First Total Synthesis of the Marine Natural Brominated Polyunsaturated Lipid Xestospongenyne as a Potent Pancreatic Lipase Inhibitory Agent

Abstract

The first total synthesis of xestospongenyne, a marine brominated polyunsaturated lipid with remarkable pancreatic lipase inhibitory activity (IC₅₀ = 0.61 μM), was achieved from commercially available hept-6-yn-1-ol with 13% overall yield. This synthesis will permit further biological study of xestospongenyne and its analogues, with the aim of producing an antiobesity drug.

Key words

lipids - xestospongenyne - total synthesis - medicinal chemistry - natural products

• References and Notes

• 1 Cooke D, Bloom S. Nat. Rev. Drug Discovery 2006; 5: 919
• 2a Birari RB, Bhutani KK. Drug Discovery Today 2007; 12: 879
• 2b Lowe ME. Gastroenterology 1994; 107: 1524
• 2c Magrioti V, Verger R, Constantinou-Kokotou V. J. Med. Chem. 2003; 47: 288
• 3 Zhou X, Xu T, Yang X.-W, Huang R, Yang B, Tang L, Liu Y. Chem. Biodiversity 2010; 7: 2201
• 4a Zhou Z.-F, Menna M, Cai Y.-S, Guo Y.-W. Chem. Rev. 2015; 115: 1543
• 4b Blunt JW, Copp BR, Munro MH. G, Northcote PT, Prinsep MR. Nat. Prod. Rep. 2005; 22: 15
• 4c Faulkner DJ. Nat. Prod. Rep. 2002; 19: 1
• 4d Faulkner DJ. Nat. Prod. Rep. 1997; 14: 259
• 4e Jiang W, Liu D, Deng Z.-W, de Voogdc NJ, Proksch P, Lin W.-H. Tetrahedron 2011; 67: 58
• 4f Liu D, Xu J, Jiang W, Deng Z.-W, de Voogdc NJ, Proksch P, Lin W.-H. Helv. Chim. Acta 2011; 94: 1600
• 4g Pham NB, Butler MS, Hooper JN. A, Moni RW, Quinn RJ. J. Nat. Prod. 1999; 62: 1439
• 4h Quinn RJ, Tucker DJ. J. Nat. Prod. 1991; 54: 290
• 5 Liang L.-F, Wang T, Cai Y.-S, He W.-F, Sun P, Li Y.-F, Huang Q, Taglialatela-Scafati O, Wang H.-Y, Guo Y.-W. Eur. J. Med. Chem. 2014; 79: 290
• 6 Gong J.-X, Wang H.-Y, He W.-F, Wang Z.-Z, Xiao W, Guo Y.-W. J. Asian Nat. Prod. Res. 2013; 15: 916
• 7 Sonogashira K. J. Organomet. Chem. 2002; 653: 46
• 8 Corey EJ, Fuchs PL. Tetrahedron Lett. 1972; 13: 3769
• 9 Zhang W, Xu H, Xu H, Tan W. J. Am. Chem. Soc. 2009; 131: 3832
• 10 (6E)-9-(Trimethylsilyl)non-6-en-8-yn-1-ol (9) PdCl₂(PPh₃)₂ (23 mg, 0.33 mmol, 1.2 mol%) was added to a solution of vinyl iodide 8 (0.66 g, 2.76 mmol) in Et₃N (10 mL) under argon, and the mixture was stirred for 45 min at r.t. HC≡CTMS (324 mg, 3.3 mmol) and CuI (132 mg, 0.69 mmol, 25 mol%) were then successively added at 0 °C, and the mixture was warmed to r.t. and stirred for 2 h. The mixture was then diluted with Et₂O and washed with 1 M aq NH₄Cl. The aqueous layer was extracted with Et₂O. The organic layers were combined, dried (MgSO₄), concentrated, and purified by flash chromatography (silica gel, 20% EtOAc/hexanes) to give a pale-yellow oil; yield: 0.46 g (80%); R_f = 0.20 (20% EtOAc–hexane). ¹H NMR (300 MHz, CDCl₃): δ = 0.17 (s, 9 H), 1.34–1.44 (m, 4 H), 1.51–1.60 (m, 2 H), 2.08–2.15 (m, 2 H), 3.60–3.66 (m, 2 H), 5.49 (dt, J = 1.6, 15.9 Hz, 1 H), 6.20 (dt, J = 7.1, 15.9 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = –0.46, 24.77, 27.94, 32.08, 32.57, 62.41, 92.22, 103.62, 109.34, 145.53. HRMS (EI): m/z [M⁺] calcd for C₁₂H₂₂OSi: 210.1440; found: 210.1433.
• 11 (6E)-9-(Trimethylsilyl)non-6-en-8-ynal (6) A solution of DMSO (1.80 mL, 25.2 mmol) in CH₂Cl₂ (15 mL) was slowly added to a solution of oxalyl chloride (1.44 mL, 16.8 mmol) in CH₂Cl₂ (70 mL) at −78 °C. After 15 min at −78 °C, a solution of alcohol 9 (1.76 g, 8.4 mmol) in CH₂Cl₂ (15 mL) was added dropwise, and the mixture was stirred for 15 min. Et₃N (5.9 mL, 42.1 mmol) was added slowly and the mixture was kept at −78 °C for 15 min. It was then allowed to warm to 0 °C and stirred for a further 30 min. H₂O was added and the mixture was diluted with Et₂O. The organic layer was separated and washed with brine. The aqueous layers were combined, extracted with Et₂O (3 × 40 mL), dried (MgSO₄), filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 10% Et₂O–hexane) to give a pale-yellow oil; 1.52 g (87%); R_f = 0.50 (15% Et₂O–hexane). ¹H NMR (400 MHz, CDCl₃): δ = –0.48 (s, 9 H), 1.41–1.49 (m, 2 H), 1.62–1.70 (m, 2 H), 2.15 (dq, J = 1.4, 7.2 Hz, 2 H), 2.46 (dt, J = 1.6, 7.3 Hz, 2 H), 5.53 (dt, J = 1.4, 15.9 Hz, 1 H), 6.20 (dt, J = 7.1, 15.9 Hz, 1 H), 9.78 (t, J = 1.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 0.48, 21.00, 27.61, 32.30, 43.20, 92.50, 103.40, 109.79, 144.75, 201.92. HRMS (EI): m/z [M⁺] calcd for C₁₂H₂₀OSi: 208.1283; found: 208.1278.
• 12 [(3E)-10,10-Dibromodeca-3,9-dien-1-yn-1-yl](trimethyl)silane (10) A solution of PPh₃ (3.80 g, 14.5 mmol) in CH₂Cl₂ (15 mL) was added to a solution of CBr₄ (4.81 g, 14.5 mmol) in CH₂Cl₂ (15 mL) at 0 °C, and the mixture was warmed to r.t., then stirred for 1 h. A solution of aldehyde 6 (1.27 g, 6.1 mmol) in CH₂Cl₂ (5 mL) was added, and the mixture was stirred for 1 h at r.t., then concentrated. The crude product was purified by flash chromatography (silica gel, pentane) to give a colorless oil; yield: 1.82 g (82%); R_f = 0.58 (hexane). ¹H NMR (300 MHz, CDCl₃): δ = 0.18 (s, 9 H), 1.41–1.46 (m, 4 H), 2.08–2.13 (m, 4 H), 5.50 (dt, J = 1.6, 15.9 Hz, 1 H), 6.20 (dt, J = 7.1, 15.9 Hz, 1 H), 6.36 (t, J = 7.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 0.01, 27.18, 27.92, 32.73, 32.74, 88.90, 92.87, 103.94, 110.08, 138.41, 145.51. HRMS (EI): m/z [M⁺] calcd for C₁₃H₂₀Br₂Si: 361.9701; found: 361.9703.
• 13 (3E)-Dec-3-ene-1,9-diyn-1-yl(trimethyl)silane (4) A 1.6 M solution of BuLi in THF (6.8 mL) was added to a solution of dibromoalkene 10 (1.8 g, 4.9 mmol) in THF at –78 °C, and the mixture was stirred for 1 h, then warmed to r.t. The solution was diluted with Et₂O and washed successively with sat. aq NH₄Cl and brine, dried (MgSO₄), filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 10% Et₂O–hexane) to give a colorless oil; yield: 0.86 g (85%); R_f = 0.38 (hexane). ¹H NMR (300 MHz, CDCl₃): δ = 0.17 (s, 9 H), 1.51–1.53 (m, 4 H), 1.94 (t, J = 2.6 Hz, 1 H), 2.11–2.21 (m, 4 H), 5.50 (dt, J = 1.5, 15.9 Hz, 1 H), 6.20 (dt, J = 7.1, 15.9 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 0.02, 18.21, 27.60, 27.76, 32.49, 68.43, 84.22, 92.79, 103.98, 110.02, 145.57. HRMS (EI): m/z [M⁺] calcd for C₁₃H₂₀Si: 204.1334; found: 204.1342.
• 14 Kim S, Kim S, Lee T, Ko H, Kim D. Org. Lett. 2004; 6: 3601
• 15 Methyl (17E)-20-(Trimethylsilyl)icos-17-ene-9,11,19-triynoate (11) To a solution of enediyne 4 (0.72 g, 3.5 mmol) in MeOH (6 mL) were added methyl 10-bromodec-9-ynoate (5; 0.91 g, 3.5 mmol), NH₂OH·HCl (14 mg, 0.2 mmol), 70% aq EtNH₂ (3 mL), and CuCl (20 mg, 0.23 mmol), and the mixture was stirred overnight. The product was isolated by extraction with Et₂O (3 × 5 mL), and the combined organic layers were washed successively with sat. aq NH₄Cl (2 mL), H₂O, and brine then dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% Et₂O–hexane) to give a colorless oil; yield: 0.74 g (55%); R_f = 0.20 (5% Et₂O–hexane). ¹H NMR (300 MHz, CDCl₃): δ = 0.20 (s, 9 H), 1.32–1.33 (m, 4 H), 1.37–1.44 (m, 2 H), 1.50–1.56 (m, 6 H), 1.60–1.67 (m, 2 H), 2.11–2.16 (m, 2 H), 2.24–2.28 (m, 4 H), 2.32 (t, J = 7.5 Hz, 2 H), 3.69 (s, 3 H), 5.52 (d, J = 15.9 Hz, 1 H), 6.20 (dt, J = 7.3, 15.9 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 0.03, 19.01, 19.17, 24.89, 27.64, 27.68, 28.23, 28.63, 28.73, 28.97, 32.47, 34.06, 51.47, 65.23, 65.58, 76.95, 77.61, 92.82, 103.96, 110.07, 145.47, 174.27. HRMS (EI): m/z [M⁺] calcd for C₂₄H₃₆O₂Si: 384.2485: found; 384.2486.
• 16 Methyl (17E)-Icos-17-ene-9,11,19-triynoate (3) To a solution of ester 11 (0.7 g, 1.8 mmol) in 2:1 MeOH–THF (9 mL) was added K₂CO₃ (0.5 mg, 3.6 mmol), and the mixture was stirred at r.t. for 2 h, then concentrated by rotary evaporation. The residue was diluted with Et₂O, then washed sequentially with 10% HCl and brine. The organic layer was dried (MgSO₄) and concentrated under vacuum to give a colorless oil of sufficient purity for the subsequent step; yield: 0.52 g (93%); R_f  = 0.15 (5% Et₂O–hexane). ¹H NMR (300 MHz, CDCl₃): δ = 1.32–1.34 (m, 4 H), 1.39–1.44 (m, 2 H), 1.50–1.55 (m, 6 H), 1.62–1.66 (m, 2 H), 2.13–2.17 (m, 2 H), 2.25–2.30 (m, 4 H), 2.32 (t, J = 7.5 Hz, 2 H), 2.80 (s, 1 H), 3.69 (s, 3 H), 5.48 (d, J = 15.8 Hz, 1 H), 6.25 (dt, J = 7.4, 15.8 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 19.02, 19.17, 24.89, 27.61, 27.65, 28.22, 28.63, 28.73, 28.97, 32.43, 34.06, 51.48, 65.22, 65.60, 75.82, 76.93, 77.64, 82.39, 108.96, 146.13, 174.27. HRMS (EI): m/z [M⁺] calcd for C₂₁H₂₈O₂: 312.2089; found: 312.2084.
• 17 Xestospongenyne (2) Pd(PPh₃)₄ (43 mg, mmol), CuI (43 mg, 3.1 mmol), and (E/Z)-Br(CH₂)₂Br (0.74 g, 4.0 mmol) were added to a solution of ester 3 (312 mg, 1.0 mmol) in Et₃N (15 mL) under N₂, and the mixture was stirred at r.t. overnight. The mixture was then diluted with CHCl₃ (50 mL) and filtered through a pad of Florisil, rinsing with CHCl₃. The solvents were removed under reduced pressure and the crude mixture was purified by column chromatography (silica gel, 5% Et₂O–hexane) as a colorless oil; yield: 221 mg (53%); R_f = 0.12 (5% Et₂O–hexane). ¹H NMR (300 MHz, CDCl₃): δ = 1.27–1.33 (m, 6 H), 1.49–1.54 (m, 6 H), 1.62–1.65 (m, 2 H), 2.14–2.16 (m, 2 H), 2.24–2.30 (m, 4 H), 2.32 (t, J = 7.5 Hz, 2 H), 3.68 (s, 3 H), 5.57 (d, J = 16.2 Hz, 1 H), 6.18 (dt, J = 7.4, 15.9 Hz, 1 H), 6.32 (d, J = 13.8 Hz, 1 H), 6.65 (d, J = 14.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 19.02, 19.17, 24.88, 27.65, 27.67, 28.23, 28.63, 28.73, 28.97, 32.67, 34.05, 51.47, 65.22, 65.62, 76.91, 77.65, 84.64, 90.52, 109.58, 117.67, 117.72, 145.32, 174.26. HRMS (EI): m/z [M + Na]⁺ calcd for C₂₃H₂₉BrNaO₂: 439.1236, 441.1228; found: 439.1249, 441.1219.
• 18 Gung B.-W, Gibeau C, Jones A. Tetrahedron: Asymmetry 2004; 15: 3973