An expedient asymmetric synthesis of platencin

Article abstract of DOI:10.1021/ja804588r

A short and efficient synthesis of enone 3, a key intermediate in the total synthesis of platencin (2), based on an intramolecular Diels-Alder reaction is described. Copyright

Full text of DOI:10.1021/ja804588r

Published on Web 07/30/2008
An Expedient Asymmetric Synthesis of Platencin
K. C. Nicolaou,* Qiao-Yan Toh, and David Y.-K. Chen*
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for
Science, Technology and Research (ASTAR), 11 Biopolis Way, The Helios Block, #03-08, Singapore 138667
Received June 19, 2008; E-mail: kcn@scripps.edu; david_chen@ices.a-star.edu.sg
Fatty acid biosynthesis (FAS) is an essential metabolic process
for all living organisms.1 As such, selective intervention of fatty
acid metabolism constitutes a useful means to treat disease. Indeed,
inhibitors of certain steps of the bacterial fatty acid biosynthetic
pathway have been targeted as potential antibacterial agents to treat
infections.2 The recent discovery of the broad-spectrum antibiotics
platensimycin (1, Figure 1)3 and platencin (2, Figure 1)4 by a Merck
team represents a milestone in the search for novel FAS inhibitors.
Through application of RNA silencing technologies, platensimycin
and platencin were identified from a high-throughput screening of
natural product extracts. While platensimycin is a selective inhibitor
of the fatty acid condensing enzyme FabF, platencin exhibits dual
activity, inhibiting both FabF and FabH. As these enzymes are
highly conserved among the clinically relevant pathogens, these
antibiotics display broad-spectrum antibacterial properties, including
activities against the drug resistant strains MRSA (methicillin-
resistant S. aureus) and VRE (vancomycin-resistant enterococci).
The promising therapeutic potentials and intriguing molecular
architectures of platensimycin (1) and platencin (2) have instigated
significant research activities in scientific and medical circles, and
a number of chemical syntheses of platensimycin,5 platencin,6 and
rationally designed analogues of platensimycin have been reported.7
Herein we disclose an expedient and asymmetric synthetic route
to enone 3 that constitutes a formal total synthesis of platencin (2),
since 3 has been previously converted to this natural product.6
As outlined in Figure 1, retrosynthetic simplification of platencin
(2) began with the initial detachment of the two side chains of the
molecule from its tricyclic core structure as shown to unravel
cyclohexenone 3, a known precursor of the target.6 Inspired by the
work of Liao and co-workers in the cycloaddition reactions of
masked o-benzoquinones,8 an intramolecular Diels-Alder reaction
of 6,6-dimethoxy-cyclohexa-2,4-dienone 4 bearing a pendent
terminal alkene was defined as the means to cast the tricyclic core
of enone 3. The stereochemical requirements of the tricyclic scaffold
of enone 3 were expected to arise from the sole stereocenter within
benzylic alcohol 5, whose absolute stereochemistry was to be
derived from an asymmetric reduction of the corresponding carbonyl
compound.
Figure 1. Structures of platensimycin (1) and platencin (2) and retrosyn-
thetic analysis of 2 leading, sequentially, to tricyclic enone 3, dienone 4,
and benzyl alcohol 5. TBDPS ) tert-butyldiphenylsilyl.
phenol 9 with 1.1 equiv of PhI(OAc)2 followed by solvent exchange
from methanol to toluene and refluxing led, via the intermediacy
of 6,6-dimethoxy-cyclohexa-2,4-dienone derivative 4, to Diels-Alder
1
adduct 10 in 75% yield and 15:1 dr (as determined by H NMR
spectroscopic analysis). The remarkably high degree of stereocontrol
by the lone stereocenter within precursor 4 in forming the three
additional stereocenters in product 10 (endo) was both interesting
and gratifying.14 Catalytic hydrogenation (Pd/C cat., H2) of 10 gave
hydroxy ketone 11 in essentially quantitative yield. The desired
elimination of the equatorially disposed secondary hydroxyl group
within 11 posed an initial challenge that was ultimately overcome
by a three-step procedure involving (i) oxidation of the secondary
hydroxyl group to the corresponding ketone (PCC);15 (ii) enol
triflate formation (PhNTf2, KHMDS); and (iii) reductive detriflation
[Pd(PPh3)2Cl2, HCO2H, n-Bu3N; 80% overall yield]. Further
reductive processing with SmI2 cleaved the gem-dimethoxy moiety
from 12 providing keto-olefin 13 in 72% yield. Addition of
MeMgBr to the latter compound furnished an inconsequential
mixture of tertiary alcohols (14, ca. 1:1) which were subjected,
without separation, to the allylic oxidation conditions described by
Shing et al. [Mn(OAc)3, t-BuOOH, O2]16 to afford enone 15, as a
mixture of diastereoisomers, in 70% yield over the two steps.
Finally, Martin’s sulfurane-mediated elimination of the tertiary
hydroxyl group from 15 resulted in the exclusive formation of the
desired exocyclic olefin (90% yield), completing the synthesis of
the targeted tricyclic enone 3 and, thus, the formal total synthesis
of platencin (2). Enone 3 exhibited identical physical properties
(1H and 13C NMR spectra, [R]D, and MS) to those previously
reported for this compound.6
The synthesis of enone 3 commenced with silyl protection
(TBDPSCl, imidazole, DMAP, 95%) of guaiacol (6)9 and proceeded
as shown in Scheme 1. ortho-Lithiation of the TBDPS-protected
guaiacol (s-BuLi, TMEDA)10 followed by treatment of the resulting
aryl lithium species with alkenyl Weinreb amide 711 gave ketone
8 in 51% yield (90% based on 57% conversion). Catalytic
asymmetric reduction of ketone 8 under the Corey-Bakshi-Shibata
(CBS) conditions12 delivered benzyl alcohol 5 in 78% yield13 and
Commencing with a readily available and inexpensive starting
material, and based on a highly efficient and stereoselective
intramolecular Diels-Alder reaction, the described chemistry offers
an expedient catalytic asymmetric route to platencin and provides
an opportunity for rapid construction of analogues of this new
antibiotic for biological and pharmacological studies.
1
90% ee (as determined by H NMR analysis of the Mosher ester
derivative). Desilylation of 5 through exposure to TBAF (92% yield)
provided phenol 9, setting the stage for the generation and
intramolecular Diels-Alder trapping of the targeted monoprotected
o-benzoquinone. Pleasingly, treatment of a methanolic solution of
9
11292 J. AM. CHEM. SOC. 2008, 130, 11292–11293
10.1021/ja804588r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Synthesis of Enone 3 a
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Acknowledgment. This paper is dedicated to Professor C.-H.
Wong on the occasion of his 60th birthday. K.C.N. is also at the
Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, and the Department of Chemistry
and Biochemistry, University of California, San Diego, 9500
Gilman Drive, La Jolla, California 92093. We thank Dr. Dattatraya
H. Dethe and Ms. Sanny G. Ing for their assistance and Ms. Doris
Tan (ICES) for high resolution mass spectrometric (HRMS)
assistance. Financial support for this work was provided by
A*STAR, Singapore.
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Supporting Information Available: Experimental procedures and
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via Internet at http://pubs.acs.org.
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