First total synthesis of eudistalbin A

Article abstract of DOI:10.1016/j.cclet.2010.03.017

Eudistalbin A was isolated from marine tunicate eudistoma album and possess cytotoxic activity (ED₅₀ < 3.2 μg/mL) in vitro against the growth of KB human buccal carinoma cells. The synthetic eudistalbin A showed potent inhibitory activity against the breast carcinoma cell line MDA-231 with an IC₅₀ value of 2.1 μmol/L using the metabolic assay MTT. All structures of new compounds were confirmed by ¹H NMR, ¹³C NMR, HRMS and optical rotation.

Full text of DOI:10.1016/j.cclet.2010.03.017

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 889–891
www.elsevier.com/locate/cclet
First total synthesis of eudistalbin A
*
Pu Yong Zhang, Jun Lei Wang, Sheng Biao Wan, Tao Jiang
School of Medicine and Pharmacy, Key Laboratory of Marine Drugs, Ministry of Education,
Ocean University of China, Qingdao 266003, China
Received 25 December 2009
Abstract
Eudistalbin A was isolated from marine tunicate eudistoma album and possess cytotoxic activity (ED50 < 3.2 mg/mL) in vitro
against the growth of KB human buccal carinoma cells. The synthetic eudistalbin A showed potent inhibitory activity against the
breast carcinoma cell line MDA-231 with an IC50 value of 2.1 mmol/L using the metabolic assay MTT. All structures of new
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compounds were confirmed by H NMR, 13C NMR, HRMS and optical rotation.
# 2010 Tao Jiang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: b-Carboline; Eudistalbin A; Pictet–Spengler reaction; Henry reaction; Total synthesis
Alkaloids with a b-carboline nucleus, containing planar tricyclic system, have been reported to be biologically
active by inhibiting topoisomerases [1,2], CDK (cyclin-dependent kinases) [3,4], NF-kappaB signaling [5] and DNA
synthesis [6], and by intercalating into DNA [7]. Marine tunicates are a typical class of b-carboline alkaloids including
eudistalbin A, eudistomidin C and eudistomin T (Fig. 1). They have been the source of secondary metabolites
possessing interesting antiviral, antibacterial and other biological activities. Eudistomin T and 6-methyl eudistomidin
C have been successfully synthesized [8,9].
Eudistalbin A was isolated from EtOH extract of the marine tunicate eudistoma album and possess cytotoxic
activity in vitro against the growth of KB human buccal carinoma cells (ED50 < 3.2 mg/mL) [10]. We report here the
total synthesis and configuration confirmation of eudistalbin A with modified methods based on literatures [9,11–13].
Structural analysis of eudistalbin A, eudistomidin C and eudistomin T reveals that they may be biosynthetically
derived in vivo from tryptophan residue, often ring-A functionalized, condensed with a second amino acid such as a
leucine, cysteine and phenylalanine. Subsequent metabolic processes, including oxidation, dehydrogenation and
decarboxylation, may then be envisioned to give rise to the corresponding three marine alkaloids structures as
described in Scheme 1 [14].
According to the biomimetic synthesis, we choose BOC-L-leucine 1 as one of starting materials in the synthesis of
eudistalbin A. The total synthetic route was shown in Scheme 2.
Firstly, Boc-L-leucine 1 was converted to the intermediate 2 using N,O-dimethylhydroxylamine and
carbonyldiimidazole (CDI) in the presence of N,N-diisopropylethylamine (DIEA) in anhydrous THF and DMF
with the yield of 89%. Compound 2 was reduced by LiAlH4 to compound 3 in 86% yield [15].
* Corresponding author.
E-mail address: jiangtao@ouc.edu.cn (T. Jiang).
1001-8417/$ – see front matter # 2010 Tao Jiang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.03.017

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P.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 889–891
Fig. 1. The structure of compounds.
Scheme 1. The route of biomimetic synthesis of eudistalbin A, eudistomidin C and eudistomin T.
Secondly, 4-bromo-2-nitrotoluene 4 was treated with N,N-dimethylformamide dimethyl acetal (DMF-DMA) and
pyrrolidine at 110 8C to give the crude intermediate 5, which was subjected to reductive cyclization with zinc in acetic
acid and afforded 6-bromoindole 6 in 55% yield. 6-Bromoindole-3-carboxaldehyde 7 was obtained from 6 by
Vilsmeier–Hacck reaction in the presence of phosphorus oxychloride (POCl3) in DMF with yield of 98%. Compound
7 was condensed with nitromethane (CH3NO2) based on the classical Henry reaction to form compound 8 in 92%
yield. Reduction of compound 8 by NaBH4 at room temperature gave compound 9 in 98% yield. Subsequently,
compound 9 was refluxed in THF with LiAlH4 to give 6-bromotryptamine 10 with 95% yield.
Pictet–Spengler condensation was performed by the addition of two mole equivalents of trifluoroacetic acid (TFA)
to a cooled equimolar solution of compound 3 and 6-bromotryptamine 10 in CH2Cl2 at À78 8C, followed by
neutralization with triethylamine, to give 1,2,3,4-tetrahydro-b-carboline 11 in 76% yield.
Scheme 2. Reagents and conditions: (a) N,O-dimethylhydroxylamine hydrochloride, CDI/DIEA/THF/DMF, rt., 89%; (b) LiAlH4/Et2O, 0–5 8C, 86%;
(c) DMF-DMA/pyrrolidine/DMF, rt.; (d) Zn, HOAc, 55%(from 4); (e) POCl3/DMF/NaOH, 98%; (f) CH3NO2/CH3COONH4/ benzene, reflux, 92%; (g)
NaBH4/THF/CH3OH, rt., 98%; (h) LiAlH4/THF, reflux, 95%; (i) 3, TFA/CH2Cl2, À78 8C, 76%; (j) DDQ/THF, 40 8C, 90%; (k) TFA/CH2Cl2, rt., 98%.

P.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 889–891
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The key step was the dehydrogenation of compound 11. As discussed earlier in other syntheses of b-carboline
alkaloids, several methods may be used, such as the use of Pd/C [11], elemental sulfur [12], Pb(OAc)4 [13] and DDQ
[9]. As a result, refluxing of compound 11 with Pd/C in xylene, elemental sulfur in xylene or with Pb(OAc)4 in glacial
acetic acid did not lead to any dehydrogenation. When using elemental sulfur or Pd/C without solvent at high
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temperature of 200 8C for a few minutes gave low yields of dehydrogenation products of compound 11. H NMR
analysis showed that loss of the Boc group occurred. Ultimately, the best method proved to be the dehydrogenation
with DDQ [9]. Compound 11 was transformed into the intermediate 12 through DDQ oxidation in THF at 40 8C with
the yield of 90%. In succession, removal of BOC group from 12 using TFA as catalyst afforded the target eudistalbin A
in 98% yield. The structures of new compounds were confirmed by 1H NMR, 13C NMR, HRMS or optical rotation
[16].
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The optical rotation of synthetic eudistalbin A (found: [a]D À10.5 (c 0.1, MeOH); [a]D À16.0 (c 0.5, DMSO))
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was identical with those of natural eudistalbin A ([a]D À10.0 (c 0.1, MeOH)) [10]. The synthetic eudistalbin A
showed potent inhibitory activity against the breast carcinoma cell line MDA-231 with an IC50 value of 2.1 mmol/L
using the metabolic assay MTT.
In conclusion, an efficient synthetic method for eudistalbin A was developed. It is highly expected that this
methodology not only can be used in the synthesis of other b-carbolines possessing an amino acid side chain, but also
be useful in the synthesis of other complex natural products. Further application of this strategy is underway in our
laboratory.
Acknowledgment
We are grateful for the financial support of Key International S&T Cooperation Projects of MOST
(No. 2008DFA31040).
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[16] Spectral data. Compound 11 [a]D À8.1 (c 0.2, MeOH); HRMS: m/z calcd. for C21H31N3O2Br+, 436.1600; found: 436.1592; 1H NMR
(600 MHz, CDCl3): d 8.75 (brs, 1H), 7.41 (s, 1H), 7.28 (d, 1H, J = 7.8 Hz), 7.13 (d, 1H, J = 7.8 Hz), 4.94 (m, 1H), 4.26 (m, 1H), 4.13 (s, 1H),
3.39 (m, 1H), 3.00 (m, 1H), 2.78 (m, 1H), 2.64 (m, 1H), 1.71 (m, 1H), 1.56 (m, 1H), 1.48 (s, 1H), 1.34 (m, 1H), 1.17 (s, 9H), 0.99 (d, 3H,
J = 6.4 Hz), 0.96 (d, 3H, J = 6.4 Hz); 13C NMR (125 MHz, CDCl3): d 156.8, 137.3, 134.6, 126.6, 122.4, 119.1, 114.8, 114.2, 110.5, 79.9, 57.8,
49.5, 44.1, 41.3, 28.3, 25.3, 23.4, 22.3, 22.0. Compound 12 [a]D À9.0 (c 0.2, MeOH); HRMS: m/z calcd. for C21H27N3O2Br+, 432.1287;
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found: 432.1283; 1H NMR (600 MHz, CDCl3): d 10.28 (brs, 1H), 8.36 (d, 1H, J = 5.0 Hz), 7.79 (d, 1H, J = 8.7 Hz), 7.71 (d, 1H, J = 5.0 Hz),
7.33 (m, 1H), 7.27 (d, 1H, J = 8.7 Hz), 5.40 (m, 1H), 2.05 (m, 1H), 1.98 (m, 1H), 1.79 (m, 1H), 1.44 (s, 9H), 0.99 (m, 6H); 13C NMR (125 MHz,
CDCl3): d 157.3, 145.4, 141.3, 138.3, 134.3, 128.7, 123.1, 122.6, 122.1, 120.6, 114.8, 113.9, 80.7, 49.9, 41.7, 28.6, 25.2, 23.4, 22.2. Eudistalbin
A: [a]D À10.5 (c 0.1, MeOH); [a]D À16.0 (c 0.5, DMSO); HRMS: m/z calcd. for C16H19N3Br+, 332.0762; found: 332.0773; 1H NMR
(600 MHz, DMSO-d6): d 8.31 (d, 1H, J = 5.0 Hz), 8.17 (d, 1H, J = 8.2 Hz), 8.01 (d, 1H, J = 5.0 Hz), 7.85 (s, 1H), 7.36 (d, 1H, J = 8.2 Hz), 4.63
(t, 1H, J = 6.9 Hz), 1.79 (m, 1H), 1.74 (m, 1H), 1.52 (m, 1H), 0.88 (d, 3H, J = 6.9 Hz), 0.83 (d, 3H, J = 6.9 Hz); 13C NMR (125 MHz, DMSO-
d6): d 148.2, 141.9, 138.4, 133.9, 128.2, 123.9, 122.7, 121.3, 120.5, 115.3, 114.1, 52.3, 45.6, 24.9, 23.4, 22.6.
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