Total synthesis of (±)-platencin

Article abstract of DOI:10.1002/anie.200800756

(Chemical Equation Presented) Resistant bacteria - beware! Platencin, a structurally novel broad-spectrum antibacterial agent, was the target of a total synthesis from o-anisic acid (see scheme). A Diels-Alder reaction with an a-substituted cyclohexenone as well as a [Ni-(cod)₂]-promoted 1,4-addition enables the concise and stereocontrolled formation of the core. A protecting group free coupling with an aniline unit completed the synthesis. cod = 1,5-cyclooctadiene.

Full text of DOI:10.1002/anie.200800756

Angewandte
Chemie
DOI: 10.1002/anie.200800756
Natural Product Synthesis
Total Synthesis of (Æ )-Platencin**
Joji Hayashida and Viresh H. Rawal*
The discovery of penicillin represents a milestone in modern
medicine.[1] Hailed as miracle drugs, penicillin and other
antibiotics have helped millions of people around the world to
fight off deadly infections and are credited with extending the
average human life span by nearly ten years. These advances
notwithstanding, the effectiveness of available antibiotics has
diminished steadily as bacteria have evolved mechanisms to
foil them.[2] Indeed, over the past decade there has been an
alarming increase in infectious pathogens that are resistant to
all commonly used antibiotics, even vancomycin, which until
recently had been the drug of last resort. This growing
prevalence of multidrug-resistant bacteria represents a major
threat to human health and makes the identification and
development of new classes of antibiotics imperative.[3]
In 2007, through mass screening of natural product
extracts, scientists from Merck reported the identification of
platencin (1),[4] a structurally novel antibacterial agent
isolated from Streptomyces platensis MA7339 (Scheme 1). A
products display similar activities, they have unique differ-
ences. For example, whereas platensimycin (2) primarily
inhibits FabF, platencin (1) inhibits both FabF and FabH.[4]
The targeting of two essential proteins rather than one should
make it harder for bacteria to develop resistance to platencin
(1).
The biological activity and unique structure of platensi-
mycin (2) have sparked the interest of chemists around the
world. An elegant total synthesis of the natural product was
reported in the same year as the structure disclosure,[6a] and
this was followed by nine other unique formal syntheses.[6,7]
By contrast, there is little work reported towards the synthesis
of platencin.[8] Herein we report an efficient total synthesis of
(Æ )-platencin (1).
Platencin shares with platensimycin the polar 3-amino-
2,4-dihydroxybenzoic acid unit, but differs in the intricacy of
the lipophilic core. Whereas platensimycin possesses a
bicyclo[3.2.1]octane carbon framework, platencin incorpo-
rates a bicyclo[2.2.2]octane skeleton. We envisioned forma-
tion of this core through a transition-metal-mediated intra-
molecular 1,4-conjugate addition reaction (Scheme 2), a
Scheme 1. Structures of platencin (1) and platensimycin (2).
year earlier, the same research group had reported the
isolation of platensimycin (2)[5] from a different strain of the
same bacteria. Both compounds display potent bactericidal
activity against a broad spectrum of bacteria, including key
antibiotic-resistant pathogens such as methicillin-resistant
Staphylococcus aureus, vancomycin-resistant enterococci, and
Streptococcus pneumoniae. These compounds inhibit the
biosynthesis of bacterial fatty acids through binding with the
initiation condensing and elongation condensing enzymes
FabH and FabF/B, respectively. Although the two natural
Scheme 2. Retrosynthetic analysis of platencin (1). TBS=tert-butyldime-
thylsilyl.
process that was also expected to install the requisite exo
methylene unit. The bisenone-containing cis-decalin 4 was
expected to come from the Diels–Alder reaction between
diene 6 and an a-substituted cyclohexa-2,5-dienone—or its
synthetic equivalent, compound 5. Finally, enone 5 would be
available through reductive allylation of o-anisic acid (7).
Scheme 3 provides an outline of the steps used to realize
the above plan. The cyclohexadienone equivalent, selenide 5
was conveniently prepared from commercially available o-
anisic acid (7). Birch reduction of 7 was followed by alkylation
of the enolate intermediate with 2,3-dibromopropene.[9] The
resulting allylated product was subjected to an acid work-up
[*] J. Hayashida, Prof. Dr. V. H. Rawal
Department of Chemistry
Universityof Chicago
5735 South Ellis Avenue, Chicago, IL 60637 (USA)
Fax: (+1)773-702-0805
E-mail: vrawal@uchicago.edu
Homepage: http://rawalgroup.uchicago.edu
[**] We thank Prof. Chong Zheng, Northern Illinois University, for X-ray
crystallographic analysis. This work was supported by the National
Institutes of Health (USA). Partial support byMerck & Co. is
gratefullyacknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 3. Synthesis of the platencin core (3). Reagents and conditions: a) Na, NH3, 1,2-dibromoethane (1 mol%), 2,3-dibromopropene
(1.25 equiv), À788C to 258C, then conc. HCl, 1,2-dichloroethane, reflux, 44%; b) LiHMDS (1.2 equiv), PhSeCl (1.3 equiv), THF, À788C, 83%;
c) (E)-1-dimethylamino-3-tert-butyldimethylsiloxy-1,3-butadiene (6; 3.0 equiv), neat, 408C, then CH2Cl2, 49% aq HF, À788C to 258C, 72%; d) H2O2
(3.0 equiv), pyridine (2.0 equiv), CH2Cl2, 258C, 71%; e) DIBALH (1.5 equiv), THF, À788C, quant; f) [Ni(cod)2] (3.0 equiv), cod (6.0 equiv), MeCN,
258C, 69%; g) TsOH (10 mol%), TsNHNH2 (1.2 equiv), THF, reflux, 98%; h) NaBH3CN (4.0 equiv), ZnCl2 (1.0 equiv), EtOH, reflux, 92%; i) MnO2
(10 equiv), CH2Cl2, 258C, 79%. cod=1,5-cyclooctadiene, DIBALH=diisobutylaluminum hydride, HMDS=hexamethyldisilazane, Ts=para-
toluenesulfonyl.
and heating, which accomplished hydrolysis of the enol ether
and decarboxylation to cleanly afford the desired 2-(2-bromo-
allyl)-cyclohex-2-enone. Standard deprotonation/selenation
provided enone 5 in 83% yield.
addition products have also been reported.[13] In the event,
although the [Ni(cod)2]-mediated cyclization of bisenone 4
was successful, it was low yielding. Examination of molecular
models indicated that allylic alcohol 8 might be a better
substrate for the cyclization, as it would exist preferentially in
the chair-chair conformation, which is required for cycliza-
tion. The desired compound was obtained in quantitative
yield and with complete regio-and stereoselectivity upon
treatment of 4 with DIBALH at À788C. As expected, the less
hindered carbonyl group was selectively reduced. The dia-
stereofacial selectivity can be understood by considering the
two chair-chair conformations (A and B) of the cis-decalin
unit. In conformation A, axial hydride addition from the less
hindered face would give the observed product. The same
facial selectivity is expected for conformation B, although
through equatorial attack.
Subjecting 8 to modified Delgado conditions—[Ni(cod)2]
with added cod—promoted the desired reaction to provide
tricyclic ketone 9 in good yield.[14] With the methylenebicyclo-
[2.2.2]octane skeleton secured, what remained were adjust-
ments to the oxidation states. In preparation for the ketone
deoxygenation, compound 9 was converted into tosylhydra-
zone 10, which was obtained as a crystalline solid in 98%
yield. The X-ray analysis for this compound confirmed the
bicyclo[2.2.2]octane connectivity assigned to the cyclization
product. Subjecting 10 to the protocol developed by Caglioti
and Magi,[15] using NaBH3CN in the presence of ZnCl2,
provided the saturated product. Finally, the allylic alcohol was
smoothly oxidized with MnO2 to afford the platencin core 3 in
79% yield.
Construction of the cis-decalin, which contains a quater-
nary center, through a Diels–Alder reaction presents a
significant challenge, as 2-alkyl-substituted cyclohexenones
are reluctant participants in these reactions.[10] Diels–Alder
reactions with such dienophiles require Lewis acid activation
or high temperature, both of which can have a deleterious
effect on highly electron-rich dienes. In this regard, we have
developed the use of 1-amino-3-siloxybutadienes as alternate
electron-rich dienes. We and others have shown such dienes to
be highly reactive in uncatalyzed Diels–Alder and hetero-
Diels–Alder reactions with a range of dienophiles.[11] Indeed,
we were pleased to observe that the Diels–Alder reaction of
enone 5 with aminosiloxy diene 6 proceeded well at 408C.
Quenching the reaction at low temperature with 49% HF
provided the requisite cis-decalin framework in 72% yield, as
an inconsequential 1:1 mixture of selenophenyl diastereo-
mers.[11i] Subsequent selenoxide formation/elimination
afforded bisenone 4 in good yield.
Bisenone 4 is set up for construction of the central
methylenebicyclo[2.2.2]octane unit, the identifying motif of
platencin. Our plan was to use a [Ni(cod)2]-promoted
reductive cyclization reaction, a process similar to that
developed by Delgado and co-workers.[12] These reactions
typically involve the 5-exo-trig cyclization of a vinyl bromide
precursor followed by b-hydride elimination of the nickel
intermediate, or its capture by a suitable nucleophile.
Interesting examples of this reaction which give 1,4-conjugate
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With the core of platencin completed, the final challenges
included diastereoselective introduction of the methyl and
propionate groups as well as the coupling of the resulting
carboxylic acid with 3-amino-2,4-dihydroxybenzoic acid
(Scheme 4). This very same functionality is present in
In summary, we have developed a concise and stereocon-
trolled route to platencin. The synthesis features: 1) a
challenging Diels–Alder reaction with an a substituted cyclo-
hexenone, 2) a [Ni(cod)2]-promoted cyclization reaction to
generate the bicyclo[2.2.2]octane framework, 3) a novel
protocol for the Tamao oxidation, and 4) a direct, protecting
group free coupling strategy for introduction of the anilide
unit. This strategy not only lends itself to the asymmetric
synthesis but also to the preparation of diverse analogues of
this important antibiotic lead compound.
Received: February 14, 2008
Published online: May 2, 2008
Keywords: antibiotics · cycloaddition · natural products ·
.
total synthesis
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Scheme 4. Completion of the synthesis of platencin (1). Reagents and
conditions: a) KHMDS (1.5 equiv), MeI (8.0 equiv), THF/HMPA,
À788C, 87%; b) (E)-1-tribenzylsilyl-3-iodo-prop-1-ene (1.5 equiv),
KHMDS (1.3 equiv), THF/HMPA, À788C, 73%; c) TBAF (5.0 equiv),
iodosobenzene (1.2 equiv), H2O2 (6.0 equiv), KHCO3 (5.0 equiv), THF,
0 to 408C, 89%; d) NaClO2 (10 equiv), NaH2PO4 (15 equiv), 2,3-
dimethylbutene (30 equiv), tBuOH/H2O, quant; e) 13 (2.0 equiv), DCC
(1.3 equiv), DMAP (2.0 equiv) Et3N (3.0 equiv), MeCN/DMF, RT, 62%.
Bn=benzyl, DCC=N,N’-dicyclohexylcarbodiimide, DMAP=4-di-
methylaminopyridine, DMF=N,N-dimethylformamide, HMPA=hexa-
methylphosphoramide, TBAF=tetra-n-butylammonium fluoride.
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advantage of the diastereoselective double-alkylation pro-
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directly, the allylation was carried out using (E)-1-tribenzyl-
silyl-3-iodo-prop-1-ene[16] to give the desired product 11 in
good yield and with complete diastereoselectivity. However,
the Tamao oxidation[17] of the vinyl silane proved difficult and
was complicated by the competing epoxidation of the enone
moiety. We discovered that the oxidation proceeded cleanly
when an equivalent of iodosobenzene was added to the
reaction.[18] This new oxidation protocol provided the desired
aldehyde product in excellent yield (89%). Subsequent
Lindgren–Kraus oxidation[19] afforded the desired carboxylic
acid 12 in quantitative yield.
In the syntheses of platensimycin and platencin, fully or
partially protected anilines (for example 13)[20] were coupled
to the core carboxylic acids.[6a,8] We reasoned that the direct
coupling of the fully unprotected aniline with the acid would
be feasible. Even if the initial coupling product was either an
anhydride or one of the two possible phenolic esters then,
based on thermodynamic considerations, the intermediate
was expected to transfer in an intramolecular fashion into the
desired amide product. As expected, treatment of carboxylic
acid 12 with DCC, DMAP, and Et3N followed by the addition
of aniline 13 afforded platencin (1) in 62% yield.
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