Isolation and synthesis of a novel β-carboline guanidine derivative tiruchanduramine from the Indian ascidian Synoicum macroglossum

Article abstract of DOI:10.1016/j.tetlet.2005.06.060

The isolation and synthesis of the racemic form of a novel β-carboline guanidine alkaloid, tiruchanduramine, a potent α-glucosidase inhibitor from the Indian ascidian, Synoicum macroglossum has been achieved.

Full text of DOI:10.1016/j.tetlet.2005.06.060

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5475–5478
Isolation and synthesis of a novel b-carboline guanidine derivative
tiruchanduramine from the Indian ascidian
Synoicum macroglossumq
K. Ravinder,a A. Vijender Reddy,a P. Krishnaiah,a P. Ramesh,b S. Ramakrishna,a
H. Laatschb and Y. Venkateswarlua,*
aNatural Products Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bDepartment of Organic and Biomolecular Chemistry, University of Go¨ttingen, Tammanstrasse 2, D-37077 Go¨ttingen, Germany
Received 26 April 2005; revised 9 June 2005; accepted 14 June 2005
Available online 1 July 2005
Abstract—The isolation and synthesis of the racemic form of a novel b-carboline guanidine alkaloid, tiruchanduramine, a potent
a-glucosidase inhibitor from the Indian ascidian, Synoicum macroglossum has been achieved.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
[Sephadex LH-20, dichloromethane/methanol (1:1)], fol-
lowed by silica gel column chromatography eluting with
CHCl3/MeOH 80:20 to yield tiruchanduramine 1.
In recent years marine ascidians have been the focus of
intensive chemical investigation as they are very rich
sources of biologically active secondary metabolites.1
A major group of these metabolites are nitrogen con-
taining compounds, particularly aromatic heterocycles.
As part of our ongoing investigation on bioactive com-
pounds from marine organisms2 we describe the isola-
Compound 1 was obtained as semi-solid, [a]D +31 (c 0.5,
MeOH) and showed a molecular mass ion at m/z 323
[M+1]+, which afforded the formula C17H19N6O by
HRFABMS (calcd 323.162, found 323.1613). The IR
bands at mmax 3221 (NH), 1681 (guanidine) and 1622
(amide) pointed to a guanidine derivative, and UV
absorptions at kmax (MeOH) 215, 234, 270, 334 and
347 nm indicated the presence of a b-carboline chromo-
phore.4 The structure of compound 1 was established by
tion of
a
novel b-carboline guanidine alkaloid
tiruchanduramine 1 isolated from an ascidian Synoicum
macroglossum, which was collected at Tiruchandur,
Tamilnadu, India during February 2002. A literature
survey revealed that the genus Synoicum has yielded sev-
eral tetraphenolic bis-spiroketals and different rubro-
lides.3 In the present study the dichloromethane/
methanol (1:1) extract of the ascidian was partitioned
between water and EtOAc. The water extract was
freeze-dried, and the residue was triturated with MeOH.
The soluble material was subjected to gel filtration
1
study of the H, 13C and 2D NMR data.
The 1H NMR spectrum of compound 1 (Table 1)
showed signals at d 8.20 (1H, d, J = 8.0 Hz), 7.28 (1H,
t, J = 7.6 Hz), 7.58 (1H, t, J = 7.6 Hz) and 7.63 (1H, d,
J = 8.0 Hz) for an ortho-disubstituted benzene ring.
Two aromatic 1H singlets at d 8.85, 8.81 and a D2O
exchangeable signal at d 12.10 (1H, s) pointed together
with the UV data to a 3- or 4-substituted b-carboline
moiety,5 which was supported by the 13C NMR spec-
Keywords: Ascidian; Synoicum macroglossum; Tiruchanduramine;
b-carboline; a-Glucosidase inhibitor.
1
trum (Table 1). The H NMR spectrum displayed fur-
q IICT Communication No. 050603. This work was presented at the
International Conference on Chemistry Biology Interface: Synergis-
tic New Frontiers (CBISNF 2004) in New Delhi, India, November
21–26, 2004 and is dedicated to Professors Sukh Dev and Alan R.
Katritzky on their outstanding contributions to organic chemistry.
ther signals in the aliphatic region at d 3.99 (1H, m),
3.77 (1H, t, J = 9.6 Hz), 3.25 (1H, dd, J = 8.2, 9.6 Hz),
3.42 (2H, m) and 1.82 (2H, m). The linear connectivity
of these aliphatic signals was established by a H,H
COSY spectrum. The 13C NMR spectrum (Table 1)
of compound 1 displayed 17 carbon signals, which
*
Corresponding author. Tel.: +91 40 271 93167; fax: +91 40 271
60512; e-mail: luchem@iict.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.060

5476
K. Ravinder et al. / Tetrahedron Letters 46 (2005) 5475–5478
Table 1. NMR data of tiruchanduramine 1
Carbon #
13C NMRa
1H NMR (J in Hz)b
H,H COSY
HMBC
1
132.2
—
8.85 (1H, s)
—
—
—
—
—
—
—
6
3, 4, 9a
—
2
3
139.5
113.9
128.16
120.9
122.1
119.9
128.5
112.2
141.0
—
—
8.81 (1H, s)
—
3, 10, 4b, 4a, 9a
4
4a
—
—
—
—
4b
5
8.20 (1H, d, J = 8.0)
7.28 (1H, t, J = 7.6)
4a, 8a, 7
7, 8a, 8
5, 8a
4b, 6
—
6
5, 7
6, 8
7
7
7.58 (1H, t, J = 7.6)
7.63 (1H, d, J = 8.0)
8
8a
—
12.10 (1H, br s)
—
—
—
—
9
9a
—
—
137.1
165.1
—
—
—
10
100
—
8.84 (1H, s)
—
0
0, 40
30, 50
40
10
2H, m)
30
(2
35.23.42
34.9
52.9
3
10, 30, 40
20, 40, 50
30, 20, 50, 70
40, 30, 70
—
1.82(2H, m)
3.99 (1H, m)
3.77 (1H, t, J = 9.6 Hz), 3.25 (1H, dd, J = 8.2, 9.6 Hz)
2
40
50
60,80,90
47.9
—
7.80 (2H, br s)
8.18 (1H, br s)
—
—
70
159.2—
—
a 75 MHz.
b 300 MHz, DMSO-d6.
included 11 aromatic and 4 aliphatic carbons, an amide
carbonyl at d 165.1 and a guanidine carbon at d 159.2.
ple, Eudistoma olivaceum are extraordinarily rich
sources of bromo-, hydroxy-, pyrrolyl- and 1-pyrrol-
inyl-b-carbolines.7 Similarly, the ascidians Eudistoma
glaucus8 and Lissoclinum fragile9 also contain b-carbo-
line derived alkaloids. To the best of our knowledge b-
carboline-3-carboxylates have not been reported from
ascidians, however, the presence of b-carboline-3-carb-
oxylates in human urine, brain tissue and bacteria is
known.5 Tiruchanduramine 1 is the first natural product
containing enduracididinamine, the decarboxylation
product of enduracididine, a rare amino acid obtained
by hydrolysis of enduracidin6 from Streptomyces fungi-
cidicus. The absolute stereochemistry has not yet been
established.
6’
H
5’
N
9’
O
5
4
1
NH
1’
4a
9a
3
4b
7’
N
H
6
7
10
N
2’
4’
H
8’
3’
N
N
8a H
9
8
1
The structure of compound 1 was finally established by
HMBC correlations. In the HMBC spectrum, the pro-
ton signals at d 3.99 (40-H, m), 3.77 (50-HA, t,
J = 9.6 Hz) and 3.25 (50-HB, dd, J = 8.2, 9.6 Hz) showed
cross-signals with the guanidine carbon C-70 at d 159.2.
The 1H and 13C NMR signals of the side chain are com-
parable with the related guanidino amino acid in endu-
racidins.6 Further, in the HMBC spectrum, the signals
2. Synthesis of ( )-tiruchanduramine
In order to confirm the structure of tiruchanduramine,
we have synthesized compound 1 in racemic form. The
retrosynthetic analysis (Scheme 1) revealed three main
fragments, b-carboline-3-carboxylic acid (A), aliphatic
side chain (B) and guanidine (C). Fragment A was syn-
thesized following a literature procedure10,11 in good
yields, starting from L-tryptophan. Fragment B was pre-
pared from homoallyl alcohol (Scheme 2).
0
at d 3.42(2 -H2, m) and 8.81 (4-H, s) showed correla-
tions with the carbonyl signal of C-10 at d 165.1. From
the foregoing spectral data, the structure of tiruchandur-
amine was confirmed as 1. Several ascidians, for exam-
H
N
O
O
NH
O
O
N
H
H2N
H2N
N
H
OR
+
NH
N
+
N
N
H
H2N
N
H
C
A
B
Scheme 1.

K. Ravinder et al. / Tetrahedron Letters 46 (2005) 5475–5478
5477
OH
O
a
b
OH
O
HO
PMBO
d
PMBO
H2N
2
3
6
c
O
e
O
O
O
PMBO
HO
4
5
Scheme 2. Reagents and conditions: (a) PMBBr, NaH, THF, 92%; (b) OsO4, NMO, acetone/water 7:3, 70%; (c) 2,2-DMP, PTSA, 82%; (d) DDQ,
DCM/water 9:1, 90%; (e) (i) p-TsCl, Py, 0 °C, 80%, (ii) NaN3, DMF, 86%, (iii) 10% Pd/C, H2, 92%.
O
O
O
O
O
N
O
N
N
H
N
H
a
c
b
Fragment A + 6
N
H
N
8
7
Boc
OH
OH
NBoc
NBoc
O
O
N
NBoc
N
H
N
H
d
N
e
1
(Tiruchanduramine hydrochloride)
N
BocNH
BocNH
N
NBoc
Boc
H
11
10
9
Scheme 3. Reagents and conditions: (a) DCC, DMAP, DCM, 62% or EDCI, HOBT, dry DMF, 65%; (b) (Boc)2O, Et3N, DCM, 92%; (c) PPTSA,
MeOH, 90%; (d) 9, TPP, DEAD, THF, 52%; (e) 2 M HCl, MeOH, rt, 4 h 63%.
But-3-en-1-ol was protected with p-methoxybenzyl bro-
mide to give compound 2, which on dihydroxylation
under standard conditions gave the diol 3. The diol
was then protected as the acetonide to give compound
4. The p-methoxybenzyl group in 4 was removed using
DDQ to give the primary alcohol 5, which was con-
verted into the amino-acetonide12 6 with in an overall
yield of 37% (Scheme 2).
ian, the Department of Ocean Development, New Delhi,
India, for financial assistance, Dr. J. S. Yadav, Director
IICT for his constant encouragement, and UGC, CSIR,
New Delhi, for providing fellowships to K.R. and
A.V.R. and a Humboldt grant to P.R.
References and notes
1. (a) Davidson, B. S. Chem. Rev. 1993, 93, 1771; (b)
Faulkner, D. J. Nat. Prod. Rep. 1993, 10, 497, 1994, 11,
355; 1995, 12, 223; 1996, 13, 75; 1997, 14, 259; 1998, 15,
113; 1999, 16, 155; 2000, 17, 7; 2001, 18, 1; 2002, 19, 1.
2. (a) Reddy, M. V. R.; Faulkner, D. J.; Venkateswarlu, Y.;
Rao, M. R. Tetrahedron 1997, 53, 3457; (b) Reddy, M. V.
R.; Rao, M. R.; Rhodes, D.; Hansen, M. S. T.; Rubbins,
K.; Bhushman, F.; Venkateswarlu, Y.; Faulkner, D. J.
J Med. Chem. 1999, 42, 1901.
3. (a) Carroll, A. R.; Healy, P. C.; Quinn, R. J.; Tranter, C.
J. Org. Chem. 1999, 64, 2680; (b) Ortega, M. J.; Zubia, E.;
Ocana, J. M.; Naranjo, S.; Salva, J. Tetrahedron 2000, 56,
3963.
The amino-acetonide 6 and fragment A were coupled to
give compound 7, which was protected using Boc anhy-
dride to yield compound 8. The acetonide group in 8
was removed under acidic (PPTSA) conditions to afford
the diol 9.13 The diol 9 was reacted with N,N0N00-tri-Boc-
guanidine 1014 under Mitsunobu conditions to give Boc-
protected tiruchanduramine 11 in 52% yield. Finally, the
Boc groups were deprotected under acidic conditions15
to give tiruchanduramine hydrochloride (1) (Scheme
3), the NMR data of which were identical with those
of the natural product.
4. Gozler, T.; Gozler, B.; Linden, A.; Hesse, M. Phytochem-
istry 1996, 43, 1425.
5. Braestrup, C.; Nielsen, M.; Olsen, C. E. Proc. Natl. Acad.
Sci. U.S.A. 1980, 77, 2288.
Tiruchanduramine 1 showed promising a-glucosidase
inhibitory activity (IC50 78.2 lg/mL) as compared with
acarbose16 at 100 lg/mL as the standard.
6. Horii, S.; Kameda, Y. J Antibiot. 1968, 21, 665.
7. Rinehart, K. L., Jr.; Kobayashi, J.; Harbour, G. C.;
Gilmore, J.; Mascal, M.; Holt, T. G.; Shield, L. S.;
Lafargue, F. J. Am. Chem. Soc. 1987, 109, 3378.
8. Kobayashi, J.; Cheng, J. F.; Ohta, T.; Nozoe, S.; Ohizumi,
Y.; Sasaki, T. J. Org. Chem. 1990, 55, 3666.
Acknowledgements
We are thankful to Dr. V. K. Meenakshi, Department of
Zoology, APC Mahalaxmi College for Women, Tutico-
rin 628 002, Tamilnadu, India, for identifying the ascid-
9. Badre, A.; Boulanger, A.; Abou-Mansour, E.; Banaigs, B.;
Combaut, G.; Francisco, C. J. Nat. Prod. 1994, 57, 528.

5478
K. Ravinder et al. / Tetrahedron Letters 46 (2005) 5475–5478
10. (a) Brossi, A.; Focella, A.; Teitel, S. J. Med. Chem. 1973,
16, 418; (b) Coutts, R. T.; Micetich, R. G.; Baker, G. B.;
Benderly, A.; Dewhurst, T.; Hall, T. W.; Locock, A. R.;
Pyrozko, J. Heterocycles 1984, 22, 131.
11. Lippke, K. P.; Schunack, W. G.; Wenning, W.; Muller, W.
¨
E. J. Med. Chem. 1983, 26, 499.
12. (a) Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem.
1990, 55, 1957; (b) Fleming, P. R.; Sharpless, K. B. J. Org.
Chem. 1991, 56, 2869.
Compound 9: Solid, mp 118.5 °C; IR (KBr): mmax 3424,
2939, 2361, 1734, 1671, 1528, 1455, 1356, 1281, 1155 cmꢀ1
1H NMR (400 MHz, CDCl3): 1.72(2H, m), 1.80 (9H, s),
;
2.36 (1H, br s), 3.08 (1H, br s), 3.44 (1H, m), 3.56 (1H, dd,
J = 8.0, 6.4 Hz), 4.64 (1H, dd, J = 8.0, 2.0 Hz), 4.80 (1H,
m), 4.00 (1H, m), 7.42(1H, t, J = 7.0 Hz), 7.64 (1H, t,
J = 7.0 Hz), 8.10 (1H, d, J = 7.6 Hz), 8.46 (1H, t,
J = 7.0 Hz), 8.78 (1H, s), 9.42(1H, s);
13C NMR:
(75 MHz, MeOH-d4): 27.9, 29.5, 34.1, 37.7, 67.3, 71.4,
86.7, 113.8, 117.3, 122.2, 124.5, 124.9, 131.1, 133.6, 137.1,
137.4, 140.4, 144.5, 151.2, 166.8; FABMS: 400 (M++1);
HRMS, obsd m/z 400.1872C 21H26N3O5 requires m/z
400.1879 [M++1].
13. All the compounds gave satisfactory analytical and
spectral data. Compound 7: Solid, mp 203–205 °C; IR
1
(KBr): mmax 3415, 1637, 1527, 1350, 1220 cmꢀ1; H NMR
(300 MHz, CDCl3): d 1.38 (3H, s), 1.46 (3H, s), 1.96 (2H,
m), 3.65 (3H, m), 4.12(1H, dd, J = 7.0, 6.0 Hz,), 4.28 (1H,
m), 7.32–7.46 (1H, m), 7.60 (1H, m), 7.82 (1H, br t), 8.20
(1H, d, J = 8.0 Hz), 8.50 (1H, br t), 8.82(1H, s), 8.9 (1H,
s), 9.54 (1H, br s); FABMS: 340 (M++1); HRMS, obsd
m/z 340.4019 C19H22N3O3 requires m/z 340.4021 [M++1];
14. Feichtinger, K.; Sings, H. L.; Baker, T. J.; Matthews, K.;
Goodman, M. J. Org. Chem. 1998, 63, 8432.
15. Miller; Craig, A.; Batey, R. A. Org. Lett. 2004, 6, 699.
16. Kim, J.-S.; Kwon, C.-S.; Son, K. H. Biosci. Biotechnol.
Biochem. 2000, 64, 2458.