Enantioselective synthesis of reported hippospongic acid A

Article abstract of DOI:10.1055/s-1998-1781

Total synthesis of hippospongic acid A, an inhibitor of gastrulation of starfish embryos, has been studied. A compound having the structure assigned to hippospongic acid A was synthesized enantioselectively. The spectral data of the synthetic compound were slightly different from those of the natural product and an alternative structure was proposed for the natural product.

Full text of DOI:10.1055/s-1998-1781

July 1998
SYNLETT
729
Enantioselective Synthesis of Reported Hippospongic Acid A
Hideaki Hioki, Hidenori Ooi, Yumi Mimura, Suzuyo Yoshio, and Mitsuaki Kodama*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
E-mail: QWH02611@niftyserve.or.jp
Received 14 April 1998
Abstract
: Total synthesis of hippospongic acid A, an inhibitor of
In this communication we describe the enantioselective synthesis of a
compound having the structure assigned to hippospongic acid A.
Furthermore, we propose an alternative structure for the natural product
on the basis of a comparison of the spectral data of the synthetic and
natural compounds.
gastrulation of starfish embryos, has been studied. A compound having
the structure assigned to hippospongic acid A was synthesized
enantioselectively. The spectral data of the synthetic compound were
slightly different from those of the natural product and an alternative
structure was proposed for the natural product.
Our synthetic strategy consists of a coupling of a geranylgeranyl unit
B
A
( ) and a hydropyran ring unit ( ), the latter of which is synthesized
3
enantioselectively from myrcene ( ) using baker's yeast reduction as the
1
Hippospongic acid A ( ) isolated from a marine sponge, Hippospongia
chirality induction method (Scheme 1) .
sp., is an attractive natural product because it exhibits potent inhibitory
activity in gastrulation of starfish embryos. In addition, a biogenetically
1
irregular triterpene structure (tail-to-tail coupling of geranylgeranyl and
geranyl diphosphates) has been assigned on the basis of spectral
analysis. The absolute stereochemistry has not been determined yet.
2
Rhopaloic acid A ( ) isolated from a marine sponge, Rhopaloeides sp.,
has a related norsesterterpene structure and exhibits potent cytotoxicity
against some human tumor cell lines and inhibitory activity in
2
gastrulation of starfish. From the interests in biological activity and a
new triterpene carbon skeleton, we investigated the total synthesis of
hippospongic acid A.
Scheme 1
A
3
For the synthesis of the hydropyran unit ( ), myrcene ( ) was first
4
converted into α-hydroxyketone in three steps in 36% overall yield
3
4
(Scheme 2). Treatment of with baker's yeast at room temp. yielded
(R)-diol (96% yield) in high enantiomeric purity. After the diol part
4
5
5
was protected as an acetonide,
oxidation in DMF using hematoporphyrin as
endoperoxide thus obtained in good yield was reduced with NaBH at
was subjected to photosensitized
a
sensitizer. The
4
6
5
6
50 °C to give 1,4-diol in 46% yield from . The diol part in was
Figure 1
protected as bisbenzoate and the acetonide group was hydrolyzed. The
7
8
resulting 1,2-diol was then converted into epoxide . Hydrolysis of the
Scheme 2

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LETTERS
SYNLETT
benzoates of 8 with alkali resulted in the concomitant formation of a
hydropyran ring to give 9 (69% from 6). Benzoylation, dehydration
References and Notes
6
(1) Ohta, S.; Uno, M.; Tokumasu, M.; Hiraga, Y.; Ikegami, S.
through mesylate, and epoxidation afforded epoxide 10 as
a
Tetrahedron Lett. 1996, 37, 7765.
diastereomeric mixture (29% for three steps). After the protective group
was changed to p-methoxybenzylether, the oxirane ring was opened
with aluminum triisopropoxide in refluxing toluene to give allylic
alcohol 11 in 60% yield from 10, which was converted into the chloride
12 in three steps (84%). Thus obtained chloride 12 was reacted with the
lithio-anion of geranylgeranyl phenyl sulfide (GG-SPh) in the presence
of DABCO and the resulting coupling product was subjected to
desulfurization using the Bouveault-Blanc conditions and then
deprotection of silylether to yield 13 (61% yield after purification by
(2) Ohta, S.; Uno, M.; Yoshimura, M.; Hiraga, Y.; Ikegami, S.
Tetrahedron Lett. 1996, 37, 2265. For the synthesis of 2, see
Takagi, R.; Sasaoka, A.; Kojima, S.; Ohkata, K. J. Chem. Soc.,
Chem. Commun. 1997, 1887; Snider, B. B.; He, F. Tetrahedron
Lett. 1997, 38, 5453.
(3) Kodama, M.; Minami, H.; Mima, Y.; Fukuyama, Y. Tetrahedron
Lett. 1990, 31, 4025; Kodama, M.; Yoshio, S.; Yamaguchi, S.;
Fukuyama, Y.; Takayanagi, H.; Morinaka, Y.; Usui, S.; Fukazawa,
Y. Tetrahedron Lett. 1993, 34, 8453.
AgNO -impregnated silica-gel chromatography) having the desired
3
23
carbon skeleton. Finally, 13 was converted into (R)-1 ([α]
+47.1°; lit.
D
(4) The absolute configuration of 5 was determined by modified
25
[α]
+37°) in a two step reaction in 69% yield. Thus, we achieved the
D
5
Mosher's method. The optical purity was >98% ee as analyzed by
enantioselective synthesis of a compound corresponding to the reported
GC using chiral Column.
1
13
hippospongic acid A. The H and C NMR spectra of the synthetic
7
(5) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakizawa, H. J. Am. Chem.
Soc. 1991, 113, 4092; Kusumi, T. J. Syn. Org. Chem. Jpn. 1993,
51, 462.
compound were similar to those of the natural product. However, the
multiplet at 2.15 ppm (H-2' ) which appeared in the H NMR spectrum
1
(500 MHz) of the natural product was not observed as a separate signal
in the spectrum (600 MHz) of the synthetic compound. Moreover, the
(6) Various dehydration conditions including SOCl in pyridine,
2
13
C NMR signals observed at 125.0, 28.3, and 25.7 ppm in the spectrum
POCl in pyridine have been examined, but the yields of the
3
of the natural product appeared at 123.5, 27.3 and 26.6 ppm,
respectively, in the synthetic compound. These facts revealed that the
structures of natural product and synthetic compound are quite similar,
desired exomethylene derivative were less than 35% because of
the formation of an unstable product (probably a compound
containing a tetrasubstituted double bond).
1
13
but not identical. Since the C NMR signals described above are
(7) Spectral data of synthetic (R)-1: H NMR (600 MHz, CDCl ) 1.43
3
assignable to C-4', C-2', and C-3', we propose an alternative structure 1'
possessing a normal triterpene carbon skeleton for hippospongic acid A.
Work on confirmation of the new structure by synthesis is currently in
progress.
(1H, m, H-4), 1.60 (12H, s, H -19', H -20', H -21', H -22'), 1.68
3
3
3
3
(3H, s, H -18'), 1.95-2.01 (6H, m, H -6', H -10', H -14'), 2.01-
3
2
2
2
2.12 (11H, m, H-4, H -2', H -3', H -7', H -11', H -15'), 2.31-2.41
2
2
2
2
2
(2H, m, H -5), 3.90 (1H, d, J = 12.6 Hz, H-7), 4.32 (1H, d, J =
2
10.1 Hz, H-3), 4.72 (1H, d, J = 12.6 Hz, H-7), 5.07-5.14 (4H, m,
H-4', H-8', H-12', H-16'), 5.26 (1H, t, J = 7.0 Hz, H-1'), 5.97 (1H,
13
s, H-8), 6.34 (1H, s, H-8); C NMR (150 MHz, CDCl ) 170.1 (C-
3
1), 140.6 (C-2), 135.8, 135.0, 134.9 (C-5', C-9', C-13'), 132.6 (C-
6), 131.2 (C-17'), 127.1 (C-8), 125.0 (C-1'), 124.4, 124.2, 124.2,
123.5 (C-4', C-8', C-12', C-16'), 75.6 (C-3), 67.1 (C-7), 39.7 (C-6',
C-10', C-14'), 33.7 (C-4), 32.9 (C-5), 28.2, 27.3 (C-2', C-3'), 26.8,
26.7, 26.6 (C-7', C-11', C-15'), 25.7 (C-18'), 17.7 (C-22'), 16.1,
16.0, 16.0 (C-19', C-20', C-21').
Figure 2
Acknowledgments We are grateful to Dr. Shinji Ohta, Hiroshima
University, for the spectra of natural hippospongic acid A. This work
was partially supported by a Grant-in-Aid for Scientific Research (No.
08680642) from the Ministry of Education, Science and Culture of
Japan.