Synthesis and characterization of aplysinopsin analogs

Article abstract of DOI:10.1007/s10870-008-9480-1

Three aplysinopsin analogs were synthesized by reacting 5-bromo-5-fluoro- and 6-bromoindole-3-carboxaldehyde with either creatinine or 2-imino-1,3-dimethyl-imidazolidin-4-one or 2-imino-1-methyl-3-ethylimidazolidin- 4-one Single crystal structures on 5-bromo-4′-de-N-methylaplysinopsin DMF solvate [from creatinine, space group P2₁/n, lattice parameters a = 13.117(3) A, b = 8.6663(15) A, c = 14.743(3) A, β = 99.538(10)° at 173 K], 5-fluoroaplysinopsin DMF solvate [from 2-imino1,3-dimethyl-imidazolidin-4-one, space group P2₁/c, lattice parameters a = 11.114(3) A, b = 19.118(2) A, c = 8.503(2) A, β = 112.290(7)°], and 6-bromoindole-3-carboxaldehyde (space group P2₁/n, lattice parameters a = 7.657(2) A, b = 7.933(2) A, c = 13.521(3) A, β = 99.046(13)°) have been determined. Characterizations include spectrometric identifications employing IR, UV, HRMS, and ¹H and ¹³C NMR. 5-Bromo-4′-de-N- methylaplysinopsin and 5-fluoroapIysinopsin exist in the E configuration. Springer Science+Business Media, LLC 2008.

Full text of DOI:10.1007/s10870-008-9480-1

J Chem Crystallogr (2009) 39:329–336
DOI 10.1007/s10870-008-9480-1
ORIGINAL PAPER
Synthesis and Characterization of Aplysinopsin Analogs
James E. Johnson Æ Diana C. Canseco Æ
Debra D. Dolliver Æ John A. Schetz Æ
Frank R. Fronczek
Received: 31 January 2008 / Accepted: 1 October 2008 / Published online: 18 October 2008
ꢀ Springer Science+Business Media, LLC 2008
Abstract Three aplysinopsin analogs were synthesized by
reacting 5-bromo-5-fluoro- and 6-bromoindole-3-carboxal-
dehyde with either creatinine or 2-imino-1,3-dimethyl-
imidazolidin-4-one or 2-imino-1-methyl-3-ethylimidazoli-
din-4-one Single crystal structures on 5-bromo-40-de-N-
methylaplysinopsin DMF solvate [from creatinine, space
include spectrometric identifications employing IR, UV,
1
13
HRMS, and H and C NMR. 5-Bromo-40-de-N-methy-
laplysinopsin and 5-fluoroaplysinopsin exist in the E
configuration.
Keywords Crystal structures ꢀ Aplysinopsin analogs ꢀ
˚
group P21/n, lattice parameters a = 13.117(3) A,
Indole alkaloids
˚
˚
b = 8.6663(15) A, c = 14.743(3) A, b = 99.538(10)ꢁ at
173 K], 5-fluoroaplysinopsin DMF solvate [from 2-imino-
1,3-dimethyl-imidazolidin-4-one, space group P21/c, lattice
˚
parameters a = 11.114(3) A, b = 19.118(2) A, c =
˚
Introduction
˚
8.503(2) A, b = 112.290(7)ꢁ], and 6-bromoindole-3-car-
boxaldehyde (space group P21/n, lattice parameters
Aplysinopsin (1) was first isolated in 1977 from the marine
sponges Thorecta aplysinopsis and Verongia spengelii [1,
2]. Subsequently, Djura and Falukner [3] isolated aplys-
inopsin (1), isoaplysinopsin (2), and two aplysinopsin
derivatives, 20-de-N-methylaplysinopsin (3), and 6-bromo-
20-de-N-methylaplysinopsin (4) from the Belize sponge
Dercitus. Several other aplysinopsins (5–8) have been
isolated from marine sponges, including two additional 6-
bromoaplysinopsins (5 and 6) [4–6], 10, 8-dihydroaplysin-
opsins [7, 8] and aplysinopsins with a carbonyl group in the
30 position [9–12].
˚
˚
˚
a = 7.657(2) A, b = 7.933(2) A, c = 13.521(3) A, b =
99.046(13)ꢁ) have been determined. Characterizations
J. E. Johnson (&)
Department of Chemistry and Physics, Texas Woman’s
University, P.O. Box 425859-5859, Denton,
TX 76204-5859, USA
e-mail: JJohnson@TWU.EDU
D. C. Canseco
Department of Biology, Texas Woman’s University,
Denton, TX 76204, USA
Various aplysinopsins have been reported to have anti-
tumor [2] or anti-filarial activity [13], and to bind to
5-HT2A and 5-HT2C serotonin receptors [4]. A structure-
affinity study [4] of a series of naturally occurring aplys-
inopsins indicated that a bromine atom in the six position
of the indole ring (4) increases selective binding for the
5-HT2C subtype. Here we report the synthesis of three
halogen containing aplysinopsin analogs (5, 11, and 15).
The method used for the synthesis of these aplysinopsin
analogs is an adaptation of a procedure reported by Djura
and Faulkner [3]. The single crystal structures were
determined for two of the aplysinopsins (11 and 15), as
D. D. Dolliver
Department of Chemistry and Physics,
Southeastern Louisiana University, Hammond, LA 70402, USA
J. A. Schetz
Department of Pharmacology and Neuroscience,
University of North Texas Health Science Center, Fort Worth,
TX, USA
F. R. Fronczek
Department of Chemistry, Louisiana State University,
Baton Rouge, LA 70803, USA
123

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J Chem Crystallogr (2009) 39:329–336
well as for 6-bromoindole-3-carboxaldehyde, which was
with ether (2 9 50 mL). Evaporation of the ether gave a
solid that was recrystallized from DMF-water to give light
orange needles (2.30 g, 32%), m.p. 309–310 ꢁC (decom-
position begins at 280 ꢁC). HRMS: M•? ? H, 318.9959.
Requires: M•? ? H, 318.9951.
used for the synthesis of 6-bromoaplysinopsin (5).
1
2
R
NR
2'
N
3'
1
IR, UV, H and 13C NMR Spectra of 11
N
4'
8
H
3
R
4
7
Selected infrared absorptions (cm-1): 3318, 3163, 1696,
5'
1661, 1624 cm-1
.
5
6
3
O
1H NMR: d 11.63 (s, 1H, NH), 9.13 [d, J = 2.7 Hz, 1H,
C(2)H], 8.19 [d, J = 1.8 Hz, 1H, C(4)H], 7.96 (s, DMF),
7.73 (s, 2H, NH2), 7.40 [d, J = 9.0 Hz, 1H, C(7)H], 7.26
[dd, J = 8.4 Hz and J = 2.1 Hz, 1H, C(6)H], 6.55 [s, 1H,
C(8)H], 3.30 (s, 3H, CH3).
2
N
X
H
1: X = R2 = H; R1 = R3 = CH3
2: X = R3 = H; R1 = R2 = CH3
3: X = R1 = R2 = H; R3 = CH3
13C NMR: d 175.49, 165.13, 162.34 (DMF), 134.33,
131.27, 129.89, 129.67, 124.10, 120.73, 113.77, 112.40,
108.98, 104.25, 35.80, 30.79 (DMF), 27.95 (DMF).
Ultraviolet–visible spectrum: kmax at 473 nm
(log e = 2.95), 450 nm (log e = 2.91), and 365 nm
(log e = 4.68).
4: X = Br; R1 = R2 = H; R3 = CH3
5: X = Br; R1 = R3 = CH3; R2 = H
6: X = Br; R1 = CH3; R2 = R3 = H
7: X = H; R1 = R2 = R3 = CH3
8: X = H; R1 = R3 = CH3; R2 = CH2CH3
Preparation of 5-Fluoroindole-3-carboxaldehyde (12)
Phosphorus(V) oxychloride (4.25 g) was added dropwise
to DMF (6 mL) cooled in an ice bath. The mixture was
kept at 0 ꢁC for 30 min. A solution of 5-fluoroindole (3 g)
in DMF (22 mL) was added dropwise, keeping the reac-
tion temperature below 10 ꢁC. After 3 h at 20 ꢁC, the
syrupy solid was poured into ice-water (180 g), neutral-
ized with 1 N NaOH, and left standing overnight. The
crude product was collected by filtration and recrystallized
from ethanol to give the 5-fluoroindole-3-carboxaldehyde
(2.15 g, 72%); m.p. 170–171 ꢁC (reported m.p. 170–
171 ꢁC) [14].
Experimental
General Methods
1H NMR spectra were acquired in d6-DMSO at 300 MHz,
and the 13C NMR spectra at 75.5 MHz using a Varian
Mercury 300 spectrometer. Ultraviolet–visible spectra
were obtained with a Thermo Electron Vision spectrometer
using DMF as a solvent. Infrared spectral data were
recorded on a Nicolet Magna 560 FTIR over the frequency
range of 4000–600 cm-1 using a Nujol mull technique.
The high resolution mass spectra were run at the University
of Minnesota on either a Finnigan MAT 95 or Bruker
BioTOF mass spectrometer (Table 1).
1
IR, H NMR Spectra of 12
Selected infrared absorptions (cm-1): 2724, 1641, 1614,
1581 cm-1
.
1H NMR: d 12.29 (s, 1H, NH), 9.93 (s, 1H, CH=O), 8.37
(s, 1H, C(2)H), 7.77 (dd, J = 3 Hz and J = 10 Hz, 1H,
C(4)H), 7.54 (dd, J = 5 Hz, and J = 9 Hz, 1H, C(7)H),
7.13 (tt, J = 9 Hz and J = 3 Hz, 1H, C(6)H).
Preparation of 5-Bromo-20-de-N-methylaplysinopsin
(11)
5-Bromoindole-3-carboxaldehyde (5.00 g) and creatinine
(2.52 g) were placed in a 100 mL three-neck round-bot-
tomed flask fitted with a nitrogen gas inlet, and a probe
from a JKEM 210 for monitoring the temperature. The
flask was then heated carefully with a Bunsen burner and
the temperature was kept at approximately 153 ꢁC for
10 min. Considerable frothing of the mixture took place
during the course of the reaction. The reaction mixture was
allowed to cool to room temperature and then extracted
Preparation of 5-Fluoroaplysinopsin (15)
5-Fluoroindole-3-carboxaldehyde (1.00 g) and 2-imino-
1,3-dimethyl-imidazolidin-4-one (14) (0.935 g) were
placed in a 100 mL three-neck round-bottomed flask fitted
with a nitrogen gas inlet, and a probe from a JKEM 210 for
monitoring the temperature. The flask was then heated
carefully with a Bunsen burner and the temperature was
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J Chem Crystallogr (2009) 39:329–336
331
Table 1 Crystal data and structure refinement
11
15
13
Empirical formula
CCDC deposition no.
fw
C13H11BrN4O ꢀ C3H7NO
CCDC 666374
392.26
C14H13FN4O ꢀ C3H7NO
CCDC 666375
345.38
C9H6BrNO
CCDC 666376
224.06
Crystal system
Space group
Monoclinic
Monoclinic
P21/c
Monoclinic
P21/n
P21/n
Cell dimensions
˚
a (A)
13.117(3)
8.6663(15)
14.743(3)
99.538(10)
1652.8(6)
173
11.114(3)
19.118(2)
8.503(2)
112.290(7)
1671.7(6)
90
7.657(2)
7.933(2)
13.521(3)
99.046(13)
811.1(3)
90
˚
b (A)
˚
c (A)
b (ꢁ)
3
˚
V (A )
T (K)
Z
4
4
4
Crystal size
qcalc (g cm-3
l (mm-1
0.03 9 0.05 9 0.32
1.576
0.22 9 0.25 9 0.30
1.372
0.10 9 0.12 9 0.20
1.835
)
)
2.507
0.101
5.010
Transm. coeff.
0.501–0.929
55.8
–
0.434–0.634
65.2
2hmax (ꢁ)
Data collected
62.2
14,846
21,615
15,724
Independent/observed (I [ 2r(I))
Rint
3928/3035
0.032
4652/3295
0.034
2902/2429
0.019
R
0.035
0.043
0.027
wR2 [I [ 2r(I)]
Data/param
0.070
0.100
0.059
3928/229
0.31, -0.30
4652/237
0.38, -0.23
2902/112
0.62, -0.44
-3
)
˚
Resid. dens. (eA
Preparation of 2-Amino-3-ethyl-1-methylimidazolidin-
kept at approximately 153 ꢁC for 10 min. Considerable
frothing of the mixture took place during the course of the
reaction. The reaction mixture was allowed to cool to room
temperature and then extracted with methanol
(4 9 50 mL). Evaporation of the methanol gave a solid
that was recrystallized from DMF-water to give orange
crystals (0.850 g, 85%), m.p. begins to decompose at
245 ꢁC, m.p. 295–300 ꢁC. HRMS: M•? ? H, 273.1149.
Requires: M•? ? H, 273.1146.
4-one (15)
Creatinine (10, 10 g) and iodoethane (22.1 g) were dis-
solved in 100 mL of 95% ethanol and refluxed for 7 days.
The solvent was removed by rotary evaporation. The crude
product was dissolved in anhydrous methanol and passed
through a basic ion exchange column (Bio-Rad AG 3-X4
washed with 200 mL of anhydrous methanol prior to use),
after 300 mL of eluent had been collected, the methanol
was removed by rotary evaporation, the product was
extracted with benzene (2 9 30 mL) and the benzene was
removed by rotary evaporation. The crude product was
recrystallized three times from acetonitrile to give a light
yellow solid (4.5 g, 36%), m.p. 201–203 ꢁC. Anal. Calcd.
For C6H12N3OI: C, 26.78, H, 4.49, N, 15.61; Found: C,
27.38, H, 4.47, 16.23.
1
IR, UV, H NMR Spectra of 15
Selected infrared absorptions (Nujol mull, cm-1): 3357,
3311, 3132, 1722, 1651, 1632 cm-1
.
1H NMR: d 11.57 (s, 1H, NH), 8.76 [d, J = 2.7 Hz, 1H,
C(2)H], 7.75 [dd, J = 2 Hz and J = 10 Hz, 1H, C(4)H],
7.42 [dd, J = 9 Hz and J = 5 Hz, 1H, C(7)H], 6.99 [tt,
J = 9 Hz and J = 2 Hz, 1H, C(6)H], 6.64 (s, br, 1H,
C=NH), 6.40 [s, 1H, C(8)H], 3.26 [s, 3H, N(20)CH3], 3.07
[s, 3H, N(40)CH3].
1
IR, H NMR Spectra of 15
Selected infrared absorptions (Nujol mull, cm-1): 3145,
Ultraviolet–visible spectrum: kmax at 376 nm (log e =
4.52).
3066, 1671, 1658, 1628 cm-1
.
123

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J Chem Crystallogr (2009) 39:329–336
1
IR, UV, H NMR Spectra of 5
1H NMR: 4.24 (s, 2H, CH2), 3.61 (q, J = 7 Hz, 2H, CH2
CH3), 3.08 (s, 3H, NCH3), 2.93 (s, 1H, NH) and 1.11 (t,
Selected infrared absorptions (Nujol mull, cm-1): 3333,
3122 (w), 3065 (w), 1724, 1646, 1632 cm-1
J = 7 Hz, 3H, CH2 CH3).
.
1H NMR: d 11.58 (s, 1H, NH), 8.69 [s, 1H, C(2)H], 7.87
[d, J = 9 Hz, 1H, C(4)H], 7.61 [d, J = 1.5 Hz, 1H, C(7)H],
7.23 [dd, J = 9 Hz and J = 1.5 Hz, 1H, C(5)H], 6.75 and
6.54 (two s, br, 0.6H and 0.4H, C=NH), 6.39 [s, 1H, C(8)H],
3.25 [s, 3H, N(20)CH3], 3.06 [s, 3H, N(40)CH3].
Preparation of 5-Bromo-30-de-N-methyl-30-
ethylaplysinopsin (19)
5-Bromoindole-3-carboxaldehyde (0.37 g) and 2-amino-3-
ethyl-1-methylimidazolidin-4-one (0.23 g) gave 19
(0.26 g, 70% yield), m.p. begins to decompose at 295 ꢁC,
m.p. 305–307 ꢁC. HRMS: M•? ? H, 347.0508. Requires
M•? ? H, 347.0502.
Ultraviolet–visible spectrum: 381 nm (log e = 4.50).
X-ray Data Collection and Structure Determination
Diffraction data for 11, 13, and 15 were collected at low
temperature on a Nonius Kappa CCD diffractometer fitted
with an Oxford Cryostream cooler and graphite-monochro-
1
IR, H NMR Spectra of 19
Selected infrared absorptions (cm-1): 3318, 3194, 3148,
˚
mated Mo Ka (0.71073 A) radiation. Data for 11 were
1716, 1666, 1612 cm-1
.
collected at 173 K, and for 13 and 15 at 90 K. Data reduction
included absorption corrections for the Br-containing com-
pounds by the multi-scan method, with HKL SCALEPACK
[16]. Structures were solved by direct methods and difference
Fourier techniques and refined by full-matrix least squares
techniques using SHELXL97 [17]. All nonhydrogen atoms
were refined anisotropically. All hydrogen atoms were visible
indifferencemaps, but were placed inidealized positions with
Uiso = 1.2Ueq for the bonded atom (1.5 for methyl groups). A
torsional parameter was refined for each methyl group, and
coordinates of N–H hydrogen atoms were refined.
1H NMR: 12.99 (d, J = 3 Hz, 1H, NH), 9.40 (s, 1H,
C=NH), 8.99 (d, J = 3 Hz, 1H, C(2)H), 8.39 (d, J = 2 Hz,
1H, C(4)H), 7.49 (d, J = 2 Hz, 1H, C(7)H), 7.36 (dd,
J = 9 and 2 Hz, 1H, C(6)H), 7.34 (s, 1H, C(8)H), 3.79 (m,
J = 7 Hz, 2H, CH2), 3.51 (s, 3H, N-CH3) and 1.19 (t,
J = 7 Hz, 3H, CH3).
Preparation of 6-Bromoindole-3-carboxaldehyde (13)
Phosphorus(V) oxychloride (1.96 g) was added dropwise
to DMF (3 mL) cooled in an ice bath. The mixture was
kept at 0 ꢁC for 30 min. A solution of 6-bromoindole
(2.00 g) in DMF (22 mL) was added dropwise, keeping the
reaction temperature below 10 ꢁC. After 3 h at 20 ꢁC, the
syrupy solid was poured into ice-water (180 g), neutralized
with 1N NaOH, and left standing overnight. The crude
product was collected by filtration and recrystallized from
ethanol or DMF to give the 6-bromoindole-3-carboxalde-
Results and Discussion
The synthesis of 5-bromo-40-de-N-methylaplysinopsin (11)
was carried out by an aldol condensation of 5-bromoin-
dole-3-carboxaldehyde (9) with creatinine(10).
O
CH3
N
H
1
hyde (13) (1.42 g, 71%); m.p. 200–201 ꢁC. The H NMR
spectrum of 13 is identical to H NMR reported by Ras-
mussen et al. [15].
NH2
Br
1
N
N
O
H
10
9
Preparation of 6-Bromoaplysinopsin (5)
∆
-H O
2
6-Bromoindole-3-carboxaldehyde (1.00 g) and 2-imino-
1,3-dimethyl-imidazolidin-4-one (14) (0.567 g) were
heated at approximately 153 ꢁC for 10 min. Considerable
frothing of the mixture took place during the course of the
reaction. The reaction mixture was extracted with methanol
(4 9 50 mL). Evaporation of the methanol gave a solid
that was recrystallized from DMF-water to give orange
needles (0.550 g, 56%), m.p. begins to decompose at
269 ꢁC, m.p. 281–282 ꢁC). HRMS: M•? ? H, 333.0346.
Requires: M•? ? H, 333.0345.
CH
NH
CH
3
NH
3
2
2
N
N
N
N
H
H
Br
Br
O
O
N
N
H
H
11A
11B
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J Chem Crystallogr (2009) 39:329–336
333
This synthesis is particularly attractive since creatinine is
commercially available and indole-3-carboxaldehydes are
either commercially available or can be readily prepared
from substituted indoles [18]. Crystals of 5-bromo-40-de-N-
methylaplysinopsin (11) suitable for a single crystal X-ray
structure determination were obtained by crystallization
from DMF. The X-ray structure shows that a molecule of
DMF is incorporated into the crystalline lattice (Fig. 1).
The structure of 11 shows that the molecule is nearly
planar, with its 19 nonhydrogen atoms having an average
the imidazole ring was determined to be in the
E configuration. Although the configurations of some
aplysinopsins have been determined from heteronuclear
coupling constants between the hydrogen on C8 and the
C50 carbonyl carbon atom [4, 10, 20], the X-ray structures
provide unambiguous assignment of the configuration
about this bond in the aplysinopsin analogs reported
herein.
Secondly, the imidazolone ring can exist in two different
tautomeric forms, one where the imine double bond is
endocyclic (11-endo) and the other
˚
deviation of only 0.028 A. The C–Br distance is
˚
1.914(2) A. The near-planarity of the molecule allows an
intramolecular close contact between the H atom on indole
0
˚
CH
NH
CH
3
3
NH
C2 and O1 . This interaction has CꢀꢀꢀO distance 2.927(2) A
and a 136ꢁ angle about H, and can be considered a C–HꢀꢀꢀO
hydrogen bond [19]. All N–H groups are also involved in
intermolecular N–HꢀꢀꢀO and N–HꢀꢀꢀN hydrogen bonds,
2
N
N
N
N
H
H
H
Br
Br
O
O
˚
having NꢀꢀꢀX distances in the range 2.785(2)–3.000(3) A,
N
N
the longest involving the NH2 group as donor and DMF
H
H
oxygen as acceptor. The shortest Br…Br distance is
11 (endo)
11 (exo)
˚
˚
4.472(1) A, approximately 0.8 A longer than twice the van
der Waals radius of Br, indicating a lack of significant Br–
Br contacts.
where the imine double bond is exocyclic (11-exo). The
crystal structure shows that the imidazolone ring exists in
1
the endocyclic tautomeric form in the solid state. The H
Compound 11 has been synthesized previously by the
reaction of 5-bromoindole-3-carboxaldehyde with creati-
nine in an acetic acid mixture containing sodium acetate
[5]. The compound was isolated as its acetate salt from the
reaction mixture and was not further purified.
NMR of 11 shows an absorption at 7.73 ppm integrating
for two hydrogen atoms. This absorption must be due to the
NH2 group, which demonstrates that the 11-endo tauto-
meric form also exits in d6-DMSO solution. While the
naturally occurring aplysinopsins 1, 5, 7, and 8 have methyl
groups on the imidazolone nitrogen atoms and therefore
must exist in the exocylic imine form, the aplysinopsins 2–
4 and 6 are capable of existing in either form. In the lit-
erature, aplysinopsins 2–4 and 6 have been reported in
either the endocyclic or the exocyclic tautomer, usually
without explanation. The aplysinopsins 3, 4, 6, and 11 were
drawn [5] as the endocyclic tautomer based on work car-
ried out on imidazolidin-4-ones, which have been shown to
There are several structural characteristics that were
resolved by our X-ray structure determination. First of all
the carbon–carbon double bond linking the indole ring to
1
exist in the endocyclic tautomer [21]. The H NMR evi-
dence to support these assignments in aplysinopsins has not
been discussed.
Another structural feature of aplysinopsin 11 concerns
the polarization of the carbon–carbon double bond linking
the indole ring with the imidazolone ring. Polarization of
this bond so that the negative charge is in the imidazolone
ring makes the ring aromatic with six p electrons and
creates a conjugated indole carbocation (see resonance
structure 11B). The X-ray structure shows that the carbon–
carbon double bond (C8–C10) linking these two rings is
˚
only slightly longer [1.347 (3) A] than a typical conjugated
˚
double bond (1.33 A) and the C3–C8 single bond is
˚
slightly shorter [1.446 (3) A] than the typical single bond
˚
adjacent to a conjugated double bond (1.54 A). This
Fig. 1 ORTEP drawing of 11, with 50% ellipsoids, showing the
numbering scheme
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J Chem Crystallogr (2009) 39:329–336
suggests that that resonance structure 11B only makes a
minor contribution to the resonance hybrid. This also
implies that the degree of overlap of the p-orbitals in the
C8–C10 double bond should be high and the barrier for
thermal Z/E isomerization should be high enough for both
the Z and E isomers of aplysinopsins and aplysinopsin
analogs to be isolated.
It is not clear from the literature on aplysinopsins
whether the two geometric isomers of these compounds
can be separated and isolated. There are reports of mix-
tures of the Z and E isomers of aplysinopsins, including
some samples that contain as much as 50% of each isomer
[9]. In one instance an aplysinopsin that was predomi-
nately in the
Z
configuration [Z/E [ 95/5] was
photoisomerized at 350 nm to give a mixture enriched in
the E isomer [10]. When this mixture was kept at room
temperature in the dark for a few days the E isomer
isomerized back to the Z isomer. It has been suggested that
synthetic analogs and naturally occurring aplysinopsins
without an alkyl group on N(20) exist predominately in the
Z configuration while aplysinopsins with an alkyl group on
N(20) are mainly in the E configuration [10]. In a review
article by Wells [11], it was reported that X-ray structures
for the Z and E isomers of methylaplysinopsin (7)
have been carried out. The reference in this review is to
unpublished work that to our knowledge has never
appeared in print.
Fig. 2 ORTEP drawing of 15, with 50% ellipsoids
CH
N
3
H
I
CH
N
3
NH
2
N
H
RI
EtOH
N
N
R
O
O
10
14: R = CH2
15: R = CH2CH3
Two other aplysinopsin analogs (18 and 19) and one
naturally occurring aplysinopsin (5) were prepared in this
work by the reaction of 5-fluoroindole-3-carboxaldehyde
(12) or 5-bromoindole-3-carboxaldehyde with the hyd-
roiodide salt of 2-imino-1,3-dimethyl-imidazolidin-4-one
(14) and the reaction of 5-bromoindole-3-carboxaldehyde
(12) with the hydroiodide salt of 2-imino-1-methyl-3-ethyl-
imidazolidin-4-one (15). The imidazolidin-4-ones 14 and
15 were prepared by alkylation of creatinine (10) [21].
Crystals of 15 were obtained by crystallization from DMF.
Again a molecule of DMF was incorporated into the
crystalline lattice. The structure of 15 is illustrated in
Fig. 2, which does not include the DMF solvent molecule.
The molecule is slightly less planar than 11, with its 20
O
H
∆
-H O
X
Y
2
N
H
16: X = F; Y = H
9: X = Br; Y = H
17: X = H; Y = Br
CH
3
NH
N
N
H
R
X
Y
O
N
˚
H
nonhydrogen atoms having a mean deviation of 0.055 A
from coplanarity, with methyl groups C60 and C70 deviat-
˚
ing the most, 0.156(1) and 0.161(1) A, respectively. The
18: X = F; Y = H; R = CH3
19: X = Br; Y = H; R = CH2CH3
5: X = H; Y = Br; R = CH3
0
˚
C–F distance is 1.3719(15) A. The C2–HꢀꢀꢀO1 interaction
is very similar to that in 11, with a CꢀꢀꢀO distance of
˚
2.889(1) A and a 135ꢁ angle about H. Both N–H groups are
involved in intermolecular hydrogen bonds, but are
The naturally occurring 5-Bromoaplysinopsin has been
(5) synthesized previously by Fattorusso et al. [6] and their
1H NMR is identical to the one that we obtained. This
compound has been reported [6] to be identical to a natu-
rally occurring aplysinopsin [6].
somewhat longer than those in 11. Nitrogen atom N1
0
˚
donates to N3 with a NꢀꢀꢀN distance of 2.9137(15) A, and
N30 donates to the solvent oxygen, with a NꢀꢀꢀO distance of
˚
3.1230(15) A.
123

J Chem Crystallogr (2009) 39:329–336
335
The only X-ray structure of an aplysinopsin or aplys-
inopsin analog that has been published was carried out on a
thioaplysinopsin (20) [22]. The X-ray
and 18 have established that these compounds exist in the Z
configuration about the C8-10 double bond. The X-ray
structure of 11 establishes that the carbon–nitrogen double
bond in the imidazolone ring is in the endocylic tautomeric
1
form in the solid state. The H NMR of 15 shows that this
double bond in the endocyclic position in DMSO solution.
O
CH
3
H
N
N
S
Supplementary Material
H
CH
N
H
3
CCDC 666374-666376 contains the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif,
by e-mailing data_request@ccdc.cam.ac.uk, or by con-
tacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; Fax: ?44-1223-
336033.
20
structure of 20 shows that this aplysinopsin analog is in the
Z configuration.
During the course of our work on the synthesis of ap-
lysinopsin analogs we obtained a crystal structure on 6-
bromoindole-3-carboxaldehyde (13), which is the indole
precursors used to prepare 5. This compound has been
found in marine sponges [12, 15, 23, 24]. The structure of
˚
13 is shown in Fig. 3. The C–Br distance is 1.9015(16) A.
The C, N, and Br atoms are coplanar to within an average
Acknowledgements The Minority Biomedical Research Support
Program of the National Institutes of Health (NIH-MBRS grant
number R25-GM55380), the Robert A. Welch Foundation (grant
number M-020) and the Texas Woman’s University Research
Enhancement Program supported this work. This work was also
supported in part by grants RO1 MH063162 and funds G67673
awarded to J.A.S. We are grateful to Dr. Wayland E. Noland at the
University of Minnesota for making arrangements for us to obtain
HRMS of three of the compounds reported in this paper. The purchase
of the diffractometer was made possible by grant number LEQSF
(1999-2000)-ENH-TR-13, administrated by the Louisiana Board of
Regents.
˚
˚
deviation of 0.017 A, with the O atom lying 0.156(1) A out
of that plane, a result of a small torsional twist about the
C3–C8 bond, 4.9(3)ꢁ. The N–H group forms a nearly linear
intermolecular hydrogen bond with the O atom, at a NꢀꢀꢀO
˚
distance of 2.821(1) A. There are no significant intermo-
lecular Br…Br contacts, the shortest such distance being
˚
4.682(1) A. The structure of indole-3-carboxaldehyde,
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