Formal Syntheses of 5,8-Disubstituted Indolizidine Alkaloids (–)-205A, (–)-207A, and (–)-235B

Abstract

Formal total syntheses of (–)-indolizidines 205A, 207A, and 235B have been accomplished using Evans aldol, Horner–Wadsworth–Emmons olefination and reductive cyclization as key reactions.

Key words

alkaloid - indolizidine - Evans aldol - Horner–Wadsworth–Emmons olefination - reductive amination

• References and Notes

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• 19 Representative Procedures 3-{(2S,3R,6R)-6-[4-(tert-Butyldimethylsilyloxy)butyl]-3-methylpiperidin-2-yl}propan-1-ol (15) To a degassed solution of azido enone 5 (240 mg, 0.50 mmol) in EtOH (0.5 M) was added 10% Pd/C (5 mol%), and the heterogeneous mixture was stirred for 6 h under a hydrogen atmosphere at r.t. After filtration through Celite, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (silica gel, hexanes–EtOAc, 95:5) to afford piperidine 14 (144 mg, 83%) as a colorless oil. R_f = 0.50 (5% EtOAc in hexanes); [α]_D ²⁷ –22.6 (c 1.10, CHCl₃). IR (KBr): 3281, 2971, 2859, 1820, 1645, 1414, 1242, 937, 779 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 4.12 (br s, 1 H), 3.68–3.44 (m, 4 H), 2.58–2.42 (m, 1 H), 2.27–2.18 (m, 1 H), 1.83–0.96 (m, 15 H), 0.85 (s, 9 H), 0.81 (d, J = 6.7 Hz, 3 H), 0.01 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 62.9, 61.2, 57.9, 39.3, 35.9, 34.9, 33.3, 29.8, 25.9, 22.4, 18.4, –5.4. ESI-MS: m/z 366 [M + Na]⁺. HRMS (EI): m/z calcd for C₁₉H₄₂O₂NSi [M + H]⁺: 344.6344; found. 344.6347. 4-[(5R,8R,8aS)-8-Methyloctahydroindolizin-5-yl]butan-1-ol (4) To 15 (93 mg, 3.4 mmol) was added 0.1 N concentrated HCl (1.7 mL) in EtOH, and the mixture was stirred for 1 h at r.t. After the completion of reaction (monitored by TLC) the EtOH was evaporated under reduced pressure and 5% HCl (1.0 mL) added. The aqueous layer was washed with Et₂O (3 × 10 mL) and then basified with 2 N NaOH solution. The aqueous layer was extracted with Et₂O (2 × 10 mL), and the combined extracts dried over Na₂SO₄, filtered, and evaporated under reduced pressure to furnish 4 (44 mg, 74%) as yellow oil. R_f = 0.50 (5% MeOH in EtOAc). [α]_D ²⁷ –93.2 (c 0.5, MeOH). IR (KBr): ν_max = 3289, 3063, 2955, 2858, 1690, 1524, 1415, 1279, 1127, 1057, 838, 775 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.61 (t, J = 6.4 Hz, 2 H), 3.30 (dt, J = 8.3, 2.0 Hz, 1 H), 2.04–1.20 (m, 18 H), 0.95 (dq, J = 11.8, 4.4 Hz, 1 H), 0.85 (d, J = 6.6 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 71.2, 63.3, 62.6, 51.8, 36.4, 33.6, 33.1, 31.1, 29.6, 29.0, 22.0, 19.6, 18.8. ESI-MS: m/z = 326 [M + H]⁺. HRMS (EI): m/e calcd for C₁₃H₂₆NO [M + H]⁺: 212.2009; found: 212.2012.