1248 J. Org. Chem.

1998, 63, 1248-1253

Synthesis of Marine Sponge Alkaloids Oroidin, Clathrodin, and

Dispacamides. Preparation and Transformation of
2-Amino-4,5-dialkoxy-4,5-dihydroimidazolines from
2-Aminoimidazoles

Anne Olofson, Kenichi Yakushijin, and David A. Horne*

Department of Chemistry, Columbia University, New York, New York 10027

Received October 3, 1997

The preparation and transformation of 2-amino-4,5-dialkoxy-4,5-dihydroimidazolines A from

2-aminoimidazoles (AIs) is described. The oxidation of 2-aminoimidazole 8 with NCS in methanol
affords cyclic guanidine adduct 9 which, upon heating, affords vinylogous AI derivative 3 and
2-aminoimidazolinone (glycocyamidine) 13. Olefin 3 comprises the core structure found in the
oroidin alkaloids. Furthermore, oxidation of 8 with Br2 and DMSO affords directly R,β-unsaturated
imidazolinone 14 which is the key structural unit comprising the dispacamides (2). A highly facile
and practical synthesis of the C11N5 marine sponge alkaloids oroidin (1a), clathrodin (1c), and
dispacamides (2) is outlined.

Marine sponges of the genera Agelas, Hymeniacidon, groups.8,9 Both groups focused on the preparation of 3 in
and Phakellia produce a structurally diverse and phar- which Wittig chemistry was used to install the olefinic
macologically interesting class of C11N5, and dimerically double bond. Moreover, the syntheses relied heavily on
related, secondary metabolites.1,2 The chemical features the use of protecting groups on nitrogen. Undoubtedly,
that distinguish these alkaloids are the presence of either alkaloids 1-3 are biogenetically related and likely de-
a brominated or nonbrominated pyrrole carboxamide rived from a common 2-aminoimidazole (AI) precursor.
unit, a 2-aminoimidazole or glycocyamidine nucleus, and In this report, we describe the facile synthesis of 1, 2,
a functionalized or unfunctionalized 3-carbon alkyl chain and 3 by the preparation and rearrangement of 2-amino-
connecting these heterocyclic moieties. Collectively, this 4,5-dialkoxy-4,5-dihydroimidazolines having the general-
group of natural products is known as the oroidin ized structure A.10
alkaloids of which oroidin (1a)3 and dispacamide (2a),4
both from the sponge Agelas sp., represent the “simplest”
structural entities. The related monobromopyrrole de-
rivatives, hymenidin (1b),5 from the sponge Hymeniaci-
don sp., and monobromodispacamide (2b)4 are also
known, as well as the debromooroidin derivative, clath-
rodin (1c).6 Metabolites 1b and 2 have been reported as
potent antagonists of serotonergic5 and histaminergic4
receptors, respectively. Closely related to oroidin (1a) is
3-amino-1-(2-aminoimidazol-4-yl)prop-1-ene (3)7 which
lacks the pyrrole moiety. This derivative has been
isolated from the Axinellidae sponges T. morchella and
P. walpersi and is a potential biosynthetic precursor to
oroidin-related metabolites. A synthesis of oroidin (1a)
and clathrodin (1c) has been reported by two research

* To whom correspondence should be addressed. Tel. (212)-854-

8634. Fax (212)-932-1289. email: horne@chem.columbia.edu.
(1) For reviews, see: (a) Kobayashi, J.; Ishibashi, M. In The
Alkaloids: Chemistry and Pharmacology; Brossi, A., Ed.; Academic Imidazolines of the type A can be considered dialkoxy
Press: New York, 1992; Vol. 41, pp 41-124. (b) Faulkner, D. J. Nat. adducts of cyclic guanidines. In unpublished investiga-
Prod. Rep. 1996, 13, 75. (c) Berlinck, R. G. S. Nat. Prod. Rep. 1996, tions from the Büchi group, 4,5-dimethoxyimidazolines
13, 377.
(2) For recent reports, see: (a) Tsukamoto, S.; Kato, H.; Hirota, H.; were obtained from the reaction of 4-acyl-2-aminoimida-
Fusetani, N J. Nat. Prod. 1996, 59, 501. (b) Cafieri, F.; Fattorusso, E.; zoles with NBS in methanol.10 A search of the literature
Mangoni, A.; Taglialatela-Scafati, O. Tetrahedron 1996, 52, 13713. revealed no additional examples. Although known, a
(3) (a) Forenza, S.; Minale, L.; Riccio, R.; Fattorusso, E. J. Chem.
Soc., Chem. Commun. 1971, 1129. (b) Garcia, E. E.; Benjamin, L. E.;
Fryer, R. I. J. Chem. Soc., Chem. Commun. 1973, 78. (8) Webber, S. E.; Little, T. L. J. Org. Chem. 1994, 59, 7299.
(4) Cafieri, F.; Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O. (9) (a) de Nanteuil, G.; Ahond, A.; Poupat, C.; Thoison, O.; Potier,
Tetrahedron Lett. 1996, 37, 3587. P. Bull. Soc. Chim. Fr. 1986, 813. (b) Daninos, S.; Al Mourabit, A.;
(5) Kobayashi, J.; Ohizumi, Y.; Nakamura, H.; Hirata, Y. Experientia Ahond, A.; Zurita, M. B.; Poupat, C.; Potier, P. Bull. Soc. Chim. Fr.
1986, 42, 1176. 1994, 131, 590. (c) Daninos-Zeghal, S.; Al Mourabit, A.; Ahond, A.;
(6) Morales, J. J.; Rodriguez, A. D. J. Nat. Prod. 1991, 54, 629. Poupat, C.; Potier, P. Tetrahedron 1997, 53, 7605.
(7) Wright, A. E.; Chiles, S. A.; Cross, S. S. J. Nat. Prod. 1991, 54, (10) Dupriest, M. Ph.D. Thesis, Massachusetts Institute of Technol-
1684. ogy, 1982.

S0022-3263(97)01829-X CCC: $15.00 © 1998 American Chemical Society

Published on Web 01/27/1998
Synthesis of C11N5 Marine Alkaloids J. Org. Chem., Vol. 63, No. 4, 1998 1249

Scheme 1 Scheme 2

small number of related dihydroxy adducts have been

isolated from the condensation of guanidines and R-dike-
tones11 and/or glyoxal.12 These limited examples il-
lustrate the stability of imidazoline adducts to isolation.
In a continuing effort toward the development of AI
chemistry,13 we focused on further investigating the lization from ethanol after which 6 is separated as an
preparation of various analogues of A and examining oil. Generally, imidazoline adducts are obtained by
their utility as key intermediates in alkaloid synthesis. trituration from the reaction mixture and are relatively
The belief was that these adducts could serve as useful stable. In each instance, the predominant diastereomer
precursors to various members of the oroidin family of formed was the trans isomer except in the case of the
marine natural products. bicyclic [4.3.0] imidazoline derivative 7 where the ring
Our initial investigations focused on the direct genera- fusion is cis. The stereochemistry of the adducts was
tion of adduct A by examining various conditions for the determined from 1H NMR data. Previous data on related
oxidation of functionalized AI substrates (Scheme 1). The systems established that the 4,5-imidazoline proton
trapping of a reactive intermediate by nucleophilic resonances for the trans isomers are upfield from those
solvent molecules was the objective. Since a number of of the cis.12 In DMSO-d6, trans adducts 4-6 produce
AI derivatives are readily available from known proce- singlets at δ 4.86, 5.10, and 4.96, respectively, whereas
dures,14 this overall approach would provide a general for the corresponding cis isomers, singlets were observed
method for the preparation of 2-amino-4,5-dialkoxy-4,5- at lower field at δ 5.12, 5.38, and 5.20, respectively. The
dihydroimidazoline derivatives. Although few in num- reactions in Scheme 2 were model reactions for the study
ber, related examples in the literature involving the of 2-amino-4-(3-aminopropyl)-1H-imidazole 8 and dihy-
addition to the 4,5-double bond of AIs can be seen in the drooroidin 15,15 which bear alkylamine and pyrrole-
intramolecular oxidative cycloaddition used for the bio- caboxamide functionalities, respectively.
mimetic synthesis of dibromophakellin,15 the intermo- AI derivative 8 can be considered a hypothetical
lecular [2 + 4] cycloaddition for the preparation of forerunner to the C11N5 natural products 1 and 2. It can
tetrahydropurine derivatives,16 and the acid-facilitated be prepared readily from ornithine methyl ester using
addition of EtOH to a bicyclic[3.3.0] AI system to give a the method of Lancini et al.17 This procedure, which
stable 2-aminoimidazolidinium cation.8 incorporates an Akabori reduction followed by condensa-
Preliminary investigations focused on AI (Scheme 2). tion of the resulting R-amino aldehyde with cyanamide,
Upon treatment of AI sulfate with N-chlorosuccinimide allows for the preparation of multigram quantities of
in methanol, a swift and clean reaction occurred that 2-aminoimidazoles from esters of R-amino acids. Oxida-
afforded trans adduct 4 in excellent yield along with trace tion of 8 with NCS in methanol gave the expected trans
amounts of the cis diastereomer. With benzyl alcohol, dimethoxy adduct 9 in good yield (Scheme 3). An
however, a 6:1 trans:cis mixture of adduct 5 was obtained interesting reversal from the model reactions in Scheme
wherein π-stacking of the phenyl rings may contribute 2 is seen with ethylene glycol. When 8 was treated with
to the overall stability of the cis isomer. The use of NCS in ethylene glycol, bicyclic adduct 10 was produced
ethylene glycol produced trans adduct 6 (and trace as the only product without formation of the correspond-
amounts of cis) as well as the bicyclic imidazoline deriv- ing disubstituted adduct. Evidently, steric interactions
ative 7 as a minor coproduct. This bicyclic product can between the aminopropyl side chain and the formation
be obtained in pure form as a colorless solid by crystal- of the incipient ethylene glycol unit preclude the genera-
tion of the bisglycol adduct.
(11) (a) Nishimura, T.; Nakano, K.; Shibamoto, S.; Kitajima, K. J. The trans stereochemistry of adduct 9 was confirmed
Heterocycl. Chem. 1975, 12, 471. (b) Nishimura, T.; Kitajima, K. J.
Org. Chem. 1976, 41, 1590. (c) Nishimura, T.; Kitajima, K. J. Org.
by 1-D selective NOESY experiments. Irradiation of the
Chem. 1979, 44, 818. C5 ring proton singlet at 4.73 ppm showed NOEs to both
(12) McClelland, R. A.; Panicucci, R.; Rauth, A. M. J. Am. Chem. methoxyl groups at 3.35 and 3.15 ppm. No enhancement
Soc. 1987, 109, 4308.
(13) (a) Xu, Y.-z.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1997, was observed to the methylene protons of the aminopro-
62, 456 (and earlier references). (b) Olofson, A.; Yakushijin, K.; Horne, pyl side chain at 1.5-1.9 ppm. Likewise, when the C5
D. A. J. Org. Chem. 1997, 62, 7918. methoxyl group (geminal to the ring proton) was irradi-
(14) Methodologies for the preparation of 2-aminoimidazoles are
described in ref 8.
(15) Foley, L. H.; Büchi, G. J. Am. Chem. Soc. 1982, 104, 1776. (17) (a) Lancini, G. C.; Lazzari, E. J. Heterocycl. Chem. 1966, 3, 152.
(16) Xu, Y.-z.; Yakushijin, K.; Horne, D. A. Tetrahedron Lett. 1993, (b) Lancini, G. C.; Lazzari, E.; Arioli, V.; Bellani, P. J. Med. Chem.
34, 6981. 1969, 12, 775.
1250 J. Org. Chem., Vol. 63, No. 4, 1998 Olofson et al.

Scheme 3a

a Key: (a) NCS, MeOH, rt, 83%; (b) NCS, ethylene glycol, rt, 80%; (c) MeOH, reflux, 11 (30%), 12 (15%); (d) 135 °C, m-xylene/methanol,

3 (55%), 13 (35%); (e) 2-(trichloroacetyl)pyrrole, DMF, rt, 75%; (f) Br2, DMSO, rt, 68%; (g) 4-bromo-2-(trichloroacetyl)pyrrole, DMF, rt,
65%; (h) Br2, CH3SO3H, 85 °C, 71%.

ated, an NOE was seen only to the ring proton and the Next, the formation of the R,β-unsaturated imidazoli-
geminal guanidine N1 proton, which resonated at 9.70 none ring system which comprises the dispacamides (2)
ppm. No enhancement was observed for the adjacent C4 was investigated. This was done using both AI derivative
methoxyl group. Irradiation of the C4 methoxyl group 8 and imidazolinone 13. Derivative 8 requires a 2-fold
showed NOEs to both the C5 ring proton and the geminal oxidation of the AI nucleus to install both the carbonyl
guanidine N3 proton, but again, no NOE was observed and olefin functionalities. Since the ability of adduct
to the vicinal C5 methoxyl group. These data establish formation occurs readily upon oxidation in protic sol-
the stereochemical relationship of the methoxyl groups vents, similar additions were envisaged with the aprotic
as trans. but nucleophilic solvent DMSO.20 The addition of DMSO
In the course of these reactions, the mechanistic followed by elimination of dimethyl sulfide would lead
pathway leading to adduct A probably involves initial directly to the R,β-unsaturated imidazolinone ring system
incorporation of halogen to AI followed by substitution found in the dispacamides. When 8 was treated with 1
with nucleophilic solvent (Scheme 1). The trans dialkoxy equiv of Br2 in DMSO, transformation to (Z)-R,β-unsatur-
adduct 9 predominates thus implicating the formation ated imidazolinone 14 resulted in good yield.21 The Z
of intermediate B with the stepwise addition of another stereochemistry of olefin 14 was firmly established by
ROH from the least hindered face. its conversion to monobromodispacamide (2b) by acyla-
An interesting feature of these adducts is their poten- tion with 4-bromo-2-(trichloroacetyl)pyrrole.22 All spec-
tial for rearrangement. This was investigated thermally tral data of synthetic 2b were in satisfactory agreement
by heating adducts 9 and 10 (Scheme 3). Refluxing 9 in with those reported for the natural product.4,23 Alterna-
methanol afforded mainly the R-substituted side chain tively, 14 can be produced from the oxidation of imida-
derivative 11 and unchanged starting material. Similar zolinone 13 with Br2 in methanesulfonic acid.
results were seen with adduct 10 in refluxing methanol Acylation of AI derivative 8 with the requisite dibro-
which gave the mixed side chain derivatives 11 and 12 mopyrrole unit produced dihydrooroidin (15) in 65% yield.
along with a significant amount of recovered starting This compound is also capable of forming dialkoxy
material. At elevated temperatures (135 °C) using an adducts, but the presence of the pyrrolecarboxamide unit
initial 1:1 solvent mixture of xylene:methanol,18 adduct necessitated modification of the reaction conditions
9 rearranged to two products, namely, vinyl imidazole 3 (Scheme 4). The amide linkage in 15 interferes with
and imidazolinone 13 in 55% and 35% yields, respec-
tively. Acylation of 3 with 2-(trichloroacetyl)pyrrole19 (20) (a) Savige, W. E.; Fontana, A. J. Chem. Soc. Chem. Commun.
1976, 599. (b) Szabo-Pusztay, K.; Szabo, L. Synthesis 1979, 276.
afforded clathrodin (1c). All spectral data of synthetic (21) The presence of a small amount (5-10%) of the E-isomer can
1c and 3 were in satisfactory agreement with those be seen in the 1H NMR spectrum (D2O): δ 3.05 (dt, 2H, J ) 8.0, 7.1),
reported for the natural material.6,7 3.15 (t, 2H, J ) 7.1), 6.06 (t, 1H, J ) 8.0).
(22) Keifer, P. A.; Schwartz, R. E.; Koker, M. E. S.; Hughes, R. G.,
Jr.; Rittschof, D.; Rinehart, K. L. J. Org. Chem. 1991, 56, 2965.
(18) The reaction was heated without a condenser, thus allowing (23) The presence of a small amount (5-10%) of the E-isomer can
the methanol to boil off. be seen in the 1H NMR spectrum (CD3OD): δ 2.98 (dt, 2H, J ) 8.2,
(19) Bailey, D. M.; Johnson, R. E.; Albertson, N. F. Org. Synth. 1971, 6.6), 3.48 (t, 2H, J ) 6.6), 6.06 (t, 1H, J ) 8.2), 6.74 (d, 1H, J ) 1.5),
51, 100. 6.90 (d, 1H, J ) 1.5).
Synthesis of C11N5 Marine Alkaloids J. Org. Chem., Vol. 63, No. 4, 1998 1251

Scheme 4a

a Key: (a) Br2, tBuOK, CH3OH, -78 °C, 75%; (b) 135 °C, m-xylene/MeOH, 1a (48%), 17 (30%); (c) Br2, DMSO, 60%.

adductformation under the usual conditions of NCS and NMR (DMSO-d6) δ 158.6 (s), 90.3 (d × 2), 54.7 (q × 2); IR (KBr)
methanol. This is due to competing intramolecular 3153, 2822, 1700, 1583, 1211 cm-1; MS m/z (relative intensity)
processes of the pyrrolecarboxamide group. To overcome 146 (M+ + 1, 100), 114 (10). Anal. Calcd for C5H11N3O2‚1/
2H2SO4: C, 30.92; H, 6.23; N, 21.64. Found: C, 30.89; H, 6.25;
this problem, a slight excess of base (tBuOK) was added
N, 21.60.
and bromine was used instead of NCS as the halogen
trans-2-Amino-4,5-dihydro-4,5-ibs(benzyloxy)-2-imida-
source. The slight excess of base generates the more zoline (5). To a stirred mixture of AI sulfate (0.60 g, 4.5
nucleophilic methoxide species which readily adds to the mmol) in 10 mL of benzyl alcohol at rt was added NCS (0.67
oxidized AI nucleus. This afforded dimethoxy adduct 16 g, 5.0 mmol). After 20 h, the reaction mixture was diluted
in good yields. The trans stereochemical assignment of with ether and decanted (3 × 100 mL). The resulting residue
adduct 16 was inferred from comparison with NMR data was dissolved in 10 mL of acetone, and the small amount of
of trans adduct 9. Adduct 16 can be converted to oroidin unreacted starting material was removed by filtration. Con-
(1a) and dihydrodispacamide (17) when heated in xylene/ centration of the filtrate afforded a gum that was washed with
ether (100 mL) and dried to give 5 as a pale yellow oil (1.26 g,
methanol. In addition, oxidation of dihydrooroidin (15) 80%). The 1H NMR of 5 showed 15% of cis isomer. 5: 1H NMR
with Br2 and DMSO gave dispacamide 2a. Starting from (DMSO-d6) δ 9.78 (bs, 2H), 8.49 (bs, 2H), 7.34 (m, 10H), 5.10
commercially available ornithine methyl ester, the overall (s, 2H), 4.64 (d, 2H, J ) 11.7), 4.55 (d, 2H, J ) 11.7); 13C NMR
synthesis of 1 and 2 required only four and three steps, (DMSO-d6) δ 158.8 (s), 137.0 (s × 2), 128.4 and 128.0 (d × 10),
respectively, and proceeded without the use of a single 89.1 (d × 2), 68.8 (t × 2); IR (Nujol) 3194, 2851, 1695, 1576,
protecting group on nitrogen. AI derivative 8 serves as a 1093 cm-1; MS m/z (relative intensity) 298 (M+ + 1, 100), 208
common intermediate to metabolites 1-3. (60), 190 (10). HRMS calcd for C17H20N3O2 (MH+) 298.1557,
found 298.1551.
In conclusion, the preparation of 2-amino-4,5-dialkoxy-
trans-2-Amino-4,5-dihydro-4,5-bis(2-hydroxyethoxy)-
4,5-dihydroimidazoline derivatives having various func- 2-imidazoline (6) and 6-Amino-5H-imidazo[4,5-b]-1,4-
tionalities from 2-aminoimidazoles is described. The dioxane (7). To a stirred mixture of AI sulfate (0.60 g, 4.5
method appears general, and the utility of these interest- mmol) in 10 mL of ethylene glycol at rt was added NCS (0.67
ing derivatives is demonstrated in their imidazoline to g, 5.0 mmol). After 20 h, the reaction mixture was diluted
vinyl imidazole and imidazolinone transformations. The with ether and decanted (3 × 100 mL). The resulting residue
facile synthesis of 1, 2, and 3 is illustrative of the was washed with acetone (3 × 100 mL) to give a mixture of 6
chemistry. Furthermore, we have shown that the AI and 7 (0.7 g, 80%) as a colorless oil. The 1H NMR in DMSO-
d6 showed a 6:1 ratio of 6:7 with a trace amount of the cis
nucleus can serve as a direct precursor to the R,β-
isomer of 6. Addition of a small amount of ethanol to this oil
unsaturated imidazolinone system found in the dispaca- and filtration gave pure 7 as a colorless solid. The filtrate,
mides and related AI alkaloids. Perhaps a similar after evaporation, yielded a colorless oil consisting of 6 with a
oxidative pathway is operative in the biogenesis of trace of 7. 6: 1H NMR (DMSO-d6) δ 9.64 (bs, 2H), 8.44 (bs,
glycocyamidine-containing metabolites such as 2. 2H), 4.96 (s, 2H), 4.85 (br, 2H), 3.51 (m × 2, 8H); 13C NMR
(DMSO-d6) δ 158.7 (s), 89.8 (d × 2), 69.1 (t × 2), 60.0 (t × 2).
7: 1H NMR (DMSO-d6 ) δ 9.08 (bs, 2H), 8.48 (bs, 2H), 5.31 (s,
Experimental Section
2H), 3.69 (m, 4H); 1H NMR (D2O) δ 5.46 (s, 2H), 3.90 (ddd,
General. Unless otherwise noted, materials were obtained 2Heq, J ) 8.4, 7.1, 6.9), 3.82 (ddd, 2Hax, J ) 8.4, 7.1, 6.9); 13C
from commercial suppliers and used without further purifica- NMR (DMSO-d6) δ 159.2 (s), 78.8 (d × 2), 58.0 (t × 2); IR (KBr)
tion except for solvents which were dried and distilled. Silica 3180, 2956, 1700, 1667, 1261 cm-1; MS m/z (relative intensity)
gel (particle size 32-63 µ) was used for flash chromatography. 143 (M+, 45), 114 (30), 86 (100). Anal. Calcd for
1H NMR spectra were measured at 300 MHz. 13C NMR C5H9N3O2‚1/2H2SO4: C, 31.25; H, 5.24; N, 21.86. Found: C,
spectra were recorded at 75 MHz. Abbreviations are as 31.30; H, 5.27; N, 21.87.
follows: AI ) 2-aminoimidazole and NCS ) N-chlorosuccin- 2-Amino-4-(3-aminopropyl)-1H-imidazole (8). A solu-
imide. tion of L-ornithine methyl ester dihydrochloride (25 g, 0.11 mol)
trans-2-Amino-4,5-dihydro-4,5-dimethoxy-2-imidazo- in 250 mL of water was cooled between 0 and 5 °C. The pH
line (4). To a stirred solution of AI sulfate (0.60 g, 4.5 mmol) was adjusted to 1.5-2.0 by addition of 15% HCl. Over the
in 10 mL of methanol at rt was added NCS (0.67 g, 5.0 mmol). course of 1 h, 5% Na/Hg (546 g, 1.1 mol) was added to the
After 30 min, methanol was removed by evaporation under solution while the temperature and pH within were main-
reduced pressure without heat. The resulting residue was tained the given range. When the pH remained constant and
washed with ether (3 × 100 mL) and acetone (100 mL), and the evolution of gas had ceased, the solution was decanted to
the solid was collected by filtration to give 4 as a colorless solid remove Hg. The pH was then adjusted to 4.3 by the addition
(0.84 g, 95%). The 1H NMR of 4 showed trace amounts of cis of 1 N NaOH. Cyanamide (48 mL, 0.57 mol) was added and
isomer. 4: 1H NMR (DMSO-d6) δ 9.56 (s, 2H), 8.35 (s, 2H), the solution heated at 95 °C for 2.5 h. Removal of the solvent
4.86 (s, 2H), 3.30 (s, 6H); (D2O) δ 5.03 (s, 2H), 3.39 (s, 6H); 13C in vacuo afforded a thick, light yellow residue which was
1252 J. Org. Chem., Vol. 63, No. 4, 1998 Olofson et al.

washed with ether (3 × 200 mL). Methanol was added to the residue washed with ether (3 × 100 mL) and acetone (2 × 100
residue and NaCl removed by filtration. The filtrate, after mL). Addition of 5 mL of methanol to the residue and
evaporation, gave a pale yellow solid. Recrystallization from filtration yielded pure 3‚2HCl as a colorless solid (0.46 g, 40%).
ethanol gave 8 as colorless needles (14.9 g, 62%): mp 213-215 Concentration of the filtrate followed by purification of the
°C; 1H NMR (DMSO-d6) δ 12.30 (s, 1H), 11.76 (s, 1H), 8.25 (s, resulting residue by flash chromatography (CH2Cl2/MeOH
3H), 7.39 (s, 2H), 6.62 (s, 1H), 2.72 (t, 2H, J ) 6.3), 2.5 (t, 2H, saturated with NH3 1:1) afforded additional 3 (0.11 g, 15%)
J ) 7.4), 1.82 (p, 2H, J ) 7.3); 1H NMR (D2O) δ 6.54 (s, 1H), and 13 (0.30 g, 35%) as free bases. Addition of concentrated
3.01 (t, 2H, J ) 7.6), 2.61 (t, 2H, J ) 7.4), 1.94 (p, 2H, J ) HCl to a methanol solution of the corresponding free base
7.6); 13C NMR (CD3OD) δ 148.7 (s), 127.2 (s), 110.4 (d), 39.9 and concentration in vacuo afforded 3‚2HCl and 13‚2HCl.
(t), 27.1 (t), 22.5 (t); IR (KBr) 3310, 1667, 1473, 1140 cm-1; 3‚2HCl: 1H NMR (DMSO-d6) δ 12.99 (br, 1H), 12.2 (br, 1H),
UV λmax (MeOH) 215 nm; MS m/z (relative intensity) 141 (M+ 8.40 (bs, 3H), 7.58 (s, 2H), 7.01 (s, 1H), 6.47 (d, 1H, J ) 16.1),
+ 1, 100), 124 (65). Anal. Calcd for C6H12N4‚2HCl: C, 33.82; 6.11 (dt, 1H, J ) 16.1, 6.3), 3.53 (bs, 2H, changes to do with
H, 6.62; N, 26.29. Found: C, 33.78; H, 6.59; N, 26.33. D2O, J ) 6.3); 1H NMR (CD3OD) δ 6.93 (s, 1H), 6.59 (s, 1H, J
trans-2-Amino-4,5-dimethoxy-4-(3-aminopropyl)-2-imi- ) 16.1), 6.16 (dt, 1H, J ) 16.1 and 7.0), 3.70 (d, 2H, J ) 7.0);
13C NMR (CD OD) δ 149.5 (s), 125.9 (s), 123.1 (d), 121.5 (d),
dazoline (9). To a stirred solution of 8 (0.60 g, 2.8 mmol) in 3
10 mL of methanol at rt was added NCS (0.41 g, 3.1 mmol). 114.0(d), 42.1 (t); UV λmax (MeOH) 265 nm; MS m/z (relative
After 1 h, methanol was removed in vacuo without heat and intensity) 139 (M+ + 1, 100), 122 (30). Anal. Calcd for
the resulting residue was washed with ether (3 × 100 mL) C6H10N4‚2HCl: C, 34.14; H, 5.73; N, 26.54. Found: C, 33.99;
and acetone (3 × 100 mL) to give 9 as an unstable colorless H, 5.70; N, 26.53. 13‚2HCl: 1H NMR (DMSO-d6) δ 12.37 (bs,
oil (0.64 g, 83%): 1H NMR (DMSO-d6) δ 9.75 (bs, 1H), 9.70 1H), 9.87 (s, 1H), 9.18 (bs, 1H), 8.91 (bs, 1H), 8.02 (bs, 3H),
(bs, 1H), 8.28 (bs, 2H), 8.14 (bs, 3H), 4.73 (s, 1H), 3.36 (s, 3H), 4.34 (t, 1H, J ) 5.1), 2.78 (q, 2H, J ) 6.5), 1.86-1.55 (m, 4H,
3.15 (s, 3H), 2.75 (q, 2H, J ) 5.7), 1.95-1.58 (m, 4H); 13C NMR J ) 7.7); 13C NMR (DMSO-d6) δ 174.9 (s), 157.9 (s), 58.5 (d),
(DMSO-d6) δ 158.0 (s), 94.4 (s), 90.1 (d), 55.9 (q), 48.8 (q), 38.7 38.4 (t), 27.6 (t), 22.4 (t); IR (KBr) 3283, 2644, 1713, 1545, 1397
(t), 27.6 (t), 21.8 (t); IR (Nujol) 3136, 2855, 1692, 1570, 1184 cm-1; UV λmax (MeOH) 205 nm; MS m/z (relative intensity)
cm-1; MS m/z (relative intensity) 203 (M+ + 1, 25), 171 (90). 157 (M+ + 1, 100), 102 (10). Anal. Calcd for C6H12N4O‚2HCl:
HRMS calcd for C8H19N4O2 (MH+) 203.1509, found 203.1500. C, 31.45; H, 6.16; N, 24.45. Found: C, 31.39; H, 6.12; N, 24.50.
6-Amino-4a-(3-aminopropyl)-5H-imidazo[4,5-b]-1,4-di- (Z)-2-Amino-5-(3-aminopropylidenyl)-2-imidazolin-4-
oxane (10). To a stirred solution of 8 (0.60 g, 2.8 mmol) in one (14). Method A. To a stirred solution of 13‚2HCl (0.10
10 mL of ethylene glycol at rt was added 1.1 equiv of NCS g, 0.44 mmol) in 1 mL of CH3SO3H was added bromine (20
(0.41 g, 3.1 mmol). After 20 h, the reaction mixture was µL, 0.44 mmol). The reaction was heated between 80 and 90
diluted with ether and decanted (3 × 100 mL). The resulting °C for 1 h. After cooling, the reaction mixture was diluted
residue was washed with acetone (3 × 100 mL) to give 10 as with ether and decanted (3 × 25 mL). The resulting solid was
an unstable colorless oil (0.61 g, 80%): 1H NMR (DMSO-d6) δ washed with acetone and filtered to give 14‚2CH3SO3H as a
9.40 (bs, 1H), 9.22 (bs, 1H), 8.42 (bs, 2H), 8.27 (bs, 3H), 5.18 tan solid (0.11 g, 71%). Method B. To a stirred solution of 8
(s, 1H), 3.76-3.62 (m, 4H), 2.78 (q, 2H, J ) 5.9), 1.82-1.69 (0.50 g, 2.3 mmol) in 6 mL of DMSO at rt was added bromine
(m, 4H); 13C NMR (DMSO-d6) δ 158.0 (s), 87.5 (s), 81.5 (d), (120 µL, 2.3 mmol). After 1 h, the reaction mixture was diluted
62.8 (t), 56.8 (t), 38.4 (t), 33.8 (t), 20.5 (t); IR (Nujol) 3404, 2740, with ether and decanted (3 × 75 mL). The resulting residue
1695, 1571, 1272, cm-1; MS m/z (relative intensity) 201 (M+ was purified by flash chromatography (MeOH saturated with
+ 1, 100); HRMS calcd for C8H17N4O2 (MH+) 201.1353, found NH3) to give 14 as a pale yellow solid. Addition of concentrated
201.1350. HCl to a methanol solution of the free base and concentration
2-Amino-4-(3-amino-1-methoxypropyl)-1H-imidazole in vacuo afforded 14‚2HCl (0.36 g, 68%) as a colorless solid.
(11). A stirred solution of 9 (0.75 g, 2.7 mmol) was refluxed 14‚2HCl: 1H NMR (DMSO-d6) δ 12.45 (br, 2H), 9.39 (br, 2H),
in 10 mL of methanol for 2 d. The solvent was removed in 8.18 (bs, 3H), 5.98 (t, 1H, J ) 7.7), 2.97 (q, 2H, J ) 6.9), 2.67
vacuo to afford a residue which consisted of starting material (q, 2H, J ) 7.2); 1H NMR (D2O) δ 6.13 (t, 1H, J ) 7.9), 3.20 (t,
9 and 11 as determined by NMR. Purification of the residue 2H, J ) 7.1), 2.71 (dt, 2H, J ) 7.9 and 7.1); 13C NMR (D2O) δ
by column chromatography (MeOH saturated with NH3) gave 164.8 (s), 156.2 (s), 130.7 (s), 117.0 (d), 38.9 (t), 25.8 (t); IR
11 (free base, 0.14 g, 30%) as a pale yellow oil: 1H NMR (KBr) 3100, 1690, 1540, 1310, 1250 cmj;1 UV λmax (MeOH) 226
(DMSO-d6 ) δ 6.35 (s, 1H), 5.11 (bs, 2H), 4.42 (br, 3H), 4.00 (t, and 271 nm; MS m/z (relative intensity) 155 (M+ + 1, 100),
1H, J ) 6.6), 3.05 (s, 3H), 2.52 (t, 2H, J ) 6.7), 1.84-1.67 (m, 138 (90). Anal. Calcd for C6H10N4O‚2HCl: C, 31.73; H, 5.33;
2H); 13C NMR (DMSO-d6) δ 149.9 (s), 131.8 (s), 113.9 (s), 74.3 N, 24.67. Found: C, 31.79; H, 5.30; N, 24.59.
(d), 54.8 (q), 38.6 (t), 38.5 (t); IR (KBr) 2944, 1584, 1489, 1344, Clathrodin (1c). To a stirred solution of 3‚2HCl (0.2 g,
1193 cm-1; MS m/z (relative intensity) 171 (M+ + 1, 100); 0.95 mmol) in 2 mL of DMF at rt were added Na2CO3 (0.11 g,
HRMS, calcd for C7H15N4O (MH+) 171.1247, found 171.1250. 1.0 mmol) and 2-(trichloroacetyl)pyrrole19 (0.25 g, 1.1 mmol).
2-Amino-4-(3-amino-1-(2-hydroxyethoxy)propyl)-1H- The mixture was stirred for 1 h and then diluted with ether
imidazole (12). A solution of 10 (0.75 g, 2.7 mmol) was and decanted (3 × 50 mL). The resulting residue was purified
refluxed in 10 mL of methanol for 2 d. The solvent was by flash chromatography (CH2Cl2/MeOH saturated with NH3
removed in vacuo to afford a residue which consisted of a 17:3) to give 1c as the free base. Addition of concentrated HCl
mixture of starting material 10, along with 11 and 12, as to a methanol solution of the free base and concentration in
determined by 1H NMR. Purification of the residue by flash vacuo gave 1c‚HCl (0.19 g, 75%). 1c‚HCl: 1H NMR (DMSO-
chromatography (MeOH saturated with NH3) gave 11 (0.14 d6) δ 12.39 (bs, 1H), 11.80 (bs, 1H), 11.49 (s, 1H), 8.33 (t, 1H,
g, 30%) and 12 (0.081 g, 15%) as free bases, both of which were J ) 5.9), 7.46 (s, 2H), 6.91 (s, 1H), 6.85 (m, 1H), 6.80 (m, 1H),
pale yellow oils. 12: 1H NMR (DMSO-d6) δ 6.32 (s, 1H), 5.08 6.21 (d, 1H, J ) 16.2), 6.15 (dt, 1H, J ) 16.2, 4.9), 6.08 (m,
(bs, 2H), 4.40 (br, 4H), 4.18 (t, 1H, J ) 6.7), 3.42 (t, 2H, J ) 1H), 3.96 (t, 2H, J ) 4.9); IR (KBr) 1682, 1620, 1565, 1410,
5.1), 3.36-3.23 (m, 2H), 2.55 (t, 2H, J ) 6.6), 1.83-1.67 (m, 1325; UV λmax (MeOH) 270 nm; MS m/z (relative intensity)
2H); 13C NMR (DMSO-d6) δ 150.0 (s), 132.9 (s), 113.7 (s), 73.4 232 (M+ + 1, 100). HRMS calcd for C11H14N5O (MH+)
(d), 69.4 (t), 60.7 (t), 38.4 (t), 37.8 (t); IR (KBr) 2812, 1693, 232.1199, found 232.1198.
1560, 1166, 1010 cm-1; MS m/z (relative intensity) 201 (M+ + Monobromodispacamide (2b). To a stirred solution of
1, 40), 139 (15), 97 (100); HRMS calcd for C8H17N4O2 (MH+) 14 (0.30 g, 1.9 mmol) in 5 mL of DMF under argon was added
201.1353, found 201.1351. 4-bromo-2-(trichloroacetyl)pyrrole22 (0.67 g, 2.3 mmol) at rt.
3-Amino-1-(2-aminoimidazol-4-yl)prop-1-ene (3) and After 72 h, the reaction mixture was diluted with ether and
2-Amino-5-(3-aminopropyl)-2-imidazolin-4-one (13). A decanted (2 × 100 mL). The resulting residue was purified
solution of 9 (1.5 g, 5.5 mmol) in 10 mL of methanol was added by flash chromatography (CH2Cl2/MeOH saturated with NH3
to 10 mL of m-xylene and heated at 135 °C for 3 h without a 8:2) to give 2b as a white solid (0.53 g, 65%). 2b (free base):
condenser. During this time, the methanol evaporated. After 1H NMR (CD OD) δ 6.90 (d, 1H, J ) 1.5), 6.75 (d, 1H, J )
3
the solution was cooled to rt, the xylene was decanted and the 1.5), 5.73 (t, 1H, J ) 7.8), 3.43 (t, 2H, J ) 6.9), 2.49 (dt, 2H, J
Synthesis of C11N5 Marine Alkaloids J. Org. Chem., Vol. 63, No. 4, 1998 1253

) 7.8, 6.9); 13C NMR (CD3OD) δ 179.0 (s), 168.0 (s), 162.7 (s), Addition of concentrated HCl to a methanol solution of the
137.0 (s), 127.5 (s), 122.8 (d), 113.3 (d), 111.6 (d), 97.5 (s), 39.5 free base and concentration in vacuo gave 1a‚HCl and 17‚-
(t), 28.6 (t); IR (KBr) 3133, 2767, 1633, 1567, 1328 cm-1; UV HCl. 1a‚HCl: 1H NMR (DMSO-d6) δ 12.78 (bs, 1H), 12.48
λmax (MeOH) 250 and 270(sh) nm; MS m/z (relative intensity) (bs, 1H), 11.85 (bs, 1H), 8.55 (t, 1H, J ) 4.9), 7.49 (bs, 2H),
326 (M+, 100). Anal. Calcd for C11H12BrN5O2: C, 40.51; H, 6.99 (d, 1H, J ) 2.9), 6.91 (s, 1H), 6.21 (d, 1H, J ) 16.1), 6.13
3.71; N, 21.47. Found: C, 40.49; H, 3.72; N, 21.40. 2b‚HCl: (dt, 1H, J ) 16.1, 4.9), 3.95 (t, 2H, J ) 4.9); IR (KBr) 3290,
1
H NMR (CD3OD) δ 6.91 (d, 1H, J ) 1.5), 6.77 (d, 1H, J ) 3160, 1685, 1564 cm-1; UV λmax (MeOH) 275 nm; MS m/z
1.5), 6.16 (t, 1H, J ) 8.0), 3.48 (t, 2H, J ) 6.7), 2.6 (dt, 2H, J (relative intensity) 394 (M+ + 5, 50), 392 (M+ + 3, 100), 390
) 8.0, 6.7); 13C NMR (CD3OD) δ 163.8 (s), 162.8 (s), 157.1 (s), (M+ + 1, 50). 17‚HCl: 1H NMR (DMSO-d6) δ 12.73 (bs, 1H),
133.0 (s), 130.5 (s), 122.9 (d), 119.2 (d), 113.4 (d), 97.5 (s), 38.9 12.28 (bs, 1H), 9.76 (bs, 1H), 9.03 (br, 1H), 8.87 (br, 1H), 8.29
(t), 28.7 (t); UV λmax(MeOH) 232 and 272 nm. Anal. Calcd (t, 1H, J ) 6.6), 6.93 (bs, 1H), 4.32 (t, 1H, J ) 6.1), 3.21 (q,
for C11H12BrN5O2‚HCl: C, 36.44; H, 3.61; N, 19.31. Found: 2H, J ) 6.6), 1.82-1.45 (m, 4H); MS m/z (relative intensity)
C, 36.40; H, 3.68; N, 19.28. 410 (M+ + 5, 50), 408 (M+ + 3, 100), 406 (M+ + 1, 50); HRMS
Dihydrooroidin (15). To a stirred solution of 8 (free base, calcd for C11H14N5O2Br2 (MH+) 405.9513, found 405.9510.
0.66 g, 4.7 mmol) in 5 mL of DMF at rt was added 4,5-dibromo- Dispacamide (2a). Method A. To a stirred solution of
2-(trichloroacetyl)pyrrole24 (1.9 g, 5.2 mmol). The mixture was 15 (0.10 g, 0.23 mmol) in 1 mL of DMSO at rt was added
stirred for 1 d and diluted with ether and decanted (3 × 75 bromine (13 µL, 0.23 mmol). After 1 h, the reaction mixture
mL). The resulting residue was purified by flash chromatog- was diluted with ether and decanted (3 × 50 mL). The
raphy (CH2Cl2/MeOH saturated with NH3 8:2) to afford 15 as resulting residue was then purified by flash chromatography
the free base. Addition of concentrated HCl to a methanol (CH2Cl2:MeOH saturated with NH3 8:2) to give 2a as a white
solution of the free base and concentration in vacuo gave 15 solid (56 mg, 60%). Method B. To a stirred solution of 14
as a white solid (1.3 g, 65%). 15: 1H NMR (DMSO-d6) δ 12.76 (0.32 g, 2.1 mmol) in DMF under argon at rt was added 4,5-
(s, 1H), 12.07 (s, 1H), 11.60 (s, 1H), 8.35 (t, 1H, J ) 5.7), 7.33 dibromo-2-(trichloroacetyl)pyrrole (0.93 g, 2.5 mmol). After 72
(s, 2H), 6.95 (d, 1H, J ) 2.7), 6.61 (s, 1H), 3.21 (q, 2H, J ) h, the reaction mixture was diluted with ether and decanted
5.9), 2.44 (t, 2H, J ) 7.3), 1.77-1.70 (m, 2H); 13C NMR (D2O) (2 × 100 mL). The resulting residue was purified by flash
δ 162.0 (s), 147.2 (s), 127.7 (s), 127.3 (s), 114.3 (d), 109.5 (d), chromatography (CH2Cl2/MeOH saturated with NH3 8:2) to
106.5 (s), 99.8 (s), 39.5 (t), 27.9 (t), 22.5 (t); MS m/z (relative give 2a as a white solid (0.69 g, 60%). 1H NMR (CD3OD) δ
intensity) 394 (M+ + 5, 50), 392 (M+ + 3, 100), 390 (M+ + 1, 6.78 (s, 1H), 5.72 (t, 1H, J ) 7.9), 3.42 (t, 2H, J ) 6.9), 2.50
50). Anal. Calcd for C11H13Br2N5O‚HCl: C, 30.90; H, 3.30; (dt, 2H, J ) 7.9, 6.9); 13C NMR (CD3OD) δ 178.8 (s), 168.0 (s),
N, 16.38. Found: C, 30.80; H, 3.48; N, 16.12. 161.9 (s), 137.1 (s), 128.8 (s), 114.3 (d), 111.6 (d), 106.1 (s),
trans-4,5-Dihydro-4,5-dimethoxydihydrooroidin (16). 99.9 (s), 39.5 (t), 28.6 (t); UV λmax (MeOH) 250 and 274 nm;
To a stirred solution of dihydrooroidin hydrochloride (15) (0.40 MS m/z (relative intensity) 405 (M+, 100), 325 (30). Anal.
g, 0.94 mmol) in 15 mL of methanol at -78 °C was added Calcd for C11H11Br2N5O2: C, 32.62; H, 2.74; N, 17.29. Found:
t-BuOK (0.0734 g, 6.5 mmol) followed by bromine (53 µL, 1.0 C, 32.57; H, 2.72; N, 17.30. 2a‚HCl: mp >215 °C; 1H NMR
mmol). After 10 min, the reaction mixture was quenched with (CD3OD) δ 6.82 (s, 1H), 6.15 (t, 1H, J ) 8.0), 3.48 (t, 2H, J )
CH3SO3H (0.45 g, 4.7 mmol), warmed to rt, and filtered. 6.9), 2.62 (dt, 2H, J ) 8.0, 6.9); 13C NMR (CD3OD) δ 163.8 (s),
Concentration of the filtrate gave a residue that was purified 161.9 (s), 156.4 (s), 128.6 (s), 119.2 (d), 114.4 (d), 106.3 (s),
by flash chromatography (CH2Cl2/MeOH 8:2) to give 16 as a 99.9 (s), 38.9 (t), 28.7 (t); IR (KBr) 3111, 2722, 1700, 1556, 1522
yellow solid (0.37 g, 75%): 1H NMR (DMSO-d6) δ 12.67 (s, 1H), cm-1; UV λmax (MeOH) 224 and 278 nm. Anal. Calcd for
9.42 (s, 1H), 9.36 (s, 1H), 8.20 (t, 1H, J ) 5.5), 8.13 (bs, 2H), C11H11Br2N5O2‚HCl: C, 29.92; H, 2.74; N, 15.86. Found: C,
6.92 (s, 1H), 4.71 (s, 1H), 3.32 (s, 3H), 3.24-3.16 (m, 2H), 3.11 29.88; H, 2.78; N, 15.78.
(s, 3H), 1.90-1.50 (m, 4H); 13C NMR (DMSO-d6) δ 158.8 (s),
157.6 (s), 128.2 (s), 112.4 (d), 104.4 (s), 97.7 (s), 94.7 (s), 90.1 Acknowledgment. We thank Dr. John Decatur for
(d), 55.8 (q), 48.9 (q), 38.4 (t), 27.7 (t), 23.9 (t); IR (KBr) 2941, his assistance in performing the NOESY experiment.
1693, 1567, 1416, 1241, cm-1 MS m/z (relative intensity) 454 Financial support from the National Institutes of Health
(M+ + 5, 30), 454 (M+ + 3, 60), 454 (M+ + 1, 30), 422 (40), 390 (GM 50929), National Science Foundation (Young In-
(20), 307 (100), 289 (60). HRMS calcd for C13H20N5O3Br2 (MH+)
vestigator Award to D.A.H.), American Chemical Society
451.9928, found 451.9926.
Petroleum Research Fund, and Kanagawa Academy of
Oroidin (1a) and Dihydrodispacamide (17). A solution
of 16 (0.30 g, 0.56 mmol) in 10 mL of methanol was added to
Science and Technology (KAST) is gratefully acknowl-
10 mL of m-xylene, and the whole was heated at 135 °C for 3 edged.
h without a condenser. During this time, the methanol
evaporated. After cooling, the xylene was decanted and the Supporting Information Available: 1H and 13C NMR
residue washed with ether (3 × 100 mL) and acetone (2 × 100 spectra for compounds 1a, 1c, and 2-17 (44 pages). This
mL). Purification of the resulting residue by flash chroma- material is contained in libraries on microfiche, immediately
tography (CH2Cl2/MeOH saturated with NH3 8:2) gave oroidin follows this article in the microfilm version of the journal, and
(1a) (0.10 g, 48%) and dihydrodispacamide (17) (0.69 g, 30%). can be ordered from the ACS; see any current masthead page
for ordering information.
(24) Bailey, D. M.; Johnson, R. E. J. Med. Chem. 1973, 16, 1300. JO9718298