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Article

Asymmetric Phase Transfer Catalysed Michael Addition of γ-Butenolide and N-Boc-Pyrrolidone to 4-Nitro-5-styrylisoxazoles

by
Diana Salazar Illera
,
Roberta Pacifico
and
Mauro F. A. Adamo
*
Centre for Synthesis and Chemical Biology, Department of Chemistry, The Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, D02 YN77 Dublin, Ireland
*
Author to whom correspondence should be addressed.
Catalysts 2022, 12(6), 634; https://doi.org/10.3390/catal12060634
Submission received: 6 March 2022 / Revised: 29 May 2022 / Accepted: 8 June 2022 / Published: 10 June 2022
(This article belongs to the Special Issue Design and Applications of Phase Transfer Catalysis)
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Versions Notes

Abstract

:
Herein we report the addition of acidic γ-butenolide and N-Boc-pyrrolidone to 4-nitro-5-styrylisoxazoles, a popular class of cinnamic ester synthetic equivalent. The reactions proceeded under the catalysis of Cinchona-based phase-transfer catalysts. Functionalised γ-butenolides were obtained in good isolated yields and moderate enantioselectivity (up to 74% ee).

1. Introduction

Polyfunctionalised heterocycles play an important role in the identification of new leads in medicinal chemistry [1]. Amongst them, γ-butenolides [2] are present in a wide number of bioactive natural compounds, including pheromones [2,3], alkaloids [4], and vitamins [5]. Substituted γ-butenolides possess antioxidant [6], anti-inflammatory [7], cytotoxic [8], antitumoral [9], anti-HIV [10], and antibiotic properties [11]. MacMillan reported the first organocatalytic Mukaiyama–Michael enantioselective reaction of silyloxy furans with α,β-unsaturated aldehydes [12]. While this procedure ensured the correspondent product in high yields and enantioselectivity, reactions that use unprotected γ-butenolides [13] are nowadays considered superior, considering they are more atom economic and the contemporary focus on the E-factor of chemical processes. Direct conjugate addition of γ-butenolide to chalcones catalysed by a thiourea-bearing primary amine [14,15] and by vicinal primary-diamine salts were also reported [16,17]. Wang et al. have recently reported a highly diastereo- and enantioselective reaction of β,γ-butenolides to chalcones catalysed by Al(Oi-Pr)3/(R)-BINOL [18]. Terada reported a highly enantioselective direct vinylogous Michael addition of functionalised furanones to nitroalkenes using a chiral guanidine-based catalyst [19]. Mukherjee used a bifunctional thiourea Quinine-derived catalyst for the addition of β,γ-unsaturated butenolides to nitroolefins [20]. Jiang reported a highly enantio- and diastereoselective direct Michael reaction of γ-substituted butenolides with oxo-arylbutenamides bearing an oxazolidinone moiety [21]. Asymmetric direct Michael additions of α,β-unsaturated γ-butyrolactams to activated alkenes is a field of increasing interest due to the versatility of the γ-substituted butyrolactam products [22,23,24,25,26]. Wang reported a Michael addition of γ-butyrolactam to styrylisoxazoles catalysed by a Quinine-derived squaramide catalyst [27]. The chemistry of β,γ-unsaturated γ-butenolides, commonly known as deconjugated butenolides, has been recently reviewed [28].

2. Aim of the Study

Our group has developed 4-nitro-5-styrylisoxazoles 1 (Figure 1) as a novel class of cinnamate ester equivalent [29,30,31,32,33,34,35,36,37,38,39]. Notoriously, cinnamate esters are less reactive in Michael conjugate additions, compared to chalcones 2, for example. For this reason, a number of cinnamate ester equivalents 3–7 have been designed and their synthetic potential demonstrated [39,40,41,42,43]. Compounds 1 are stable solids and reacted in Michael reactions as an acceptor. A special feature of compounds 1 is the presence of two electrophilic centres that can be independently reacted [29,30], with the exocyclic “soft” one that found extensive application in 1,6-conjugate enantioselective additions, particularly under organocatalytic conditions [44,45,46,47,48,49,50,51,52,53]. Compounds 1 were also used in a large-scale industrial context, for example in the preparation of active pharmaceutical ingredients (APIs) (R)-Baclophen [54] and (S)-Pregabalin [55]. A key feature of 4-nitro-5-styrylisoxazoles in synthesis is their ability to undergo a base-promoted hydrolysis in which the 4-nitroisoxazole core becomes a carboxylate, which is known as the Sarti Fantoni reaction [56,57].
Considering the reactivity of γ-butenolides as Michael donors [9,10,11,12,13,14,15,16,17,24] and our ongoing interest in exploring the reactivity of compounds 1 [27,29] we became interested in studying the reactivity of 1 and γ-butenolides under phase-transfer catalysis (PTC). PTC holds several advantages versus other organocatalyses as it is scalable and the preparation of PTC catalysts is streamlined compared to other bifunctional entities. Herein, we report our results on the catalytic enantioselective vinylogous Michael addition of γ-lactones and γ-lactams to 3-methyl-4-nitro-5-styrylisoxazoles 1 which run under the catalysis of Cinchona-derived quaternary ammonium salts. This reaction provided the corresponding adducts, in good yield and moderate diastereo- and enantioselectivity.

3. Preliminary Results and Reaction Optimisation

In a test experiment, we have reacted compound 1 with an excess (5 equiv.) of γ-butanolide 8 under the catalysis of tetrabutylammonium bromide (Scheme 1). This experiment provided diastereoisomers 9a in 68% and 10a in 26% isolated yields, respectively (dr 2.6).
Compounds 9a and 10a were separated by column chromatography and fully characterised as syn-9a and anti-10 via NOESY and TOCSY NMR experiments: in particular, compound 9a displayed resonances compatible with the two C-H on the two chiral centres in a syn relationship; conversely, compound 10a showed signals typical for the opposite anti relative stereochemistry. With this result in hand, we conducted a screening of catalyst, solvent, base, and temperature, the results of which are reported below.
The reaction of 1 and 8 was initially studied under the catalysis of commercially available Cinchona-derived catalysts 11–14 (Table 1) and in the presence of different inorganic bases (Table 1); subsequently, the effect of dilution and temperatures (Table 2) was taken in consideration. The results identified Quinidinium salt 14 and solid potassium carbonate (Table 1, entry 21) as the best combination of catalyst/base, providing the highest isolated yields and the highest ee for the syn diastereoisomer 9a. Noteworthily, catalyst 11 provided compound 9a in the same 48% ee, but of the opposite enantiomer, which is expected given the pseudo-enantiomeric relationship between 11 and 14. The yield of 9a was, however, much inferior when 11 was employed (Table 1, entry 3). This suggested that the methoxy group in 11 and 14 must be close to the reaction site, which can be explained based on the mode of interaction of the nitro group of 1 and the Cinchona-based quaternary ammonium salts (vide infra) [47].
As it has been observed in a similar Michael addition of 1 that runs under phase-transfer catalysis using species 11–14, [45,46,54] the concentration of the reagents affected the reaction outcome, with experiments running at higher dilution providing an increased enantioselectivity. This has been previously explained considering that at higher dilution the background uncatalysed reaction of 1 and 8 was more efficiently suppressed. Similarly, an increase in the product ee was often observed upon decreasing the temperature of the reaction. For this reason, we have repeated the reaction of 1 and 8 under the catalysis of 14 (Table 2) at increasing dilutions and at different temperatures.
The screening of temperature and dilution (Table 2) showed that taking the concentration from 0.1 M to 0.02 M and keeping the temperature at 0 °C improved the ee of 9a which was obtained in 61% ee (Table 2, entry 3). Further dilution from 0.02 M to 0.03 M (Table 2, entries 3 and 5) did not affect the enantioselectivity. Temperatures lower than 0 °C were detrimental when the reaction (Table 2, entries 4 and 6) was run at the highest dilution.
We have selected for this study the temperature of −37 °C and 0 °C, as we have shown in related Michael initiated processes of 1 that Quininium salts performed best at 0 °C; meanwhile, Quinidinium salts performed best at −37 °C. This is probably a reflection of the intensity and directionality of the interactions exerted by Quininium and Quinidinium PTCs and reagent 1 [45,46,54].
With the most suitable set of conditions in hand, we prepared a small family of Quinidinium derivatives 14–20 (Table 3). Compounds 14–20 were selected as bearing different aryl substituents at the nitrogen, which included electron-withdrawing substituents (i.e., 15–18), bulky groups (i.e., 19), and an alkylated hydroxyl group at C9 (i.e., 20).
Catalysts 15 and 17 provided syn-9a in the highest ee (Table 3, entries 2 and 4); however, 15 provided faster reaction rates and higher yields of syn-9a. Therefore, the introduction of fluorine and related electron-withdrawing groups was proved to be beneficial. Introduction of bulky aryls at nitrogen provided syn-9a in a similar, yet inferior, enantioselectivity and yield (Table 3, entry 6). Importantly, the alkylation of the C9-OH led to the formation of syn-9a and anti-10a as racemates (Table 3, entry 7), indicating a bifunctional mode of catalysis for compounds 14–20 [47].
With a set of optimised reaction conditions in hand, we next explored the scope of reaction by reacting a small family of 4-nitro-5-styrylisoxazoles 1a–f (Table 4) with lactone 8.

4. Study of Scope of Reaction

Data collected showed that compounds 1 containing either electron-withdrawing groups (Table 4, entries 2, 3, and 6) or electron-donating groups (Table 4, entry 4) were equally good Michael acceptors, affording the corresponding products 9a–f in good isolated yields and ee up to 74% for syn-9c. The minor anti-10a–f diastereomers were obtained in modest yields and enantioselectivity; however, this result provided useful information for interpretation of the reaction mechanism. It was also noted that larger diastereomeric ratios were obtained for substrates 1d–f holding electron-donating groups (Table 4, entries 4 and 5).

5. Determination of Products’ Absolute Configuration

In order to establish the absolute configuration of compounds syn-9a and anti-10a and having proven the impossibility of obtaining crystals suitable for X-ray analysis, we have proceeded as follows: Firstly, we have reacted compound 1 and N-Boc-pyrrolidone 21 (Table 5) under the catalysis of quaternary ammonium salts 14 and 15. These reactions provided syn-22 and anti-22, the absolute configuration of which was established by Wang [27].
An analysis of the HPLC traces and measurement of the optical rotation, compared to those reported by Wang, [27] allowed us to conclude that under the catalysis of 14 and 15, syn-22 was obtained predominately as the (R)(S) enantiomer and anti-22 as the (R)(R) enantiomer (Table 5). Secondly, we have verified the sign of specific rotation of syn-9a, which was shown to be (+), as the one of syn-22. Finally, we compared the outcome of the addition of 1 and 8 with other Cinchona quaternary ammonium salt catalysed Michael reactions we have reported and related these data to the extensive 1H NMR titration study we have carried out on ammonium salts [47]. This seminal study undoubtedly identified specific +N-C-H to NO2 H-bonds formed by Cinchona quaternary ammonium salts with many H-bond acceptors, including 4-nitro-5-styrylisoxazoles 1. This study also demonstrated the bifunctional mode [58] of catalysis of quaternary ammonium species bearing a free OH and provided a model to explain the enantioselective outcome of several Michael reactions of 1.
It was noted that when Quininium or Cinchonidinium salts were used, the pro-(R) face of alkene in 1 reacted with nucleophiles, such as nitromethane [54], bromomalonate esters [44], malonoisonitrile [45], and malonate esters [46], with exquisite enantiocontrol; conversely, when the pseudo-enantiomeric Quinidinium and Cinchoninium were used, the reaction of 1 and nucleophiles occurred selectively at the pro-(S) face (Scheme 2) [55]. This stereoselective outcome can be explained considering the formation of adducts 24 and 25 where two H-bonds formed by the NO2 of 1 and the benzylic protons of 11 or 12 orient either the pro-(S) face or the pro-(R) towards the nucleophile. The energy of each H-bond formed by +NC-H and NO2 has been calculated at −9 Kcal/mol [47]. In conclusion, considering (i) the absolute configuration of compounds syn-22 and anti-22 obtained using Quinidinium-based quaternary ammonium salts 14 and 15, (ii) the sign of optical rotation of compounds syn-22 and anti-22 that is the same recorded for syn-9a and anti-10a, and (iii) the stereochemical model (Scheme 2) obtained via 1H NMR titration studies [47], we inferred the (R)(S) absolute stereochemistry for the major enantiomer of syn-9a and the (R)(R) for the major enantiomer of anti-10a.
The assignment of (R)(S) absolute stereochemistry to syn-9a, and of (R)(R) to anti-10a (Figure 2), brings the question of where the difference in enantioselectivity originates. It should be noted that the Michael addition of 8 to 1 under the catalysis of 15 is irreversible. Conversely, the chiral centre in the butanolide ring can be altered by a deprotonation–re-protonation process, which we know is active considering that 2–4% of compound 28 was often isolated (Figure 2). This fact unwraps the possibility of an inter-diastereomer thermodynamic interconversion (Figure 2) in which each diastereomer can evolve into the other one by a base-promoted isomerisation via compound 28 (or its enolate). This process would explain the different enantio-enrichment of the two diastereomers obtained.

6. Materials and Methods

6.1. General Experimental Section

NMR experiments were performed on a Bruker Avance 400 instrument and samples were obtained in CDCl3 referenced to 7.26 ppm for 1H and 77.16 for 13C. Coupling constants (J) are in Hz. Multiplicities are reported as follows: s, singlet; d, doublet; dd, doublets of doublets; t, triplet; q, quartet; m, multiplet; c, complex; and br, broad. Mass spectra were recorded on a Micro mass LCT spectrometer using electrospray (ES) ionisation techniques. All reagents and solvents were used as purchased from Aldrich (Burlington, MA, USA) unless otherwise stated. Reactions were monitored for completion by TLC (EM Science, silica gel 60 F254). Flash chromatography was performed using silica gel 60 (0.040–0.063 mm, 230–400 mesh) or alumina (activated, neutral, Brockmann activity I). The enantiomeric excess (ee) of the products was determined by chiral stationary phase HPLC (Daicel Chiral Technologies, Hyderabad, India, Daicel Chiralpak AD), using a UV detector operating at 217 nm and 227 nm. Infrared (IR) spectra were recorded as thin films between NaCl plates using a Bruker Tensor27 FT-IR Instrument (Bruker, Coventry, UK), Absorption maximum (Vmax) was reported in wave numbers (cm−1) and only selected peaks were reported.

6.2. General Procedure for the Quaternization of the Cinchona-Derived Catalysts 14–18

To a suspension of the appropriate base (650 mg, 2.0 mmol, 1.0 equiv.) in THF (12.0 mL) the required benzyl bromide (2.6 mmol, 1.3 equiv.) was added. The resulting mixture was heated at 60 °C for 16 h. Then the reaction was allowed to reach room temperature, then diluted with CH2Cl2 (10 mL) and washed with H2O (3 × 15 mL). The organic phase was dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude material was purified by column chromatography (chloroform/methanol 95:5) affording 14–18 as a purple solid. The obtained product was in accordance with the literature.
  • (1S,2R,4S)-1-Benzyl-2-((S)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium Bromide, 14 [59]
White solid, 770 mg, 78% yield; Rf = 0.39 (chloroform/methanol 90:10). 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 4 Hz, 1H), 7.84–7.94 (m, 1H), 7.77 (d, J = 4 Hz, 1H), 7.65–7.72 (m, 2H), 7.51 (d, J = 3 Hz, 1H), 7.23–7.37 (m, 4H), 7.18 (dd, J = 9, 3 Hz, 1H), 6.69 (d, J = 6 Hz, 1H), 6.50 (d, J = 3 Hz, 1H), 5.90 (ddd, J = 17, 10, 7 Hz, 1H), 5.78 (d, J = 12 Hz, 1H), 5.37 (d, J = 12 Hz, 1H), 5.13–5.27 (m, 2H), 4.45–4.61 (m, 1H), 3.95–4.14 (m, 2H), 3.75–3.86 (m, 3H), 3.33–3.52 (m, 2H), 2.90 (d, J = 12 Hz, 1H), 2.30–2.46 (m, 2H), 1.85 (br, s, 2H), 1.69–1.82 (m, 2H), 1.20 (t, J = 7.0 Hz, 1H), 0.95 (t, J = 5 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ 157.9, 147.2, 144.1, 142.7, 135.6, 134.0, 131.6, 130.3, 129.0, 127.0, 126.2, 120.7, 120.6, 118.0, 102.7, 67.9, 66.4, 62.7, 56.5, 56.1, 54.0, 38.1, 27.2, 24.0, 21.7.
  • (1S,2R,4S)-2-((S)-Hydroxy(6-methoxyquinolin-4-yl)methyl)-1-((perfluorophenyl)methyl)-5-vinylquinuclidin-1-ium Bromide, 15 [59]
White solid, 948 mg, 81% yield; Rf = 0.32 (chloroform/methanol 90:10). 1H NMR (400 MHz, MeOD) δ 10.93 (d, J = 5 Hz, 1H), 10.17 (d, J = 10 Hz, 1H), 10.06 (t, J = 5 Hz, 1H), 9.74–9.53 (m, 2H), 9.32 (ddd, J = 14, 13, 7 Hz, 1H), 8.79 (s, 1H), 8.29–8.14 (m, 1H), 7.56–7.20 (m, 3H), 7.14–6.91 (m, 6H), 6.68–6.41 (m, 1H), 6.41–6.15 (m, 4H), 6.00 (s, 1H), 5.71 (dd, J = 17, 8 Hz, 4H), 5.46 (dt, J 3, 2 Hz, 1H), 4.90 (dd, J 17, 8 Hz, 1H), 4.76–4.59 (m, 1H), 4.47 (s, 1H), 4.22–3.95 (m, 3H); 13C NMR (101 MHz, MeOD) δ 160.1, 148.2, 145.2, 144.8, 137.5, 131.8, 129.9, 129.2, 127.4, 123.4, 121.5, 118.1, 102.7, 69.8, 67.4, 58.3, 58.1, 56.9, 56.5, 53.2, 39.1, 27.8, 24.8, 22.3.
  • (1S,2R,4S)-1-(2,4-Dimethoxy-6-nitrobenzyl)-2-((S)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium Bromide, 16 [59]
Yellow solid, 768 mg, 64% yield; Rf = 0.34 (chloroform/methanol 90:10). 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 2H), 8.21 (s, 2H), 8.05 (d, J = 9 Hz, 2H), 7.90 (s, 2H), 7.67 (s, 2H), 7.36 (d, J = 9 Hz, 2H), 7.25 (d, J = 7 Hz, 2H), 6.78–6.50 (m, 4H), 6.55 (d, J = 11 Hz, 2H), 6.11 (dd, J = 13, 7 Hz, 2H), 5.81 (d, J = 12 Hz, 2H), 5.40–5.12 (m, 4H), 4.80 (s, 2H), 4.13 (s, 5H), 4.04 (d, J = 12 Hz, 6H), 4.04–3.94 (m, 8H), 3.94–3.81 (m, 4H), 3.70 (s, 3H), 3.37 (s, 3H), 2.89 (d, J = 18 Hz, 3H), 2.56 (t, J = 16 Hz, 5H), 1.89–1.67 (m, 7H), 1.09 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 158.8, 153.7, 150.5, 142.9, 135.5, 123.0, 120.6, 119.7, 118.8, 115.7, 109.1, 68.0, 58.4, 56.6, 56.0, 55.1, 54.6, 38.6, 26.8, 25.6, 24.3, 21.4.
  • (1S,2R,4S)-1-(3,5-bis(Trifluoromethyl)benzyl)-2-((S)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium Bromide, 17 [59]
White solid, 1146 mg, 91% yield; Rf = 0.35 (chloroform/methanol 90:10). 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 18, 8 Hz, 2H), 7.97–7.42 (m, 3H), 7.06 (d, J = 9 Hz, 1H), 6.75–6.27 (m, 2H), 5.88 (d, J = 13 Hz, 2H), 5.32–5.08 (m, 1H), 4.19 (s, 1H), 3.84 (s, 2H), 3.26–3.00 (m, 1H), 2.86–2.52 (m, 1H), 2.48–2.17 (m, 3H), 2.18 (d, J = 16 Hz, 2H), 1.81-1-71 (m, 3H), 0.88-0.66 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 154.2, 146.6, 143.5, 133.9, 131.4, 128.4, 120.4, 120.1, 117.9, 102.7, 94.79, 63.7, 60.1, 54.7, 54.5, 39.3, 26.3, 23.8, 22.0.
  • (1S,2R,4S)-1-(2-Cyanobenzyl)-2-((S)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium Bromide, 18 [59]
Yellow solid, 894 mg, 76% yield; 1H NMR (CD3OD, 400 MHz) δ 8.72–8.85 (m, 1H), 8.16 (t, J = 2 Hz, 1H), 7.96–8.09 (m, 3H), 7.91 (d, J = 5 Hz, 1H), 7.73–7.82 (m, 1H), 7.56 (dd, J = 9, 3 Hz, 1H), 7.48 (d, J = 3 Hz, 1H), 6.58 (d, J = 2 Hz, 1H), 6.00–6.20 (m, 1H), 5.50 (s, 1H), 5.24–5.35 (m, 2H), 5.14 (d, J = 12 Hz, 1H), 4.47 (s, 1H), 4.10 (s, 3H), 3.85–4.03 (m, 2H), 3.59 (s, 1H), 3.13 (d, J = 11 Hz, 1H), 2.00 (br, s, 1H), 1.83–1.96 (m, 2H), 1.06–1.23 (m, 1H). 13C NMR (CD3OD, 101 MHz) δ 160.2, 148.3, 145.4, 144.8, 139.4, 138.3, 137.6, 135.4, 131.9, 131.6, 130.4, 127.4, 122.8, 114.8, 103.2, 69.6, 67.1, 64.1, 58.3, 56.5, 38.9, 30, 22.4.

6.3. General Procedure for the Organocatalytic Vinylogous Michael Addition of γ-Butenolide to 4-Nitro-5-Styrylisoxazoles: Preparation of Compounds syn-9a–f and anti-10a–f

To a solution of styrylisoxazole 1a–f (1 equiv., 0.1 mmol) in toluene (3 mL) were added sequentially the phase-transfer catalyst 15 (0.1 equiv., 0.01 mmol) and the 2(5H)-furanone 8 (5 equiv., 0.5 mmol, 0.35 mL). The reaction mixture was stirred for 5 minutes at 0 °C. Finally, the base (5 equiv., 0.5 mmol) was added. The reaction mixture was stirred at 0 °C for 48 h. Then, the reaction was quenched with a saturated solution of NH4Cl (6 mL) and extracted with toluene (6 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, PE:EtOAc, 3:2) to give syn-9a–f and anti-10a–f. The ee values of the product were determined by CSP-HPLC using a Chiralpak AD column (n-hexane/iPrOH 90:10/80:20, flow rate 1/0.75 mL/min).
  • (S)-5-((R)-2-(3-Methyl-4-nitroisoxazol-5-yl)-1-phenylethyl)furan-2(5H)-one, syn-9a
Brown oil, 23.3 mg, 74% yield. Rf = 0.3 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3) δ 7.35–7.20 (m, 5H), 7.18 (dd, J 8, 2 Hz, 1H), 6.15 (dd, J = 8 J 2 Hz, 1H), 5.23 (dt, J = 9, 2 Hz, 1H), 3.84–3.79 (m, 2H), 3.42–3.36 (m, 1H), 2.46 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 172.4, 155.8, 154.8, 136.9, 129.6, 128.9, 128.0, 123.0, 85.7, 47.9, 31.0, 11.9 ppm; [α]D25 = +34.7 (c = 1.0 in CHCl3); 69% ee; t1 = 28 min, t2 = 34 min. HRMS: calculated for [M + Na]+, C16H14N2O5Na: 337.0800, found: 337.0803.
  • (R)-5-((R)-2-(3-Methyl-4-nitroisoxazol-5-yl)-1-phenylethyl)furan-2(5H)-one anti-10a
Brown oil, 5.0 mg, 16% yield. Rf = 0.23 (petroleum spirits/ethyl acetate, 3:2). 1H NMR (400 MHz, CDCl3) δ 7.33–7.16 (m, 6H), 5.99 (dd, J = 6, 2 Hz, 1H), 5.32 (m, 1H), 3.93–3.81 (m, 2H), 3.73–3.69 (m, 1H), 2.48 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 172.5, 172.4, 156.0, 153.9, 135.2, 129.3, 128.7, 128.4, 123.5, 84.6, 45.8, 30.0, 29.7, 11.9; [α]D25 = −2.5 (c = 1.0 in CHCl3); 26% ee; t1 = 33 min, t2 = 37 min; HRMS (see Supplementary Materials): calculated for [M + Na]+, C16H14N2O5Na: 337.0800, found: 337.0807.
  • (S)-5-((R)-1-(4-Fluorophenyl)-2-(3-methyl-4-nitroisoxazol-5-yl)ethyl)furan-2(5H)-one syn-9b
Brown oil, 23 mg, 69% yield. Rf = 0.3 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3): δ 7.24–7.16 (m, 3H), 7.07–7.00 (m, 2H), 6.18 (dd, J = 6, 2 Hz, 1H), 5.21 (dt, J = 9, 2 Hz, 1H), 3.82–3.73 (m, 2H), 3.43 (dd, J = 12, 6 Hz, 1H), 2.47 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 172.1, 155.9, 154.3, 132.8, 129.8, 129.7, 123.3, 116.8, 116.6, 85.6, 47.0, 30.7, 11.9; 19F NMR (100.6 MHz, CDCl3): −112.64; [α]D25 = +76.7 (c = 1.0 in CHCl3); 73% ee; t1 = 39 min, t2 = 52 min; HRMS (see Supplementary Materials): calculated for [M + Na]+, C16H13N2O5FNa: 355.0706, found: 355.0702.
  • (R)-5-((R)-1-(4-Fluorophenyl)-2-(3-methyl-4-nitroisoxazol-5-yl)ethyl)furan-2(5H)-one anti-10b
Brown oil, 7 mg, 21% yield. Rf = 0.23 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3): δ 7.31–7.16 (m 1H), 7.17–7.14 (m, 2H), 6.99–6.95 (m, 2H), 5.99 (dd, J = 6, 2 Hz, 1H), 5.30 (m, 1H), 3.91–3.81 (m, 2H), 3.70 (dd, J 12, 4 Hz, 1H), 2.50 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 172.2, 156.1, 153.8, 130.2, 123.7, 116.5, 84.4, 45.2, 30.3, 11.9; 19F NMR (100.6 MHz, CDCl3): −113.05; [α]D25 = −6.7 (c = 1.05 in CHCl3); 37% ee; t1 = 66 min, t2 = 70 min; HRMS (see Supplementary Materials): calculated for [M + Na]+, C16H13N2O5FNa: 355.0706, found: 355.0701.
  • (S)-5-((R)-2-(3-Methyl-4-nitroisoxazol-5-yl)-1-(4-nitrophenyl)ethyl)furan-2(5H)-one syn-9c
Brown oil, 21 mg, 59% yield. Rf = 0.3 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J= 9 Hz, 2H), 7.47 (d, J = 9 Hz, 2H), 7.28 (dd, J = 6, 2 Hz, 2H), 6.24 (dd, J = 6, 2 Hz, 1H), 5.27 (dt, J 8, 2 Hz, 1H), 3.82–3.74 (m, 2H), 3.66 (dd, J = 12, 4 Hz, 1H), 2.48 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 171.7, 171.4, 156.0, 153.5, 148.3, 144.4, 129.4, 124.7, 124.0, 84.6, 46.9, 29.7, 11.9; [α]D25 = +68.2 (c = 1.0 in CHCl3); 74% ee; t1 = 24 min, t2 = 50 min; HRMS (see Supplementary Materials): calculated for [M + Na]+, C16H18N3O7Na: 382.0651, found: 382.0665.
  • (R)-5-((R)-2-(3-Methyl-4-nitroisoxazol-5-yl)-1-(4-nitrophenyl)ethyl)furan-2(5H)-one anti-10c
Brown oil, 11 mg, 31% yield. Rf = 0.23 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 9 Hz, 2H), 7.39 (d, J = 9 Hz, 2H), 7.33 (dd, J = 6, 2 Hz, 1H), 6.00 (dd, J = 6, 2 Hz, 1H), 5.38–5.37 (m, 1H), 4.00–3.93 (m, 2H), 3.82–3.79 (m, 1H), 2.50 ppm (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 171.7, 171.4, 156.2, 153.3, 142.5, 129.7, 124.5, 124.0, 83.6, 45.8, 30.4, 11.9; [α]D25 = −7.3 (c = 1.0 in CHCl3); 38% ee; t1 = 48 min, t2 = 78 min; HRMS (see Supplementary Materials): calculated for [M + Na]+, C16H18N3O7Na: 382.0651, found: 382.0663.
  • (S)-5-((R)-2-(3-Methyl-4-nitroisoxazol-5-yl)-1-(p-tolyl)ethyl)furan-2(5H)-one syn-9d
Brown oil, 25.2 mg, 77% yield. Rf = 0.3 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3) 7.17 (d, J = 6 Hz, 1H), 7.05–7.15 (m, 4H), 6.14 (dd, J = 6, 2 Hz, 1H), 5.20 (dt, J = 9, 2 Hz, 1H), 3.66–3.87 (m, 2H), 3.35 (dd, J = 10, 6 Hz, 1H), 2.46 (s, 3H), 2.31 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 172.5, 172.4, 155.8, 154.9, 138.7, 133.8, 130.3, 127.8, 122.9, 85.9, 47.5, 31.1, 21.4, 11.9 ppm; [α]D25 = +79.7 (c = 1.0 in CHCl3); 71% ee; t1 = 36 min, t2 = 47 min. HRMS (see Supplementary Materials): calculated for [M + Na]+, C17H16N2O5Na: 351.0957, found: 351.0960.
  • (R)-5-((R)-2-(3-Methyl-4-nitroisoxazol-5-yl)-1-(p-tolyl)ethyl)furan-2(5H)-one anti-10d
Brown oil, 5.2 mg, 16% yield. Rf = 0.3 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3): δ 7.31 (dd, J = 6, 2 Hz, 1H), 7.00–7.12 (m, 4H), 5.99 (dd, J = 6, 2 Hz, 1H), 5.25–5.33 (m, 1H), 3.77–3.91 (m, 2H), 3.58–3.73 (m, 1H), 2.49 (s, 3H), 2.27 (s, 3H); 3C NMR (100.6 MHz, CDCl3): δ 172.5, 156.0, 154.0, 138.5, 132.1, 130.0, 128.3, 123.5, 84.8, 45.5, 29.8, 21.4, 12.0; [α]D25 = −4.3 (c = 1.0 in CHCl3); 35% ee; t1 = 22 min, t2 = 26 min. HRMS (see Supplementary Materials): calculated for [M + Na]+, C17H16N2O5Na: 351.0957, found: 351.0962.
  • (S)-5-((R)-1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2-(3-methyl-4-nitroisoxazol-5-yl)ethyl)furan-2(5H)-one syn-9e
Brown oil, 28 mg, 75% yield. Rf = 0.3 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3): δ 7.20 (dd, J = 6, 2 Hz, 1H), 6.72 (d, J = 9 Hz, 1H), 6.65 (d, J = 2 Hz, 1H), 6.58 (dd, J = 9, 2, 1H), 5.15 (dt, J = 9, 2 Hz, 1H) 4.23 (s, 4H) 3.72–3.83 (m, 2H) 3.27 (td, J = 9, 7 Hz, 1H) 2.48 (s, 3H) ppm; 13C NMR (100.6 MHz, CDCl3): δ 172.5, 172.4, 155.8, 154.9, 144.3, 144.0, 129.9, 122.9, 120.9, 118.3, 116.7, 85.9, 64.6, 64.6, 47.2, 31.2, 12.0 ppm; [α]D25 = +85.2 (c = 1.0 in CHCl3); 65% ee; t1 = 23 min, t2 = 29 min. HRMS (see Supplementary Materials): calculated for [M + Na]+, C18H16N2O7Na: 395.0855 found: 395.0858.
  • (R)-5-((R)-1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2-(3-methyl-4-nitroisoxazol-5-yl)ethyl)furan-2(5H)-one anti-10e
Brown oil, 5.6 mg, 15% yield. Rf = 0.3 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3): δ 7.33 (dd, J = 6, 2 Hz, 1H), 6.75 (d, J = 9 Hz, 1H), 6.67–6.63 (m 2H), 6.02 (dd, J = 6, 2 Hz, 1H), 5.27–5.24 (m, 1H), 4.21 (s, 4H), 3.81–3.74 (m, 2H), 3.3.65–3.58 (m, 1H), 2.50 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 172.6, 172.5, 156.0, 153.9, 144.0, 143.8, 128.3, 123.5, 121.2, 118.0, 117.4, 84.8, 64.6, 64.6, 45.1, 30.0, 12.0 ppm; [α]D25 = −8.5 (c = 1.0 in CHCl3); 38% ee; t1 = 37 min, t2 = 57 min. HRMS (see Supplementary Materials): calculated for [M + Na]+, C18H16N2O7Na: 395.0855 found: 395.0859.
  • (S)-5-((R)-1-(2,6-Dichlorophenyl)-2-(3-methyl-4-nitroisoxazol-5-yl)ethyl)furan-2(5H)-one syn-9f
Brown oil, 21.0 mg, 55% yield. Rf = 0.3 (v, 3:2); 1H NMR (400 MHz, CDCl3): δ 7.36–7.21 (m, 3H), 7.07 (dd, J = 6, 1 Hz, 1H), 6.16 (dd, J = 6, 2 Hz, 1H), 5.97–6.03 (m, 1H), 4.31–4.19 (m, 2H), 4.16–4.06 (m, 1H), 2.49 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 172.1, 171.9, 154.4, 137.1, 135.1, 132.3, 130.8, 130.6, 129.7, 123.1, 82.4, 45.4, 28.6, 12.0, 11.9 ppm; [α]D25 = +81.3 (c = 1.0 in CHCl3); 46% ee; t1 = 27 min, t2 = 47 min. HRMS (see Supplementary Materials): calculated for [M + Na]+, C16H12N2O5Cl2Na 405.0021 found: 405.0020.
  • (R)-5-((R)-1-(2,6-Dichlorophenyl)-2-(3-methyl-4-nitroisoxazol-5-yl)ethyl)furan-2(5H)-one anti-10f
Brown oil, 15.4 mg; 38% yield. Rf = 0.3 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3): δ 7.74 (dd, J = 6, 2 Hz, 1H), 7.33 (dd, J = 8, 2 Hz, 1H), 7.29–7.15 (m, J 2H), 6.27 (dd, J = 6, 2 Hz, 1H), 5.89 (dt, J = 9, 2 Hz, 1H), 4.42 (td, J = 9, 5 Hz, 1H), 4.19–4.13 (m, 1H), 3.79 (dd, J = 12, 5 Hz, 1H), 2.51 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 172.1, 171.9, 154.4, 137.1, 135.1, 132.3, 130.8, 130.6, 129.7, 123.1, 82.4, 45.4, 28.6, 12.0, 11.9 ppm; [α]D25 = −3.7 (c = 1.0 in CHCl3); 18% ee; t1 = 27min, t2 = 29 min. HRMS (see Supplementary Materials): calculated for [M + Na]+, C16H12N2O5Cl2Na 405.0021 found: 405.0016.
  • 5-(2-(3-Methyl-4-nitroisoxazol-5-yl)-1-phenylethyl)furan-2(3H)-one 28
For the experiment reported in Table 2, entry 5: 4 mg, 6% yield, brown oil; Rf = 0.6 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (4400 MHz, CDCl3 δ 7.27–7.40 (m, 5H), 5.23–5.27 (m, 1H), 4.25–4.34 (m, 1H), 3.82 (dd, = J 8, 2 Hz, 2H), 3.22 (t, J = 2 Hz, 2H), 2.52 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 175.8, 172.1, 154.6, 137.3, 129.4, 128.6, 128.1, 101.0, 43.0, 34.2, 31.3, 12.0 ppm; HRMS (see Supplementary Materials): calculated for [M + Na]+, C16H14N2O5Na: 337.0800, found: 337.0803.

6.4. General Procedure for the Organocatalytic Vinylogous Michael Addition of γ-Butyrolactam 21 to 4-Nitro-5-styrylisoxazole 1: Preparation of syn-22 and anti-22

To a solution of styrylisoxazole 1 (1 equiv., 0.1 mmol) in toluene (3 mL) were added sequentially the phase-transfer catalyst 14 or 15 (0.1 equiv., 0.01 mmol) and the Boc-pyrrolone 21 (5 equiv., 0.5 mmol, 91.6 mg). The reaction mixture was stirred for 5 min at 0 °C. Finally, K2CO3 (5 equiv., 0.5 mmol, 69.1 mg) was added. The reaction mixture was stirred at 0 °C for 48 h. The reaction was quenched with a saturated solution of NH4Cl (6 mL) and extracted with toluene (6 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, PE:EtOAc, 3:2) to give the two syn-22 and anti-22.
  • tert-Butyl (S)-2-((R)-2-(3-methyl-4-nitroisoxazol-5-yl)-1-phenylethyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate syn-22 [27]
Brown oil, 23.6 mg, 57% yield. Rf = 0.6 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3): δ 7.40–7.28 (m, 5H), 7.07 (dd, J 6, 2 Hz, 1H), 6.25 (dd, J 6, 2 Hz, 1H), 4.84 (app quint, J 2 Hz, 1H), 4.49 (m, 1H), 3.49 (dd, J = 15, 10 Hz, 1H), 3.33 (dd, J = 15, 6 Hz, 1H), 2.46 (s, 3H), 1.65 (s, 9H); 13C NMR (100.6 MHz, CDCl3): δ 172.9, 169.0, 156.0, 149.6, 146.7, 137.5, 129.6, 129.3, 128.6, 128.2, 84.4, 67.3, 43.3, 28.5, 25.2, 12.0 ppm; [α]D25 = +54.6 (c = 1.0 in CHCl3); 46% ee; t1 = 39 min, t2 = 43 min. HRMS (see Supplementary Materials): calculated for [M]+, C21H23N3O6Na: 436.1485 found: 436.1480.
  • tert-Butyl (R)-2-((R)-2-(3-methyl-4-nitroisoxazol-5-yl)-1-phenylethyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate anti-22 [27]
Brown oil, 3.7 mg, 8% yield. Rf = 0.5 (petroleum spirits/ethyl acetate, 3:2); 1H NMR (400 MHz, CDCl3) 7.36 (dd, J = 6, 2 Hz, 1H), 7.23–7.22 (m, 3H), 7.01–6.99 (m, 2H), 6.00 (dd, J 6, 2 Hz, 1H), 4.79 (m, 1H), 4.30 (m, 1H), 3.84 (dd, J 15, 8 Hz, 1H), 3.74 (dd, J = 15, 8 Hz, 1H), 2.52 (s, 1H), 1.59 (s, 9H); 13C NMR (100.6 MHz, CDCl3): δ 172.3, 156.0, 146.4, 135.1, 129.2, 128.8, 128.6, 83.9, 65.0, 44.6, 31.3, 28.5, 12.0 ppm; [α]D25 = +25.5 (c = 1.0 in CHCl3); 67% ee; t1 = 52 min, t2 = 56 min. HRMS (see Supplementary Materials): calculated for [M + Na]+, C21H23N3O6Na: 436.1485 found: 436.1481.

7. Conclusions

In conclusion, we have studied the reactivity of 4-nitro-5-stirylisoxazoles 1a–f and γ-butenolide and herein reported our data for the optimisation of such reaction under Cinchona-based phase-transfer catalysis. The reaction of a family of compounds 1a–f proceeded with full conversion, generating diastereoisomeric syn-9a–f and anti-10a–f in a ca. 3 to 1 ratio. Diastereoisomers syn-9a–f were obtained in good isolated yields and good enantioselectivity, up to 74% ee. The data collated, alongside a previously reported 1H NMR titration experiment of Cinchona-based quaternary ammonium salts and 4-nitroisoxazoles [48], allowed discussing a stereochemical model which is herein presented (Scheme 3) to justify the observed enantioselectivity.
We have demonstrated that a solution of catalysts such as 15 and 4-nitroisoxazoles 1a establishes a tight complex via H-bonding of the ammonium N+C-H and the nitro group. Hence, when in solution, 1a and 15 will form complex 29. We also demonstrated that O-alkylated quaternary ammonium salts provided racemic syn-9a, which stands for the engagement of the hydroxy group in 15 with the enolate arising from deprotonation of 8. [58] Notably, in compound 15 and its complexes 29 and 30 (Scheme 3), the hydroxy functionality and the benzylic protons oriented reagents 1a and 8 via their pro-(R) and pro-(S) faces, respectively, providing a rationale for the formation of the major compound observed, syn-9a, after the dissolution of 31.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal12060634/s1: copies of 1H NMR, 13C NMR, and HPLC traces for compounds 9a–f, 10a–f, and 22.

Author Contributions

Conceptualization and supervision, M.F.A.A.; methodology, validation, formal analysis, writing—original draft preparation, D.S.I. Spectroscopic data acquisition and preparation, R.P. All authors have read and agreed to the published version of the manuscript.

Funding

We acknowledge the Institute of Crystallography IC-CNR, Bari (Italy) for a grant to M.F.A.A.; we also acknowledge the Research Office RCSI for support to D.S.I. We Acknowledge the Irish Research Council (IRC) for a scholarship to R. P. (GOIPG/2018/3165).

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 12 00634 g001 550
Figure 1. Cinnamate synthetic equivalents 1–7.
Figure 1. Cinnamate synthetic equivalents 1–7.
Catalysts 12 00634 g001
Catalysts 12 00634 sch001 550
Scheme 1. Reaction of 1 and butanolide 8.
Scheme 1. Reaction of 1 and butanolide 8.
Catalysts 12 00634 sch001
Catalysts 12 00634 sch002 550
Scheme 2. Stereochemical model for the reactions of 1 under the catalysis of Cinchona-based quaternary ammonium salts.
Scheme 2. Stereochemical model for the reactions of 1 under the catalysis of Cinchona-based quaternary ammonium salts.
Catalysts 12 00634 sch002
Catalysts 12 00634 g002 550
Figure 2. Inter-diastereomer thermodynamic interconversion of compounds 9 and 10.
Figure 2. Inter-diastereomer thermodynamic interconversion of compounds 9 and 10.
Catalysts 12 00634 g002
Catalysts 12 00634 sch003 550
Scheme 3. Stereochemical model for the reactions of 1a and 8 under the bifunctional mode of catalysis of 15.
Scheme 3. Stereochemical model for the reactions of 1a and 8 under the bifunctional mode of catalysis of 15.
Catalysts 12 00634 sch003
Table
Table 1. Screening of Cinchona-derived catalysts 11–14 and base screening a,b,c.
Table 1. Screening of Cinchona-derived catalysts 11–14 and base screening a,b,c.
Catalysts 12 00634 i001
EntryPTCBasePhaseTime (h)syn-9aanti-10a
Y (%)ee (%)Y (%)ee (%)
111Na2CO3solid7212-5-
250% w/w1688-7.7-
3K2CO3solid7216−4830
450% w/w9618−4120
5K3PO4solid969-28-
650% w/w16812-14-
712Na2CO3solid16812-13-
850% w/w966-7-
9K2CO3solid9615-12-
1050% w/w9622255012
11K3PO4solid9610-7-
1250% w/w7217-15-
1313Na2CO3solid-----
1450% w/w481320450
15K2CO3solid243222518
1650% w/w72----
17K3PO4solid242911217
1850% w/w24311996
1914Na2CO3solid16814-7-
2050% w/w12017-21-
21K2CO3solid24584850
2250% w/w727---
23K3PO4solid246---
2450% w/w216----
a Reaction conditions: 1 (1.0 equiv., 0.2 mmol), 8 (5.0 equiv.), base (5.0 equiv.), cat (0.1 equiv.), toluene (2.0 mL), room temperature. b Isolated yields after silica gel chromatography. c The ee values were determined by HPLC on a chiral stationary phase.
Table
Table 2. Solvent dilution and temperature screening a,b,c.
Table 2. Solvent dilution and temperature screening a,b,c.
EntryTemp/°CDilutionTimesyn-9aanti-10a
Y (%)ee (%)Y (%)ee (%)
10 °C0.1 M24 h7248220
2−37 °C0.1 M48 h6941250
30 °C0.02 M15 d65611818
4−37 °C0.02 M-----
50 °C0.03 M72 h65582418
6−37 °C0.03 M-----
a Reaction conditions: 1 (1.0 equiv., 0.2 mmol), 8 (5.0 equiv.), K2CO3 (5.0 equiv.), 14 (0.1 equiv.), toluene; b Isolated yields after column chromatography.c ee determined by HPLC on a chiral stationary phase.
Table
Table 3. Catalyst screening a,b,c.
Table 3. Catalyst screening a,b,c.
Catalysts 12 00634 i002
EntryCatalystsyn-9aanti-10a
ee (%)Y (%)ee (%)Y (%)
11458691822
21569652622
31621613618
41770211017
5185538012
61964353212
720543013
a Reaction conditions: 1 (1.0 equiv., 0.2 mmol), 8 (5.0 equiv.), K2CO3 (5.0 equiv.), cat 14–20 (0.1 equiv.), toluene (6.0 mL), T 0 °C, 72 h. b Isolated yields after column chromatography. c Enantioselctivity determined by HPLC on a chiral stationary phase.
Table
Table 4. Scope of the preparation of γ-butyrolactone-containing compounds a,b,c.
Table 4. Scope of the preparation of γ-butyrolactone-containing compounds a,b,c.
Catalysts 12 00634 i003
EntrySubstr.ArProd.Y (%)ee %Prod.Y (%)ee %dr
11aC6H5syn-9a7469anti-10a16264.6
21b4-F-C6H4syn-9b6973anti-10b21373.2
31c4-NO2-C6H4syn-9c5974anti-10c31381.9
41d4-CH3-C6H4syn-9d7771anti-10d16354.8
51e2,3-(O-(CH2)2)-C6H3syn-9e7565anti-10e15385.0
61f2,6-di-Cl-C6H3syn-9f5546anti-10f38181.5
a Reaction conditions: 1a–f (1.0 equiv., 0.1 mmol), 8 (5.0 equiv.), K2CO3 (5.0 equiv.), 15 (0.1 equiv.), solvent (3.0 mL) scale T 0 °C, 72 h. b Isolated yields after column chromatography.c ee determined by HPLC on a chiral stationary phase.
Table
Table 5. Preparation of γ-lactam-containing compound 22 a,b,c.
Table 5. Preparation of γ-lactam-containing compound 22 a,b,c.
Catalysts 12 00634 i004
EntryCatalystdrdsyn-22.anti-22.
Y (%)ee (%)Y (%)ee (%)
11493:75743861
21595:56948967
a Reaction conditions: 1 (1.0 equiv. 0.1 mmol), 21 (5.0 equiv.), K2CO3 (5.0 equiv.), 14 or 15 (0.1 equiv.), Toluene (3.0 mL), T 0 °C, 72 h. b Isolated yields after column chromatography; c Enantiomeric excess determined by HPLC on a chiral stationary phase. d The dr value was determined from the crude reaction mixture by 1H NMR data.
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Salazar Illera, D.; Pacifico, R.; Adamo, M.F.A. Asymmetric Phase Transfer Catalysed Michael Addition of γ-Butenolide and N-Boc-Pyrrolidone to 4-Nitro-5-styrylisoxazoles. Catalysts 2022, 12, 634. https://doi.org/10.3390/catal12060634

AMA Style

Salazar Illera D, Pacifico R, Adamo MFA. Asymmetric Phase Transfer Catalysed Michael Addition of γ-Butenolide and N-Boc-Pyrrolidone to 4-Nitro-5-styrylisoxazoles. Catalysts. 2022; 12(6):634. https://doi.org/10.3390/catal12060634

Chicago/Turabian Style

Salazar Illera, Diana, Roberta Pacifico, and Mauro F. A. Adamo. 2022. "Asymmetric Phase Transfer Catalysed Michael Addition of γ-Butenolide and N-Boc-Pyrrolidone to 4-Nitro-5-styrylisoxazoles" Catalysts 12, no. 6: 634. https://doi.org/10.3390/catal12060634

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