Tetrahedron Letters
Synthetic access to arsenic-containing phosphatidylcholines
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Nikolaus Guttenberger , Ronald A. Glabonjat, Sebastian Tassoti, Kevin A. Francesconi
Institute of Chemistry, NAWI Graz, University of Graz, Universitaetsplatz 1, 8010 Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
We wish to disclose the first synthesis of 1-O-hexadecanoyl-2-O-((15-(dimethylarsinoyl)pentadecanoyl)
oxy)-sn-glycero-3-phosphocholine, which belongs to the group of arsenic-containing phosphatidylcholi-
nes (AsPCs), recently discovered in herring caviar. The synthesized product will serve as a model com-
pound to study biological and toxicological properties of arsenolipids in food.
Received 3 April 2017
Revised 16 May 2017
Accepted 17 May 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Arsenic
Arsenolipid
AsPC
Natural product
Seafood contributes to a large extent to the human exposure to
arsenic.1 In marine organisms, arsenic is mainly incorporated into
organic molecules and the most abundant species, the water-sol-
uble arsenobetaine, has proven to be rather non-toxic.1 There is,
however, a lack of toxicity data for lipid-soluble arsenicals,1 so-
called arsenolipids, which typically account for 10–30% of the total
arsenic content in marine organisms.2 Preliminary toxicological
studies with arsenic-containing hydrocarbons indicate significant
cytotoxicity3,4 to human cells and it was shown that these mole-
cules are able to cross the blood-brain barrier of the fruit fly.5 Var-
ious arsenolipids, including arsenic-containing derivatives of fatty
acids6, hydrocarbons7,8, fatty alcohols8 and phosphosugars9,10 have
been found in many types of marine organisms. Recently, five
contained unsaturated fatty acid moieties. Herein, we wish to dis-
close our successful efforts to synthesize the previously unknown
AsPC 1 (Scheme 1). The synthesis towards 1 was achieved in eight
steps starting from
x-pentadecanolide with an overall yield of
ꢀ5.6 % (longest linear sequence) and will give access to various
naturally-occurring AsPCs in the future. In devising our approach,
we became intrigued by the protocol of Fasoli et al. for the dibutyl-
tin-catalyzed synthesis of lyso-PCs, such as 7, starting from glyc-
erophosphoryl choline (6).12 Isopropanol was found to be the
optimal solvent for this transformation, as it allowed an effective
formation of the cyclic tin-ketal as well as the subsequent acyla-
tion reaction. D’Arrigo et al.13 applied this strategy for a one-pot
synthesis of several mixed short/long chain phosphatidylcholines
using an established method14 for the acylation of lyso-PCs. Based
on our recent effective DIC/DMAP esterifications for the synthesis
of arsenic-containing triacylglycerides,15 and the known DCC/
DMAP esterification of lyso-PCs,16 we speculated that an esterifica-
tion of lyso-PCs would be the most promising strategy for the con-
struction of AsPCs. We decided to apply the thioxo (As=S) form of
arsenic-containing fatty acid (AsFA) instead of the oxo (As=O) form
in the esterification step, as the thioxo AsFA offered benefits in
terms of workup17 and considering the basicity18 of As=O. Further-
more, a final thioxo-oxo transformation19 is a simple procedure.
The synthesis of AsPC 1 commenced with the construction of
known AsFA 2, according to the literature.6,15 The sequence 3?2
has been published in our previous manuscript15 and is shortly
arsenic-containing phosphatidylcholines (AsPCs) and
a phos-
phatidylethanolamine (AsPE) have been identified in herring caviar
and salmon caviar, respectively (Fig. 1).11 Given the fact that AsPCs
are likely to be widespread among fatty fish,11 possible health
implications of this group of compounds should be taken into
account. In addition, their biological role remains to be clarified.
To elucidate the biological role and toxicological properties of
AsPCs, it is essential to have synthetic access to this type of com-
pound. As a target model compound for analytical and toxicologi-
cal testing, we chose AsPC 1, which contains palmitic acid and its
arsenic analogue esterified with glycerophosphoryl choline.
Although AsPC 1 was not one of the five AsPCs identified in the her-
ring caviar, it promised to be a stable substrate and more readily
accessible by synthesis than the AsPCs identified so far, all of which
summarized: methyl 15-hydroxy-pentadecanoate
4
was
synthesized via an acid-catalyzed opening of
x-pentadecanolide
and an ensuing Appel reaction20 using CBr4/PPh3 was performed
to give 5.21,22
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Corresponding author.
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.