Synthesis of two arsenic-containing cyclic ethers: model compounds for a novel group of naturally-occurring arsenolipids

Article abstract of DOI:10.1016/j.tetlet.2016.08.097

Two previously unknown arsenic-containing cyclic ethers have been synthesized, namely (((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)dimethylarsine oxide and its C-1 epimer (((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)dimethylarsine oxide as its trifluoroacetate salt. The compounds serve as model compounds for a new group of unidentified arsenolipids observed in a unicellular alga and sediments.

Full text of DOI:10.1016/j.tetlet.2016.08.097

Tetrahedron Letters 57 (2016) 4578–4580
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of two arsenic-containing cyclic ethers: model compounds
for a novel group of naturally-occurring arsenolipids
Nikolaus Guttenberger a, Ronald A. Glabonjat a, Kenneth B. Jensen a, Klaus Zangger b,
Kevin A. Francesconi a,
⇑
a Institute of Chemistry-Analytical Chemistry, NAWI Graz, University of Graz, Universitaetsplatz 1, 8010 Graz, Austria
b Institute of Chemistry-Organic/Bioorganic Chemistry, NAWI Graz, University of Graz, Heinrichstraße 28, 8010 Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Two previously unknown arsenic-containing cyclic ethers have been synthesized, namely (((2R,3R,4S,5R)-
3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)dimethylarsine oxide and its C-1 epimer
(((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)dimethylarsine oxide as
its trifluoroacetate salt. The compounds serve as model compounds for a new group of unidentified
arsenolipids observed in a unicellular alga and sediments.
Received 13 July 2016
Revised 21 August 2016
Accepted 30 August 2016
Available online 31 August 2016
Ó 2016 Published by Elsevier Ltd.
Keywords:
Arsenolipid
Arsenic
Cyclic ether
The natural product chemistry of arsenic in the sea has contin-
ued to attract interest since the first reports of arsenobetaine in
lobster1 and of arsenosugars in algae.2 Although these water-sol-
uble organoarsenicals can be abundant in seafood, they are consid-
ered to present no toxicological risk to humans and interest in their
presence in organisms has centred largely on describing their
biosynthetic pathways. The focus in recent years has changed,
however, following the identification of several types of lipid-
soluble forms of arsenic, the so-called arsenolipids, which account
for typically 10–30% of the total arsenic content in marine organ-
isms.3 The types of arsenolipids identified so far include, arsenic-
containing derivatives of fatty acids, hydrocarbons and fatty
alcohols,4–7 and more recently arsenic-containing phosphatidyl-
cholines8 and ethanolamines.8 In addition to raising fundamental
questions of the possible biological role of arsenolipids, in mem-
branes, for example, issues regarding their possible toxicity have
been raised following the observation that some of the arsenolipids
show cytotoxicity to human cells,9,10 and they are able to cross the
blood–brain barrier of the fruit fly.11
molecules. To gain evidence for the proposed structure for the new
arsenolipid, we synthesized two of the possible cyclic ether iso-
mers and compared their chromatographic and mass spectromet-
ric properties with those of the acid-hydrolysed natural product
from Dunaliella tertiolecta. The cyclic ethers 1 and 2 (Fig. 1) can
be formally considered as CH2-extended arsenic-containing ribose
derivatives,12–19 lacking the anomeric centre.
This manuscript reports the synthesis of the two epimers 1
and 2 of the previously unknown arsenic-containing cyclic ether
((3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)
dimethylarsine oxide.
The synthesis of the trifluoroacetate salt of cyclic ether 1 started
from inexpensive and readily available
D
-(À)-ribose and was
achieved in a straightforward 8-step synthesis in a combined yield
of 4% (Scheme 1). The synthesis towards the central intermediate 5
has already been described in the literature20,21 and was performed
analogously. Starting from
D
-(À)-ribose, vicinal alcohol protection
was achieved using acetone and sulfuric acid to give 3. Primary
alcohol protection at position C-5 using TBS-Cl yielded 4. A
Corey–Chaykovsky reaction22,23 using trimethylsulfoxonium
iodide and potassium tert-butoxide gave the central intermediate
5 in a yield of 59%.20,21
Our recent investigations on the natural occurrence of arseno-
lipids have revealed the presence of a novel compound class in a
unicellular alga, Dunaliella tertiolecta, and in sediments. The prop-
erties and mass spectrometric data of these compounds suggested
a cyclic ether as one of the most promising base structures with a
long and variable hydrocarbon chain imparting lipophilicity to the
In order to transform the newly introduced primary alcohol into
a suitable leaving group, an Appel reaction24,25 using PPh3 and CCl4
was performed to give 6 in a yield of 66%. Introduction of Me2(As)
was achieved using Me2AsI/Na14,16,26 and the resulting arsine was
then oxidized with H2O2 to the considerably more polar arsine
oxide 7 in a combined yield of 40% (2 steps).14,16 Silyl ether depro-
⇑
Corresponding author. Tel.: +43 316 380 5301; fax: +43 316 380 9845.
E-mail address: kevin.francesconi@uni-graz.at (K.A. Francesconi).
http://dx.doi.org/10.1016/j.tetlet.2016.08.097
0040-4039/Ó 2016 Published by Elsevier Ltd.

N. Guttenberger et al. / Tetrahedron Letters 57 (2016) 4578–4580
4579
O
As
O
As
ing reduction using NaBH4 gave the known 9 in a yield of 14%
(27% recovered starting material).20 The low yield can be attributed
to an incomplete epimerization (starting material was recovered)
and to difficulties in product isolation.
HO
HO
O
O
HO OH
HO
OH
The primary alcohol was then transformed into the correspond-
ing chloride (again PPh3/CCl4) to give 10 in a satisfactory yield of
54%.24,25 Introduction of Me2(AsO) using Me2AsI/Na14,16,26 gratify-
ingly gave 11 in a yield of 12% (2 steps), without any additional oxi-
dation step needed (spontaneous oxidation: no H2O2 addition).
Compound 11 was isolated as a colourless solid, whereas epimer
7 was isolated as yellow oil. Silyl ether deprotection using TBAF
gave 12 in a yield of 99%. Acetonide deprotection using TFA/H2O
(10+1 v/v) afforded 2, surprisingly, without the accompanying
TFA salt formation as observed for 1.14,16 Interestingly, compound
2 turned out to be not basic as no protonation occurred even at
pH = 0.85 (D2O). Further investigations will be directed towards
this exceptional observation.
1
2
Figure 1. Epimers 1 and 2 as model compounds for a novel group of naturally-
occurring arsenolipids.
tection was performed using TBAF to give 8 in a yield of 69%, and
acetonide deprotection was achieved using TFA/H2O (10+1 v/v)
to afford 1 as its TFA salt in a yield of 69%.14,16 When the TFA salt
of 1 was applied to a cation-exchange column, which was washed
with water then aqueous NH3, we obtained 1 in its free form,
which is clearly shown by a ca. 0.5 ppm upfield shift in 1HNMR
27
of the methyl groups attached to arsenic. The pKa value of 1-
Having in hand epimers 1 and 2, we next compared the chro-
matographic and mass spectroscopic properties of the synthesized
model compounds with those of the acid-hydrolysed natural product
from Dunaliella tertiolecta (see Supporting information for further
details). The natural arsenical and the two model compounds
were treated with 0.25 molÁLÀ1 HCl (50 °C, 12 h) and the hydroly-
HCl was measured to be ꢀ3.5.
Cyclic ether 2 was synthesized in a similar manner (Scheme 2).
Starting from the central intermediate 5,20,21 epimerization in
position C-1 was achieved in
a three-step procedure, as
already described for this compound in the literature:20 a Swern-
oxidation28–31 was followed by treatment with Et3N and an ensu-
HO
HO
TBSO
TBSO
OH
O
O
(a)
O
O
OH
OH
OH
(b)
OH
(c)
59%
76%
74%
O
O
HO
O
O
O
O
(-)-D-ribose
3
4
5
(d)
66 %
O
O
CF3
H
O
O
As
O
As
HO
TBSO
HO
As
TBSO
Cl
O
O
O
O
(f)
(e)
(g)
69%
69%
40%
(2 steps)
HO
OH
O
O
O
O
O
O
TFA salt of 1
8
7
6
Scheme 1. Synthesis of the TFA salt of 1. Reagents and conditions: (a) 0.1 equiv H2SO4, acetone, rt, 18 h; (b) 1.2 equiv imidazole, 0.97 equiv TBS–Cl, DCM, rt, 16 h; (c) 1.5 equiv
KOtBu, 1.5 equiv trimethylsulfoxonium iodide, DMSO, 0 °C–>rt, 2.5 h; (d) 1.6 equiv PPh3, 0.2 equiv imidazole, CCl4, 95 °C, 16 h; (e) Na/Me2AsI, THF, rt, 4 h then H2O2, THF,
45 min; (f) 1.1 equiv TBAF, THF, 0 °C–>rt, overnight; (g) TFA/H2O 10+1 (v/v), 10 min. TBS: tert-butyl-dimethylsilyl.
TBSO
TBSO
TBSO
OH
Cl
OH
O
O
O
(b)
(a)
54 %
14 %
O
O
O
O
O
O
27 % recovered s.m.
5
10
9
12 % (c)
O
O
As
O
O
As
HO
HO
As
TBSO
O
O
(e)
(d)
69 %
99 %
O
O
HO
OH
O
O
2
12
11
Scheme 2. Synthesis of 2. Reagents and conditions: (a) 4.2 equiv DMSO, 2.2 equiv (COCl)2, DCM, 2.5 h, À78 °C, Et3N; then: Et3N, rt, 48 h, DCM/iPrOH; then: NaBH4, MeOH/
Et2O; (b) 1.5 equiv PPh3, 0.2 equiv imidazole, CCl4, 90 °C, 15 h; (c) Na/Me2AsI, THF, rt, 15 h; (d) 1.1 equiv TBAF, THF, 0 °C–>rt, overnight; (e) TFA/H2O 10+1 (v/v), 10 min. TBS:
tert-butyl-dimethylsilyl.

4580
N. Guttenberger et al. / Tetrahedron Letters 57 (2016) 4578–4580
Table 1
ESI-HRMS comparison between the natural unknown arsenical and the synthesized model compounds 1 and 2. Samples were hydrolysed using 0.25 molÁLÀ1 HCl
m/z (calculated)
Composition
Relative intensity
Natural unkn.
Compound 1
Compound 2
55.0542
73.0284
83.0491
85.0284
102.9523
104.9680
111.0441
122.9786
138.9735
251.0276
269.0364
C4H7
C3H5O2
C5H7O
2.1
2.4
17.0
0.0
2.0
11.5
100.0
5.8
6.3
5.8
5.7
6.6
8.5
13.1
3.3
19.0
1.9
11.9
2.1
62.3
100.0
3.6
6.3
6.9
20.8
0.0
2.4
0.7
0.0
0.0
C4H5O2
C2H4As
C2H6As
C6H7O2
C2H8OAs
C2H8O2As
C8H16O4As
C8H18O5As
0.0
100.0
14.6
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two model compounds gave similar retention times (compound 1:
rt ꢀ4.0 min, compound 2: rt ꢀ4.1 min), somewhat shorter than that
for the hydrolysed natural arsenical (rt ꢀ5.2 min). Mass spectromet-
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three compounds, but significant differences in signal intensities of
the respective fragments (Table 1). On the basis of these data show-
ing non-identity with the cyclic ether, we speculate that a (deoxy)-
pyranose with the same molecular formula could be also considered
as a possible base structure for the new lipid group.
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containing cyclic ethers 1 and 2, which were used as model
compounds for a novel type of arsenolipid identified in Dunaliella
tertiolecta. The obtained data provide important information for
structure elucidation of this novel type of arsenolipid; further stud-
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The Austrian Science Fund (FWF I2412-B21) is thanked for
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