Total synthesis of (-)-platensimycin, a novel antibacterial agent

Article abstract of DOI:10.1021/jo802261f

An enantioselective synthesis of platensimycin, a novel antibiotic natural product that inhibits bacterial β-ketoacyl-(acyl-carrier-protein) synthase (FabF), is described. Our synthetic strategy for the construction of the oxatetracyclic core involved an

Full text of DOI:10.1021/jo802261f

Total Synthesis of (-)-Platensimycin, a Novel Antibacterial Agent
Arun K. Ghosh* and Kai Xi
Departments of Chemistry and Medicinal Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
akghosh@purdue.edu
ReceiVed October 8, 2008
An enantioselective synthesis of platensimycin, a novel antibiotic natural product that inhibits bacterial
ꢀ-ketoacyl-(acyl-carrier-protein) synthase (FabF), is described. Our synthetic strategy for the construction
of the oxatetracyclic core involved an intramolecular Diels-Alder reaction. Our preliminary studies
provided a complex tetracyclic product by first undergoing an interesting 1,5-hydride shift followed by
a Diels-Alder reaction. Further optimization of the diene’s electronic properties, by incorporation of a
methoxy group, led to the oxatetracyclic core of platensimycin. The three required chiral centers, including
two all-carbon quaternary chiral centers, were built in the intramolecular Diels-Alder step. The synthesis
utilized natural (+)-carvone as the key chiral starting material, which determined the stereochemistry of
the final product. The synthesis also featured an efficient Petasis olefination, a hydroboration sequence,
a Gais’s asymmetric Horner-Wadsworth-Emmons reaction, and a mercury salt catalyzed enol ether
isomerization.
Introduction
no observed toxicity in mice.4 (-)-Platensimycin possesses a
novel mechanism of action. It blocks bacterial fatty acid
biosynthesis by targeting a key enzyme, bacterial ꢀ-ketoacyl-
(acyl-carrier-protein) synthase (FabF), which catalyzes the
crucial carbon-carbon bond formation in the chain-elongation
step. Before the discovery of (-)-platensimycin, only weak
antibiotics were known to target FabF.7 Platensimycin exhibited
no cross-resistance to other key antibiotic-resistant strains,
including methicillin-resistant Staphylococcus aureus, vanco-
mycin-resistant Staphylococcus aureus, and vancomycin-
resistant Enterococcus faecium. Unfortunately, (-)-platensimy-
cin is not a good drug candidate due to its poor pharmacokinetic
properties.8 However, it constitutes an important lead structure,
which provided a starting template for structural modifications
and drug development.
Antibiotic resistance is a serious medical problem worldwide.
Currently, available antibiotic drugs are becoming less and less
effective due to the emergence of a range of lethal resistant
strains.1 Therefore, the development of new antibiotics exhibit-
ing novel mechanisms of action has become an urgent priority.
Since the early 1960s, the discovery of novel antibiotics from
natural products has been quite limited.2,3 Recent isolation of
(-)-platensimycin (1, Figure 1), from a strain of Streptomyces
platensis, by Merck has cast a new light on antibiotic research.4-6
(-)-Platensimycin shows potent antibacterial activity against
a broad range of Gram-positive organisms, in ViVo efficacy, and
* Corresponding author. Phone: 765-494-5323. Fax: 765-496-1612.
(1) Walsh, C. Antibiotics: actions, origins, resistance; ASM Press: Wash-
ington, D.C., 2003.
(2) Singh, S. B.; Barrett, J. F. Biochem. Pharmacol. 2006, 71, 1006–1015.
(3) Butler, M. S.; Buss, A. D. Biochem. Pharmacol. 2006, 71, 919–929.
(4) Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.; Kodali, S.; Galgoci,
A.; Painter, R.; Parthasarathy, G.; Tang, Y. S.; Cummings, R.; Ha, S.; Dorso,
K.; Motyl, M.; Jayasuriya, H.; Ondeyka, J.; Herath, K.; Zhang, C. W.; Hernandez,
L.; Allocco, J.; Basilio, A.; Tormo, J. R.; Genilloud, O.; Vicente, F.; Pelaez, F.;
Colwell, L.; Lee, S. H.; Michael, B.; Felcetto, T.; Gill, C.; Silver, L. L.; Hermes,
J. D.; Bartizal, K.; Barrett, J.; Schmatz, D.; Becker, J. W.; Cully, D.; Singh,
S. B. Nature 2006, 441, 358–361.
(5) Singh, S. B.; Jayasuriya, H.; Ondeyka, J. G.; Herath, K. B.; Zhang, C. W.;
Zink, D. L.; Tsou, N. N.; Ball, R. G.; Basilio, A.; Genilloud, O.; Diez, M. T.;
Vicente, F.; Pelaez, F.; Young, K.; Wang, J. J. Am. Chem. Soc. 2006, 128, 11916–
11920.
Due to its intriguing structure, especially the complex
hydrophobic oxatetracyclic core, and its excellent biological
activity, (-)-platensimycin has grasped the attention of many
(7) Young, K.; Jayasuriya, H.; Ondeyka, J. G.; Herath, K.; Zhang, C. W.;
Kodali, S.; Galgoci, A.; Painter, R.; Brown-Driver, V.; Yamamoto, R.; Silver,
L. L.; Zheng, Y. C.; Ventura, J. I.; Sigmund, J.; Ha, S.; Basilio, A.; Vicente, F.;
Tormo, J. R.; Pelaez, F.; Youngman, P.; Cully, D.; Barrett, J. F.; Schmatz, D.;
Singh, S. B.; Wang, J. Antimicrob. Agents Chemother. 2006, 50, 519–526.
(8) Herath, K. B.; Attygalle, A. B.; Singh, S. B. J. Am. Chem. Soc. 2007,
129, 15422–15423.
(6) Habich, D.; von Nussbaum, F. ChemMedChem 2006, 1, 951–954.
10.1021/jo802261f CCC: $40.75
Published on Web 01/05/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1163–1170 1163

Ghosh and Xi
FIGURE 1. Structure of (-)-platensimycin 1 and ketone intermediate 2.
synthetic chemists around the world.9 The first total synthesis
of platensimycin as a racemic mixture was achieved by Nicolaou
and co-workers.10 Since then, a number of formal syntheses
targeting the same ketone intermediate (2, Figure 1) in racemic
or optically active forms have appeared in the literature.11-19
Syntheses and biological evaluation of several structural ana-
logues have also been reported.20-23 More recently, Nicolaou
and co-workers reported a detailed synthesis and structure-activity
relationship study.24 We recently reported a highly stereose-
lective synthesis of the oxatetracyclic core of (-)-platensimycin
by using an intramolecular Diels-Alder reaction as the key
step.25 Based upon the results of our preliminary Diels-Alder
reaction, we devised a route for the total synthesis of platen-
simycin. Herein, we report a detailed account of our studies
leading to the total synthesis of (-)-platensimycin.
Results and Discussion
Our synthetic plan is outlined in Figure 2. Strategic discon-
nection of (-)-platensimycin at the amide bond provided a
protected aniline precursor 326 and platensic acid 4.27 This
TMSE-protected aniline derivative has been recently utilized
in a platencin synthesis by Nicolaou and co-workers.26 Platensic
acid 4 can be derived from ester 5 by elongation of the side
chain and subsequent oxidation to provide an enone moiety.
The cagelike (-)-platensimycin core 5 contains seven chiral
centers. We planned to construct this core structure by using
FIGURE 2. Retrosynthesis of (-)-platensimycin (1).
an intramolecular Diels-Alder reaction. The intramolecular
Diels-Alder reaction is a powerful strategy for the construction
of stereochemically defined polycyclic compounds in a single-
step operation.28 Thus, disconnection of ester 5 between the
C4-C5 and C8-C9 single bonds provided the simpler bicyclic
precursor triene 6. Both trisubstituted olefins in triene 6 could
be obtained by Wittig olefination reactions29,30 or by
Horner->Wadsworth-Emmons reactions of the corresponding
ketone and aldehyde.31,32 The precursor of triene 6 could be
obtained from bicyclic ketone 7. The protected primary alcohol
functionality in ketone 7 could be prepared by a hydroboration
oxidation sequence from the corresponding enol ether derived from
lactone 8. The olefination of lactone 8 can be achieved by Petasis
olefination.33 The known lactone 8 can be synthesized from the
commercially available natural product (+)-carvone 9.
(9) Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 2548–
2555.
(10) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem., Int. Ed. 2006,
45, 7086–7090.
(11) Zou, Y. F.; Chen, C. H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B.
Org. Lett. 2007, 9, 1825–1828.
(12) Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem., Int.
Ed. 2007, 46, 3942–3945.
(13) Nicolaou, K. C.; Tang, Y. F.; Wang, J. H. Chem. Commun. 2007,
1922–1923.
(14) Li, P. F.; Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129,
9534–9535.
(15) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921–4923.
(16) Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2007, 46, 8074–
8075.
(17) Kim, C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew.
Chem., Int. Ed. 2008, 47, 4009–4011.
(18) Matsuo, J.-i.; Takeuchi, K.; Ishibashi, H. Org. Lett. 2008, 10, 4049–
4052.
(19) Nicolaou, K. C.; Pappo, D.; Tsang, K. Y.; Gibe, R.; Chen, D. Y. K.
Angew. Chem., Int. Ed. 2008, 47, 944–946.
(20) Nicolaou, K. C.; Lister, T.; Denton, R. M.; Montero, A.; Edmonds, D. J.
Angew. Chem., Int. Ed. 2007, 46, 4712–4714.
(21) Singh, S. B.; Herath, K. B.; Wang, J.; Tsou, N.; Ball, R. G. Tetrahedron
Lett. 2007, 48, 5429–5433.
Our synthesis of the known lactone 8 is summarized in
Scheme 1. (+)-Carvone 9 was converted to lactone 8 by a
modified literature procedure.34-36 Initial treatment of 9 with
Hg(OAc)2 in a mixture of THF and H2O followed by reduction
with NaBH4 can provide ketones 11 and 12, as reported.
However, this reaction generates a stoichiometric amount of
mercury as a byproduct which is not convenient for large-scale
synthesis. We therefore devised a stepwise approach to these
(22) Nicolaou, K. C.; Tang, Y. F.; Wang, J. H.; Stepan, A. F.; Li, A.; Montero,
A. J. Am. Chem. Soc. 2007, 129, 14850–14851.
(23) Yeung, Y.-Y.; Corey, E. J. Org. Lett. 2008, 10, 3877–3878.
(24) Nicolaou, K. C.; Stepan, A. F.; Lister, T.; Li, A.; Montero, A.; Tria,
G. S.; Turner, C. I.; Tang, Y.; Wang, J.; Denton, R. M.; Edmonds, D. J. J. Am.
Chem. Soc. 2008, 130, 13110–13119.
(28) Fallis, A. G. Can. J. Chem. 1984, 62, 183–234.
(29) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 87, 1318–1330.
(30) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654–1666.
(31) Horner, L.; Hoffmann, H.; Wippel, H. G. Chem. Ber. 1958, 91, 61–63.
(32) Wadsworth, W.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733–
1738.
(25) Ghosh, A. K.; Xi, K. Org. Lett. 2007, 9, 4013–4016.
(26) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J. Angew. Chem., Int. Ed.
2008, 47, 1780–1783.
(27) Herath, K. B.; Zhang, C.; Jayasuriya, H.; Ondeyka, J. G.; Zink, D. L.;
Burgess, B.; Wang, J.; Singh, S. B. Org. Lett. 2008, 10, 1699–1702.
(33) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392–6394.
(34) Weinges, K.; Reichert, H. Synlett 1991, 785–786.
(35) Weinges, K.; Reichert, H.; Huberpatz, U.; Irngartinger, H. Liebigs Ann.
Chem. 1993, 403–411.
(36) Weinges, K.; Reichert, H.; Braun, R. Chem. Ber. 1994, 127, 549–550.
1164 J. Org. Chem. Vol. 74, No. 3, 2009

Total Synthesis of (-)-Platensimycin
SCHEME 1. Synthesis of Lactone 8
SCHEME 2. Synthesis of Ketone 7
ketones.37 As shown, treatment of (+)-carvone with NBS and
H2O provided bromide 10 in 89% yield.
Radical cyclization of 10 in the presence of n-Bu3SnH and a
catalytic amount of AIBN in refluxing benzene furnished
ketones 11 and 12 in 85% combined yield as a 1:1 mixture.
This mixture was separated by silica gel chromatography.
Baeyer-Villiger oxidation of ketone 12 with m-CPBA in
dichloromethane at reflux gave the corresponding seven mem-
bered lactone, which was opened by the adjacent tertiary alcohol
to form the five membered lactone 8 in 90% yield. Ketone 11
was subjected to the same reaction which gave the seven-
membered lactone 13 in 73% yield. Saponification of lactone
13 followed by lactonization under acidic conditions provided
lactone 8 in 85% yield with inversion of the quaternary chiral
center.
Lactone 8 was previously oxidized to ester 14 in a single
operation using m-CPBA.34-36 However, this reaction proved
to be extremely sluggish, and the yield was low (∼20%).
Therefore, we explored a stepwise and more reliable route to
this acetate, which is shown in Scheme 2. The secondary alcohol
in lactone 8 was first oxidized to the corresponding ketone using
Swern oxidation.38
It is noteworthy to mention that quenching the Swern
oxidation with Et3N partially epimerized the ketone product.
The use of sterically more hindered i-Pr2NEt rectified this
problem. The resulting ketone was successfully converted to
ester 14 by a Baeyer-Villiger oxidation with trifluoroperoxy-
acetic acid.39 Saponification of crude ester 14 gave the corre-
sponding secondary alcohol, which was protected with TBSCl
to provide the silyl ether 15 in 83% yield over four steps. Petasis
olefination33 of lactone 15 with Cp2TiMe2 in toluene at 90 °C
provided the corresponding enol ether. This product was
subjected to hydroboration with 9-BBN followed by oxidation
with H2O2 to provide the desired primary alcohol 16 and its
diastereomer 17 as a 2:1 mixture in 81% yield.40 It is important
to note that reaction times longer than 3 h led to diminished
yield due to the isomerization of the double bond. While
hydroboration by 9-BBN on the enol ether is expected mainly
from the less hindered convex face, the selectivity in the
hydroboration step is surprisingly modest. The low selectivity
may be due to developing nonbonding interaction between the
ring junction methyl group and the bulky borane reagent’s
approach on the enol ether from the convex face in the transition
state. The diastereomeric alcohols 16 and 17 were separated
by flash chromatography, and the major diastereomer 16 was
protected with TBDPSCl to provide the corresponding bis-silyl
ether in 98% yield. Selective cleavage of the secondary TBS
ether with a catalytic amount of DDQ in a 9:1 mixture of THF/
H2O furnished the secondary alcohol in 93% yield.41,42 Swern
oxidation of this alcohol afforded ketone 7 in 96% yield.
Our many attempts to transform the primary alcohol 17 to
the desired diastereomer 16 by oxidation of the primary alcohol
and epimerization of the corresponding aldehyde or ester were
not successful. However, we were able to partially convert 17
to 16 following the reaction sequence shown in Scheme 2.
Alcohol 17 was first converted to an iodide by reaction with I2
and PPh3 in 91% yield. Reductive opening of the iodide with
zinc dust in EtOH provided terminal olefin 18 in 85% yield.
Epoxidation of 18 with m-CPBA generated the epoxide and
subsequent epoxide opening by the adjacent alcohol afforded
16 and 17 as a mixture (1:1.2) in good yield. The mixture can
be separated by silica gel chromatography.
Our initial investigation of the crucial intramolecular
Diels-Alder reaction is outlined in Scheme 3. The diene
functionality in 22 was installed using a Horner-Wadsworth-
Emmons reaction. As shown in Figure 2, the geometry of the
trisubstituted olefin is expected to determine the orientation of
the diene in the transition state for the Diels-Alder reaction.
The approach of the flexible dienophile toward the diene will
determine the configuration of the cagelike oxatetracyclic
structure. It appears that by controlling the diene’s geometry,
(37) Srikrishna, A.; Hemamalini, P. J. Org. Chem. 1990, 55, 4883–4887.
(38) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
(39) Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett
1990, 533–535.
(40) Lambert, W. T.; Hanson, G. H.; Benayoud, F.; Burke, S. D. J. Org.
Chem. 2005, 70, 9382–9398.
(41) Crouch, R. D. Tetrahedron 2004, 60, 5833–5871.
(42) Tanemura, K.; Suzuki, T.; Horaguchi, T. J. Chem. Soc., Perkin Trans.
1 1992, 2997, 2998.
J. Org. Chem. Vol. 74, No. 3, 2009 1165

Ghosh and Xi
SCHEME 3. Intramolecular Diels-Alder Reaction of
Aldehyde 22
We initially utilized an electron-withdrawing ester group as
the dienophile. The intramolecular Diels-Alder reaction of this
substrate under thermal or Lewis acid catalyzed conditions did
not provide any desired product. A Diels-Alder reaction without
the R-methyl group on the dienophile was also unsuccessful,
providing no desired cycloadduct. We then planned to examine
an aldehyde functionality on the dienophile. Swern oxidation
of alcohol 21 furnished the crude aldehyde which was treated
with the corresponding Wittig reagent to provide unsaturated
aldehyde 22 in 68% yield. A dilute solution (0.005M) of
aldehyde 22 in mesitylene, in the presence of a catalytic amount
of 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical inhibi-
tor,46 was heated in a sealed tube at 220 °C for 2 h. The
intramolecular Diels-Alder product 23 was isolated as a single
isomer in 15% yield together with byproduct 24 isolated in 20%
1
yield. An examination of the H NMR spectrum of compound
24, revealed that this compound resulted from an intramolecular
Diels-Alder reaction of substrate 25. Conceivably, this ther-
modynamically more stable substrate was formed from 22 via
a 1,5-hydride shift under the elevated reaction temperature.
Our further attempts to carry out the Diels-Alder reaction
at lower temperatures in the presence of various Lewis acids
were unsuccessful. We therefore focused our attention on
improving the yield of desired cycloadduct 23. In this context,
we planned to incorporate an alkoxy group on the diene and
carry out the Diels-Alder reaction with an R,ꢀ-unsaturated ester
as the dienophile. Since the diene is more substituted, a 1,5-
hydride shift will be less likely to occur. Furthermore, the
presence of an alkoxy group will presumably improve reactivity
of the diene and the intramolecular Diels-Alder reaction may
be accelerated.
The synthesis of this new Diels-Alder substrate and the
resulting intramolecular Diels-Alder reaction is outlined in
Scheme 4. Protection of alcohol 20 as a THP ether followed
by removal of TBDPS with TBAF gave alcohol 26 in nearly
quantitative yield over two steps. Swern oxidation of alcohol
26 provided the corresponding aldehyde, which was subjected
to a Horner-Wadsworth-Emmons olefination with triethyl
phosphonoacetate to give the dienophile moiety as a separable
mixture (5:1) of E/Z-unsaturated esters. Removal of the THP
group on the E-isomer with camphorsulfonic acid in EtOH
furnished alcohol 27 in 65% overall yield. Alcohol 27 was
converted to the Diels-Alder substrate 28 in two steps involving
Dess-Martin oxidation of the allylic alcohol followed by Wittig
olefination of the resulting aldehyde. Triene derivative 28 was
obtained in 77% yield as an inseparable mixture (1:1) of E/Z
enol ethers. This mixture of enol ethers was subjected to the
intramolecular Diels-Alder reaction. In principle, both expected
methoxy diastereomers can be transformed into the oxatetra-
cyclic enone derivative. Thus, substrate 28 was heated in a
sealed tube at 200 °C for 2 h. This has provided the Diels-Alder
adduct 29 as a single isomer in 39% isolated yield, and Z-enol
ether (28-Z) was recovered in 38% isolated yield. The Z-isomer
did not undergo Diels-Alder reaction presumably due to the
developing nonbonding steric interactions between the terminal
methoxy group and the methylene group on the bicyclic ring
as shown in Scheme 4. The stereochemistry of the oxatetracyclic
core 29 was initially established by extensive NMR experiments
(1H, 13C, COSY, NOESY, HMQC, and HMBC). Subsequently,
the X-ray crystal structure of 29 (see the Supporting Information)
conclusively established the stereochemical outcome.
one can set the stereochemistry of the product. Since the ketone
7 carbonyl possesses an R-methylene group on each side, the
steric differentiation is marginal. The ring junction methyl group,
however, may be utilized to improve selectivity. Our initial
attempt of a selective olefination using a normal Horner-Wads-
worth-Emmons olefination with LHMDS and triethyl phospho-
noacetate provided only marginal selectivity for the E-olefin
1
(3:2, by H NMR analysis). Thus, we explored asymmetric
olefination with chiral phosphonoacetate reagent 19, which was
synthesized by transesterification of trimethyl phosphonoacetate
with (+)-phenylnormenthol.43-45 The Horner-Wadsworth-
Emmons reaction of 7 using chiral phosphonoacetate 19 at -50
1
°C furnished a mixture (4.5:1 by H NMR analysis) of the
corresponding unsaturated E- and Z-esters in 94% yield. The
E,Z mixture can be separated by flash chromatography on silica
gel. DIBAL reduction of the E-unsaturated ester afforded allylic
alcohol 20 in 86% yield, and (+)-phenylnormenthol was
recovered in 95% yield. Dess-Martin oxidation of the allylic
alcohol afforded the aldehyde that was reacted with the
corresponding Wittig reagent to provide the diene functionality.
Removal of the TBDPS group with TBAF in THF furnished
primary alcohol 21 in 80% yield over three steps. Swern oxidation
of alcohol 21 gave the corresponding aldehyde, which was
subjected to a Wittig reaction or a Horner-Wadsworth-Emmons
olefination to provide substrates for the exploration of the key
intramolecular Diels-Alder reaction.
(43) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656–4661.
(44) Hatakeyama, S.; Satoh, K.; Sakurai, K.; Takano, S. Tetrahedron Lett.
1987, 28, 2713–2716.
(45) Gais, H. J.; Schmiedl, G.; Ossenkamp, R. K. L. Liebigs Ann., Recl.
1997, 2419–2431.
(46) Coppinger, G. M. J. Am. Chem. Soc. 1964, 86, 4385–4388.
1166 J. Org. Chem. Vol. 74, No. 3, 2009

Total Synthesis of (-)-Platensimycin
SCHEME 4. Intramolecular Diels-Alder Reaction of New
Substrate 28
SCHEME 6. Synthesis of Platensic Acid 4
Diels-Alder adduct was not detected under these reaction
conditions. This is possibly due to a steric interaction between
the dienophile methyl group and the ring methylene in 6. This
steric hindrance is much more severe when compared to that
of the proton and the methylene group in compound 28. As a
consequence, the activation energy of the reaction is higher,
and it may be necessary to increase the reaction temperature.47
The reaction temperature was raised to 270 °C and maintained
at this temperature for 5 h. This provided the Diels-Alder
adduct 5 in 36% isolated yield. The unreacted starting material
6 was isolated in 45% yield as a mixture of E/Z (1:2.2) enol
ethers along with a small amount (<7%) of compound 32. The
identity of compound 32 was established by an independent
synthesis from triene 33 which was obtained as a minor isomer
during the Horner-Wadsworth-Emmons olefination. Formation
of 33 from 6 resulted after olefin isomerization. While we used
BHT as a radical inhibitor in this reaction, it appears that the
electron rich triene still underwent olefin isomerization to some
degree.
SCHEME 5. Synthesis of Core Structure 5
Mercury salts such as Hg(OAc)2 and Hg(TFA)2 have been
widely used in transetherification and related annulation reac-
tions.48 We explored the possibility of using a mercury salt to
isomerize the major Z-enol ether present (E/Z ) 4:9) in the
recovered starting material 6. Recovered 6 was treated with a
catalytic amount of Hg(TFA)2 in the presence of Et3N and stirred
at 23 °C for 4 h until the crude NMR showed nearly a 1:1 ratio
of E/Z enol ethers. The yield was modest (<64%) probably due
to decomposition of the enol ether. The Diels-Alder reaction
of this isomerized substrate 6 provided additional desired product
5 giving a combined yield of 44% for 5. Compound 32 was
1
formed in less than 7% yield (by H NMR analysis).
The synthesis of platensic acid 4 from compound 5 is outlined
in Scheme 6. Reduction of the ester in 5 with LAH afforded
the corresponding alcohol that was oxidized to the aldehyde
intermediate with Dess-Martin periodinane. Horner-Wads-
worth-Emmons olefination of this crude aldehyde was carried
The successful intramolecular Diels-Alder reaction of enol
ether 28 prompted us to incorporate the desired methyl group
on the dienophile. The synthesis of the corresponding Diels-Alder
substrate and its conversion to oxatetracyclic core 5 is shown
in Scheme 5. Alcohol 31 containing an R-methyl ester was
prepared in 91% yield over three steps following the similar
route which yielded 27. It was converted to triene 6 in 82%
yield as an inseparable mixture of E/Z enol ethers (2:3 ratio).
This triene mixture was subjected to a thermal Diels-Alder
reaction at 200 °C for 12 h. Unfortunately, the desired
(47) We did not examine Lewis acid catalysts for substrate 6 because our
attempts with Lewis acid catalyzed reaction with aldehyde 22 and some other
designed substrates were unsuccessful. Also, we were concerned about the
stability of the enol ether in the diene moiety in the presence of Lewis acids.
(48) Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79, 2828–
2833.
J. Org. Chem. Vol. 74, No. 3, 2009 1167

Ghosh and Xi
SCHEME 7. Synthesis of (-)-Platensimycin 1
for 4 h. Amide 41 was isolated in 56% yield. Removal of the
TMSE group with tris(dimethylamino)sulfonium difluorotrim-
ethylsilicate (TSAF) in DMF at 40 °C for 1 h furnished (-)-
platensimycin 1 in 85% yield. Spectral data (1H and 13C NMR)
and optical rotation ([R]23 -49.2, c 0.24, MeOH) of the
D
synthetic (-)-platensimycin are consistent with those reported
for natural (-)-platensimycin ([R]23 -51.1, c 0.13, MeOH).5
D
Conclusion
In summary, we have achieved an enantioselective total
synthesis of (-)-platensimycin. An intramolecular Diels-Alder
reaction has been developed to construct the oxatetracyclic core
of platensimycin. This Diels-Alder reaction has set three chiral
centers including two all-carbon quaternary chiral centers in a
single operation. We have optimized the desired cycloaddition
pathways by incorporation of a methoxy group on the diene,
which prevented the undesired 1,5-hydride shift that led to a
complex and undesired Diels-Alder adduct. We utilized (+)-
carvone as the key starting material, which determined the
stereochemistry of the final (-)-platensimycin. A modified
protocol was developed for the efficient preparation of bicyclic
lactone 8 from (+)-carvone. Other key transformations include
a Petasis olefination, a hydroboration sequence, a Gais’ asym-
metric Horner-Wadsworth-Emmons reaction, and a mercury
salt catalyzed enol ether isomerization reaction. Structural
modifications of (-)-platensimycin are the subject of current
investigation in our laboratories.
out in THF at reflux. Compound 34 was isolated in 87% yield
over three steps as an inseparable mixture (3:1) of E/Z-
unsaturated esters. Hydrogenation of 34 over Pearlman’s catalyst
provided ester 35 which was subjected to a RuO4-based
oxidation reaction.49 This successfully provided ketone 36 in
70% isolated yield. Ketone 36 was transformed to the corre-
sponding TMS enol ether in 70% yield; however, oxidation of
Experimental Section
Intramolecular Diels-Alder Products 5 and 32. To a solution
of 6 (627 mg, 2.05 mmol) in chlorobenzene (160 mL) was added
BHT (46 mg, 0.21 mmol) at 23 °C. The reaction mixture was
transferred into a sealed tube and heated to 270 °C for 5 h. The
reaction was cooled to 23 °C concentrated in vacuo. Flash
chromatography on silica gel (15% ethyl acetate in hexane with
1% Et3N) afforded 225 mg (0.74 mmol, 36%) of compound 5 and
282 mg (0.92 mmol, 45%) of a mixture of starting material 6 (E/Z
50
this enol ether with Pd(OAc)2 or IBX51 furnished enone 37
in very low yields (<20%). Ketone 36 was converted to the
corresponding selenide with PhSeCl in EtOAc in the presence
of 1 drop of concentrated HCl. Oxidation of this selenide
derivative intermediate with NaIO4 gave enone 37 in 62% yield.
Saponification of enone 37 with NaOH in EtOH provided
platensic acid 4, which was used for the next step without further
purification.
With platensic acid 4 in hand, we then focused on the
synthesis of aniline derivative 40, utilized by Nicolaou and co-
workers in their synthesis of platencin.26 Scheme 7 depicts the
synthesis of TMSE-ester 40 and its subsequent conversion to
platensimycin. The synthesis of trimethylsilylethyl ester 39 from
methyl ester 38 was previously described by Giannis and co-
workers.52 We modified the transesterification step by using only
2 equiv of 2-(trimethylsilyl)ethanol and an excess of bulky and
cheap t-BuOH as the solvent.53 This reaction successfully
provided the desired ester 39 in 53% yield. Hydrogenolysis of
39 over Pd-C furnished aniline fragment 40 in 95% yield. With
both platensic acid 4 and aniline 40 in hand, the completion of
platensimycin synthesis was carried out as follows. Platensic
acid 4 was treated with Et3N and the peptide coupling reagent
HATU in DMF for 10 min. A solution of aniline 40 in DMF
was then added, and the reaction mixture was stirred at 23 °C
1
) 4:9 by H NMR analysis of crude mixture) and compound 32.
To a solution of the above mixture (282 mg, 0.92 mmol) in THF
(10 mL) at 23 °C were added Et3N (64 µL, 0.46 mmol) and
Hg(TFA)2 (40 mg, 0.09 mmol). The reaction mixture was stirred
at 23 °C for 4 h and then quenched with NaHCO3 (satd). The
aqueous layer was extracted with Et2O. The combined organic
extracts were dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. Flash chromatography on silica gel (15% ethyl
acetate in hexanes with 1% Et3N) afforded 181 mg (0.6 mmol, 64%)
of a mixture of E/Z (1:1.1) enol ethers 6 and compound 32 (∼
5:1). This mixture was dissolved in chlorobenzene (50 mL), and
BHT (13 mg, 0.06 mmol) was added at 23 °C. The reaction mixture
was put into a sealed tube and heated at 270 °C for 8 h. The reaction
was cooled to 23 °C, and the solution was concentrated in vacuo.
Flash chromatography on silica gel (15% ethyl acetate in hexanes
with 1% Et3N) afforded 40 mg (<7%) compound 32 and 52 mg
(total 277 mg, 0.9 mmol, 44%) of compound 5: IR (neat) 1732,
1465, 1377; 1H NMR (500 MHz, CDCl3) δ 5.84 (dd, J ) 10.0, 5.0
Hz, 1H), 5.55 (d, J ) 10.0 Hz, 1H), 4.83 (brs, 1H), 4.18 (m, 2H),
3.45 (d, J ) 5.5 Hz, 1H), 3.29 (s, 3H), 2.77 (brs, 1H), 2.25 (t, 1H),
2.00-1.94 (m, 1H), 1.88-1.82 (m, 2H), 1.79 (dd, J ) 12.0, 4.0
Hz, 1H), 1.57-1.51 (m, 2H), 1.48 (d, J ) 11.0 Hz, 1H), 1.41 (s,
3H), 1.30 (s, 3H), 1.28 (t, 3H); 13C NMR (125 MHz, CDCl3) δ
175.2, 138.6, 122.3, 87.1, 82.0, 78.8, 60.8, 57.7, 55.6, 48.5, 46.1,
44.9, 44.0, 42.8, 41.0, 23.6, 19.9, 14.7; HRMS (EI) [M]+ calcd for
C18H26O4 306.1831, found 306.1830.
(49) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936–3938.
(50) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013.
(51) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew.
Chem., Int. Ed. 2002, 41, 996–1000.
(52) Heretsch, P.; Giannis, A. Synthesis 2007, 2614–2616.
(53) Baumhof, P.; Mazitschek, R.; Giannis, A. Angew. Chem., Int. Ed. 2001,
40, 3672–3674.
Unsaturated Ester 34. To a suspension of LiAlH4 (36 mg, 0.9
mmol) in Et2O (15 mL) at -40 °C was added a solution of 5 (277
1168 J. Org. Chem. Vol. 74, No. 3, 2009

Total Synthesis of (-)-Platensimycin
mg, 0.9 mmol) in Et2O (5 mL). The reaction mixture was then
stirred at 0 °C for 30 min. The reaction was quenched with a
solution of potassium sodium tartrate, and the mixture was
vigorously stirred until the organic layer was clear. The aqueous
layer was extracted with Et2O, and the combined organic extracts
were dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo to give the crude alcohol. To a stirred solution of the crude
alcohol in CH2Cl2 (10 mL) were added NaHCO3 (400 mg) and
Dess-Martin periodinane (500 mg, 1.2 mmol). The reaction mixture
was stirred at 23 °C for 1 h. A solution of Na2S2O3 (2 g) in saturated
NaHCO3 solution was added, and the aqueous layer was extracted
with CH2Cl2. The combined organic extracts were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo to give the
crude aldehyde. To a stirred solution of triethyl phosphonoacetate
(1 mL, 5 mmol) and 18-crown-6 (2.4 g, 9 mmol) in THF (20 mL)
at 0 °C were added KHMDS (0.5 M in toluene, 9 mL, 4.5 mmol)
and a solution of the crude aldehyde in THF (5 mL). The reaction
mixture was stirred at reflux for 12 h. The reaction was cooled to
23 °C, quenched with NH4Cl (satd), and extracted with Et2O. The
combined organic extracts were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. Flash chromatography on silica
gel (20% ethyl acetate in hexane) afforded 261 mg (0.78 mmol,
87% over three steps) of 34 as a mixture of E/Z (3:1) unsaturated
esters.
12 h. THF was removed, and the aqueous layer was extracted with
EtOAc. The combined organic extracts were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Flash chromatography
on silica gel (25% ethyl ether in hexanes) afforded 10 mg (0.03
mmol, 62%) of 37: [R]23D -28.1 (c 0.42, CHCl3); IR (neat) 2965,
1731, 1672, 1181 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.46 (d, J
) 10.0 Hz, 1H), 5.88 (d, J ) 10.0 Hz, 1H), 4.39 (brs, 1H), 4.10
(m, 2H), 2.40 (t, 1H), 2.35 (brs, 1H), 2.28-2.16 (m, 2H), 2.11-2.04
(m, 1H), 2.04-1.98 (m, 2H), 1.85 (dd, J ) 11.0, 3.5 Hz, 1H),
1.78-1.69 (m, 2H), 1.60 (d, J ) 11.0 Hz, 1H), 1.44 (s, 3H), 1.23
(t, 3H), 1.22 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.1, 173.2,
153.3, 127.2, 86.9, 76.4, 60.3, 54.8, 46.2, 45.9, 44.6, 43.1, 40.5,
30.6, 29.2, 24.4, 22.9, 14.1; HRMS (ESI) [M + Na]+ calcd for
C19H26O4Na 341.1729, found 341.1727.
(-)-Platensimycin TMSE Ester 41. To a stirred solution of
enone 37 (15 mg, 0.05 mmol) in EtOH (1 mL) was added NaOH
(1.0 M, 1 mL, 1.0 mmol). The reaction mixture was stirred at 23
°C for 30 min, and then 1 M HCl was added until pH ≈ 2. The
mixture was extracted with chloroform, and the combined organic
extracts were dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. The crude platensic acid 4 was used for the next
1
step without further purification: H NMR (500 MHz, CDCl3) δ
6.46 (d, J ) 10.0 Hz, 1H), 5.88 (d, J ) 10.0 Hz, 1H), 4.42 (brs,
1H), 4.08 (dq, J ) 2.5 Hz, 1H), 2.40 (t, 1H), 2.35-2.31 (m, 2H),
2.30-2.21 (m, 2H), 2.12-2.05 (m, 1H), 2.01 (dd, J ) 12.0, 4.0
Hz, 1H), 1.86 (dd, J ) 11.0, 4.0 Hz, 1H), 1.79-1.69 (m, 2H),
1.60 (d, J ) 11.0 Hz, 1H), 1.44 (s, 3H), 1.22 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 203.2, 177.8, 153.5, 127.1, 87.1, 76.4, 54.7,
46.2, 45.8, 44.6, 43.0, 40.4, 30.4,28.8, 24.3, 22.8.
Saturated Ester 35. To a stirred solution of 34 (21 mg, 0.06
mmol) in EtOH (2 mL) was added Pd(OH)2/C (3.5 mg) in one
portion. This reaction mixture was stirred under H2 at 23 °C for
12 h. The reaction mixture was filtered through Celite, and the
filtrate was concentrated in vacuo. Flash chromatography on silica
gel (8% ethyl acetate in chloroform) afforded 20 mg (0.06 mmol,
To a solution of the crude platensic acid 4 in DMF (0.2 mL)
were added HATU (56 mg, 0.14 mmol) and Et3N (34 µL, 0.24
mmol). The reaction mixture was stirred at 23 °C for 10 min before
a solution of 2-(trimethylsilyl)ethyl-3-amino-2,4-dihydroxybenzoate
40 (39 mg, 0.14 mmol) in DMF (0.2 mL) was added via cannula.
The reaction mixture was stirred at 23 °C for 4 h, brine was added,
and the mixture was extracted with chloroform. The combined
organic extracts were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. Flash chromatography on silica gel (15%
acetone in hexanes) afforded 14.4 mg (0.03 mmol, 56%) of ester
41: [R]23D -29.4 (c 0.51, CHCl3); IR (neat) 2360, 2338, 1697; 1H
NMR (500 MHz, CDCl3) δ 11.80 (s, 1H), 11.03 (s, 1H), 8.09 (s,
1H), 7.55 (d, J ) 9.0 Hz, 1H), 6.50 (d, J ) 9.5 Hz, 2H), 5.92 (d,
J ) 10.0 Hz, 1H), 4.42 (m, 3H), 2.52 (ddd, J ) 14.5, 11.5, 6.0 Hz,
1H), 2.45-2.31 (m, 3H), 2.14-2.07 (m, 1H), 2.06 (dd, J ) 12.0,
3.5 Hz, 1H), 2.10 (d, J ) 11.5 Hz, 1H), 1.90 (dd, J ) 12.0, 6.0
Hz, 1H), 1.89 (dd, J ) 11.5, 3.5 Hz, 1H), 1.78 (dd, J ) 11.5, 6.5
Hz, 1H), 1.63 (d, J ) 11.0 Hz, 1H), 1.45 (s, 3H), 1.27 (s, 3H),
1.13 (m, 2H), 0.08 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 203.5,
173.5, 170.4, 154.6, 153.8, 127.2, 127.0, 114.2, 111.0, 104.3, 86.9,
76.3, 63.6, 54.8, 46.6, 46.1, 46.0, 44.5, 43.0, 40.5, 32.0, 31.5, 24.1,
22.9, 17.3, -1.6; HRMS (ESI) [M + Na]+ calcd for C29H39NO7-
SiNa 564.2394, found 564.2396.
1
94%) of 35: H NMR (500 MHz, CDCl3) δ 4.32 (brs, 1H), 4.07
(q, 1H), 3.18 (s, 3H), 2.87 (d, J ) 3.0 Hz, 1H), 2.24-2.15 (m,
3H), 1.98-1.88 (m, 3H), 1.88-1.80 (m, 2H), 1.80-1.66 (m, 2H),
1.66-1.60 (m, 1H), 1.58 (dd, J ) 14.0, 4.0 Hz, 1H), 1.44 (dt, J )
3.5 Hz, 1H), 1.30 (s, 3H), 1.29 (d, J ) 9.5 Hz, 1H), 1.23-1.18 (m,
1H), 1.20 (t, 3H), 0.98 (s, 3H), 0.91 (d, J ) 10.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 174.4, 85.6, 82.0, 76.7, 60.1, 56.3, 55.4,
48.6, 45.3, 44.3, 43.3, 40.2, 38.0, 34.4, 28.4, 23.2, 22.5, 20.0, 14.1;
HRMS (ESI) [M + Na]+ calcd for C20H32O4Na 359.2198, found
359.2201.
Ketone 36. To a stirred solution of compound 35 (202 mg, 0.60
mmol) in CCl4 (8 mL), CH3CN (8 mL), and H2O (12 mL) was
added NaIO4 (643 mg, 3 mmol) in one portion. The reaction mixture
was stirred at 23 °C for 10 min before RuCl3 (15 mg, 0.06 mmol)
was added. The reaction mixture was stirred at 23 °C for 48 h.
The reaction was quenched with saturated NaHCO3 solution and
extracted with EtOAc. The combined organic extracts were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel (40% ethyl ether in hexane) afforded
134 mg (0.42 mmol, 70%) of 36: [R]23 -27.9 (c 0.38, CHCl3);
D
1
IR (neat) 2360, 1730, 1173 cm-1; H NMR (500 MHz, CDCl3) δ
4.30 (brs, 1H), 4.08 (dq, J ) 2.5 Hz, 1H), 2.54 (dt, J ) 6.0 Hz,
1H), 2.32-2.22 (m, 4H), 2.04-1.92 (m, 5H), 1.82 (dt, J ) 5.0
Hz, 2H), 1.77-1.69 (m, 1H), 1.62 (dd, J ) 11.0, 3.5 Hz, 1H),
1.58 (dq, J ) 14.0 Hz, 1H), 1.46-1.40 (m, 1H), 1.43 (d, J ) 11.0
Hz, 1H), 1.37 (s, 3H), 1.22 (t, 3H), 1.18 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 214.5, 173.4, 86.1, 77.2, 60.3, 55.0, 50.0, 48.9,
44.6, 44.3, 42.5, 40.5, 36.1, 33.8, 32.8, 29.6, 23.4, 22.9, 14.1; HRMS
(ESI) [M + Na]+ calcd for C19H28O4Na 343.1888, found 343.1887.
Enone 37. To a stirred solution of 36 (16 mg, 0.05 mmol) in
EtOAc (1 mL) were added PhSeCl (12 mg, 0.06 mmol) and 1 drop
of HCl (concd). The reaction mixture was stirred at 23 °C for 5 h
before saturated NaHCO3 solution was added. The aqueous layer
was extracted with EtOAc, and the combined organic extracts were
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The crude product was purified by passing it through a short column
of silica gel. To a stirred solution of the selenide intermediate in a
mixture of THF (1 mL) and H2O (1.5 mL) was added NaIO4 (45
mg, 0.21 mmol). The reaction mixture was stirred at 23 °C for
(-)-Platensimycin (1). To a solution of compound 41 (10 mg,
0.02 mmol) in DMF (0.2 mL) was added TASF (10 mg, 0.04
mmol). The reaction mixture was stirred at 40 °C for 1 h. The
reaction was cooled to 23 °C, brine was added, and the mixture
was extracted with chloroform. The combined organic extracts were
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
Flash chromatography on silica gel (60% acetone in hexanes
followed by acetone, hexanes, acetic acid 60:40:1) afforded 7 mg
(0.016 mmol, 85%) of (-)-platensimycin 1:, [R]23D -49.2 (c 0.24,
1
MeOH); H NMR (500 MHz, C5D5N) δ 10.48 (s, 1H), 8.09 (d, J
) 8.5 Hz, 1H), 6.85 (d, J ) 9.0 Hz, 1H), 6.34 (d, J ) 10.0 Hz,
1H), 5.92 (d, J ) 10.0 Hz, 1H), 4.46 (s, 1H), 2.86-2.77 (m, 1H),
2.77-2.62 (m, 2H), 2.42 (s, 1H), 2.17 (t, 1H), 2.06-1.97 (m, 1H),
1.92-1.84 (m, 1H), 1.79 (d, J ) 11.5 Hz, 1H), 1.70 (d, J ) 10.5
Hz, 1H), 1.58-1.51 (m, 1H), 1.46 (d, J ) 11.0 Hz, 1H), 1.37 (s,
3H), 1.12 (s, 3H); 13C NMR (125 MHz, C5D5N) δ 203.2, 174.7,
174.4, 158.3,158.0, 154.0, 129.4, 127.2, 115.3, 110.0, 107.1, 86.8,
J. Org. Chem. Vol. 74, No. 3, 2009 1169

Ghosh and Xi
76.4, 55.0, 46.7, 46.6, 46.1, 45.0, 43.0, 40.8, 32.1, 31.8, 24.4, 23.2;
HRMS (ESI) [M + Na]+ calcd for C24H27NO7Na 464.1685, found
464.1686.
Supporting Information Available: Full experimental details
1
and characterization of selected compounds; copies of H and
13C NMR spectra of selected compounds; comparison of 1H and
13C NMR spectra of synthetic and natural (-)-platensimycin.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support of this work was
provided in part by the National Institutes of Health and Purdue
University. We thank Dr. Phillip E. Fanwick (Purdue University)
for assistance with the X-ray crystal structure analysis.
JO802261F
1170 J. Org. Chem. Vol. 74, No. 3, 2009