The manuscript “Enantioselective Conia-Ene-Type Cyclizations of Alkynyl Ketones through Cooperative Action of B(C6F5)3, N‑Alkylamine and a Zn-Based Catalyst” by Wasa and co-workers describes a cooperative catalytic system of a Frustrated Lewis Pair (FLP) composed of B(C6F5)3 and an alkylamine with a chiral pi-acidic Zinc bis-oxazoline complex. This cooperative catalytic system can promote enantioselective Conia-ene-type cyclizations of weakly acidic alkynyl mono-carbonyl substrates. The results shown in the manuscript are of great interest for researchers working in the fields of cooperative catalysis and will open new opportunities for the uses of FLP in catalysis. Furthermore, the Conia-ene is a very useful reaction for the synthesis of carbocycles, especially 5 membered rings, and there are not too many protocols for the enantioselective and more elusive 5-endo-dig modality. The methodology is scalable and can also be extended to the 5-exo-dig modality. Another very important and strong point of this research is that the catalytic system promotes Conia-ene reactions with weakly acidic substrates while avoiding self-quenching of the Lewis acid and Bronsted base components. By using a combination of a FLP and a Lewis acid, the authors are expanding the scope of the substrates that can undergo Conia-ene cyclization. The results of this research could be extrapolated to other methodologies involving unactivated pro-nucleophiles and electrophiles. The manuscript in its current state is at a very high standard. I would like to add a few comments and suggestions that could perhaps make some improvements and motivate further research.

Suggestions

-The abstract does not give a background of the research presented in the manuscript and does not clearly introduce the problem object of this study. Most readers will only spend a few seconds reading the title and the abstract. If the abstract is not clear or engaging enough, the readers will not read the main body of the manuscript. The authors should highlight in the abstract the relevance of the Conia-ene reaction in synthesis and the fact that high enantioselectivity levels are achieved for the more elusive 5-endo-dig modality of this reaction.

-The authors observe high levels of enantioselectivity even with alkyl ketones which are substrates that have not worked very well in most of the previous works in the area of enantioselective Conia-ene reaction. One interesting case is the paper published by Shibata and co-workers (Angew. Chem. Int. Ed. 2012,51, 4131 –4135) that uses a chiral bis-oxazoline based Zinc catalyst to promote 5-endo-dig carbocyclizations of B-Ketoesters with alkynes and describes low levels of enantioselectivity with alkyl ketones. It would be interesting testing the substrates used by Shibata with the catalytic system described in this manuscript.

-The authors observe poor conversion and enantioselectivity with a terminal alkyne. It would be interesting to see the results of testing substrates with internal alkynes where R is a halogen, I or Br. Iodo and Bromo derivatives are easy to synthesise from the terminal alkyne in the presence of AgNO3 and NXS (X=I, Br). If the reaction is successful, having and halogen would add value to the cyclised products allowing reactions of hydro dehalogenation (leading to the same final product as the substrates with a terminal alkyne) and further modifications through Palladium catalysed cross-coupling reactions (see Angew.Chem.Int.Ed., 2004,43,5350–5352 and Org. Lett., 2007, 9, 2823–2826).

Minor concerns/typos

-In the introduction page 1, third paragraph, first line second column “structures that bear cyclopentene derivatives (e.g. T to II, Figure 1A) or exo-methylene moiety” instead of “structures that bear exo-methylene moiety (e.g. T to II, Figure 1A) or cyclopentene derivatives”

-In table 4. Caption. According to the discussion of results in page 4, paragraph 1, line 6. Conditions for 1j, 1k,1o-1s should be using PMP and conditions for 1m, 1n, 1l using 1-Methylpiperidine, instead of 1j-1l, 10-1s using PMP and only 1m, 1n only using 1-Methylpiperidine.