Compound 3t

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Compound data: CIF

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

To silver fluoride (9.5 mg, 0.0750 mmol, 30.0 mol%), (DHQD)₂PHAL (hydroquinidine 1,4-phthalazinediyldiether) (19.5 mg, 0.0250 mmol, 10.0 mol%) and CsF (76.0 mg, 0.500 mmol, 2.00 equiv) in a 20.0 mL dried Schlenk tube were added DBDMH (71.5 mg, 0.250 mmol, 1.00 equiv), CH₃CN (2.00 mL) and DCM (1.00 mL). Trifluoromethyl 4-fluorobenzenesulfonate (130 µL, 0.750 mmol, 3.00 equiv) was added to the reaction and the resulting mixture was stirred for 30 min at 25 ^oC, then cooled to -20 ^oC. (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate (1t) (76.3 mg, 0.250 mmol, 1.00 equiv) in DCM (0.200 mL) was added dropwise and the reaction mixture was stirred at -20 ^oC for further 24 h. The reaction was quenched with saturated aqueous solution of Na₂SO₃ (1.0 mL), then followed by saturated aqueous solution of NH₄Cl (2.0 mL) at -20 ^oC. The aqueous layers were extracted with CH₂Cl₂ (8.0 mL × 3). The combined organic layers were dried over anh. MgSO₄. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with hexanes/EtOAc 200:1 (v/v), to afford 90.3 mg (S)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-((S)-2-bromo-1-(trifluoromethoxy)-ethyl)phenyl) propanoate (3t) as a white solid (77% yield). R_f = 0.30 (hexanes/EtOAc 10:1 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃) δ 7.28 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 5.26 (dd, J = 7.7, 5.0 Hz, 1H), 4.99 (d, J = 8.5 Hz, 1H), 4.60 (d, J = 7.6 Hz, 1H), 3.70 (s, 3H), 3.68 – 3.59 (m, 1H), 3.53 (dd, J = 11.2, 4.9 Hz, 1H), 3.19 – 3.07 (m, 1H), 3.07 – 2.98 (m, 1H), 1.40 (s, 9H).¹³C NMR (101 MHz, CDCl₃) δ 172.3, 155.1, 137.8, 135.4, 129.9 (d, J = 14.9 Hz), 126.6, 121.5 (q, J = 257.1 Hz), 80.2, 79.6, 54.4, 52.4, 38.4, 33.5, 28.4. ¹⁹F NMR (376 MHz, CDCl₃) δ -58.31 (s, 3F). Mass Spectrometry: HRMS-ESI (m/z): Calcd for C₁₈H₂₃BrF₃NNaO₅ [M+Na]⁺, 492.0604. Found, 492.0598. d.r. = 1.7:1 HPLC (Phenomenex Lux 5u chiralpak Cellulose-1, i-PrOH/hexane = 5/95, 0.3 mL/min, 220 nm) t₁ = 68.521 min (major), t₂ = 77.008 min (minor). [α]_D²⁰= +57.6 (c 0.25, CHCl₃).

Synthesis of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate: to a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate (4.50 g, 15.2 mmol, 1.00 equiv) in 30.0 mL of pyridine at 0 °C was slowly added trifluoromethanesulfonic anhydride (3.00 mL, 18.2 mmol, 1.20 equiv). The resulting mixture was stirred at 0 °C for 5 min and then allowed to warm to 23 °C and stirred at this temperature for 25 h. The resulting mixture was poured into water and extracted with ethyl ether. The ether extract was washed sequivuentially with water (50 ml), 10% aqueous hydrochloric acid solution (100 ml), water (50 ml), and a concentrated sodium chloride solution. The combined organic layers were dried over anh. MgSO₄. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with hexanes/EtOAc 4:1 (v/v), to afford 5.33 g (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate as a white solid (82% yield). R_f = 0.4 (hexanes/EtOAc 3:1 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃) δ 7.25 – 7.16 (m, 4H), 5.04 (d, J = 8.2 Hz, 1H), 4.59 (q, J = 6.9 Hz, 1H), 3.70 (s, 3H), 3.10 (ddd, J = 54.1, 13.9, 6.2 Hz, 2H), 1.40 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 172.1, 155.2, 148.8, 137.2, 131.3, 121.5, 118.9 (q, J = 321.9 Hz), 80.3, 54.4, 52.5, 38.0, 28.4. Mass Spectrometry: HRMS-ESI (m/z): Calcd for C₁₆H₂₀F₃NO₇SNa [M+Na]⁺, 450.0810. Found, 450.0804.

Synthesis of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-vinylphenyl)propanoate (1t): To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)- oxy)phenyl)propanoate (5.33 g, 12.5 mmol, 1.00 equiv) in 50 mL of 1,4-dioxane were added tri-n-butylethenylstannane (3.70 mL, 12.5 mmol, 1.00 equiv), LiCl (1.49 g, 35.0 mmol, 2.80 equiv), Pd(PPh₃)₄ (289 mg, 0.250 mmol, 0.0200 equiv), and a few crystals of 2,6-di-tert-butyl-4-methyl-phenol. The resulting suspension was heated to reflux (98 °C) for 4 h, cooled to room temperature, and treated with 6.00 mL of pyridine and 12.0 mL of pyridinium fluoride (1.40 M solution in THF, 17.4 mmol). The resulting mixture was stirred at 23 °C for 16 h. The mixture was diluted with diethyl ether, filtered through a small pad of Celite, and washed with water, 10% HCl, water, and a concentrated sodium chloride solution. The combined organic layers were dried over anh. MgSO₄. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with hexanes/EtOAc 3:1 (v/v), to afford 2.80 g (S)-methyl 2-((tert-butoxycrbonyl)amino)-3-(4-vinylphenyl)propanoate (1t) as a white solid (74% yield). R_f = 0.5 (hexanes/EtOAc 3:1 (v/v)). NMR Spectroscopy: ¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 6.68 (dd, J = 17.6, 10.8 Hz, 1H), 5.72 (d, J = 17.5 Hz ,1H), 5.23 (d, J = 10.9 Hz, 1H), 4.96 (m, 1H), 4.57 (m, 1H), 3.72 (s, 3H), 3.07 (qd, J = 13.9, 5.9 Hz, 2H), 1.42 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 172.4, 155.2, 136.4, 136.4, 135.7, 129.6, 126.5, 113.8, 80.1, 54.5, 52.4, 38.1, 28.4. Mass Spectrometry: HRMS-ESI (m/z): Calcd for C₁₇H₂₃NO₄Na [M+Na]⁺, 328.1525. Found, 328.1522.