Formal Synthesis of Kanamienamide

Abstract

A formal total synthesis of the anticancer natural product kanamienamide has been accomplished. This communication describes two approaches to the macrocyclic core of the natural product. The key features of the route include an efficient macrolactamization, a Corey–Bakshi–Shibata asymmetric reduction, and a Stork–Zhao–Wittig olefination.

Key words

natural products - total synthesis - kanamienamide - macrocycles - lactams - lactones

• References and Notes

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• 26 11-[5-Iodopent-4-en-1-yl]-3-isobutyl-4,6,8-trimethyl-1-oxa-4-azacycloundecane-2,5-dione (2) Dess–Martin periodinane (42 mg, 0.1 mmol) was added to a stirred solution of compound 15 (23 mg, 65 µmol) and NaHCO₃ (25 mg, 0.3 mmol) in CH₂Cl₂ (5 mL), and the mixture was stirred at r.t. for 0.5 h. A 2.0 M aqueous solution of Na₂S₂O₃ (1 mL, 2 mmol) was added, and the mixture was extracted with EtOAc (30 mL). The organic layer was washed with brine (10 mL), dried (Na₂SO₄), and concentrated under reduced pressure to obtain the corresponding aldehyde as a colorless oil that was used in the next step without further purification. A 2.0 M solution of NaHMDS in THF (0.14 mL, 0.28 mmol) was added to an ice-cooled suspension of ICH₂P⁺Ph₃ I^– (160 mg, 0.3 mmol) in THF (5 mL). After 2 min, the mixture was cooled to –78 °C, and a solution of the aldehyde obtained above in THF (5 mL) was added dropwise. The mixture was maintained at –78 ° C for an additional 4 h, and then the reaction was quenched with sat. aq NH₄Cl (2 mL). The mixture was extracted with EtOAc (2 × 20 mL), and the organic extracts were combined, dried ­(Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography [silica gel, EtOAc–hexane (1:5)] to give 2 as a colorless oil; yield: 20 mg, (65%); [α]_D ²⁰ –48.0 (c = 1.5, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 6.22 (dt, J = 7.4, 1.3 Hz, 1 H), 6.16–6.09 (m, 1 H), 5.09–5.00 (m, 1 H), 4.53 (dd, J = 8.6, 6.8 Hz, 1 H), 2.87 (s, 3 H), 2.86–2.79 (m, 1 H), 2.19–2.09 (m, 2 H), 1.90–1.80 (m, 3 H), 1.75 (t, J = 11.4 Hz, 1 H), 1.67–1.52 (m, 3 H), 1.44–1.37 (m, 2 H), 1.37–1.29 (m, 1 H), 1.17–1.07 (m, 3 H), 1.09 (d, J = 6.7 Hz, 3 H), 1.07–0.96 (m, 1 H), 0.98 (d, J = 6.7 Hz, 3 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.85 (d, J = 6.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 178.9, 173.0, 140.6, 83.2, 77.1, 58.6, 43.4, 38.5, 35.0, 34.5, 34.3, 33.8, 31.6, 30.8, 29.0, 24.9, 23.8, 23.4, 22.4, 21.0, 18.8. HRMS (ESI): m/z [M + H]⁺ Calcd for C₂₁H₃₇INO₃: 478.1813; found: 478.1816.