Synthesis of the Natural Product Iotrochamide B

Article abstract of DOI:10.1007/s10600-019-02724-5

Iotrochamide B is the first cinnamoyl amino acid reported from the marine sponge Iotrochota sp. The total synthesis of the marine indole alkaloid iotrochamide B was achieved by condensation of 6-bromo-L-tryptophan (3) and (Z)-2-methoxy-3-phenylacrylic acid (6). The key step was the synthesis of 6-bromo-L-tryptophan ((S)-3) from racemic N-acetyltryptophan by optical resolution using (S)-(–)-1-phenylethylamine. This work provides an efficient method for future synthesis of iotrochamide B derivatives.

Full text of DOI:10.1007/s10600-019-02724-5

DOI 10.1007/s10600-019-02724-5
Chemistry of Natural Compounds, Vol. 55, No. 3, May, 2019
SYNTHESIS OF THE NATURAL PRODUCT IOTROCHAMIDE B
S. Y. Wang, J. Zhao,* and H. D. Que
Iotrochamide B is the first cinnamoyl amino acid reported from the marine sponge Iotrochota sp. The total
synthesis of the marine indole alkaloid iotrochamide B was achieved by condensation of 6-bromo-L-tryptophan
(3) and (Z)-2-methoxy-3-phenylacrylic acid (6). The key step was the synthesis of 6-bromo-L-tryptophan
((S)-3) from racemic N-acetyltryptophan by optical resolution using (S)-(–)-1-phenylethylamine. This work
provides an efficient method for future synthesis of iotrochamide B derivatives.
Keywords: marine natural product, bromoindole alkaloid, iotrochamide B, total synthesis.
A growing number of bromoindole alkaloids are being discovered from a variety of marine invertebrates, including
bryozoans, coelenterates, sponges, and tunicates. Adding to their interest is the fact that they display a wide range of biological
activity [1, 2]. The indole alkaloid iotrochamide B, found in the Australian sponge Iotrochota sp., was shown to inhibit
Trypanosoma brucei brucei with IC values of 4.7 μM, and displayed medium cytotoxic activity to HEK293 (100 0%
50
inhibition at 70 μM). [3]. Iotrochamide B is the first cinnamoyl amino acid reported from the marine sponge Iotrochota sp.
Since only small quantities of iotrochamide B (8) are available in nature, efficient methods for the total synthesis of these
compounds have been required to provide these alkaloids and the related compounds for launching a thorough biological
investigation. In this paper, we developed an efficient approach to synthesize iotrochamide B. 6-Bromoindole (1) is the starting
material for 6-bromo-L-tryptophan [4]. Substitution reaction of 1 with L-serine in acetic acid and acetic anhydride gave
racemic N-acetyl-6-bromotryptophan ((RS)-2) in 90% yield [5], followed by optical resolution using (S)-(–)-1-phenylethylamine
which afforded N-acetyl-6-bromo-L-tryptophan (S)-2 in 60% yield. The deacetylation of an N-acetyltryptophan (S)-2
using aqueous NaOH afforded 6-bromo-L-tryptophan in 85% yield (Scheme 1) [6]. Condensation of benzaldehyde with
N-acetylglycine in refluxing acetic anhydride and sodium acetate gave the oxazole intermediate 4 in 72% yield. Hydrolysis of
this oxazole intermediate with 3 M HCl provided (Z)-2-hydroxy-3-phenylacrylic acid (5) in 68% yield. Methylation of 5 with
dimethyl sulfate in 10% NaOH followed by acidification with HCl furnished the methylated product (Z)-2-methoxy-3-
phenylacrylic acid (6) in 80% yield (Scheme 2) [7]. Condensation of 6-bromo-L-tryptophan methyl ester with (Z)-2-methoxy-
3-phenylacrylic acid (6) with EDCI and HOBt in DMF gave iotrochamide B methyl ester in 50% yield [8]. The hydrolysis of
iotrochamide B methyl ester using LiOH in THF–MeOH–H O afforded iotrochamide B in 70% yield (Scheme 2).As far as we
2
know, the total synthesis of iotrochamide B has not been reported.
O
O
O
-
+
O
NHAc
OR
1
OH
NHAc
H N
3
c
a
b
NHR
N
H
N
H
N
H
N
H
Br
Br
Br
Br
(S)-2: R = Ac, R = H
1
1
(RS)-2
(S)-2-(–)-1-Phenylethylamine
d
(S)-3: R = R = H
1
e
7: R = H, R = CH
1
3
a. L-Serine, AcOH, Ac O, 73°C, 2h, 90%; b. (S)-(–)-1-phenylethylamine, MeOH, 60%; c. 1M NaOH, toluene, 1N HCl, pH 3;
2
d. 25% NaOH, reflux, 6h, 85%; e. MeOH, SOCl , ice bath, 80%
2
Scheme 1
School of Pharmacy, Xinxiang Medical University, 453000, Xinxiang, P. R. China, e-mail: zhzijie820@163.com.
Published in Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2019, pp. 428–430. Original article submitted December 6, 2017.
0009-3130/19/5503-0499 ©2019 Springer Science+Business Media, LLC
499

O
O
CHO
OH
a
c
d
b
O
OH
N
CH
3
4
5
O
HOOC
O
5
1
7
3
N
H
3a'
3'
7
5'
OH
OMe
1'
11
e, f
OCH
3
9
N
7a' H
Br
7'
6
8
a. N-acetylglycine, Ac O, CH COONa, reflux, 1 h, 72% yield; b. 3M HCl, reflux, 3 h,
2
3
68%; c: 10% NaOH, (CH ) SO , r.t., 4 h; d. 3M HCl, r.t., 0.5 h, 80%; e. EDC⋅HCl, HOBt,
3 2
4
DMF, triethylamine, r.t., overnight, 50%; f. LiOH, H O, MeOH, THF, r.t., overnight, 70%
2
Scheme 2
EXPERIMENTAL
All reagents and solvents were of reagent grade or purified according to standard methods. Column chromatography
(CC): silica gel (200–300 mesh; Qingdao Marine Chemical Factory, China). TLC: silica gel GF plates (10–40 μm; Qingdao
254
1
Marine Chemical Factory, China). H NMR was recorded on a BrukerAvance 400 spectrometer usingTMS as internal standard.
HR-ESI-MS was obtained on an Agilent Quadrupole-Time of Flight instrument.
Preparation of N-Acetyl-6-bromo-DL-tryptophan ((RS)-2). L-Serine (1.05 g, 10 mmol) was dissolved in a solution
of 6-bromoindole (980 mg, 5 mmol) in AcOH (12 mL) and Ac O (4 mL), and the mixture was stirred for 2 h at 73°C under
2
argon. After cooling, the reaction mixture was diluted with diethyl ether (30 mL) and adjusted to pH 11 with 30% NaOH. Ether
(45 mL) was further added, and the whole partitioned. The ether layer was further extracted with 1 mol/L NaOH (30 mL × 2),
and a small amount of Na S O was added to the combined alkali solution, which was then neutralized with conc. HCl,
2 2
4
concentrated to 1/2 volume, acidified with 5% HCl to adjust to pH 3 using congo red as an indicator, and extracted with EtOAc
(100 mL × 3). The EtOAc layer was washed with H O (30 mL × 2), dried over Na SO , and concentrated in vacuo with
2
2
4
addition of benzene several times to remove the vapor of HCl gas to give (RS)-2 (1.45 g, 90.0%) as light brown crystals,
1
mp 84–86°C (acetone). H NMR (400 MHz, acetone-d , δ, ppm, J/Hz): 1.89 (3H, s, COCH ), 3.18, 3.31 (each 1H, dd, J = 8,
6
3
16, H-3), 4.76 (1H, dt, J = 5.5, 7.5, H-2), 7.14 (1H, dd, J = 4, 8, H-5′), 7.16 (1H, d, J = 3.0, H-2′), 7.56 (1H, d, J = 8, H-4′), 7.58
+
79
(1H, d, J = 4, H-7′), 10.27 (1H, br, H-1′). HR-ESI-MS m/z 325.0188 [M + H] (calcd for C H O N Br , 325.0188).
13 14
3 2
Preparation of N-Acetyl-6-bromo-L-tryptophan (S)-2.A solution of (RS)-2 (1.4 g, 4.3 mmol) in methanol (20 mL)
and (S)-(–)-1-phenylethylamine (907.5 mg, 1.5 equiv.) was refluxed for 4 h in a 50-mL round bottom flask. The mixture
was ice-cooled to allow crystallization, and then the precipitates were filtered and dried. The crystals afforded the salt of
(S)-N-acetyl-6-bromo-L-tryptophan-(S)-(–)-1-phenylethylamine. The salt was dissolved in H O and adjusted to pH 10 with 1 M
2
NaOH. The alkali solution was further extracted with toluene (45 mL); then the water layer was acidified with 1 N HCl to
pH 3 and concentrated to 1/2 volume to allow crystallization. The solid formed was N-acetyl-6-bromo-L-tryptophan (S)-2
25
1
(972 mg, 60%). [α] +8.20° (c 0.73, acetone). The H NMR data coincided with that of (RS)-2.
D
Preparation of 6-Bromo-L-tryptophan (S)-3. N-Acetyl-6-bromo-L-tryptophan ((S)-2) (900 mg, 2.77 mmol) was
dissolved in 25% NaOH (5 mL) and refluxed for 6 h. The solution was acidified with 1 mol/L HCl to pH 3. Filtration afforded
25
1
6-bromo-L-tryptophan (S)-3 (688.1 mg, 85%). [α] –22.44° (c 0.73, acetone). H NMR (400 MHz, DMSO-d , δ, ppm,
D
6
J/Hz): 2.96 (1H, dd, J = 8.0, 12.0, Ha-3), 3.22 (1H, dd, J = 4.0, 12.0, Hb-3), 3.83 (1H, dd, J = 4.0, 9.0, H-2), 7.10 (1H, dd, J = 2.0,
13
8.0, H-5′), 7.20 (1H, br.s, H-2′), 7.53 (1H, d, J = 2.0, H-7′), 7.62 (1H, d, J = 8.0, H-4′). C NMR (100 MHz, DMSO-d , δ,
6
ppm): 27.35 (t, C-3), 55.15 (d, C-2), 110.49 (s, C-3′), 114.14 (s, C-7′), 114.26 (s, C-6′), 120.83 (d, C-4′), 121.57 (d, C-5′),
+
125.65 (d, C-2′), 126.88 (s, C-3a′), 137.65 (s, C-7a′), 170.14 (s, COOH). HR-ESI-MS m/z 283.0092 [M] (calcd for
79
C H O N Br , 283.0082).
11 12
2 2
Preparation of (Z)-2-Hydroxy-3-phenylacrylic Acid (5). A mixture of benzaldehyde (2.12 g, 20 mmol),
N-acetylglycine (3.56 g, 30 mmol), and sodium acetate (2.46 g, 30 mmol) in acetic anhydride (15 mL) was stirred at reflux for
1 h. The reaction was quenched with ice water and vigorously stirred for 1 h in an ice bath to allow precipitation. Filtration
afforded 4 (yellow powder, 4.03 g, 72%). A suspension of oxazole derivative 4 (3.74 g, 20 mmol) in aq. HCl (3 M, 20 mL) was
500

stirred at reflux for 3 h. The mixture was cooled to room temperature to allow crystallization. Filtration afforded (Z)-2-hydroxy-
1
3-phenylacrylic acid (5). Pale yellow crystal, yield 68%. H NMR (400 MHz, DMSO-d , δ, ppm, J/Hz): 6.39 (1H, s, CH),
6
+
7.23–7.37 (3H, m, ArH), 7.75 (2H, d, J = 7.2, ArH), 9.24 (1H, s, OH), 13.21 (1H, s, COOH). ESI-MS m/z 165 [M + H] .
Preparation of (Z)-2-Methoxy-3-phenylacrylic Acid (6). Dimethyl sulfate (5 mL) was added dropwise into a
suspension of compound 5 (10 mmol) in 10% NaOH (15 mL) in an ice-water bath, and the mixture was stirred at room
temperature for 4 h. After that, 3 M HCl (15 mL) was added and the whole stirred for another 0.5 h to precipitate. Filtration
1
afforded compound 6, yield 80%, pale yellow powder. H NMR (400 MHz, DMSO-d , δ, ppm, J/Hz): 3.74 (3H, s, OCH ),
6
3
+
6.93 (1H, s, CH), 7.34–7.45 (3H, m, ArH), 7.78 (2H, d, J = 7.2, ArH), 13.00 (1H, s, COOH). ESI-MS m/z 179 [M + H] .
Preparation of Iotrochamide B (8). 6-Bromo-L-tryptophan (566 mg, 2 mmol) was suspended in methanol, and the
suspension was stirred in an ambient ice bath under thionyl chloride atmosphere until the suspension became clear. The
product solution was rotary evaporated under reduced pressure. Methanol was then added and the whole rotary evaporated to
remove the hydrogen chloride. Amass of white solid was obtained 7 (475 mg, 80%). Asolution of (Z)-2-methoxy-3-phenylacrylic
acid (6) (178 mg, 1 mmol) in DMF was added to triethylamine (2 mmol), EDC⋅HCl (286.5 mg, 1.5 mmol), and HOBt (202 mg,
1.5 mmol). After addition of the appropriate amine 7 (356.4 mg, 1.2 mmol), the mixture was stirred overnight, then dissolved
in H O and extracted with EtOAc. The EtOAc layer was washed with H O, dried over Na SO , and evaporated under vacuum
2
2
2
4
to afford a crude substance, which was purified by column chromatography using CH Cl –EtOAc (1:1) to provide the methyl
2
2
ester of iotrochamide B (228.5 mg, 50%). A preparation of iotrochamide B methyl ester (220 mg, 0.48 mmol) and LiOH
(72 mg, 3 mmol) in THF–MeOH–H O (4:2:1 mL) was stirred overnight. All the volatiles were removed, and the white solid
2
residue was acidified with 7 mL of HCl (1 N), filtered, and washed with H O to afford the titled compound, which was purified
2
25
by column chromatography using CH Cl –EtOAc (1:1) to provide brown crystals (309.5 mg, 70%). [α] –21.5° (c 0.1,
MeOH). H NMR (400 MHz, DMSO-d , δ, ppm, J/Hz): 3.20 (1H, dd, J = 9.0, 15.0), 3.26 (1H, dd, J = 4.8, 15.0), 3.46 (3H, s),
2
2
D
1
6
4.59 (1H, ddd, J = 4.8, 7.8, 9.0), 6.58 (1H, s), 7.10 (1H, dd, J = 1.8, 8.4), 7.20 (1H, d, J = 2.4), 7.29 (1H, dd, J = 7.8, 7.8), 7.37
(2H, dd, J = 7.8, 7.8), 7.50 (1H, d, J = 8.4), 7.52 (1H, d, J = 8.4), 7.62 (2H, d, J = 7.8), 8.19 (1H, br.d, J = 7.8), 10.97 (br.s).
+
79
HR-ESI-MS m/z 465.0416 [M + Na] (calcd for C H O N NaBr , 465.0420).
21 19
4 2
ACKNOWLEDGMENT
This work was supported by Scientific Research Fund of Xinxiang Medical University grants [2013QN121].
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 110, 4489 (2010).
S. R. Ibrahim, G. A. Mohamed, and M. A. Fouad, Nat. Prod. Res., 23, 86 (2009).
Y. J. Feng, R. A. Davis, and M. L. Sykes, Bioorg. Med. Chem. Lett., 22, 4873 (2012).
M. P. Moyer, F. John, J. F. Shiurba, and H. Rapoport, J. Org. Chem., 51, 5106 (1986).
Y. Konda-Yamada, C. Okada, and K. Yoshida, Tetrahedron, 58, 7851 (2002).
X. B. Su, Q. H. Zhang, and Y. Q. Wu, Chin. J. Org. Chem., 22, 496 (2002).
L. Shi, L. Wang, and Z. Wang, Eur. J. Med. Chem., 47, 585 (2012).
Y. Z. Liu, L. Q. Shang, and H. Fang, Bioorg. Med. Chem., 17, 7398 (2009).
501