Short, Enantioselective Total Syntheses of Fugomycin and Desoxyfugomycin via Sonogashira Alkynylation of α-Bromobutenolides

Abstract

The potent antifungal antibiotics (+)-fugomycin and (+)-desoxyfugomycin were synthesized in 3–4 steps with high overall efficiency (51–53%) and optical purity (ee > 97%). The syntheses illustrate a highly effective protocol for accomplishing racemization-free Sonogashira coupling of chiral α-bromobutenolides, and the usefulness of the Movassaghi–Jacobsen method for preparing the latter from epoxides.

Key words

alkynes - enynes - fungicides - hydrogenation - lactones - natural products - total synthesis

• References and Notes

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• 19 Racemic 7b was prepared from β-angelica lactone¹⁴ by using Krafft’s iodination-elimination procedure [I₂ (2 equiv), K₂CO₃ (1.2 equiv), DMAP (1.0 equiv), THF–H₂O (1:1), r.t., 24 h, 24% yield; see also: Krafft, M. E.; Cran, J. W. Synlett 2005, 1263. Data for 7b: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.72 (d, J = 1.6 Hz, 1 H), 5.10 (qd, J = 6.8, 1.6 Hz, 1 H), 1.46 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.1, 162.3, 85.5, 81.9, 18.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₅H₆IO₂: 224.9413; found: 224.9388.
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• 24 Synthesis of Alkynylbutenolide (S)-8: A flame-dried vial charged with bromide 7a (50.2 mg, 0.284 mmol), Pd(PPh₃)₂Cl₂ (19.4 mg, 0.028 mmol, 0.1 equiv) and CuI (8.1 mg, 0.042 mmol, 0.15 equiv) was placed under vacuum for 20 min and then purged with nitrogen. Degassed 1,4-dioxane (3 mL) was added and the mixture was stirred under nitrogen for 0.5 h at r.t., after which, degassed Hünig’s base (140 μL, 0.847 mmol, 3.0 equiv) and 1-hexyne (95 μL, 0.847 mmol, 3.0 equiv) were slowly added by using a cannula. The mixture was stirred at r.t. for 1.5 h, filtered through a small pad of Celite and activated charcoal (EtOAc rinsing), concentrated, and purified by flash chromatography (EtOAc–hexanes, 2%) to furnish (S)-8 (39.8 mg, 79%) as a pale-yellow oil. R_f = 0.40 (EtOAc–hexanes, 20%); [α]_D ²² +34.9 (c 0.85, CHCl₃); ee > 97% [HPLC: ChiralCel AD-H; n-hexane–i-PrOH, 98:2; 0.4 mL/min; t _R = 39.1 (major), 41.1 (minor) min]. ¹H NMR (400 MHz, CDCl₃): δ = 7.33 (d, J = 1.8 Hz, 1 H), 5.11 (qd, J = 6.8, 1.8 Hz, 1 H), 2.40 (t, J = 7.1 Hz, 2 H), 1.58 (m, 4 H), 1.44 (d, J = 6.8 Hz, 3 H), 0.92 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.9, 155.1, 118.6, 98.9, 78.1, 70.1, 30.5, 22.2, 19.5, 19.1, 13.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₅O₂: 179.1072; found: 179.1080.
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• 28 Synthesis of (S)-(+)-Desoxyfugomycin 2: To a solution of alkynylbutenolide (S)-8 (42.4 mg, 0.238 mmol) in MeOH (4 mL) was added 5% Pd/BaSO₄ (1 mg), followed by a solution of pyridine in MeOH (830 μL, 0.014 mmol, 0.06 equiv). The vessel was flashed with hydrogen gas and the mixture was shaken under 3 atm of hydrogen at r.t. for 8 h, after which time, over 90% conversion into 2 had occurred according to NMR spectroscopic analysis. After filtration of the mixture over a Celite pad and concentration of the filtrates, purification by flash chromatography (EtOAc–hexanes, 2%) afforded (S)-desoxyfugomycin 2 (37.7 mg, 88%) as a pale-yellow oil. R_f = 0.36 (EtOAc–hexanes, 20%); [α]_D ²² +14.4 (c 0.86, CHCl₃) {Lit.^4a [α]_D ²⁰ +14.0 (c 0.46, CHCl₃)}; ee > 97% [HPLC: ChiralCel AD-H; n-hexane–i-PrOH, 98:2; 0.4 mL/min; t _R = 21.1 (major), 22.5 (minor) min]. ¹H NMR (400 MHz, CDCl₃): δ = 7.16 (s, 1 H), 6.06 (dm, J = 11.5, 1 Hz, 1 H), 5.94 (dt, J = 11.5, 7.0 Hz, 1 H), 5.11 (br q, J = 7.0 Hz, 1 H), 2.25 (qd, J = 7.0, 1.5 Hz, 2 H), 1.48–1.33 (m, 4 H), 1.46 (d, J = 7.0 Hz, 3 H), 0.91 (t, J = 7.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 149.0, 140.2, 128.8, 116.7, 77.8, 31.5, 29.7, 22.6, 19.5, 14.1. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₇O₂: 181.1229; found: 181.1215.
• 29 Data for (S)-10: [α]_D ²² –60.0 (c 0.99, CHCl₃); ee > 98% [HPLC: ChiralCel OD-H; n-hexane–i-PrOH, 90:10; 0.5 mL/min; t _R = 10.4 (major), 11.2 (minor) min]. ¹H NMR (400 MHz, CDCl₃): δ = 7.53 (d, J = 2.0 Hz, 1 H), 5.00 (m, 1 H), 3.93 (dd, J = 10.9, 4.3 Hz, 1 H), 3.84 (dd, J = 10.9, 5.0 Hz, 1 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.4, 150.8, 114.0, 82.8, 62.7, 25.8, 18.3, –5.38, –5.41. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₂₀BrO₃Si: 307.0365; found: 307.0353.
• 30 Data for (S)-11: [α]_D ²² –14.1 (c 1.06, CHCl₃); ee > 97% [HPLC: ChiralCel AD-H; n-hexane–i-PrOH, 98:2; 0.4 mL/min; t _R = 16.5 (major), 18.3 (minor) min]. ¹H NMR (400 MHz, CDCl₃): δ = 7.37 (d, J = 1.6 Hz, 1 H), 5.02 (m, 1 H), 3.90 (dd, J = 10.7, 4.6 Hz, 1 H), 3.77 (dd, J = 10.7, 5.4 Hz, 1 H), 2.41 (t, J = 7.2 Hz, 2 H), 1.56–1.43 (m, 4 H), 0.92 (t, J = 7.4 Hz, 3 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.7, 151.9, 119.6, 98.9, 81.7, 70.1, 63.3, 30.4, 25.9, 22.1, 19.4, 18.3, 13.7, –5.4 (2 C) –5.34, –5.37. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₉O₃Si: 309.1886; found: 309.1891.
• 31 Synthesis of (S)-(+)-Fugomycin 1: To a solution of (S)-11 (28.2 mg, 0.091 mmol) in EtOAc–MeOH (9:1, 0.9 mL) was added 5% Pd/BaSO₄ (9 mg), followed by a solution of pyridine in EtOAc–MeOH (9:1, 0.67 mL, 0.011 mmol, 0.12 equiv). The vessel was flashed with hydrogen gas and the mixture was shaken under hydrogen (1 atm) for 1 h at r.t., after which time, a mixture consisting of TBS-protected fugomycin (93%), starting material (3%), and the corresponding n-hexylbutenolide (4%) was obtained. Purification by chromatography over silica gel containing 10% silver nitrate (n-hexane–CH₂Cl₂, 10:3) afforded essentially pure TBS-protected fugomycin (25.7 mg) as a colorless oil. The oil was dissolved in MeOH (1 mL) and Dowex 50WX8 (H⁺ form, 50 mg) was added. After stirring at r.t. for 26 h, the mixture was filtered and concentrated in vacuo. Purification of the residue by flash chromatography (n-hexane–MeOH, 200:3) provided (S)-fugomycin 1 as a white solid. Mp 48–50 °C (Lit.^4a colorless oil); [α]_D ²² +19.7 (c 0.45, CHCl₃); ee > 97% [HPLC: ChiralCel AD-H; n-hexane–i-PrOH, 90:10; 0.4 mL/min; t _R = 14.6 (major), 13.3 (minor) min]. ¹H NMR (400 MHz, CDCl₃): δ = 7.16 (br s, 1 H), 6.09 (br d, J = ca. 12 Hz, 1 H), 5.96 (dt, J = 11.5, 7.0 Hz, 1 H), 5.12 (br s, 1 H), 4.00 (br dd, J = 12.2, 3.8 Hz, 1 H), 3.77 (dd, J = 12.2, 5.4 Hz, 1 H), 2.26 (m, 2 H), 1.51–1.30 (m, 4 H), 0.92 (t, J = 7.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.1, 144.2, 140.8, 130.5, 116.5, 82.0, 63.4, 31.4, 29.8, 22.6, 14.1. Anal. Calcd for C₁₁H₁₆O₃: C, 67.32; H, 8.22. Found: C, 67.37; H, 8.23.