Diastereoselective Synthesis of Tetrahydrofurano[2,3-g]indolizidines and 8-Aminoindolizidines from l-Asparagine

Abstract

8-Aminoindolizidines were synthesized from l-asparagine as the chiral starting material. The key dibenzylamino succinimide intermediate was synthesized in two steps. Three homologs of chiral hydroxy lactams tethered with hydroxyalkenes were synthesized from the succinimide through a sequence involving N-alkylation, cross-olefin metathesis, and hydride reduction. The dibenzylamino group gave stereocontrol of the key N-acyliminium ion cyclization of these hydroxy lactams. 5-Substituted aminoindolizidines were synthesized with high diastereoselectivity at C6. A tandem cyclization of an N-(6-hydroxyhex-3-en-1-yl) γ-hydroxy lactam resulted in the formation of a tetrahydrofurano[2,3-g]indolizidine system.

Key words

diastereoselective synthesis - aminoindolizidines - tandem cyclization - furanoindolizidines - asparagine

• References and Notes


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• 25 3-(Dibenzylamino)-N-(but-3-en-1-yl)succinimide (11); Typical Procedure K₂CO₃ (54 mg, 0.39 mmol), KI (3.2 mg, 0.019 mmol), and 4-bromobut-1-ene (24 μL, 0.23 mmol) were added to a solution of 3-(dibenzylamine)succinimide (10; 57 mg, 0.19 mmol) in DMF (5 mL) under argon at rt, and the mixture was stirred for 2 h. H₂O (20 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with H₂O (5 × 10 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give a green oil; yield: 52 mg (77%); R_f = 0.63 (hexane–EtOAc, 4:1); [α]_D ²⁰ –45.5 (c 0.6, CHCl₃). IR (film): 3084, 3029, 2939, 2847, 1774, 1702, 1398, 1360, 1195, 1130 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.45–7.08 (m, 10 H), 5.71 (ddt, J = 17.1, 10.2, 7.0 Hz, 1 H), 5.11–4.90 (m, 2 H), 3.87 (dd, J = 8.9, 5.4 Hz, 1 H), 3.80 (d, J = 13.5 Hz, 2 H), 3.67–3.52 (m, 4 H), 2.70 (dd, J = 18.5, 9.0 Hz, 1 H), 2.57 (dd, J = 18.5, 5.4 Hz, 1 H), 2.33 (q, J = 7.0 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 177.2, 175.2, 138.3 (2 C), 134.5, 128.7 (4 C), 128.5 (4 C), 127.4 (2 C), 117.5, 57.2, 54.6, 37.7, 32.1 (2 C). ESI-HRMS: m/z calcd [M + Na]⁺ for C₂₂H₂₄N₂NaO₂: 371.1730; found: 371.1725. 3-(Dibenzylamino)-N-[6-(benzoyloxy)hex-3-en-1-yl]succinimide (29); Typical Procedure But-3-en-1-yl benzoate (28; 840 mg, 4.76 mmol) and 2nd-generation Grubbs catalyst (6.5 mg, 6.9 μmol) were added to a solution of the butenylsuccinimide 11 (240 mg, 0.69 mmol) in anhyd CH₂Cl₂ (10 mL) under argon at rt, and the mixture was refluxed at 40 °C overnight. The mixture was then concentrated under reduced pressure and the crude product was purified by flash chromatography [silica gel, hexane–EtOAc (4:1)] to give a yellow oil; yield: 267 mg (78%); R_f = 0.39 (hexane–EtOAc, 4:1); [α]_D ²⁰ –24.8 (c 1.6, CHCl₃). IR (film): 3061, 3029, 2944, 2847, 1699, 1272, 1160, 1112, 712, 698 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 8.01 (d, J = 8.2 Hz, 2 H), 7.70–7.12 (m, 13 H), 5.66–5.40 (m, 2 H), 4.25 (t, J = 7.2 Hz, 2 H), 3.92 (dd, J = 8.8, 4.9 Hz, 1 H), 3.82 (d, J = 13.4 Hz, 2 H), 3.62 (d, J = 13.4 Hz, 2 H), 3.56 (t, J = 7.0 Hz, 2 H), 2.74 (dd, J = 18.6, 9.0 Hz, 1 H), 2.60 (dd, J = 18.6, 5.3 Hz, 1 H), 2.52–2.25 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 175.4, 173.3, 164.6, 136.3 (2 C), 131.0, 127.7, 127.0 (4 C), 126.6 (4 C), 125.6 (2 C), 62.3, 55.5, 52.7 (2 C), 36.2, 30.1, 29.2, 16.6. ESI-HRMS: m/z calcd [M + H]⁺ for C₃₁H₃₃N₂O₄: 497.2440; found: 497.2440. 3-(Dibenzylamino)-5-hydroxy-1-(6-hydroxyhex-3-en-1-yl)pyrrolidin-2-one (30); Typical Procedure DIBAL-H (0.62 mL, 1.2 M, 0.75 mmol) was added to a solution of succinimide 11 (122 mg, 0.25 mmol) in anhyd CH₂Cl₂ (10 mL) under argon at –78 °C, and the mixture was stirred for 2 h at 0 °C. Sat. aq. NaHCO₃ (5 mL) was added dropwise and the resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography [silica gel, hexane–EtOAc (1:5)] to give an orange oil; yield: 91 mg (92%); R_f = 0.29 (hexane–EtOAc, 1:5); [α]_D ²⁰ –20.7 (c 1.0, CHCl₃). IR (film): 3412, 3028, 2925, 2880, 1674, 1453, 1433, 1264, 1074, 1028, 732, 698 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.55–7.08 (m, 10 H), 5.61–5.18 (m, 2 H), 4.75–4.92 (m, 1 H), 3.84 (d, J = 13.7 Hz, 2 H), 3.62 (d, J = 13.7 Hz, 2 H), 3.60–3.34 (m, 5 H), 3.33–3.10 (m, 2 H), 2.50–2.00 (m, 5 H), 1.80–1.60 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 172.4, 138.7 (2 C), 129.4, 128.0 (4 C), 127.6, 127.2 (4 C), 126.1 (2 C), 78.9, 64.0, 60.5, 57.8, 53.4 (2 C), 39.0, 34.5, 31.3, 29.9, 28.7. ESI-HRMS: m/z calcd [M + H]⁺ for C₂₄H₃₁N₂O₃: 395.2329; found: 395.2331. (3aS,8S,9aR,9bS)-8-(Dibenzylamino)octahydrofuro[2,3-g]indolizin-7(3aH)-one (32) and (2S,8aR)-2-(Dibenzylamino)-8-(2-hydroxyethyl)-1,5,6,8a-tetrahydroindolizin-3(2H)-one (33); Typical Procedure TMSOTf (0.13 mL, 0.70 mmol) was added to a solution of hydroxy lactam 30 (95 mg, 0.24 mmol) in dry CH₂Cl₂ (5 mL) under argon at 0 °C, and the mixture was stirred for 3 h at 0 °C to rt. Sat. aq. NaHCO₃ (5 mL) was added dropwise, and the resulting mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography [silica gel, hexane–EtOAc (1:2)] to give 32 [yield: 47 mg (52%)] and 33 [yield: 20 mg (22%)] as pale-yellow oils. 32 R_f = 0.51 (hexane–EtOAc, 1:5); [α]_D ²⁰ –13.8 (c 1.3, CHCl₃). IR (film): 3027, 2926, 2878, 1677, 1452, 1430, 1257, 1145, 1074, 733, 698 cm^–1. ¹H NMR (300 MHz, CDCl₃) δ7.67–7.11 (m, 10 H), 4.35 (dd, J = 13.4, 4.3 Hz, 1 H), 4.15–3.80 (m, 4 H), 3.82–3.60 (m, 3 H), 3.35 (dt, J = 10.0, 4.3 Hz, 1 H), 3.20 (dt, J = 10.6, 3.5 Hz, 1 H), 2.67 (dt, J = 13.0, 3.6 Hz, 1 H), 2.29–1.90 (m, 2 H), 1.80–1.50 (m, 2 H), 1.42 (dd, J = 12.0, 5.5 Hz, 1 H), 1.34 (dd, J = 12.0 Hz, 1 H), 1.11 (dq, J = 10.4, 7.1 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 175.5, 139.5 (2 C), 128.9 (4 C), 128.4 (4 C), 127.3 (2 C), 81.2, 76.6, 66.9, 59.8, 55.1 (2 C), 50.7, 37.5, 29.9, 28.2, 28.0. ESI-HRMS calculated for C₂₄H₂₉N₂O₂ [M+H]⁺: 377.2229; found: 377.2229. 33 R_f = 0.40 (hexane–EtOAc, 1:5); [α]_D ²⁰ –8.4 (c 1.3, CHCl₃). IR (film): 3412, 3028, 2925, 2880, 1674, 1453, 1433, 1264, 1074, 1028, 732, 698 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.60–7.12 (m, 10 H), 5.54 (d, J = 4.7 Hz, 1 H), 4.24 (dd, J = 12.0, 6.0 Hz, 1 H), 4.19–4.05 (m, 1 H), 4.20–3.79 (m, 3 H), 3.78–3.57 (m, 5 H), 2.79 (dt, J = 12.0, 4.5 Hz, 1 H), 2.39–2.10 (m, 3 H), 2.09–1.50 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.2, 137.7 (2 C), 133.9, 127.1 (4 C), 126.5 (4 C), 125.3 (2 C), 119.7, 59.1, 58.2, 53.9, 52.9, 35.8, 34.5, 28.2, 28.0, 24.4. ESI-HRMS calculated for C₂₄H₂₉N₂O₂ [M+H]⁺: 377.2229; found: 377.2229.