Angewandte
Chemie
DOI: 10.1002/anie.201307200
Biomimetic Synthesis Hot Paper
Biomimetic Total Synthesis of (Æ)-Merochlorin A**
Henry P. Pepper and Jonathan H. George*
Dedicated to Professor Sir Jack E. Baldwin on the occasion of his 75th birthday
Merochlorins A (1) and B (2) are isomeric chlorinated
meroterpenoids with unique polycyclic ring systems, and
were recently isolated from the marine bacterium Strepto-
[1]
myces sp. strain CNH-189. Merochlorin A has a compact
[
2]
bicyclo[3.2.1]octanone core with four contiguous stereocen-
ters, three of which are quaternary. The structure of 1 was
[1b]
initially elucidated using 2D NMR studies. However, later
[
1a]
X-ray studies
and our synthetic work indicate that its
structure should be represented as shown in Scheme 1 (the
configurations of the stereocenters at C9 and C10 of 1 were
originally misassigned). Further to its structural interest, 1 is
a potent antibiotic against Clostridium difficile (MIC =
À1
0
.15 mgmL ) and various multi-drug resistant Staphylococcus
À1 [1b]
aureus strains (MIC = 2–4 mgmL ).
It is therefore an
excellent lead candidate for the development of novel
antibiotics. However, the mechanism of action of 1 is
unknown, and given its scarcity in nature a chemical synthesis
is desirable.
Merochlorin B has a 6-5-5-fused ring system with three
contiguous stereocenters and an a-chloroenone motif. The
unprecedented structures of 1 and 2 suggest an unusual
[
1a]
biosynthesis. This was investigated by Moore et al., who
partially sequenced the genome of the CNH-189 bacterium to
reveal a merochlorin gene cluster containing 41 genes (mcl1-
mcl41). The key genes implicated in the biosynthesis of the
merochlorins were found to encode a 1,3,6,8-tetrahydroxy-
naphthalene synthase (mcl17), an aromatic prenyl transferase
[3]
(
mcl23), a vanadium-dependent haloperoxidase (VHPO;
mcl24), and a protein containing an iron–sulfur cluster
mcl30). On the basis of their bioinformatic analysis, Moore
(
Scheme 1. Our proposed biosynthesis of merochlorins A and B. The
key genes encoding the proteins responsible for a specific transforma-
tion are given in brackets.
and co-workers proposed a biosynthesis of 1 and 2 involving
VHPO-dependent chlorination or oxidation of an alkene as
the prelude to a cyclization cascade to form the polycyclic ring
[
1a]
systems. However, their proposed cyclization mechanism is
by their own admission) highly speculative, and we herein
aromatization of the acyclic polyketide 3, catalyzed by the
mcl17 polyketide synthase. We then propose that 4 undergoes
alkylation (mcl23) to give 5 and chlorination (mcl24) to give 6.
Oxidative dearomatization of 6 (perhaps catalyzed by the
putative protein that contains the Fe–S cluster and is encoded
by mcl30) would then generate phenoxonium ion 7 which
could cyclize through a [5+2] cycloaddition to give 1 or
a [3+2] cycloaddition to give 2. These cycloadditions are
presumably stepwise in mechanism. Previously, intramolecu-
lar [5+2] cycloadditions have been proposed to occur
between para-quinones and alkenes in the biosynthesis of a-
(
propose an alternative biosynthetic mechanism (Scheme 1).
In common with the biosynthesis described by Moore et al.,
we suggest that the starting point for the biosynthesis of 1 and
2
is the formation of 1,3,6,8-tetrahydroxynaphthalene (4) by
[*] H. P. Pepper, Dr. J. H. George
School of Chemistry and Physics, University of Adelaide
Adelaide, SA 5005 (Australia)
E-mail: jonathan.george@adelaide.edu.au
[
4]
[5]
and b-pipitzol and elisapterosin B, which has inspired
[
**] This work was supported by the Australian Research Council in the
form of a Discovery Early Career Researcher Award (DE130100689)
awarded to J.H.G. We thank Dr. Christopher Sumby (University of
Adelaide) for X-ray crystallographic studies.
[
6]
elegant biomimetic syntheses of these molecules. However,
we believe our suggested pathway to merochlorin A is the
first proposal of a biosynthesis to involve an intramolecular
[
5+2] cycloaddition directly initiated by an oxidative dear-
omatization.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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