A simple, efficient, and enantiocontrolled synthesis of a near-structural mimic of platensimycin

Article abstract of DOI:10.1021/ol801400a

(Chemical Equation Presented) A close structural relative of platensimycin was synthesized efficiently in nine steps.

Full text of DOI:10.1021/ol801400a

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3877-3878
A Simple, Efficient, and
Enantiocontrolled Synthesis of a
Near-Structural Mimic of Platensimycin
Ying-Yeung Yeung and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge,
Massachusetts 02138
corey@chemistry.harVard.edu
Received June 20, 2008
ABSTRACT
A close structural relative of platensimycin was synthesized efficiently in nine steps.
Despite the pressing need for new types of antibiotics to
combat the emergence of drug-resistant strains of pathogenic
microbes, very few useful naturally produced and novel
antimicrobial compounds have been identified in recent years.
A rare exception is the discovery by Merck of platensimycin
(1), a potent inhibitor of microbial fatty acid biosynthesis.1
That fact and the fascinating structure of 1 have stimulated
much recent research on synthetic approaches to platensi-
mycin and related structures. Several quite interesting and
diverse synthetic sequences for the synthesis of platensimycin
via the key tetracyclic ketone 2 have been described.2 In
our laboratory,3 the core tetracycle 2 was constructed
enantioselectively and expeditiously from the achiral quinone
Scheme 1
of the carbons of 2 are generated in the early intermediate 4
which was produced enantioselectively from the achiral
precursor 3.
In this paper, we describe a totally new and exceedingly
simple synthesis of platensimycin analogue 5, a compound
monoketal 3 via the chiral conjugate adduct 4 (Scheme 1).3
This route is interesting not only because it is short, highly
enantioselective, and stereocontrolled but also because all
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10.1021/ol801400a CCC: $40.75
Published on Web 07/30/2008
2008 American Chemical Society

that differs form platensimycin only in the replacement of
one of the methylene bridges by oxygen and the excision of
the other methylene bridge.
catalyst A.7,8 Reduction of the formyl group of 8 followed
by desilylation provided the keto diol 9 in 84% overall yield.
Treatment of 9 with a catalytic amount of AuCl3 in MeOH
at 23 °C for 1 h afforded the tricyclic core of 5, ketone 10,
in 85% yield and >98% ee after one crystallization from
EtOAc-hexanes, mp 140-142 °C.9 The structure of 10 was
fully confirmed by single-crystal X-ray diffraction analysis.8
The saturated ketone 10 was then R-methylated and R,ꢀ-
dehydrogenated by the following sequence: (1) treatment
with lithium hexamethyldisilazide (LiHMDS) in THF at -78
°C followed by reaction with methyl iodide, (2) R′-depro-
tonation and conversion to the R′-phenylseleno ether using
LiHMDS followed by PhSeBr in THF at -78 °C, and (3)
treatment with H2O2-pyridine in CH2Cl2 at 23 °C to give
the R,ꢀ-enone 11 in 75% overall yield.
Exposure of the enone 11 to potassium tert-butoxide and
methyl acrylate in THF effected Michael addition to form a
keto methyl ester which upon saponification yielded the keto
acid 12 (63% overall yield). The acid 12 was coupled to the
amino group of the bis-methoxymethyl ether of methyl 2,4-
dihydroxy-3-aminobenzoate after carbonyl activation using
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) to give the amide ester 13
which after saponification gave the required platensimycin
analogue 5 in 58% overall yield from 12.10
The O-CH2 bridge across the tetrahydropyran ring of 5
serves to maintain a conformation of the core that is very
similar to that for platensimycin. Evidence in the literature
suggests that 5 will have excellent antimicrobial activity.4
An interesting aspect of our synthesis of 5 is the assembly
of all of the carbon atoms of the bridged ring core and also
the two initial stereocenters (as a vicinal pair) with excellent
diastereo- and enantioselectivity in the very first step (Scheme
2). [4 + 2]-Cycloaddition of the diene 65 to the enynal 76
Scheme 2
We have also used the carboxylic acid 12 to synthesize a
number of other carboxamido benzoic analogues of 5. The
antibiotic activities of 5 and these new analogues relative to
platensimycin are now under study. Initial results indicate
that 5 is a potent antibiotic.
Supporting Information Available: Experimental pro-
cedures and characterization data for all reactions and
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL801400A
(4) (a) Nicolaou, K. C.; Tang, Y.; Wang, Y.; Stepan, A. F.; Li, A.;
Montero, A. J. Am. Chem. Soc. 2007, 129, 14850–14851. (b) Nicolaou,
K. C.; Lister, T.; Denton, R. M.; Montero, A.; Edmonds, D. J. Angew.
Chem., Int. Ed. 2007, 46, 4712–4714.
(5) This diene was prepared in 92% yield from 5-[[(1,1-dimethyleth-
yl)dimethylsilyl]oxy]-4-penten-2-one (see Piggott, M. J.; Wege, D. Aust.
J. Chem. 2003, 56, 691–702. ) by reaction with triisopropylsilyl triflate
and triethylamine in CH2Cl2 at -78 °C for 1 h and then 0 °C for 12 h.
(6) The aldehyde 7 was made from 2-methylenyl-4-pentyn-1-ol (see
Mesnard, D.; Miginiac, L. J. Organomet. Chem. 1991, 420, 163–170.) by
oxidation with activated MnO2 in CH2Cl2 at 23 °C for 8 h.
(7) (a) Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966–
8967. (b) Corey, E. J.; Loh, T.-P.; Roper, T. D.; Azimioara, M. D.; Noe,
M. C. J. Am. Chem. Soc. 1992, 114, 8290–8292. (c) Corey, E. J.; Guzman-
Perez, A.; Loh, T.-P. J. Am. Chem. Soc. 1994, 116, 3611–3612.
(8) Experimental details and analytical and physical data are given in
the Supporting Information.
(9) (a) Antoniotti, S.; Genin, E.; Michelet, V.; Genet, J.-P. J. Am. Chem.
Soc. 2005, 127, 9976–9977. (b) Barluenga, J.; Die´guez, A.; Ferna´ndez, A.;
Rodríguez, Fan˜ana´s, F. J. Angew. Chem., Int. Ed. 2006, 45, 2091–2093.
(10) The similarity of optical rotation of 5 ([R]23 -68.5, c ) 0.2,
D
acetone) and the natural platensimycin (1) ([R]23D -51.1, c ) 0.1, MeOH)
confirmed the absolute configuraton of 5, which also corresponds to that
expected from previous studies with catalyst A (see ref 7).
produced the required key intermediate 8 in 60% yield and
with 93:7 enantioselectivity using the Corey-Loh chiral
3878
Org. Lett., Vol. 10, No. 17, 2008