Total synthesis of the marine bromotyrosine alkaloid Moloka'iakitamide

Article abstract of DOI:10.1248/cpb.57.1147

The first total synthesis of moloka'iakitamide (1), a recently reported bromotyrosine alkaloid from Pseudoceratina arabica with oxalamide moiety, was achieved in 7 steps from commercially available tyramine (26% overall).

Full text of DOI:10.1248/cpb.57.1147

October 2009
Notes
Chem. Pharm. Bull. 57(10) 1147—1149 (2009)
1147
Total Synthesis of the Marine Bromotyrosine Alkaloid Moloka’iakitamide
Makoto YOSHIDA and Kentaro YAMAGUCHI*
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University; 1314–1 Shido, Sanuki, Kagawa
769–2193, Japan. Received June 9, 2009; accepted July 13, 2009; published online July 16, 2009
The first total synthesis of moloka’iakitamide (1), a recently reported bromotyrosine alkaloid from Pseudo-
ceratina arabica with oxalamide moiety, was achieved in 7 steps from commercially available tyramine (26%
overall).
Key words total synthesis; bromotyrosine alkaloid; marine sponge; moloka’iakitamide; tyramine; 2-chloro-1,3-dimethylimida-
zolinium chloride
Bromotyrosine alkaloids, well known as one of biologi- (Chart 3). Thus, the first total synthesis of moloka’iakitamide
cally active substances, possess a wide range of biological (1) was completed.
1
activities including anti human immunodeficiency virus 1
The H- and 13C-NMR data of our synthetic moloka’iaki-
(HIV-1) activity,1) anti methicillin-resistant Staphylococcus tamide (1) were not in complete accordance with those re-
aureus (MRSA) activity,2) anti multidrug-resistant Mycobac-
terium tuberculosis activity,3) and anti-angiogenic activity.4)
These are also known as therapeutically important G protein-
coupled receptors, the histamine H2 and H3 receptors5,6) and
the adrenergic a1D and a2A receptors6) antagonist. Because of
these interesting activities, a number of synthetic studies on
these alkaloids have been reported.6—16) Moloka’iakitamide
(1)17) has been isolated from the Red Sea sponge Pseudo-
ceratina arabica (Pseudoceratinidae) and shows significant
parasympatholytic effects on isolated rabbit heart and je-
junum, and weakly antifungal activity, contains one bromoty-
rosine unit and oxalamide moiety (Fig. 1). In this paper we
present the first total synthesis of moloka’iakitamide (1).
Results
As outlined in Chart 1, retrosynthetic analysis of
moloka’iakitamide (1) envisaged an alkylation of brominated
tyramine (2) with protected amine derivative (3), followed by
an amide coupling between oxamic acid (4).
Chart 1. Retrosynthetic Analysis of Moloka’iakitamide (1)
Our synthesis began with commercially available tyramine
(5). Introduction of a bromine atom at 5 was carried out by
reported method in 2 steps.15) Di-brominated phenol (6) was
treated with iodide (8), which was prepared from N-(3-hy-
droxyproyl)phthalimide (7),18) in the presence of potassium
carbonate (K2CO3) and benzyltriethylammonium chloride
(BTAC) provided ether (9) in high yields (Chart 2).
After dephthalimidation of 9 with hydrazine monohydrate
in ethanol to give amine (10), followed by coupling with
oxamic acid (4) using 2-chloro-1,3-dimethylimidazolinium
chloride (DMC) as a dehydrating agent,19) the N-Boc-
moloka’iakitamide (11) was afforded in moderate yield. De-
protection of N-Boc function in 11 with acidic condition, and
the residue was made alkaline to give moloka’iakitamide (1)
Reagent and conditions: (a) see ref. 15, 63% in 2 steps; (b) see ref. 18, 78%; (c)
K2CO3, BTAC, CH3CN, rt, 48 h, quant.
Fig. 1. Structure of Moloka’iakitamide (1), a Bromotyrosine Alkaloid
from Pseudoceratina arabica
Chart 2. Synthesis of Moloka’iakitamide (1) Part 1: Alkylation of Tyra-
mine Derivative
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: yamaguchi@kph.bunri-u.ac.jp

1148
Vol. 57, No. 10
ported for natural moloka’iakitamide (1) by Badr et al.17) On
the other hand, moloka’iakitamide trifluoroacetate (1-TFA),
which was prepared from 1 and trifluoroacetic acid, were
spectroscopically identical with reported data (Table 1).
Thus, the original report of natural moloka’iakitamide (1) by
Badr et al.,17) characterized a protonated salt form, such as 1-
TFA, and not the free-base 1.
In conclusion, we succeeded in the first total synthesis of
moloka’iakitamide (1) from commercially available tyramine
as a starting material. The overall yield was 26% for
moloka’iakitamide (1) from tyramine (5) in 7 steps.
(0.00 ppm) in CDCl3 or residual methanol (CH3OH) (3.31 ppm) in CD3OD
as internal standard for 1H-NMR. Using the middle resonance of CDCl3
(77.0 ppm) or CD3OD (49.0 ppm) as an internal standard for 13C-NMR. ESI-
MS were recorded on a JEOL JMS-T100LC mass spectrometer. There used
for TLC Silica gel 60 F254 plates (Merck No. 5715) and for column chro-
matography spherical Silica gel 60, particle size 63—210 mm (Kanto Chem-
ical No. 37564-85 for normal, No. 37565-84 for neutral). All reagents and
solvents are available from commercial sources and were used as received.
2-Chloro-1,3-dimethylimidazolinium chloride (DMC) was purchased from
Tokyo Kasei Co. Inc. Compound 6 and 8 were prepared according to the lit-
erature procedure.15,18)
Synthesis of Ether (9) A mixture of phenol (6) (410 mg, 1.04 mmol),
iodide (8) (325 mg, 1.03 mmol), BTAC (24 mg, 0.105 mmol), and K2CO3
(290 mg, 2.10 mmol) in CH3CN (6.0 ml) was stirred at rt for 48 h. The reac-
tion mixture was poured into water, and extracted with AcOEt. The organic
layer was washed with water and brine, dried over Na2SO4, and evaporated.
The residue was purified by SiO2-column chromatography (eluent:
toluene/AcOEtꢀ22 : 1) to give 9 as a colorless amorphous (602 mg, quant.).
Experimental
All manipulations were carried out under air atmosphere. IR spectra were
recorded on a JASCO FT/IR-6300 spectrophotometer; ATRꢀattenuated
total reflectance system. NMR spectra were recorded on a JEOL JNM-
1
IR (ATR) n: 3332, 1775, 1706, 1673 cmꢁ1. H-NMR (400 MHz, CDCl3) d:
1
ECX400 (400 MHz for H and 100 MHz for 13C). Using tetramethylsilane
1.44 (9H, s), 2.27 (2H, m), 2.71 (2H, t, Jꢀ6.7 Hz), 3.31 (2H, dt, Jꢀ6.7,
6.6 Hz), 3.99 (2H, t, Jꢀ7.3 Hz), 4.08 (2H, t, Jꢀ6.2 Hz), 4.58 (1H, br), 7.31
(2H, s), 7.71 (2H, m), 7.86 (2H, m). 13C-NMR (100 MHz, CDCl3) d: 28.4
(CH3), 29.1 (CH2), 34.9 (CH2), 35.5 (CH2), 41.4 (CH2), 70.9 (CH2), 79.5
(C), 118.2 (C), 123.2 (CH), 132.1 (C), 132.9 (CH), 133.9 (CH), 137.8 (C),
151.7 (C), 155.7 (C), 168.3 (C). ESI-MS m/z: 603 [C24H26Br729N2O5ꢂNa]ꢂ,
605 [C24H26Br79Br81N2O5ꢂNa]ꢂ, 607 [C24H26Br821N2O5ꢂNa]ꢂ. HR-ESI-MS
m/z: 605.00907 (Calcd for [C24H26Br79Br81N2O5ꢂNa]ꢂ, 605.00857).
Synthesis of Amine (10) To a solution of ether (9) (140 mg, 0.24 mmol)
in EtOH (1.5 ml) hydrazine monohydrate (0.40 g) was added, and the mix-
ture was stirred at rt for 24 h. The reaction mixture was diluted with AcOEt,
washed with water and brine, dried over K2CO3, and evaporated to yield 10
as a pale brown oil (101 mg, 93%). This material was used without further
1
purification. IR (ATR) n: 3365, 1697 cmꢁ1. H-NMR (400 MHz, CD3OD)
d: 1.40 (9H, s), 1.99 (2H, m), 2.69 (2H, t, Jꢀ6.9 Hz), 2.95 (2H, t, Jꢀ
6.9 Hz), 3.22 (2H, t, Jꢀ6.9 Hz), 4.03 (2H, t, Jꢀ6.0 Hz), 7.42 (2H, s).
13C-NMR (100 MHz, CD3OD) d: 28.8 (CH3), 33.8 (CH2), 35.8 (CH2), 39.9
(CH2), 42.4 (CH2), 72.5 (CH2), 80.0 (C), 118.8 (C), 134.6 (CH), 140.0 (C),
152.7 (C), 158.3 (C). ESI-MS m/z: 451 [C16H24Br729N2O3ꢂH]ꢂ, 453
[C16H24Br79Br81N2O3ꢂH]ꢂ, 455 [C16H24Br821N2O3ꢂH]ꢂ. HR-ESI-MS m/z:
451.02582 (Calcd for [C16H24Br729N2O3ꢂH]ꢂ, 451.02319).
Synthesis of N-Boc-moloka’iakitamide (11) To a solution of amine
(10) (80 mg, 0.18 mmol), oxamic acid (4) (18 mg, 0.20 mmol), and Et3N
(0.10 ml, 0.72 mmol) in N,N-dimethylformamide (DMF) (1.5 ml) 2-chloro-
1,3-dimethylimidazolinium chloride (DMC, 34 mg, 0.20 mmol) was added,
and the mixture was stirred at rt for 2 h. The reaction mixture was poured
into water, and extracted with AcOEt. The organic layer was washed with
water and brine, dried over Na2SO4, and evaporated. The residue was puri-
fied by SiO2-column chromatography (eluent: CHCl3/AcOEtꢀ7 : 2) to give
11 as a colorless amorphous (56 mg, 61%). IR (ATR) n: 3381, 3356, 3311,
Reagent and conditions: (a) H2NNH2·H2O, EtOH, rt, 24 h, 93%; (b) DMC, Et3N,
DMF, rt, 2 h, 61%; (c) CF3COOH, CH2Cl2, rt, 18 h, then NaOH aq., 72%; (d)
CF3COOH, CH2Cl2, rt, 1 h, quant.
1
3222, 1681, 1652 cmꢁ1. H-NMR (400 MHz, CDCl3) d: 1.44 (9H, s), 2.11
(2H, m), 2.72 (2H, t, Jꢀ6.9 Hz), 3.33 (2H, dt, Jꢀ6.7, 6.4 Hz), 3.68 (2H, dt,
Jꢀ6.5, 6.4 Hz), 4.07 (2H, t, Jꢀ6.8 Hz), 4.57 (1H, br), 5.59 (1H, br), 7.32
(1H, br), 7.34 (2H, s), 7.85 (1H, br). 13C-NMR (100 MHz, CDCl3) d: 28.3
Chart 3. Synthesis of Moloka’iakitamide (1) Part 2: Formation of Ox-
alamide Moiety
Table 1. 1H- and 13C-NMR Spectroscopic Data for Moloka’iakitamide (1)a)
Synthetic 1
1-TFA
Natural 1b)
H (J in Hz)
Position
d
H (J in Hz)
dC
d
H (J in Hz)
dC
d
dC
1
139.2
132.9
117.7
151.3
36.8
42.6
70.8
29.1
37.4
136.8
132.9
118.0
152.0
31.7
39.9
70.7
28.9
36.6
137.5
132.9
118.1
152.1
31.7
40.0
70.7
28.9
36.5
2, 6
3, 5
4
1ꢃ
2ꢃ
1ꢄ
2ꢄ
3ꢄ
4ꢄ
5ꢄ
7.43 s
7.57 s
7.57 s
2.67 t (7.1)
2.82 t (7.1)
4.02 t (6.0)
2.08 m
2.95 t (7.4)
3.21 t (7.4)
4.09 t (6.0)
2.15 m
2.93 t (7.5)
3.19 t (7.5)
4.10 t (6.5)
2.14 quin. (6.5)
3.60 t (6.5)
3.55 t (6.9)
3.61 t (6.8)
160.5
162.7
160.4
162.5
160.4
162.5
a) The NMR data were obtained at 400/100 MHz for 1H/13C. b) Reported by Badr et al.17)

October 2009
1149
(CH3), 29.1 (CH2), 34.8 (CH2), 37.1 (CH2), 41.4 (CH2), 70.5 (CH2),
79.5 (C), 118.0 (C), 132.9 (CH), 138.0 (C), 151.2 (C), 155.9 (C),
159.5 (C), 161.9 (C). ESI-MS m/z: 544 [C18H25Br729N3O5ꢂNa]ꢂ, 546
[C18H25Br79Br81N3O5ꢂNa]ꢂ, 548 [C18H25Br821N3O5ꢂNa]ꢂ. HR-ESI-MS m/z:
546.00479 (Calcd for [C18H25Br79Br81N3O5ꢂNa]ꢂ, 546.00382).
2) Kim D., Lee I. S., Jung J. H., Yang S.-I., Arch. Pharmacol. Res., 22,
25—29 (1999).
3) Encarnacion-Dimayuga R., Ramirez M. R., Luna-Herrera J., Pharm.
Biol., 41, 384—387 (2003).
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M., Tetrahedron, 61, 7211—7218 (2005).
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bier A. J., Lovenberg T. W., Carruthers N. I., Bioorg. Med. Chem. Lett.,
16, 897—900 (2006).
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A. J., Chem. Eur. J., 7, 4280—4295 (2001).
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(2004).
Synthesis of Moloka’iakitamide (1) To a solution of N-Boc-moloka’i-
akitamide (11) (56 mg, 0.11 mmol) in CH2Cl2 (1.0 ml) trifluoroacetic acid
(0.1 ml) was added, and the mixture was stirred at rt for 18 h. The reaction
mixture was poured into water, and washed with Et2O. The aqueous layer
was alkalized with 20% NaOH aq. and extracted with CHCl3. The organic
layer was washed with water and brine, dried over K2CO3, and evaporated to
afford 1 as a colorless amorphous (32 mg, 72%). IR (ATR) n: 3367,
3341, 3301, 1641 cmꢁ1 1H-NMR (400 MHz, CD3OD) d: 2.08 (2H, m),
.
2.67 (2H, t, Jꢀ7.1 Hz), 2.82 (2H, t, Jꢀ7.1 Hz), 3.55 (2H, t, Jꢀ6.9 Hz),
4.02 (2H, t, Jꢀ6.0 Hz), 7.43 (2H, s). 13C-NMR (100 MHz, CD3OD) d:
29.1 (CH2), 36.8 (CH2), 37.4 (CH2), 42.6 (CH2), 70.8 (CH2), 117.7
(C), 132.9 (CH), 139.2 (C), 151.3 (C), 160.5 (C), 162.7 (C). ESI-
MS m/z: 422 [C13H17Br729N3O3ꢂH]ꢂ, 424 [C13H17Br79Br81N3O3ꢂH]ꢂ,
426 [C13H17Br821N3O3ꢂH]ꢂ. HR-ESI-MS m/z: 423.96916 (Calcd for
[C13H17Br79Br81N3O3ꢂH]ꢂ, 423.96945).
10) Harburn J. J., Rath N. P., Spilling C. D., J. Org. Chem., 70, 6398—
6403 (2005).
11) Hayakawa I., Teruya T., Kigoshi H., Tetrahedron Lett., 47, 155—158
(2006).
Synthesis of Moloka’iakitamide Trifluoroacetate (1-TFA) To a solu-
tion of moloka’iakitamide (1) (30 mg, 0.071 mmol) in CH2Cl2 (1.0 ml) triflu- 12) Godert A. M., Angelino N., Woloszynska-Read A., Morey S. R.,
oroacetic acid (0.1 ml) was added, and the mixture was stirred at rt for 1 h.
The reaction mixture was evaporated to yield 1-TFA as a colorless amor-
phous (39 mg, quant.). IR (ATR) n: 3392, 3276, 1682, 1652 cmꢁ1. 1H-NMR
(400 MHz, CD3OD) d: 2.15 (2H, m), 2.95 (2H, t, Jꢀ7.4 Hz), 3.21 (2H,
t, Jꢀ7.4 Hz), 3.61 (2H, t, Jꢀ6.8 Hz), 4.09 (2H, t, Jꢀ6.0 Hz), 7.57 (2H, s).
13C-NMR (100 MHz, CD3OD) d: 28.9 (CH2), 31.7 (CH2), 36.6 (CH2),
39.9 (CH2), 70.7 (CH2), 118.0 (C), 132.9 (CH), 135.8 (C), 152.0 (C),
160.4 (C), 162.5 (C). ESI-MS m/z: 422 [C13H17Br279N3O3ꢂH]ꢂ,
424 [C13H17Br79Br81N3O3ꢂH]ꢂ, 426 [C13H17Br281N3O3ꢂH]ꢂ, 444
James S. R., Karpf A. R., Sufrin J. R., Bioorg. Med. Chem. Lett., 16,
3330—3333 (2006).
13) Ortlepp S., Sjoegren M., Dahlstroem M., Weber H., Ebel R., Edrada
R., Thoms C., Schupp P., Bohlin L., Proksch P., Mar. Biotechnol., 9,
776—785 (2007).
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(1998).
15) Yoshida M., Yamaguchi K., Chem. Pharm. Bull., 56, 1362—1363
(2008).
[C13H17Br279N3O3ꢂNa]ꢂ,
446
[C13H17Br79Br81N3O3ꢂNa]ꢂ,
448
16) Ullah N., Arafeh K. M., Tetrahedron Lett., 50, 158—160 (2009).
17) Badr J. M., Shaala L. A., Abou-Shoer M. I., Tawfik M. K., Habib
A.-A. M., J. Nat. Prod., 71, 1472—1474 (2008).
[C13H17Br281N3O3ꢂNa]ꢂ. HR-ESI-MS m/z: 445.95558 (Calcd for
[C13H17Br79Br81N3O3ꢂNa]ꢂ, 445.95139).
ˇ
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43, 4747—4751 (2002).
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