Synthesis of racemic, n-benzylated neoechinulin a and isoneoechinulin A1

Article abstract of DOI:10.1055/s-0029-1219812

Two N-benzylated analogues of the antioxidant, radical scavenging, and neUrosprotective alkaloid neoechinulin A were prepared. Since, according to SAR studies, stereochemistry does not play an important role, both analogues were prepared in racemic form, using enaminone chemistry. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219812

LETTER
1197
Synthesis of Racemic, N-Benzylated Neoechinulin A and Isoneoechinulin A1
Synthesis
e
of
N
-Benzy
r
latedN
e
n
oechinulin
A
e
and Isone
j
oechinulinAWagger, Uroš Grošelj, Jurij Svete, Branko Stanovnik*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, PO Box 537, 1000 Ljubljana, Slovenia
Fax +386(1)2419220; E-mail: branko.stanovnik@fkkt.uni-lj.si
Received 3 February 2010
indole moiety, is crucial for concomitant antioxidative,
Abstract: Two N-benzylated analogues of the antioxidant, radical
antinitration, and cytoprotective activity.18 Though the
mechanism of action of neoechinulin A still remains un-
scavenging, and neuroprotective alkaloid neoechinulin A were pre-
pared. Since, according to SAR studies, stereochemistry does not
certain, it is postulated that the alkaloid’s cytoprotective
properties are due to its ability to induce antioxidizing en-
zymes by reacting with biomacromolecules; or that neo-
echinulin A can directly react with RNS and/or ROS
(reactive oxygen species) and alkyl radicals.18 To clarify
this question, additional research has to be conducted in-
volving SAR of novel neoechinulin A analogues. Since
the absolute stereochemistry of the center in position 6 of
neoechinulin A is not important for biological activity,18a
we proposed preparing two racemic analogues 1 and 2,
with the N-benzyl group in position 1 of the diketopipera-
zine ring. This would increase lipophilicity of the ana-
logues 1 and 2 compared to neoechinulin A and also
reduce the number of hydrogen-bond donors, resulting in
additional SAR information. Analogue 1 possesses the
isoprenyl group of neoechinulun A at the indole 2-posi-
tion; whereas analogue 2 features the prenyl group
(Figure 1).
play an important role, both analogues were prepared in racemic
form, using enaminone chemistry.
Key words: N-benzylated alkaloid analogues, neoechinulin A,
diketopiperazines, enaminones, 2-isoprenylated, 2-prenylated in-
doles
Neoechinulin A is a simple indole alkaloid most abun-
dantly produced by microorganisms of Aspergillus sp.,
such as A. amstelodami,2 A. ruber3 and A. repens,4 others
including Eurotium rubrum,5 Xylaria euglossa,6 Chaeto-
mium globosum,7 and plants like Bridelia ferruginea.8
The alkaloid has been isolated from these species by sev-
eral research groups and also its total synthesis was al-
ready accomplished.9 In the literature there are several
reports on the strong antioxidant, radical scavenging, and
neuroprotective properties of neoecinulin A. Doi et al. re-
ported antioxidative activities in ferric thiocyanate and
thiobarbituric acid tests in which neoechinulin A showed
better antioxidative activity than a-tocopherol.4 Son et al.
demonstrated very good free radical scavenging activity
of neoechinulin A in a DPPH (1,1-diphenyl-2-picrylhy-
drazyl) assay;10 while Arai et al. reported neuronal cell
protective properties of neoechinulin A against peroxy-
nitrite, a very potent reactive nitrogen species (RNS) ca-
pable of oxidizing biomolecules and nitrating tyrosine
residues. Peroxynitrite is formed from nitric oxide and su-
peroxide, endogenous free radicals present in several
pathogenic processes including sepsis,11 Alzheimer’s and
Parkinson’s disorders.12 Neoechinulin A thus represents
an interesting lead compound for the design of new thera-
peutics for the treatment of peroxynitrite caused disorders.
H
1''
N
2''
H
O
N 4
5
3'
3
6
1 N
2
O
H
neoechinulin A
H
H
N
N
H
N
H
N
O
O
Recently, we have demonstrated that enaminones can be
successfully used in the synthesis of various heterocyclic
systems13 and some simple diketopiperazine-based indole
alkaloid analogues with the a,b-unsaturated Trp moiety,
such as dipodazine,14 tryprostatin B,15 and others like
meridianines16 and aplysinopsines.17 Based on our previ-
ous work and the SAR studies of Arai et al.,18 we envis-
aged preparing novel neoechinulin A analogues. As
reported earlier, the diketopiperazine structure of neo-
echinulin A, together with its exocyclic double bond and
N
O
N
O
1
2
Figure 1 Neoechinulin A and analogues 1 and 2
The synthesis of both analogues started from the methyl
ester of (R,S)-alanine hydrochloride (3), which was reduc-
tively N-benzylated with benzaldehyde using sodium cy-
anoborohydride to give the N-benzyl methyl ester of
(R,S)-alanine (4). This was then reacted with chloroacetyl
chloride to form the methyl ester of (R,S)-N-benzly-N-
SYNLETT 2010, No. 8, pp 1197–1200
x
x.
x
x.
2
0
1
0
Advanced online publication: 09.04.2010
DOI: 10.1055/s-0029-1219812; Art ID: D03410ST
© Georg Thieme Verlag Stuttgart · New York

1198
J. Wagger et al.
LETTER
O
PhCHO
Cl
O
O
NaCNBH3, Et3N
O
O
Cl
N
NH3(g), MeOH
81%
N
N
HCl⋅H2N
H
MeOH, TOF
95%
Et3N, CH2Cl2
73%
O
O
NH
O
O
O
3
4
Cl
6
5
Scheme 1 Synthesis of diketopiperazine precursor 6
chloroacetyl alanine (5) that was cyclized with ammonia ductive detosylation of 2-prenylated N-tosylindole (16)
in methanol into (R,S)-1-benzyl-6-methylpiperazine-2,5- with Mg powder in methanol (Scheme 3).15b
dione (6, Scheme 1).
Next 2-isoprenylindole (9) and 2-prenylindole (10) were
Previously we have already reported on compound 6 in coupled with the enaminone 8, affording targets 1 and 2.
the context of its chiral solvating properties19 and dipo- In the case of reaction of 2-isoprenylindole (9) with en-
dazine analogues synthesis.14 Diketopiperazine 6 was aminone 8, the reaction yield was much lower in compar-
then reacted with t-BuO-bisdimethylaminomethane ison to reaction of 2-prenylated indole (10) with
(Bredereck’s reagent, 7) to furnish (Z)-(R,S)-1-ben- enaminone 8. The reason for this is presumably the greater
zyl[(dimethylamino)methylidene]-6-methylpiperazine-2,5-
dione (8, Scheme 2).
steric shielding of nucleophilic position 3 of indole deriv-
ative 9 than in 10. We have previously used bulkier sub-
stituents at position 2 of indole for similar coupling
reactions, 2-phenylindole for example, but the yields were
always better than in the case of 2-isoprenylated indole
(9).14,15a In the case of 2-phenylindole the phenyl ring is
perpendicular to the indole ring and is thus sterically
much less demanding for such coupling reactions than 2-
isoprenylated derivative 9, where the indole core is at-
tached to the quaternary sp3 carbon of the isoprenyl chain
(Scheme 4).
t-BuOCH(NMe)2
O
O
N
7
N
NH
75%
NH
O
O
6
8
NMe2
Scheme 2 Synthesis of enaminone 8 for direct coupling with 2-iso-
prenylindole (9) and 2-prenylindole (10)
The structures of 1 and 2 were determined spectroscopi-
cally (NMR, IR) by MS and in the case of prenylated an-
alogue 2 by elemental analysis. Their spectroscopic data
are in agreement with those reported for neoechinulin A.9
Both compounds were isolated as Z-isomers as estab-
lished by HMBC spectroscopy on the basis of the long-
range coupling constant 3J(C,H) between the methylidene
proton C3¢–H and carbonyl C atom C2=O determined from
the antiphase splitting of the corresponding cross-peak
(Figure 2).22
2-Isoprenylindole (9) was prepared using a similar proce-
dure to that reported by Danishefsky in his tryprostatin B
synthesis (where the analogous 2-isoprenylated tryp-
tophan derivative was prepared20) from 9-(3-methylbut-2-
enyl)-9-borabicyclo[3.3.1.]nonane (12), prepared by
modified procedure of Brown,21 and 3-chloroindole (13).
We found out that this is a very simple two-step, one-pot
synthesis of 2-isoprenylated indole (9). 2-Prenylated in-
dole (10) was prepared from prenylbromide 14 with the
lithiated derivative of N-tosylindole (15), followed by re-
H
N
H
H
B
N
11
Cl
13
N
BH
B
THF, r.t.
– HCl
85%
Et3N, THF, r.t.
9-BBN
12
9
Cl
Ts
Ts
Ts
Br
H
Mgo, MeOH, )))
N
N
N
N
LDA, THF
–78 °C
14
Li
r.t.
52%
83%
15
16
10
Scheme 3 Synthesis of 2-isoprenylindole (9) and 2-prenylindole (10)
Synlett 2010, No. 8, 1197–1200 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Benzylated Neoechinulin A and Isoneoechinulin A
1199
H
N
H
N
H
H
N
N
NMe2
H
H
N
H
O
N
O
O
N
10
9
AcOH, reflux
13%
AcOH, reflux
62%
N
O
N
O
N
O
1
8
2
Scheme 4 Coupling of 2-isoprenylindole (9) and 2-prenylindole (10) with enaminone 8 – synthesis of targets 1 and 2
and the reaction mixture was stirred at r.t. for 3.5 h. After that time,
Et3N (1.23 mL, 8.82 mmol) and 3-chloroindole (13) (1.11 g, 7.35
mmol) were added, and the reaction mixture was stirred for an ad-
ditional 17 h. Saturated aq NaCl was poured in the reaction mixture,
and THF was removed under vacuum. The aqueous phase was ex-
tracted with CH2Cl2 (3 × 25 mL), and the combined organic phases
dried over Na2SO4 and concentrated under vacuum. The brown oily
residue was purified by column chromatography (EtOAc–
PE = 1:40), and the product was isolated as yellow oil; yield 1.17 g
(85%). IR (KBr): nmax = 3422, 2968, 1637, 1542, 1459, 1406, 1289,
1234, 998, 918, 786, 749, 736 cm–1. 1H NMR (300 MHz, CDCl3): d
= 1.48 (6 H, s, 2 × CH3), 5.12 (1 H, dd, J1 = 1.1 Hz, J2 = 17.3 Hz,
CH), 5.10 (1 H, dd, J1 = 1.1 Hz, J2 = 10.4 Hz, CH), 6.05 (1 H, dd,
J1 = 10.3 Hz, J2 = 17.6 Hz, CH), 6.51 (1 H, dd, J1 = 0.9 Hz, J2 = 2.1
Hz, Ar), 7.06 (1 H, dt, J1 = 1.2 Hz, J2 = 6.1 Hz, Ar), 7.12 (1 H, dt,
J1 = 1.2 Hz, J2 = 7.0 Hz, Ar), 7.25–7.33 (1 H, m, Ar), 7.50–7.60 (1
H, m, Ar), 7.86 (1 H, br s, NH). 13C NMR (75.5 MHz, CDCl3): d =
27.6, 38.4, 98.2, 110.6, 112.4, 119.8, 120.3, 121.5, 128.8, 136.1,
146.0, 146.3. MS (EI): m/z = 185 [M+]. HRMS (EI): m/z calcd for
C13H15N [M+]: 186.1283; found: 186.1279.
HN
C2
7.06 ppm
H
N
3'
O
3J(C,H) = 4.8 Hz
H
159.9 ppm
O
N
(Z)-2
Figure 2 Configuration around exocyclic double bond was determi-
ned by using a NMR HMBC experiment
In summary, two N-benzylated analogues 1 and 2 of neo-
echinulin A have been prepared, using direct coupling of
2-isoprenylated (9) and 2-prenylated (10) indoles with
enaminone 8. This synthetic methodology represents a vi-
able alternative to Horner–Wadsworth–Emmons olefina-
tion, frequently used for synthesis of a,b-unsaturated-a-
amino acids. Both analogues 1 and 2 are more lypophilic
in comparison to neoechinulin A and represent valuable
compounds in additional SAR studies for clarification of
its antinitration, antioxidative, and cytoprotective mecha-
nism of action.
(Z)-1-Benzyl-3-[(dimethylamino)methylidene]-6-methylpipera-
zine-2,5-dione (8)
For the experimental data on compound 8 see ref. 13.
(Z)-(1)-Benzyl-6-methyl-3-{[2-(2-methylbut-3-ene-2-yl)-1H-
indol-3-yl]methylidene}-piperazine-2,5-dione (1)
To enaminone 8 (0.547 g, 2 mmol) dissolved in glacial AcOH (4
mL), 2-isoprenylindole (9) (0.621 g, 3.35 mmol) was added, and the
reaction mixture was refluxed for 7 h. The mixture was then cooled
and concentrated under vacuum, and the residue was purified by
column chromatography (EtOAc–PE = 1:2). The yellow oil thus
obtained was crystallized from CH2Cl2 and heptane; yield 0.107 g
(13%) of pale yellow solid, mp 249–252 °C. IR (KBr): nmax = 3365,
3328, 2973, 1703, 1657, 1610, 1492, 1449, 1433, 1391, 1340, 1248,
11911149, 995, 917, 878, 751, 702, 609 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.56 (3 H, d, J = 6.9 Hz, CH3), 4.02 (1 H, q, J = 6.9 Hz,
CH), 4.17 (1 H, d, J = 15.0 Hz, CH), 5.20 (1 H, dd, J1 = 0.7 Hz,
J2 = 17.4 Hz, CH), 5.23 (1 H, dd, J1 = 0.7 Hz, J2 = 10.6 Hz, CH),
5.42 (1 H, d, J = 15.0 Hz, CH), 6.09 (1 H, dd, J1 = 10.6 Hz, J2 = 17.4
Hz, CH), 7.10–7.23 (2 H, m, Ar), 7.30–7.42 (7 H, m, Ar), 8.28 (1 H,
br s, NH). 1H NMR (300 MHz, DMSO-d6): d = 1.47 (3 H, d, J = 6.3
Hz, CH3), 1.48 (3 H, s, CH3), 1.51 (3 H, s, CH3), 3.94 (1 H, q, J = 6.9
Hz, CH), 4.33 (1 H, d, J = 14.6 Hz, CH), 5.04 (1 H, d, J = 14.8 Hz,
CH), 5.06 (1 H, dd, J1 = 1.1 Hz, J2 = 17.6 Hz CH), 5.07 (1 H, dd,
J1 = 1.2 Hz, J2 = 10.2 Hz, CH), 6.09 (1 H, dd, J1 = 10.9 Hz,
J2 = 16.9 Hz, CH), 6.96–7.20 (4 H, m, 3 H of Ar, CH), 7.26–7.46 (6
H, m, Ar), 9.18 (1 H, s, NH), 11.05 (1 H, s, NH). 13C NMR (75.5
MHz, DMSO-d6): d = 18.5, 27.4, 27.7, 46.9, 56.0, 103.8, 111.5,
111.7, 112.4, 118.9, 119.3, 120.6, 123.8, 126.1, 127.4, 127.9, 128.6,
135.1, 137.2, 144.3, 145.1, 159.6, 166.0. MS (EI): m/z = 414
[MH+]. HRMS (EI): m/z calcd for C26H27N3O2: 414.2182 [MH+];
found: 414.2170.
3-Chloroindole (13)
Indole (2.93 g, 25 mmol) was disolved in DMF (18 mL) at 0 °C, and
NCS (3.67 g, 27.5 mmol) was added. After 15 min at 0 °C, the re-
action mixture was stirred at r.t. for an additional 45 min, and then
the reaction mixture was poured in 150 mL of ice-cold water and
K2S2O5 (2.15 mg). The precipitate was filtered, dissolved in CH2Cl2
(30 mL) and extracted with H2O (4 × 30 mL). The organic phase
was then dried over Na2SO4 and concentrated at 100 mbar and
25 °C. The residual yellowish-green solid of crude 3-chloroindol
(13) showed spectroscopic data corresponding to the literature da-
ta;23 yield 3.25 g (86%), compound decomposed on heating. IR
(KBr): nmax = 3409, 3126, 3051, 1719, 1617, 1519, 1453, 1332,
1289, 1205, 1087, 1000, 929, 810, 740, 596 cm–1; H NMR (300
1
MHz, DMSO-d6): d = 7.05–7.14 (1 H, m, Ar), 7.14–7.23 (1 H, m,
Ar), 7.38–7.45 (1 H, m, Ar), 7.45–7.47 (2 H, m, Ar), 11.33 (1 H, s,
1
NH). H NMR (300 MHz, CDCl3): d = 7.15–7.18 (1 H, m, Ar),
7.19–7.28 (2 H, m, Ar), 7.25–7.39 (1 H, m, Ar), 7.60–7.67 (1 H, m,
Ar), 8.05 (1 H, br s, NH). MS (EI): m/z = 151 [M+].
2-(2-Methylbut-3-en-2-yl)-1-H-indole (9)
All glass ware was dried in a vacuum oven at 100 °C, for an hour
before use. To 9-BBN (29.4 mL, 0.5 M in THF) 3-methylbuta-1,2-
diene (11) (1.44 mL,14.7 mmol) was added under inert atmosphere,
Synlett 2010, No. 8, 1197–1200 © Thieme Stuttgart · New York

1200
J. Wagger et al.
LETTER
(Z)-1-Benzyl-6-methyl-3-{[2-(3-methylbut-2-enyl)-1H-indol-
3yl]methylene}piperazine-2,5-dione (2)
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T.; Kobayashi, S. Synlett 2006, 677.
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J. R.; Son, B. W. Chem. Pharm. Bull. 2004, 52, 375.
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To enaminone 8 (0.547 g, 2 mmol) dissolved in glacial AcOH (4
mL), 2-prenylindole (10) (0.371 g, 2 mmol) was added, and the re-
action mixture was refluxed for 2 h. The mixture was then cooled
and concentrated under vacuum, and the residue was purified by
column chromatography (EtOAc–PE = 1:2). The resultant orange
foam was crystallized from MeOH–H2O; yield 0.514 g (62%) of
yellow solid, mp 138–141 °C. IR (KBr): nmax = 3258, 3063, 2976,
1661, 1624, 1539, 1494, 1444, 1406, 1351, 1256, 1164, 1098, 984,
880, 788, 743 cm–1. 1H NMR (300 MHz, DMSO-d6): d = 1.45 (3 H,
d, J = 6.9 Hz, CH3), 1.72 (6 H, s, 2 × CH3), 3.42 (1 H, dd, J1 = 7.0
Hz, J2 = 16.9 Hz, CH), 3.51 (1 H, dd, J1 = 7.0 Hz, J2 = 16.9 Hz,
CH), 3.96 (1 H, q, J = 6.9 Hz, CH), 4.30 (1 H, d, J = 15 Hz, CH),
5.07 (1 H, d, J = 15.0 Hz, CH), 5.31 (1 H, dd, J1 = 7.0 Hz, J2 = 7.1
Hz, CH), 7.00–7.25 (3 H, m and s, Ar and CH), 7.25–7.43 (7 H, m,
Ar), 9.44 (1 H, s, NH), 11.30 (1 H, s, NH). 13C NMR (75.5 MHz,
DMSO-d6): d = 17.7, 18.3, 25.5, 25.9, 46.9, 56.1, 104.7, 111.0,
111.2, 119.0, 119.5, 120.3, 120.8, 123.2, 126.4, 127.4, 127.8, 128.6,
133.0, 135.9, 137.3, 140.0, 159.9, 166.2. HMBC: d = 7.06 (CH),
159.9 (CO, J = 4.8 Hz). MS (EI): m/z = 414 [MH+]. HRMS (EI):
m/z calcd for C26H27N3O2: 414.2182 [MH+]; found: 414.2171. Anal.
Calcd for C26H27N3O2: C, 75.52; H, 6.58; N, 10.16. Found: C,
75.29; H, 6.39; N, 10.21.
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Acknowledgment
Financial support from the Slovenian Research Agency through
grants P0-0502-0103, P1-0179 and J1-6689-0103-04 is gratefully
acknowledged. We thank the pharmaceutical companies Krka d.d.
(Novo mesto, Slovenia) and Lek d.d., a Sandoz Company (Ljubljana,
Slovenia) for financial support.
References and Notes
(1) The term isoneoechinulin A is proposed by authors of this
work and refers to the prenyl group replacing the isoprenyl
group in neoechinulin A. This nomenclature is used for
naming compound 2.
(2) (a) Dossena, A.; Marchelli, R.; Pochini, A. J. Chem. Soc.,
Chem. Commun. 1975, 779. (b) Casnati, G.; Pochini, P.;
Ungaro, R. Gazz. Chim. Ital. 1973, 103, 141.
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(5) Li, D.-L.; Li, X.-M.; Li, T.-G.; Dang, H.-Y.; Wang, B.-G.
Helv. Chim. Acta 2008, 91, 1888.
(6) Wang, X.-N.; Tan, R.-X.; Liu, J.-K. J. Antibiot. 2005, 58,
268.
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Ebel, R.; Proksch, P.; Wang, B.-G. J. Nat. Prod. 2006, 69,
1622.
(8) Pettit, G. R.; Hogan, F.; Xu, J.-P.; Tan, R.; Nogawa, T.;
Cichacz, Z.; Pettit, R. K.; Du, J.; Ye, Q.-H.; Cragg, G.-M.;
Harald, C. L.; Hoard, M. S.; Goswami, A.; Searcy, J.;
Tackett, L.; Doubek, D. L.; Williams, L.; Hooper, J. N. A.;
Schmidt, J. M.; Chapuis, J.-C.; Tackett, D. N.; Craciunescu,
F. J. Nat. Prod. 2008, 71, 438.
(22) A crystal structure of isoprenylated analogue 1 was
established from monocrystal, but the diffraction data were
poor for the isoprenylated region of the molecule; although
the X-ray structure obtained unambiguously showed a Z
orientation around the exocyclic double bond.
(23) Brennan, M. R.; Erickson, K. L.; Szmalc, F. S.; Tansey,
M. J.; Thornton, J.; Janice, M. Heterocycles 1986, 24, 2879.
Synlett 2010, No. 8, 1197–1200 © Thieme Stuttgart · New York

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