Angewandte
Chemie
DOI: 10.1002/anie.201410063
Natural Products
Total Syntheses of Linear Polythiazole/Oxazole Plantazolicin A and Its
Biosynthetic Precursor Plantazolicin B**
Zoe E. Wilson, Sabine Fenner, and Steven V. Ley*
Abstract: Plantazolicin A, a linear decacyclic natural product,
exhibits desirable selective activity against the causative agent
of anthrax toxicity. The total synthesis of plantazolicin A and
its biosynthetic precursor plantazolicin B was successfully
achieved by an efficient, unified, and highly convergent route
featuring dicyclizations to form 2,4-concatenated oxazoles and
the mild synthesis of thiazoles from natural amino acids. This
report represents the first synthesis of plantazolicin B and
includes the first complete characterization data for both
natural products.
efficient, and convergent strategy for both 1a and 1b, which
we report herein.
Our strategy was based upon a late-stage peptide coupling
of two equally sized fragments, 3 and either 2a or 2b
(Scheme 1). Our quest to obtain the left-hand fragment of
both 1a and 1b was designed based on the union of three
components: the tripeptide 9 and two thiazole-containing
fragments, that is, 5 and either 4a or 4b. The planned
installation of arginine-derived thiazole 4a or 4b as the
penultimate step of these fragments would allow a highly
unified approach to the synthesis of both natural products.
Initial attempts at employing a modified Hantzsch thiazole
synthesis[6] for 4a and 4b were low yielding and unreliable,
echoing the recently published works on similar fragments by
the groups of Sꢀssmuth and Mitchell, where the preparation
of the required thioamide precursors in particular were low
yielding (13%[5] and 25%,[3a] respectively) and required the
use of unpleasant sulfurating reagents. Therefore it was
decided to attempt a more biomimetic approach to these
thiazoles, based on the condensation of an amino-acid-
derived aldehyde with a cysteine ester hydrochloride, fol-
lowed by oxidation of the resultant thiazolidine.[7] It was
hoped that the use of 9 as a coupling partner would allow the
formation of the two adjacent 5-methyl oxazole rings in
a single step by using a modification of Wipfꢁs conditions for
the cyclization of b-hydroxy amides.[8]
P
lantazolicin A (1a) and its biosynthetic precursor planta-
zolicin B (1b) represent a new class of ribosomally synthe-
sized thiazole/oxazole natural products isolated from the soil
bacterium Bacillus amyloliquefaciens FZB42 (Scheme 1).[1,2]
The biosynthesis of these molecules has been shown to
involve the extensive post-translational modification of a 14-
amino-acid peptide to give 1b, which has two pentaheter-
ocyclic regions, one of which is not fully oxidized in an
unusual overall linear structure. Plantazolicin B (1b) under-
goes dimethylation at the N-terminus to afford 1a.[3] Sub-
sequent investigations by Mitchell et al. has shown that the
absolute stereochemistry of 1a is derived from all natural l-
amino acids.[4]
Plantazolicin A (1a) has been reported to exhibit anti-
biotic activity against related gram-positive bacteria, includ-
ing, notably, the causative agent of anthrax toxicity, Bacillus
anthracis (strain STERN), whereas 1b is inactive.[1a,4] The
challenging linear structures of these molecules, in combina-
tion with the desirable biological activity of 1a, makes them
attractive targets for total synthesis. Sꢀssmuth and co-workers
have recently reported the synthesis of 1a[5] and Mitchell et al.
have reported the preparation of shortened analogues of the
left-hand half, as drawn, of 1a.[3a] However, the total synthesis
of the desmethyl precursor 1b has not been reported to date.
The primary goal of our research was to develop a unified,
The synthesis of the right-hand fragment 3 was based on
the union of the tetraoxazole 6 and dipeptide 7. It was thought
that a double cyclization/oxidation, this time of serine
residues, could also be employed during the construction of
6
[9] after two successive coupling then cyclization/oxidation of
serine residues to form the dioxazole 10. Overall, it was
proposed that both fragments could be obtained from
inexpensive natural l-amino-acid starting materials, which
correspond directly to those used in the biosynthesis of these
natural products. The only exception to this would be the use
of the l-allo-threonine 21 to allow a Deoxo-Fluor-mediated
oxazolidine formation, as this proceeds with inversion of the
configuration at the b-position of the amino acid.[8,10]
The assembly of left-hand fragments 2a and 2b com-
menced with the straight forward preparation of 9 through
two successive couplings using 1-hydroxybenzotriazole
hydrate (HOBt) and N-(3-dimethylaminopropyl)-N’’-ethyl-
carbodiimide hydrochloride (EDCI) with diisopropylethyl-
amine as a base in dichloromethane in an overall yield of 78%
(Scheme 2).
[*] Dr. Z. E. Wilson, Dr. S. Fenner, Prof. S. V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
E-mail: svl1000@cam.ac.uk
[**] We gratefully acknowledge Prof. D. A. Mitchell (University of Illinois
at Urbana-Champaign) for providing an authentic sample of
plantazolicin A and advice on purification, Peter Grice and Duncan
Howe for assistance with NMR spectroscopy, and generous funding
from the Royal Society (Newton International Fellowship—Z.E.W.),
the German Academic Exchange Service DAAD (S.F.), and the
Engineering and Physical Sciences Research Council.
Next, attention turned to the formation of known thiazole
8 (Scheme 3). Threonine-derived Weinreb amide 24 was
readily synthesized from the Boc-threonine 14 before reduc-
tion using diisobutylaluminium hydride (DIBAL-H), gave the
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!
Wilson, Zoe E.
