Introduction

For many years, enantiomers have been separated using chiral resolution. This involves separating the two enantiomers by converting the racemic mixture into a pair of diastereoisomers with the help of a chiral compound. The resulting diastereoisomers can be separated based on their physical properties using crystallization, distillation, or chromatography . Sometime later, kinetic resolution (KR) emerged. This method is based on the different reaction rates of each enantiomer in a racemic mixture when they are reacted with a reagent, a chiral catalyst, or an enzyme. This process results in obtaining the less reactive enantioenriched enantiomer in the reaction mixture and is the most practical method applied in the pharmaceutical industry . However, research in this field has developed new resolution methods known as deracemization and dynamic kinetic resolution (DKR) . Currently, organocatalysis has enabled more efficient processes with low catalyst loading. It involves the kinetic resolution of alcohols, amines, and esters using chiral phosphoric acids and sulfoximines with enals using chiral N-heterocyclic carbene (NHC) catalysts . Additionally, these processes have been conducted using organometallic catalysis , enzymatic catalysis , aminocatalysis , and hydrogen-bonding catalysis .

The Michael addition reaction is a versatile synthetic methodology that allows the formation of new carbon–carbon and carbon–heteroatom bonds through the coupling of electron-poor olefins with a wide range of nucleophiles, with many organocatalyzed asymmetric examples highlighted in the literature . We have observed that the enantioenriched 1,5-dicarbonyl Michael adducts, synthesized via organocatalyzed reaction of cinnamaldehyde with benzyl phenyl ketone, undergo racemization when treated with inorganic bases , which had led us to check the equilibrium between Michael and the retro-Michael reaction (Scheme 1). These observations have prompted us to conduct further research into this reaction for potential applications in the kinetic resolution of these adducts.

Scheme 1: Previous work.

In the literature, we found that 1,5-diketones and 1,5-ketoaldehydes have been utilized in retro-Michael reactions catalyzed by NaOH or KOH at extremely high reaction temperatures . Some examples are also described under milder conditions, where the starting compounds are obtained with good chemical yields . These reactions have been utilized in the enantioselective synthesis of aryl sulfoxides through the arylation of sulfonate anions in the presence of palladium catalysts . They have also been used in the synthesis of the neuraminidase inhibitor (−)-oseltamivir and the organocatalytic synthesis of 2-cyclohexen-1-ones via a Michael/Michael/retro-Michael cascade reaction .

Our research has shown that the Jørgensen–Hayashi catalyst is a highly promising organocatalyst, facilitating enantioselective Michael addition reactions with high yields and excellent levels of enantiocontrol . In our studies on the organocatalytic enantioselective synthesis of 1,5-ketoaldehydes , we found that the prolinol derivative A is an outstanding catalyst for the enantioselective preparation of these adducts (Scheme 2). We are currently investigating whether this catalyst or the bistrifluoromethyl-substituted analog B could enable the retro-Michael reaction of only one enantiomer of the racemic mixture, potentially leading to a kinetic resolution of the 1,5-dicarbonyl compounds (Scheme 2).

Scheme 2: Hypothesis, retro-Michael reaction, and its application in kinetic resolution.

Results and Discussion

An initial attempt was made to determine if the retro-Michael (ReM) reaction occurs, its enantio- and diastereoselectivity, and the influence of different experimental parameters on its scope and stereoselectivity. The reaction was studied on a 1:2 mixture of the racemic diastereoisomers syn-1 and anti-1 (prepared according to our previous protocol) using 20 mol % of catalyst A and 20 mol % of p-nitrobenzoic acid (PNBA) as co-catalyst in different solvents at room temperature. The results obtained are summarized in Scheme 3 and Table 1.

Scheme 3: Model reaction.

Table 1: Solvent screening for the kinetic resolution of rac-1.

Entry Solvent Time (h) era ReM (%)b 1 CH2Cl2 3 28:72   2 CH2Cl2 5 22:78   3 CH2Cl2 24 40:60 36 4 CHCl3 3 37:63   5 CHCl3 5 35:65   6 CHCl3 24 29:71   7 CHCl3 72 35:65 33 8 Et2O 3 38:62   9 Et2O 5 34:66   10 Et2O 24 38:62 40 11 iPrOH 24 37:63   12 iPrOH 72 44:56 25 13 MeOH 3 36:64   14 MeOH 5 35:65 15 15 EtOH 24 38:62   16 EtOH 72 33:67 15 17 TBME 24 33:67   18 TBME 72 32:68 37 19 H2O 100 51:49 1 20 hexane 72 31:69 30 21 toluene 3 22:78   22 toluene 5 19:81   23 toluene 24 28:72 45

aer of the anti-diastereoisomer determined by chiral HPLC analysis. bReM (% of retro-Michael reaction) determined by 1H NMR.

The progress of the reaction was monitored using thin-layer chromatography (TLC) and 1H NMR analysis of the reaction mixture. The percentage of the retro-Michael reaction was calculated by comparing the signal of the starting 1,5-dicarbonyl adduct (rac-1) with the enal (cinnamaldehyde) product of the retro-Michael reaction. To determine whether the reaction favors one stereoisomer over the other and to assess its enantioselectivity, aliquots of the reaction mixture were taken at defined time intervals and analyzed by HPLC using a chiral column after passing them through a short silica gel pad.

Some interesting conclusions can be made from the data in Table 1. Firstly, the retro-Michael reaction occurs, to a greater or lesser extent, in all the solvents tested except in water (Table 1, entry 19), where the mixture remains unchanged after 100 hours. The enantiomeric ratio of the diastereomer anti-1 depends on the solvent used, with toluene (Table 1, entry 22) providing the best results. Finally, enantioselectivity increased until a specific time, and after that, the enantiomeric ratio decreased (compare entries 1–3 and 21–23 in Table 1).

The interesting result is that the major enantiomer in the enantioenriched mixture is now the opposite of the one obtained when the ketone and the α,β-unsaturated aldehyde are reacted in the presence of the catalyst A . This can be explained by considering the principle of microscopic reversibility. In the reversible process, the catalyst forms the same enamine intermediate preferentially formed in the Michael reaction. This means that the adduct anti-(3R,4S)-1 reacts more quickly than the anti-(3S,4R)-1, forming the enamine E (Scheme 4) that participates in the retro-Michael reaction, producing the starting ketone and the enal and enantio-enriching the reaction mixture in anti-(3S,4R)-1.

Scheme 4: Kinetic resolution of the Michael adduct 1.

Subsequently, toluene was chosen as the solvent due to its ability to provide the highest enantiomeric ratio. The influence of catalyst, co-catalyst, and temperature on the reaction progress and enantioselectivity was further investigated. Different essays using 0.028 M toluene solutions were carried out, and the results are summarized in Table 2. The reaction also occurs without a co-catalyst but is slower, resulting in a lower enantiomeric ratio than in an acidic medium.

Table 2: Screening of catalyst and co-catalyst for kinetic resolution.

Entry Catalyst (mol %) Additive (mol %) Temp. Time (h) ReM (%)a erb 1 A (20) – rt 5 28 31:69 2 A (20) PNBA (20) rt 5 33 19:81 3 A (20) PNBA (20) rt 24 43 28:72 4 A (20) BA (20) rt 4 25 25:75 5 A (20) BA (20) rt 24 37 49:51 6 B (20) PNBA (20) rt 4 27 32:68 7 B (20) PNBA (20) rt 24 35 24:76 8 B (20) BA (20) rt 24 40 47:53 9 A (20) K2CO3 (20) rt 22 12 46:54 10 A (60) PNBA (60) rt 15 27 27:73 11 A (20) PNBA (100) rt 15 20 25:75 12 A (5) PNBA (20) rt 6 30 30:70 13 A (5) PNBA (20) rt 24 34 25:75 14 A (20) PNBA (20) −18 °C 100 0 50:50 15 A (20) PNBA (20) 0 °C 6 25 35:65 16 A (20) PNBA (20) 0 °C 24 27 33:67 17 A (20) PNBA (20) 31 °C 0,16 14 43:57 18 A (20) PNBA (20) 31 °C 0,33 38 31:69 19 A (20) PNBA (20) 31 °C 0,66 44 28:72 20 A (20) PNBA (20) 31 °C 3 30 35:65

aDetermined by 1H NMR. bDetermined by chiral HPLC analysis.

The obtained results show that the diphenylprolinol derivative A provides a better enantiomeric ratio than that achieved with the α,α-bis[3,5-bis(trifluoromethyl)phenyl]prolinol derivative B (compare entry 2 versus entry 6 in Table 2). Furthermore, we studied the effect of using an organic acid as the co-catalyst for forming the enamine intermediate from 1 and for the retro-Michael reaction. We observed that benzoic acid (BA) as a co-catalyst provides a lower er than that achieved with PNBA as a co-catalyst (compare entries 2 and 3 with 4 and 5, or 7 with 8 in Table 2). In contrast, using a base as an additive slows the retro-Michel reaction and makes the reaction product a nearly racemic mixture (Table 2, entry 9).

Searching for the best reaction conditions, we varied the amounts of catalyst and additive (entries 10–13, Table 2), but none of the tests performed led to an improvement in enantioselectivity. We also studied the influence of the reaction temperature by performing two tests at 0 °C (entries 15 and 16, Table 2). We observed that the reaction occurs more slowly, and the enantiomeric excess reached is lower than at room temperature. Additionally, when the reaction mixture was stirred at −18 °C, no change was observed after 100 hours (entry 14, Table 2). These results led us to raise the reaction temperature to 31 °C (entries 17–20, Table 2). We observed that the retro-Michael reaction occurs more rapidly than at 20 °C (entry 2, Table 2). However, the enantiomeric ratio decreases as the reaction time increases.

Based on these results, we considered conducting tests to monitor how the percentage of ReM and enantiomeric ratio change over time (Table 3). With this aim, a 0.028 M mixture of racemic diastereomers 1 in toluene containing 20 mol % of catalyst A and 20 mol % of PNBA was stirred at room temperature. The data showed the highest enantiomeric ratio after four hours of reaction (entry 2, Table 3). However, it was also observed that when the retro-Michael process reached 50% extension, the enantiomer ratio decreased to approximately 1:2 (entry 4, Table 3). Furthermore, after 170 hours of reaction, the mixture became racemic, and the percentage of the retro-Michael process increased to 60% (entry 5, Table 3).

Table 3: Monitoring the kinetic resolution of 1 over time.

Entry Time (h) era ReM (%)b 1 0 50:50 0 2 4 16:84 31 3 24 28:72 43 4 47 36:64 50 5 170 49:51 60

aDetermined by chiral HPLC analysis. bDetermined by 1H NMR.

These results can be explained by proposing that the catalyst initially promotes deracemization by rapidly reacting with the enantiomer (3R,4S) of the diastereomer anti-1. Over time, the initial equilibrium is established either because the catalyst begins to react with the syn-diastereomer or because, once the retro-Michael reaction has occurred, the catalyst promotes the Michael reaction, leading to the formation of the enantiomer (3R,4S) and consequently returning to the racemate.

Then, we decided to investigate how concentration affects the rate and selectivity of the reaction at room temperature (Table 4). The retro-Michael reaction mainly occurs at a concentration of 0.17 M, producing a nearly racemic mixture of anti-1 (entries 1 and 2, Table 4). Lowering the concentration to 0.10 M slows the reaction and improves the enantiomeric ratio (entries 3 and 4, Table 4), but a nearly racemic mixture is obtained again with longer reaction times (entry 5, Table 4). However, reducing the concentration to 0.014 M increases the enantioselectivity (entries 6 and 7, Table 4), and an excellent enantiomeric ratio was maintained over time (entries 8 and 9, Table 4). These results suggest that at very dilute concentrations, the decomposition of the enantiomer (3R,4S)-1 is favored, preserving the (3S,4R)-1 untransformed and avoiding the equilibrium reversal towards the formation of the Michael adduct, thereby preserving the enantiomeric purity of the isolated product.

Table 4: Study of the concentration's effect on kinetic resolution.

Entry [M] Time (h) ReM (%)a erb 1 0.17 14 40 45:55 2 0.17 38 55 46:54 3 0.10 28 30 40:60 4 0.10 46 45 38:62 5 0.10 117 58 48:52 6 0.014 9 32 16:84 7 0.014 32 35 14:86