Toward an enantioselective synthesis of (-)-zampanolide: Preparation of the C9-C20 region

Article abstract of DOI:10.1021/ol301383a

Progress toward the synthesis of the microtubule-stabilizing agent, (-)-zampanolide, is reported. Construction of the 2,6-cis-tetrahydropyran ring was accomplished utilizing ether transfer methodology in conjunction with an intramolecular radical cyclization reaction. Efficient installation of the C16-C20 side chain relied on a one-pot cross-metathesis/olefination sequence, Sharpless epoxidation, and selective reduction of a vinyl epoxide.

Full text of DOI:10.1021/ol301383a

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3408–3411
Toward an Enantioselective Synthesis
of (ꢀ)-Zampanolide: Preparation of the
C9ꢀC20 Region
Matthew R. Wilson and Richard E. Taylor*
Department of Chemistry and Biochemistry and the Walther Cancer Research Center,
University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame,
Indiana 46556-5670, United States
taylor.61@nd.edu
Received May 18, 2012
ABSTRACT
Progress toward the synthesis of the microtubule-stabilizing agent, (ꢀ)-zampanolide, is reported. Construction of the 2,6-cis-tetrahydropyran ring
was accomplished utilizing ether transfer methodology in conjunction with an intramolecular radical cyclization reaction. Efficient installation of the
C16ꢀC20 side chain relied on a one-pot cross-metathesis/olefination sequence, Sharpless epoxidation, and selective reduction of a vinyl epoxide.
Polyketide natural products represent a privileged scaf-
fold for the discovery of novel drugs as their structural
features and molecular complexity occupy newly defined
regions of chemical space.1 Resultingly, a great amount of
effort has been directed toward developing new synthetic
methods for the construction of complex polyketides. Our
laboratory has been interested in the use of total synthesis
to enable biological evaluation and characterization of
their properties at the molecular level.2 In an effort to
provide access to structural units not readily available by
known synthetic methods, we have recently developed a
protocol for the efficient generation of 1,3-syn mono diol
ethers from readily accessible alkoxy ether protected
homoallylic alcohols.3 The methodology involves treat-
ment of an alkoxy ether with iodine monochloride (ICl) at
low temperature providing a diverse array of orthogonally
protected diol ethers upon nucleophilic quench. As an
example, a thiophenol quench followed by sulfide oxida-
tion and base-promoted cyclization affords functionalized
sulfonyl pyrans which upon subsequent manipulation
allows entry to 2,6-cis and trans-trisubstituted tetrahydro-
pyrans (Figure 1).4
Figure 1. Synthetic approach to 2,6-cis- and trans-pyrans.4
As our ether transfer methodology has successfully been
employed for the synthesis of a number of biologically
active natural products,5 a more recent application to
alternative structures with unsaturation adjacent to the
(4) Kartika, R.; Taylor, R. E. Angew. Chem., Int. Ed. 2007, 46, 6874.
(5) (a) Kartika, R.; Frein, J. R.; Taylor, R. E. J. Org. Chem. 2008, 73,
5592–5594. (b) Kartika, R.; Gruffi, T. R.; Taylor, R. E. Org. Lett. 2008,
10, 5047–5050. (c) Liu, K.; Arico, J. W.; Taylor, R. E. J. Org. Chem.
2010, 75, 3953–3975.
(1) Shang, S.; Tan, D. S. Curr. Opin. Chem. Biol. 2005, 9, 248–258.
(2) Begaye, A.; Trostel, S.; Zhao, Z.; Taylor, R. E.; Schriemer, D. C.;
Sackett, D. L. Cell Cycle 2011, 10, 3387–3396.
(3) Liu, K.; Taylor, R. E.; Kartika, R. Org. Lett. 2006, 8, 5393–5395.
r
10.1021/ol301383a
Published on Web 06/21/2012
2012 American Chemical Society

pyran ring warranted the exploration of activating allylic
and benzylic alkoxy ethers (Figure 2). In order to investi-
gate the effects of proximal sp2-hybridization on our
methodology, we sought to focus on the highly potent
polyketide, (ꢀ)-zampanolide 1.
Ghosh11 laboratory. Despite isolation from two marine
organisms and several total syntheses, samples of zampa-
nolide remain scarce.12 Moreover, no analogues have been
reported to date. From a structural standpoint, the 20-
membered macrolactone contains a cis-2,6-trisubstituted
tetrahydropyran, ample unsaturation, and an unusual
exocyclic N-acylhemiaminal side chain that has been
documented to be critical for biological activity. Herein,
we describe our initial approach toward the C9ꢀC20
fragment of (ꢀ)-zampanolide 1.
Our initial strategy relied on our recently developed
methodology to assemble the 4-alkoxy-2,6-cis-tetrahydro-
pyran from an advanced sulfonyl pyran fragment. The
synthesis commenced with the preparation of benzyloxy
methyl ether (BOM) 3 as a model system to assess the
viability of our ether transfer methodology with the allylic
alkoxy ether (Scheme 1). Allylation of known aldehyde13
2
followed by alkylation with commercially available
BOMCl provided the model substrate 3 in excellent yield
over two steps. Unfortunately, treatment of the allylic
ether 3 with ICl at ꢀ78 °C did not provide the expected
product but gave a complex mixture. This result is in
accord with the lack of selectivity observed by Smith and
our laboratory with polyolefinic substrates utilizing iodine
monobromide for iodocarbonate cyclization.14 Circum-
vention of this undesirable reactivity was envisioned by
replacing the E-trisubstituted olefin as a bulky silyl pro-
tected hydroxyl group. However, treatment of BOM ether
4 withICl resultedina Bartlett cyclization15 toaffordfuran
diastereomers 5 and low yields of desired product 6.16
Presumably, generation of the intermediate oxonium ion
leading toether transfer may be impededby the presence of
electronegative substituents (sp2-hybridization in 3 and
-OTBDPS in 4) adjacent to the reacting alkoxymethyl
ether.
Figure 2. Unsaturated biologically active polyketides.
Zampanolide was initially isolated from the marine
sponge Fasciospongia rimosa by Tanaka and Higa in
1996.6 This interesting compound was also found recently
by Northcote et al. in the Tongan marine sponge, Cacos-
pongia mycofijiensis, along with the well-known polyke-
tides laulimalide and latruncalin A.7 The latter report
demonstrated that zampanolide stabilizes microtubules
and blocks cell division in the G2/M phase of the cell cycle
similar to paclitaxel, pelorusides, and the epothilones.
Moreover, zampanolide exhibits potent cytotoxic activity
(1ꢀ5 nM) against multiple cancer cell lines including P388,
HT29, A549, and MEL28.8 The impressive biological
activity and unique structural features have attracted
considerable attention from the synthetic community. In
2001, Smith and co-workers disclosed the first total synthe-
sis of the unnatural (þ)-zampanolide and established its
absolute and relative stereochemistry.9 Subsequent synth-
eses emerged from Hoye,10 Tanaka,8 and most recently the
Scheme 1. Model Systems
(6) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535–5538.
(7) Field, J. J.; Singh, A. J.; Kanakkanthara, A.; Halafihi, T.; Northcote,
P. T.; Miller, J. H. J. Med. Chem. 2009, 52, 7328–7332.
(8) Uenishi, J.; Iwamoto, T.; Tanaka, J. Org. Lett. 2009, 11, 3262–
3265.
(9) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc.
2001, 123, 12426–12427.
(10) Hoye, T. R.; Hu, M. J. Am. Chem. Soc. 2003, 125, 9576–9577.
(11) Ghosh, A. K.; Cheng, X. Org. Lett. 2011, 13, 4108–4111.
(12) The marine polyketide, (þ)-dactylolide, which contains an
identical pyran substituted macrocyclic lactone without the acyl hemi-
aminal side chain, has been synthesized several times: (a) Smith, A. B.,
III; Safonov, I. G. Org. Lett. 2002, 4, 635–637. (b) Aubele, D. L.; Wan,
S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485–3488.
(c) Sanchez, C. C.; Keck, G. E. Org. Lett. 2005, 7, 3053–3056. (d) Ding,
F.; Jennings, M. P. Org. Lett. 2005, 7, 2321–2324. (e) Louis, I.;
Hungerford, N. L.; Humphries, E. J.; McLeod, M. D. Org. Lett. 2006,
8, 1117–1120. (f) Ding, F.; Jennings, M. P. J. Org. Chem. 2008, 73, 5965–
5976. (g) Zurwerra, D.; Gertsch, J.; Altmann, K.-H. Org. Lett. 2010, 12,
2302–2305. (h) Yun, S. Y.; Hansen, E. C.; Volchkov, I.; Cho, E. J.; Lo,
W. Y.; Lee, D. Angew. Chem., Int. Ed. 2010, 49, 4261–4263. (i) Lee, K.;
Kim, H.; Hong, J. Angew. Chem., Int. Ed. 2012, 51, 5735–5738. For
additional synthetic efforts, see: (j) Loh, T.-P.; Yang, J.-Y.; Feng, L.-C.;
Zhou, Y. Tetrahedron Lett. 2002, 43, 7193–7196. (k) Reddy, C. R.;
Srikanth, B. Synlett 2010, 1536–1538.
The inefficient ether transfer observed with these two
substrates compelled us to revise our synthetic strategy. To
this end, we opted to conceal the C8ꢀC9 olefin as a benzyl
ether in hopes we could deprotect and install the C13 and
C8ꢀC9 alkenes simultaneously as previously reported by
(13) Castagnolo, D.; Botta, L.; Botta, M. J. Org. Chem. 2009, 74,
3172–3174.
(14) (a) Duan, J. J. W.; Smith, A. B., III. J. Org. Chem. 1993, 58,
3703–3711. (b) Taylor, R. E.; Jin, M. Org. Lett. 2003, 5, 4959–4961.
(15) Rychnovsky, S. D.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103,
3963–3964.
(16) Alternative protecting groups at this position did not resolve the
problem.
Org. Lett., Vol. 14, No. 13, 2012
3409

McLeod and co-workers in their synthesis of the structu-
rally related polyketide, (ꢀ)-dactylolide.17 Moreover, the
BOM ether 9 would serve as an interesting competition
experiment to probe the benzyloxy transfer in the presence
of an unactivated primary benzyl ether. The synthesis
commenced with preparation of the 1,3-syn diol mono-
ether 11 as illustrated in Scheme 2.
diastereoselectivity (>20:1). Reduction of the methyl ester
with LAH followed by GriecoꢀSharpless olefination23
provided 16 in 78% yield, over two steps (Scheme 3).
Having secured quantities of olefin 16 necessary for com-
pletion of the total synthesis, we turned our attention
toward the construction of the C16ꢀC20 fragment.
Scheme 3. Synthesis of Terminal Olefin 18
Scheme 2. Synthesis of 1,3-syn Diol Mono Ether 13
Here we anticipated utilizing a geometrically selective
cross-metathesis reaction to construct the C16ꢀC17
E-trisubstituted olefin. Previous efforts11 exploiting a cross-
metathesis approach with terminal and 1,1-disubstituted
olefin coupling partners often lacked E/Z-selectivity re-
quiring the use of isomerization to regenerate the desired
E-olefin geometry.24 With this in mind, we opted to use
methacrolein as a coupling partner to secure the desired
trans-olefin geometry and provide a reactive functional
handle for installation of the remaining two carbons. The
recent emergence of tandem catalysis with Grubbs’ and
Hoveyda ruthenium alkylidene catalysts encouraged us to
explore a sequential cross-metathesis/olefination sequence25
for installation of all four carbons in a single step. Much
to our delight, exposure of terminal olefin 16 to excess
methacrolein in the presence of HoveydaꢀGrubbs’ second-
generation catalyst 17 (5 mol %) followed by Hornerꢀ
WadsworthꢀEmmons olefination of the intermediate
aldehyde gave dienonate 18 in high yield as a single
geometrical isomer (E,E > 20:1) (Scheme 4). The C19-
stereocenter was envisioned to arise from Sharpless
epoxidation26 of a dienol fragment followed by selective
reduction at the most electrophilic carbon to unveil the
enantiomerically pure secondary alcohol. Reduction of
the dienoate with DIBAL-H followed by SAE and in situ
silyl protection gave the TBS-protected 2,3-epoxy alcohol
19 in 62% yield, over three steps, with excellent diaster-
eoselectivity. Interestingly, it proved imperative to in situ
protect the resulting 2,3-epoxy alcohol due to difficulty
The enantiomerically pure epoxide 7 was prepared from
(R)-aspartic acid via modification of a known procedure
previously reported in the literature.18 Regioselective ep-
oxide opening with vinyl magnesium bromide in the pre-
sence of catalytic CuI followed by benzyloxy methyl ether
alkylation gave the BOM ether 9 in excellent yield. Elec-
trophilic activation of the resulting ether with ICl at low
temperature provided the desired 1,3-syn diol monoether
11 in a disappointingly low 45% yield. However, pyran 12
(1:1 dr) resulting from Bartlett cyclization14 of the primary
benzyl ether was also isolated in 10% yield. Confronted
with a similar problem during their synthesis of (þ)-
spongistatin 2, it was discovered by Smith and co-workers
that use of a p-bromobenzyl ether prevented an undesir-
able cyclization of a neighboring benzyl ether by decreas-
ing the electron density on the oxygen.19 Inspired by this
result, we were pleased to find the reaction of p-bromo-
benzyl 10 with ICl at ꢀ78 °C provided upon aqueous
workup exclusively 1,3-syn diol monoether 13 in 65% yield
as an 8:1 mixture of diastereomers.20
Our efforts next were directed toward the preparation of
the terminal olefin within 16 (Scheme 3). Thus, tributyl-
phosphine-catalyzed conjugate addition21 of secondary
alcohol 13 to methyl propiolate based on previously
optimized conditions5b yielded β-alkoxyacrylate 14. Intra-
molecular radical cyclization promoted by triethylborane
in the presence of 1-ethylpiperidinium hypophosphate22
gave pyran methyl ester 15 in excellent yield and
(17) Ignace, L.; Hungerford, N. L.; Humphries, E. J.; McLeod, M. D.
Org. Lett. 2006, 8, 1117–1120.
(18) Frick, J. A.; Klassen, J. B.; Bathe, A.; Abramson, J. M.; Rapoport,
(23) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485–1486.
H. Synthesis 1992, 621–623.
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1753. (b) Ghosh, A. K.; Cheng, X. Org. Lett. 2011, 13, 4108–4111.
(25) (a) Chatterjee, A. K.; Choi, T. -L.; Sanders, D. P. J. Am. Chem.
Soc. 2003, 125, 11360–11370. (b) Murelli, R. P.; Snapper, M. L. Org.
Lett. 2007, 9, 1749–1752. (c) Sirasani, G.; Paul, T.; Andrade, R. B.
Tetrahedron 2011, 67, 2197–2205.
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S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
(27) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J.
J. Org. Chem. 1998, 63, 2948–2953.
(19) Smith, A. B., III; Lin, Q.; Doughty, V. A.; Zhuang, L.; McBriar,
M. D.; Kerns, J. K.; Boldi, A. M.; Murase, N.; Moser, W. H.; Brook,
C. S.; Bennett, C. S.; Nakayama, K.; Sobukawa, M.; Trout, R. E.
Tetrahedron 2009, 65, 6470–6488.
(20) While the thiophenol trapping conditions work well in this
system, the hydrolytic workup providing 13 is a more appropriate
intermediate for this synthetic sequence.
(21) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241–244.
(22) Lee, E.; Han, H. O. Tetrahedron Lett. 2002, 43, 7295–7296.
3410
Org. Lett., Vol. 14, No. 13, 2012

by acetonide formation provided 20 in 77% yield for the
one-pot process.
Scheme 4. Completion of C16ꢀC20 Fragment
In summary, we have developed an efficient, enantiose-
lective route to a protected C9ꢀC20 fragment of (ꢀ)-
zampanolide utilizing ourelectrophile-induced ethertrans-
fer methodology. The route is highlighted by a radical
cyclization, one-pot cross-metathesis/olefination sequence,
Sharpless epoxidation, and regioselective reduction of a
vinyl epoxide. Coupling of the advanced C9ꢀC20 inter-
mediate to a previously prepared C1ꢀC8 fragment and
conversion to (ꢀ)-zampanolide are currently underway in
our laboratory. Moreover, further studies investigating the
ether transfer of allylic and benzylic substrates is in progress.
Results along these lines will be reported in due course.
Acknowledgment. Support of this work by the National
Institutes of Health is gratefully acknowledged (GM084922).
isolating the unstable vinyl epoxide on silica gel.27 Com-
pletion of the C9ꢀC20 fragment was accomplished
via regioselective opening of the vinyl epoxide with
DIBAL-H28 at low temperature. Desilylation followed
Supporting Information Available. Full experimental
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(28) (a) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719–
2722. (b) Furstner, A.; Bouchez, L. C.; Morency, L.; Funel, J. A.;
Liepins, V.; Poree, F. H.; Gilmour, R.; Laurich, D.; Beaufils, F.;
Tamiya, M. Chem.;Eur. J. 2009, 15, 3983.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
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