Arsenicin A, A natural polyarsenical: Synthesis and crystal structure

Article abstract of DOI:10.1021/om900998q

The synthesis of the natural polyarsenical Arsenicin A and its crystal structure are described. The molecule has the adamantane-type structure of arsenic trioxide in which three of the oxygen atoms have been replaced by methylene groups to generate four arsenic stereocenters of the same configuration in each enantiomer of the racemate.

Full text of DOI:10.1021/om900998q

32 Organometallics 2010, 29, 32–33
DOI: 10.1021/om900998q
Arsenicin A, A Natural Polyarsenical: Synthesis and Crystal Structure
Di Lu, A. David Rae, Geoff Salem, Michelle L. Weir, Anthony C. Willis, and S. Bruce Wild*
Research School of Chemistry, Australian National University, Canberra, Australian Capital Territory 0200,
Australia
Received November 16, 2009
Scheme 1. Synthesis of the Tetrakis(tertiary arsine)
(RAs*,RAs*)-(()-/(RAs*,SAs*)-2
Summary: The synthesis of the natural polyarsenical Arsenicin
A and its crystal structure are described. The molecule has the
adamantane-type structure of arsenic trioxide in which three of
the oxygen atoms have been replaced by methylene groups to
generate four arsenic stereocenters of the same configuration
in each enantiomer of the racemate.
The first natural polyarsenical, Arsenicin A, has recently
been isolated in trace amounts from the New Caledonian
sponge Echinochalina bargibanti and shown to have potent
bactericidal and fungicidal activities on human pathogenic
strains.1 A novel adamantane-type structure related to that
of arsenic trioxide in the solid state was proposed for
Arsenicin A on the basis of the synthesis of a model com-
pound and detailed spectroscopic measurements and theo-
retical calculations.1,2 In view of the discovery that arsenic
trioxide (As2O3, Trisenox) brings about complete remission
in a large proportion of patients suffering from acute pro-
myelocytic leukemia (APL), a subtype of acute myeloid
leukemia (AML),3 we have synthesized Arsenicin A to
confirm its structure and to carry out detailed investigations
of its biological activity.
Scheme 2. Synthetic Sequence Leading to Synthesis of Arsenicin
A, (RAs*,RAs*,RAs*,RAs*)-(()-1
The putative structure of Arsenicin A, (RAs*,RAs*,RAs*,
RAs*)-(()-1, resembles the adamantane-type structure of
As4O6 in which three of the oxygen atoms have been replaced
by methylene groups.1 Indeed, the C2 arrangement of the
four arsenic stereocenters in the proposed structure sug-
gested a two-step synthesis of Arsenicin A from the tetrakis-
(tertiary arsine) (RAs*,RAs*)-(()-/(RAs*,SAs*)-2, which was
synthesized from methylenebis(phenylarsinic acid)4 as
shown in Scheme 1.5
The reaction of (RAs*,RAs*)-(()-/(RAs*,SAs*)-2 with an
excess of anhydrous hydrogen iodide in dichloromethane
generated the hexaiodoarsine (RAs*,RAs*)-(()-/(RAs*,SAs*)-
3, which, upon hydrolysis with aqueous ammonia, afforded
(RAs*,RAs*,RAs*,RAs*)-(()-1 by dehydration of the inter-
mediate hexahydroxoarsine (RAs*,RAs*)-(()/(RAs*,SAs*)-4,
as indicated in Scheme 2. The product was isolated in 43%
yield as air-stable, colorless prisms having mp 182-184 °C
following column chromatography of the crude product on
silica and recrystallization from benzene and was character-
ized by NMR spectroscopy, high-resolution mass spectro-
metry, elemental analysis, and an X-ray crystal structure
determination.
*To whom correspondence should be addressed. Fax: þ(0)2 6125
0750. Tel: þ(0)2 6125 4236. E-mail: sbw@rsc.anu.edu.au.
(1) Mancini, I.; Guella, G.; Frostin, M.; Hnawia, E.; Laurent, D.;
Debitus, C.; Pietra, F. Chem. Eur. J. 2006, 12, 8989.
(2) Tahtinen, P.; Saielli, G.; Guella, G.; Mancini, I.; Bagno, A. Chem.
Eur. J. 2008, 14, 10445.
(3) (a) Evens, A. M.; Tallman, M. S.; Gartenhaus, R. B. Leuk. Res.
2004, 28, 891. (b) Miller, W. H.Jr.; Schipper, H. M.; Lee, J. S.; Singer, J.;
Waxman, S. Cancer Res. 2002, 62, 3893. (c) Chen, H.; MacDonald, R. C.; Li,
S.; Krett, N. L.; Rosen, S. T.; O'Halloran, T. V. J. Am. Chem. Soc. 2006, 128,
13348.
1
The H NMR spectrum of (RAs*,RAs*,RAs*,RAs*)-(()-1
(4) Sommer, K. Z. Anorg. Allg. Chem. 1970, 377, 120.
in chloroform-d is consistent with the presence of three
methylene groups, two of which are magnetically equivalent
due to the C2 symmetry of the molecule. Thus, two sets of
(5) Synthesis of (RAs*,RAs*)-(()-/(RAs*,SAs*)-2: the reduction of
methylenebis(phenylarsinic acid)4 with an 8-fold excess of sodium
borohydride in methanol at -78 °C gave (RAs*,RAs*)-(()-/(RAs*,
SAs*)-methylenebis(phenylarsine) in 53% yield after distillation. De-
protonation of the bis(secondary arsine) with 2 equiv of n-butyllithium
in the presence of tetramethyl-1,2-ethylenediamine (TMEDA) gave
[Li(TMEDA)]2[CH2(AsPh)2], which was isolated as a yellow crystalline
solid and treated with 2 equiv of (chloromethyl)diphenylarsine6 in THF.
The pure tetraarsine was isolated as a colorless liquid following elution
with dichloromethane-n-hexane from a silica plate with use of a
Chromatotron.
1
doublets were observed in the H NMR spectrum for the
external methylene protons, one at δ 2.42 for H(12) and
H(22) and the other at δ 1.38 for H(11) and H(21), both of
which have identical coupling constants (2JHH =13.8 Hz),
and a singlet for the internal methylene protons at δ 2.23 for
H(31) and H(32), as shown in Figure 1. (The peak in the
spectrum at δ 1.58 is due to a trace of water in the solvent.)
(6) Sommer, K. Z. Anorg. Allg. Chem. 1970, 377, 128.
r
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Communication
Organometallics, Vol. 29, No. 1, 2010 33
Figure 2. Structure of the S enantiomer of synthetic Arsenicin
A. The ellipsoids are shown at the 30% probability level.
Figure 1. 1H NMR spectrum (800 MHz, chloroform-d) of
Arsenicin A.
O-As-O=101.6(9), C-As-O=100.4(8). For the related
compound 1,3,5,7-tetraarsa-2,4,6,8-tetraoxaadamantane,
As4O4(CH2)2, which crystallizes in the space group P21/c,
The 13C{1H} NMR spectrum for the compound in the
same solvent (chloroform-d) contained singlets at δ 17.2 for
C(3) and δ 23.1 for C(1) and C(2). These NMR spectroscopic
data agree with those reported for the polyarsenical isolated
from the New Caledonian marine sponge Echinochalina
bargibanti.1 The HR-EI mass spectrum of Arsenicin A
contains a peak for the molecular ion at m/z 389.7183
(C3H6As4O3 requires m/z 389.7181).
˚
the mean interatomic distances (A) and angles (deg) are as
follows: As-C=1.962(16), As-O=1.795(18), As-C-As=
119.4(6), As-O-As = 129.0(12), O-As-O = 101.8(7),
C-As-O=99.3(10).8
The novel adamantane-type structure of Arsenicin A
poses challenging questions about its biosynthesis and rela-
tionship to the variety of known marine organoarsenicals.9 It
is hoped that the synthesis presented here will facilitate
further chemical and biological work on this unusual natural
product.
Arsenicin A crystallizes from benzene as a racemic com-
pound in the centrosymmetrical space group P1.7 The unit
cell of the structure contains two independent pairs of
molecules, the molecules in each pair being related by an
inversion center. The structure of one of the indepen-
dent molecules of (SAs,SAs,SAs,SAs)-1 is shown in Figure 2.
The molecule has approximate C2 symmetry, the 2-fold
rotation axis passing through O(2) and C(3). The mean
Acknowledgment. We thank Professor George
Koutsantonis of the University of Western Australia for
alerting us to the existence of this interesting compound.
˚
bond lengths (A) and angles (deg) in the structure are as
follows: As-C=1.949(18), As-O=1.791(17), As-C-As=
120.9(7), As-O-As = 130.0(12), C-As-C = 99.4(11),
Supporting Information Available: Text, figures, and a CIF
file giving full experimental procedures, spectroscopic data,
copies of 1H and 13C NMR spectra, and crystallographic data
for (RAs*,RAs*,RAs*,RAs*)-(()-1. This material is available free
of charge via the Internet at http://pubs.acs.org. Crystal data are
also available from the Cambridge Crystallographic Database
as file number CCDC 752018.
(7) Crystal data for (RAs*,RAs*,RAs*,RAs*)-(()-1: C3H6As4O3; tri-
clinic; space group P1; unit cell dimensions a = 7.3954(6) A, b =
˚
˚
˚
11.4072(10) A, c=11.5554(9) A, R=118.772(3)°, β=90.380(3)°, γ=
3
-3
˚
90.766(3)°; V=854.30(12) A ; Z=4; calculated density 3.030 Mg m
;
˚
T=295 K; λ=0.710 73 A; 14 095 reflections collected; 3884 independent
reflections (Rint=0.092); θmax=27.5°; absorption corrected by integra-
tion via Gaussian method implemented in maXus (2000); refinement
method full-matrix least squares on F2; no. of data/parameters 3884/182;
GOF=0.99; final R1 (F2 > 2σ(F2))=0.062, wR2 (F2)=0.182. All of the
crystals of this compound examined were twinned. The nature of the
twinning was identified and the ratio of the two components refined.
(8) Kopf, J.; von Deuten, K.; Klar, G. Inorg. Chim. Acta 1980, 38, 67.
(9) Francesconi, K. A.; Keuhnelt, D. In Environmental Chemistry of
Arsenic; Frankenberger, W. T., Jr., Ed.; Marcel Dekker: New York, 2002;
Chapter 3, pp 51-116.