Diastereoselective Synthesis of Enantiopure γ-Butenolide-butyrolactones towards Pseudopterogorgia Lactone Furanocembranoid Substructures

Abstract

A diastereoselective methodology for preparing trans-γ-lactone-γ-butenolides through vinylogous aldol additions of siloxyfuranes to enantiopure cyclopropylcarbaldehyde followed by a tin-catalyzed retroaldol–lactonization cascade is reported. This synthetic approach is applied to a short synthesis of an exo-trienol furan lactone substructure relevant to bielschowskysin and other related coral diterpenoid natural products.

Key words

marine furanocembranoids - asymmetric synthesis - ­vinylogous Mukaiyama addition - lactones - furans

• References and Notes


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• 7 Representative Procedure for Butenolide-Lactone Synthesis (8d) Under a nitrogen atmosphere, BF₃ ·OEt₂ (0.28 mL, 2.21 mmol) was added via syringe to a solution of cyclopropylcarboxaldehyde (+)-4 (500 mg, 2.01 mmol) in anhyd CH₂Cl₂ (20 mL) at –78 °C. After stirring for 30 min, a solution of 6d in CH₂Cl₂ (2.11 mmol) was added slowly, resulting in an orange-colored solution. After stirring for 16 h at –78 °C, sat. aq NaHCO₃ (45 mL) was added, and the mixture was allowed to warm to r.t. The layers were separated, and the aqueous layer was extracted three times with EtOAc (45 mL each). The combined organic layers were washed with brine (45 mL), H₂O (45 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo to give the carbinol cyclopropane 9d which was used for the next step without further purification. A round-bottomed flask, equipped with Dean–Stark trap was charged with crude cyclopropyl carbinol 9d (approx. 1 equiv) followed by ethylene glycol (224 μL, 4.02 mmol, 2 equiv) and Sn catalyst 10 (5 mol%). The mixture was gently refluxed for 12 h, after which the crude mixture was evaporated and purified by chromatography on silica gel (EtOAc–hexanes = 3:1) to furnish compound 8d. (2S,3S,2′S)-3-[1,3]Dioxolan-2-yl-3′-methyl-3,4-dihydro-2H,2′H-[2,2′]bifuranyl-5,5′-dione (8d) Yield 331 mg (65%), [α]_D ²⁵ +3.6 (c 0.3, MeOH), colorless crystals, mp 97–98 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.87 (m, 1 H), 4.94 (d, J = 4.1 Hz, 2 H), 4.69 (dt, J = 11.7, 5.8 Hz, 1 H), 4.10–3.86 (m, 4 H), 3.03 (td, J = 9.9, 4.4 Hz, 1 H), 2.79 (m, 1 H), 2.49 (dd, J = 18.0, 5.4 Hz, 1 H), 2.16 (dd, J = 12.3, 1.0 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 175.1, 172.2, 164.3, 118.3, 103.3, 84.5, 75.7, 65.8, 40.1, 29.4, 14.0. HRMS (EI): m/z calcd for C₁₂H₁₃O₆ 253.0712 [M – H]⁺; found: 253.0710. IR (neat): 2932, 2902, 2864, 1779, 1730, 1646, 1402, 1266, 1188, 1147, 1089, 1019, 975, 899 cm^–1
• 8 Details on this X-ray crystal structure can be obtained from the Cambridge Crystallographic Data Center quoting CCDC 901653; see also the Supporting Information.
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• 12 A mixture of 12 (50 mg, 0.21 mmol), ethyl methacrylate (105 μL, 0.84 mmol), Pd(OAc)₂ (2.4 mg, 0.011 mmol), Cu(OAc)₂·H₂O (84 mg, 0.42 mmol), and LiOAc (55 mg, 0.84 mmol) was stirred in DMF (1 mL) at 117 °C under air. After cooling, the reaction mixture was extracted with EtOAc and dried (Na₂SO₄). Compound 13 was purified by preparative reversed-phase HPLC using a gradient-elution method with increasing amounts of MeCN in H₂O. 2-{(2′S,3′S)-3′-[1,3]Dioxolan-2-yl-3-methyl-5′-oxo-2′,3′,4′,5′-tetrahydro[2,2′]bifuranyl-5-ylmethyl}acrylic Acid Ethyl Ester (13) Yield 38 mg (52%). [α]_D ²⁵ +54.4 (c 0.4, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 6.24 (t, J = 3.3 Hz, 1 H), 5.91 (s, 1 H), 5.52 (t, J = 4.2 Hz, 1 H), 5.41 (m, 1 H), 4.92 (t, J = 3.9 Hz, 1 H), 4.22 (m, 2 H), 4.05–3.87 (m, 4 H), 3.57 (d, 2 H), 3.13 (m, 1 H), 2.87 (m, 1 H), 2.63 (m, 1 H), 2.03 (t, 3 H), 1.30 (t, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.9, 165.8, 152.1, 143.0, 135.9, 125.5, 119.8, 109.5, 101.6, 72.2, 64.3, 59.4, 41.2, 29.6, 28.3, 13.0, 8.9. HRMS (EI): m/z calcd for C₁₈H₂₂O₇ [M]⁺: 350.1366; found: 350.1364. IR (neat): 2962, 2904, 1779, 1714, 1634, 1406, 1260, 1196, 1024, 947, 795 cm^–1.
• 13 A solution of 13 (15 mg, 0.042 mmol) in a mixture of MeOH (50 μL) and Et₂O (35 μL) was stirred and cooled to –40 °C. Bromine (7.1 μL, 0.044 mmol) in dry MeOH (0.1 mL) was added dropwise over 5 min. After addition, stirring was continued for an additional 10 min. The mixture was saturated with NH₃ gas to pH 8, allowed to warm to r.t., diluted with Et₂O and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 EtOAc–hexanes) to afford a 1:1 mixture of 15 and 3-epi-15. 2-[(2S,2′S,3′S)-3′-[1,3]Dioxolan-2-yl-2-methoxy-3-methyl-5′-oxo-2′,3′,4′,5′-tetrahydro-2H-[2,2′]bifuranyl-(5Z)-ylidenemethyl]acrylic Acid Ethyl Ester (15) Yield 8.8 mg, 55%. ¹H NMR (300 MHz, CDCl₃): δ = 6.34 (s, 1 H), 6.18 (q, J = 1.4 Hz, 1 H), 5.41 (d, J = 5.1 Hz, 1 H), 4.85 (d, J = 3.5 Hz, 1 H), 4.50 (d, J = 2.1 Hz, 1 H), 4.28–4.18 (m, 2 H), 4.00–3.85 (m, 4 H), 3.47 (s, 2 H), 3.14 (s, 2 H), 2.84 (m, 1 H), 2.68 (m, 1 H), 2.42 (m, 1 H), 1.95 (s, 3 H), 1.31 (t, J = 3.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 176.7, 166.9, 157.6, 141.2, 133.7, 127.1, 124.1, 115.0, 103.9, 94.0, 81.1, 65.8, 61.3, 50.9, 50.4, 38.4, 28.9, 14.1, 12.4. HRMS (EI): m/z calcd for C₁₉H₂₄O₈ [M]⁺: 380.1471; found: 380.1478. IR (neat): 2904, 1782, 1710, 1636, 1447, 1366, 1244, 1130, 1021, 957, 942, 852 cm^–1.
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