as organocatalysts in the direct tri-component asymmetric Mannich reaction. Eight of ten aziridines were prepared previously, their preparation methods and their characterizations have been published in a recent paper. However, the application of these compounds in the Mannich reaction of aromatic aldehydes, p-anisidine and hydroxyacetone is novel and the results obtained with these catalysts, especially those reached with the last two compounds (9 and 14) warrant publication of the work in the journal Catalysts. Thus, I suggest acceptance of the manuscript for publication following minor revisions, as detailed below.

There are few typos and in a few places, the language used should be corrected (use of articles, the use of plural nouns, etc.). Furthermore “configuration at amine moiety” (line 104) is not correct, should be at the carbon next to the amine moiety. In title 2.2. “1-10” must be corrected to 1-9, 14; similarly in line 112 “9 and 10” should be 9 and 14; in line 33, “metal-based ligands”, should be metal-based complexes; and so on. In line 28, 29 the authors could cite a recent review on cascade reactions using heterogeneous organocatalysts, proving the usefulness of the asymmetric organocatalysis in sustainable processes.

In tables, the authors should give the reaction conditions (such as the amount of catalysts, substrates, temperature, time) as footnotes.

Related to Table 2, the compound resulted using the aldehyde substituted in orto position was obtained in lower yield and ee, as compared with the others. This could be mentioned and maybe commented in the text.

Although the authors observed that aziridines having free NH-aziridine subunit were the most efficient, this was not enough highlighted. These findings are (in my opinion) the most important and should be mentioned even in the abstract and the conclusion section.

The tentative transition-states (A and B) were sketched using a catalyst having tertiary N-aziridine moiety (R-5). This should be paralleled with that formed from S-5, the enantiomer which leads to the opposite product enantiomer. However, this does not means that similar transition-state is formed when S-9 is used, which due to the secondary amine moiety may form enamine-type intermediate. How the authors can rule out the occurrence of this type of intermediate? Maybe this explains the better results obtained with the secondary amines.

 

Finally, following these minor modifications I suggest publication of the work.

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf