Tetrahedron Letters
Synthesis of aurachin D and isoprenoid analogues
from the myxobacterium Stigmatella aurantiaca
⇑
Lisa Dejon, Andreas Speicher
FR 8.1 Chemistry–Organic Chemistry, Saarland University, D-66041 Saarbrücken, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2013
Revised 13 September 2013
Accepted 16 September 2013
Available online 25 September 2013
Aurachins, a family of isoprenoid quinoline alkaloids isolated from the myxobacterium Stigmatella auran-
tiaca, possess multiple interesting bioactivities and were subject of intensive studies of biosynthesis. In
this Letter, we describe the efficient few step total synthesis of the parent compound aurachin D and
two isoprenoid analogues via Conrad–Limpach cyclization. The main antimicrobial and cytotoxic profiles
of these derivatives were explored.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aurachin D
Total synthesis
Natural products
Myxobacteria
Quinoline alkaloids
Aurachins are a family of secondary metabolites produced by
the myxobacterium Stigmatella aurantiaca strain Sg a15 and pos-
sess numerous bioactivities, such as anti-bacterial, anti-fungal
and anti-plasmodial properties.1 Furthermore, these isoprenoid
quinoline alkaloids are potent inhibitors of mitochondrial respira-
tion by targeting the cytochrome b6/f-complex, as well as the
complexes I and III in the respiratory chain.2
OH
N
AuaB-E
COOH
NH2
2-methyl-4-hydroxy-
quinoline
anthranilic acid
AuaA
A
plausible biosynthesis pathway for aurachins A–L was
O
deduced from feeding studies.3 The puzzle of the modular aurachin
biosynthesis in Stigmatella aurantiaca involving polyketide syn-
thases (AuaB–E), a prenyl transferase (AuaA) as well as a Rieske
oxygenase (AuaF) for N-oxidation was extensively studied.4–8 As
outlined in Scheme 1, the biosynthesis starts with anthranilic acid
to generate aurachin D (1) as the first aurachin in this sequence.
Biological N-oxidation then yields aurachin C (2) which can be con-
verted into other aurachins in further biosynthetic steps. Studies
on the biosynthesis of these polyketide-derived secondary metab-
olites are still under progress and potential intermediates are
essential for enzymatic studies and feeding experiments.
aurachin D (1)
N
H
AuaF
O
N
OH
AuaG,H
aurachin C (2)
more aurachines (A,B,F-L)
Thus, 1 can be considered as the starting aurachin type com-
pound giving access to the aurachin family. Surprisingly, none of
the aurachins have been the subject of total synthesis to date.9
Consequently, we decided to synthesise aurachin D (1) and some
isoprenyl derivatives to enable further biosynthetical as well as
biological investigations.
Scheme 1. Proposed biosynthesis of the aurachin family produced by Stigmatella
aurantiaca (AuaA–F: enzymes involved).
chain at 3-position. By means of the retrosynthesis (Scheme 2),
two main possibilities to introduce the isoprenoid side chain can
be considered, either after the synthesis of the quinolone nucleus
(path a) or before the cyclization to the heterocycle (path b). In
both cases, the heterocyclic core can be obtained by Conrad–Limp-
ach cyclization10 which leads to aniline and the appropriate ethyl
acetoacetate as starting materials.
The structure of aurachin D (1) is based on the 2-methyl-4-
quinolone core, substituted with an unsaturated farnesyl side
⇑
Corresponding author. Tel.: +49 681 302 2749; fax: +49 681 302 2029.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.