Enantioselective Synthesis of Slagenins A-C

Article abstract of DOI:10.1021/ol0268034

(Matrix Presented) An enantioselective synthesis of slagenins A-C (1a-c) is described in which their absolute stereochemistries were established. The key step in the synthesis involved the efficient condensation of 2-methoxy-dihydro-furan-3-one 9 and urea

Full text of DOI:10.1021/ol0268034

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3951-3953
Enantioselective Synthesis of Slagenins
A−C
Biao Jiang,* Jia-Feng Liu, and Sheng-Yin Zhao
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, Peoples Republic of China
jiangb@pub.sioc.ac.cn
Received August 28, 2002
ABSTRACT
An enantioselective synthesis of slagenins A−C (1a−c) is described in which their absolute stereochemistries were established. The key step
in the synthesis involved the efficient condensation of 2-methoxy-dihydro-furan-3-one 9 and urea to construct the slagenin bicycle core.
Slagenins A-C (1a-c) (Figure 1) comprise a group of
cytotoxic secondary marine metabolites recently isolated
from the Okinawan sponge Agelas nakamurai.1,2 These
structurally interesting bromopyrrole alkaloids possess a
highly functionalized tetrahydrofuro[2,3-d]imidazolidin-2-
one moiety in which the relative stereochemistry was
elucidated by 2D NMR spectroscopy. Because slagenins are
available in nature in only minute amounts and may be of
significant interest for more detailed pharmacological in-
vestigations, it was the goal of the current project to develop
efficient total synthesis for these bromopyrrole alkaloids.
While the first total synthesis of racemic slagenins A-C was
reported by Horne from ornithine,3,4 we achieved the
enantioselective synthesis for the antipodes of slagenins B
and C and established the absolute stereochemistry of
naturally isolated slagenin B and C, which was assigned as
(9R,11R,15R)-1b and (9R,11S,15S)-1c, respectively.5 Herein,
we report an enantioselective synthesis of slagenins A-C
from L-xylose and further confirmation of their absolute
stereochemistry.
Slagenins possess a cis-fused tetrahydrofuro[2,3-d]imida-
zolidin-2-one moiety with three stereogenic centers, one of
which is the C11 quarternary carbon center. The key to the
synthetic scheme is the generation of these three stereogenic
centers in the moiety. In the literature, only two reports
describe the preparation of tetrahydrofuro[2,3-d]imidazolidin-
2-one skeletons: one starting from urea and 2-aminosugars;6
another by oxidative cyclization of â-hydroxyimidazolone.3
We have developed a route using the condensation reaction
of urea and glyoxal to prepare the slagenin bicycle skeleton,
by which we synthesized the antipodes of slagenins B and
C.5 Since the condensation reaction proved to be a very direct
(1) Tsuda, M.; Uemoto, H.; Kobayashi, J. Tetrahedron Lett. 1999, 40,
5709.
(2) Several bromopyrrole alkaloids have been isolated from marine
sponge Agelas nakamurai: Uemoto, H.; Tsuda, M.; Kobayashi, J. J. Nat.
Prod. 1999, 62, 1581.
(3) Sosa, A. C. B.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000, 2,
3443.
(4) For a latter account of hypothetical biogenetic mechanism studies,
see: Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237.
(5) Jiang, B.; Liu, J.-F.; Zhao, S.-Y. Org. Lett. 2001, 3, 4011.
Figure 1. Structures of natural slagenins A-C.
10.1021/ol0268034 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/02/2002

Scheme 1a
a Reagents and conditions: (a) (1) 2.0 equiv of CuSO4, H2SO4, acetone, rt, 24 h; (2) 0.1 mol/L HCl, rt, 1 h; (b) 1.0 equiv of BzCl, 2.0
equiv of Py, dry CH2Cl2, 0 °C, 1 h, 80% yield from L-xylose; (c) (1) 1.4 equiv of NaH, 1.6 equiv of CS2, overnight, then 2.6 equiv of MeI,
1.5 h, dry THF, rt, (2) 1.5 equiv of Bu3SnH, 0.05 equiv of AIBN, benzene, reflux, 4 h, 68% two steps; (d) 1.3 equiv of NaOMe/MeOH,
2 h, 93%; (e) (1) 1.5 equiv of TsCl, 3.0 equiv of Py, CHCl3, rt, overnight, 98%, (2) 4 equiv of NaN3, DMF, 90 °C, overnight, 99%; (f) 1%
I2-MeOH, reflux, 18 h, 94%; (g) Dess-Martin oxidation, 81%.
and efficient way for the slagenin core, we envisioned that
urea might be condensed with 2-methoxy-dihydro-furan-3-
one, which was easily prepared from simple sugar, to
construct the tetrahydrofuro[2,3-d]imidazolidin-2-one skel-
eton of slagenins. The (9R)-chiral center in slagenins (refer
to the numbering system of slagenin) could be derived from
the C4-chiral carbon in L-xylose.
yield)12 and following Dess-Martin oxidation (in 81%
yield)13 (Scheme 1).
With the key intermediate 9 in hand, we tried to directly
condense it with urea under acidic conditions. Thus, a
treatment of compound 9 with aqueous HCl and then
condensation with urea in situ afforded 10a and 10b in 75%
yield in a ratio of 1.1:1, which could not be separated from
each other by silica gel chromatography. Hydrogenation of
this mixture over 10% Pd/C in methanol and the following
acylation with 4-bromo-2-(trichloroacetyl)pyrrole in DMF,
to our surprise, produced only a single compound 1a in a
yield of 69% (Scheme 2). The NMR (1H, 13C, and NOESY),
Starting from L-xylose, the 3-deoxy-L-ribose derivative 6
was prepared by adapting reported procedures.7 Ketalization
of L-xylose, in acetone in the presence of anhydrous CuSO4
and a catalytic amount of concentrated H2SO4, followed by
selective hydrolysis with 0.1 N HCl afforded 1,2-O-isopro-
pylidene-R-L-xylofuranose (3).8 Selective protection of the
5-OH using BzCl in pyridine-CH2Cl2 at 0 °C gave ester 4
in 80% yield from L-xylose.9 Following conversion of the
3-hydroxyl group to the 3-xanthate in situ, the alcohol 4 was
deoxygenated by the action of tributyltin hydride and AIBN
to give 5 in a yield of 68%.10 Removal of the benzyl
protecting group in 5 afforded primary alcohol 6 in 93%
yield. Treatment of 6 with TsCl and pyridine in CHCl3 gave
the corresponding tosylate, which was transformed to the
azide 7 in 97% yield for two steps.11 The key intermediate,
2-methoxy-dihydro-furan-3-one 9, was obtained by metha-
nolysis of compound 7 with refluxing 1% I2-MeOH (in 94%
Scheme 2a
(6) Avalos, M.; Babiano, R.; Cintas, P.; Jime´nez, J. L.; Palacios, J. C.;
Valencia, C. Tetrahedron 1993, 49, 2676.
(7) (a) Nicolaou, K. C.; Daines, R. A.; Uenishi, J.; Li, W. S.; Papahatjis,
D. P.; Chakraborty, T. K. J. Am. Chem. Soc. 1987, 109, 2208. Nicolaou,
K. C.; Daines, R. A.; Uenishi, J.; Li, W. S.; Papahatjis, D. P.; Chakraborty,
T. K. J. Am. Chem. Soc. 1988, 110, 4673. (b) For another report of the
preparation of compound 6 from diacetone-L-glucose, see: Jones, M. F.;
Noble, S. A.; Robertson, C. A.; Storer, R.; Highcock, R. M.; Lamont, R.
B. J. Chem. Soc., Perkin Trans. 1 1992, 1427.
(8) Baker, B. R.; Schaub, R. E. J. Am. Chem. Soc. 1955, 77, 5900.
(9) Gumina, G.; Schinazi, R. F.; Chu, C. K. Org. Lett. 2001, 3, 4177.
(10) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574. (b) Jacobson, K. A.; Siddiqi, S. M.; Olah, M. E.; Ji, X.-d.;
Melman, N.; Bellamkonda, K.; Meshulam, Y.; Stiles, G. L.; Kim, H. O. J.
Med. Chem. 1995, 38, 1720.
(11) A preparation of the antipode of compound 7 from glucose was
reported: Bentley, N.; Dowdeswell, C. S.; Singh, G. Heterocycles 1995,
41, 2499.
a Reagents and conditions: (a) (1) 0.1 mol/L HCl, THF, reflux,
8 h; (2) 1.2 equiv of urea, 0.01 mol/L HCl, rt, 48 h, 75% yield
from 9; (b) (1) H2, Pd/C, methanol, (2) 4-bromo-2-(trichloro-
acetyl)pyrrole, DMF, rt, 69% for two steps.
3952
Org. Lett., Vol. 4, No. 22, 2002

IR, and mass spectral data for compound 1a were in
satisfactory agreement with those reported for naturally
isolated slagenin A.1 Comparison of the specific rotation of
Scheme 3a
20
synthetic 1a {[R]D +7.7° (c 0.8, MeOH)} with naturally
27
isolated slagenins A {[R]D +11° (c 1.2, MeOH)} estab-
lished the absolute configuration of naturally isolated slagenin
A to be (9R,11R,15R)-1a.
For the synthesis of slagenins B and C, compound 9 was
heated with urea in 5% HCl-methanol solution to afford
inseparable diastereoisomers 11a and 11b in a ratio of 3.8:1
with a yield of 77%. Following our previous reported
procedure,5 slagenins B (1b) and C (1c) were isolated by
flash chromatography in 80% yield with a ratio of 3.8:1.
The NMR (1H, 13C, and NOESY), IR, and mass spectral data
for synthetic 1b and 1c were fully in agreement with those
reported for naturally isolated slagenins B and C.1 Compari-
20
son of the specific rotation of synthetic 1b {[R]D +44.8°
a Reagents and conditions: (a) 1.5 equiv of urea, 5% HCl-
methanol, reflux, 10 h, 77%; (b) (1) H2, Pd/C, methanol, (2)
4-bromo-2-(trichloroacetyl)pyrrole, DMF, rt, 80% for two steps.
26
(c 0.5, MeOH)} with naturally isolated slagenin B {[R]D
20
+33° (c 0.2, MeOH)] and synthetic 1c {[R]D -36.1° (c
0.8, MeOH)} with naturally isolated slagenin C {[R]D25 -35°
(c 0.2, MeOH)} further confirmed the absolute configuration
of naturally isolated slagenins B and C to be (9R,11R,15R)-
1b and (9R,11S,15S)-1c, respectively. In summary, a total
synthesis of slagenins A-C (1a-c) has been accomplished
in which their absolute stereochemistries were further
established. The key to the synthesis involved the efficient
condensation of 2-methoxy-dihydro-furan-3-one 9 and urea
to prepare the cis-fused tetrahydrofuro[2,3-d]imidazolidin-
2-one skeleton.
Acknowledgment. We are grateful for financial support
from the Shanghai Municipal Committee of Science and
Technology. We also thank Prof. David A. Horne (Oregon
State University) for providing NMR data for synthetic
slagenin.
Supporting Information Available: NMR (1H, 13C,
NOESY) spectra for synthetic slagenins A (1a), B (1b), and
C (1c). This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) (a) Huang, B.-G.; Bobek, M. Carbohydr. Res. 1998, 308, 319. (b)
Lu, D.-M.; Min, J.-M.; Zhang, L.-H. Carbohydr. Res. 1998, 317, 193.
(13) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
OL0268034
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