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

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.

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

References

1a Sack RL. Lewy AJ. Parrot K. Singer CM. McArthur AJ. Blood ML. Bauer VK. Eur. J. Med. Chem.  1995,  30:  661 

1b Dollins AB. Zhdanova IV. Wurtman RJ. Lynch HJ. Deng MH. Proc. Natl. Acad. Sci. U.S.A.  1994,  91:  1824 

1c Zhdanova IV. Wurtman RJ. Lynch HJ. Ives JR. Dollins AB. Morabito C. Matheson JK. Schomer DL. Clin. Pharmacol. Ther.  1995,  57:  552 

2a Petrie K. Conaglen JV. Thompson L. Chamberlain K. Br. Med. J.  1989,  298:  705 

2b Arendt J. Aldhous M. Marks V. Annu. Rev. Chronopharmacol.  1986,  3:  49 

3 Odani A. Ferini-Strambi L. Zucconi M. Stankof B. Frachini F. Smirne S. Neuro Report  1994,  6:  132 

4a Reiter RJ. Menendez-Pelaez A. Poeggeler B. Tan D.-X. Pablos MI. Acuna-Castroviejo D. Advances in Pineal Research   Moller M. Pevet P. John Libbey and Co.; London: 1994.  p.403 

4b Marshall K.-A. Reiter RJ. Poeggeler B. Aruoma OI. Halliwell B. Free Radical Biol. Med.  1996,  21:  307 

4c Cuzzocrea S. Zingarelli B. Gilad E. Hake P. Salzman AL. Szabo CJ. Pineal Res.  1997,  23:  106 

4d Reiter RJ. Tang L. Garcia JJ. Munos-Hoyos A. Life Sci.  1997,  62:  853 

4e Antunes F. Barclay LRC. Ingold KU. King M. Norris JQ. Scaiano JC. Xi P. Free Radical Biol. Med.  1999,  26:  117 

5 Zhang H. Squadrito GL. Uppu R. Pryor WA. Chem. Res. Toxicol.  1999,  12:  526 

6 Turjanski AG. Rosenstein RE. Estrin DA. J. Med. Chem.  1998,  41:  3684 

7

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.

8 Hirata F. Hayaishi O. Tokuyama T. Senboh S. J. Biol. Chem.  1974,  249:  1311 

9 Nakagawa M. Okajima H. Hino T. J. Am. Chem. Soc.  1977,  99:  4424 

10 Kondo Y. Kojima S. Sakamoto T. J. Org. Chem.  1997,  62:  6507 

11

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

12a Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  4467 

12b Sonogashira K. In Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Fleming L. Pergamon Press; New York: 1991.  Chap. 2.4.

These compounds have been prepared form Weinreb amides, see:

13a Gomtsyan A. Org. Lett.  2000,  2:  11 

13b Gomtsyan A. Koenig RJ. Lee C.-H. J. Org. Chem.  2001,  66:  3613 

14

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 Na₂SO_4, 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⁺].

15

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).

16

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).

17

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).