Organocatalytic diastereo- and atroposelective construction of N–N axially chiral pyrroles and indoles

The construction of N–N axially chiral motifs is an important research topic, owing to their wide occurrence in natural products, pharmaceuticals and chiral ligands. One efficient method is the atroposelective dihydropyrimidin-4-one formation. We present herein a direct catalytic synthesis of N–N atropisomers with simultaneous creation of contiguous axial and central chirality by oxidative NHC (N-heterocyclic carbenes) catalyzed (3 + 3) cycloaddition. Using our method, we are able to synthesize structurally diverse N–N axially chiral pyrroles and indoles with vicinal central chirality or bearing a 2,3-dihydropyrimidin-4-one moiety in moderate to good yields and excellent enantioselectivities. Further synthetic transformations of the obtained axially chiral pyrroles and indoles derivative products are demonstrated. The reaction mechanism and the origin of enantioselectivity are understood through DFT calculations.

The manuscript by Lu and co-workers reports an oxidative NHC-catalyzed atroposelective synthesis of N-N axially chiral compounds from (iso)thioureas and enals.The yields and the enantioselectivities of reactions are generally good, but the diastereoselectivities are mostly modest.Although the method is somewhat interesting, this work is not suitable for Nat.Commun.due to the reasons elaborated below.
With regard to the novelty of this work: (a) N-N axially chiral chemistry: the organo-catalyzed atroposelective formation of the N-N bond with pyrrole/indole scaffold has been reported by many research groups (refs 9-18).I do not think that the authors make any conceptual contributions in this submission.(b) NHC chemistry: NHC-catalyzed selective addition of isothioureas to enals to access 5,6-dihyropyrimidin-4-ones has been reported by the Chi group, however that pioneering work is not cited in this manuscript (Org.Chem.Front., 2021, 8, 743).NHC-catalyzed atroposelective cycloaddition reaction between thioureas and ynals has also been developed by the Jin group, however this work is not appropriately cited as reference 49.Very recently, the first NHC-catalyzed atroposelective synthesis of N-N axially chiral compounds has been reported by Biju group, which is not cited herein (ChemRxiv, 2023, 10.26434/chemrxiv-2023-7zxsn).Compared with the abovementioned literature examples, the work herein can be considered as the following-up studies.In short, the closely related works need to be cited appropriately, in a right context -the authors obviously did not do that.Some minor points: the scope of the reaction is rather narrow, and the usefulness of the product/method was not sufficiently demonstrated.
Reviewer #2 (Remarks to the Author): In this manuscript, Lu and coworkers reported a direct synthesis of N-N atropisomers with simultaneous creation of contiguous axial and central chirality by oxidative NHC catalyzed [3 + 3] cyclization of isothioureas with enals, the strategy also enabled facile access to N-N axially chiral indoles from thioureas with ynals.Structurally diverse N-N axially chiral pyrroles and indoles with vicinal central chirality were obtained in moderate to good diastereoselectivities and excellent enantioselectivities.Although this reaction strategy has been used in the C-N axis chiral construction, the reaction synthesizes a series of novel N-N axis chiral molecules with a novel skeleton through this strategy, which is of great significance.Overall, the manuscript can be accepted for publication in Nature Comm.after the following issues are addressed.1)On line 55 of the second page, the authors indicated that they could synthesize the N-N axis chirality of the indole through 3+3 reaction, but this part was all about the synthetic pyrrole axis chirality, and the authors needed to investigate the applicability of the indole substrate.
2)The product 7d should have two axial chirality, C-N and N-N.The authors need to explain here, give diastereoselectivity results, and explain the reduced enantioselectivity of the reaction.
3)The definition of the pictures in the single crystal part and the calculation part of the paper is too low, so the author needs to change to the pictures with high definition.
4)In the supporting information section, the compound structure formula format is not uniform, and the carbon spectrum of the product should retain one decimal number.1, the authors should give the diastereoselectivity under different conditions, does the diastereoselectivity of the reaction change by changing the base or the solvent.6)In this paper, many forms are not uniform, including Spaces before and after brackets, which the author needs to modify carefully.Also in fig 5, scheme 6 should be changed to figure 6. 8, the reactant of eq.3, alkyne is omitted.8)In the gram preparation experiment, can the amount of catalyst for the reaction be reduced?Reviewer #3 (Remarks to the Author):

7)In Table
This manuscript by Lu, Wong and coworkers reported atroposelective synthesis of N-N axially chiral indoles and pyrroles via NHC-catalyzed asymmetric formal (3+3) cycloadditions of indole or pyrrolebased platform molecules with enals or ynals.More importantly, N-N axially chiral indoles bearing both axial and central chirality were synthesized in high diastereoselectivity with simultaneously controlling the multiple chiral elements.This approach has a wide substrate scope, and this class of axially chiral compounds has high rotational barrier and configurational stability.Moreover, the authors performed DFT calculations to reveal the origins of the diastereoselectivity and the role of the substituents on the N-phenyl ring of the triazolium catalyst.This work has some important features: (1) This work has realized the first catalytic asymmetric N-N axially chiral indoles bearing both axial and central chirality.In recent years, the construction of N-N axially chiral skeletons and the construction of axially chiral indole-based frameworks have become emerging research areas with great significance.Particularly, simultaneously controlling the multiple chiral elements (axial chirality and central chirality) in a high diastereo-and enantioselective manner is very challenging.This work has solved this great challenge and accomplished high diastereo-and enantioselective synthesis of N-N axially chiral indoles bearing both axial and central chirality, which is a breakthrough in the related fields.
(2) This work has provided a powerful strategy for constructing N-N axially chiral indole and pyrrolebased scaffolds.The authors designed and synthesized indole and pyrrole-based isothioureas and thioureas as competent platform molecules, which can readily undergo formal (3+3) cycloadditions under NHC catalysis.In fact, this class of isothioureas and thioureas platform molecules are promising for undergoing other useful transformations, which will open an avenue for constructing different types of N-N axially chiral indole and pyrrole-based scaffolds.
(3) This work has offered an in-depth understanding of the origins of the diastereoselectivity and the role of the NHC catalyst.By theoretical investigations, the authors have disclosed the reason for the observed high diastereoselectivity and the activation mode of chiral NHC catalyst to the substrates, which will enlighten the design of the strategy for controlling the multiple chiral elements in the related transformations.
Therefore, this work has high originality, novelty and significance, which will absorb intense and wide interests of scientists from heterogenous research areas such as synthetic chemistry, asymmetric catalysis, medicinal chemistry and materials science.For the above features and reasons, this work is strongly recommended for publication in Nature Communications after addressing some minor issues as follows.
(1) In the title and other places, it is suggested to change "cyclization" into "(3+3) cycloaddition" because "cyclization" commonly denotes an intramolecular reaction.In addition, it is suggested that the authors briefly mention that organocatalytic asymmetric (3+3) cycloaddition is a powerful method for constructing six-membered rings, which might trigger them to design this powerful strategy.
(2) In the introduction, it is suggested that the authors mention that the construction of axially chiral indole-based frameworks has become an important research area with the citation of a recent review (Acc.Chem.Res.2022, 55, 2562).In addition, they should also mention that simultaneously controlling the multiple chiral elements (axial chirality and central chirality) in a high diastereo-and enantioselective manner is very challenging with the citation of a recent review (Acc.Chem.Res.2022, 55, 2545) and recent publications (For example: Fundamental Research, 2023, 3, 237; J. Org.Chem.2023, DOI: 10.1021/acs.joc.2c02303).
(4) The supplementary materials are in high quality.But there are some minor issues to be corrected.
In page S5, the scheme should be drawn in the format of ACS 1996.
In page S6, the range of melting point for compound 1n is too large, which should be re-checked.
In page S16, in the general procedure, the authors mention the use of glovebox.Is it necessary to use glovebox for this organocatalytic reaction?Have the authors tried the reaction without the use of glovebox?In addition, they mentioned "The vial was then sealed and the reaction mixture was allowed to stir at 30 oC for overnight."But it is not clear whether this step should also be performed in glovebox.Please clarify this issue.
In section "7.Characterizations of N-N axially chiral pyrroles and indoles", the absolute configuration of axial chirality should be described as "Ra" or "Sa" (a should be subscript).
Reviewer #4 (Remarks to the Author): In this work, the authors report a direct catalytic synthesis of N-N atropisomers with simultaneous creation of contiguous axial and central chirality by oxidative NHC catalyzed [3 + 3] cyclization.Overall, I found this research interesting and well-written.I support its publication in Nature Communications if the following minor issues are properly addressed.
1.I recommend carrying out DFT calculations to understand the origins of enantioselectivity and provide a chiral induction model.This would add more value to the study and enhance its relevance to the field.
2. NLE experiments would be helpful to confirm the proposed mechanistic model.
3. I am concerned that no sufficient information on the computational details is provided in the manuscript or SI.It is essential to ensure that the calculations are reliable, especially regarding the conformational search.Therefore, I urge the authors to provide the detailed information on this aspect, including the structures and energies of all the calculated conformers.