The first total synthesis of racemic Hydroxymoloka'iamine

Article abstract of DOI:10.1515/znb-2009-0719

The first total synthesis of racemic hydroxymoloka'iamine, a new brominated metabolite isolated from Red Sea sponge Pseudoceratna arabica, was achieved in a high-yield reaction sequence.

Full text of DOI:10.1515/znb-2009-0719

Note
879
with an excess of 1,3-dibromopropane in DMF using
potassium carbonate as base afforded the desired tri-
bromide 4 in very high yield (97 %). The subsequent
reaction of 4 with a stoichiometric amount of trimeth-
The First Total Synthesis of Racemic
Hydroxymoloka’iamine
Nisar Ullah
◦
ylphenylammonium tribromide in THF at 0 C to r. t.
Chemistry Department, King Fahd University of Petroleum
and Minerals, Dhahran 31261, Saudi Arabia
was unclean and gave the desired α-bromoketone 5
in 60 % yield along with a significant amount of un-
wanted side products. However, the problem was over-
come by the addition of trimethylphenylammonium
tribromide in po◦rtions to a solution of tribromide 4
in THF at −15 C and aging the reaction overnight
Reprint requests to Professor Nisar Ullah.
Fax: + 966 3 860 4277. E-mail: nullah@kfupm.edu.sa
Z. Naturforsch. 2009, 64b, 879 – 882;
received April 4, 2009
◦
at 0 C, which rendered the desired α-bromoketone 5
The first total synthesis of racemic hydroxymoloka’iam-
ine, a new brominated metabolite isolated from Red Sea
sponge Pseudoceratna arabica, was achieved in a high-yield
reaction sequence.
in high yield (90 %). At this stage we focused on dis-
placement of the two bromo substituents with azide. To
this end, sodium azide was added to a stirred solution
of α-bromoketone 5 in a mixture of ethanol and THF
(4 : 1). Stirring the mixture first at r. t. followed by heat-
ing at 60 ◦C afforded a low yield of the desired diazide
6 (23 %) along with a few side products which made
column chromatography purifications very tedious. In
a second attempt the reaction was tried in DMF while
the mixture was stirred at 50 ◦C overnight which gave
the desired product 6 in an acceptable yield (49 %).
The reduction of the azido group to the amine with
triphenylphosphine followed by crystallization to the
PTSA salt yielded the aminoketone 7 in 70 % yield [6],
which in turn was subjected to reduction with sodium
borohydride at 0 ◦C in a mixture of THF and water to
afford the target hydroxylmoloka’iamine in an over all
yield of 14 % from 5 (Scheme 1).
Key words: Total Synthesis, Natural Product, Bromination
Introduction
The enormous promise that the sea holds to provide
potential lead pharmaceuticals has attracted great inter-
est from the scientific community in the recent years.
In an effort to isolate bio-active ingredients from ma-
rine sources, investigation of the Red Sea sponge Pseu-
doceratna arabica has led to the isolation and structure
elucidation of the new brominated metabolite hydr-
oxymoloka’iamine (1) [1]. This compound features
a bromotyramine skeleton and has structural resem-
blance with the known metabolite moloka’iamine [2].
The evaluation of the cytotoxic activity against human
colon tumor cells (HCT-116) of 1 has demonstrated
Because of the difficulty in purification by the col-
umn chromatography of the diazide 6, coupled with
the low overall yield in the synthesis of 1 from 5,
we envisioned that reducing the α-bromoketone 5 to
the α-bromoalcohol, and condensation with ammonia,
should give the desired target compound 1. Thus, ke-
that it was not toxic at a test dose of 10 µg mL−1
,
and such discoveries have important implications for
further biological investigations of this class of com-
pounds [1]. As a part of our ongoing research in the
total synthesis of bio-active natural products [3, 4], we
now wish to report a facile synthesis of racemic hy-
droxymoloka’iamine (1).
◦
tone 5 was reduced with sodium borohydride at 0 C
in a mixture of THF and water to get the α-bromo-
alcohol 8, which was treated with an excess of ammo-
◦
nium hydroxide at 55 C for 12 h to afford the target
compound 1 in an excellent overall yield (54 % from
5) (Scheme 2). The spectral data of our synthetic 1 co-
incided with those of the natural material [1].
Results and Discussion
The synthesis of hydroxylmoloka’iamine com-
menced with the bromination of the 4-hydroxyaceto-
phenone with bromine in acetic acid to get the known
hydroxyacetophenone dibromide 3 in 93 % yield [5].
Conclusion
In conclusion we have accomplished the first syn-
The use of sodium acetate as base proved to be effec- thesis of racemic hydroxylmoloka’iamine (1) in an
tive to improve the yield. The O-alkylation of the latter overall high-yield reaction sequence.
c
0932–0776 / 09 / 0700–0879 $ 06.00 ꢀ 2009 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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880
Note
Scheme 1. Synthesis of hydroxylmoloka’iamine (1) via the diazide intermediate 6.
Scheme 2. Synthesis of hydroxylmoloka’iamine (1) via the bromoalcohol intermediate 8.
Experimental Section
(1.87 g, 13.6 mmol) in portions, followed by the addition
of 1,3-dibromopropane (5.49 g, 27.2 mmol), and the mix-
ture was stirred at r. t. for 24 h. The reaction mixture was
taken in ethyl acetate (100 mL) and washed successively
with H2O (25 mL), 1 N HCl (2 × 20 mL), sat. NaHCO3
(20 mL), and brine (15 mL), and dried over sodium sulfate
and evaporated. Column chromatography of the light-yellow
oily material, eluting with ethyl acetate : hexanes (1 : 9) and
then changing to (2 : 8) gave the product as a light-orange
thick oil (2.74 g, 97 %). – IR (neat): ν = 3030, 2890, 1692,
1535, 1460, 1365, 1265, 1180, 1010, 910, 735, 630 cm−1. –
1H NMR (500 MHz, CDCl3): δ = 2.36 (m, 2H, 2ꢀꢀ-H), 2.57
(s, 3 H, COCH3), 3.73 (t, 2 H, J = 6.7 Hz, 3ꢀꢀ-H), 4.20
(t, 2 H, J = 5.8 Hz, 1ꢀꢀ-H), 8.10 (s, 2 H, 2ꢀ-H, 6ꢀ-H). –
13C NMR (125.7 MHz, CDCl3): δ = 26.8 (COCH3), 29.7
(2ꢀꢀ-C), 33.3 (3ꢀꢀ-C), 71.0 (1ꢀꢀ-C), 118.4 (3ꢀ-C, 5ꢀ-C), 132.9
(2ꢀ-C, 6ꢀ-C), 135.5 (1ꢀ-C), 157.0 (4ꢀ-C), 194.2 (CO). – MS
1-(3,5-Dibromo-4-hydroxyphenyl)ethanone (3)
Bromine (3.02 g, 19 mmol) in acetic acid (3 mL) was
added dropwise to a mixture of 4-hydroxyacetophenone
(1.22 g, 9 mmol) and sodium acetate (2.29 g, 27.9 mmol)
in acetic acid (20 mL) at r. t. over 10 min. The reaction mix-
ture was stirred for 0.5 h at r. t., H2O (20 mL) was added, and
the solid was filtered, washed with H2O and dried under high
vacuum to afford the product as a brown solid (2.46 g, 93 %).
The physical and spectral data of 3 were identical with those
of the literature [5].
1-(3,5-Dibromo-4(3-bromopropoxy)phenyl)ethanone (4)
To a solution of compound 3 (2 g, 6.8 mmol) in DMF
(20 mL) at 5 to 10 ◦C was added potassium carbonate
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Note
881
(70 eV): m/z (%) = 414 (24), 317 (14), 290 (10), 279 and when the solution was homogeneous, PTSA (0.8 g,
(100). – C11H11Br3O2 (414.92): calcd. C 31.84, H 2.67; 4.2 mmol) was added in small portions. The reaction mix-
found C 31.81, H 2.70.
ture was stirred for 24 h. The resulting solid was filtered
and allowed to dry under vacuum to get the product as
an off-white solid (0.42 g, 70 %). M. p. 264 – 265 C. – IR
2-Bromo-1-(3,5-dibromo-4-(3-bromopropoxy)phenyl)-
ethanone (5)
◦
(neat): ν = 3070, 2880, 2010, 1690, 1590, 1545, 1451, 1370,
1270, 1170, 1003, 910, 740 cm−1. – 1HNMR (500 MHz,
[D6]DMSO): δ = 2.26 (s, 3 H, CH3), 2.27 (s, 3 H, CH3),
2.44 (m, 2 H, 2ꢀꢀ-H), 3.88 (t, 2 H, J = 6.4 Hz, 3ꢀꢀ-H), 4.22 (t,
2 H, J = 5.5 Hz, 1ꢀꢀ-H), 4.52 (s, 2 H, 2-H), 7.12 (d, 4 H, J =
8.0 Hz, aromatic-H), 7.48 (d, 4 H, J = 8.0 Hz, aromatic-H),
8.06 (s, 2 H, H-2ꢀ, 6ꢀ-H), 8.10 (broad s, 3 H), 8.14 (broad
s, 3 H). – 13C NMR (125.7 MHz, [D6]DMSO): δ = 20.7
(CH3), 29.9 (2ꢀꢀ-C), 45.1 (3ꢀꢀ-C), 46.2 (2-C), 71.1 (1ꢀꢀ-C),
118.8 (3ꢀ-C, 5ꢀ-C), 125.6 (aromatic-C), 128.2 (aromatic-C),
131.8 (2ꢀ-C, 6ꢀ-C), 135.5 (aromatic-C), 137.8 (1ꢀ-C), 144.9
(aromatic-C), 157.3 (4ꢀ-C), 191.4 (CO). – MS (70 eV): m/z
(%) = 366 (12), 308 (16), 279 (100).
To a solution of compound 4 (2 g, 4.82 mmol) in THF
(30 mL) at −15 C was added trimethylphenylammonium
◦
tri◦bromide (1.9 g, 5.1 mmol), and the mixture was stirred at
0 C for 12 h. The solid was filtered, and to the filtrate was
added ethyl acetate (50 mL). The mixture was washed suc-
cessively with H2O (20 mL) and brine (15 mL), and the or-
ganic layer was dried over Na2SO4 and evaporated to leave a
dark-orange oil, which was resolved on a silica column elut-
ing with ethyl acetate : hexanes (1 : 9) to get the product as an
off-white crystalline solid (2.14 g, 90 %). M. p. 67 – 68 ◦C. –
IR (neat): ν = 3050, 2937, 2890, 1698, 1540, 1451, 1372,
1280, 1177, 1004, 907, 853, 734, 630 cm−1. – 1H NMR
(500 MHz, CDCl3): δ = 2.43 (m, 2 H, 2ꢀꢀ-H), 3.73 (t, 2 H, J =
6.4 Hz, 3ꢀꢀ-H), 4.22 (t, 2 H, J = 5.5 Hz, 1ꢀꢀ-H), 4.38 (s, 2 H,
2-H), 8.12 (s, 2 H, 2ꢀ-H, H-6ꢀ-H). – 13C NMR (125.7 MHz,
CDCl3): δ = 29.6 (2ꢀꢀ-C), 30.0 (2-C), 33.2 (3ꢀꢀ-C), 71.1
(1ꢀꢀ-C), 118.9 (3ꢀ-C, 5ꢀ-C), 131.8 (2ꢀ-C, 6ꢀ-C), 135.4 (1ꢀ-C),
157.3 (4ꢀ-C), 188.0 (CO). – MS (70 eV): m/z (%) = 494
(20), 399 (26), 372 (9), 279 (100), 121 (20). – C11H10Br4O2
(493.81): calcd. C 26.75, H 2.04; found C 26.73, H 2.06.
2-Bromo-1-(3,5-dibromo-4-(3-bromopropoxy)phenyl)-
ethanol (8)
To a solution of compound 5 (0.2 g, 0.40 mmol) in a mix-
ture of THF and H2O (4 : 2, 6 mL) at 0 ◦C was added sodium
borohydride (0.019 g, 0.5 mmol) and after being stirred for
0.5 h, H2O (5 mL) was added. After extraction of the mixture
with ethyl acetate (2 × 15 mL), the organic layer was washed
with brine (5 mL), dried over sodium sulfate and evaporated.
Column chromatography of the colorless oily material elut-
ing with ethyl acetate : hexanes (1 : 9) gave the product as a
colorless thick oil (0.18 g, 90 %). – IR (neat): ν = 3325, 3030,
2937, 2890, 1545, 1450, 1370, 1281, 1175, 1003, 905, 853,
735, 630 cm−1. – 1H NMR (500 MHz, CDCl3): δ = 2.40
(m, 2 H, 2ꢀꢀ-H), 2.69 (d, 1 H, J = 3.1 Hz, OH), 3.48 (dd, 1
H, J = 10.6, 8.8 Hz, 2-H), 3.60 (dd, 1 H, J = 10.3, 3.3 Hz,
2-H), 3.73 (t, 2 H, J = 6.4 Hz, 3ꢀꢀ-H), 4.13 (t, 2 H, J = 5.8 Hz,
1ꢀꢀ-H), 4.86 (dd, 1 H, J = 8.8, 3.3 Hz, 1-H), 7.55 (s, 2 H, 2ꢀ-H,
6ꢀ-H). – 13C NMR (125.7 MHz, CDCl3): δ = 29.9 (2ꢀꢀ-C),
33.4 (3ꢀꢀ-C), 39.5 (2-C), 70.8 (1ꢀꢀ-C), 72.1 (1-C), 118.5 (3ꢀ-C,
5ꢀ-C), 130.3 (2ꢀ-C, 6ꢀ-C), 138.8 (1ꢀ-C), 152.8 (4ꢀ-C). – MS
(70 eV): m/z (%) = 496 (8), 416 (11), 398 (19), 335 (9), 296
(18), 278 (100), 215 (50). – C11H12Br4O2 (495.83): calcd.
C 26.65, H 2.44; found C 26.63, H 2.46.
2-Azido-1-(4-(3-azidopropoxy)-3,5-dibromophenyl)-
ethanone (6)
To a solution of compound 5 (1 g, 2.02 mmol) in DMF
(15 mL) was added sodium azide (0.27 g, 4.14 mmol) in one
portion, and the mixture was heated at 50 ◦C for 12 h. After
addition of H2O (10 mL), the reaction mixture was extracted
with ethyl acetate (25 mL). The organic layer was washed
successively with 1 N HCl (2 ×,10 mL), sat. NaHCO3
(15 mL) and brine (10 mL), dried over sodium sulfate and
evaporated. Column chromatography of the dark-orange oily
material eluting with ethyl acetate : hexanes (1 : 9) gave the
product as a dark-orange thick oil (0.41 g, 49 %). – IR (neat):
ν = 3073, 2954, 2197, 2104, 1698, 1580, 1539, 1452, 1379,
1250, 1000, 919, 737 cm−1. – 1H NMR (500 MHz, CDCl3):
δ = 2.45 (m, 2 H, 2ꢀꢀ-H), 3.83 (t, 2 H, J = 6.3 Hz, 3ꢀꢀ-H),
4.23 (t, 2 H, J = 5.6 Hz, 1ꢀꢀ-H), 4.49 (s, 2 H, 2-H), 8.05 (s,
2 H, 2ꢀ-H, 6ꢀ-H). – 13C NMR (125.7 MHz, CDCl3): δ = 30.0
(2ꢀꢀ-C), 48.7 (3ꢀꢀ-C), 54.8 (2-C), 71.2 (1ꢀꢀ-C), 118.8 (3ꢀ-C,
5ꢀ-C), 131.9 (2ꢀ-C, 6ꢀ-C), 135.4 (1ꢀ-C), 157.4 (4ꢀ-C), 195.2
(CO). – MS (70 eV): m/z (%) = 418 (3), 362 (18), 279
(100). – C11H10Br2N6O2 (418.04): calcd. C 31.60, H 2.41,
N 20.10; found C 31.56, H 2.46, N 20.03.
Hydroxylmoloka’iamine (1)
From compound 7: Sodium borohydride (0.130 g, 3.36
mmol) was added to a solution of compound 7 (0.4 g,
0.56 mmol) in a mixture of THF and H2O (4 : 2, 6 mL) at
◦
0 C, and the reaction mixture was stirred for 1 h at this
temperature. The pH of the mixture was adjusted to 9 by
1 N NaOH, the mixture was extracted with ethyl acetate
(2 × 10 mL), and the organic layer was washed with brine
2-Amino-1-(4-(3-aminopropoxy)-3,5-dibromophenyl)-
ethanone p-toluenesulfonic acid salt (7)
To a solution of compound 6 (0.35 g, 0.84 mmol) in THF (5 mL), dried over sodium sulfate and evaporated to get the
(10 mL) was added triphenylphosphine (0.22 g, 0.84 mmol), product as a colorless thick oil, which was purified on a silica
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882
Note
column. Elution with MeOH : CHCl3 (5 : 95), then changing hydroxide (3 mL). The reaction mixture was stirred at 55 ◦C
to 25 : 75, gave the product as a white solid (0.082 g, 40 %). for 12 h, then extracted with ethyl acetate (2 × 10 mL),
The physical and spectral data of our synthetic 1 were iden- and the organic layer was washed with brine (5 mL), dried
tical with those of the natural material [1].
over sodium sulfate, evaporated, and purified on a col-
From compound 8: To a solution of compound 8 (0.16 g, umn as described for compound 7 to get the desired 1
0.32 mmol) in THF (1 mL) was added aqueous ammonium (0.07 g, 60 %).
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