Preparation of Keto-Isoxazole Polyketide Synthons

Abstract

The Dess-Martin periodinane (DMP) oxidation of alcohols, proceeds in good to excellent yield in the presence of the isoxazole ring, and other nitrogen-containing functional groups. The DMP route allows for the preparation of highly branched polyketide synthetic equivalents.

isoxazole - oxazoline - dihydropyridine - periodinane - oxidation

References

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General Procedure for the Dess-Martin Oxidation of Isoxazolyl Alcohols:
To an oven dried round bottom flask (50mL) was added 2.3 g (11.5 mmol) of the isoxazole alcohol and a magnetic stir bar, under a N₂ (g)atmosphere. An amount of 40 mL of freshly distilled CH₂Cl₂ were added and the solution stirred until the isoxazole alcohol completely dissolved. 4.87 g (1.0 equiv) of Dess-Martin periodinane were added in one portion and the solution stirred for 2-3 h as the reaction progress was monitored by thin layer chromatography. Upon depletion of the starting alcohol the reaction was concentrated under vacuum and diluted with diethyl ether (100 mL). The periodinane byproduct, which precipitates was then filtered and the diethyl ether solution combined with 25 mL sat. NaHCO₃, and 25 mL of sat. sodium sulfide in a 250 mL flask. The biphasic mixture was stirred vigorously for 15 min and then transferred to a separatory funnel. The organic phase was separated, washed with brine (25 mL), dried with anhyd Na₂SO₄, and concentrated. Purity was determined by ¹H NMR and the compounds purified by column chromatography (hexanes:EtOAc) on silica gel. Final compounds were fully characterized by ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis.
3-Isoxazolecarboxylic Acid 5-(2-Phenyl-1-keto-ethyl)-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl Ester ( 2). Yield 74%, colorless oil. ¹H NMR: δ = 0.38 (s, 3 H), 1.02 (s, 3 H), 1.33 (t, 3 H), 1.66 (s, 3 H), 2.84 (d, J = 11 Hz, 2 H), 3.12 (d, J = 11 Hz, 2 H), 4.19 (s, 2 H), 4.36 (q, 2 H), 7.16-7.27 (m, 5 H). ¹³C NMR: δ = 14.3, 22.1, 22.7, 29.2, 49.2, 63.4, 72.3, 72.8, 96.3, 122.1, 128.1, 129.4, 130.3, 132.2, 157.8, 162.1, 163.9, 188.2. Accurate Mass for C₂₁H₂₅NO₆: calcd 387.1682. Found: 387.1691.
3-Isoxazolecarboxylic Acid 5-[(2,2-Ketophenyl) Ethyl]-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl Ester ( 4). Yield 96%, clear solid. ¹H NMR: δ = 0.67 (s, 3 H), 1.09 (s, 3 H), 1.33 (t, J = 7.2 Hz, 3 H), 1.61 (s, 3 H), 3.31 (dd, J = 10.8 Hz, 4 H), 4.37 (q, J = 7.2 Hz, 2 H), 4.51 (s, 2 H), 7.45 (m, 2 H), 7.57 (m, 1 H), 7.82, (m, 2 H). ¹³C NMR: δ = 14.1, 21.6, 22.5, 29.3, 29.6, 34.6, 62.5, 71.8, 96.3, 115.2, 125.5, 128.1, 128.4, 143.0, 156.5, 161.0, 168.6, 197.6. Anal. Calcd for C₂₁H₂₅NO₆: C, 65.10; H, 6.50; N, 3.62. Found: C, 64.77; H, 6.38; N, 3.69.
3-[4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-methylisoxazol-5-yl]-1-phenylpropan-1-one ( 6). Isoxazolyl alcohol 5 (420 mg, 1.35 mmol) was placed in a dry 50 mL round bottom flask and taken up in 20 mL freshly distilled CH₂Cl₂. Dry pyridine (0.80 mL, 9.9 mmol) was added to the reaction flask via syringe. A second flask was charged with 10 mL CH₂Cl₂ to which was added 1.5 equiv DMP (880 mg, 2.1 mmol). Flask 2 was cannulated into flask 1 dropwise over 2 min. The reaction was monitored by TLC until no starting material remained (ca 2 h), at which time 10 mL each of sat. Na₂S₂O₃ and NaHCO₃ solutions were added to the reaction flask. The reaction mixture was stirred vigorously until phases became homogenous (about 15 min). After extraction with Et₂O (3 × 15 mL), the combined organic layers were washed with 30 mL sat. NaCl solution, then dried over MgSO₄, filtered, concentrated and purified by flash chromatography (1:1 petroleum ether:EtOAc) to produce compound 6 as a yellow solid (360 mg, 86%). If run without pyridine as a buffer, the yield was much lower (268 mg, 39%). ¹H NMR (300 MHz, CDCl₃): δ = 1.32 (s, 3 H), 2.44 (s, 3 H), 3.46 (m, 4 H), 3.99 (s, 2 H), 7.47-8.00 (m, 5 H). ¹³C NMR (500 MHz, CDCl₃): δ = 197.8, 173.7, 159.8, 155.7, 136.4, 133.4, 128.7, 128.1, 106.0, 78.4, 67.5, 35.7, 28.5, 21.9, 11.8. Anal. Calcd for C₁₈H₂₀N₂O₃: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.01; H, 6.57; N, 8.80.
4-[4-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-methylisoxazol-5-yl]butan-2-one ( 8). Prepared from isoxazolyl alcohol 7 to produce 8 as a golden oil (350 mg, 78%). If run without pyridine as buffer, the yield was much lower (279 mg, 49%). ¹H NMR (300 MHz, CDCl₃): δ = 1.31 (s, 3 H), 2.18 (s, 3 H), 2.41 (s, 3 H), 2.88 (t, J = 7.6 Hz, 2 H), 3.27 (t, J = 7.6 Hz, 2 H), 3.97 (s, 2 H). ¹³C NMR (500 MHz, CDCl₃): δ = 206.2, 173.4, 159.7, 155.6, 105.8, 78.4, 67.5, 40.2, 29.8, 28.5, 21.4, 11.8. Anal. Calcd for C₁₃H₁₈N₂O₃: C, 62.38; H, 7.25; N, 11.19. Found: C, 61.54; H, 7.29; N, 10.83. Diethyl 2,6-Dimethyl-4-[3-methyl-5-(2-oxo-2-phenylethyl)isoxazol-4-yl]-1,4-dihydropyridine-3,5-dicarboxylate ( 14). Prepared from IDHP alcohol 13 to produce compound 14 as a pale yellow solid (970 mg, 97%). ¹H NMR (300 MHz, CDCl₃): δ = 1.13 (t, J = 7.1 Hz, 6 H), 2.12 (s, 6 H), 2.27 (s, 3 H), 4.03 (m, 4 H), 4.30 (s, 2 H), 4.86 (s, 1 H), 5.51 (s, 1 H), 7.37-7.90 (m, 5 H). ¹³C NMR (500 MHz, CDCl₃): δ = 193.7, 167.6, 163.2, 160.3, 144.0, 136.6, 133.8, 129.1, 128.7, 122.7, 101.9, 60.4, 37.1, 29.6, 19.8, 14.8, 10.6. Anal. Calcd for C₂₅H₂₈N₂O₆: C, 66.36; H, 6.24; N, 6.19. Found: C, 65.98; H, 6.43; N, 6.19.