Synthetic routes for naturally-occurring arsenic-containing ribosides

Article abstract of DOI:10.1016/j.tetlet.2006.05.128

The synthesis of (R)-2′,3′-dihydroxypropyl 5-deoxy-5-dimethylarsinoyl-β-d-riboside, (S)-2′-hydroxy-3′-sulfonylpropyl 5-deoxy-5-dimethylarsinoyl-β-d-riboside and (S)-2′-hydroxy-3′-sulfooxypropyl 5-deoxy-5-dimethylarsinoyl-β-d-riboside, common naturally-occ

Full text of DOI:10.1016/j.tetlet.2006.05.128

Tetrahedron Letters 47 (2006) 5293–5296
Synthetic routes for naturally-occurring
arsenic-containing ribosides
Pedro Traar and Kevin A. Francesconi*
Institute of Chemistry, Analytical Chemistry, Karl-Franzens University Graz, Universitaetsplatz 1, 8010 Graz, Austria
Received 11 May 2006; accepted 22 May 2006
Available online 12 June 2006
Abstract—The synthesis of (R)-20,30-dihydroxypropyl 5-deoxy-5-dimethylarsinoyl-b-D-riboside, (S)-20-hydroxy-30-sulfonylpropyl 5-
deoxy-5-dimethylarsinoyl-b-D-riboside and (S)-20-hydroxy-30-sulfooxypropyl 5-deoxy-5-dimethylarsinoyl-b-D-riboside, common
naturally-occurring arsenicals in algae and molluscs, is reported.
Ó 2006 Elsevier Ltd. All rights reserved.
The observation that marine algae can contain exceed-
ingly high concentrations of arsenic was first reported1
at a pharmaceutical conference by Jones in the 1920s.
Because algal products are widely used in the pharma-
ceutical industry, Jones attempted to allay possible fears
in regard to their arsenic content, and indeed, he postul-
ated that many of the beneficial effects of these products
might be ascribed to their, at that time, unknown arsenic
compounds. The structures of these compounds were
subsequently found2 to be a novel group of arsenic-
containing ribosides, termed oxo-arsenosugars, and
on-going work has shown3 that these arsenicals are in
all marine algae and most marine animals, particularly
those feeding directly on algae such as molluscs.
Although 17 oxo-arsenosugars have been identified so
far, most of this ‘arsenosugar-arsenic’ is associated with
just four compounds (Fig. 1).
The engaging structures of oxo-arsenosugars, together
with their pivotal role in the cycling of arsenic in the
sea and human health issues related to their presence
in seafoods, have generated moderate interest in their
biosynthesis, environmental fate and toxicology. Re-
cently, this interest has increased because of two factors.
First, the discovery that thio analogues4–7 of oxo-arseno-
sugars are also natural constituents of marine organisms
and the suggestion that these thio-arsenosugars may be
integral to arsenic transformations; and second, the real-
isation that arsenosugars are extensively metabolised in
sheep8 and humans9,10 to a multitude of arsenic meta-
bolites including several thio-arsenicals of currently
unknown toxicity. Investigations into the biosynthesis,
metabolism and toxicity of arsenosugars are dependent
on the availability of reasonable quantities of pure
compound. To date, only compound 1 and its sulfur
2´
-
Me
As
1´
3´
O
O
OH
O
O
SO3
5
O
R
OH
OH
O
-
O
OSO3
(1)
(2)
4
R=
1
Me
O
P
OH
(3)
3
2
O
OH
OH
OH
-
OH
O
OH
(4)
Figure 1. Major arsenosugars present in marine biota.
Keywords: Arsenic-containing ribosides; Arsenosugar.
*
Corresponding author. Tel.: +43 316 380 5301; fax: +43 316 380 9845; e-mail: kevin.francesconi@uni-graz.at
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.128

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P. Traar, K. A. Francesconi / Tetrahedron Letters 47 (2006) 5293–5296
11
analogue of the four arsenosugars commonly found in
marine organisms have been synthesised,11–14 whereas
the two predominant arsenosugars, compounds 2 and
3, have so far proved difficult to synthesise and studies,
for example, by McSheehy et al.,15 with these com-
pounds have, by necessity, been performed with
small analytical quantities of natural product isolated
from algal sources in the original studies over 20 years
ago.2,16
enesulfonic acid in CH2Cl2 gave glycoside 6 (68%
based on 5).
AcO
O
AcO
O
OBn
O
O
O
OBn
O
Me
Me
OAc OAc
OAc OAc
(6)
(5)
We report here the synthesis of the two major oxo-arse-
Removal of the ester groups by stirring compound 6 in
MeOH with OHꢀ resin gave triol 7 (82%), which was
converted into chloride 8 (68%) by the use of Ph3P
and CCl4 in pyridine.17 Although the arsenic group
has been successfully introduced by nucleophilic substi-
tution at C5 with sodium dimethyliodoarsine (Me2As-
Na),11,18,19 we found that the combined use of lithium
and sodium to form the nucleophile gave more consis-
tent and higher yields. The so-obtained trialkylarsine 9
was not isolated but directly converted into arsine oxide
10 (H2O2, NMR: Tables 1 and 2) in 66% yield. Treat-
ment of 10 with aqueous CF3COOH gave compound 1
in 80% yield (NMR: Tables 1 and 2).
nosugars found in seafood, namely (S)-20-hydroxy-30-sul-
fonylpropyl
5-deoxy-5-dimethylarsinoyl-b-D-riboside
(compound 2) and (S)-20-hydroxy-30-sulfooxypropyl 5-
deoxy-5-dimethylarsinoyl-b-D-riboside (compound 3) as
the ammonium salts, together with their thio-analogues,
14 and 16. The key to the synthetic procedure was the no-
vel use of sulfur which served as a pseudo-protecting
group for the arsenic atom, while the required functional
groups were introduced to the aglycone portion of the
molecules. The synthesis conveniently provides these four
compounds together with the previously synthesised
compound 1, thereby allowing comprehensive studies of
their environmental and toxicological significance.
The synthesis involves direct introduction of (S)-1,2-di-
O-benzylglycerol to a fully protected acetyl b-D-ribose,
delivery of the arsenic group at C5, ‘protection’ of
arsenic by forming an arsine sulfide, derivatisation steps
at the aglycone, and re-generation of the desired oxo-
arsenic moiety. Thus the commercially available
1,2,3,5-tetra-O-acetyl-b-D-ribose was treated with (S)-
1, 2-di-O-benzylglycerol and BF3OEt2 in CH3CN to give
glycoside 5 (85%). We recommend this glycosidation as
a simpler alternative to that previously reported.11–14
Hydrogenolysis (Pd/C 5%, MeOH) of 5 and treatment
of the formed diol with 2, 2-dimethoxypropane/p-tolu-
R
O
O
O
O
Me
Me
OH
OH
(7) R= OH
(8) R= Cl
(9) R= Me2As
(10) R= Me2As(O)
Table 1. 1H NMR [400 MHz (compounds 10, 12, 1) and 360 MHz (2, 3)] spectral data of selected compounds
1H NMR
H-1 (d) H-2 (d)
H-3 (d) H-4 (d) H-5 (d)
H-10 (d)
H-20 (d) H-30 (d)
AsMe2 CMe2
COMe
(d)
(d)
(d)
10 (CDCl3) 4.93 s
12 (CDCl3) 5.02 s
4.05 m
5.26 m
4.05 m
5.26 m
4.34 m
4.62 m
4.29 m
4.29 m
4.29 m
2.59 dd
J 13.2, 5.2
2.27 dd
J 13.2, 8.8
2.46 dd
J 13.2, 11.2 J 10.0, 6.4
2.36 dd
J 13.2, 2.0
2.69 dd
J 13.8, 3.0
2.54 dd
J 13.8, 10.3
2.76 dd
3.70 m
4.22 m
3.89 m
3.94 m
4.29 m
4.09 m
4.05 m
3.70 m
3.68 dd
J 11.2, 3.6 1.85 2s
3.57 dd
J 11.2, 6.4
1.77,
1.75 2s 1.35 2s
1.40,
3.42 dd
J 10.0, 5.6
3.74 dd
1.89,
2.12,
2.07 2s
3.53 dd
J 10.0, 4.0.
3.79 dd
J 10.6, 6.2
3.64 m
1 (D2O)
2 (D2O)
3 (D2O)
5.06 s
5.06 s
5.05 s
4.17 d J 4.0 4.29 m
4.17 d J 3.0 4.29 m
4.17 d J 3.4 4.29 m
3.64 m
1.92,
1.89 2s
3.83 dd
J 10.6, 5.6
3.67 dd
3.18 dd
J 14.4, 5.4 1.96 2s
3.06 dd
J 14.4, 6.7
4.09 m
1.99,
J 13.8, 2.7
2.63 dd
J 13.8, 10.1 J 10.6, 3.4
2.75 dd
3.85 dd
1.98,
J 13.9, 2.9
2.60 dd
J 10.6, 4.4
3.64 dd
1.94 2s
J 13.9, 10.1 J 10.6, 3.2
Chemical shifts (d) are given in ppm relative to internal standard (TMS, 0 ppm) or partially protonated solvent (HDO, 4.83 ppm).

P. Traar, K. A. Francesconi / Tetrahedron Letters 47 (2006) 5293–5296
5295
Table 2. 13C NMR [100 MHz (compounds 10, 12, 1) and 90 MHz (2, 3)] spectral data of selected compounds
13C NMR
C-1 (d) C-2 (d) C-3 (d) C-4 (d) C-5 (d) C-10 (d) C-20 (d) C-30 (d) AsMe2 CMe2 CMe2 CO
COMe
(d)
(d)
(d)
(d)
10 (CDCl3) 108.0
12 (CDCl3) 105.4
75.0
76.2
77.1
76.1
78.9
77.3
37.1
38.8
37.8
36.7
36.9
68.7
69.3
70.7
71.3
74.3
70.4
72.0
67.0
66.6
63.1
64.2
54.4
16.1,
15.3
19.3
109.4
26.7,
25.2
75.0, 74.4
170.3, 20.5
170.1
1 (D2O)
2 (D2O)
3 (D2O)
109.4
108.2
108.3
76.2
74.9
77.7
76.4
16.3,
15.9
15.1,
14.8
15.3,
15.1
77.5, 76.7, 75.2
69.2, 68.9, 68.6
Chemical shifts (d) are given in ppm relative to CDCl3 (77 ppm). For spectra in D2O, C1 carbon was set to reported chemical shift.16
We had intended to protect the residual free hydroxyl
groups of the riboside moiety of 10 and then remove
Me
S
As
O
R2
O
the isopropylidene group on the aglycone to give a diol
suitable for the introduction of the desired functional
groups. However, problems were immediately encoun-
tered when acetylation was attempted on arsenical 10,
stemming from the unexpected reactivity and polar nat-
ure of the arsinoyl moiety and the resulting difficulty in
finding reaction conditions compatible with reactants
and substrate. The arsine derivative 9, although suit-
ably less polar, proved very difficult to handle and
was not further considered. In our quest for a more pli-
able intermediate, we converted oxide 10 (pyridine,
H2S) to sulfide which readily acetylated (Ac2O) to give
the fully protected arsine sulfide 11 (77% based on 10).
Cleavage of the acetal group (CF3COOH/H2O)
delivered diol 12 (82%, NMR: Tables 1 and 2), which
in stark contrast to its oxide analogue, proved very
amenable to the formation of the desired sulfonate
and sulfuric acid ester derivatives.
Me
OH
OR1 OR1
(13) R1= Ac; R2= OTs
-
(14) R1= H; R2= SO3
-
(15) R1= Ac; R2= OSO3
-
(16) R1= H; R2= OSO3
22
Reaction of 12 with Et3N:SO3 in pyridine (over-
night) led to the protected sulfuric acid ester 15
(58%), which after deacylation (NaOMe) gave the
crude arsine sulfide, compound 16. Oxidation
(H2O2) and purification as described for compound
2 gave the desired compound 3 as an oil (62%, based
on compound 15).
Me
As
Me
As
S
O
S
O
O
OH
O
O
Me
Me
O
Me
OH
Me
The 1H and 13C NMR data (Tables 1, and 2) and
chromatographic behaviour for the synthetically pre-
pared compounds 1, 2 and 3 are in good agreement
with the natural products isolated from the brown
alga Ecklonia radiata.16 The described synthetic
scheme provides the previously synthesised com-
pound 1 in 17% overall yield in 7 steps and delivers
two new synthetic products, sulfonate 2 and sulfuric
acid ester 3, each in 5% overall yield in 10 steps,
together with their thio-analogues.
OAc OAc
OAc OAc
(11)
(12)
Reaction of 12 with Bu2SnO, p-TsCl, and Et3N in
CH2Cl220 gave monotosylate 13 (72%), which was simul-
taneously deprotected and sulfonated by treatment with
Na2SO3 in water/MeOH 2+1 v/v to yield sulfonate
14.21 Several attempted monotosylation reactions per-
formed on the arsine oxide analogue of 12 failed, further
indicating the currently unexplained, strongly negative
influence of the dimethylarsinoyl group. Oxidation of
crude 14 (H2O2) and purification by ion exchange
chromatography (Sephadex DEAE/0.05 M Tris buffer,
pH = 8.0), size exclusion chromatography (Sephadex
G-15/water; Sephadex LH-20/MeOH) and passage
through cation exchange resin in the ammonium form
gave compound 2 as an oil (60%, based on monotosylate
13).
Acknowledgements
The Austrian Science Fund (FWF P16816) is thanked
for financial support. Robert V. Stick, Gerald Saischek,
Alice Rumpler, Rudolf Pietschnig and Wolfram
Wielandt are gratefully thanked for helpful and support-
ive discussions.

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P. Traar, K. A. Francesconi / Tetrahedron Letters 47 (2006) 5293–5296
11. McAdam, D. P.; Perera, A. M. A.; Stick, R. V. Aust. J.
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