Organocatalytic desymmetrization provides access to planar chiral [2.2]paracyclophanes

Planar chiral [2.2]paracyclophanes consist of two functionalized benzene rings connected by two ethylene bridges. These organic compounds have a wide range of applications in asymmetric synthesis, as both ligands and catalysts, and in materials science, as polymers, energy materials and dyes. However, these molecules can only be accessed by enantiomer separation via (a) time-consuming chiral separations and (b) kinetic resolution approaches, often with a limited substrate scope, yielding both enantiomers. Here, we report a simple, efficient, metal-free protocol for organocatalytic desymmetrization of prochiral diformyl[2.2]paracyclophanes. Our detailed experimental mechanistic study highlights differences in the origin of enantiocontrol of pseudo-para and pseudo-gem diformyl derivatives in NHC catalyzed desymmetrizations based on whether a key Breslow intermediate is irreversibly or reversibly formed in this process. This gram-scale reaction enables a wide range of follow-up derivatizations of carbonyl groups, producing various enantiomerically pure planar chiral [2.2]paracyclophane derivatives, thereby underscoring the potential of this method.

1) Introduction section: "Organocatalytic approaches are excellent tools ...... such as amino acids and alkaloids."I suggest shrink or delete these words, since I do not find direct / close relationships of these expressions to the current work, and, in addition, many organic catalysts such as some trivalent phosphines are not stable.2) Introduction section: "Consequently, asymmetric organocatalysis ...... such as [2.2]paracyclophane derivatives."This is not correct, since several works have already appeared online with organocatalytic approaches to access chiral [2.2]paracyclophane derivatives.I have read a closely related work in Nat.Commun.(2023,14,5239), which I believe should be cited here.
3) Page 3, Line 62: "but only one study has reported such an approach thus far......" I do not believe this was correct...At least the above work in Nat.Commun.should be mentioned.4) Line 71, "NHC precursors easily accessible from......." I suggest delete "easily", since it is not exactly correct: many NHCs are difficult to prepare.5) Line 73, ref. 46 is strange.It is not suitable to cite a review here.Typical examples include but not limited to "Angew Chem Int Ed, 2016, 55: 1820-1824; Org Lett, 2019, 21: 6169-6172; Angew Chem Int Ed, 2022, 61: e202117340; Chin J Org Chem, 2022, 42: 2504-2514" should be cited here.In addition, I do not think these works are "central-to-axial" transfer.These are direct atroposelective esterifications.6) Line 82, I do not think the current work involves "central-to-planar chirality transfer process".The current work is a direct asymmetric esterification.By the way, the "central-toplanar chirality transfer" should be deleted.I suggest "N-Heterocyclic Carbene-Catalyzed Desymmetric Esterificatoin for access to Planar Chiral [2.2]Paracyclophanes". 7) For the reaction mechanism, I suggest to move more information from the SI to the main text.For instance, the process for the determination of kR/kS and VR/VS in Scheme 3c, and their function should be indicated.8) The authors described the control experiment, analyzed the results and proposed the reaction process (desymmetrization and KR for different substrates).However, the reason that caused this difference should also be explained.Is it resulted from intramolecular Hbonding, or some steric hindrance?Please provide a complete postulated catalytic mechanism clarifying the stereoselective inductions with the two reaction substrates clearly described.9) Close related reviews on the NHC-catalyzed KRs and desymmetrizations should be cited: Synlett 2013, 24, 1165-1169; Chem.Asian J. 2018, 13, 2149-2163; Chem.Asian J. 2018, 13, 2184-2194; Synthesis 2019, 51, 1871-1891; Sci.China Chem.2023, 66, https://doi.org/10.1007/s11426-022-1657-0.

Reviewer #2 (Remarks to the Author):
This work reports a novel organocatalytic desymmetrization of diformyl [2,2]paracyclophanes, using NHC cataysts under oxidative conditions in the presence of various alcohols.This method delivers in a single step enantioenriched bifunctional paracyclophanes bearing both an aldehyde and an ester functionality, with a chemical diversity introduced on the ester group (22 examples).Thioesters can also be obtained, albeit with lower efficiency in term of yield and optical purities.Two different substrates have been used in this study : a centrosymmetric pseudo-para diformyl [2,2]paracyclophane, and a pseudo-gem (not pseudo-ipso) diformyl [2,2]paracyclophane exhibiting a plane of symmetry (not a center).For the first substrate, yields a ranging from 59 to 93% and e.r. are between 82:18 and 99:1 with primary alcohols.The reaction is less efficient with secondary alcohols, and is not working with tBuOH or phenols.Best results are obtained with the pseudo gem substrate, with e.r.generally better than 99:1 and yields between 56 and 96%.Although the desymmetrization of centrosymmetric pseudo-para diformyl [2,2]paracyclophane has already been reported using asymmetric transfer hydrogenation ((ref.43 cited in the paper), the desymmetrization of pseudo gem substrate is a groundbreaking novelty since it was reported to give Cannizzaro type reactions under reductive conditions (ref.43).Furthermore, the authors conducted a very elegant and convincing mechanistic investigation to explain the observed stereocontrol of the reaction.It appears that the high enantioselectivity obtained from the pseudo-para bis-aldehyde is the result of an enantioconvergent process that combines desymetrization and kinetic resolution, with a reversible formation of the Breslow intermediate, whereas the perfect enantioselectivity obtained from the pseudo-gem substrate is the result of a non-reversible enantioselective formation of Breslow intermediate.All in all, this new methodology enables in a very simple manner access to very useful chiral building blocks.It will clearly impact the field of chiral paracyclophane chemistry.The experimental part is very well described, with many additional details on parameter optimizations and all the products are well characterized.Several crystal structures secure the relative and absolute configuration determination.I recommend publication, after a few improvements of the manuscript.
-centrosymmetry: compound 1b is NOT centrosymmetric!It has a plane of symmetry.This has to be corrected in all the manuscript.-nomenclature: the description of substituted paracyclophanes has been proposed by Hopf.According to his pioneering work, compound 1b should be described as a "pseudo-gem" compound and not a "pseudo-ipso" compound.
-"substrate scope".I do agree that the scope of the reaction is broad if one considers the ester point of diversity, but the scope of the "substrate" is not, since only 2 different compounds are desymmetrized in this work.I suggest to modify the "substrate scope " (Page 7, line 125) for a "reaction scope", and to remove the discussion on the so-called "restricted substrate scope" (page 3, line55) of ref 43.
-kinetic resolution.The maximum product yield of a kinetic resolution can be greater that 50%, but with e.e. lower than 100% Page 3, line 61, the sentence has to be modified "the maximum enantiopure product yield is only 50%) -green process (page 5, lines 104-105).I do agree that electrooxydation is a green process, but here, 2 equiv. of TBAI are needed, and the side product of the reaction is probably HI.I'm not sure that this protocol is "greener" than the use of DQ, even if TBAI is called a "promoter" by the authors of this method.
-The use of unprotected sterols leads to the chemoselective esterification of primary alcohol.The selectivity is explained by the different rates of reaction between primary and secondary alcohols.However, the reaction took 48h, instead of 15h with lauryl alcohol.Could the final selectivity be the result of transesterification of transient secondary alcohols, leading to the formation of a single isomer?-On the non-reversibility of the formation of Breslow intermediate for pseudo-gem substrate.Is it possible that alcoholate II (supporting info, page S26) reacts with the proximal aldehyde to form in a reversible manner an hemiacetal ?This competitive pathway could explain the difference between the two mechanisms.Could the authors design an experiment to monitor/trap this putative intermediate?May be using one equivalent of NCH, and no oxidant nor alcohol.
-Supporting information: The numbering of the pre-catalysts is not the same as in the manuscript.Ref 2: Two papers are cited, only the first one refers to the preparation of compounds 1a and 1b.

Reviewer #3 (Remarks to the Author):
This paper describes an efficient and versatile protocol for organocatalytic desymmetrization esterification of centrosymmetric diformyl [2.2]paracyclophanes through NHC catalysis under mild conditions.The work is very meaningful for organic chemists.So I recommend this paper be published on this journal after the following points are considered.1.In the line of 46, "4 carboxy [2.2]paracyclophane" should be written as "4carboxy[2.2]paracyclophane".2.In the line of 151, "we introduced another centrosymmetric [2.2]paracyclophane, namely pseudo-ipso-diformylparacyclophane" is misstated, pseudo-ipso-diformylparacyclophane is plane-symmetric.3.In the Scheme 3: Mechanistic studies, control experiments (Scheme3C, left), "The model reaction with a lowered amount of oxidant (55 mol%) produced 3a in 88:12 er with traces of the diesterification product", but in the scheme, "Desymmetrization: kR/kS = 5.4/1" might be wrong.4.In the line of 213, "This operationally simple and effective strategy has a wide substrate scope" is a little exaggerated.For the [2.2]paracyclophane,only two substrates were introduced.5.For the synthetic utility, there are many reactions involving the aldehyde-group, how about reductive amination, witting reaction and so on.6.As for the pseudo-para [2.2]paracyclophane, the optimized reaction condition is at room temperature, how about at 0℃?When at 0℃, would the enantiopurity of 3f and 3h be improved?And at 0℃, would the reaction mechanisms for both [2.2]paracyclophanes be same?7.The synthetic utility of this method should be fully demonstrated.At least one of the examples listed in Figure 1 should be synthesized using this method.1) Introduction section: "Organocatalytic approaches are excellent tools ...... such as amino acids and alkaloids."I suggest shrink or delete these words, since I do not find direct / close relationships of these expressions to the current work, and, in addition, many organic catalysts such as some trivalent phosphines are not stable.
Once again, we thank the reviewer for carefully reading our manuscript and for the efforts to ensure the accuracy of all statements and word choice.As suggested, we have deleted "easily" in the revised manuscript.We sincerely thank the reviewer for such a thorough review of our manuscript.We fully agree with the reviewer's opinion, and we have modified the manuscript accordingly, i.e, have moved the reference related to NHC-catalyzed atroposelective esterification of aromatic aldehydes to this sentence (now ref.  2022)) here, currently reference 53.We believe that we now cite all relevant studies in the current version of the manuscript because the other studies mentioned by the reviewer (two published in ACIE and one in Org Letters) are not directly related to the mentioned topic.So, after a carefully analysis of the reviewer's suggestion, we decided not to cite them.As for the term used to describe the reactions, we have replaced "central-to-axial" by "atroposelective".The corresponding sentence now reads: "For example, oxidative NHC catalysis was applied to the atroposelective desymmetrization of aromatic dialdehyde, producing axially chiral monoesters".Once again, we thank the reviewer for enhancing the accuracy of our manuscript.6) Line 82, I do not think the current work involves "central-to-planar chirality transfer process".The current work is a direct asymmetric esterification.By the way, the "central-to-planar chirality transfer" should be deleted.I suggest "N-Heterocyclic Carbene-Catalyzed Desymmetric Esterificatoin for access to Planar Chiral [2.2]Paracyclophanes".
We thank the reviewer for the suggestion, and in line with our response to the previous comment (5), we have modified the title of the manuscript as follows: "Organocatalytic Desymmetrization Provides Access to Planar Chiral [2.2]Paracyclophanes". 7) For the reaction mechanism, I suggest to move more information from the SI to the main text.For instance, the process for the determination of kR/kS and VR/VS in Scheme 3c, and their function should be indicated.
52, previously ref.46 in the original version of the manuscript) and cited the study suggested by the reviewer (Chin et al., Chin.J. Org.Chem.42, 2504-2514 (