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Abstract: A general and scalable access to the aeruginosin
family of marine natural products, exhibiting potent inhibito-
ry activity against serine proteases, is reported. This was ena-
bled by the strategic use of two recently implemented Pd-
catalyzed C(sp3)ÀH activation reactions. The first method al-
lowed us to obtain the common 2-carboxy-6-hydroxyoctahy-
droindole (Choi) core of the target molecules on a large
scale, whereas the second method provided a rapid and di-
vergent access to various hydroxyphenyllactic (Hpla) subu-
nits, including halogenated ones. This unique strategy, to-
gether with an optimization of the fragment coupling se-
quence allowed the synthesis of four aeruginosins, that is,
98A–C and 298A from the chiral pool. Among them, aerugi-
nosin 298A was synthesized on an unprecedentedly large
scale. In addition, halogenated aeruginosins 98A and 98C
were synthesized for the first time, thanks to a fine-tuning of
the final hydrogenation step.
Introduction
a terminal guanidine, a hydrophobic amino acid, and a d-hy-
droxyphenyllactic (Hpla) subunit which may include halogen
(Cl, Br) atoms (1b, 1d, 1e). The structure of aeruginosin 298A
(1a) was initially elucidated by Murakami and co-workers, who
misassigned the configuration of the hydrophobic amino acid
as l-leucine.[2] Later, the first total syntheses of this molecule
were independently reported by the groups of Bonjoch[5] and
Wipf,[6] and revealed a d-configuration for the leucine moiety.
To access aeruginosins 1a–e, we first considered classical
retrosynthetic disconnections at the amide bonds, leading to
the four fragments 2–5 (Scheme 1). Different approaches have
been reported to construct the bicyclic Choi core 2 in previous
total syntheses of aeruginosins 298A (1a). The groups of Bon-
joch,[5] Wipf,[6] and Shibasaki[7] employed intramolecular Mi-
chael-type additions to build the CÀN bond of the pyrrolidine
ring from precursors that were either obtained from l-tyrosine
by a reductive[5] or an oxidative[6] process, or by catalytic asym-
metric phase-transfer alkylation of a glycine derivative.[7] These
Michael addition based strategies all furnished a mixture of
diastereoisomers, which required an additional equilibration
step to obtain the desired stereoisomer. In their synthesis of
aeruginosin 98B (1c), Trost and co-workers, employed a differ-
ent strategy, based on an intramolecular asymmetric Tsuji–
Trost reaction, which directly led to a hexahydroindole inter-
mediate possessing the required configuration.[8] In light of
these precedents,[9] we envisioned that our recently developed
intramolecular palladium(0)-catalyzed C(sp3)ÀH alkenyla-
tion[10,11] would allow access to compound 2 in a straightfor-
ward and scalable manner, thereby enabling the collective syn-
thesis of aeruginosins. The required bromocyclohexene precur-
sor 6 should be accessible from abundant l-alaninol 10 in
a few steps only. In order to access Hpla fragments 5, which
may include potentially labile halogen atoms, in a straightfor-
ward manner, a divergent approach from a common precursor
would be ideal. We envisioned that the intermolecular palla-
dium(II)-catalyzed directed CÀH arylation of a suitable deriva-
tive of d-lactic acid would fulfill such an objective. Indeed,
Daugulis and co-workers initially introduced the use of the bi-
dentate 8-aminoquinoline directing group to perform the
direct C(sp3)ÀH arylation of alkyl carboxylic acids at the b posi-
tion.[12] Since this discovery, important developments were ach-
ieved in this field, including the introduction of new directing
groups, thereby establishing it as one of the most powerful
and practical strategies to construct valuable arylated alkyl
Aeruginosins are marine natural products that have been iso-
lated from sponges and cyanobacterial water blooms, and
which include more than 20 congeners.[1] Among these, aerugi-
nosin 298A (1a), 98A–C (1b–d), and 101 (1e) have shown
potent in vitro inhibition of various serine proteases, including
thrombin and trypsin (Scheme 1, Table 1). These enzymes are
involved in a number of important physiological processes, in
particular, the blood coagulation cascade. Aeruginosins 1a–
e have been isolated from dried algae with yields in the range
of 0.01—0.05%.[2–3] This low availability, combined with their
interesting biological properties, stresses the need for an effi-
cient and modular total synthesis of these marine com-
pounds.[4] Structurally, aeruginosins display four different units
linked by three amide bonds: a 2-carboxy-6-hydroxyoctahy-
droindole (Choi) core containing a free (1a) or sulfated (1b–e)
hydroxy group, a C-terminus (l-argol or agmatine) containing
Table 1. Structures of target aeruginosins.
Compound
R1
R2
R3
R4 R5
aeruginosin 298A (1a)
H
H
H
H
À
À
aeruginosin 98A (1b)
SO3
Cl
H
aeruginosin 98B (1c)
aeruginosin 98C (1d)
aeruginosin 101 (1e)
SO3À agmatine
SO3À agmatine
d-allo-Ile
d-allo-Ile Br
d-allo-Ile Cl Cl
H
H
SO3
agmatine
[a] D. Dailler, Dr. G. Danoun, B. Ourri, Prof. Dr. O. Baudoin
UniversitØ Claude Bernard Lyon 1, CNRS UMR 5246
Institut de Chimie et Biochimie MolØculaires et SupramolØculaires
CPE Lyon, 43 Boulevard du 11 Novembre 1918
69622 Villeurbanne (France)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2015, 21, 9370 – 9379
9371
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