An efficient synthesis of 6-hydroxymelatonin, a human metabolite of melatonin

Article abstract of DOI:10.1016/S0040-4039(02)02763-6

A four-step synthesis of 6-hydroxymelatonin 5, major human metabolite of melatonin 1, is reported starting from melatonin. The synthesis involves in the keys steps a regioselective Friedel-Crafts acylation followed by a Baeyer-Villiger oxidation. The overall yield is 48%.

Full text of DOI:10.1016/S0040-4039(02)02763-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1511–1513
An efficient synthesis of 6-hydroxymelatonin, a human
metabolite of melatonin
Omar Karam,* Fabien Zunino,* Vincent Chagnaut, Marie Paule Jouannetaud and
Jean Claude Jacquesy
Laboratoire ‘Synthe`se et Re´activite´ des Substances Naturelles’, UMR 6514, 40, Avenue du Recteur Pineau,
F-86022 Poitiers Cedex, France
Received 26 November 2002; revised 29 November 2002; accepted 30 November 2002
Abstract—A four-step synthesis of 6-hydroxymelatonin 5, major human metabolite of melatonin 1, is reported starting from
melatonin. The synthesis involves in the keys steps a regioselective Friedel–Crafts acylation followed by a Baeyer–Villiger
oxidation. The overall yield is 48%. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Hydroxylation is an important route by which mam-
mals detoxify aromatic compounds. The major
metabolic process for removal of melatonin 1 is by
hydroxylation of benzene rings in liver microcosms.4
The resulting 6-hydroxymelatonin 5 is conjugated as a
sulfate ester (55–80%) and a glucuronide (5–30%), and
excreted in urine.5 The use of 6-hydroxymelatonin 5 in
combination with a progesterone and/or an estrogen
has been reported as a method for contraception by an
ovulation-inhibiting effect.6
5-Methoxy N-acetyltryptamine (1), the compound
known as melatonin, is a hormone produced and
secreted in the pineal gland.1 The exact role of this
hormone has not yet been determined, the most impor-
tant action of melatonin being in reproductive activity
of animals.2 The possible involvement of melatonin 1 in
seasonal affective disorder, circadian rhythm disorder,
depression or aging has also been reported.3
Scheme 1.
* Corresponding authors. Tel.: +33-(0)5-49-453702; fax: +33-(0)5-49-453501; e-mail: omar.karam@univ-poitiers.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02763-6

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O. Karam et al. / Tetrahedron Letters 44 (2003) 1511–1513
The synthesis of the 6-hydroxymelatonin 5 has been
reported starting from non-commercial 6-benzyloxy-5-
methoxyindole,7 utilizing the Mannich base methodol-
ogy (six steps, 23%),8 or by the Knoevenagel
condensation route (five steps, 19%).9
References
1. Lerner, A. B.; Case, J. D. J. Am. Chem. Soc. 1959, 81,
6084–6085.
2. (a) Reiter, R. J. Endocrine Rev. 1991, 12, 151–180; (b)
Kennaway, D. P. Pineal Res. Rev. 1984, 2, 113–140.
3. (a) Wehr, T. A.; Rosenthal, N. F. Am. J. Psychiatry 1989,
146, 829–839; (b) Lewy, A. J.; Sack, R. L. US Patent
5,242,941, 1994; (c) Rubin, R. T.; Heist, E. K.; McGeory,
S. S.; Hanada, K.; Lesser, I. M. Arch. Gen. Psychiatry
1992, 49, 558–567; (d) Armstrong, S. M.; Redman, J. R.
Med. Hypothesis 1991, 34, 300–309.
In this paper, we describe a more efficient four-step
synthesis of this metabolite from melatonin.
2. Results and discussion
Whereas the elaboration of the tryptamine side-chain is
readily effected by conventional means, versatile meth-
ods for the introduction of functionality into the benzene
ring are lacking and usually involve classical electrophile
substitution or prior incorporation of the substitution in
the de novo indole ring construction.10 Direct oxidation
of melatonin with ozone or m-chloroperbenzoic acid
(m-CPBA),11 singlet oxygen,12 or a mixture of HCl and
DMSO,13 always affects the pyrrole ring of melatonin 1.
Herein, we report a more efficient synthesis of 6-hydroxy-
melatonin 5 prepared as outlined in Scheme 1.
4. Kopin, I. J.; Pare, C. M.; Axelrod, J.; Weisbach, H. J.
Biol. Chem. 1961, 236, 3072–3075.
5. (a) Slsak, M. E.; Markey, S. P.; Colburn, R. W.; Zavadil,
A. P.; Kopin, I. J. Life Sci. 1979, 25, 803–806; (b) Greer,
M.; Williams, C. M. Clin. Chim. Acta 1967, 15, 165–168;
(c) Fellenberg, A. J.; Phillipou, G.; Seamark, R. F.
Endocr. Res. Commun. 1980, 7, 167–175.
6. Cohen, M. WO Patent 9,014,084A1, 1990.
7. Julia, M.; Manoury, P.; Voillaume, C. Bull. Soc. Chim.
1965, 5, 1417–1423.
8. Taborsky, R. G.; Delviges, P.; Page, I. H. J. Med. Chem.
1965, 8, 855–858.
The improvement of the synthesis is based on the choice
of the N-protecting groups of melatonin 1. Therefore,
compound 2 was prepared to favour acylation on the
benzene ring, the N-acylation protecting the pyrrole
ring.14
9. Hall, D. E.; Jackson, A. H. J. Chem. Soc. (C) 1967,
1681–1682.
10. (a) Sundberg, R. G. The Chemistry of Indoles; Academic
Press: New York, 1970; (b) Besswick, P. J.; Greenwood,
C. S.; Mowlem, T. J.; Nechvatal, G.; Widdowson, D. A.
Tetrahedron 1988, 44, 7325–7334.
The reaction of melatonin 1 with ethyl chloroformate,
tetrabutylammonium hydrogenosulfate (TBAHS) and
sodium hydroxide in dichloromethane gave the carba-
mate 2 in good yield (93%).
11. Hirata, F.; Hayaishi, O.; Tokuyama, T.; Senoh, S. J.
Biol. Chem. 1974, 249, 1311–1313.
12. Nakagawa, M.; Chiba, J.; Hino, T. Heterocycles 1978, 9,
385–390.
13. Hugel, H. M. Org. Prep. Proc. Int. 1995, 27, 3–31.
14. (a) Jackson, A. H.; Naido, B.; Smith, A. E.; Bailey, A. S.;
Vandervala, M. H. J. Chem. Soc., Chem. Commun. 1978,
779–781; (b) Edward, J. G.; David, G. R.; Victor, S. J.
Org. Chem. 1995, 60, 1484–1485; (c) Shin-ichi, N.; Kat-
sunori, T.; Toshio, G. Tetrahedron Lett. 1994, 35, 2699–
2700; (d) Shin-ichi, N.; Katsunori, T.; Toshio, G.
Synthesis 1994, 10, 1018–1020.
A regioselective Friedel–Crafts acylation at the 6-posi-
tion of 2,15 using acetyl chloride and aluminium chloride
for 60 min at 20°C, afforded the desired compound 3a16
(84% yield). Structure of compound 3a was determined
1
using COSY H–1H and HMQC spectra. It should be
pointed out that phenol 3b was formed (95%) when the
reaction was carried out overnight under the same
conditions.
15. Preparation of 2: To a stirred suspension of melatonin 1
(1.01 g, 4.3 mmol) and sodium hydroxide (5.2 g, 0.13
mol) was added ethylchloroformate (1.75 mL, 18.3 mmol)
and tetrabutylammonium hydrogensulfate (1.46 g, 4.3
mmol) in dichloromethane (92 mL). The mixture was
then stirred for 1 h at rt. The reaction mixture was
filtered, and the organic phase was washed three times
with water, dried over MgSO4, and evaporated to dry-
ness. Upon the addition of ether a white solid was
obtained. Recrystallization from ether gave white crys-
talline 2 (1.24 g, 93%): mp 100–101°C; IR (CHCl3): wmax
Baeyer–Villiger oxidation of compound 3a, with m-
CPBA in dichloromethane in the presence of trifl-
uoroacetic acid at 20°C for 60 min, afforded compound
417 in good yield (83%). Removal of the acyl and
carbamate groups was accomplished under basic condi-
tions (NaOH/MeOH) furnishing 6-hydroxymelatonin 518
in 65% yield.
1
3. Conclusion
3289, 1731, 1652 cm−1; H NMR (CDCl3, 300 MHz): l
8.00 (1H, d, J=8.2 Hz, H-7), 7.41 (1H, s, H-2), 7 (1H, s,
J=2.3, H-4), 6.94 (1H, dd, J=9, 2.6 Hz, H-6), 5.82 (1H,
sl, NH), 4.44 (2H, q, J=7.1 Hz, H-12), 3.86 (3H, s,
CH3O), 3.57 (2H, q, 6.9 Hz, H-9), 2.87 (2H, t, J=6.75
Hz, H-8), 1.98 (3H, s, NCOCH3), 1.48 (3H, t, J=6.3 Hz,
H-13); 13C NMR (CDCl3, 75 MHz): l 118.25 (C-2),
116.07 (C-7), 113.30 (C-6), 101.77 (C-4), 63.07 (C-12),
55.75 (CH3O), 39.04 (C-9), 25.14 (C-8), 23.34 (NCOCH3),
14.45 (C-13); EIMS: m/z 304 [M]+ (60), 245 (100), 232
This work constitutes an efficient direct functionalization
of the benzene moiety of melatonin 1. Selective 6-substi-
tution can be achieved via carbamate protection and
Friedel–Crafts acetylation. The utility of this methodol-
ogy for the modification of indole derivatives in total
synthesis is noteworthy. This strategy provided access to
the major melatonin metabolite 5 in four steps with a
satisfactory overall yield (48%) from melatonin.

O. Karam et al. / Tetrahedron Letters 44 (2003) 1511–1513
1513
(30), 160 (95). Anal. calcd for C16H20N2O4: C, 63.14; H,
6.62; N, 9.20. Found: C, 63.40; H, 6.83; N, 9.26%.
m-CPBA (800 mg, 4.6 mmol) at 0°C and the mixture was
stirred at rt for 2 h. Na2HPO4 (3.5 mmol) and Na2SO3
(3.5 mmol) were added successively to the mixture, and
the suspension was vigorously stirred for 30 min. Insolu-
ble materials were filtered off and the filtrate was quickly
washed with chilled NaHCO3 solution, dried, and con-
centrated. The residue was purified by column chro-
matography eluted with CHCl3:MeOH (95:5) to give 4
16. Preparation of 3a: To a suspension of AlCl3 (7.17 g, 53
mmol) in 1,2-dichloroethane (210 mL) was added
acetylchloride (5 mL, 70 mmol) dropwise at 0°C. The
mixture was stirred at rt for 5 min. To this solution was
added 2 (3 g, 9.8 mmol) in 1,2-dicholorethane (150 mL).
The resulting mixture was stirred for an additional 30
min at rt, then poured into water (50 mL) and extracted
with dichloroethane. The combined extracts were then
dried over MgSO4 and evaporated under reduced pres-
sure to give 3a as white solid. Recrystallization from
ethylacetate gave white crystalline 3a (2.87 g, 84%): mp
1
(1.05 g, 83%): H NMR (CDCl3, 300 MHz): l 7.85 (1H,
sl, H-7), 7.37 (1H, s, H-2), 7.06 (1H, s, H-4), 5.05 (1H, sl,
NH), 4.42 (2H, q, J=7.1 Hz, H-13), 3.87 (3H, s, CH3O),
3.48 (2H, q, J=6.8 Hz, H-9), 2.82 (2H, t, J=6.75 Hz,
H-8), 2.34 (3H, s, CH3CO), 1.91 (3H, s, NCOCH3), 1.43
(3H, t, J=7.1 Hz, H-14); 13C NMR (CDCl3, 75 MHz): l
123.499 (C-2), 110.496 (C-7), 101.896 (C-4), 63.598 (C-
13), 56.639 (CH3O), 39.376 (C-9), 25.445 (C-8), 23.542
(NCOCH3), 21.038 (CH3COO), 14.772 (C-14); EIMS:
m/z 362 [M]+ (35), 320 (80), 261 (100), 176 (67). Anal.
calcd for C18H22N2O6: C, 59.66; H, 6.12; N, 7.73. Found:
C, 59.43; H, 6.25; N, 7.62%.
1
184–185°C; IR (CHCl3): wmax 3403, 1721, 1660 cm−1; H
NMR (CDCl3, 300 MHz): l 8.35 (1H, s, H-7), 7.48 (1H,
s, H-2), 7.03 (1H, s, H-4), 6.51 (1H, t, J=5.5 Hz, NH),
4.42 (2H, q, J=7.1 Hz, H-13), 3.94 (3H, s, CH3O), 3.57
(2H, q, J=6.8 Hz, H-9), 2.87 (2H, t, J=6.9 Hz, H-8),
2.62 (3H, s, CH3CO), 2.00 (3H, s, NCOCH3), 1.44 (3H, t,
J=7.2 Hz, H-14); 13C NMR (CDCl3, 75 MHz): l 125.5
(C-2), 118.24 (C-7), 100.68 (C-4), 63.36 (C-13), 55.79
1
18. Spectral data for 5: H NMR (CDCl3, 300 MHz): l 7.86
(1H, s, NH), 7.00 (1H, s, H-8), 6.93 (1H, s, H-7), 6.85
(1H, s, H-2), 5.73 (1H, s, OH), 5.44 (1H, sl, NHCO), 3.95
(3H, s, CH3O), 3.60 (2H, q, J=6.5 Hz, H-8), 2.94 (2H, t,
J=6.8 Hz, H-9), 1.94 (3H, s, H-10); 13C NMR (CDCl3,
75 MHz): l CH aromatics, 57 (CH3O), 40 (C-8), 26
(C-9), 24 (C-10).
(CH3O), 39.05 (C-9), 31.82 (C6 H3CO), 25.09 (C-8), 23.25
(C-11), 14.37 (C-14); EIMS: m/z 346 [M]+ (60), 287 (100),
272 (85), 202 (86). Anal. calcd for C18H22N2O5: C, 62.42;
H, 6.40; N, 8.09. Found: C, 62.48; H, 6.50; N, 8.13%.
17. Preparation of 4: To a solution of 3a (1.22 g, 3.5 mmol)
and trifluoroacetic acid (0.3 mL, 4 mmol) was added 80%