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Synlett 2013; 24(20): 2691-2694
DOI: 10.1055/s-0033-1339926
letter
© Georg Thieme Verlag Stuttgart · New York

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

John Boukouvalas*
Département de Chimie, Pavillon Alexandre-Vachon, Université Laval, 1045 Avenue de la Médecine, Quebec City, Quebec G1V 0A6, Canada   Fax: +1(418)6567916   eMail: john.boukouvalas@chm.ulaval.ca
,
Nicolas Bruneau-Latour
Département de Chimie, Pavillon Alexandre-Vachon, Université Laval, 1045 Avenue de la Médecine, Quebec City, Quebec G1V 0A6, Canada   Fax: +1(418)6567916   eMail: john.boukouvalas@chm.ulaval.ca
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Publikationsverlauf

Received: 11. Juli 2013

Accepted after revision: 12. September 2013

Publikationsdatum:
28. Oktober 2013 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • 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. Rf = 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.
  • 27 Pouwer RH, Schill H, Williams CM, Bernhardt PV. Eur. J. Org. Chem. 2007; 4699
  • 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. Rf = 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.