Brønsted acid-catalysed enantioselective construction of axially chiral arylquinazolinones

The axially chiral arylquinazolinone acts as a privileged structural scaffold, which is present in a large number of natural products and biologically active compounds as well as in chiral ligands. However, a direct catalytic enantioselective approach to access optically pure arylquinazolinones has been underexplored. Here we show a general and efficient approach to access enantiomerically pure arylquinazolinones in one-pot fashion catalysed by chiral phosphoric acids. A variety of axially chiral arylquinazolinones were obtained in high yields with good to excellent enantioselectivities under mild condition. Furthermore, we disclosed a method for atroposelective synthesis of alkyl-substituted arylquinazolinones involving Brønsted acid-catalysed carbon–carbon bond cleavage strategy. Finally, the asymmetric total synthesis of eupolyphagin bearing a cyclic arylquinazolinone skeleton was accomplished with an overall yield of 32% in six steps by utilizing the aforementioned methodology.

The axially chiral arylquinazolinones are valuable structural units in pharmaceutical agents, and could be used as chiral ligand for asymmetric catalysis. Chiral phosphoric acids have been extensively used in enantioselective catalysis. The manuscript describes the chiral phosphoric acids-catalyzed methodology for novel axially chiral arylquinazolinones with high enantiopurity and structural diversity. Furthermore, a new method involving phosphoric acidcatalysed carbon-carbon bond cleavage for atroposelective construction of alkyl substituted arylquinazolinones was also disclosed. A large-scale experiment documents the applicability of this reaction and a reasonable transition state model is put forth as well by control experiments. The nice work seems to have been well conducted with sufficient details, and can be of utility to researchers interested in the organic chemistry and medicinal chemistry. Thus I recommend the publication of this manuscript in this journal after following modification is made: Many products were obtained only < 90%ee using this method. Can enantiopurity of all these procucts be enriched to >95% ee by using recrystallization?

Reviewer #3 (Remarks to the Author):
The authors report a remarkable approach to enantiopure, axially chiral arylquinazolinones that involves reacting an aldehyde with an amido aniline in the presence of an oxidant. The reaction is catalyzed by a chiral phosphoric acid and gives the corresponding products in high enantioselectivity. Mechanistic studies reveal that the reaction proceeds via diasteroselective and enantioselective aminal formation followed by oxidation to give the axially chiral product. A very elegant application of the method in the synthesis of Eupolyphagin is also described. The language needs some improvement.

Our responses to the Reviewers Reviewer #1 (Remarks to the Author):
Tan and co-workers describe in this manuscript enantioselective synthesis of axially chiral arylquinazoines by means of chiral phosphoric acid. Recently, enantioselective synthesis of axially chiral compounds has attracted much attention of synthetic organic chemists. Based on the control experiments, the authors confirmed that the enantioselectivity was determined by the step of intramolecular amidation of imines. This is a nice piece of work and this reviewer recommends publication of this manuscript in Nature Communications in the present form.
Our response: We deeply appreciate these encouraging comments of the referee and sincerely thank the referee for strong support for publication in Nature Comunications.

Reviewer #2 (Remarks to the Author):
The axially chiral arylquinazolinones are valuable structural units in pharmaceutical agents, and could be used as chiral ligand for asymmetric catalysis. Chiral phosphoric acids have been extensively used in enantioselective catalysis. The manuscript describes the chiral phosphoric acids-catalyzed methodology for novel axially chiral arylquinazolinones with high enantiopurity and structural diversity. Furthermore, a new method involving phosphoric acid-catalysed carbon-carbon bond cleavage for atroposelective construction of alkyl substituted arylquinazolinones was also disclosed. A large-scale experiment documents the applicability of this reaction and a reasonable transition state model is put forth as well by control experiments. The nice work seems to have been well conducted with sufficient details, and can be of utility to researchers interested in the organic chemistry and medicinal chemistry. Thus I recommend the publication of this manuscript in this journal after following modification is made: Many products were obtained only < 90%ee using this method. Can enantiopurity of all these procucts be enriched to >95% ee by using recrystallization?
Our response: We very much appreciate these supportive comments of the referee and sincerely thank the referee for bring the issue to our attention. The products as solid showed in the following table were obtained < 90% ee. We conducted several experiments to enrich their ees by using recrystallization except 3f, 4j, 4k and 6e which were obtained as oil. The solid was dissolved in refluxing solvent and then the solution was cooled down to room temperature slowly. Until no more solid precipitated, the mixture was filtered and the ees of the filtrate and filter cake (solid) were determined by using chiral HPLC. The filter cake afforded 3u, 6b and 6c with moderate to good yield and excellent ee (>95%). However, in the case of 3h, 6a and 6d, the products with satisfactory ee (>95) and good yield were existing in the filtrate. Only oil formed when the solution of 4i in PE or n-Hexane was cooled down and the ees of the precipitated oil has no difference with that of the filtrate. Similarly, our attempt to enrich the ee of 3p through recrystallization in several solvent systems was failed. The related results have been added to the revised Supplementary Information.

Reviewer #3 (Remarks to the Author):
The authors report a remarkable approach to enantiopure, axially chiral arylquinazolinones that involves reacting an aldehyde with an amido aniline in the presence of an oxidant. The reaction is catalyzed by a chiral phosphoric acid and gives the corresponding products in high enantioselectivity. Mechanistic studies reveal that the reaction proceeds via diasteroselective and enantioselective aminal formation followed by oxidation to give the axially chiral product. A very elegant application of the method in the synthesis of Eupolyphagin is also described. The language needs some improvement.
Our response: We very much appreciate these comments of the referee and sincerely thank the referee for recommending for publication in Nature Comunications. According to the referee's valuable suggestion, we have carefully modified the manuscripts and asked one of my colleagues to polish English.