Synthesis of barettin

Article abstract of DOI:10.1016/j.tet.2003.11.031

The indole alkaloid barettin (with bromine in 6-position), isolated from the marine sponge Geodia Barretti, has been synthesised via a Horner-Wadsworth-Emmons type reaction from 6-bromoindole-3-carboxaldehyde to introduce the dehydro-functionality. Subsequent deprotection and cyclisation afforded the natural product in Z-conformation.

Full text of DOI:10.1016/j.tet.2003.11.031

Tetrahedron 60 (2004) 961–965
Synthesis of barettin
a,b
Ann-Louise Johnson, Jan Bergman,
a,b,*
c
Martin Sj o¨ gren and Lars Bohlin
c
a
Unit for Organic Chemistry, CNT, Department of Biosciences at Novum, Karolinska Institute, Novum Research Park,
SE-141 57 Huddinge, Sweden
b
S o¨ dert o¨ rn University College, SE-141 04 Huddinge, Sweden
Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574,
SE-751 23 Uppsala, Sweden
c
Received 11 August 2003; revised 20 October 2003; accepted 13 November 2003
Abstract—The indole alkaloid barettin (with bromine in 6-position), isolated from the marine sponge Geodia Barretti, has been synthesised
via a Horner–Wadsworth–Emmons type reaction from 6-bromoindole-3-carboxaldehyde to introduce the dehydro-functionality.
Subsequent deprotection and cyclisation afforded the natural product in Z-conformation.
q 2003 Elsevier Ltd. All rights reserved.
1
. Introduction
laborious due to problems with the basic guanidino group in
the arginine side chain. In our case, the guanidino group was
protected by tert-butoxycarbonyl groups, via the excellent
method by Bernatowicz et al. Thus the Cu(II)-ornithine
complex (prepared from L-ornithine·HCl) is guanylated at
The structure of the pharmacologically active indole
alkaloid barettin, isolated in 1986 from the cold water
sponge Geodia barretti by Lidgren et al., has been the
subject of debate during several years. The originally
proposed structure for barettin, the diketopiperazine 1, was
disproved by an independent total synthesis of 1, as well as
5
6
1
d
1
N with a protected derivative of 1-guanylpyrazole, N -[N,
0
N -bis(tert-butoxycarbonyl)amidino]pyrazole (4) to give the
v
v
0
Cu(II)-complex of N ,N -bis(tert-butoxycarbonyl)-pro-
tected arginine derivative 5 in good yields, prepared as
2
the E-isomer 2 a year later (Fig. 1). However, a recent
3
5
a
publication by S o¨ lter et al. presented isolation and structure
elucidation of a diketopiperazine from G. barretti, collected
described in the literature. Compound 5 was further N -
protected with di-t-butyl dicarbonate in the presence of
a
in Norway. The German group found the diketopiperazine
4
to be a condensation product of 6-bromo-D-tryptophan and
arginine, i.e. compound 3, which they believed represented
the actual structure of barettin. Now we have indeed
confirmed these findings after a reinvestigation of isolated
material, combined with a total synthesis of compound 3.
ethylenediaminetetraacetic acid (EDTA) to afford N -(tert-
0
v
v
butoxycarbonyl)-N ,N -bis(tert-butoxycarbonyl)-L-argi-
nine (6) in a reasonable yield (79%) (Scheme 1).
Using this protected arginine derivative, the saturated
analogue of 3 (i.e. 9) was prepared via standard peptide
coupling procedures with 6-bromo-D,L-tryptophan methyl
ester (7), obtained via esterification of commercially
available 6-bromo-D,L-tryptophan. Removal of the pro-
tecting groups of the resulting dipeptide 8 with trifluoro-
2
. Results and discussion
7
acetic acid (TFA) and subsequent cyclisation afforded
Synthesis of arginine-containing peptides is often very
Figure 1.
Keywords: Geodia Barretti; Barettin; N-Boc protection of arginine; HWE-reaction.
*
Corresponding author at present address: Unit for Organic Chemistry, CNT, Department of Biosciences at Novum, Karolinska Institute, Novum Research
Park, SE-141 57 Huddinge, Sweden. Tel.: þ46-8-608-9204; fax: þ46-8-608-1501; e-mail address: jan.bergman@biosci.ki.se
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.031

962
A.-L. Johnson et al. / Tetrahedron 60 (2004) 961–965
2 2 2 3 2 2
Scheme 1. (a) Cu(Orn) ·CuCl , DIEA, formamide/dioxane, rt 5 h. (b) EDTA·4Na·2H O, NaHCO , Boc O, H O/acetone, rt 12 h.
cyclo-6-bromo-D,L-Trp-L-Arg or 8,9-dihydrobarettin (9) as
a mixture of diastereomers. Although 8,9-dihydrobarettin
has previously been identified as a congener of barettin in G.
barretti, the specific rotation of the natural product still
Hydrogenolysis of methyl 2-benzyloxycarbonylamino-2-
1
0
(diethoxyphosphinyl)-acetate (11) afforded the free amine
which was immediately reacted with the amino acid
0
derivative 6 in presence of 1-ethyl-3-(3 -dimethylamino-
8
remains to be determined. Here, no efforts were made to
propyl)carbodiimide hydrochloride (EDCI), which gave the
dipeptide 12 in 64% yield. The phosphonoglycinate 12 was
further condensed with 6-bromo-1-(tert-butoxycarbonyl)-
separate the diastereomeric mixture. However, despite
several attempts, using e.g. 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) and trichloroisocyanuric acid
1
1
indole-3-carboxaldehyde (13) using 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) as the base to furnish the desired
compound 14. The yield in this particular reaction has so far
been only moderate, usually around 55%. Although the low
yield might indicate formation of the E-isomer, we were
only able to detect the desired Z-isomer of 14. However,
there are indications in the literature that Z-isomers are
formed predominately using DBU as the base in this type of
(
3
TCCA), we were not able to dehydrogenate 9 to compound
. Neither did it prove to be possible to use 6-bromo-D-
9
tryptophan ethyl ester (10) as starting material, since all
attempted peptide coupling with compounds 6 and 10 failed
(
Scheme 2).
Another route towards functionalised dehydroamino acids
involves Horner–Wadsworth–Emmons type reactions.
1
2
reactions. Using potassium tert-butoxide (t-BuOK) as
Scheme 2. (a) 6, EDCI, HOBt, DIEA, CH
2
Cl , rt 18 h. (b) (i) TFA, CH
2
2
Cl , rt 12 h. (ii) 0.1 M HOAc/1-BuOH, NMM, reflux 6 h.
2
2 2 2 2 2 2 2
Scheme 3. (a) (i) H , Pd/C, EtOH, 4.5 h. (ii) 6, EDCI, HOBt, DIEA, CH Cl , rt 18 h. (b) 12, DBU, CH Cl , 2788 to rt 20 h. (c) (i) TFA, CH Cl , rt 12 h. (ii)
0.1 M HOAc/1-BuOH, NMM, reflux 6 h.

A.-L. Johnson et al. / Tetrahedron 60 (2004) 961–965
963
base in the same reaction resulted in an even lower yield.
Several acidic hydrogen atoms present in compound 12
might also account for the poor yield but variation of the
amount of base used failed to improve the results.
(q), 27.6 (q), 25.5 (t). HRMS (FABþ) m/z calcd for
þ
C H N O (MþH) 475.2768, found 475.2767.
2
1 39 4 8
3.1.2. 6-Bromo-D,L-tryptophan methyl ester·HCl (7). 6-
Bromo-D,L-tryptophan (1.42 g, 5.00 mmol) was suspended
The four Boc-protecting groups in 14 were removed by
treatment with TFA at ambient temperature overnight. The
solvent was then removed and the residue in the flask
dissolved in 1-butanol containing 0.1 M acetic acid, with
addition of N-methylmorpholine (NMM). After 5 h at reflux
the solvents were removed, giving barettin (3) in 62% yield
in MeOH (18 mL) at 0 8C. SOCl (0.37 mL, 5.05 mmol)
2
was added dropwise and the mixture kept at 0 8C for an
additional 0.5 h. The solution was refluxed for 1.5 h and
thereafter allowed to cool. The solvent was evaporated
leaving a quantitative yield of 6-bromo-D,L-tryptophan
methyl ester·HCl (7) as a pinkish solid: mp 240.0–
(
Scheme 3).
242.5 8C; IR (KBr): 3274, 2876, 1743, 1590, 1500, 1445,
1
1 1
246, 1105, 1080, 802 cm2 ; H NMR (DMSO-d ): d 11.37
6
The analytical data of this synthetic material agreed
8
(s, 1H), 8.70 (br s, 2H), 7.57 (d, J¼1.6 Hz, 1H), 7.50 (d,
completely with those of the natural product. The NMR
data of 3 are in agreement with those reported by S o¨ lter
J¼8.5 Hz, 1H), 7.30 (d, J¼2.3 Hz, 1H), 7.15 (dd, J¼1.7,
13
8.5 Hz, 1H), 4.22 (t, J¼6.3 Hz, 1H), 3.63 (s, 3H), 3.38–3.34
3,13
et al.
(m, 2H); C NMR (DMSO-d ): d 169.7 (s), 137.1 (s), 126.1
6
(
(
d), 126.0(s), 121.5 (d), 119.9 (d), 114.1 (d), 113.9 (s), 106.8
s), 52.7 (q), 52.6 (d), 25.8 (t). HRMS (FABþ) m/z calcd for
7
2 14 2 2
9
þ
C H N O Br (MþH) 297.0239, found 206.0232.
1
3
. Experimental
a
v
v
0
3
.1.3. N -(Boc)-N ,N -bis(Boc)-L-Arg-6-bromo-D,L-
3
.1. General
TrpOMe (8). A mixture of 6-bromo-D,L-tryptophan methyl
ester·HCl (7) (999 mg, 3.00 mmol), arginine derivative 6
(1.42 g, 3.00 mmol), EDCI (690 mg, 3.60 mmol) and HOBt
(486 mg, 3.60 mmol) in CH Cl (20 mL) was stirred at 0 8C.
1
NMR spectra were recorded at 300 MHz for H and 75 MHz
1
3
for C, respectively. NMR spectra were recorded in
DMSO-d or CDCl , using the solvent signal as reference.
2
2
Et N (0.84 mL, 6.00 mmol) was added and the solution was
3
6
3
d Values are given in ppm, coupling constants are given in
Hz. The IR spectra were acquired using a FT-IR instrument.
Optical rotation values were determined in a polarimeter
equipped with a 1 mL cell measuring 10 cm using the
emission wavelength of a sodium lamp; concentrations are
given in g/100 mL. High-resolution mass spectroscopic
allowed to reach room temperature overnight. The reaction
mixture was transferred to a separatory funnel, additional
CH Cl (15 mL) was added and the organic phase was
2
2
washed with H O (2£20 mL), brine (20 mL) and dried over
2
MgSO . The solvent was evaporated and the residue
4
purified by column chromatography (hexane/EtOAc
60:40) to give the protected dipeptide 8 as a clear oil
(1.36 g, 60%): IR (KBr): 3333, 2979, 2936, 1723, 1647,
(
HRMS) analyses were performed by E. Nilsson, University
of Lund, Sweden. Melting points were determined on a
capillary melting point apparatus. Chromatographic separ-
ations were performed on silica gel 60 (230–400 mesh). All
reagents used were purchased from Aldrich, Lancaster,
Merck or Biosynth and were used as received. All solvents
were purified by distillation or were of analytical grade.
1620, 1368, 1163, 1135 cm2 ; H NMR (DMSO-d ): d
1
1
6
11.50 (s, 1H), 11.01 (d, J¼5.0 Hz, 1H), 8.26–8.19 (m, 2H)
7.51 (s, 1H) 7.45 (d, J¼8.5 Hz, 1H) 7.19 (dd, J¼2.0, 8.4 Hz,
1H), 7.12 (dd, J¼1.2, 8.4 Hz, 1H), 6.86–6.76 (m, 1H),
4.53–4.51 (m, 1H), 4.02–3.97 (m, 1H), 3.59–3.54 (m, 3H),
1
3
3.25–2.98 (m, 4H), 1.47–1.34 (m, 31H); C NMR
(DMSO-d ): d 172.0 (s), 171.9 (s), 171.8 (s), 163.1 (s),
a
v
v
0
butoxycarbonyl)-L-arginine (6). To a suspension of
3
.1.1. N -(tert-Butoxycarbonyl)-N ,N -bis(tert-
6
155.2 (s), 152.1 (s), 136.9 (136.8) (s), 126.1 (126.0) (s),
125.0 (124.9) (d), 121.2 (d), 119.8 (119.7) (d), 113.9 (d),
113.7 (s), 109.7 (109.6) (s), 82.8 (s), 78.1 (s), 78.1 (s), 52.8
(52.7) (d), 51.8 (51.7) (q), 39.7 (39.6) (t), 31.2 (d), 29.3 (t),
28.1 (q), 28.0 (q), 27.6 (q), 27.0 (26.8) (t), 25.1 (24.9) (t).
Figures within brackets refer to doublets arising due to the
presence of diastereomers. HRMS (FABþ) m/z calcd for
v,v
5
Cu[Arg (Boc)2]2
(5)
(4.03 g,
5.00 mmol),
EDTA·4Na·2H O (2.23 g, 6.00 mmol) and NaHCO3
2
(
1.68 g, 20.0 mmol) in H O (30 mL), a solution of Boc O
2 2
(
2.40 g, 11.0 mmol) in acetone (30 mL) was added drop-
wise. The reaction mixture was stirred at room temperature
for 12 h when the solvent was evaporated. The aqueous
7
9
þ
mixture was acidified with 5% KHSO , until ,pH 3. The
C H N O Br (MþH) 753.2823, found 753.2835.
4
33 50 6 9
resulting gummy precipitate was extracted with EtOAc
(
with H O (100 mL), brine (100 mL) and dried over MgSO .
3£40 mL) and the combined organic phases were washed
3.1.4. 8,9-Dihydrobarettin (9). The dipeptide 8 (1.14 g,
1.52 mmol) was dissolved in CH Cl (15 mL) and TFA
2
4
2
2
Evaporation furnished a yellow oil which was purified by
column chromatography using hexane/EtOAc (60:40) as
(2.32 mL, 30.31 mmol) was added at room temperature.
The reaction mixture was stirred for 5 h, and then
evaporated to dryness. The residue was dissolved in
1-butanol (15 mL) containing 0.1 M AcOH. NMM
(0.17 mL, 1.52 mmol) was added and the reaction mixture
was refluxed for 12 h and thereafter allowed to cool. The
2
1
eluent, yielding 6 as a colourless glass (3.77 g, 79%): [a]D
þ78 (c 0.1, MeOH); IR (KBr): 3332, 2980, 1722, 1634,
2
1
1
1
616, 1368, 1332, 1158, 1136, 1052 cm
;
H NMR
(
DMSO-d ): d 12.53 (s, 1H), 11.49 (s, 1H), 8.29–8.25 (m,
6
1
H), 7.08 (d, J¼8.0 Hz, 1H), 3.85–3.82 (m, 1H), 3.27–3.25
reaction mixture was washed with H O (2£20 mL), brine
2
1
3
(
m, 2H), 1.57–1.35 (m, 31H); C NMR (DMSO-d ): d
6
(20 mL) and dried over MgSO . The solvent was evaporated
4
1
7
74.1 (s), 163.1 (s), 155.6 (s), 155.3 (s), 152.1 (s), 82.9 (s),
8.1 (s), 78.0 (s), 53.3 (d), 39.6 (t), 28.2 (q), 28.1 (t), 28.0
affording cyclo-6-bromo-D,L-Trp-L-Arg or 8,9-dihydro-
barettin (9) as a yellowish solid (474 mg 74%): IR (KBr):

964
A.-L. Johnson et al. / Tetrahedron 60 (2004) 961–965
3
1
1
7
339, 3201, 2959, 2934, 2873, 1668 (br), 1456, 1330, 1202,
EtOAc/hexane (70:30) as eluent afforded the title compound
21
136, 802 cm2 ; H NMR (DMSO-d ): d 11.08 (s, 1H),
1
1
12 as a clear oil. Yield: 2.35 g (64%): [a]D 278 (c 0.2,
MeOH); IR (KBr): 3332, 2978, 2933, 1752, 1719, 1680,
1639, 1617, 1367, 1330, 1252, 1164, 1134, 1050,
6
1.02 (s, 1H), 8.15 (br s, 2H), 8.01 (s, 1H), 7.92 (s, 1H),
.54–7.51 (m, 4H), 7.45 (t, J¼5.5 Hz, 1H), 7.24 (t,
1 1
1025 cm2 ; H NMR (CDCl ): d 11.45 (s, 1H), 8.34–8.30
J¼5.3 Hz, 1H), 7.30–6.70 (m, 6H), 7.10–7.05 (m, 4H),
3
4
3
1
.13–4.03 (m, 2H), 3.63–3.59 (m, 1H), 3.32–2.97 (m, 3H),
.03–2.97 (m, 4H), 2.81–2.71 (m, 2H), 1.55–1.27 (m, 4H),
(m, 1H), 7.27–7.19 (m, 1H), 5.42–5.32 (m, 1H), 5.19 (d,
J¼8.9 Hz, 1H), 4.22–4.06 (m, 4H), 3.78 (s, 3H), 3.43–3.39
1
3
2
.10–0.62 (m, 4H); C NMR (DMSO-d ): d 168.0 (167.4)
6
(m, 2H), 1.86–1.27 (m, 38 H). MS (ESI) m/z 680 (M2H) ;
þ
682.3428, found 682.3439.
(
1
s), 167.0 (166.7) (s), 156.9 (156.8) (s), 136.8 (136.7) (s),
26.9 (126.7) (s), 125.7 (125.5) (d), 121.2 (121.1) (d), 120.8
HRMS (FABþ) m/z calcd for C H N O P (MþH)
2
8 53 5 12
(
(
120.7) (d), 113.8 (113.7) (d), 113.6 (113.5) (s), 109.0
108.8) (s), 55.4 (55.3) (d), 53.3 (52.9) (d), 40.4 (40.2) (t),
9.2 (t), 28.7 (28.6) (t), 23.5 (23.1) (t). Figures within
a
v
v
0
3.1.7. N -(Boc)-N ,N -bis(Boc)-L-Arg-6-bromo-D-(1-
Boc)TrpOMe (14). The arginine derivative 12 (710 mg,
1.04 mmol) dissolved in CH Cl (5 mL) was added
2
brackets refer to doublets arising due to the presence of
2
2
diastereomers. HRMS (FABþ) m/z calcd for
dropwise to a solution of DBU (0.31 mg, 2.09 mmol) in
CH Cl (5 mL) at 278 8C under a nitrogen atmosphere.
7
2
9
þ
C H N O Br (MþH) 421.0988, found 421.0996.
1
7
22
6
2
2
After 30 min 6-bromo-1-(tert-butoxycarbonyl)-indole-3-
1
1
3
.1.5. 6-Bromo-D-tryptophan metyl ester (10). 2-Nitro-
carboxaldehyde (13) (338 mg, 1.04 mmol) in CH Cl
2 2
1
4
pent-2-enoic acid ethyl ester (1.59 g, 8.40 mmol) was
mixed with 6-bromoindole (1.37 g, 7.00 mmol) under a
nitrogen atmosphere at ambient temperature. A mixture of
(5 mL) was added. The reaction mixture was allowed to
reach room temperature. After 18 h the mixture was
evaporated to dryness and the residue dissolved in EtOAc
Et O/hexane (1:1) was added after 12 h and the yellow
2
(20 mL), washed with H O (2£20 mL) and brine (30 mL).
2
precipitate formed was collected and washed with further
Et O/hexane (1:1) to give 3-(6-bromo-1H-indol-3-yl)-2-
The organic phase was dried over MgSO and evaporated,
4
leaving a yellow oil which was purified by column
chromatography. Elution with hexane/EtOAc (80:20 to
2
nitro-acrylic acid ethyl ester (808 mg), which was used
without further purification. A second crop was collected
from the mother liquid (362 mg) to give a total yield of
2
1
60:40) afforded 14 as a yellow oil (490 mg, 55%): [a] þ
D
748 (c 0.2, MeOH); IR (KBr): 3330, 2978, 2933, 1721, 1641,
1619, 1368, 1333, 1251, 1155, 1135, 1051 cm2 ; H NMR
1
1
1
.17 g (54%).
(CDCl ): d 11.46 (s, 1H), 8.52–8.41 (m, 1H), 8.31 (s, 1H),
3
SnCl ·2H O (2.36 g, 10.5 mmol) was dissolved in 3 M HCl
2
8.19 (s, 1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.53 (d, J¼8.5 Hz,
1H), 7.39 (dd, J¼1.7, 8.5 Hz, 1H), 5.72 (d, J¼8.1 Hz, 1H),
4.51–4.37 (m, 1H), 3.81 (s, 3H), 3.60–3.55 (m, 1H), 3.49–
2
in MeOH (20 mL) at 0 8C. 3-(6-Bromo-1H-indol-3-yl)-2-
nitro-acrylic acid ethyl ester (1.02 g, 3.00 mmol) was added
to the solution in small portions during 0.5 h. The mixture
was kept at 0 8C for 1 h. The precipitate formed was
collected by filtration and washed with a small amount of
ether. The hydrochloride of 10 was obtained as a pinkish
solid (560 mg, 54%): mp 189 8C (dec); IR (KBr): 3140,
1
3
3.39 (m, 1H), 2.02–1.86 (1H), 1.72–1.25 (m, 39H);
NMR (CDCl ): d 171.0 (s), 165.3 (s), 163.4 (s), 156.8 (s),
C
3
155.9 (s), 153.4 (s), 148.9 (s), 135.6 (s), 128.6 (d), 128.3 (s),
126.5 (d), 124.6 (d), 123.2 (s), 120.4 (d), 118.8 (s), 118.7 (d),
114.1 (s), 85.2 (s), 83.4 (s), 80.2 (s), 79.6 (s), 54.4 (d), 52.8 (q),
40.0 (t), 29.1 (t), 28.5 (q), 28.3 (q), 28.2 (q), 26.1 (t). MS (ESI)
2
1 1
2
996, 2502, 1675, 1653, 1565, 1272, 1145 cm ; H NMR
2
(
(
(
(
DMSO-d ): d 12.32 (s, 1H), 8.19 (d, J¼2.8 Hz, 1H), 7.75
m/z 849 and 851 (M2H) ; HRMS (FABþ) m/z calcd for
6
7
8 56 6 11
9
þ
d, J¼1.7 Hz, 1H), 7.75–7.24 (br, 3H), 7.56 (s, 1H), 7.29
dd, J¼1.7, 8.5 Hz, 1H), 4.33 (q, J¼7.1, 14.1 Hz, 2H), 1.39
C H N O Br (MþH) 851.3190, found 851.3199.
3
13
t, J¼7.1 Hz, 3H); C NMR (DMSO): d 164.0 (s), 136.6 (s),
3.1.8. Barettin (3). TFA (0.91 mL) was added a solution of
compound 7 (500 mg, 0.59 mmol) in CH Cl (10 mL) and
1
(
29.9 (d), 126.0 (s), 123.3 (d), 120.0 (d), 119.0 (d), 118.1
s), 115.1 (s), 114.7 (d), 107.8 (s), 61.6 (t), 14.2 (q). HRMS
2
2
stirred at room temperature for 8 h. The solvent was
evaporated and the residue dissolved in 1-BuOH (10 mL)
containing 0.1 M HOAc. After addition of NMM (0.06 mL,
7
13 2 2
9
þ
(
found 308.0160.
FABþ) m/z calcd for C H N O Br (M) 308.0160,
1
3
0.59 mmol) the reaction mixture was heated at reflux for
4.5 h. The mixture was allowed to cool and thereafter
a
v
v
0
amino)-2-(diethoxyphosphinyl)-acetate (12). A solution
3
.1.6. Methyl 2-(N -(Boc)-N ,N -bis(Boc)-L-arginyl-
washed with H O (2£15 mL), brine (10 mL) and dried over
2
1
0
of compound 11 (2.13 g, 5.94 mmol) in EtOH (60 mL)
was hydrogenated in the presence of Pd/C (5%; 213 mg) at
room temperature for 4.5 h. The reaction mixture was
filtered through celite and the filtrate evaporated leaving a
clear oil. The free amine was immediately dissolved in
CH Cl (10 mL) and added to an ice-cold mixture of the
MgSO . Evaporation of the solvent under reduced pressure
4
afforded barettin (3) as a dark yellow solid (153 mg, 62%).
The NMR data of 3 are in agreement with those reported by
3
,13
26
1
S o¨ lter et al.
3, MeOH)].
[a]D 232.58 (c 2, MeOH), [lit [a] 2258 (c
D
2
2
arginine derivative 6 (2.56 g, 5.40 mmol), HOBt (803 mg,
.94 mmol), EDCI (1.14 mg, 5.94 mmol) and DIEA
1.03 mL, 5.94 mmol) in CH Cl (15 mL). The reaction
5
(
2
2
References and notes
mixture was allowed to reach room temperature. After 15 h
the solvent was evaporated and the residue was taken up in
EtOAc (150 mL) then washed with H O (30 mL) and brine
1. Lidgren, G.; Bohlin, L.; Bergman, J. Tetrahedron Lett. 1986,
27, 3283.
2
(
evaporated. Purification by column chromatography with
30 mL). The organic phase was dried over MgSO and
2. Lieberknecht, A.; Griesser, H. Tetrahedron Lett. 1987, 28,
4275.
4

A.-L. Johnson et al. / Tetrahedron 60 (2004) 961–965
965
3
4
5
. S o¨ lter, S.; Dieckmann, R.; Blumenberg, M.; Francke, W.
Tetrahedron Lett. 2002, 43, 3385.
. The formally correct name for 6-bromo-D-tryptophan is
Perekalin, V. V.; Ploanskaya, A. S. J. Org. Chem. USSR
(Engl. Transl.) 1973, 9, 1082. Hengartner, U.; Valentine, D.;
Johnson, K. K.; Larscheid, M. E.; Pigott, F.; Scheidl, F.; Scott,
J. W.; Sun, R. C.; Townsend, J. M.; Williams, T. H. J. Org.
Chem. 1979, 44, 3741.
2
-amino-3-(6-bromo-1H-indol-3-yl)-acrylic acid.
. Wu, Y.; Matsueda, G. R.; Bernatowicz, M. Synth. Commun.
993, 23, 3055.
1
10. Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53.
6
. Kurtz, A. C. J. Biol. Chem. 1949, 180, 1253.
1
1. Via N-protection of 6-bromo-1H-indolyl-3-carboxaldehyde:
Da Settimo, A.; Saettone, M. F.; Nannipieri, P.; Barili, P.
Gazz. Chim. Ital. 1967, 97, 1304.
7
. Cyclisation of the dipeptide ester was carried out by the acetic
acid-catalysed method, see: Suzuki, K.; Sasaki, Y.; Endo, N.;
Mihara, Y. Chem. Pharm. Bull. 1981, 29, 233.
1
1
2. Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487.
8
9
. Sj o¨ gren, M.; G o¨ ransson, U.; Johnson, A.-L.; Dahlstr o¨ m, M.;
Andersson, R.; Bergman, J.; Jonsson, P. R.; Bohlin, L. J. Nat.
Prod. In press.
13
3
3. In the C NMR data reported previously, C-5 in the indole
nucleus was assigned a chemical shift of 224.52 ppm. We
assume that this is a misprint, since the corresponding signal in
. 6-Bromo-D-tryptophan ethyl ester was prepared via stannous
chloride reduction of 3-(6-bromo-1H-indol-3-yl)-2-nitro-
acrylic acid ethyl ester. For analogous reactions, see:
Aboskalova, N. I.; Babievskii, K. K.; Belikov, V. M.;
13
our C NMR spectrum resonates at 124.5 ppm.
1
4. Kamlet, M. J. Org. Chem. 1959, 24, 714.