A concise ring-expansion route to the compact core of platensimycin

Article abstract of DOI:10.1002/anie.200903347

Oxatropanes from oxiranes: An expedient assembly of the compact platensimycin core is described. The synthetic approach relies on a Suzuki cross-coupling, a late-stage dearomatization reaction, and a copper-catalyzed vinyl oxirane ring expansion for accessing the oxatropane moiety of the natural product.

Full text of DOI:10.1002/anie.200903347

Angewandte
Chemie
DOI: 10.1002/anie.200903347
Natural Products
A Concise Ring-Expansion Route to the Compact Core of
Platensimycin**
Nicholas A. McGrath, Emily S. Bartlett, Satapanawat Sittihan, and Jon T. Njardarson*
Recently, researchers at Merck disclosed a new natural
product, platensimycin (1; Figure 1),[1] which was obtained
by screening a large collection of South African soil samples
Figure 2. Synthetic approaches to complete the platensimycin core.
We envisioned a concise retrosynthetic plan for the total
synthesis of platensimycin (Scheme 1). Platensic acid (2) was
our immediate target as it serves later as the branch point for
accessing all the other members of this natural product family.
We proposed that 2 could be accessed from 4 by a retro-
Figure 1. The structures of platensimycin and platensic acid.
using a novel antibiotic assay approach. Characterization
revealed a unique compact core connected to a highly
oxygenated and unusual aromatic ring through a propionate
tether. Platensimycin has a novel mechanism of action,
inhibiting the b-ketoacyl-(acyl carrier protein) synthase
(FabF) in the bacterial fatty acid synthetic pathway.[2] Several
new members of this class have since been reported.[3] These
differ only in functionalization of the carboxylate terminus.
This attractive natural product target has also encouraged
researchers to engineer strains to improve its production.[4]
Despite a flurry of synthetic activity, only two groups have
completed the total syntheses of platensimycin (1).[5] All other
reported efforts have focused on constructing the platensi-
mycin core 3.[6] To highlight the diversity of these synthetic
approaches we have chosen to emphasize the last bond
formed to complete the platensimycin core as reported by
each research group (Figure 2). Recently, a series of deriva-
tives obtained by modifying platensimycin have been
reported.[7] Alternatively, several research groups have devel-
oped analogues of platensimycin,[8] some of which were
equipotent with the natural product.[8a–c] These results bode
well for analogue approaches utilizing diverted total synthetic
strategies.[9]
Scheme 1. Platensimycin retrosynthetic analysis. Bn=benzyl.
Michael ring-opening reaction and subsequent hydrolysis of
the resulting ester. Radical cyclization of bromide 5 would
then be expected to afford the platensimycin carbocyclic core
4. Oxidative dearomatization of 7 and in situ trapping of the
ketal 6 with methyl acrylate was expected to provide 5 as the
only cycloadduct. In this one remarkable transformation, the
aromatic core would be unraveled and primed for the
subsequent cyclization step. At the same time, the quaternary
center bearing the side chain with the desired oxidation state
would be installed by a substrate and regiocontrolled Diels–
Alder cycloaddition. Oxatropane 7 would originate from
vinyl oxirane 8 using our newly described copper-catalyzed
ring-expansion protocol.[10] Epoxidation of the diene obtained
from enone 9 could also serve as the asymmetric entry point
for this synthesis, which in turn would be assembled in two
steps from 10[11] and 11 using a Heck coupling and then an
intramolecular condensation.
[*] N. A. McGrath, E. S. Bartlett, S. Sittihan, Prof. J. T. Njardarson
Department of Chemistry and Chemical Biology, Baker Laboratory
Cornell University, Ithaca, NY 14853-1301 (USA)
Fax: (+1)607-255-4137
E-mail: jn96@cornell.edu
[**] We would like to thank NIH-NIGMS (RO1 GM086584) and Cornell
University for support of this synthetic program. Fellowships from
an NIH Chemical Biology Interface Grant (NAM) and the Hunter
Rawlings Presidential Scholar Program (EAB) are gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903347.
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Our synthetic efforts commenced with vanillin[12] which
was regioselectively brominated and protected by using
known procedures (12, Scheme 2).[13] This substrate was
Scheme 3. Oxidative dearomatization/cyclization attempts. IBDA=
iodobenzene diacetate.
give the desired cycloadduct 24. Our calculations had
indicated that the structure of the new six-membered ring
would bring the radical-accepting olefin into closer proximity
with the primary radical, and therefore make the cyclization
more likely. Unfortunately all attempts to form 25 were not
successful, again giving only the product of bromide reduc-
tion.
Scheme 2. Synthesis of the functionalized aryl-fused oxatropane.
DMF=N,N-dimethylformamide, LDA=lithium diisopropylamide,
Tf =trifluorosulfonyl, Tr=triphenylmethyl, hfacac=hexafluoroacetyl
acetonate.
We decided to evaluate a slightly different substrate to
À
determine whether our proposed C C cyclization strategy to
form the platensimycin core was feasible (Scheme 4). To this
end oxatropane 18 was converted into 26 by alkene reduction
and hydrogenolysis of the benzyl protecting group. Deoxy-
genation was then accomplished by converting 26 into an aryl
triflate and then effecting reductive cleavage using palladium
and formic acid to give 27. A remarkably mild phenolic
subjected to Heck coupling conditions in the presence of
allylic alcohol 11, which furnished keto aldehyde 13.[14] The
methyl branching is key to the rapid assembly of the fused
ring system 14, ensuring that under the thermodynamic
conditions employed, the initial five-membered ring aldol
product cannot dehydrate and instead undergoes a retro aldol
to give exclusively the seven-membered ring enone. Triflate
formation to give 15 was accomplished by deprotonation with
LDA[15] and trapping of the resulting enolate with N-phenyl-
triflamide. Palladium-mediated carbonylation afforded dien-
oate 16 in excellent yield.[16] Regioselective epoxidation was
accomplished using the highly reactive trityl hydroperox-
ide,[17] and our new copper-catalyzed ring-expansion protocol
formed oxatropane 18.
Methyl enolate 18 (Scheme 3) was fully reduced stereo-
selectively to form 19 using lithium triethyl borohydride.
Primary bromide 20 was accessed using carbon tetrabromide
and triphenylphosphine, and the arylbenzyl ether was
removed by employing a transfer-hydrogenolysis protocol.
Oxidation of 21 using IBDA afforded dimethyl ketal 22 which
underwent a facile Diels–Alder dimerization. This process
was slow enough, however, to test the proposed cyclization.
Unfortunately, all efforts to access 23 using either radical or
anionic conditions did not form the desired core, giving
À
instead only the product of bromide reduction and no C C
Scheme 4. Intramolecular alkylative dearomatization. DIBAL-H=diiso-
butylaluminum hydride, TES=triethylsilyl, Ts=4-toluenesulfonyl,
TBAF=tetra-n-butylammonium fluoride.
bond formation.[18] Regardless, diene 22 could be trapped
in situ after oxidative dearomatization with methyl acrylate to
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silylation of the remaining arylmethyl ether with triethylsi-
lane and tris(pentafluorophenyl)borane furnished TES-pro-
tected phenol 28.[19] The ester was reduced with DIBAL-H to
give primary alcohol 29, which was directly activated for
displacement by conversion into the tosylate 30. When this
cyclization precursor was heated with TBAF it rapidly
underwent the alkylative cyclization in excellent yield to
form the platensimycin core 31. The 1H and 13C NMR spectra
of 31 are identical to those previously reported,[6e,f] thus
completing our formal synthesis of platensimycin.
In summary, we have developed a very efficient route to
the compact platensimycin core. Our architectural assembly
relied on the use of a new copper-catalyzed oxirane ring-
expansion in combination with an alkylative dearomatization
to complete the core. Other notable features of this synthetic
approach include an underutilized phenol ether deprotection,
nucleophilic enoate epoxidation, and a mild introduction of a
substituted alkyl ketone using a trifluoroborate cross-cou-
pling.
Received: June 19, 2009
Published online: October 1, 2009
This success inspired us to improve the synthetic approach
by starting with brominated anisaldehyde 32 rather than the
vanillin analogue 12 (Scheme 5). This approach would allow
Keywords: copper · natural products · oxiranes · platensimycin ·
total synthesis
.
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