Efficient Synthesis of (–)-Hanishin, (–)-Longamide B, and (–)-Longamide B Methyl Ester through Piperazinone Formation from 1,2-Cyclic Sulfamidates

Abstract

We describe a simple chiral-pool synthesis of (–)-longamide B, (–)-longamide B methyl ester, and (–)-hanishin. The key feature of the total synthesis is the formation of a piperazinone from a 1,2-cyclic sulfamidate and methyl 2-pyrrolecarboxylate, which permits efficient construction of the pyrrolopiperazinone core scaffold.

Key words

heterocycles - hanishin - longamide B - asymmetric synthesis - piperazinones - sulfamidates

• References and Notes

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• 11 (4S)-4-(2-Hydroxyethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (20) t-BuOK (33 mg, 0.29 mmol) was added to a mixture of sulfamidate 15 (101 mg, 0.27 mmol) and methyl pyrrole-2-carboxylate (8) (33 mg, 0.32 mmol) in MeCN (5.0 mL) at 0 °C, and the mixture was stirred at r.t. for 1.5 h. The reaction was quenched with 10% aq citric acid, and the mixture was extracted with EtOAc. The extracts were washed with sat. aq NaHCO₃ and brine, then dried (MgSO₄) and concentrated under reduced pressure. To a mixture of the residue in MeOH (2.0 mL) was added 4 M HCl in 1,4-dioxane (2.0 mL) at r.t., and the mixture was stirred at r.t. for 1 h. The mixture was evaporated under reduced pressure and the residue was washed with Et₂O and dried under reduced pressure. A mixture of the residue and Et₃N (0.22 mL, 1.6 mmol) in MeOH (7.0 mL) was stirred at r.t. for 1.5 h and then overnight at 50 °C. The mixture was the concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 10% MeOH–EtOAc) to give 20 as an off-white solid. Yield: 36 mg (75%); mp 130–134 °C; [α]_D ²⁷ –76.8 (c 0.59, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 6.93 (dd, J = 2.8, 1.6 Hz, 1 H), 6.75 (dd, J = 4.0, 1.2 Hz, 1 H), 6.11 (dd, J = 3.6, 2.4 Hz, 1 H), 4.34–4.38 (m, 1 H), 3.72 (dd, J = 13.2, 4.4 Hz, 1 H), 3.51–3.57 (m, 1 H), 3.35–3.42 (m, 2 H), 1.81–1.94 (m, 2 H). ¹³C NMR (100 MHz, CD₃OD): δ = 163.38, 125.33, 123.94, 114.84, 110.27, 59.06, 52.47, 45.43, 36.43. HRMS-ESI: m/z [M + Na] calcd for C₉H₁₂N₂NaO₂: 203.0791; found: 203.0794. (4S)-6,7-Dibromo-4-(2-hydroxyethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (21) NBS (87 mg, 0.49 mmol) was added to a solution of 20 (44 mg, 0.24 mmol) in DMF (4.0 mL) at –20 °C, and the mixture was stirred at the 20 °C for 15 min then at r.t. overnight. The reaction was then quenched with sat. aq NaHCO₃ and extracted with EtOAc. The extracts were washed with H₂O and brine then dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 5% MeOH–EtOAc) to give a colorless solid. Yield: 72 mg (87%); mp 139–142 °C; [α]_D ²⁷ –25.6 (c 0.23, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 6.91 (s, 1 H), 4.57–4.60 (m, 1 H), 3.80 (ddd, J = 13.8, 4.4, 0.8 Hz, 1 H), 3.63–3.69 (m, 3 H), 1.94–2.02 (m, 1 H), 1.80–1.87 (m, 1 H). ¹³C NMR (100 MHz, CD₃OD): δ = 159.72, 124.63, 115.85, 106.89, 100.72, 59.12, 52.34, 43.10, 34.39. HRMS-ESI: m/z [M + Na] calcd for C₉H₁₀Br₂N₂NaO₂: 360.9005; found: 360.8996. (S)-(–) -Longamide B (1) White solid; yield: 51 mg (74%); mp 225–227 °C; [α]_D ²⁸ –5.6 (c 0.40, MeOH) {Lit.^4a mp 208–210 °C; [α]_D ²⁰ –5.51 (c 1, MeOH)}. ¹H NMR (400 MHz, CD₃OD): δ = 6.93 (s, 1 H), 4.78–4.81 (m, 1 H), 3.88 (ddd, J = 13.8, 4.4, 1.6 Hz, 1 H), 3.66 (dd, J = 14.0, 0.8 Hz, 1 H), 2.84 (dd, J = 16.8, 11.2 Hz, 1 H), 2.53 (ddd, J = 16.6, 3.2, 1.2 Hz, 1 H). ¹³C NMR (100 MHz, CD₃OD): δ = 173.45, 161.08, 126.21, 116.59, 107.98, 101.66, 52.14, 43.76, 36.71. HRMS-ESI: m/z [M – H] calcd for C₉H₇Br₂N₂O₃: 348.8829; found: 350.8803.