Synlett 2022; 33(14): 1377-1382
DOI: 10.1055/a-1806-6089
cluster
Organic Chemistry in Thailand

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

Punlop Kuntiyong
,
Nantachai Inprung
,
Sineenart Attanonchai
,
Wichita Kheakwanwong
,
Pijitra Bunrod
,
Sunisa Akkarasamiyo
The funding for this work was provided by the Thailand Research Fund (TRF) grants RSA6180040, DBG6080007, and The National Research Council of Thailand (NRCT) grant 2562#11892.


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.

Supporting Information



Publication History

Received: 14 February 2022

Accepted after revision: 23 March 2022

Accepted Manuscript online:
23 March 2022

Article published online:
25 April 2022

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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%); Rf = 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%); Rf = 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%); Rf = 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 Rf = 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 Rf = 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.