Stereoselective Synthesis of Fluoroalkylated Butanolides

Abstract

Starting from fluoroalkylated, optically active acyl oxazolidinones the corresponding di- and trisubstituted butanolides were prepared in enantiomerically pure form. Using a divergent synthetic route highly functionalized fluoroalkylated building blocks are accessible.

Key words

fluorine - fluoroalkylation - lactones - stereoselective synthesis - chiral auxiliaries

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• 16 Typical Procedure for the TiCl₄-Mediated Aldol Reaction of 9a with Acroleine: (S)-4-Benzyl-3-[(2S,3R)-3-hydroxy-2-(3,3,3-trifluoropropyl)pent-4-enoyl]oxazolidin-2-one (10a)The substrate 9a (500 mg, 1.66 mmol, 1.00 equiv) was dissolved in CH₂Cl₂ (11.3 mL) and TiCl₄ (191 μL, 1.74 mmol, 1.05 equiv) was added dropwise to the vigorously stirred solution at 0 °C. The yellow suspension was stirred at 0 °C for 5 min before (–)-sparteine (953 μL, 4.15 mmol, 2.50 equiv) was slowly added. The black solution was stirred at 0 °C for 20 min. Freshly distilled acroleine (144 μL, 2.16 mmol, 1.30 equiv) was added dropwise. The resulting solution was stirred for 3 h at 0 °C. The reaction was then allowed to warm to r.t. and aq half-saturated NH₄Cl (10 mL) was added. The aqueous layer was extracted with CH₂Cl₂ (4 × 10 mL). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product (dr > 95:5, ¹⁹F NMR) was purified flash column chromatography (SiO₂, EtOAc–hexane = 1:2) to afford 447 mg (75%, 1.25 mmol) of syn-aldol derivate 10a as a light yellow oil; [α]_D ²² +42.6 (c 1.00, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 2.27 (br d, J = 2.8 Hz, 1 H, OH), 2.43 (m_c, 1 H, CH₂CF₃), 2.68 (dd, J = 13.4, 10.1 Hz, 1 H, CH ₂Ph), 2.83–2.90 (m, 1 H, CH₂CF₃), 3.35 (dd, J = 13.4, 3.4 Hz, 1 H, CH ₂Ph), 4.19–4.20 (m, 2 H, OCH₂), 4.44 (m_c, 1 H, CHCH=CH₂), 4.53 (ddd, J = 10.9, 4.6, 2.0 Hz, 1 H, COCH), 4.69–4.74 (m, 1 H, NCH), 5.29–5.40 (m, 2 H, CHCH=CH ₂), 5.88 (ddd, J = 17.0, 10.5, 5.7 Hz, 1 H, CHCH=CH₂), 7.21–7.36 (5 H, Ph) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 31.3 (q, J _CF = 29.3 Hz, CH₂CF₃), 37.4 (CH₂Ph), 42.0 (m_c, COCH), 55.6 (NCH), 66.2 (OCH₂), 72.8 (CHCH=CH₂), 117.9 (CHCH=CH₂), 126.8 (q, J _CF = 277 Hz, CH₂ CF₃), 127.4 (para ArC), 129.0 (ortho ArC), 129.3 (meta ArC), 135.1 (ArC), 136.2 (CHCH=CH₂), 153.4 (OCON), 172.5 (NCOC) ppm. ¹⁹F NMR (376 MHz, CDCl₃): δ = –64.8 (t, J = 11.0 Hz, 3 F, CF₃) ppm. IR (film): 650, 702, 935, 1015, 1102, 1150, 1211, 1260, 1364, 1392, 1700, 1780, 2923, 3483 cm^–1. ESI-HRMS: m/z [M + Na]⁺ calcd. for [C₁₇H₁₈F₃NNaO₄]⁺: 380.1080; found: 380.1080.
• 17 Typical Procedure for the Synthesis of Hydroxy-γ-butyrolactones: (3S,4S,5R)-4-Hydroxy-5-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)dihydrofuran-2(3H)-one (11a)To a stirred suspension of K₂OsO₄·2H₂O (17.3 mg, 0.047 mmol, 10 mol%) in acetone–H₂O (8:1, 0.40 mL), NMO (110 mg, 0.940 mmol, 2.00 equiv) was added in one portion at r.t. After 5 min, the mixture was cooled to 0 °C, and a solution of 10a (168 mg, 0.470 mmol, 1.00 equiv) in acetone–H₂O (8:1, 1.60 mL) was slowly added. The reaction mixture was stirred at 0 °C and allowed to warm to r.t. overnight (15 h). The reaction was quenched by the addition of 45% aq NaHSO₃ solution (0.4 mL) and stirring was continued for 30 min at r.t. After removal of the solvent, the residue was extracted with EtOAc (4 × 2 mL). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product (dr = 92:8, ¹⁹F NMR) was purified by flash column chromatography (SiO₂, CH₂Cl₂–MeOH, 20:1 → 12:1) to afford 52.0 mg (0.242 mmol, 51%) of hydroxy-γ-butyrolactone 11a as colorless solid; mp 92–95 °C; [α]_D ²² +21.1 (c 0.50, C₃H₆O). ¹H NMR (500 MHz, C₃D₆O): δ = 2.55–2.64 (m, 1 H, CH₂CF₃), 2.67–2.77 (m, 1 H, CH₂CF₃), 2.94 (m_c, 1 H, COCH), 3.73 (ddd, J = 12.6, 6.2, 3.9 Hz, 1 H, CHCH ₂OH), 3.91 (ddd, J = 12.6, 5.1, 2.3 Hz, 1 H, CHCH ₂OH), 4.26–4.29 (m, 2 H, CHCH₂OH, CHCH₂OH), 4.37–4.41 (m, 1 H, CHCHOH), 5.02 (d, J = 6.0 Hz, 1 H, CHCHOH) ppm. ¹³C NMR (126 MHz, C₃D₆O): δ = 33.4 (q, J _CF = 29.9 Hz, CH₂ CF₃), 44.5 (q, J _CF = 2.5 Hz, COCH), 61.1 (CHCH₂OH), 72.8 (CHCHOH), 86.3 (CHCH₂OH), 128.0 (q, J _CF = 276 Hz, CF₃), 174.9 (OCOC) ppm. ¹⁹F NMR (376 MHz, C₃D₆O): δ = –64.8 (d, J = 11.3 Hz, CF₃) ppm. IR (film): 652, 703, 833, 993, 1047, 1087, 1100, 1162, 1262, 1281, 1444, 1754, 3339, 3491 cm^–1. ESI-HRMS: m/z [M + Na]⁺ calcd for [C₇H₉F₃NaO₄]⁺: 237.0345; found: 237.0349.

For other examples of dihydroxylations of allylic alcohols, see ref. 9c and:
• 18a Donohoe TJ, Waring MJ, Newcombe NJ. Synlett 2000; 149
• 18b Donohoe TJ, Newcombe NJ, Waring MJ. Tetrahedron Lett. 1999; 40: 6881