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Synlett 2002(3): 0495-0497
DOI: 10.1055/s-2002-20476
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Synthesis of the Kynurenamines K1 and K2, Metabolites of Melatonin

Gary Amiet, Helmut M. Hügel*, Faizul Nurlawis
RMIT University, Department of Applied Chemistry, GPO Box 2476V Melbourne 3001 Victoria, Australia
Fax: +61(3)99257477; e-Mail: helmut.hugel@rmit.edu.au;
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Publication History

Received 30 November 2001
Publication Date:
05 February 2007 (online)

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Abstract

An efficient synthesis of the kynurenamines K1 and K2, the major brain and antioxidant metabolites of melatonin 1 is described. Regioselective lithiation of tert-butyl(4-methoxyphenyl) carbamate and iodination provided the (2-iodoaryl)carbamate which when coupled with N-acetyl-propargylamine underwent a Sonogashira reaction. Simultaneous alkyne hydration and N-formyl­ation produced K2, whereas alkyne hydration only, produced K2.

Key words

kynurenamine synthesis - ortho lithiation - Sonogashira coupling - arylpropargylamine - alkyne hydration

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Metabolites of melatonin formed either in the peripheral or CNS are potent inhibitors of the calcium-dependent release of dopamine from retina. K2, (IC50: 10 nM) which is formed in the CNS are potent activators of melatonin receptor sites in retina.

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Reaction of 2 with γ-butyrolactone gave the required keto-alcohol product.

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To a solution of tert-butyl (4-methoxyphenyl) carbamate (10.0 g, 44.82 mmol) in dry THF (112 mL) under N2 at
-78 °C, was added a solution of tert-butyllithium in pentane (68.56 mL, 116.53 mmol). After 15 min the solution was warmed to -20 °C and kept at that temperature for 2.5 h whereupon a solution of 1,2-iodoethane (18.95 g, 67.23 mmol) in dry THF (40 mL) was added. The reaction mixture was stirred at ambient temperature overnight. After quenching with sat. aq Na2S2O3 solution (170 mL), the reaction mixture was extracted with Et2O (3 × 270 mL). The organic phase was washed with brine (160 mL), dried over Na2SO4, filtered and concentrated. Flash chromatography (hexane/Et2O, 10:1) afforded 3 (9.97 g. 63.74%) as colorless prisms, mp 49-51 °C. IR (KBr): 3346 (s), 2978 (m), 1700 (s), 1515 (s), 1163 (s)cm-1; 1H NMR (200 MHz, CDCl3): δ = 7.75 (d, J = 9.1 Hz, 1 H), 7.23 (d, J = 2.9 Hz), 6.85 (dd, J = 2.9, 9.0 Hz), 6.55 (br, 1 H), 3.76 (s, 3 H), 1.53 (s, 9 H); 13C NMR (90 MHz, CDCl3): δ = 155.9, 153.0, 132.3, 123.6, 114.8, 80.7, 55.6, 28.3; MS: m/z = 349 [M+].

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To a solution of 3 (1.75 g, 5 mmol), PdCl2[PPh3]2 (140.3 mg, 0.2 mmol), CuI (85 mg, 0.45 mmol), in dry Et3N (9.12 mL) at r.t. under N2 atmosphere, was slowly added N-acetyl propargylamine (0.65 g, 6.65 mmol) (30 min). The reaction mixture was stirred at r.t. for 1 h and then partitioned between Et2O (25 mL) and brine (7 mL). The organic layer was dried over MgSO4, filtered and evaporated to give 176 mg. Flash chromatography (ethyl acetate/hexane, 2:1) afforded 4, tert-butyl(2-[3′-N-acetylaminopropargyl]-4-methoxy phenyl) carbamate, (122 mg, 76.7%) as white crystals, mp 114-118 °C. IR (KBr): 3328 (s), 1698 (s), 1652 (s), 1525 (s), 1292 (s), 1163 (s)cm-1; 1H NMR (200 MHz, CDCl3): δ = 7.97 (d, J = 9.89 Hz, 1 H), 6.96 (br, 1 H), 6.96-6.83 (mt, 2 H), 6.05 (br, 1 H), 4.33 (d, J = 5.11 Hz, 2 H), 3.75 (s, 3 H), 2.05 (s, 3 H), 1.53 (s, 9 H); 13C NMR (90 MHz, CDCl3): δ = 199.91, 154.32, 152.69, 133.13, 119.68, 116.28, 115.83, 111.91, 91.42, 80.55, 78.50, 55.36, 29.91, 28.20, 22.79; HRMS (ES, Na): m/z = 341.1473 ([M + Na]+; calcd for C17H22N2O4Na: 341.3564).

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Mercuric sulfate (0.36 g, 1.13 mmol), distd H2O (2.75 mL), formic acid (19.25 mL) and DCM (11 mL) were magnetically stirred in a 100 mL round bottom flask until the mixture had dissolved. To this solution, 4 (0.36 g, 1.12 mmol) was added over 0.5 h and stirring at 42 °C was continued for 4 h. Solid NaHCO3 was added to adjust solution to pH 7-8 and the reaction mixture was freeze dried followed by extraction with EtOAc (3 × 50 mL). The organic phase was washed with H2O (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (EtOAc-MeOH, 30:1) afforded K 1 (0.165 g, 62%) as fine white needles, mp 142-144 °C and K 2 (0.0421 g, 14.1%), mp K 1 IR (KBr): 3331 (m), 1687 (s), 1671 (s), 1649 (s), 1540 (s), 1195 (s)cm-1; 1H NMR (200 MHz, CDCl3): δ = 11.15 (br, 1 H), 8.53 (d, J = 9.16 Hz, 1 H), 8.31 (d, J = 1.65 Hz, 1 H), 7.26 (d, J = 2.75 Hz, 1 H), 7.03 (dd, J = 2.75, 9.16 Hz), 6.99 (dd, J = 2.75, 9.16 Hz), 6.2 (br, 1 H), 3.72 (s, 3 H), 3.6-3.4 (m, 2 H), 3.2-3.1 (m, 2 H), 1.86 (s, 3 H); 13C NMR (90 MHz, CDCl3): δ = 203.20, 170.242, 159.35, 154.83, 133.10, 123.07, 120.66, 118.07, 115.46, 55.64, 39.64, 34.42, 23.19; HRMS (ES, Na): m/z = 287.1004 ([M + Na]+; calcd for C13H16N2O4Na: 287.2662).

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Mercuric sulfate (0.36 g, 1.13 mmol), 10% H2SO4 (25 mL) and CH3OH (10 mL) were magnetically stirred in a 100 mL round bottom flask until the mixture had dissolved. To this solution, 4 (0.36 g, 1.12 mmol) was added over 0.5 h and stirring at 42 °C was continued for 5 h. Solid NaHCO3 was added to adjust solution to pH 7-8 and the reaction mixture was freeze dried followed by extraction with EtOAc (3 × 50 mL). The organic phase was washed with H2O (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (EtOAc-MeOH, 30:1) afforded K 2 (0.154 g, 58%) as yellow powder, mp 86-88 °C. IR (KBr): 3446 (s), 3339 (s), 2937 (s), 1731 (s), 1651 (s), 1557 (s), 1237 (s)cm-1; 1H NMR (200 MHz, CDCl3): δ = 7.13 (d, J = 2.93 Hz, 1 H), 6.99 (dd, J = 2.93, 8.9 Hz, 1 H), 6.95 (dd, J = 2.93, 8.9 Hz, 1 H), 6.3 (br, 1 H), 5.8-5.0 (br, 2 H); 13C NMR (90 MHz, CDCl3): δ = 200.87, 170.10, 150.14, 145.04, 123.94, 118.83, 117.32, 112.95, 55.91, 38.72, 34.49, 23.30; HRMS (ES, Na): m/z = 259.1054 ([M + Na]+; calcd for C12H16N2O3Na: 259.2623).