Synthesis of slagenins A, B, and C.

Article abstract of DOI:10.1021/ol000233v

[structure: see text] A short synthesis of the marine sponge metabolites slagenins A (1), B (2), and C (3) is described. The synthetic route features the preparation of beta-hydroxyimidazolone 4 from ornithine and its subsequent oxidative cyclization to the slagenin core.

Full text of DOI:10.1021/ol000233v

ORGANIC
LETTERS
2
000
Vol. 2, No. 22
443-3444
Synthesis of Slagenins A, B, and C
3
Ana Carolina Barrios Sosa, Kenichi Yakushijin, and David A. Horne*
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331
horned@ucs.orst.edu
Received August 15, 2000
ABSTRACT
A short synthesis of the marine sponge metabolites slagenins A (1), B (2), and C (3) is described. The synthetic route features the preparation
of â-hydroxyimidazolone 4 from ornithine and its subsequent oxidative cyclization to the slagenin core.
Slagenins A (1), B (2), and C (3) comprise a group of
1). This strategy is based on the relevant transformation of
2-aminoimidazoles to dialkoxyimidazolines with NCS and
alcohols (eq 1). The success of this approach depends on
cytotoxic secondary marine metabolites recently isolated
1
3
from the sponge Agelas nakamurai. These structurally
interesting natural products possess a highly functionalized
tetrahydrofuro[2,3-d]imidazolidin-2-one core in which the
relative stereochemistry was elucidated by 2D NMR spec-
troscopy. No prior synthesis of slagenins has appeared in
the literature, and only one report describes the preparation
of tetrahydrofuro[2,3-d]imidazolidin-2-one skeletons starting
the intramolecular cyclization of 4 and trapping the resulting
reactive intermediate with methanol or water.
2
from urea and 2-aminosugars. To our knowledge, the
biosynthetic pathway to slagenins remains unknown but the
amino acid ornithine appears to be an attractive precursor.
In this Letter, we report a total synthesis of slagenins A, B,
and C from intermediates derived from this hypothetical
forerunner.
Figure 1. Synthetic plan.
Starting from commercially available ornithine, Fisher
esterifcation afforded methyl ester 5 which upon reduction
4
under Akabori conditions followed by condensation with
potassium cyanate produced imidazolone 6 as a colorless
The synthetic approach centers on the introduction of the
â-hydroxy substituent in imidazolone 4 and its subsequent
oxidative cyclization to the requisite slagenin core (Figure
5
(
3) Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1998, 63,
248.
(4) Initially performed with thiocyanate, see: (a) Akabori, S. Ber. 1933,
1
(
1) Tsuda, M.; Uemoto, H.; Kobayashi, J. Tetrahedron Lett. 1999, 40,
709.
2) Avalos, M.; Babiano, R.; Cintas, P.; Jim e´ nez, J. L.; Palacios, J. C.;
Valencia, C. Tetrahedron 1993, 49, 2676.
5
66, 157. (b) Lawson, A.; Morley, H. V. J. Chem. Soc. 1955, 1695.
(5) All new compounds gave satisfactory spectral data ( H and 13C NMR
and HRMS).
1
(
1
0.1021/ol000233v CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/29/2000

9
base. When a methanol solution of 4 was treated with NCS
23 °C, 30 min), a 1:1 diastereomeric mixture of slagenins
B (2) and C (3) was produced in 90% yield (Scheme 3).
(
Scheme 1
Scheme 3
Pure samples of each were obtained through separation by
flash chromatography. Upon heating in the presence of acid,
both 2 and 3 were converted to slagenin A (1). Slagenin A,
which bears an exo pyrrole carboxamide group, was obtained
as the sole product and the presumably less stable endo
diastereomer was not observed under these conditions. NMR,
IR, and MS spectral data for synthetic slagenins A, B, and
C were in satisfactory agreement with those reported for the
solid (Scheme 1). Multigram quantities of 6 can be conve-
niently prepared by this method. Although the direct install-
ment of the double bond in 8 from 6 proved to be
problematic, treatment of 6 with NCS in methanol afforded
R-methoxy derivative 7 in good yield. Trifluoroacetic acid
caused elimination of MeOH which produced olefin 8 in
modest amounts.6
10
natural material.
In summary, a relatively short synthesis of slagenins A,
B, and C has been accomplished from ornithine. The
synthetic scheme incorporates several key steps that are
conceivably biomimetic in nature. The genera Agelas is
particularly known for its production of bioactive natural
The direct introduction of a hydroxyl substituent to the
â-position in imidazolone 8 proved difficult. However,
reports of allylic amides undergoing cyclization to oxazolines
7
suggested an alternative solution. Acylation of amine 8 with
11
products that are related to oroidin. The chemistry outlined
8
4
-bromo-2-(trichloroacetyl)pyrrole gave amide 9 as a color-
here is entirely applicable to this closely related alkaloid
family, and work in this area is currently in progress.
less solid (Scheme 2). With 9 in hand, conversion to
oxazoline 10 in near quantitative yield was achieved in
methanesulfonic acid. Aqueous acid caused cleavage of the
oxazoline in 10, producing alcohol 4 upon neutralization with
Acknowledgment. Financial support from the National
Institutes of Health (GM 50929) is gratefully acknowledged.
Supporting Information Available: 1H and 13C NMR
spectra for slagenins A (1), B (2), and C (3) and compounds
Scheme 2a
4
and 6-10. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL000233V
(6) Acid-facilitated dimerization of 7 and/or 8 predominates under these
conditions. Current efforts are underway to optimize this step.
(
7) MacManus, S. P.; Carroll, J. T. J. Org. Chem. 1970, 35, 3768.
(8) 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.
9) Initial acid cleavage led to an intermediate ester which upon treatment
with base facilited acyl transfer producing amide 4.
10) The following typographical errors for 13C chemical shift values in
(
(
ref 1 are noted in a personal communication from Professor Kobayashi:
C2 of slagenin A should be 120.7 ppm and the listed values for C8 of
slagenins B and C should be interchanged.
(11) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7 and earlier reports in
this series.
a
(
i) 4-Bromo-2-(trichloroacetyl)pyrrole, DMF, rt, 1 h; (ii) 5%
HCl, reflux, 2 h, then neutralize with NaOH.
3444
Org. Lett., Vol. 2, No. 22, 2000