A Practical Synthesis of (Z)-Debromohymenialdisine

Full text of DOI:10.1021/jo991277o

610
J . Org. Chem. 2000, 65, 610-611
Sch em e 1a
A P r a ctica l Syn th esis of
(Z)-Debr om oh ym en ia ld isin e
Ana Carolina Barrios Sosa, Kenichi Yakushijin, and
David A. Horne*
Department of Chemistry, Oregon State University,
Corvallis, Oregon 97331
Received August 11, 1999
(Z)-Debromohymenialdisine [(Z)-DBH (1)], first isolated1a
in 1980 from the caribbean sponge Phakellia flabellata,
is a biologically significant member of the “oroidin” family
of sponge metabolites.2 Its corresponding (E) isomer is
also known, having been isolated in 1996 from the
common shallow-water sponge Stylotella aurantium.3
Recently, a number of reports centering on (Z)-DBH and
related analogue hymenialdisine (2)1b have appeared
describing the modulation of protein kinase C and the
proinflammatory transcription factor, nuclear factor κB
(NFκB).4 NFκB is believed to be involved in the regulated
gene expression of the inflammatory enzyme, cyclooxy-
genase (COX-II).4b Together, these proteins play impor-
tant roles as mediators of inflammation associated with
arthritis. In addition, DBH has been shown to slow joint
deterioration and cartilage degradation associated with
osteoarthritis in animal models and is currently under
development as a promising new drug candidate.5 At
present, there is no known pharmaceutical agent for the
treatment of osteoarthritis, which is the most common
manifestation of arthritic disease. Ongoing investigations
have reached the point where a practical synthesis of
DBH is needed for preclinical/clinical trials. Only limited
supplies are available from natural sources. To address
this problem, we report6 a practical synthetic approach
to (Z)-DBH (1) as well as the first synthesis of (Z)-3-
a
Key: (a) ref 9, 90%; (b) CH3SO3H, 45 °C, 4 d then 2-AI, 45 °C,
4 d, 60%; (c) 2 equiv Br2, 23 °C, HOAc/NaOAc, 85%; (d) H2, 10%
Pd/C, NaOAc, 75%.
bromohymenialdisine (3), a sponge metabolite from
Stylissa carteri.7
(Z)-DBH (1) has been the subject of two prior synthe-
ses.8,9 The synthesis reported by our group9 in 1997 relies
on the preparation of hymenin (7) which serves as the
basis for the present investigation. Initial modifications
to the original hymenin synthesis focused on developing
a one-pot conversion of acetal 59 to hymenin (7) from
readily available materials, namely, amine 410 and 4,5-
dibromopyrrol-2-yl trichloromethyl ketone11 (Scheme 1).
This one-pot, two-step procedure commences with an
intramolecular ring closure to afford intermediate 6
followed by an acid-facilitated coupling of 2-aminoimi-
dazole (2-AI). This modification circumvents the depro-
tection and isolation of the corresponding aldehyde as
well as the isolation of pyrroloazepinone 6, which was
done in the original synthesis. The overall transformation
can be readily accomplished on a multigram scale in
which racemic hymenin is produced in 60% overall yield.
Next, a method for installing the R,â unsaturated
aminoimidazolidinone functionality of (Z)-DBH was pur-
sued which required a two-fold oxidation of hymenin (7).
* Corresponding author. Phone: (541)-737-8180. Fax: (541)-737-
2062. E-mail: horned@ucs.orst.edu.
(1) (a)Sharma, G. M.; Buyer, J . S.; Pomerantz, M. W. J . Chem. Soc.,
Chem. Commun. 1980, 435-436. (b) Cimino, G.; De Rosa, S.; De
Stefano, S.; Mazzarella, L.; Puliti, R.; Sodano, G. Tetrahedron Lett.
1982, 23, 767-768.
(2) Faulkner, D. J . Nat. Prod. Rep. 1999, 16, 155-198 and earlier
reports in this series.
(3) Williams, D. H.; Faulkner, D. J . Nat. Prod. Lett. 1996, 9, 57-
64.
(4) (a) Breton, J . J .; Chabot-Fletcher, M. J . Pharmacol. Exp. Ther.
1997, 282, 459-466. (b) Roshak, A.; J ackson, J . R.; Chabot-Fletcher,
M.; Marshall, L. A. J . Pharmacol. Exp. Ther. 1997, 283, 955-961. (c)
SmithKline Beecham Corporation, Protein Kinase C Inhibitor, U.S.
Patent 5,616,577, 1997. (d) SmithKline Beecham Corporation, Medica-
ment, U.S. Patent 5,565,448, 1996.
(5) (a) OsteoArthritis Sciences, Inc. The Reagents of the University
of California. Use of Debromohymenialdisine for Treating Osteoar-
thritis. U.S. Patent 5,591,740, 1997. (b) Vaslos, G.; DiBenedetto, P.;
Gagne, T.; Tubo, R.; McPherson, J . Z-Debromohymenialdisine Blocks
IL-1-Induced Gene Expression In Chondrocytes in Vitro. Presented at
The American College of Rheumatology, 63rd Annual Scientific Meet-
ing, Boston, MA, 1999. (c) Huibregste, B.; Chappell-Afonso, K.; Dimke,
D.; J ohnson, J .; McPherson, J .; Oldham, C.; Palmer, J .; Tubo, R.;
Wickham, A.; Vasios, G. Z-Debromohymenialdisine Shows Disease-
Modifying Activity In Animal Model Of Osteoarthritis. Presented at
The American College of Rheumatology, 63rd Annual Scientific Meet-
ing, Boston, MA, 1999.
(7) Supriyono, A.; Schwarz, B.; Wray, V.; Witte, L.; Mu¨ller, W. E.
G.; van Soest, R.; Sumaryono, W.; Proksch, P. Z. Z. Naturforsch. 1995,
50c, 669-674.
(8) Annoura, H.; Tatsuoka, T. Tetrahedron Lett. 1995, 36, 413-416.
(9) Xu, Y-z.; Yakushijin, K.; Horne, D. A. J . Org. Chem. 1997, 62,
456-464.
(6) (a) Oregon State University. Method for Making Debromohy-
menialdisine and Analogues Thereof. Patent application, 1999. (b)
Columbia University. Bicyclic Aminoimidazoles. U.S. Patent 5,834,-
609, 1998.
(10) Gribble, G. W.; Switzer, F. L. Synth. Commun. 1987, 17, 377-
383.
(11) Bailey, D. M.; J ohnson, R. E. J . Med. Chem. 1973, 16, 1300-
1302.
10.1021/jo991277o CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/23/1999

Notes
J . Org. Chem., Vol. 65, No. 2, 2000 611
purification. 1H NMR and 13C NMR spectra were recorded on
300 and 400 MHz spectrometers.
While a number of reagents can be envisaged to ac-
complish this transformation, treatment of hymenin (7)
with 2 equiv of bromine in an acetic acid/sodium acetate
system cleanly provided the desired natural product, (Z)-
3-bromohymenialdisine (3), in good yield. Spectral data
of synthetic 3 were in satisfactory agreement with those
reported for the natural material.7 No evidence of forma-
tion of the less thermodynamically stable E isomer was
observed.12 Comparison of 13C chemical shift values of 3
for the free base (C12 ) 176.7, C14 ) 166.7 ppm) and
HCl salt (C12 ) 163.2, C14 ) 154.1 ppm) revealed a
significant upfield shift upon protonation of the guanidino
and imidazolidinone (CdO) carbons. This is consistent
with earlier studies reported for neutral and protonated
glycocyamidines.13 Although tautomerism of (Z)-DBH has
been reported,3 we were unable to detect tautomerism
of the dibromo analogue (Z)-3 by 1H and 13C NMR
spectroscopy upon dilution of the free base. Finally,
reduction of the brominated pyrrole moiety of 3 was
achieved with high chemoselectivity over the C10-C11
double bond using hydrogen and Pd/C to afford good
yields of (Z)-DBH (1). The conjugative nature and steric
hindrance of this double bond is believed to contribute
to the selectivity of this reduction.
Efforts were also pursued in the oxidation of 2,3-
didebromohymenin (7, R ) H)9 to (Z)-DBH (1). This
approach met with limited success. Reagents such as
Cu(OAc)2 and base-catalyzed air oxidations produced (Z)-
DBH but in a less efficient manner.
In summary, a practical synthesis of (Z)-DBH (1) has
been accomplished in four steps from readily available
starting materials (34% overall yield from amine 4).
Compared to the original (Z)-DBH synthesis, which
produced low yielding mixtures of (Z)-DBH (1) and
hymenialdisine (2), the present route represents a sig-
nificant improvement in both efficiency and practicality.
Noteworthy is the fact that the synthesis does not require
the use of protecting groups on any of the five nitrogen
functionalities or rely on chromatographic techniques for
purification. The route should be directly amenable to
scale-up processes.
(()-Hym en in (7). A solution of acetal 5 (75.5 g, 0.2 mol) was
heated in methanesulfonic acid (400 mL) at 45 °C for 4 d. Next,
2-aminoimidazole‚1/2H2SO4 (31.2 g, 0.24 mol) was added and
the reaction was stirred an additional 4 d at 45 °C. The reaction
was diluted with at least 10 volumes of ether and decanted (2×)
to afford a sticky residue. Trituration from ethanol afforded
hymenin (7) as the methanesulfonic salt9 (60 g, 60% yield) which
was used directly in the next reaction.
(Z)-3-Br om oh ym en ia ld isin e (3). To a stirred solution of
hymenin (7)‚CH3SO3H (7.5 g, 15 mmol) and sodium acetate (6.3
g, 75 mmol) in acetic acid (240 mL) was added bromine (1.6 mL,
30 mmol) at 23 °C. The reaction was stirred for 1 h, concentrated,
and azeotroped with hot ethanol several times to afford a solid.
The solid was extracted with hot ethanol, decolorized with
activated charcoal, and filtered. Concentration of the filtrate
afforded a solid which was rinsed with a minimum amount of
water to remove any remaining inorganic salts. The resulting
material was dried under vacuum to afford 3 (5.13 g, 85% yield)
as a colorless solid. 1H NMR (DMSO-d6) δ 3.15 (bs, 4H), 6.58
(bs, 1H, exch. D2O), 7.88 (bs, 2H, exch. D2O), 8.80 (bs, 1H, exch.
D2O), 13.09 (bs, 1H, exch. D2O); 13C NMR (DMSO-d6) δ 33.7 (t),
38.6 (t), 98.1 (s), 106.4 (s), 114.1 (s), 123.3 (s), 126.2 (s), 130.2
(s), 163.8 (s), 166.9 (s), 176.7 (s). IR (KBr) 3343 (br), 1697, 1657,
1626, 1280 cm-1. HRFABMS calcd for C11H10O2N579Br2 (MH+)
401.9202, found 401.9201. 3‚HCl: 1H NMR (DMSO-d6) δ 3.25
(bs, 4H), 8.07 (bs, 1H), 8.50 (bs, 1H), 9.30 (bs, 2H), 10.92 (bs,
1H), 13.4 (bs, 1H). 13C NMR (DMSO-d6) δ 35.2 (t), 38.6 (t), 98.5
(s), 107.4 (s), 120.7 (s), 123.7 (s), 125.9 (s), 127.3 (s), 154.1 (s),
162.5 (s), 163.3 (s). IR (film) 3273 (br), 1749, 1706, 1641, 1282
cm-1
.
(Z)-Debr om oh ym en ia ld isin e (1). A mixture of (Z)-3-bro-
mohymenialdisine (3)‚HCl (3.2 g, 8.0 mmol) in methanol (200
mL) containing 10% Pd/C (1.0 g) and sodium acetate (3.2 g, 40
mmol) was placed under a balloon of hydrogen. After 10 h, the
reaction mixture was filtered through Celite and the resulting
filtrate was concentrated and azeotroped with ethanol several
times to afford a yellow solid. The solid was washed with a
minimal amount of water to remove inorganic salts. The solid
was dissolved in hot methanol, decolorized with activated
charcoal, and filtered. Upon concentration of the filtrate, (Z)-
DBH‚CH3OH crystallized from solution as light-yellow crystals
(1.6 g, 75% yield).
Ack n ow led gm en t . We thank Professor Peter
Proksch at J ulius-von-Sachs-Institut fu¨r Biowissen-
schaften for providing us with spectroscopic data for (E)-
and (Z)-3-bromohymenialdisine. Financial support from
the National Institute of Health (GM50929) is gratefully
acknowledged.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, materials were
obtained from commercial suppliers and used without further
(12) (a) Inaba, K.; Sato, H.; Tsuda, M.; Kobayashi, J . J . Nat. Prod.
1998, 61, 693-695. (b) Eder, C.; Proksch, P.; Wray, V.; Steube, K.;
Bringmann, G.; van Soest, R. W. M.; Sudarsono; Ferdinandus, E.;
Pattisina, L. A.; Wiryowidagdo, S.; Moka, W. J . Nat. Prod. 1999, 62,
184-187.
(13) Olofson, A.; Yakushijin, K.; Horne, D. A. J . Org. Chem. 1998,
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Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of the free base of the synthetic (Z)-3-bromohy-
menialdisine (3). This material is available free of charge via
the Internet at http://pubs.acs.org.
J O991277O