Tetrahedron Letters
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,
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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-
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Corresponding author. Tel.: +43 316 380 5301; fax: +43 316 380 9845.
0040-4039/Ó 2016 Published by Elsevier Ltd.