Efficient route to the pineal hormone melatonin by radical-based indole synthesis

Article abstract of DOI:10.1081/SCC-120024751

The hormone melatonin, which is known to have a range of important biological effects, has been prepared in a high-yielding route that features formation of the indole nucleus by radical cyclization. Mediation of the radical cyclization by tristrimethylsilylsilane (TTMSS) is more efficient than by N-ethylpiperidine hypophosphite.

Full text of DOI:10.1081/SCC-120024751

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Efficient Route to the Pineal Hormone Melatonin by
Radical-Based Indole Synthesis
Douglas W. Thomson a , Aurélien G. J. Commeureuc a , Stefan Berlin a & John A. Murphy a
a Department of Pure and Applied Chemistry , University of Strathclyde , Glasgow, UK
Published online: 15 Aug 2006.
To cite this article: Douglas W. Thomson , Aurélien G. J. Commeureuc , Stefan Berlin & John A. Murphy (2003) Efficient Route
to the Pineal Hormone Melatonin by Radical-Based Indole Synthesis, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 33:20, 3631-3641, DOI: 10.1081/SCC-120024751
To link to this article: http://dx.doi.org/10.1081/SCC-120024751
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 20, pp. 3631–3641, 2003
Efficient Route to the Pineal Hormone
Melatonin by Radical-Based Indole Synthesis
´
Douglas W. Thomson, Aurelien G. J. Commeureuc,
*
Stefan Berlin, and John A. Murphy
Department of Pure and Applied Chemistry,
University of Strathclyde, Glasgow, UK
ABSTRACT
The hormone melatonin, which is known to have a range of important
biological effects, has been prepared in a high-yielding route that
features formation of the indole nucleus by radical cyclization.
Mediation of the radical cyclization by tristrimethylsilylsilane
(TTMSS) is more efficient than by N-ethylpiperidine hypophosphite.
Key Words: Melatonin; Radical; Synthesis; Indole.
*Correspondence: J. A. Murphy, Merck-Pauson Professor, Department of Pure
and Applied Chemistry, University of Strathclyde, 295 Cathedral St., Glasgow
G1 1XL, UK; Fax: (+44) 141 548 4822; E-mail: john.murphy@strath.ac.uk.
3631
DOI: 10.1081/SCC-120024751
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3632
Thomson et al.
INTRODUCTION
Melatonin 1[1] is a naturally occurring hormone produced by the
pineal gland in vertebrates. Its synthesis and secretion is increased at
night,[2] raising plasma levels, and leading to the onset of sleep. It is
useful in treating some sleep disorders; oral administration of melatonin
can lead to improved sleep patterns with accelerated onset of sleep.
Recognition of this led to melatonin being widely used to overcome ‘‘jet-
lag.’’ Melatonin also has a role in protection against oxidative stress,[3]
both by direct quenching of reactive free radicals and by regulating the
activity of anti-oxidant enzymes. Another more recent discovery is mela-
tonin’s ability to inhibit a key step in the onset of Alzheimer’s disease.[4]
Thus the Alzheimer amyloid Ab-peptide aggregates to form insoluble
amyloid fibrils, which are essential pathological markers of the disease.
Melatonin, in conjunction with other compounds, can inhibit fibril forma-
tion, leading to the suggestion that reduced levels of melatonin in the brain
with ageing might be one of the contributing factors to the onset of the
disease. Melatonin is freely available in some countries, but not in others
due to fears about its possible side-effects. It is known to inhibit the assem-
bly of microtubules,[5] the transient cytoskeletal structures that play a
crucial role in many cell functions, notably mitosis.
In principle, this inhibition of microtubule formation can be turned
to good effect, since many anti-cancer compounds act in this way, i.e., by
inhibiting cell-division in rapidly dividing cancer cells, and this is what
kindled our interest. Many of the current anti-cancer drugs that act in
this way are highly complex structures e.g., vinblastine 2, but a drive
is underway to produce much simpler structures, and this is greatly
aided both by the publication[6] of a detailed structure in 1998 for a
tubulin-taxol complex, as well as by the rapid advances in computational
methods allowing the rational planning of tubulin-binding structures.
Scheme 1.

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Pineal Hormone Melatonin
3633
Moreover, a number of simpler anti-cancer leads have recently been
discovered,[7] and for this reason, flexible routes to melatonin and related
labelled and unlabelled structures are timely. A number of syntheses of
melatonin have been accomplished,[8] but the recent elegant synthesis
by Zard’s group[9] demonstrated the first approach using radicals,
although harsh conditions (conc. sulfuric acid) were needed for the
final deprotection step; we now demonstrate an alternative but very
simple and direct approach featuring radical cyclization as the key step.
We recently announced[10] a new synthesis of tricyclic indoles such
as tetrahydrocarbolines 4 by cyclization of aryl radicals, derived from
arenediazonium salts 3 (X ¼ N2BF4) or from aryl iodides 3 (X ¼ I),
onto vinyl bromides (Sch. 2). The complementary approach[11] of
cyclization onto an alkyne rather than a vinyl bromide could not be
used to make such derivatives, but is attractive in the preparation of
simpler indoles such as melatonin.
Our proposal was to cyclize the radical derived from iodoarene 9,
which in turn should be easily made from 5.
In practice, iodoanisidine 5 was protected as its methanesulfonamide
6. The protecting group also serves to acidify the N-H bond and activate
it for the Mitsunobu coupling that follows. Thus coupling with 4-
phthalimidobut-2-yn-1-ol 8, in turn prepared by Mitsunobu coupling of
2-butyne-1,4-diol and phthalimide, afforded the product 9 ready for
radical cyclization. Cyclization was attempted under different conditions,
with ethylpiperidine hypophosphite (EPHP) and tristrimethylsilylsilane
(TTMSS). Cyclization with EPHP was successful in initially producing
a mixture of indole 11 and indolenine 10; this mixture was easily
converted in situ into the indole by addition of a trace of p-toluenesul-
fonic acid, but the overall reaction yield (45%) was disappointing;
although no other product was detected, two plausible side-reactions
could occur: (a) Addition of the phosphorus radicals to the alkyne and
(b) Addition to the oxygen of the imide carbonyl group. Happily, TTMSS
was much more successful. The product from the TTMSS reaction was
again directly treated with p-toluenesulfonic acid to afford indole 11 in
Scheme 2.

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3634
Thomson et al.
74% yield. Liberation of the two amine groups and selective acetylation
led to melatonin 1, identical to authentic material.
This route, featuring radical-induced indole synthesis as the key
step therefore gives convenient and simple access to melatonin, and pro-
vides a trigger for further studies aimed at uncovering structure-activity
relationships in its broad array of intriguing biological actions.
EXPERIMENTAL SECTION
General
NMR spectra were recorded on a Bruker DPX400 spectrometer,
operating at 400 MHz for 1H NMR and 100.61 MHz for 13C NMR,
respectively. All NMR experiments were carried out in CDCl3.
Chemical shifts are reported in parts per million (ppm). Coupling
constants J are reported in Hertz (Hz). The following abbreviations are
1
used for the multiplicities in H NMR: s, singlet; d, doublet; t, triplet;
Scheme 3. Reagents and conditions: (i) MsCl, DMAP, py, rt, 14 h, 96%; (ii)
Ph3P, but-2-yn-1,4-diol, DIAD, THF, 0ꢀC-rt, 62%; (iii) Ph3P, DIAD, THF,
0ꢀC-rt, 82%; (iv) TTMSS, AIBN, PhMe, Á, 12 h, then TsOH (cat.), Á, 2 h,
74%; (v) EPHP, AIBN, toluene, then TsOH, CH2Cl2, 8 h, Á, 45%; (vi) N2H4,
EtOH, Á, 3 h, 85%; (vii) KOH, MeOH, 9 h, Á, 84%; (viii) Ac2O, 18 h, rt, 90%.

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Pineal Hormone Melatonin
3635
q, quartet; m, multiplet; dd, double doublet; b s, broad singlet. Infrared
spectra are recorded on a Perkin Elmer ‘‘spectrum One FT-IR’’ spectro-
meter. Melting points were determined using either a Griffin or a
Gallenkamp melting point apparatus and are uncorrected. Column
chromatography was performed using Prolabo 35–75 mm particle sized
silica gel 60 (200–400 mesh). All reagents were obtained from commercial
suppliers and where necessary solvents were dried and/or distilled before
use. All petroleum ether was of boiling range 40–60ꢀC and distilled before
use. Dichloromethane was distilled from calcium hydride, toluene from
sodium, and THF from sodium/benzophenone. Diethyl ether was dried
over sodium wire.
N-(2-Iodo-4-methoxyphenyl)methanesulfonamide 6
4-Amino-3-iodoanisole[12] 5 (4.025 g, 16.2 mmol, 1.00 equiv.) and
4-dimethylaminopyridine (197 mg, 1.62 mmol, 0.10 equiv.) were dissolved
in pyridine (25 mL), under argon. The solution was cooled to 0ꢀC when
methanesulfonylchloride (1.31 mL, 17.0 mmol, 1.05 equiv.) was added
dropwise. The solution was stirred at room temperature for 14 h. The
pyridine was then removed in vacuo and the crude material diluted with
CH2Cl2. The organic phase was extracted with hydrochloric acid (2 M),
NaHCO3 (sat.) and brine (sat.). The organic phase was then dried over
MgSO4, filtered and evaporated to afford pure N-(2-iodo-4-methoxy-
phenyl )methanesulfonamide 6 as a white solid (5.072 g, 96%). M.p.
116–117ꢀC Found: (MNH4)þ, 344.9770. C8H14IN2O3S requires:
(MNH4), 344.9770. ꢀmax (KBr)/cmꢁ1: 3262 (NH), 3002 (Ar-H), 2836
(CH), 1594 (Ar), 1567 (Ar or NH), 1488 (CH), 1317, and 1147 (SO2).
ꢁH (CDCl3): 2.97 (3H, s, SO2CH3), 3.80 (3H, s, OCH3), 6.34 (1H, b s,
NH), 6.94 (1H, dd, J 8.9, 2.8, ArH), 7.36 (1H, d, J 2.8, ArH), and 7.55
(1H, d, J 8.9, ArH). ꢁC (CDCl3): 40.2 (CH3), 56.0 (CH3), 94.8 (C), 115.7
(CH), 124.5 (CH), 125.9 (CH), 130.8 (C), and 158.5 (C). m/z: (EI) 327
(Mþ, 22%), 248 (100), 106 (100).
4-Phthalimidobut-2-yn-1-ol 8
2-Butyne-1,4-diol (1.755 g, 20 mmol, 1.50 equiv.), phthalimide 7
(2.000 g, 14.0 mmol, 1.00 equiv.) and triphenylphosphine (3.565 g,
14.0 mmol, 1.00 equiv.) were dissolved in dry THF (80 mL), under
nitrogen, and cooled to 0ꢀC. Diisopropyl azodicarboxylate (2.82 mL,
14.0 mmol, 1.00 equiv.) was added dropwise over 1 h. The mixture was

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3636
Thomson et al.
raised to room temperature and stirred additionally for 18 h. The
solvent was removed in vacuo and the residue was purified by column
chromatography (40:60 ethyl acetate-petroleum ether) to afford 4-
phthalimidobut-2-yn-1-ol 8 as a white solid (1.81 g, 62%). M.p.
166–167ꢀC [Lit.[13] 168–170ꢀC]. ꢀmax (KBr)/cmꢁ1. 3449 (O-H), 1767 and
1719 (C¼O), 1428, 1397, 1350, 1126, 724. ꢁH (CDCl3): 2.01 (1H, s, OH),
4.25 (2H, t, J 1.9, CH2), 4.99 (2H, t, J 1.9, CH2), 7.73–7.77 (2H, m, ArH),
7.87–7.91 (2H, m, ArH). ꢁC (CDCl3): 27.8 (CH2), 51.6 (CH2), 79.8 (C),
81.9 (C), 124.1 (CH), 132.5 (C), 134.8 (CH), 167.6 (C).
N-[4-(1,3-Dioxodihydroisoindol-2-yl)but-2-ynyl]-N-(20-iodo-40-
methoxyphenyl)methanesulfonamide 9
N-(2-Iodo-4-methoxyphenyl)methanesulfonamide
6 (1.40 g, 4.28
mmol, 1.20 equiv.), 4-phthalimidobut-2-yn-1-ol 8, (767 mg, 3.57 mmol,
1.00 equiv.) and triphenylphosphine (1.160 g, 4.45 mmol, 1.25 equiv.) were
dissolved in dry THF (20 mL), under nitrogen, and cooled to 0ꢀC.
Diisopropyl azodicarboxylate (0.88 mL, 4.45 mmol, 1.25 equiv.) was
added dropwise over 20 min. The mixture was raised to room temperature
and stirred for 18 h. The solvent was removed in vacuo and the residue
purified by column chromatography (50:50 petroleum ether-ethyl acetate)
to afford N-[4-(1,3-dioxodihydroisoindol-2-yl )-but-2-ynyl ]-N-(2 0-iodo-40-
methoxyphenyl )methanesulfonamide 9 as a white solid (1.530 g, 82%).
M.p. 159–160ꢀC (Found: [MNH4]þ, 542.0243. C20H21IN3O5S requires
[MNH4], 542.0247). ꢀmax (KBr)/cmꢁ1 3091 (Ar-H), 2925 (CH), 1769 and
1721 (C¼O), 1591 (Ar), 1486 (CH), 1341 and 1150 (SO2). ꢁH (CDCl3): 3.13
(3H, s, SO2CH3), 3.77 (3H, s, OCH3), 4.00 (1H, br d, J 18.3, SO2NCH2),
4.47 (2H, t, J 1.8, CONCH2), 4.68 (1H, br d, J 18.3, SO2NCH2), 6.83 (1H,
dd, J 8.7, 2.9, ArH), 7.39 (1H, d, J 2.9, ArH), 7.48 (1H, d, J 8.7, ArH),
7.75–7.79 (2H, m, ArH) and 7.88–7.91 (2H, m, ArH). ꢁC (CDCl3): 27.4
(CH2), 41.1 (CH2), 41.2 (CH3), 55.9 (CH3), 78.1 (C), 80.1 (C), 103.0 (C),
115.1 (CH), 123.8 (CH), 125.4 (CH), 131.3 (CH), 132.2 (C), 133.8 (C),
134.6 (CH), 160.2 (C) and 167.2 (C). m/z: (CI) 542 (Mþ, 15%), 416 (18),
219 (100).
2-[2-(1-Methanesulfonyl-5-methoxy-1H-indol-3-
yl)ethyl]isoindole-1,3-dione 11 (using TTMSS)
N-[4-(1,3-Dioxodihydroisoindol-2-yl)-but-2-ynyl]-N-(20 -iodo-40-
methoxyphenyl)methanesulfonamide 9, (200 mg, 0.38 mmol, 1.00 equiv.)

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Pineal Hormone Melatonin
3637
was dissolved in dry toluene (46 mL), under argon, and heated to reflux.
A solution of tristrimethylsilylsilane (0.141 mL, 0.46 mmol, 1.20 equiv.)
and azoisobutyronitrile (6 mg, 0.038 mmol, 0.01 equiv.) in dry toluene
(7 mL) was added to the refluxing solution using a syringe pump over
5 h. The solution was refluxed overnight, after which p-toluenesulfonic
acid (73 mg, 0.038 mmol, 1.00 equiv.) was added. The solution was
refluxed for an additional 2 h. The solvent was removed in vacuo
to afford a brown oil which was purified by column chromatog-
raphy (75:25 petroleum ether-ethyl acetate) to afford 2-[2-(1-methanesul-
fonyl-5-methoxy-1H-indol-3-yl)ethyl]isoindole-1,3-dione
11
as
a
yellow solid (111 mg, 74%). M.p. 176–178ꢀC (Found: [MNH4]þ,
416.1275. C20H22N3O5S requires [MNH4], 416.1280). ꢀmax (KBr)/cmꢁ1
3026 (Ar-H), 2960 (CH), 1769 and 1710 (C¼O), 1612 (Ar), 1478 (CH),
1364 and 1172 (SO2). ꢁH (CDCl3): 2.99 (3H, s, SO2CH3), 3.08 (2H, t, J
7.4, CH2), 3.87 (3H, s, OCH3), 4.02 (2H, t, J 7.4, NCH2), 6.96 (1H, dd,
J 8.8, 2.4, ArH), 7.14 (1H, d, J 2.4, ArH), 7.28 (1H, s, ArH), 7.72–7.75
(2H, m, ArH), 7.78 (1H, d, J 8.8, ArH) and 7.79–7.85 (2H, m, ArH).
ꢁC (CDCl3): 24.4 (CH2), 37.8 (CH2), 40.3 (CH3), 55.9 (CH3), 102.1
(CH), 114.5 (CH), 114.5 (CH), 119.5 (C), 123.5 (CH), 124.5
(CH), 130.2 (C), 131.9 (C), 132.3 (C), 134.3 (CH), 157.0 (C) and
168.4 (C). m/z: (EI) 398 (Mþ, 14%), 319 (10), 251 (15), 238 (18), 160 (100).
2-[2-(1-Methanesulfonyl-5-methoxy-1H-indol-3-
yl)ethyl]isoindole-1,3-dione 11 (Using 1-EPHP)
N -[4-(1,3-Dioxodihydroisoindol-2-yl)but-2-ynyl]-N-(2-iodo-4-
methoxyphenyl) methanesulfonamide 9 (220 mg, 0.42 mmol, 1.00 equiv.),
1-ethylpiperidinium hypophosphite (751 mg, 4.20 mmol, 10.0 equiv.) and
azoisobutyronitrile (27 mg, 0.17 mmol, 0.40 equiv.) were dissolved in dry
toluene (30 mL), under nitrogen, and brought to reflux. The solvent was
removed in vacuo and then diluted with CH2Cl2. After extraction with
water, brine (sat.) and drying over MgSO4, a yellowish oil was obtained.
Subsequent purification by column chromatography (75:25 petroleum
ether–ethyl acetate) gave an apparent mixture of the indolenine 10
along
with
2-[2-(1-methanesulfonyl-5-methoxy-1H-indol-3-yl)ethyl]
isoindole-1,3-dione 11. The solid was dissolved in CH2Cl2 and a crystal
of p-toluenesulfonic acid was added. After 8 h, the solution was filtered
through a silica plug and eluted with ethyl acetate. Removal of the
solvent gave the desired product 11 (75 mg, 45%). Spectral data were
identical to those reported above.

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3638
Thomson et al.
2-(1-Methanesulfonyl-5-methoxy-1H-indol-3-yl)ethylamine 12
2-[2-(1-Methanesulfonyl-5-methoxy-1H-indol-3-yl)ethyl]isoindole-
1,3-dione 11 (800 mg, 2.00 mmol, 1.00 equiv.) and hydrazine monohy-
drate (0.389 mL, 8.03 mmol, 4.00 equiv.) were dissolved in ethanol
(30 mL) and refluxed for 3 h. The solvent was removed in vacuo and
the residue dissolved in CH2Cl2. The residue was extracted with aqueous
NaOH (2 M) and subsequently with brine (sat). The combined organic
extracts were dried over MgSO4, filtered and evaporated to give a
white solid which was purified by column chromatography (90:10:0,
then 89:10:1 CH2Cl2-MeOH-Et3N) to afford 2-(1-methanesulfonyl-5-
methoxy-1H-indol-3-yl)ethylamine 12 as a white solid (473 mg, 85%).
M.p. 127–129ꢀC (Found: [MH]þ, 269.0958. C12H17N2O3S requires
[MH ], 269.0960). ꢀmax (KBr/cmꢁ1) 3429 and 3366 (NH2), 3108 (Ar-H),
2930 (CH), 1612 (NH2 or Ar), 1595 (NH2 or Ar), 1477 (CH), 1353 and
1170 (SO2). ꢁH (CDCl3): 1.51 (2H, b s, NH2) 2.86 (2H, t, J 6.8, CH2), 3.05
(3H, s, SO2-CH3), 3.05–3.11 (2H, m, NCH2), 3.90 (3H, s, OCH3), 7.01
(1H, dd, J 8.9, 2.4, ArH), 7.05 (1H, d, J 2.4, ArH), 7.27 (1H, s, ArH) and
7.82 (1H, d, J 8.9, ArH). ꢁC (CDCl3): 29.4 (CH2), 40.3 (CH3), 41.6 (CH2),
56.0 (CH3), 102.6 (CH), 114.0 (CH), 114.3 (CH), 120.7 (C), 124.1 (CH),
130.3 (C), 132.1 (C) and 156.8 (C). m/z: (CI) 286 (MNHþ4 , 10%), 269
(MH, 100), 191 (37).
5-Methoxytryptamine 13
2-(1-methanesulfonyl-5-methoxy-1H-indol-3-yl)ethylamine 12 (125 mg,
0.47 mmol, 1.00 equiv.) was dissolved in thoroughly degassed 5%
KOH/MeOH solution and heated to reflux for 9 h. The solution was
then diluted with water and extracted with diethyl ether. The combined
organic layers were extracted with brine (sat) and dried over MgSO4. The
solvent was removed in vacuo to afford a purple solid which was purified
by column chromatography (50:50:0, then 79:20:1 CH2Cl2-MeOH-Et3N)
to afford 5-methoxytryptamine 13 as white crystals (73 mg, 84%). M.p.
122–125ꢀC (Lit.[14], 122ꢀC). ꢀmax (KBr/cmꢁ1) 3335, 3284 (N-H), 3040,
2871 (C-H), 1623, 1585, 1489, 1239, 1218, 1010, 792, 639. ꢁH (CDCl3):
1.41 (2H, s, NH2), 2.92 (2H, t, J 6.8, CH2), 3.08 (2H, t, J 6.8, CH2), 3.91
(3H, s, OMe), 6.90 (1H, dd, J 8.7, 2.4, Ar-H), 7.04 (s, 1H, Ar-H), 7.09
(1H, d, J 2.4, Ar-H), 8.23 (1H, s, N-H). ꢁC (CDCl3): 29.7 (CH2), 42.5
(CH2), 56.2 (CH3), 101.0 (CH), 112.1 (CH), 112.4 (CH), 113.7 (C), 123.1
(CH), 128.1 (C), 131.8 (C), 154.1 (C).

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Pineal Hormone Melatonin
3639
Melatonin 1
5-Methoxytryptamine 13 (100 mg, 0.52 mmol, 1.00 equiv.) was
dissolved in acetic anhydride (0.5 mL), under nitrogen, and the solution
stirred for 18 h. Water (2 mL) was then added to the solution and this was
stirred for 0.5 h. Solid sodium bicarbonate was added until the solution
had a pH 6–7. The reaction mixture was extracted with CH2Cl2 and the
combined extracts dried over MgSO4, filtered and evaporated. The
residue was purified by column chromatography (90:10 CH2Cl2-
MeOH) to afford melatonin 1 as a white solid (108 mg, 90%). M.p.
112–114ꢀC [Lit.[14] 117ꢀC]. ꢀmax (KBr/cmꢁ1) 3304 (N-H), 3082, 2928,
2873, 2828 (C-H), 1629, 1587, 1557, 1489, 1213, 1041. ꢁH (CDCl3): 1.90
(3H, s, Ac), 2.96 (2H, t, J 6.6, CH2), 3.61 (2H, dt, J 6, 6.6, CH2), 3.89 (3H,
s, CH3), 5.68 (1H, s, N-H), 6.89 (1H, dd, J 8.8, 2.4, Ar-H), 7.02 (1H, m,
Ar-H), 7.06 (1H, d, J 2.4, Ar-H), 7.28 (1H, d, J 8.8, Ar-H), 8.31 (1H, s,
NH). ꢁC (CDCl3): 25.6 (CH3), 25.5 (CH2), 39.9 (CH2), 56.1 (CH), 100.7
(CH), 112.2 (CH), 112.6 (C), 112.8 (CH), 123.0 (CH), 127.9 (C), 131.8
(C), 154.3 (C), 170.4 (C).
ACKNOWLEDGMENTS
We thank the ‘‘Stiftelsen Bengt Lundqvists minne’’ and the ‘‘C F
Liljewalchs resestipendiefond’’ for a visiting fellowship (to S.B.), the
Royal Society for a Leverhulme Senior Research Fellowship to (J.M.)
and EPSRC Mass Spectrometry Service, Swansea for mass spectra.
REFERENCES
1. Lerner, B.; Case, J.D.; Takahashi, Y.; Lee, T.H.; Mori, W. Structure
of melatonin. J. Am. Chem. Soc. 1959, 80, 6084–6085.
2. (a) Zhdanova, I.V.; Wartman, R.J.; Regan, M.M.; Taylor, J.A.; Shi,
J.P.; Leclair, O.U. Melatonin treatment for age-related insomnia. J.
Clin. Endocr. Metab. 2001, 86, 4727–4730; (b) Lynch, H.J.;
Wurtman, R.J.; Moskowitz, M.A.; Archer, M.C.; Mo, M.H. Daily
rhythm in human urinary melatonin. Science 1975, 187, 169–171.
3. (a) Reiter, R.J.; Acuna-Castroviejo, D.; Tan, D.X.; Burkhardt, S. Free
radical-mediated molecular damage-mechanisms for the protective
actions of melatonin in the central nervous system. Ann. N.Y. Acad.
Sci. 2001, 939, 200–215; (b) Barlow-Walden, L.R.; Reiter, R.J.;
Abe, M.; Pablos, M.; Menendez-Pelaez, A.; Chen, L.-D.; and

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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3640
Thomson et al.
Poeggelar, B. Melatonin stimulates brain glutathione–peroxidase
activity. Neurochem. Int. 1995, 26, 497–502; (c) Reiter, R.J.
Functional pleiotropy of the neurohormone melatonin-antioxidant
protection and neuroendocrine regulation. Front. Neuroendocrinol
1995, 16, 383; (d) Tan, D.X.; Poeggeler, B.; Reiter, R.J.; Chen, L.D.;
Chen, S.; Manchester, L.C.; Barlow-Walden, L.R. The pineal
hormone melatonin inhibits DNA-adduct formation induced by the
chemical carcinogen safrole in vivo. Cancer Lett. 1993, 70, 65–71.
4. Poeggeler, B.; Miravalle, L.; Zagorski, M.G.; Wisniewski, T.;
Chyan, Y.-J.; Zhang, Y.; Shao, H.; Bryant-Thomas, T.; Vidal, R.;
Frangione, B.; Ghiso, J.; Pappolla, M.A. Melatonin reverses the
profibrillogenic activity of apolipoprotein e4 on the alzheimer
amyloid a beta peptide. Biochemistry 2001, 40, 14995–15001.
5. Jordan, A.; Hadfield, J.A.; Lawrence, N.J.; McGown, A.T. Tubulin
as a target for anticancer drugs: agents which interact with the
mitotic spindle. Med. Res. Rev. 1998, 18, 259–296; Banerjee, S.;
Kerr, V.; Winston, M.; Kelleher, J.K.; Margulis, L. J. Protozool
melatonin: inhibition of microtubule-based oral morphogenesis in
Stento Coeruleus. 1972, 19, 108–113.
6. Nogales, E.; Wolf, S.G.; Downing, K.H. Structure of the alpha beta
tubulin dimer by electron crystallography. Nature 1998, 391,
199–203.
7. Edmondson, S.; Danishefsky, S.J.; Sepp-Lorenzino, L.; Rosen, N.
Total synthesis of spirotryprostatin A, leading to the discovery of
some biologically promising analogues. J. Am. Chem. Soc. 1999,
121, 2147–2155.
8. (a) Somei, M.; Fukui, Y.; Hasegawa, M.; Oshikiri, N.; Hayashi, T.
Syntheses of melatonin and its derivatives. Heterocycles 2000, 53,
1725–1725; (b) Hwang, K.J.; Lee, T.S. A practical synthesis of
N-acetyl-5-methoxytryptamine (melatonin). Synth. Commun. 1999,
29, 2099–2104 and references therein.
9. (a) Quiclet-Sire, B.; Sortais, B.; Zard, S.Z. A convergent approach
to 2-substituted-5-methoxyindoles. application to the synthesis of
Melatonin. Chem. Commun. 2002, 1692–1693 (and 1988).
10. (a) Murphy, J.A.; Scott, K.A.; Sinclair, R.S.; Lewis, N. A new
synthesis of indoles. Tetrahedron Lett. 1997, 38, 7295–7298; (b)
Murphy, J.A.; Scott, K.A.; Sinclair, R.S.; Martin, C.G.; Kennedy,
A.R.; Lewis, N. A radical based addition–elimination route for the
preparation of indoles. J. Chem. Soc. Perkin Trans. 2000, 1,
2395–2408.
11. (a) Dittami, J.P.; Ramanathan, H. Intramolecular radical cycliza-
tion reactions—an approach to the indole alkaloids. Tetrahedron

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Pineal Hormone Melatonin
3641
Lett. 1988, 29, 45–48; (b) Boger, D.L.; Ishizaki, T.; Kitos, P.A.;
Suntornwat, O. Synthesis of n-(tert-butyloxycarbonyl)-CBI, CBI,
CBI-CDPI1, and CBI-CDPI2-enhanced functional analogs of
cc-1065 incorporating the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]-
indol-4-one (CBI) left-hand subunit. J. Org. Chem. 1990, 55,
5823–5832; (c) Boger, D.L.; Coleman, R.S. Total synthesis of
(ꢂ)-N2-(Phenylsulfonyl)-CPI, (ꢂ)-CC-1065, (þ)-CC-1065, ent-(-)-
CC-1065, and the precise, functional agents (ꢂ)-CPI-CDPI2,
(þ)-CPI-CDPI2, and (ꢁ)-CPI-CDPI2 [(ꢂ)-(3bR*,4aS*)-, (þ)-
(3bR,4aS)- and (ꢁ)-(3bS,4aR)-Deoxy-CC-1065]. J. Amer. Chem.
Soc. 1988, 110, 4796–4807; (d) Inanaga, J.; Ujikawa, O.;
Yamaguchi, M. SmI2-promoted aryl radical cyclization—a new
synthetic entry into heterocycles. Tetrahedron Lett. 1991, 32,
1737–1740; (e) Hodgson, D.M.; Wells, C. Chromium(II)-mediated
nickel(ii)-catalyzed cyclizations of (iodoaryl)-substituted alkynes
and alkynals. Tetrahedron Lett. 1994, 35, 1601–1604.
12. Lizos, D.E.; Murphy, J.A. Concise synthesis of (ꢂ)-horsfiline and
(ꢂ)-coerulescine by tandem cyclization of iodoaryl alkenyl azides.
Org. Biomol. Chem. 2003, 1, 117–122.
13. Allan, R.D.; Johnston, G.A.R.; Twitchin, B. Synthesis of analogues
of GABA. V. trans and cis isomers of some 4-amino-3-halogenobut-
2-enoic Acids. Aust. J. Chem. 1980, 33, 1115–1122.
14. Revial, G.; Jabin, I.; Lirn, S.; Pfau, M. Aromatization of 1,6,7,7a-
tetrahydro-2H-indol-2-ones by a novel process. Preparation of key-
intermediate methyl 1-benzyl-5-methoxy-1H-indole-3-acetate and
the syntheses of serotonin, melatonin, and bufotenin. J. Org.
Chem. 2002, 67, 2252–2256.
Received in the UK April 23, 2003

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