Synthesis of novel spiro-isoxazoline and spiro-isoxazolidine derivatives of tomentosin

Abstract

A series of novel enantiomerically pure spiro-isoxazolidines and spiro-isoxazolines were synthesized regioselectively by 1,3-dipolar cycloaddition using respectively two dipoles, nitrones and nitrile oxides, on the exocyclic double bond of the B ring of tomentosin (α-methylene-γ-butyrolactone), a sesquiterpene lactone extracted from Dittrichia viscosa.

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Introduction

Plants have a long history as therapeutics in the treatment of human diseases and have been a continuous source of inspiration for the development of new medicines. Among them, the genus Inula (Asteraceae) comprises more than 100 species, many of which are widely used in traditional medicine for a variety of biological purposes including anti-inflammatory, anti-cancer and antibacterial activities.^1–3 Numerous compounds of interest have been isolated and identified from these plants such as flavonoids, monoterpenes, triterpenoids, and polyphenols. This genus is also a rich source of sesquiterpene acids and lactones. Many studies have focused on sesquiterpene lactones since they exhibit a wide range of biological properties^4–6 and have candidates in different phases of clinical trials such as parthenolide, costunolide, helenalin, and artemisinin (Fig. 1). The cytotoxicity of sesquiterpene lactones was partly attributed to the presence of potential alkylating agents such as the α-methylene-γ-lactone moiety, which are prone to covalently react with biological nucleophiles, e.g., L-cysteine, in a Michael-type addition.^7–12 This highly electrophilic structure may also be the origin of a major contact allergen effect and plants that contain sesquiterpene lactones are held responsible for an increasing number of cases of contact dermatitis.^13–15

Fig. 1 Examples of biologically active sesquiterpene lactones.

Using this reactive site, various structural modifications have been carried out to obtain less toxic and more reactive candidates and lately the introduction of spiro-heterocyclic molecular frameworks has aroused particular interest among medicinal chemists.^16,17 For example, the Ding and Kumar groups^18–20 recently synthesized spiro-isoxazoline and spiro-isoxazolidine derivatives of parthenin, α-santonin and artemisinin and promising anti-cancer activities were obtained. As part of the Moroccan plant development program,^21–25 Dittrichia viscosa L. Greuter, an invasive perennial weed, was particularly examined.^26,27 This plant is used either as extracts or essential oil in traditional Moroccan medicine for its antipyretic, antiseptic and anti-inflammatory properties.^28,29 Easily accessible, it is a renewable source of sesquiterpene lactones such as tomentosin (1),^30,31 also known as xanthalongin. This molecule is straightforwardly isolated in respectively 1.5% with respect to the dry weight of the aerial part of the plant (Fig. 1).^32,33 Tomentosin was already reported to act as a cytotoxic and anti-inflammatory agent^34–36 but despite this biological potential, it has received little pharmacological attention so far. Therefore, we propose herein the introduction of an isoxazoline and an isoxazolidine functionality to form libraries of structurally original spiro-bicyclic analogues of tomentosin by 1,3-dipolar cycloaddition with two dipoles, nitrones and nitrile oxides on the exocyclic double bond of the B ring of tomentosin (Fig. 2).

Fig. 2 Sesquiterpene lactones, ring B of tomentosin.

Results and discussion

The spiroisoxazoline derivatives of tomentosin were synthesized through a 1,3-dipolar cycloaddition of various aldoximes 2 with the exocyclic ring B double bond (Scheme 1).

Scheme 1 Synthesis of spiro-isoxazoline derivatives of tomentosin.

Nitrile oxides 2 were prepared by converting various aromatic aldehydes to the corresponding oximes via the reaction with hypochlorite anion present in bleach. The bleach was used in two steps: initially to produce chlorooxime and then thanks to its basicity to induce dehydrohalogenation, leading to the nitrile oxide. Experimentally, aldoxime was mixed with the tomentosin in THF, and then a bleach solution (14.5% of chlorine) was added dropwise during 12 hours. Only one diastereoisomer was isolated and characterized by NMR spectroscopic analysis and mass spectrometry. The ¹H NMR spectra of the spiroisoxazoline derivatives of tomentosin 3a showed the disappearance of the alkene protons along with the appearance of two doublets at respectively 3.42 and 3.58 ppm that confirm the selectivity of the nitrile oxide cycloaddition. The reaction took place whatever the substituent in the para position of the aryl entity, whether electron donating (CH₃, OCH₃) or electron-attracting (F). When a poor or electron-rich heteroaryl was used, the reaction did not take place and only the starting material was recovered.

The spiroisoxazolidine derivatives of tomentosin were obtained through 1,3-dipolar cycloaddition of various nitrones 4 in refluxing dry benzene (Scheme 2).^37–39 Nitrones 4 were straightforwardly obtained according to the literature procedure in which nitroaryls were first reduced in the presence of zinc and acetic acid to obtain the corresponding aryl hydroxylamines that were condensed with various aromatic aldehydes.⁴⁰

Scheme 2 Synthesis of spiro-isoxazolidine derivatives of tomentosin.

The spiro-isoxazolidines 5 were obtained as one diastereomer after purification by flash chromatography. The operating conditions are compatible with the introduction of nitrones with aryl entities bearing electron-donating (CH₃, OCH₃) or electron-attracting (CF₃, F) substituents. The use of nitrones with heteroaryl entities was carried out successfully. It should be noted that the use of toluene instead of benzene, for environmental reasons, did not unfortunately allow us to obtain the products. The structures of the spiroisoxazolidines were confirmed by their ¹H, ¹³C and 2 D NMR spectroscopic data as described for 5q (Fig. 3). The ¹H and ¹H-COSY data showed the correlation of H-7 with H-8 and H-8 with H-16. Further, the HMBC experiment showed the correlation of H-7 and H-8 with C-17 and H-7 with C-16 (Fig. 3).

Fig. 3 Selected ¹H, ¹H–COSY and HMBC correlations of 5q.

In the ¹H NMR comparison with the literature data, Reddy et al.¹⁸ obtained two diastereomers. Each diastereomer was isolated and the clear chemical shift deviation of the benzylic proton adjacent to the nitrogen atom in the isoxazolidine ring between two diastereomers was observed in ¹H NMR. In the major isomer this proton appeared at 5 ppm, but in the minor isomer this signal shifted toward a more shielding region and appeared approximately at 4 ppm.

Experimental section

General information

All reagents were purchased from commercial suppliers and were used without further purification. The reactions were monitored by thin-layer chromatography (TLC) analysis using silica gel (60 F254) plates. Compounds were visualized by UV irradiation. Flash column chromatography was performed on silica gel 60 (230–400 mesh, 0.040–0.063 mm). ¹H and ¹³C NMR spectra were recorded on a Bruker AVANCE II spectrometer at 250 MHz (¹³C, 62.9 MHz) and on a Bruker AVANCE III HD nanobay at 400 MHz (¹³C 101 MHz). Chemical shifts are given in parts per million from tetramethylsilane (TMS) or deuterated solvents (MeOH-d₄, CDCl₃) as internal standard. The following abbreviations were used for the proton spectra multiplicities: b: broad, s: singlet, d: doublet, t: triplet, q: quartet, p: pentuplet, m: multiplet. Coupling constants (J) are reported in hertz (Hz). High-resolution mass spectra (HRMS (ESI)) were performed on a Maxis Bruker 4G.

General procedure for the synthesis of spiro-isoxazolines

The appropriate aldehyde (1 equiv.) was diluted in CH₂Cl₂ (10 mL) and stirred at room temperature. Hydroxylamine (2 equiv.) and NaOH (2 equiv.) were added and the mixture was heated to reflux for 4 h. Ethanol was evaporated under reduced pressure then the crude mixture was diluted with water (10 mL) and AcOEt (10 mL) then extracted with AcOEt (3 × 10 mL). The combined organic layers were dried with MgSO₄, filtered and concentrated under reduced pressure to lead to the aldoxime intermediate. The aldoxime was diluted in THF (10 mL) then tomentosin (0.2 equiv.) and bleach (5 mL) were added dropwise. The reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with water (10 mL) and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried with MgSO₄, filtered and concentrated under reduced pressure providing a crude product, which was purified by flash chromatography on silica gel.

13-[Amino, phenyl-methyl]-11, N-epoxy-tomentosin (3a). Following the general procedure, using tomotensin (80 mg, 0.32 mmol), column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 3a (88 mg, 0.24 mmol, 75%) as a yellow oil; [α]²⁰_D −38.8 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.66 (dt, J = 7.6, 1.4 Hz, 2H), 7.46–7.36 (m, 3H), 5.43 (dd, J = 9.4, 3.5 Hz, 1H), 4.91 (ddd, J = 11.3, 6.5, 4.5 Hz, 1H), 3.58 (d, J = 16.8 Hz, 1H), 3.42 (d, J = 16.9 Hz, 1H), 2.84 (ddd, J = 13.1, 6.7, 3.1 Hz, 1H), 2.59–2.15 (m, 7H), 2.13 (s, 3H), 1.94 (ddd, J = 23.2, 11.4, 7.4 Hz, 2H), 1.16 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 173.7 (C), 156.1 (C), 145.1 (C), 130.8 (C), 128.9 (2 CH), 128.5 (CH), 127.0 (2 CH), 120.7 (CH), 89.0 (C), 80.1 (CH), 46.1 (CH), 42.6 (CH₂), 37.6 (CH₂), 36.6 (CH₂), 33.1 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.7 (CH₂), 21.2 (CH₃); HRMS (ESI⁺): calc. For C₂₂H₂₅NO₄ [M + H]⁺ 368.1856; found 368.1856.

13-[Amino, (p-tolyl)-methyl]-11, N-epoxy-tomentosin (3b). Following the general procedure, using tomotensin (80 mg, 0.32 mmol), column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 3b (89 mg, 0.23 mmol, 72%) as a colorless oil; [α]²⁰_D +46.0 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 5.43 (dd, J = 9.4, 3.5 Hz, 1H), 4.90 (ddd, J = 11.4, 6.5, 4.6 Hz, 1H), 3.56 (d, J = 16.8 Hz, 1H), 3.40 (d, J = 17.0 Hz, 1H), 2.84 (ddd, J = 13.0, 6.6, 3.0 Hz, 1H), 2.59–2.39 (m, 3H), 2.38 (s, 3H), 2.36–2.15 (m, 4H), 2.13 (s, 3H), 2.02–1.86 (m, 2H), 1.16 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 173.8 (C), 156.1 (C), 145.1 (C), 141.1 (C), 129.6 (2 CH), 127.0 (2 CH), 125.7 (C), 120.7 (CH), 88.8 (C), 80.1 (C), 46.2 (CH), 42.6 (CH₂), 37.7 (CH₂), 36.6 (CH₂), 33.1 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.7 (CH₂), 21.6 (CH₃), 21.2 (CH₃); HRMS (ESI⁺): calc. For C₂₃H₂₇NO₄ [M + H]⁺ 382.2012; found 382.2012.

13-[Amino, (4-methoxyphenyl)-methyl]-11, N-epoxy-tomentosin (3c). Following the general procedure, using tomotensin (80 mg, 0.32 mmol), column chromatography on silica gel (petroleum ether/ethyl acetate 5/5) provided 3c (87 mg, 0.22 mmol, 68%) as a colorless oil; [α]²⁰_D +41.9 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.63–7.57 (m, 2H), 6.95–6.90 (m, 2H), 5.43 (d, J = 3.7 Hz, 1H), 4.92 (ddd, J = 11.3, 6.6, 4.4 Hz, 1H), 3.85 (s, 3H), 3.56 (d, J = 16.8 Hz, 1H), 3.39 (d, J = 16.8 Hz, 1H), 2.84 (ddd, J = 13.0, 6.6, 3.1 Hz, 1H), 2.61–2.15 (m, 7H), 2.14 (s, 3H), 2.03–1.87 (m, 2H), 1.17 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 173.9 (C), 161.6 (C), 155.7 (C), 145.2 (C), 128.6 (2 CH), 121.1 (C), 120.8 (CH), 114.4 (2 CH), 88.7 (C), 80.1 (CH), 55.5 (CH₃), 46.3 (CH), 42.6 (CH₂), 37.9 (CH₂), 36.6 (CH₂), 33.1 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.8 (CH₂), 21.3 (CH₃); HRMS (ESI⁺): calc. For C₂₃H₂₇NO₅ [M + H]⁺ 398.1962; found 398.1961.

13-[Amino, (4-fluorophenyl)-methyl]-11, N-epoxy-tomentosin (3d). Following the general procedure, using tomotensin (80 mg, 0.32 mmol), column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 3d (86 mg, 0.22 mmol, 69%) as a colorless oil; [α]²⁰_D +76.0 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.66 (dd, J = 8.6, 5.3 Hz, 2H), 7.10 (t, J = 8.5 Hz, 2H), 5.43 (dd, J = 9.4, 3.5 Hz, 1H), 4.91 (ddd, J = 11.3, 6.6, 4.5 Hz, 1H), 3.54 (d, J = 16.8 Hz, 1H), 3.40 (d, J = 16.9 Hz, 1H), 2.84 (ddd, J = 13.0, 6.6, 3.0 Hz, 1H), 2.60–2.14 (m, 7H), 2.13 (s, 3H), 2.01–1.87 (m, 2H), 1.16 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 207.9 (C), 173.6 (C), 164.1 (d, J = 251.7 Hz, C), 155.2 (C), 145.2 (C), 129.0 (d, J = 8.5 Hz, 2 CH), 124.9 (d, J = 3.5 Hz, CH), 120.6 (CH), 116.1 (d, J = 22.0 Hz, 2 CH), 89.1 (C), 80.14 (CH), 46.1 (CH), 42.6 (CH₂), 37.6 (CH₂), 36.6 (CH₂), 33.1 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.7 (CH₂), 21.2 (CH₃); HRMS (ESI⁺): calc. For C₂₂H₂₄FNO₄ [M + H]⁺ 386.1762; found 386.1762.

General procedure for the synthesis of spiro-isoxazolidines

The appropriate nitrone (1.1 equiv.) was added to a solution of tomentosin (1 equiv.) in benzene (2 mL). The resulting suspension was heated to reflux for 12 h. Then the reaction mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel to provide the expected spiro-isoxasolidine.

13-[(Phenylamine), phenyl-methyl]-11, N-epoxy-tomentosin (5a). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (70 mg, 0.35 mmol), column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5a (104 mg, 0.23 mmol, 72%) as a yellowish oil; [α]²⁰_D +45.6 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J = 7.8 Hz, 2H), 7.41–7.35 (m, 2H), 7.34–7.28 (m, 1H), 7.21–7.12 (m, 2H), 6.96–6.86 (m, 3H), 5.44–5.37 (m, 1H), 5.14–5.07 (m, 1H), 4.96–4.89 (m, 1H), 2.85 (td, J = 12.3, 11.0, 5.4 Hz, 2H), 2.60–2.17 (m, 7H), 2.15 (s, 3H), 2.13–2.07 (m, 1H), 1.92 (ddd, J = 19.2, 12.8, 7.4 Hz, 2H), 1.14 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.2 (C), 174.9 (C), 151.4 (C), 145.0 (C), 140.7 (C), 129.3 (2 CH), 128.9 (2 CH), 128.2 (CH), 126.9 (2 CH), 122.8 (CH), 121.4 (CH), 115.8 (2 CH), 85.6 (C), 80.0 (CH), 70.4 (CH), 46.0 (CH), 43.9 (CH₂), 42.9 (CH₂), 36.9 (CH₂), 33.4 (CH), 31.0 (CH₂), 30.3 (CH₃), 23.1 (CH₂), 21.4 (CH₃); HRMS (ESI⁺): calc. For C₂₈H₃₁NO₄ [M + H]⁺ 446.2325; found 446.2325.

13-[(Phenylamine), (p-tolyl)-methyl]-11, N-epoxy-tomentosin (5b). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (74 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5b (104 mg, 0.22 mmol, 69%) as a yellowish oil; [α]²⁰_D +59.7 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J = 7.7 Hz, 2H), 7.17 (ddd, J = 13.8, 6.8, 2.7 Hz, 4H), 6.96–6.87 (m, 3H), 5.42 (dd, J = 9.4, 3.5 Hz, 1H), 5.06 (dd, J = 9.5, 6.7 Hz, 1H), 4.91 (ddd, J = 11.4, 6.5, 4.4 Hz, 1H), 2.91–2.76 (m, 2H), 2.60–2.37 (m, 4H), 2.36 (s, 3H), 2.34–2.17 (m, 3H), 2.15 (s, 3H), 2.13–2.06 (m, 1H), 1.93 (dt, J = 14.5, 11.5 Hz, 2H), 1.14 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 174.8 (C), 151.3 (C), 144.7 (C), 137.8 (C), 137.4 (C), 129.8 (2 CH), 128.7 (2 CH), 126.7 (2 CH), 122.6 (CH), 121.1 (CH), 115.7 (2 CH), 85.3 (C), 79.7 (CH), 70.1 (CH), 45.8 (CH), 43.8 (CH₂), 42.7 (CH₂), 36.7 (CH₂), 33.2 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.9 (CH₂), 21.2 (CH₃), 21.2 (CH₃); HRMS (ESI⁺): calc. For C₂₉H₃₃NO₄ [M + H]⁺ 460.2480; found 460.2482.

13-[(Phenylamine), (4-methoxyphenyl)-methyl]-11, N-epoxy-tomentosin (5c). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (80 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 5/5) provided 5c (103 mg, 0.22 mmol, 68%) as a yellow oil; [α]²⁰_D +38.0 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.35 (m, 2H), 7.16 (t, J = 7.4 Hz, 2H), 6.97–6.87 (m, 5H), 5.42 (dd, J = 9.3, 3.5 Hz, 1H), 5.03 (dd, J = 9.5, 6.7 Hz, 1H), 4.90 (ddd, J = 11.4, 6.7, 4.5 Hz, 1H), 3.81 (s, 3H), 2.87–2.78 (m, 2H), 2.60–2.17 (m, 7H), 2.15 (s, 3H), 2.10 (dt, J = 13.9, 4.2 Hz, 1H), 1.99–1.84 (m, 2H), 1.14 (d, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 174.9 (C), 159.4 (C), 151.2 (C), 144.7 (C), 132.1 (C), 128.7 (2 CH), 128.0 (2 CH), 122.8 (CH), 121.1 (CH), 116.0 (2 CH), 114.5 (2 CH), 85.2 (C), 79.7 (CH), 70.0 (CH), 55.4 (CH₃), 45.8 (CH), 43.7 (CH₂), 42.7 (CH₂), 36.7 (CH₂), 33.2 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.9 (CH₂), 21.2 (CH₃); HRMS (ESI⁺): calc. For C₂₉H₃₃NO₅ [M + H]⁺ 476.2429; found 476.2431.

13-[(Phenylamine), (4-fluorophenyl)-methyl]-11, N-epoxy-tomentosin (5d). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (76 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5d (103 mg, 0.22 mmol, 69%) as a yellow oil; [α]²⁰_D −78.6 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.47 (dd, J = 8.3, 5.3 Hz, 2H), 7.24–7.17 (m, 2H), 7.09 (t, J = 8.4 Hz, 2H), 6.99–6.89 (m, 3H), 5.44 (dd, J = 9.4, 3.4 Hz, 1H), 5.11 (dd, J = 9.4, 6.7 Hz, 1H), 4.94 (ddd, J = 11.4, 6.6, 4.5 Hz, 1H), 2.86 (ddd, J = 19.2, 9.8, 4.8 Hz, 2H), 2.62–2.20 (m, 7H), 2.17 (s, 3H), 2.11 (t, J = 4.2 Hz, 1H), 2.01–1.86 (m, 2H), 1.17 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 174.7 (C), 162.5 (d, J = 246.4 Hz, C), 151.0 (C), 144.8 (C), 136.1 (d, J = 3.2 Hz, C), 128.8 (2 CH), 128.4 (d, J = 8.0 Hz, 2 CH), 122.9 (CH), 121.1 (CH), 116.0 (d, J = 21.6 Hz, 2 CH), 115.8 (2 CH), 85.4 (C), 79.8 (CH), 69.6 (CH), 45.8 (CH), 43.6 (CH₂), 42.6 (CH₂), 36.7 (CH₂), 33.2 (CH), 30.8 (CH₂), 30.0 (CH₃), 22.9 (CH₂), 21.2 (CH₃); HRMS (ESI⁺): calc. For C₂₈H₃₀FNO₄ [M + H]⁺ 464.2228; found 464.2231.

13-[(Phenylamine), (4-trifluoromethylphenyl)-methyl]-11, N-epoxy-tomentosin (5e). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (94 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 5/5) provided 5e (102 mg, 0.20 mmol, 62%) as a colorless oil; [α]²⁰_D +85.6 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.68–7.59 (m, 4H), 7.24–7.15 (m, 2H), 6.98–6.92 (m, 1H), 6.88 (d, J = 7.9 Hz, 2H), 5.40 (dd, J = 9.4, 3.4 Hz, 1H), 5.23–5.16 (m, 1H), 4.94 (ddd, J = 11.4, 6.3, 4.6 Hz, 1H), 2.91–2.80 (m, 2H), 2.59–2.17 (m, 7H), 2.15 (s, 3H), 2.10 (q, J = 4.7, 4.1 Hz, 1H), 2.00–1.82 (m, 2H), 1.15 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 174.5 (C), 151.0 (C), 144.9 (C), 145.0 (C), 130.4 (d, J = 32.4 Hz, C), 128.9 (2 CH), 127.1 (2 CH), 126.1 (q, J = 3.8 Hz, C), 124.1 (d, J = 273.2 Hz, 2 CH), 122.9 (CH), 121.0 (CH), 115.4 (2 CH), 85.6 (C), 79.9 (CH), 69.6 (CH), 45.8 (CH), 43.4 (CH₂), 42.6 (CH₂), 36.7 (CH₂), 33.1 (CH), 30.8 (CH₂), 30.1 (CH₃), 23.0 (CH₂), 21.3 (CH₃); HRMS (ESI⁺): calc. For C₂₉H₃₀F₃NO₄ [M + H]⁺ 514.2197; found 514.2199.

13-[(Phenylamine), (4-dimethylaminophenyl)-methyl]-11, N-epoxy-tomentosin (5f). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (85 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 3/7) provided 5f (93 mg, 0.19 mmol, 59%) as a brown oil; [α]²⁰_D +48.9 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J = 8.4 Hz, 2H), 7.16 (t, J = 7.7 Hz, 2H), 6.98–6.89 (m, 3H), 6.73 (d, J = 8.4 Hz, 2H), 5.43 (dd, J = 9.3, 3.5 Hz, 1H), 4.98 (dd, J = 9.7, 6.5 Hz, 1H), 4.89 (ddd, J = 11.4, 6.9, 4.3 Hz, 1H), 2.96 (s, 6H), 2.89–2.75 (m, 2H), 2.60–2.18 (m, 7H), 2.15 (s, 3H), 2.10 (dd, J = 10.5, 3.4 Hz, 1H), 1.95 (ddd, J = 21.0, 9.5, 2.7 Hz, 2H), 1.14 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 175.0 (C), 151.3 (C), 150.4 (C), 144.7 (C), 128.6 (2 CH), 127.7 (2 CH), 127.3 (C), 122.7 (CH), 121.2 (CH), 116.2 (2 CH), 112.9 (2 CH), 85.1 (C), 79.6 (CH), 70.2 (CH), 45.8 (C), 43.8 (CH₂), 42.7 (CH₂), 40.7 (2 CH₃), 36.7 (CH₂), 33.3 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.8 (CH₂), 21.2 (CH₃); HRMS (ESI⁺): calc. For C₃₀H₃₆N₂O₄ [M + H]⁺ 489.2744; found 489.2747.

13-[(Phenylamine), ((4-hydroxy-3-methoxy)phenyl)-methyl]-11, N-epoxy-tomentosin (5g). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (86 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 3/7) provided 5g (78 mg, 0.16 mmol, 50%) as an orange oil; [α]²⁰_D −68.0 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.21–7.14 (m, 2H), 7.01 (d, J = 1.9 Hz, 1H), 6.98–6.89 (m, 5H), 5.67 (s, 1H), 5.45–5.39 (m, 1H), 5.03 (dd, J = 9.6, 6.5 Hz, 1H), 4.91 (ddd, J = 11.3, 6.7, 4.3 Hz, 1H), 3.88 (s, 3H), 2.87–2.77 (m, 2H), 2.60–2.17 (m, 7H), 2.14 (s, 3H), 2.10 (dt, J = 13.7, 4.1 Hz, 1H), 1.99–1.88 (m, 2H), 1.14 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.1 (C), 174.8 (C), 151.3 (C), 147.1 (C), 145.4 (C), 144.8 (C), 132.1 (C), 128.7 (2 CH), 122.7 (CH), 121.2 (CH), 119.7 (CH), 115.8 (2 CH), 114.8 (CH), 108.9 (CH), 85.3 (C), 79.7 (CH), 70.3 (CH), 56.2 (CH₃), 45.8 (CH), 43.8 (CH₂), 42.6 (CH₂), 36.7 (CH₂), 33.2 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.9 (CH₂), 21.2 (CH₃); HRMS (ESI⁺): calc. For C₂₉H₃₃NO₆ [M + H]⁺ 492.2381; found 492.2380.

13-[(p-Tolylamine), phenyl-methyl]-11, N-epoxy-tomentosin (5h). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (74 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5h (105 mg, 0.23 mmol, 72%) as a yellowish oil; [α]²⁰_D −34.8 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 7.4 Hz, 2H), 7.40–7.33 (m, 2H), 7.33–7.27 (m, 1H), 6.98 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 5.41 (dd, J = 9.4, 3.5 Hz, 1H), 5.04 (dd, J = 9.5, 6.6 Hz, 1H), 4.90 (ddd, J = 11.3, 6.8, 4.4 Hz, 1H), 2.89–2.78 (m, 2H), 2.60–2.25 (m, 7H), 2.23 (s, 3H), 2.15 (s, 3H), 2.10 (dt, J = 13.8, 4.1 Hz, 1H), 1.99–1.87 (m, 2H), 1.14 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 174.9 (C), 148.6 (C), 144.7 (C), 140.1 (C), 132.6 (C), 129.3 (2 CH), 129.0 (2 CH), 128.0 (CH), 126.9 (2 CH), 121.1 (CH), 116.6 (2 CH), 85.2 (C), 79.7 (CH), 70.5 (CH), 45.9 (CH), 43.7 (CH₂), 42.7 (CH₂), 36.7 (CH₂), 33.2 (CH), 30.8 (CH₂), 30.0 (CH₃), 22.8 (CH₂), 21.2 (CH₃), 20.8 (CH₃); HRMS (ESI⁺): calc. For C₂₉H₃₃NO₄ [M + H]⁺ 460.2481; found 460.2482.

13-[(p-Tolylamine), (4-methoxyphenyl)-methyl]-11, N-epoxy-tomentosin (5i). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (85 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 5/5) provided 5i (108 mg, 0.22 mmol, 69%) as a brown oil; [α]²⁰_D +94.3 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 6.88 (dd, J = 10.0, 8.3 Hz, 4H), 5.42 (dd, J = 9.4, 3.5 Hz, 1H), 4.96 (dd, J = 9.7, 6.4 Hz, 1H), 4.88 (ddd, J = 11.4, 6.8, 4.3 Hz, 1H), 3.80 (d, J = 1.1 Hz, 3H), 2.86–2.75 (m, 2H), 2.60–2.25 (m, 7H), 2.23 (s, 3H), 2.15 (s, 3H), 2.09 (dt, J = 13.7, 4.3 Hz, 1H), 1.99–1.86 (m, 2H), 1.14 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 175.1 (C), 159.4 (C), 148.4 (C), 144.7 (C), 132.8 (C), 131.6 (C), 129.3 (2 CH), 128.2 (2 CH), 121.1 (CH), 117.1 (2 CH), 114.4 (2 CH), 85.0 (C), 79.7 (CH), 70.3 (CH), 55.4 (CH₃), 46.0 (CH), 43.7 (CH₂), 42.7 (CH₂), 36.7 (CH₂), 33.3 (CH), 30.8 (CH₂), 30.0 (CH₃), 22.8 (CH₂), 21.2 (CH₃), 20.8 (CH₃); HRMS (ESI⁺): calc. For C₃₀H₃₅NO₅ [M + H]⁺ 490.2586; found 490.2588.

13-[(p-Tolylamine), (4-fluorophenyl)-methyl]-11, N-epoxy-tomentosin (5j). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (81 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5j (96 mg, 0.20 mmol, 63%) as a yellowish oil; [α]²⁰_D +55.8 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.43 (dd, J = 8.4, 5.3 Hz, 2H), 7.05 (t, J = 8.5 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 5.42 (dd, J = 9.4, 3.5 Hz, 1H), 5.02 (dd, J = 9.6, 6.4 Hz, 1H), 4.89 (ddd, J = 11.4, 6.8, 4.4 Hz, 1H), 2.85–2.78 (m, 2H), 2.60–2.25 (m, 7H), 2.23 (s, 3H), 2.15 (s, 3H), 2.10 (dt, J = 13.7, 4.1 Hz, 1H), 1.98–1.86 (m, 2H), 1.14 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 174.9 (C), 162.5 (d, J = 246.4 Hz, C), 148.3 (C), 144.8 (C), 135.7 (d, J = 3.2 Hz, C), 133.0 (C), 129.4 (2 CH), 128.6 (d, J = 8.1 Hz, 2 CH), 121.1 (CH), 116.9 (2 CH), 115.9 (d, J = 21.5 Hz, 2 CH), 85.2 (C), 79.8 (CH), 70.0 (CH), 46.0 (CH), 43.6 (CH₂), 42.7 (CH₂), 36.7 (CH₂), 33.2 (CH), 30.8 (CH₂), 30.0 (CH₃), 22.9 (CH₂), 21.2 (CH₃), 20.8 (CH₃); HRMS (ESI⁺): calc. For C₂₉H₃₂FNO₄ [M + H]⁺ 478.2387; found 478.2388.

13-[(p-Tolylamine), (4-trifluoromethylphenyl)-methyl]-11, N-epoxy-tomentosin (5k). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (98 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 5/5) provided 5k (104 mg, 0.20 mmol, 62%) as a yellowish oil; [α]²⁰_D +98.7 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.63 (t, J = 6.1 Hz, 4H), 7.00 (d, J = 8.1 Hz, 2H), 6.83 (d, J = 8.1 Hz, 2H), 5.40 (dd, J = 9.5, 3.4 Hz, 1H), 5.13 (dd, J = 9.4, 6.7 Hz, 1H), 4.91 (ddd, J = 11.3, 6.7, 4.5 Hz, 1H), 2.84 (dd, J = 12.6, 6.6 Hz, 2H), 2.59–2.25 (m, 7H), 2.24 (s, 3H), 2.15 (s, 3H), 2.13–2.06 (m, 1H), 1.91 (dd, J = 13.7, 11.3 Hz, 2H), 1.14 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 174.7 (C), 148.3 (C), 144.9 (C), 144.5 (C), 133.0 (C), 130.3 (d, J = 32.5 Hz, C), 129.5 (2 CH), 127.2 (2 CH), 126.0 (q, J = 3.7 Hz, 2 CH), 124.1 (d, J = 272.1 Hz, C), 121.0 (CH), 116.5 (2 CH), 85.4 (C), 79.9 (CH), 69.9 (CH), 45.9 (CH), 43.5 (CH), 42.6 (CH), 36.7 (CH₂), 33.2 (CH), 30.8 (CH₂), 30.0 (CH₃), 22.9 (CH₂), 21.2 (CH₃), 20.8 (CH₃); HRMS (ESI⁺): calc. For C₃₀H₃₂F₃NO₄ [M + H]⁺ 528.2355; found 528.2356.

13-[(4-Fluorophenylamine), phenyl-methyl]-11, N-epoxy-tomentosin (5l). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (76 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5l (102 mg, 0.22 mmol, 68%) as a yellowish oil; [α]²⁰_D +57.9 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.48–7.43 (m, 2H), 7.40–7.28 (m, 3H), 6.96–6.83 (m, 4H), 5.45–5.37 (m, 1H), 4.99 (dd, J = 9.8, 6.4 Hz, 1H), 4.87 (ddd, J = 11.4, 7.0, 4.1 Hz, 1H), 2.89–2.78 (m, 2H), 2.62–2.18 (m, 7H), 2.15 (s, 3H), 2.10 (dt, J = 13.8, 4.2 Hz, 1H), 2.00–1.83 (m, 2H), 1.14 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 175.1 (C), 159.3 (d, J = 241.6 Hz, C), 147.0 (d, J = 2.5 Hz, C), 144.8 (C), 139.5 (C), 129.1 (2 CH), 128.3 (CH), 127.0 (2 CH), 120.9 (CH), 118.6 (d, J = 8.0 Hz, 2 CH), 115.4 (d, J = 22.6 Hz, 2 CH), 85.1 (C), 79.7 (CH), 71.1 (CH), 45.7 (CH), 43.9 (CH₂), 42.7 (CH₂), 36.7 (CH₂), 33.5 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.8 (CH₂), 21.2 (CH₃); HRMS (ESI⁺): calc. For C₂₈H₃₀FNO₄ [M + H]⁺ 464.2231; found 464.2231.

13-[(4-Fluorophenylamine), (p-tolyl)-methyl]-11, N-epoxy-tomentosin (5m). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (81 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5m (95 mg, 0.20 mmol, 62%) as a yellowish oil; [α]²⁰_D +66.4 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.30 (m, 2H), 7.17 (d, J = 7.8 Hz, 2H), 6.97–6.82 (m, 4H), 5.42 (dd, J = 9.2, 3.7 Hz, 1H), 4.94 (dd, J = 9.9, 6.3 Hz, 1H), 4.85 (ddd, J = 11.4, 7.0, 4.1 Hz, 1H), 2.90–2.75 (m, 2H), 2.60–2.40 (m, 5H), 2.35 (s, 3H), 2.32–2.19 (m, 2H), 2.15 (s, 3H), 2.10 (dt, J = 13.7, 4.2 Hz, 1H), 2.02–1.85 (m, 2H), 1.14 (d, J = 6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 175.2 (C), 159.3 (d, J = 241.5 Hz, C), 147.0 (d, J = 2.5 Hz, C) 144.8 (C), 138.1 (C), 136.3 (C), 129.8 (2 CH), 127.0 (2 CH), 120.9 (CH), 118.8 (d, J = 7.9 Hz, 2 CH), 115.3 (d, J = 22.5 Hz, 2 CH), 85.0 (C), 79.7 (CH), 70.9 (CH), 45.7 (CH), 44.0 (CH₂), 42.7 (CH₂), 36.7 (CH₂), 33.5 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.7 (CH₂), 21.3 (CH₃), 21.1 (CH₃); HRMS (ESI⁺): calc. For C₂₉H₃₂FNO₄ [M + H]⁺ 478.2386; found 478.2388.

13-[(4-Fluorophenylamine), (4-methoxyphenyl)-methyl]-11, N-epoxy-tomentosin (5n). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (86 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 5/5) provided 5n (94 mg, 0.19 mmol, 59%) as a yellowish oil; [α]²⁰_D +71.0 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.32 (m, 2H), 6.98–6.82 (m, 6H), 5.46–5.40 (m, 1H), 4.93–4.80 (m, 2H), 3.81 (s, 3H), 2.89–2.72 (m, 2H), 2.61–2.18 (m, 7H), 2.15 (s, 3H), 2.10 (dt, J = 13.7, 4.2 Hz, 1H), 2.03–1.85 (m, 2H), 1.14 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 175.3 (C), 159.6 (C), 159.4 (d, J = 241.7 Hz, C), 146.9 (d, J = 2.5 Hz, C), 144.8 (C), 130.9 (C), 128.3 (2 CH), 120.9 (CH), 119.2 (d, J = 8.0 Hz, 2 CH), 115.3 (d, J = 22.5 Hz, 2 CH), 114.5 (2 CH), 84.9 (C), 79.6 (CH), 70.9 (CH), 55.4 (CH₃), 45.7 (CH), 43.9 (CH₂), 42.7 (CH₂), 36.7 (CH₂), 33.6 (CH), 30.8 (CH₂), 30.1 (CH₃), 22.7 (CH₂), 21.1 (CH₃); HRMS (ESI⁺): calc. For C₂₉H₃₂FNO₅ [M + H]⁺ 494.2336; found 494.2337.

13-[(Phenylamine), (pyridin-4-yl)-methyl]-11, N-epoxy-tomentosin (5o). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (70 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 2/8) provided 5o (76 mg, 0.17 mmol, 53%) as a yellowish oil; [α]²⁰_D +15.1 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.66–8.58 (m, 2H), 7.52–7.39 (m, 2H), 7.23–7.15 (m, 2H), 7.01–6.82 (m, 3H), 5.40 (dd, J = 9.2, 3.4 Hz, 1H), 5.14 (dd, J = 9.1, 7.0 Hz, 1H), 4.95 (ddd, J = 11.3, 6.6, 4.5 Hz, 1H), 2.89–2.82 (m, 2H), 2.66–2.17 (m, 7H), 2.14 (s, 3H), 2.13–2.07 (m, 1H), 2.00–1.80 (m, 2H), 1.14 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 207.9 (C), 174.3 (C), 150.8 (C), 150.6 (2 CH), 150.0 (C), 145.0 (C), 129.0 (2 CH), 122.9 (CH), 121.6 (2 CH), 121.0 (CH), 115.1 (2 CH), 85.8 (C), 80.0 (CH), 68.9 (CH), 45.7 (CH), 42.8 (CH₂), 42.6 (CH₂), 36.7 (CH₂), 33.1 (CH), 30.8 (CH₂), 30.1 (CH₃), 23.0 (CH₂), 21.3 (CH₃); HRMS (ESI⁺): calc. For C₂₇H₃₀N₂O₄ [M + H]⁺ 447.2277; found 447.2278.

13-[(Phenylamine), (furan-2-yl)-methyl]-11, N-epoxy-tomentosin (5p). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (66 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5p (87 mg, 0.20 mmol, 63%) as a yellowish oil; [α]²⁰_D +71.3 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.44 (dd, J = 1.8, 0.9 Hz, 1H), 7.25–7.18 (m, 2H), 6.99 (dd, J = 8.4, 7.1 Hz, 3H), 6.35 (dd, J = 3.3, 1.8 Hz, 1H), 6.31 (dt, J = 3.3, 0.7 Hz, 1H), 5.45 (ddd, J = 7.9, 2.5, 1.2 Hz, 1H), 5.10 (dd, J = 8.2, 7.0 Hz, 1H), 4.93 (ddd, J = 11.3, 6.6, 4.6 Hz, 1H), 2.88–2.72 (m, 2H), 2.60–2.18 (m, 7H), 2.15 (s, 3H), 2.14–2.07 (m, 1H), 2.03–1.90 (m, 2H), 1.15 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.0 (C), 174.6 (C), 151.6 (C), 150.5 (C), 144.7 (C), 142.9 (CH), 128.8 (2 CH), 123.4 (CH), 121.4 (CH), 116.5 (2 CH), 110.7 (CH), 108.5 (CH), 85.7 (C), 80.1 (CH), 64.7 (CH), 46.3 (CH), 42.7 (CH₂), 38.5 (CH₂), 36.7 (CH₂), 33.0 (CH), 30.9 (CH₂), 30.1 (CH₃), 23.0 (CH₂), 21.3 (CH₃); HRMS (ESI⁺): calc. For C₂₆H₂₉NO₅ [M + H]⁺ 436.2118; found 436.2118.

13-[(Phenylamine), (thiophen-3-yl)-methyl]-11, N-epoxy-tomentosin (5q). Following the general procedure, using tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (72 mg, 0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5q (99 mg, 0.22 mmol, 68%) as a yellowish oil; [α]²⁰_D −17.0 (c 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.36 (dd, J = 5.0, 3.0 Hz, 1H), 7.28 (dt, J = 3.0, 1.0 Hz, 1H), 7.22–7.14 (m, 3H), 6.96 (ddt, J = 8.3, 3.3, 1.7 Hz, 3H), 5.41 (dt, J = 7.8, 2.4 Hz, 1H), 5.16 (dd, J = 9.0, 6.6 Hz, 1H), 4.91 (ddd, J = 11.3, 6.7, 4.4 Hz, 1H), 2.82 (ddd, J = 19.3, 11.2, 4.9 Hz, 2H), 2.60–2.17 (m, 7H), 2.15 (s, 3H), 2.10 (dt, J = 13.8, 4.1 Hz, 1H), 2.00–1.85 (m, 2H), 1.14 (d, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 208.2 (C), 175.0 (C), 151.2 (C), 145.0 (C), 141.3 (C), 129.0 (2 CH), 127.2 (CH), 126.2 (CH), 123.3 (CH), 122.4 (CH), 121.4 (CH), 116.5 (2 CH), 85.6 (C), 80.1 (CH), 67.0 (CH), 46.3 (CH), 42.9 (CH₂), 42.4 (CH₂), 36.9 (CH₂), 33.4 (CH), 31.0 (CH₂), 30.3 (CH₃), 23.2 (CH₂), 21.4 (CH₃); HRMS (ESI⁺): calc. For C₂₆H₂₉NO₄S [M + H]⁺ 452.1887; found 452.1890.

Conclusions

In summary, we described here the synthesis of interesting spiro-isoxazolidine and isoxazoline derivatives of tomentosin by a 1,3-dipolar cycloaddition of respectively nitrones and nitrile oxides to the natural compound. We used an enantiomerically pure and natural starting material, thereby limiting the chemical impact on the environment. This procedure allowed us to generate enantiomerically pure spiro compounds in one diastereoisomer form with a limited number of steps.

Acknowledgements

This work was supported by the Region Centre, France in the ValPAMMeT Program and was carried out in collaboration with the Meknes-Tafilalet area in Morocco.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra25869g

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