Concise syntheses of 5,6-dibromotryptamine and 5,6-dibromo-N,N- dimethyltryptamine en route to the antibiotic alternatamide D

Article abstract of DOI:10.1016/j.tetlet.2011.05.126

Concise syntheses of the natural products 5,6-dibromotryptamine, 5,6-dibromo-N,N-dimethyltryptamine and the bromotryptamine antibiotic alternatamide D have been accomplished starting from the common intermediate, 5,6-dibromoindole-3-carbaldehyde.

Full text of DOI:10.1016/j.tetlet.2011.05.126

Tetrahedron Letters 52 (2011) 4042–4044
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise syntheses of 5,6-dibromotryptamine and
5,6-dibromo-N,N-dimethyltryptamine en route to the antibiotic
alternatamide D
Jonathan Sperry
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Concise syntheses of the natural products 5,6-dibromotryptamine, 5,6-dibromo-N,N-dimethyltryptamine
and the bromotryptamine antibiotic alternatamide D have been accomplished starting from the common
intermediate, 5,6-dibromoindole-3-carbaldehyde.
Received 18 April 2011
Revised 16 May 2011
Accepted 27 May 2011
Available online 2 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
5,6-Dibromoindole
Alternatamide
Tryptamine
Alkaloid
Natural product
Alternatamides A–D (1–4) are four bromotryptamine peptide
antibiotics isolated from the Atlantic bryozoan Amathia alternata
in 1997 by Fenical and co-workers1 (Fig. 1). The indole nuclei pres-
ent in alternatamides A–D are decorated with varying degrees of
bromination, and of particular interest to our laboratory is alter-
natamide D (4), the member of the family that possesses a rare
5,6-dibromoindole moiety that has only been observed in a very
small number of natural products to date.2 Furthermore, there is
a total absence of synthetic work directed towards the alternata-
mides. Due to our ongoing interest in the synthesis of natural prod-
ucts possessing rare bromination patterns3 and for reasons
outlined above, we initiated a synthesis of alternatamide D (4).
A retrosynthetic consideration of alternatamide D (4) suggests
disconnection of the amide bond is the most straightforward op-
of the nNOS inhibitor, 5,6-dibromo-20-demethylaplysinopsin.3 Prior
to our report, aldehyde 7 was only available as a side product (5%)
from the bromination of indole-3-carbaldehyde7 or in seven steps
from 6-nitroindoline.8 Herein we report the further utility of 7,
describing its use in an efficient synthetic route to 5,6-dibromotryp-
tamines that has ultimately led to the synthesis of three natural
products (Scheme 2). In a recent noteworthy development, Mollica
et al. reported the first asymmetric route to a 5,6-dibromotrypto-
phan derivative that relied on the selective monobromination of
6-bromoisatin followed by reduction to 5,6-dibromoindole,9 thus
providing a valuable addition to current methods available for the
synthesis of this heterocyclic moiety.
With multigram quantities of 5,6-dibromoindole-3-carbalde-
hyde (7) readily available,3 the synthesis of 5,6-dibromotrypta-
tion, leaving 5,6-dibromotryptamine (5) and N-methyl-L-leucine
(6)4 (Scheme 1). 5,6-Dibromotryptamine (5) is itself a natural
product isolated from a variety of marine sources5 and our initial
thoughts were aimed at the synthesis of 5. Although 5,6-dibromot-
ryptamine has been reported as a starting material for the prepara-
tion of several b-carboline compounds as potential CNS drugs, no
details were disclosed regarding its synthesis.6
Recently, we disclosed the efficient, large scale synthesis of 5,6-
dibromoindole-3-carbaldehyde (7) by the validation of an historic
dibromination of an indole-3-carboxylate.3 This intermediate was
subsequently used in the first synthesis and structural validation
O
NHMe
HN
Br
X1
X2
N
R
R = Me, X1 = X2 = Br
1 Alternatamide A.
2 Alternatamide B. R = H, X1 = X2 = Br
3 Alternatamide C. R = H, X1 = H, X2 = Br
4 Alternatamide D. R = H, X1 = Br, X2 = H
E-mail address: j.sperry@auckland.ac.nz
Figure 1. Alternatamides A–D.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.126

J. Sperry / Tetrahedron Letters 52 (2011) 4042–4044
4043
hydrogenation conditions11 resulting in extensive debromination
of the indole ring. However, employing in situ generated BH3ꢀTHF12
gratifyingly effected nitroalkene reduction with no detriment to
the dibrominated indole, affording 5,6-dibromotryptamine (5) in
good yield. The spectroscopic data of 5 were in good agreement
with the literature values.5a,13 As an aside, 5,6-dibromotryptamine
(5) was subjected to reductive dialkylation affording 5,6-dibromo-
N,N-dimethyltryptamine (9), a natural product with significant
antidepressant properties.14 The spectroscopic data of 9 matched
those of the natural product.13,14a
Due to the small amount of impurities present and its tendency
to undergo degradation after an extended period, 5,6-dibromot-
ryptamine (5) was converted into its tert-butyloxycarbonyl (Boc)
derivative 10 and subjected to purification by flash chromatogra-
phy. The Boc group was then removed from 10 with anhydrous
HCl in 1,4-dioxane, giving the hydrochloride salt of 5,6-dibromot-
ryptamine (5ꢀHCl) that is stable for months at room temperature
(Scheme 2).
O
NHMe
HN
Br
Br
amide
formation
N
H
4
NH2
HO2C
NHMe
Br
Br
N
H
5,6-dibromotryptamine
N-methyl-L-leucine
6
5
Scheme 1. Retrosynthetic analysis of alternatamide D (4).
With 5ꢀHCl in hand, the final steps towards the synthesis of
alternatamide D (4) could now be completed. Unfortunately,
NO2
5ꢀHCl failed to undergo amide coupling with N-methyl-
L-leucine
MeNO2
NH4OAc
reflux, 3 h
(6) despite attempting a plethora of peptide coupling agents. This
result was not surprising as there is a dearth of examples reporting
N-methylleucine as a willing participant in amide couplings,15,16
presumably due to the unprotected secondary amine present in
6. This problem was solved by subjecting 5ꢀHCl and Boc-N-
Br
Br
CHO
Br
Br
83%
N
H
N
H
8
7
BF3.Et2O
NaBH4
Table 1
66%
THF
NMR data of synthetic and natural alternatamide D (4)
reflux, 4 h
O
NMe2
NH2
NaBH3CN
HCHO (aq.)
MeOH-AcOH
r.t., 30 min
.
TFA
10
HN
9
NHMe7'
1'
2'
3'
Br
Br
Br
Br
8
6'
Br
4
4'
5
3a
3
62%
6
N
N
H
2
5'
Br
H
7a
N1
H
9
5
7
(Boc)2O
Et3N
THF, r.t.
30 min
89%
Atom
no.
Natural alternatamide D1
Synthetic alternatamide D13
NHBoc
NH2.HCl
1H (d) (300 MHz,
13C (d)
1H (d)
(400 MHz,
CDCl3)
13C (d)
(100 MHz,
CDCl3)
Br
Br
4 M HCl in
1,4-dioxane
r.t., 3h
Br
Br
CDCl3)
(50 MHz,
CDCl3)
96%
N
N
H
N1
C2
8.53 (1H, s)
7.08 (1H, s)
8.27 (1H, br s)
7.05 (1H, d, J
2.2 Hz)
H
5.HCl
10
124.2
124.0
C3
C3a
C4
C5
C6
C7
C7a
C8
112.6
128.4
123.0
117.0
114.5
115.9
135.9
113.2
128.7
123.3
117.4
114.9
116.0
136.1
25.3
HO2C
NBocMe
7.85 (1H, s)
7.66 (1H, s)
7.87 (1H, s)
11,
1)
HATU
HOAt, iPr2NEt
11
CH2Cl2, r.t., 2 h
7.67 (1H, s)
2.93 (2H, m)
O
.TFA
2) TFA, CH2Cl2
r.t., 3 h
(77 %, 2 steps)
2.92 (2H, dd, J 6.4 25.0
NHMe
and 6.8 Hz)
3.58 (2H, m)
7.58 (1H, s)
HN
C9
39.3
3.60 (2H, m)
7.32 (1H, br s)
39.3
Br
Br
N10
C10
C20
C30
171.4
62.5
171.4
63.6
42.7
3.63 (1H, m)a
2.93 (1H, m)
1.27 (1H, m)
1.57 (1H, m)
1.57 (1H, m)
0.87 (3H, d, J
6.3 Hz)
0.94 (3H, d, J
6.3 Hz)
2.29 (3H, s)
4
N
1.25 (1H, m) 1.56 41.4
(1H, m)
H
C40
C50
1.56 (1H, m)
0.84 (3H, d, J
6.4 Hz)
0.92 (3H, d, J
6.4 Hz)
25.0
22.3
25.4
22.0
Scheme 2. Synthesis of naturally occurring 5,6-dibromotryptamines.
C60
C70
22.7
33.9
23.3
35.4
mine (5) was undertaken. The Henry reaction of 7 in nitromethane
at reflux in the presence of ammonium acetate proceeded
smoothly, furnishing the novel nitroalkene 8. Initially, the key
reduction of 8 to the desired 5,6-dibromotryptamine (5) gave dis-
appointing results, with lithium aluminium hydride10 and various
2.31 (3H, s)
a
The chemical shift of the proton at C20 was incorrectly reported in the original
isolation paper and should read ꢁ2.91 ppm.

4044
J. Sperry / Tetrahedron Letters 52 (2011) 4042–4044
methyl-
L
-leucine (11) to HATU and HOAt in the presence of Hünig’s
tra) associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2011.05.126.
base,17 giving Boc-alternatamide D13 that was immediately depro-
tected with trifluoroacetic acid (TFA) in dichloromethane, gratify-
ingly affording alternatamide D (4)13 (Scheme 2). The NMR data
of natural and synthetic 4 is shown in Table 1. The amide coupling
was presumed to proceed without racemisation as a uronium-
based coupling agent was employed.17
References and notes
1. Lee, N.-K.; Fenical, W.; Lindquist, N. J. Nat. Prod. 1997, 60, 697.
2. See Refs. 3–9 in Ref. 3 below.
3. (a) Boyd, E. M.; Sperry, J. Synlett 2011, 826; (b) While this paper was under
review, a report by Grainger and co-workers describing their own investigation
into the bromination of indole-3-carboxylate appeared: Parsons, T. B.;
Ghellamallah, C.; Male, L.; Spencer, N.; Grainger, R. S. Org. Biomol. Chem.
2011, doi:10.1039/C1OB05522D, available online 14.05.2011.
The 1H NMR spectroscopic data of natural and synthetic 4 were
in good agreement, apart from the chemical shift of the proton at
C20 (d 3.63 vs d 2.93, Table 1). After some initial confusion, commu-
nication with the authors of the isolation paper confirmed that the
chemical shift of C20 was incorrectly quoted in the isolation report
and should in fact read d 2.91 and not d 3.63 as quoted originally.1
The 1H NMR data of synthetic and natural alternatamide D were
now in good agreement. The 13C NMR spectroscopic data were also
in good agreement with the literature values (Table 1).1,13 Sadly,
due to the length of time elapsed since its isolation from the natu-
ral source, it was not possible to obtain an authentic sample of
alternatamide D (4) for direct comparison with our synthetic
material.
4. For alternatamides A–C (1–3), the stereochemistry of the N-methylleucine side
chain was confirmed as
the N-methylleucine in alternatamide D (4) is assumed.
L L-configuration of
(20S) by degradation studies. The
5. (a) Van Lear, G. E.; Morton, G. O.; Fulmor, W. Tetrahedron Lett. 1973, 4, 299; (b)
Tasdemir, D.; Bugni, T. S.; Mangalindan, G. C.; Concepción, G. P.; Harper, M. K.;
Ireland, C. M. Z. Naturforsch., C 2002, 57, 914; (c) Pimentel, S. M. V.; Bojo, Z. P.;
Roberto, A. V. D.; Lazaro, J. E. H.; Mangalindan, G. C.; Florentino, L. M.; Lim-
Navarro, P.; Tasdemir, D.; Ireland, C. M.; Concepción, G. P. Mar. Biotechnol. 2003,
5, 395.
6. Goldstein, S.; Poissonnet, G.; Parmentier, J.-G.; Brion, J.-D.; Millan, M.; Dekeyne,
A.; Boutin, J. US Patent, 6350757, 2002; Chem. Abstr. 2001, 134, 115944.
7. Da Settimo, A.; Saettone, M. F.; Nannipieri, E.; Barili, P. Gazz. Chim. Ital. 1967, 97,
1304.
8. (a) Ohta, T.; Somei, M. Heterocycles 1989, 29, 1663; (b) Ohta, T.; Yamato, Y.;
Tahira, H.; Somei, M. Heterocycles 1987, 26, 2817; (c) Terent’ev, A. P.;
Preobrazhenskayz, A. S.; Bobkov, A. S.; Sorkina, G. M. Zh. Obshch. Khim. 1959,
29, 2541; (d) 6-Nitroindoline costs >NZ$220 for 5 g (Sigma–AldrichÒ).
9. Mollica, A.; Stefanucci, A.; Feliciani, F.; Lucente, G.; Pinnen, F. Tetrahedron Lett.
2011, 52, 2583.
10. Bagley, M. C.; Moody, C. J.; Pepper, A. G. Tetrahedron Lett. 2000, 41, 6901.
11. Bernauer, K.; Mahboobi, S. Helv. Chim. Acta 1988, 71, 2034.
12. Varma, R. S.; Kabalka, G. W. Synth. Commun. 1985, 15, 843.
13. See Supplementary data for full experimental details.
14. (a) Djura, P.; Stierle, D. B.; Sullivan, B.; Faulkner, D. J.; Arnold, E.; Clardy, J. J. Org.
Chem. 1980, 45, 1435; (b) Kochanowska, A. J.; Rao, K. V.; Childress, S.; El-Alfy,
A.; Matsumoto, R. R.; Kelly, M.; Stewart, G. S.; Sufka, K. J.; Hamann, M. T. J. Nat.
Prod. 2008, 71, 186.
15. There are limited examples of N-methylleucine being used in amide couplings
with an amine coupling partner. For one example, see: Fink, B. E.; Chen, L.;
Chen, P.; Dodd, D. S.; Gaval, A. V.; Kim, S.-H.; Vaccaro, W.; Zhang, L. H. US
Patent, 20100323994, 2009; Chem. Abstr. 2009, 151, 245681.
16. The coupling of the free base 5 with 11 led to poor yields (20–30%) of the
desired amide product. Thus, the hydrochloride salt 5ꢀHCl was used as the
amine coupling partner to ensure good yields.
In conclusion, we have disclosed an efficient synthetic route to
5,6-dibromotryptamines which has been subsequently applied to
the synthesis of the three natural products alternatamide D (4),
5,6-dibromotryptamine (5) and 5,6-dibromo-N,N-dimethyltrypta-
mine (9). Further work towards the synthesis of natural products
possessing rare halogenation patterns is in progress.
Acknowledgements
The University of Auckland for financial support (Project No.
3625886). Professor William Fenical is thanked for invaluable dis-
cussions regarding the spectroscopic data of alternatamide D (4).
Supplementary data
Supplementary data (full experimental procedures for the prep-
aration of the natural products 4, 5 and 9, along with relevant spec-
17. Han, S. Y.; Kim, Y. A. Tetrahedron 2004, 60, 2447.