Chiral Aziridine Phosphines as Highly Effective Promoters of Asymmetric Rauhut–Currier Reaction

: A series of chiral enantiomerically pure aziridines containing a phosphine moiety were synthesized and successfully applied as organocatalysts in asymmetric intramolecular Rauhut– Currier reactions of p -quinone derivatives. The desired chiral phenols were achieved in high chemical yields and with satisfactory values of enantiomeric excess (up to 98% ee , in some cases). The stereochemical course of the title reaction may be controlled by the use of an appropriate enantiomer of the catalyst. The individual enantiomers of the organocatalyst led to the formation of speciﬁc enantiomers of the chiral product.

Taking into account all the aforementioned information and based on the experience of our group in working with chiral aziridine catalysts [36][37][38][39], we decided to continue our research on the use of organophosphorus derivatives of chiral aziridines in asymmetric synthesis [40][41][42][43][44]. Thus, in order to test the possibility of extending the applicability of our chiral aziridine phosphines, we decided to study their catalytic activity in an asymmetric intramolecular Rauhut-Currier reaction.
our chiral aziridine phosphines, we decided to study their catalytic activity in an asymmetric intramolecular Rauhut-Currier reaction.
Symmetry 2022, 14, x FOR PEER REVIEW 2 of 8 our chiral aziridine phosphines, we decided to study their catalytic activity in an asymmetric intramolecular Rauhut-Currier reaction.

Asymmetric Intramolecular Rauhut-Currier Reaction in the Presence of Aziridines 1-8
Having the enantiomerically pure aziridine-phosphines 1-8 in hand, we decided to check their catalytic activity in the asymmetric intramolecular Rauhut-Currier reaction of p-quinone derivative 9 obtained from salicylaldehyde.(Z)-2-((tert-Butyl)-5-isopropyl-4oxocyclohexa-2,5-dien-1-ylidene)methyl)phenyl acrylate 9 was stirred in dichloromethane at room temperature in the presence of 10 mol% of chiral catalysts 1-8 over 48 h (Scheme 1) [26].All the results of the above asymmetric transformations comprising chemical yields, enantiomeric excess (ee), and absolute configurations of chiral products 10 are collected in Table 1.All the results of the above asymmetric transformations comprising chemical yields, enantiomeric excess (ee), and absolute configurations of chiral products 10 are collected in Table 1.
Symmetry 2022, 14, 1631 3 of 8 Inspection of the data collected in Table 1 reveals some findings.As anticipated, based on our previous studies [40][41][42][43][44], organocatalysts 1-4 bearing a methylene group connecting a phenyl ring of phosphine with a three-membered system of aziridine showed rather moderate activity in the title reaction, affording product 10 in moderate-to-high (51-81%) chemical yields, and with low-to-moderate enantiomeric excess values (30-66% of ee) (Table 1, entries 1-4).In turn, the application of the catalyst 5 and catalyst 6 (without the above methylene linker and with an isopropyl chain in an aziridine subunit) gave much better results in terms of yield and, especially, enantiomeric excess (Table 1, entries 5-6).Their analogs 7 and 8 with isobutyl and phenyl substituents were also more active in comparison with the methylene-linked systems of 1-4, but in these cases, the differences were not so pronounced (Table 1, entries 7-8).Moreover, the application of the enantiomeric forms of catalysts 1-2 (Table 1, entries 1-2) and 5-6 (Table 1, entries 5-6) resulted in the creation of the opposite enantiomers of product 10, which is in line with our previous findings [40][41][42][43][44].In these cases, the differences in the enantiomeric excesses of products having the opposite absolute configurations seem somewhat surprising (52%, 66%, and 91%, and 99% of ee, respectively).Such discrepancies may sometimes result from the different chemical and optical purities of both enantiomeric catalysts.Finally, we also tried to lower the catalyst loading to 5 mol%; however, this resulted in a reduction in both the chemical yield and the enantiomeric excess.

Organocatalytic Asymmetric Rauhut-Currier Reaction in the Presence of the Phosphine 6-Scope of the Substrates
The aziridine phosphine 6 showed the best catalytic activity in the asymmetric intramolecular Rauhut-Currier reaction of substrate 9. Hence, we decided to extend the scope of its applicability in the further asymmetric Rauhut-Currier intramolecular cyclization reactions using the other or more p-quinone derivatives 11-15 bearing various substituents in an aromatic ring (Scheme 2).All the results are summarized in Table 2. Inspection of the data collected in Table 1 reveals some findings.As anticipated, based on our previous studies [40][41][42][43][44], organocatalysts 1-4 bearing a methylene group connecting a phenyl ring of phosphine with a three-membered system of aziridine showed rather moderate activity in the title reaction, affording product 10 in moderateto-high (51-81%) chemical yields, and with low-to-moderate enantiomeric excess values (30-66% of ee) (Table 1, entries 1-4).In turn, the application of the catalyst 5 and catalyst 6 (without the above methylene linker and with an isopropyl chain in an aziridine subunit) gave much better results in terms of yield and, especially, enantiomeric excess (Table 1, entries 5-6).Their analogs 7 and 8 with isobutyl and phenyl substituents were also more active in comparison with the methylene-linked systems of 1-4, but in these cases, the differences were not so pronounced (Table 1, entries 7-8).Moreover, the application of the enantiomeric forms of catalysts 1-2 (Table 1, entries 1-2) and 5-6 (Table 1, entries 5-6) resulted in the creation of the opposite enantiomers of product 10, which is in line with our previous findings [40][41][42][43][44].In these cases, the differences in the enantiomeric excesses of products having the opposite absolute configurations seem somewhat surprising (52%, 66%, and 91%, and 99% of ee, respectively).Such discrepancies may sometimes result from the different chemical and optical purities of both enantiomeric catalysts.Finally, we also tried to lower the catalyst loading to 5 mol%; however, this resulted in a reduction in both the chemical yield and the enantiomeric excess.

Organocatalytic Asymmetric Rauhut-Currier Reaction in the Presence of the Phosphine 6-Scope of the Substrates
The aziridine phosphine 6 showed the best catalytic activity in the asymmetric intramolecular Rauhut-Currier reaction of substrate 9. Hence, we decided to extend the scope of its applicability in the further asymmetric Rauhut-Currier intramolecular cyclization reactions using the other or more p-quinone derivatives 11-15 bearing various substituents in an aromatic ring (Scheme 2).All the results are summarized in Table 2.  Careful analysis of the results collected in Table 2 reveals that (S)-configured chiral aziridine-phosphine 6 constitutes an efficient catalyst which is prone to successfully catalyzing the asymmetric organocatalytic intramolecular Rauhut-Currier reactions of variously substituted p-quinone derivatives.Much to our disappointment, the RC reaction employing 7-NEt 2 -substituted derivative 15 completely failed (Table 2, entry 5).Attempts to repeat it with higher catalyst loading and at elevated temperatures also resulted in isolation of the starting material.Moreover, TLC analysis of reaction mixture and 1 H NMR of the recovered starting material 15 revealed its partial decomposition.
Finally, in order to prove the importance of the phosphine moiety for the course of the title reaction, a model intramolecular Rauhut-Currier reaction of derivative 9 was performed in the presence of aziridine-phosphine oxide 21 (Scheme 3).As anticipated, based on our previous studies on the asymmetric Morita-Baylis-Hillman reaction [44], not even traces of the product 10 formation were observed.This phenomenon confirms the decisive importance of the phosphine moiety for the course of the asymmetric Rauhut-Currier reaction (i.e., the vinyl Morita-Baylis-Hillman reaction), and it also indicates the validity of the previously proposed transition state model [44].Careful analysis of the results collected in Table 2 reveals that (S)-configured chiral aziridine-phosphine 6 constitutes an efficient catalyst which is prone to successfully catalyzing the asymmetric organocatalytic intramolecular Rauhut-Currier reactions of variously substituted p-quinone derivatives.Much to our disappointment, the RC reaction employing 7-NEt2-substituted derivative 15 completely failed (Table 2, entry 5).Attempts to repeat it with higher catalyst loading and at elevated temperatures also resulted in isolation of the starting material.Moreover, TLC analysis of reaction mixture and 1 H NMR of the recovered starting material 15 revealed its partial decomposition.
Finally, in order to prove the importance of the phosphine moiety for the course of the title reaction, a model intramolecular Rauhut-Currier reaction of derivative 9 was performed in the presence of aziridine-phosphine oxide 21 (Scheme 3).As anticipated, based on our previous studies on the asymmetric Morita-Baylis-Hillman reaction [44], not even traces of the product 10 formation were observed.This phenomenon confirms the decisive importance of the phosphine moiety for the course of the asymmetric Rauhut-Currier reaction (i.e., the vinyl Morita-Baylis-Hillman reaction), and it also indicates the validity of the previously proposed transition state model [44].

Materials
Dichloromethane (DCM) (anhydrous, 99.8%) was purchased from Merck (Merck KgaA, Darmstadt, Germany) and used without purification.Ethyl acetate and n-hexane were distilled before use.NMR spectra were recorded on a Bruker (Bruker, Billerica, MA, USA) apparatus at 600 and 150 MHz with the use of CDCl3 as a solvent and TMS as an internal standard.The data are reported as s = singlet, d = doublet, t = triplet, dd = doublet of doublets, dt = doublet of triplets, and m = multiplet.Optical rotations were measured Scheme 3. Attempt at the asymmetric Rauhut-Currier reaction in the presence of phosphine oxide 21.

Materials
Dichloromethane (DCM) (anhydrous, 99.8%) was purchased from Merck (Merck KgaA, Darmstadt, Germany) and used without purification.Ethyl acetate and n-hexane were distilled before use.NMR spectra were recorded on a Bruker (Bruker, Billerica, MA, USA) apparatus at 600 and 150 MHz with the use of CDCl 3 as a solvent and TMS as an internal standard.The data are reported as s = singlet, d = doublet, t = triplet, dd = doublet of doublets, dt = doublet of triplets, and m = multiplet.Optical rotations were measured on an Anton Paar MCP500 polarimeter with a sodium lamp at room temperature.Thin layer chromatography (TLC) was carried out using Merck 60 F 254 silica gel plates (Merck KgaA, Darmstadt, Germany).Column chromatography was performed on Merck

Scheme 3 .
Scheme 3. Attempt at the asymmetric Rauhut-Currier reaction in the presence of phosphine oxide 21.