Three-Component Coupling–Oxidative Amidation–Heterocycloannulation: Synthesis of the Indole Alkaloids Hamacanthin A and trans-2,5-Bis(3′-Indolyl)piperazine

Abstract

Concise and highly convergent syntheses of antifungal marine bis(indole) alkaloids, hamacanthin A and trans-2,5-bis(3′-indolyl)piperazine is described. The total synthesis of hamacanthin A is ­accomplished via the oxidative amidation–chemoselective heterocycloannulation of 2,2-dibromo-1-(1H-indol-3-yl)ethanone with 1-(1H-indol-3-yl)ethane-1,2-diamine. The reduction of desbromo hamacanthin with aluminum borohydride afforded the alkaloid trans-2,5-bis(3′-indolyl)piperazine. Two novel and convenient protocols for the synthesis of indolyl-1,2-diaminoethane are also developed in moderate to good yields.

Key words

bis(indole) alkaloids - hamacanthin A - trans-2,5-bis(3′-indolyl)piperazine - oxidative amidation - regioselective heterocycloannulation

• References and Notes

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• 17 General Procedure for the Oxidative Amidation–Heterocycloannulation; Synthesis of Hamacanthin A Derivatives: A solution of 2,2-dibromo-1-(6-bromo-1H-indol-3-yl)ethanone (5b; 0.2 g. 0.506 mmol) was prepared in anhyd dimethyl sulfoxide (6 mL; moisture content should be less than 0.5%, otherwise some keto acid will form in the reaction) under an argon atmosphere and the reaction mixture was slowly heated to 70–75 °C over a period of 1–2 h. The reaction mixture was then maintained at that temperature further for about 14–16 h. The reaction mixture was cooled to 50–55 °C. In another round bottom flask charged with diamine 4b (0.192 g, 0.757 mmol), Et₃N (0.255 g, 2.53 mmol) and anhyd dimethyl sulfoxide (4 mL) and stirred for 10–15 min the above prepared sulfonium bromide was added into the reaction mass, slowly heated to 80–85 °C and stirred for 24 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to 30–35 °C, then diluted with H₂O, (100 mL) and extracted with EtOAc (4 × 30 mL). The combined organic layer was then washed with H₂O (3 × 30 mL) and brine solution and dried over sodium sulfate. The EtOAc layer was then concentrated under reduced pressure. Pure sample was obtained by column chromatography (0.145 g, 60% yield) as a brown-colored solid. Hamacanthin A (1a): yield: 60%; brown-colored solid. IR (KBr): 3418, 3372, 2839, 2940, 2843, 1665, 1578, 1431, 1130, 1113, 799 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 4.05–4.17 (m, 2 H, H for CH₂N), 5.02 (ddd, J = 1.6, 4.3, 11.3 Hz, 1 H, CHN), 7.14 (dd, J = 1.8, 8.6 Hz, 1 H, H indole), 7.20 (dd, J = 1.8, 8.6 Hz, 1 H, H indole), 7.30 (d, J = 2.2 Hz, 1 H, H indole), 7.62 (d, J = 1.8 Hz, 1 H, H indole), 7.69 (d, J = 8.2 Hz, 1 H), 8.30 (d, J = 8.6 Hz, 1 H, H indole), 8.45 (d, J = 2.8 Hz, 1 H, H indole), 8.79 (d, J = 2.8 Hz, 1 H, H indole), 11.16 (s, 1 H, NH indole), 11.60 (s, 1 H, NH indole). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 46.4 (CHN), 53.6 (CH₂N), 110.6 (C indole), 111.7 (C indole), 112.7 (C indole), 113.2 (CH indole), 113.7 (CH indole), 118.7 (CH indole), 118.9 (C indole), 121.3 (CH indole), 123.4 (CH indole), 124.5 (CH indole), 124.6 (CH indole), 125.6 (CH indole), 127.7 (CH indole), 133.1 (CH indole), 134.9 (C indole), 136.4 (C indole), 157.4, 157.7 (Cq, C=O). LRMS (ESI): m/z = 485, 487, 489 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₅N₄OBr₂: 484.9613; found: 484.9622.
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• 19 trans-2,5-Bis(3′-indolyl)piperazine (3a): Into an oven-dried round-bottom flask a mixture of 6′,6′′didebromohamacanthin (1c; 0.2 g, 0.609 mmol), NaBH₄ (0.035 g, 0.914 mmol) and anhyd AlCl₃ (0.182 g, 1.371 mmol) in THF (4 mL) and AcOH (2 mL) was stirred for 6 h at r.t. and a solid was slowly precipitated out. It was filtered and washed with Et₂O which afforded the title compound (3a; 0.168 g, 72% yield) as its acetate salt.Light yellow solid; yield: 72%. IR (KBr): 3146, 1629, 1501, 1456, 1386 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.67 (dd, J = 13.7, 6.9 Hz, 2 H), 3.18 (dd, J = 11.3, 2.3 Hz, 2 H), 4.44 (dd, J = 10.7, 2.3 Hz, 2 H), 7.03 (t, J = 7.8 Hz, 2 H), 7.11 (t, J = 7.3 Hz, 2 H), 7.39 (d, J = 8.3 Hz, 2 H), 7.44 (s, 2 H), 7.75 (d, J = 7.9 Hz, 2 H), 11.13 (br s, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 22.9, 45.4, 49.8, 111.8, 121.5, 123.5, 125.7, 136.0, 170.5. LRMS (ESI): m/z = 317 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₁N₄: 317.1776; found: 317.1766.
• 20 Tonsiengsom F, Miyake FY, Yakushijin K, Horne DA. Synthesis 2006; 49-49