Synthesis and Biological Activity of 2-(2-Amino-2-phenylethyl)-5-oxotetrahydrofuran-2-carboxylic Acid: A Microwave-Assisted 1,3-Dipolar Cycloaddition Approach

Abstract

The microwave-assisted 1,3-dipolar cycloaddition of furanyl and benzyl oximes and several methyl acrylates effectively provided several isoxazoline when mediated by diacetoxyiodobenzene. The selected isoxazoline, methyl-5-(3-methoxy-3-oxopropyl)-3-phenyl-4,5-dihydro isoxazole-5-carboxylate, was rapidly transformed to the γ-lactone carboxylic acid, 2-(2-amino-2-phenylethyl)-5-oxotetrahydrofuran-2-carboxylic acid, in reasonable yield. The biological activity of this γ-lactone carboxylic acid increased the growth of E. coli organisms by about 44% and has a potential significance in stem cell research.

Key words

microwave-assisted 1,3-dipolar cycloaddition reaction - isoxazoline - 5-oxo-tetrahydrofuran-2-carboxylic acid derivatives - diacet­oxyiodobenzene - DAG-lactone derivatives - γ-lactone carboxylic acid

Publication History

Received: 13 April 2021

Accepted after revision: 27 July 2021

Accepted Manuscript online:
27 July 2021

Article published online:
18 August 2021

• References and Notes

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• 29 General Synthesis of Oximes 5a and 5b A mixture of aldehyde (52.0 mmol), hydroxylamine chloride (78.1 mmol), and a solution of 1:1 ethanol/water (30 mL) were stirred for 10 min at r.t. The resulting solution was slowly added to 2 M KOH (aq, 32 mL, 62.5 mmol). The mixture was stirred for an additional 3 h, this led to the formation of a white suspension. At this point, 1 M HCl (aq, 10.0 mL) was added to the reaction mixture, and the mixture was extracted with CH₂Cl₂ (2 × 20 mL). The organic layer was then dried with anhydrous Na₂SO₄ and evaporated to give the crude oxime product. Flash column chromatography of the crude product with 20% EtOAc/cyclohexane eluent gave the desired oximes. Benzaldehyde Oxime (5a) Yield 97%, clear oil. IR (neat): ν_max = 3337(O-H), 1693, 1635, 1449, 1302, 1210 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.38–7.40 (m, 3 H), 7.57–7.60 (m, 2 H), 8.17 (s, 1 H), 8.70 (br s, 1 H). Furfural Oxime (5b) Isolated as a 1:3 mixture of oximes, 93% yield, beige solid, mp 47.8–76.7 °C. IR (neat): ν_max = 3166 (O–H), 3087, 2873, 1647, 1569, 1478, 1233, 971, 821 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.47 (dd, J = 3.4, 1.8 Hz, 0.25 H), 6.55 (ddd, J = 2.0, 1.7, 0.4 Hz, 0.75 H), 6.65 (d, J = 3.4 Hz, 0.25 H), 7.36 (d, J = 3.4 Hz, 0.25 H), 7.49 (m, 1 H), 7.54 (s, 0.75 H), 8.03 (s, 0.25 H), 9.46 (br s, 0.25 H), 9.97 (br s, 0.75 H). ¹³C NMR (75 MHz, CDCl₃): δ (minor isomer) = 111.8, 113.0, 140.4, 144.5, 147.3; δ (major isomer) = 112.6, 118.5, 137.3, 143.7, 145.3.
• 30 Synthesis of Dimethyl-2-methylene Glutarate (6a) Methyl acrylate (21.5 g, 250 mmol) was cooled to –10 °C and tributylphosphine (5.1 g, 25 mmol) was added under an N₂ atmosphere in a 250 mL round-bottom flask. The reaction was allowed to warm to r.t. with stirring over 1.5 h. The reaction mixture was concentrated by rotary evaporation to give the crude product 6a. Flash column chromatography of the crude product with 10% EtOAc/cyclohexane eluent gave pure 6a (11.8 g, 56%) as an oil. IR (neat): ν_max = 2996, 2953, 2846, 1718 (C=O ester), 1631 (C=C), 1437 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 6.11 (s, 1 H), 5.53 (s, 1 H), 3.68 (s, 3 H), 3.59 (s, 3 H), 2.56 (t, J = 7.2 Hz, 2 H), 2.45 (t, J = 7.2 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 173.2, 167.2, 138.8, 126.1, 52.0, 51.7, 33.0, 27.4.
• 31 General Procedure for the MW-Assisted 1,3-Cycloaddition Reaction Alkene 6a, 6b, or 6c (1.2 equiv), diacetoxyiodobenzene (1.2 equiv), and oxime 5a or 5b (1.0 equiv) were added to a MW vial (10 mL), then 5 mL of methanol were added, and the vessel was placed in the cavity of the MW reactor. Under the reactor’s monomode setting, the vial was irradiated (200 W, 180 °C) for 5–10 min with 1 min of hold time. The reaction was monitored by TLC until all the oxime was consumed. Solvent was evaporated via vacuum, and the residue was purified by column chromatography: silica gel (120 mesh, column packed in hexane) with 10–30% ethyl acetate/hexane as eluent. Each isoxazoline was afforded as a yellow oil. The reported yields were based on isolated pure product. Methyl 5-(3-Methoxy-3-oxopropyl)-3-phenyl-4,5-dihydro-isoxazole-5-carboxylate (7a) Yield from microwave reaction, 70%. IR (neat): ν_max = 3002, 2955, 1732, 1601, 1258, 905, 759 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.23–2.60 (m, 4 H), 3.33 (d, J = 17.3 Hz, 1 H), 3.67 (s, 3 H), 3.81 (s, 3 H), 3.83 (d, J = 17.3 Hz, 1 H), 3.36–7.45 (m, 3 H), 7.62–7.65 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 28.8, 32.0, 43.5, 52.0, 53.2, 88.0, 126.9, 128.8, 128.9, 130.6, 156.3, 172.0, 173.0. HRMS (ESI): m/z calcd for C₁₅H₁₇NO₅Na [M + Na]⁺: 314.1004; found: 314.1007. Methyl 5-(2-Methoxy-2-oxoethyl)-3-phenyl-4,5-di-hydro isoxazole-5-carboxylate (7b) Yield 67%. IR (neat): ν_max = 2955, 1740, 1640, 1438, 1203, 817, 714 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.00 (d, J = 16.5 Hz, 1 H), 3.30 (d, J = 16.5 Hz, 1 H), 3.53 (d, J = 17.3 Hz, 1 H), 3.75 (s, 3 H), 3.85 (s, 3 H), 4.05 (d, J = 17.3 Hz, 1 H), 7.43 (m, 3 H), 7.69 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 41.0, 43.9, 52.3, 53.5, 85.9, 127.1, 128.8, 129.0, 130.8, 156.8, 170.0, 170.4. Methyl 3-Phenyl-4,5-dihydroisoxazole-5-carboxylate (7c) Oil, yield 76%. IR (neat): ν_max = 3031 (aromatic C–H), 3004, 1739 (C=O), 1571, 1601 (C=N), 759 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.65 (d, J = 3.8 Hz, 1 H), 3.68 (app t, J = 0.9 Hz, 1 H), 3.80 (s, 3 H), 5.20 (dd, J = 10.4, 7.8 Hz, 1 H), 7.39–7.49 (m, 3 H), 7.63–7.1 (m, 2 H). Methyl 3-(Furan-2-yl)-5-(3-methoxy-3-oxopropyl)-4,5-dihydro isoxazole-5-carboxylate (7d) Yield 35%. IR (neat): ν_max = 3002, 1716, 1634, 1441, 1266 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.48–2.59 (m, 4 H), 3.28 (d, J = 17.2 Hz, 1 H), 3.69 (s, 3 H), 3.81 (s, 3 H), 3.83 (d, J = 17.2 Hz, 1 H), 6.51 (dd, J = 3.5, 1.8 Hz, 1 H), 6.75 (d, J = 3.5 Hz, 1 H), 7.53 (d, J = 1.8 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 28.8, 31.9, 43.4, 52.1, 53.3, 87.9, 112.1, 112.6, 144.2, 144.9, 148.7, 171.9, 173.0.
• 32 Synthesis of Dimethyl 2-{2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}-2-hydroxypentanedioate (13) To a solution of isoxazoline 7a (0.544 g, 1.87 mmol) in 12 mL of EtOH/THF (v/v = 1:3) under N₂ atmosphere at r.t. was added di-tert-butyl dicarbonate (0.613 g, 2.81 mmol) and NiCl₂ (1.21 g, 9.34 mmol). The mixture was then stoppered and stirred for 10 min. The glass stopper was then removed, and NaBH₄ (0.353 g, 9.34 mmol) was added in three portions over 30 min, and the flask was again stoppered. After 2 h, the reaction mixture was filtered through a pad of Celite and the filtrate concentrated on a rotary evaporator. Flash column chromatography of the resulting crude oil using 10–30% ethyl acetate/CH₂Cl₂ gave the amino alcohol 13, as a white solid, dr = 3:1 (0.26 g, 35%); mp 111.5–113.0 °C. IR (neat): ν_max = 3509, 3381, 1725, 1693, 1512, 1368, 758 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.39 and 1.42 (both s, 9 H), 1.90–2.52 (m, 6 H), 3.56–4.02 (m, 7.5 H), 4.68 (br s, 0.25 H), 5.01 (app t, J = 10.2 Hz, 0.75 H), 5.05 (apparent t, J = 10.7 Hz, 0.25 H), 5.35 (d, J = 6.5 Hz, 0.25 H), 7.22–7.35 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 28.4, 28.5, 35.2, 35.5, 45.1, 45.4, 45.8, 50.4, 51.9, 53.0, 53.6, 75.0, 76.0, 79.7, 80.0, 126.3, 126.6, 127.5, 128.7, 128.8, 142.5, 142.8, 155.2, 155.4, 173.6, 175.5, 176.2. HRMS (ESI): m/z calcd for C₂₀H₂₉NO₇Na [M + Na]⁺: 418.1842; found: 418.1839.
• 33 Synthesis of 2-(2-Amino-2-phenylethyl)-5-oxotetrahydro-furan-2-carboxylic Acid (14) A 10 mL MW vial containing amino alcohol 13 (20.0 mg, 0.05 mmol) in 3 mL of 6 M HCl (aq) was stoppered and heated in a microwave reactor at (170 °C, 200 W) for 5 min. The reaction mixture was then transferred to a round-bottom flask and concentrated by rotatory evaporation, then further lyophilized to give 14 as a white solid (14.4 mg, quantitative yield), mp 81.0–86.2 °C. IR (neat): ν_max = 3538–2913 (O–H carboxylic acid), 1774, 1715, 1609, 938, 7667 cm^–1. ¹H NMR (300 MHz, D₂O): δ = 2.11–3.05 (m, 6 H), 4.55 (dd, J = 8.4, 4.8 Hz, 0.8 H), 4.99 (dd, J = 7.5, 5.7 Hz, 0.2 H), 7.33–7.44 (m, 5 H). ¹³C NMR (75 MHz, D₂O): δ = 27.3, 31.8, 39. 8, 52.3, 85.5, 85.9, 125.6, 127.4, 127.7, 129.0, 129.6, 135.4, 174.5, 179.6. HRMS (ESI): m/z calcd for C₁₃H₁₄NO₄ [M – H]^–: 248.0923; found: 248.0927.
• 34 Biological Activity of Compounds 13 and 14 against E. coli Compounds 13 and 14 were each dissolved in dimethyl sulfoxide (DMSO) to prepare stock solutions with a concentration of 1 mg/mL. These compounds were tested against E. coli by adding the DMSO solutions of each of 13 and 14 to a culture tube containing phosphate saline buffer (PBS) to a total volume of 2 mL. Each tube contained microbial inoculum (20 μL of cells), and the suspension was adjusted to 0.5 McFarland scale. The absorbance of these tubes’ content was adjusted to 0.064 at 625 nm using a Varian Cary 50 Scan UV Visible spectrophotometer. The solution of E. coli, culture medium, and 13 or 14 (100 μg/mL solution) were incubated at 37 °C for 24 h. The absorbance of each compound and the control were measured at 625 nm. The average absorbance from two reading was then determined: control (0.5195), compound 13 (0.6244), and compound 14 (0.7475).