Enantioselective total synthesis of (-)-zampanolide, a potent microtubule-stabilizing agent

Article abstract of DOI:10.1021/ol201626h

An enantioselective total synthesis of zampanolide has been accomplished using a novel DDQ/Bronsted acid promoted cyclization as the key reaction. The synthesis features cross-metathesis to construct the trisubstituted olefin and a ring-closing metathesis

Full text of DOI:10.1021/ol201626h

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4108–4111
Enantioselective Total Synthesis of
(ꢀ)-Zampanolide, a Potent
Microtubule-Stabilizing Agent
Arun K. Ghosh* and Xu Cheng
Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval
Drive, West Lafayette, Indiana 47907, United States
akghosh@purdue.edu
Received June 16, 2011
ABSTRACT
An enantioselective total synthesis of zampanolide has been accomplished using a novel DDQ/Brønsted acid promoted cyclization as the key
reaction. The synthesis features cross-metathesis to construct the trisubstituted olefin and a ring-closing metathesis to form the macrolactone.
The final N-acyl aminal formation was stereoselectively accomplished by an organocatalytic reaction.
The isolation of taxol in the 1970s and subsequent
decade-long studies led to the approval of paclitaxel as
an important anticancer drug.1 Paclitaxel inhibits cell
division by stabilizing microtubule assembly.2 Since the
discovery of this unique mechanism of action, the search
for new agents has become the subject of immense interest.
In recent years, epothilones and discodermolide-based
antitumor therapeutics have received significant atten-
tion.3 Also, laulimalide and pelorusides were identified as
an exciting new generation of microtubule-stabilizing
agents.4 Both laulimalide and pelorusides have exhibited
intriguing synergistic effects with taxol, maintained potent
activity against taxol-resistant cell lines, and are not sub-
strates for P-glycoprotein-mediated drug efflux pumps.5,6
More recently, Northcote, Miller, and co-workers re-
ported that (ꢀ)-zampanolide 1 (Figure 1), a 20-membered
macrolide, also possesses potent microtubule-stabiliz-
ing properties.7
Zampanolide (1) was originally isolated by Tanaka
and Higa from the marine sponge Fasciospongia rimosa
in Okinawa in 1996.8 More recently, (ꢀ)-zampanolide 1
was isolated from a Tongan marine sponge, Cacospongia
mycofijiensis, and reported to block cell division in the
G2/M of the cell cycle.7 Uenishi and co-workers reported
the potent cytotoxic activity of (ꢀ)-zampanolide against
SKM-1 and U937 cell lines with IC50 values of 1.1 and
2.9 nM, respectively.9 Furthermore, it is potent against HL-
60, 1A9 cells, and especially against A2780AD, which is
quite resistant to paclitaxel.7 Zampanolide’s natural abun-
dance is very scarce which has resulted in only limited
biological studies. Zampanolide possesses a unique unsa-
turatedmacrocyclicstructuralfeaturecontainingonlythree
stereogenic centers and a chiral N-acyl aminal side chain.
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r
10.1021/ol201626h
Published on Web 07/12/2011
2011 American Chemical Society

Figure 1. (ꢀ)-Zampanolide 1 (natural form) and (þ)-dactylolide
2 (enantiomer of natural form).
The chemistry and biology of zampanolide have at-
tracted much synthetic attention. Smith and co-workers
achieved the first total synthesis of (þ)-zampanolide, the
unnatural antipode, in 2001.10 Subsequently, both Hoye et
al. in 200311 and Uenishi et al.9 in 2009, reported the total
synthesis of natural (ꢀ)-zampanolide. These syntheses
established that the natural (ꢀ)-zampanolide core is the
opposite enantiomer of the related natural product (þ)-
dactylolide (2). Dactylolide displayed only modest cyto-
toxicity. Since its discovery by Riccio and co-workers in
2001,12 a number of total syntheses13ꢀ19 and a synthetic
approach to (þ)-dactylolide have been reported.20 It ap-
pears that theN-acyl aminal side chain of(ꢀ)-zampanolide
is important for its potent cytotoxic properties. The key
N-acylation reaction typically9 provided only a 12% yield
of zampanolide along with its epimer and N-acylated
product, suggesting that an improvement is necessary for
the synthesis of structural variants. Herein, we report an
enantioselective synthesis of (ꢀ)-zampanolide that can be
amenable to the synthesis of N-acyl aminal derivatives.
Our synthetic strategy for (ꢀ)-zampanolide (1) is shown
in Figure 2. We planned to synthesize the macrocyclic core
in a convergent manner to prepare a variety of structural
analogs. Our strategic bond disconnection of the sen-
sitive N-acyl aminal side chain at C20 provides macro-
lactone 3, which can be formed from alcohol 4 and acid 5
by esterification followed by ring-closing metathesis.
A similar RCM strategy was first employed by Hoye and
Figure 2. Synthetic plan for (ꢀ)-zampanolide 1.
Hu.11 The trisubstituted olefin in 4 would be installed by a
cross metathesis of 6. The tetrahydropyran ring 6 would be
constructed by an oxidative cyclization reaction of a
cinnamyl ether derived from β-hydroxy ester 7. The poly-
ene carboxylic acid 5 would be assembled by a Reformatsky
reaction with γ-bromo unsaturated ester 8 followed by
Wittig olefination of the corresponding aldehyde.
As shown in Scheme 1, the synthesis commenced with
known ester 7, which was readily prepared with excellent
enantioselectivity using Noyori hydrogenation as the key
step.21 Selective protection of the primary alcohol as a
TBDPS ether provided 9. Etherification of the secondary
alcohol with tert-butyl cinnamyl carbonate in the presence
of a catalytic amount of Pd(PPh3)4 afforded cinnamyl
ether 10 in 73% yield. The ethyl ester 10 was converted
to allylsilane 11 by employing a modified procedure of
Narayanan and Bunnelle toprovide 11 in 81% yield.22 Our
subsequent plan was to carry out an oxidative Sakurai type
cyclization to construct the 4-methylenetetrahydro-2H-
pyran ring stereoselectively. For this transformation, we
initially explored an oxidative cyclization reaction with
DDQ, as benzylic/allylic ethers have been converted to
carbocation intermediates using DDQ with or without
Lewis acids by Mukaiyama and Hayashi,23 She et al.,24
(10) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem.
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C.; Gomez-Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775–778.
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Org. Lett., Vol. 13, No. 15, 2011
4109

glycidyl derivative with isopropenylmagnesium bromide
followed by protection of the resulting alcohol as TES-
ether. Our attempted cross-metathesis of 6 with 12 under a
variety of conditions did not provide any cross-metathesis
product. Assuming the lack of reactivity of the styrene
chain, we planned to convert the styrene chain into a
methylene chain. This was achieved by selective dihydrox-
ylation of the styrene chain with ADmix-R followed by diol
cleavage with NaIO4 to provide the corresponding alde-
hyde as described by Smith and Dong.27 Wittig olefination
of the resulting aldehyde with methylene phosphorane
afforded 13 in 78% yield (3 steps). Cross-metathesis28 of
13 with 12 using Grubbs’ second generation catalyst (10 mol
%) in CH2Cl2 at reflux for 9 h provided an E/Z olefin
mixture (1.7:1) in 57% yield. The mixture was treated with
Scheme 1. Synthesis of Tetrahydropyran 14
HF py to remove all silyl groups. The resulting alcohols
3
were separated by silica gel chromatography. Photoche-
mical isomerization of the Z-isomer 15 provided a 51%
yield (68% brsm) of trisubstituted olefin 14.
The synthesis of polyene carboxylic acid 5 is shown in
Scheme 2. Allyl bromide 8 was prepared as an E/Z mixture
(1.3:1) using the procedure of Fallis and Lei.29 Reformats-
ky reaction of the mixture of bromides 8 with acrolein
resulted in allylic alcohol 16 (47% yield) and unsaturated
δ-lactone 17 (36% yield) after separation by silica gel chro-
matography. DIBAL-H reduction of 17 followedby Wittig
reaction with (carbethoxymethylene)triphenylphosphorane
afforded allylic alcohol 18. Protection of the resulting
alcohol as a PMB-ether followed by saponification of the
ester provided acid 5 in 62% yield (2 steps).
Scheme 2. Synthesis of Polyene Carboxylic Acid 5
and Floreancig et al.25 The reaction with DDQ at ꢀ40 °C
for3 daysresultedin only30ꢀ35% desired product 6 along
with unidentified side products possibly due to the pre-
sence of the allylsilane functionality. The same reaction in
the presence of a variety of Lewis acids also provided
similar results. However, oxidative cyclization with DDQ
in the presence of a mild Brønsted acid such as PPTS
provided the best results. Reaction of 11 with 1.5 equiv of
DDQ and 1.5 equiv of PPTS at ꢀ38 °C in acetonitrile for
3 h afforded 6 in 81% yield as a single diastereomer (by 1H
NMR analysis). The NOESY data fully corroborated the
depicted cis-stereochemistry of 6. Presumably, the cycliza-
tion proceeded through a ZimmermanꢀTraxler transition
state where all substituents are equatorially oriented.26
Our synthetic strategy then called for the elaboration of
the E-trisubstituted olefin in 4 by a cross-metathesis reac-
tion. The corresponding olefin substrate 12 was obtained
in an optically active form by opening a PMB-protected
The synthesis of macrolactone 3 is shown in Scheme 3.
The primary alcohol in 14 was selectively oxidized with
TEMPO in the presence of PhI(OAc)2. The resulting
aldehyde was subjected to Wittig olefination with methy-
lenetriphenylphosphorane to provide 19 in 60% yield
(2 steps). Esterification of acid 5 with alcohol 19 under
Yamaguchi conditions using 2,4,6-trichlorobenzoyl chloride
(23) Hayashi, Y.; Mukaiyama, T. Chem. Lett. 1987, 1811–1814.
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Am. Chem. Soc. 2003, 125, 11360–11370.
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(29) Lei, B.; Fallis, A. G. Can. J. Chem. 1991, 69, 1450–1456.
4110
Org. Lett., Vol. 13, No. 15, 2011

Scheme 3. Synthesis of (ꢀ)-2
Scheme 4. Synthesis of (ꢀ)-Zampanolide
and DMAP furnished ester 20 in 91% yield. Ring-closing
metathesis using Grubbs’ second generation catalyst (12
mol %) in benzene at 60 °C for 20 h afforded 3 as a mixture
(1:1) of diastereomers at the C7 chiral center. Removal of
both PMB-ethers by treatment with DDQ provided the
corresponding diol. DessꢀMartin oxidation of the diol
furnished (ꢀ)-2, the unnatural antipode of dactylolide
(52% for the 3 steps).
(ꢀ)-zampanolide in 51% yield and epi-zampanolide 23
in 18% yield after separation/purification by HPLC
(Scheme 4). We have also investigated the corresponding
mismatched reaction with (R)-TRIP; however, this reac-
tion afforded a 1:1 mixture of (ꢀ)-1 and epi-1. Again, the
formation of bis-amide 24 was not observed. The spectral
data (1H NMR and 13C NMR) of synthetic 1 ([R]22D ꢀ94,
c 0.08, CH2Cl2) is in agreement with that of natural
zampanolide (Lit.8 [R]22D ꢀ101, c 0.12, CH2Cl2).
The conversion of (ꢀ)-2 to (ꢀ)-zampanolide 1 required
the addition of a carboxamide to the aldehyde to form a N-
acylaminal. Such directaddition inoneprevioussynthesis9
afforded only a 12% yield of (ꢀ)-zampanolide, 12% yield
of epimeric product 23, and 16% yield of bis-amide 24.
In an effort to improve this reaction, we investigated
Brønsted acid-catalyzed N-acyl aminal formation under
a variety of reaction conditions. In one of our initial
successful attempts, reaction of (ꢀ)-2 with carboxamide 21
in the presence of diphenylphoshoric acid clearly provided
a mixture of all three products, (ꢀ)-zampanolide, epi-
zampanolide, and bis-amide 24, although analysis of the
mixture showed that (ꢀ)-zampanolide formation was
favored slightly. Encouraged by this result, we then in-
vestigated N-acyl aminal formation between aldehyde (ꢀ)-
2 and amide 21 in the presence of matched chiral phos-
phoric acid (S)-TRIP30,31 (22, 20 mol %) at 23 °C for 12 h.
These reaction conditions provided excellent chemo-
selectivity toward monoaddition, and the formation of
bis-amide 24 was not observed. The reaction furnished
In summary, we have accomplished an enantioselec-
tive synthesis of (ꢀ)-zampanolide. The synthesis features
a novel intramolecular oxidative cyclization reaction, a
cross-metathesis reaction to construct a trisubstituted
olefin, a ring-closing metathesis to form a highly functio-
nalized macrolactone, and a chiral phosphoric acid cata-
lyzed stereoselective N-acyl aminal formation that stereo-
selectively furnished (ꢀ)-zampanolide and no bis-amide
by-product. The present synthesis is amenable to the syn-
thesis of structural variants of (ꢀ)-zampanolide, and further
investigations of important analogs are in progress.
Acknowledgment. This research is supported in part by
the National Institutes of Health.
Supporting Information Available. Experimental proce-
dures and 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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