1
13
yield. The H and C NMR spectra of synthetic 1 in CD
3
OD
1
and the H NMR spectrum in DMSO-d
reported for the natural product.
6
are identical to those
Scheme 4
.
Autoxidation of R-Ketoamide 16
1
Protected anchinopeptolide D 7a, which has the same
stereochemistry as eusynstyelamide B (2), readily equilibrates
with 6a, which has the same stereochemistry as eusynstye-
lamide A (1), in CD
contrast, Tapiolas and co-workers reported that eusynstye-
lamide A (1) does not equilibrate on heating in CD OD or
3
OD at reflux for 1 h (see Scheme 2). In
3
during prolonged storage. They also isolated mixtures of all
three isomers 1-3 from some samples of E. latericius, but
only eusynstyelamide A (1) from other samples. Ireland
reported the isolation of only a single compound, to which
he assigned the structure eusynstyelamide (4), but which is
1
actually eusynstyelamide A (1). Therefore, the formation
However, the enol form 16E is readily accessible, and it,
or the enolate, is easily oxidized by oxygen to 3-hydroper-
oxy-3-(indol-3-yl)pyruvamide 19, especially under the basic
conditions needed for the aldol dimerization. The mass
of eusynstyelamide A precursor 17 as the major isomer from
6 is consistent with the isolation of 1 as the sole isomer
1
from some samples of E. latericius and from E. misakiensis.
Eusynstyelamide A (1) does not equilibrate under the
strongly acidic conditions needed to cleave the Boc groups.
It is also does not equilibrate on storage in CD
decomposition occurs in basic (NaOD) CD
+
spectrum of fresh 16 shows a strong M . After storage, the
+
+
sample showed an M and an MO
2
for the hydroperoxide
OD. Extensive
OD.
of equal intensity. There is limited precedent for this facile
autoxidation in the literature. Autoxidation of 3-(4-hydroxy-
3
3
Protected anchinopeptolide D 7a and 6a equilibrate readily,
but eusynstyelamide A (1) and B (2) do not. The aldol
dimerization of both 16 and 5 gave adduct 10 with high
selectivity. However, hemiaminal formation afforded mainly
eusynstyelamide A precursor 17 from 16 and mainly anchi-
nopeptolide D precursor 7a, which has the same stereochem-
istry as eusynstyelamide B (2), from 5. The different side
chains must be responsible for the differences in both the
rates of equilibration and the stereochemistry of hemiaminal
formation, but it is not clear why.
In conclusion, we have developed an efficient six-step
route to eusynstyelamide A (1) from 6-bromoindole (11),
methyl glycidate (12), and protected agmatine 14 in 13%
overall yield. If oxygen is carefully excluded from the
reaction, the key NaOH-catalyzed aldol dimerization of 16
proceeded efficiently to give Boc-protected eusynstyelamide
A 17.
3
2
-iodophenyl)pyruvic acid gave 3-(4-hydroxy-3-iodophenyl)-
-hydroxy-3-hydroperxoycinnamic acid (the enol tautomer
1
7
of the 3-hydroperoxyarylpyruvic acid). Radical-initiated
autoxidation of the enol tautomer of 3-(4-hydroxyphe-
nyl)pyruvic acid provided 3-hydroperoxy-3-(4-hydroxyphe-
nyl)pyruvic acid. Hydroperoxide 19 decomposed to give
a complex mixture of products including 6-bromoindole-3-
1
8
19
carboxaldehyde (20), a natural product that may be derived
by a similar mechanism from 6-bromotryptophan.
Having established that the unexpected sensitivity of 16
to oxygen was causing side reactions, especially under basic
conditions, we were able to successfully carry out the desired
aldol dimerization under carefully controlled oxygen-free
conditions. A solution of 16 in THF was carefully degassed,
and aqueous 0.25 M NaOH solution was added. The solution
was stirred for 2 days under nitrogen to give Boc-protected
eusynstyelamide A 17 in 37% yield from 15 and impure Boc-
protected eusynstyelamide B 18 in <4% yield from 15.
Acknowledgment. We are grateful to the National Insti-
tutes of Health (GM-50151) for support of this work.
Cleavage of the four Boc groups of 17 in 1:1 TFA/CH
for 1 h at 25 °C afforded eusynstyelamide A (1) in ∼95%
2 2
Cl
Supporting Information Available: Complete experi-
(
(
17) Cahnmann, H. J.; Funakoshi, K. Biochemistry 1970, 9, 90–98.
18) (a) Jefford, C. W.; Kn o¨ pfel, W.; Cadby, P. A. J. Am. Chem. Soc.
mental procedures, comparison of the NMR spectral data of
1
1
978, 100, 6432–6436. (b) Jefford, C. W.; Kn o¨ pfel, W.; Cadby, P. A.
Tetrahedron Lett. 1978, 3585–3588.
19) (a) Wratten, S. J.; Wolfe, M. S.; Andersen, R. J.; Faulkner, D. J.
natural and synthetic eusynstyelamide A, and copies of H
13
and C NMR spectral data. This material is available free
(
Antimicrob. Agents Chemother. 1977, 11, 411–414. (b) Rasmussen, T.;
Jensen, J.; Anthoni, U.; Christophersen, C.; Nielsen, P. H. J. Nat. Prod.
of charge via the Internet at http://pubs.acs.org.
1
993, 56, 1553–1558.
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