Synthesis of Mauritiamine

Full text of DOI:10.1021/jo9715682

7
918
J . Org. Chem. 1997, 62, 7918-7919
Syn th esis of Ma u r itia m in e†
2
sp carbon appendages is certainly the most challenging
aspect of the research. The most efficient approach to
this construction was envisaged to follow a biomimetic
pathway involving the heterodimerization of intermedi-
ates A and B. In principle, these intermediates could
Anne Olofson, Kenichi Yakushijin, and
David A. Horne*
Department of Chemistry, Columbia University,
New York, New York 10027
Received August 22, 1997
Herein, we describe a synthesis of the marine alkaloid
mauritiamine (1) in which the key step centers on the
oxidative dimerization of a pivotal 2-aminoimidazole
derivative in a manner that may prove relevant to its
biosynthesis.
be derived from oroidin (2). The latter derivative, B (R′
) H), is simply the enol tautomer of dispacamide (3).
From previous work in our laboratory on the synthesis
Marine sponges produce a broad spectrum of structur-
5
ally diverse and pharmacologically interesting class of
of hymenin, stevensine, and hymenialdisines, the gly-
1
C
11
N
5
and dimerically related, secondary metabolites.
cocyamidine functionality found in secondary metabolites
such as 3 can be derived readily from 2-aminoimidazoles.
Therefore, the initial phase of the synthesis focused on
the preparation of olefin 7 (3-amino-1-(2-aminoimidazol-
4-yl)prop-1-ene) from its dihydro derivative 5 (Scheme
1).
Mauritiamine (1), isolated as a racemate from Agelas
mauritiana, is a recently discovered member of this
2
alkaloid group that possesses potent antifouling activity.
The structure of 1 was determined by spectral analysis.
Closely related to 1 are the sponge metabolites oroidin
3
4
(
2) and dispacamide (3). Both oroidin (2) and dispaca-
Starting with ornithine methyl ester (4), transforma-
tion to the corresponding AI derivative 5‚2HCl was
mide (3) have been isolated from a number of different
Agelas species, including A. mauritiana. These metabo-
lites can be considered hypothetical progenitors in the
biosynthesis of 1.
6
accomplished using the method of Lancini et al. While
side chain oxidations of alkyl derivatives of heteroaro-
matic compounds by halogens are known in aprotic
7
solvents, AI derivatives, however, are generally insoluble
in such solvents. The development of an alternative
approach to install the olefin functionality found in
aminoimidazoles 1 and 2 was required. When 5 was
treated with N-chlorosuccinimide (1 equiv) in methanol
(
23 °C, 1 h), conversion to the imidazoline adduct, 6‚2HCl,
8,9
was achieved in 83% yield.
This dialkoxy cyclic guani-
dine adduct10 was anticipated to serve as a useful
precursor for the introduction of the alkene functionality
upon rearrangement. Few, related examples in the
literature involving the addition to the 4,5-double bond
of AIs can be seen in the intramolecular oxidative cyclo-
addition used for the biomimetic synthesis of dibro-
mophakellin11 and the intermolecular [2 + 4] cycloaddi-
1
2
tion to afford tetrahydropurine derivatives that we have
reported previously. The trans stereochemical assign-
(
5) Xu, Y.-z.; Yakushijin, K.; Horne, D. A. J . Org. Chem. 1997, 62,
56.
6) (a) Lancini, G. C.; Lazzari, E. J . Heterocycl. Chem. 1966, 3, 152.
b) Lancini, G. C.; Lazzari, E.; Arioli, V.; Bellani, P. J . Med. Chem.
969, 12, 775.
7) (a) Baciocchi, E.; Clementi, S.; Sebastiani, G. V. J . Chem. Soc.,
4
(
(
1
(
Perkin Trans. 2 1976, 266. (b) Angelini, G.; Giancaspro, C.; Illuminati,
G.; Sleiter, G. J . Org. Chem. 1980, 45, 1786.
(8) In previous unpublished investigations from the B u¨ chi group on
the synthesis of saxitoxin, 4,5-dimethoxyimidazolines were obtained
from the reaction of 4-acyl-2-aminoimidazoles with NBS in methanol.
Dupriest, M. Ph.D. Thesis, Massachusetts Institute of Technology,
1982.
Synthetically, the creation of the R,R-disubstituted
-aminoimidazolinone unit 1 bearing the two different
2
(9) In the presence of base, 5 (free base) produced compound I as
the major product.
*
To whom correspondence should be addressed. Tel.: (212) 854-
8
634. Fax: (212) 932-1289. E-mail: horne@chem.columbia.edu.
Dedicated to Professor Gilbert Stork on the occasion of his 75th
†
birthday.
(1) For reviews, see: (a) Kobayashi, J .; Ishibashi, M. In The
Alkaloids: Chemistry and Pharmacology; Brossi, A., Ed.; Academic
Press: New York, 1992; Vol. 41, pp 41-124. (b) Faulkner, D. J . Nat.
Prod. Rep. 1996, 13, 75. (c) Berlinck, R. G. S. Nat. Prod. Rep. 1996,
(10) A limited number of related dihydroxy adducts has been
reported from the reaction of guanidines with glyoxal and R-dike-
tones: (a) Nishimura, T.; Nakano, K.; Shibamoto, S.; Kitajima, K. J .
Heterocycl. Chem. 1975, 12, 471. (b) Nishimura, T.; Kitajima, K. J .
Org. Chem. 1976, 41, 1590. (c) Nishimura, T.; Kitajima, K. J . Org.
Chem. 1979, 44, 818. (d) McClelland, R. A.; Panicucci, R.; Rauth, A.
M. J . Am. Chem. Soc. 1987, 109, 4308.
(11) Foley, L. H.; B u¨ chi, G. J . Am. Chem. Soc. 1982, 104, 1776.
(12) Xu, Y.-z.; Yakushijin, K.; Horne, D. A. Tetrahedron Lett. 1993,
34, 6981.
1
3, 377.
(2) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. J . Nat. Prod.
1
996, 59, 501.
(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.
(4) Cafieri, F.; Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O.
Tetrahedron Lett. 1996, 37, 3587.
S0022-3263(97)01568-5 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 23, 1997 7919
Sch em e 1a
a
Key: (a) Na/Hg, H2NCN, 70%; (b) NCS, MeOH, 83%; (c) MeOH/xylene, 135 °C, 7 (60%); (d) NCS, TFA, rt; (e) MeOH/xylene, 135 °C,
(42%), 9 (12%), 10 (23%); (f) 4,5-dibromo-2-(trichloroacetyl)pyrrole, DMF, rt, 65%.
8
ment of the methoxyl groups of 6 was made based on 1-D
spectral data for synthetic 1 were in satisfactory agree-
ment with those reported for the natural material.
selective NOESY analysis.13
2,19
Rearrangement of 6‚2HCl was investigated thermally
The exact process by which 7 undergoes oxidative
dimerization is unclear at this time. In TFA, oxidation
of 7 by NCS is believed to produce intermediates C and
D. Intermediate C arises from 1,2-addition of Cl and
3 2
CF CO H while 1,4-addition followed by elimination of
by heating in a 1:1 mixture of methanol/m-xylene. After
3
h at 135 °C (during which MeOH was allowed to
+
evaporate), 6 was converted to vinyl derivative 7 in 60%
yield.1
4,15
Olefin 7 is also a sponge metabolite isolated
from Axinellidae sp.16 Next, the oxidative dimerization
of this metabolite was examined. Initially, olefin 7‚2HCl
was exposed to NCS (1 equiv, 23 °C, 30 min) in TFA.
Removal of TFA afforded a residue that was heated in a
solution of MeOH/m-xylene while allowing MeOH to
evaporate. This afforded imidazolinone 8 (42%), chloro-
hydrin 9 (12%), and dimer 10 (23%) after chromatogra-
HCl affords D. Upon the addition of MeOH/m-xylene and
heating, C is converted to intermediate A (R ) H, X )
3 2
Cl) by elimination of CF CO H and to chlorohydrin 9 by
methanolysis of the trifluoroacetyl group. Nucleophilic
addition to intermediate A upon methanolysis of the
trifluoroacetyl moiety of D followed by elimination of HCl
produces dimer 10.
Starting from ornithine methyl ester (4), the synthesis
of mauritiamine (1) required only five steps and no
protecting groups. The key transformation is the oxida-
tive dimerization of vinyl AI 7, which notably lacks the
pyrrole carboxamide group. Perhaps a similar pathway
is operative in the biogenesis of 1.
1
7
phy over silica.
Acylation of 10 with 4,5-dibromo-2-
trichloroacetylpyrrole18 produced mauritiamine (1). The
(13) Irradiation of the C5 ring proton singlet at 4.73 ppm showed
NOE’s to both methoxyl groups (3.35 and 3.15 ppm), whereas no
enhancement was observed to the methylene protons of the amino-
propyl side chain.
(
14) Initially, the rearrangement was attempted in refluxing MeOH.
Ack n ow led gm en t. We are grateful to Professor
The major product obtained under these conditions is compound II.
Nobuhiro Fusetani and Dr. Sachiko Tsukamoto for
1
13
sending us the H and C NMR spectra of 1 and for
their correspondences. We thank Professors Koji Na-
kanishi and Gilbert Stork for helpful discussions. We
also thank Dr. J ohn Decatur for his assistance in
performing the NOESY experiment. Financial support
from the National Institutes of Health (R01-GM50929),
National Science Foundation (Young Investigator Award
to D.A.H.), American Chemical Society Petroleum Re-
search Fund, and Kanagawa Academy of Science and
Technology (KAST) is gratefully acknowledged.
(
15) All previously reported syntheses of vinyl AI derivatives related
to 2 and 7 utilized Wittig chemistry in creating the olefinic double bond
and relied heavily on the use of numerous protecting groups. See: (a)
de Nanteuil, G.; Ahond, A.; Poupat, C.; Thoison, O.; Potier, P. Bull.
Soc. Chim. Fr. 1986, 813. (b) Daninos, S.; AlMourabit, A.; Ahond, A.;
Zurita, M. B.; Poupat, C.; Potier, P. Bull Soc. Chim. Fr. 1994, 131,
5
90. (c) Webber, S. E.; Little, T. L. J . Org. Chem. 1994, 59, 7299.
16) Wright, A. E.; Chiles, S. A.; Cross, S. S. J . Nat. Prod. 1991, 54,
684.
17) Compound 9 was isolated as a 9:1 mixture of erythro:threo
diastereomers. The threo isomer, (2S,3S)-2-chloro-3-hydroxy-3-(2-
aminoimidazol-4-yl)propylamine, is known as girolline, potent
(
1
(
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for compounds 1 and 5-10 (7 pages).
a
antitumor agent isolated from the marine sponge Pseudaxinissa
cantharella. (a) Ahond, A.; Bedoya-Zurita, M.; Colin, M.; Fizames, C.;
Laboute, P.; Lavelle, F.; Laurent, D.; Poupat, C.; Pusset, J .; Pusset,
M.; Thoison, O.; Potier, P. C. R. Seances Acad. Sci. Paris, Ser. 2 1988,
J O9715682
(19) The 13C chemical shift values reported for mauritiamine (1) in
ref 2 correspond to a neutral glycocyamidine species that was found
to be unstable (Fusetani, N. Personal communication). We have
observed significant differences in C chemical shifts between neutral
and protonated glycocyamidine derivatives, which will be the subject
of a future publication.
3
07, 145. (b) Bedoya-Surita, M.; Ahond, A.; Poupat, C.; Potier, P.
Tetrahedron 1989, 45, 6713. (c) Chiaroni, A.; Riche, C.; Ahond, A.;
Poupat, C.; Pusset, M.; Potier, P. C. R. Seances Acad. Sci. Paris Ser.
1
3
2
1991, 312, 49.
18) Bailey, D. M.; J ohnson, R. E. J . Med. Chem. 1973, 16, 1300.
(