Synthesis of a pladienolide B analogue with the fully functionalized core structure

Article abstract of DOI:10.1021/ol201464m

Starting from (R)-(-)-linalool (6), terminus differentiation and chain extension via aldol type reactions led to ketophosphonate 16 (C1-C8 building block). In a Horner-Wadsworth-Emmons reaction, 16 reacted with aldehyde 22, which contained the vicinal ant

Full text of DOI:10.1021/ol201464m

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3940–3943
Synthesis of a Pladienolide B
Analogue with the Fully
Functionalized Core Structure
†
†
‡
Sarah Muller, Timo Mayer, Florenz Sasse, and Martin E. Maier*
,†
€
€
€
Institut fu€r Organische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, 72076
Tu€bingen, Germany, and Abteilung Chemische Biologie Helmholtz-Zentrum fu€r
Infektionsforschung, Inhoffenstrasse 7, 38124 Braunschweig, Germany
martin.e.maier@uni-tuebingen.de
Received May 31, 2011
ABSTRACT
Starting from (R)-(ꢀ)-linalool (6), terminus differentiation and chain extension via aldol type reactions led to ketophosphonate 16 (C1ꢀC8 building
block). In a HornerꢀWadsworthꢀEmmons reaction, 16 reacted with aldehyde 22, which contained the vicinal anti-MeꢀOH pattern and a vinyl
iodide function, to provide the C1ꢀC13 part of pladienolide B. After Shiina macrolactonization, reduction of the enone 26 gave the core structure
27. A Stille cross-coupling of vinyl iodide 27 with tributylphenylstannane eventually furnished analogue 30.
A living cell can be considered as a very complex factory.
While there might be many menial tasks, most of the
cellular processes are highly complex. Disfunctions in
key processes cause diseases, like cancer. In deciphering
biological processes, natural products are still an impor-
tant tool and the discovery of natural products often
identifies new biological targets to treat diseases. Illustra-
tive examples in this regard are the pladienolides and
FR901464 (Figure 1). Appropriately labeled and modified
derivatives of pladienolide B1ꢀ3 (1) and FR9014644,5 (4)
showed that the strong antitumor activities ofthese natural
products are connected with interference of the splicing
process.6ꢀ8 Protein production in eukaryotic cells requires
removal of introns from the initial transcript, the pre-
mRNA, by the spliceosome before the mature mRNA is
released to the cytosol. The splicing process involves well
organized binding and release of several small nuclear
ribonucleoproteins (snRNPs), like U1, U2, U4/U6ꢀU5
†
€
Institut f€ur Organische Chemie, Universitat T€ubingen.
‡ Abteilung Chemische Biologie Helmholtz-Zentrum f€ur Infektionsforschung.
(1) (a) Sakai, T.; Sameshima, T.; Matsufuji, M.; Kawamura, N.;
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N.; Okuda, A.; Kawamura, N.; Mizui, Y. J. Antibiot. 2004, 57, 180–187.
(2) Stereochemistry: Asai, N.; Kotake, Y.; Niijima, J.; Fukuda, Y.;
Uehara, T.; Sakai, T. J. Antibiot. 2007, 60, 364–369.
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Okamoto, K.; Shimizu, H.; Yamori, T.; Yoshimatsu, K.; Asada, M.
J. Antibiot. 2004, 57, 188–196.
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Takase, S.; Terano, H.; Okuhara, M. J. Antibiot. 1996, 49, 1196–1203.
(b) Nakajima, H.; Hori, Y.; Terano, H.; Okuhara, M.; Manda, T.;
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Kiyosue, Y.; Shimizu, H.; Uesugi, M.; Ishihama, Y.; Iwata, M.; Mizui,
Y. Nat. Chem. Biol. 2007, 3, 570–575.
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Tashiro, E.; Nojima, T.; Hagiwara, M.; Ishigami, K.; Watanabe, H.;
Kitahara, T.; Yoshida, T.; Nakajima, H.; Tani, T.; Horinouchi, S.;
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r
10.1021/ol201464m
Published on Web 06/27/2011
2011 American Chemical Society

to the pre-mRNA. As ribozymes they are responsible for
the transesterification reactions that cut out the introns.9
During the early stages of the splicing process the U2
snRNP binds with two protein subunits SF3a and SF3b to
the RNA. Affinity-based studies showed that pladienolide
B and spliceostatin A (5), a stable derivative of FR901464,
bind to a subunit of SF3b, the protein SAP130.6ꢀ8 The
disturbed splicing process is probably detected by check
points causing cell cycle arrest.
Therefore, these natural products represent interesting
lead structures for synthesis programs. A derivative of
pladienolide B, E7107 (3), was even advanced to clinical
trials, although the outcome of this study has not yet been
published. The groupof Webb preparedseveral derivatives
of FR901464 that contributed to the structureꢀactivity
relationship.10 They argue that 1 and 4 are similar in that
the epoxy group and the O-acetyl groups have the same
distance in both molecules.
According to our synthetic plan (Figure 2) the side chain
would be attached by a cross-coupling reaction at the
C13ꢀC14 bond, with a vinyl iodide substituent emerging
from the macrolactone. The allylic alcohol at C7 was
envisioned to come from an enone precursor A which
offered the possibility of creating the C8ꢀC9 double bond
by a HornerꢀWadsworthꢀEmmons (HWE) reaction.
This could even be used for macrolactone formation.
Alternatively, Yamaguchi and Mitsunobu lactonization
were considered. This led to the two building blocks C and D.
The tertiary alcohol function in D could derive from the
natural product (R)-(ꢀ)-linalool. Inthis paper we illustrate
the synthesis of the pladienolide B core featuring a vinyl
iodide side chain that presents itself for cross-coupling
reactions.
Pladienolide B (1) was isolated by scientists from Eisai
Co., Ltd. from Streptomyces platensis Mer-11107.1,2
Among several related macrolides, pladienolide B and D
were the most active ones with IC50 values in the low nano-
molar range in the cell proliferation assay with the human
colon cancer cell line WiDr (1, 0.86 nM; 2, 5.9 nM).11 They
were discovered in a screen that revealed compounds which
inhibit the reaction of tumor cells to hypoxia (oxygen
deficiency). The structural features of pladienolide B include
a 12-membered macrolactone ring containing a vicinal diol
with one of the alcohols being allylic and the other one
tertiary. Challenging features in the side chain are the con-
jugated E,E-diene and the epoxide function. So far one total
synthesis by Kotake et al.,11 a synthesis of the macrolactone
part lacking the complete side chain,12 and the synthesis of
the side chain were reported.13 The Burkart group could also
demonstrate the attachment of the side chain to a model
lactone by Stille coupling.13
Figure 2. Retrosynthetic plan for pladienolide B (1).
First, (R)-(ꢀ)-linalool (6) was converted to the corre-
sponding MEM ether (MEMCl, iPr2NEt, room tempera-
ture) in almost quantitative yield. Next, the higher sub-
stituted double bond was oxidized to the corresponding
diol 8 using osmium-catalyzed dihydroxylation. Oxidative
cleavage of the diol 8 (NaIO4, THF/H2O) furnished
aldehyde 9.14 This aldehyde (0.6 equiv) was entered into
a Nagao acetate aldol reaction15 withthiazolidinethione 10
in the presence of Sn(OTf)2 (1.34 equiv) and N-ethylpiper-
idine (1.46 equiv) in CH2Cl2 at ꢀ78 °C to provide aldol
(10) (a) Lagisetti, C.; Pourpak, A.; Jiang, Q.; Cui, X.; Goronga, T.;
Morris, S. W.; Webb, T. R. J. Med. Chem. 2008, 51, 6220–6224.
(b) Lagisetti, C.; Pourpak, A.; Goronga, T.; Jiang, Q.; Cui, X.; Hyle,
J.; Lahti, J. M.; Morris, S. W.; Webb, T. R. J. Med. Chem. 2009, 52,
6979–6990.
(11) Kanada, R. M.; Itoh, D.; Nagai, M.; Niijima, J.; Asai, N.; Mizui,
Y.; Abe, S.; Kotake, Y. Angew. Chem., Int. Ed. 2007, 46, 4350–4355.
Corrigendum: Angew. Chem., Int. Ed. 2007, 46, 8734.
(12) Skaanderup, P. R.; Jensen, T. Org. Lett. 2008, 10, 2821–2824.
(13) Mandel, A. L.; Jones, B. D.; La Clair, J. J.; Burkart, M. D.
Bioorg. Med. Chem. Lett. 2007, 17, 5159–5164.
(14) For related sequences starting from linalool, see: (a) Li, G.;
Yang, X.; Zhai, H. J. Org. Chem. 2008, 74, 1356–1359. (b) Sabitha, G.;
Prasad, M. N.; Bhikshapathi, M.; Yadav, J. S. Synthesis 2010, 807–810.
(c) Canterbury, D. P.; Micalizio, G. C. Org. Lett. 2011, 13, 2384–2387.
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T.; Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391–2393. (b)
Nagao, Y.; Dai, W. M.; Ochiai, M.; Shiro, M. J. Org. Chem. 1989, 54,
5211–5217. (c) Delaunay, D.; Toupet, L.; Corre, M. L. J. Org. Chem.
1995, 60, 6604–6607.
Figure 1. Structures of spliceosome inhibitors of the pladieno-
lide and FR901464 type.
Org. Lett., Vol. 13, No. 15, 2011
3941

product 11 in 75% yield.16 Silylation of the alcohol
(TBSOTf, 2,6-lutidine) was followed by transesterification
to methyl ester 13. At this stage the terminal double bond
was cleaved by ozonolysis yielding aldehyde 14 in good
yield. To prepare ketophosphonate 16, aldehyde 14 was
reacted with lithiated dimethyl methyl phosphonate
at ꢀ100 °C. Oxidation of the obtained alcohol 15 with
the DessꢀMartin reagent delivered ketophosphonate 16
(Scheme 1).
Scheme 2. Synthesis of Aldehyde 22 by an anti Aldol Reaction
Scheme 1. Synthesis of Ketophosphonate 16 from (R)-(ꢀ)-
Linalool
The crucial HWE reaction between phosphonate 16 and
aldehyde 22 turned out to be rather challenging. Most of
the known literature methods were inefficient and see-
mingly led to destruction of the sensitive aldehyde 22.
Eventually, performing the reaction with dried BaO in
Et2O, which contained a trace of water, produced enone 23
in a very efficient way.19 Toward the seco acid 25, methyl
ester 24 was saponified with trimethyltin hydroxide in
dichloroethane,20 since basic hydrolysis was detrimental
in this case. Subsequently, selective cleavage of the triethyl-
silyl ether using DDQ21 in a CH3CN/H2O mixture deliv-
ered seco acid 25. Macrolactonization was initially tried
under Yamaguchi conditions. However, in this case, the
yield never exceeded 50%. In contrast, lactonization with
the Shiina anhydride in the presence of DMAP induced
lactone formation in almost quantitative yield.22,23 We
next faced the problem of diastereoselective enone reduc-
tion. This was performed using Luche conditions (NaBH4,
CeCl3 7H2O) in MeOH but led to the C7 epimer 27. The
3
stereochemistry at C7 was inferred from the corresponding
Mosher ester.24 Thus, in benzene-d6 as a solvent the
expected shift differences were observed for the Mosher
esters prepared from 27. For example, the 6-CH3 group in
the (S)-27 Mosher derivative is shifted to higher field due
to the influence of the phenyl group. By way of contrast,
9-H experienced a high field shift in the (R)-27 Mosher
derivative. To show that the vinyl iodide is suitable for
chain extension, we performed a Stille cross-coupling with
ꢀ
(19) (a) Ibarra, C. A.; Arias, S.; Fernandez, M. J.; Sinisterra, J. V.
J. Chem. Soc., Perkin Trans. 2 1989, 503–508. (b) Paterson, I.; Yeung,
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The otherfragmentaldehyde 22was prepared essentially
according to the literature.17 A MasamuneꢀAbiko aldol
reaction18 between aldehyde18andchiralester17followed
by silylation of the aldol product provided ester 20 in good
overall yield (Scheme 2). Reduction of ester 20 with DI-
BAL-H (2.5 equiv) in CH2Cl2 furnished primary alcohol 21.
Its oxidation delivered the C9ꢀC13 fragment, aldehyde 22.
ꢀ
(20) (a) Mascaretti, O. A.; Furlan, R. L. E. Aldrichimica Acta 1997,
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Chem. 2004, 69, 1822–1830. (b) Shiina, I. Tetrahedron 2004, 60, 1587–
1599. (c) Shiina, I.; Hashizume, M.; Yamai, Y.-s.; Oshiumi, H.; Shima-
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(16) Performing the aldol reaction at a later stage with the enone
present caused problems during cleavage of the auxiliary.
(17) Menche, D.; Hassfeld, J.; Li, J.; Mayer, K.; Rudolph, S. J. Org.
Chem. 2009, 74, 7220–7229.
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3942
Org. Lett., Vol. 13, No. 15, 2011

tributylphenylstannane in the presence of Pd(PPh3)4, CuTC,
and Ph2PO2ꢀNBu4þ in DMF.25 This way styrene 28 could be
obtained in 80% yield. The acetate group was then introduced
by a modified Mitsunobu reaction26,27 in 65% yield. Finally,
both protecting groups were removed from lactone 29 with
PPTS in MeOH resulting in pladienolide analogue 30 in 51%
yield after preparative TLC (Scheme 3).
Scheme 3. Formation of Enone 23 by a
HornerꢀWadsworthꢀEmmons Reaction Followed by
Macrolactonization of the Derived seco Acid to Lactone 26a
In a cell proliferation assay28,29 against L929 mouse fibro-
blasts, pladienolide analogue 30 was inactive up to 4 μgmLꢀ1
.
This underscores the role of the epoxide-containing side chain
for binding and supports the hypothesis of Webb.10
In summary, we demonstrated a novel strategy to the
core structure of pladienolide B. Starting from the mono-
terpene (R)-(ꢀ)-linalool (6), ketophosphonate 16 was pre-
pared. After oxidative cleavage of the higher substituted
double bond on 6, an acetate aldol reaction set the stereo-
center at C3. The aldehyde function, derived from the
other double bond, allowed for extension to the ketopho-
sphonate 16. An HWE reaction of 16 with aldehyde 22
produced enone 23. The corresponding seco acid 25 could
be cyclized in very high yield to the macrolactone 26 using
the Shiina reagent. The C7 stereocenter was established by
Luche reduction followed by Mitsunobu reaction to in-
troduce the acetate group. In a Stille reaction with phenyl-
stannane, we were able to show that the vinyl iodide allows
for the introduction of substituents to the side chain.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft (Grant MA 1012/24-1) and the
Fonds der Chemischen Industrie is gratefully acknowledged.
This work was carried out within the framework of COST
action CM0804ꢀChemical Biology with Natural Products.
We thank Bettina Hinkelmann (HZI Braunschweig) and
Tatjana Hirsch (HZI Braunschweig) for excellent technical
assistance with the cytotoxicity assay.
Supporting Information Available. Experimental pro-
cedures and characterization for all new compounds
reported and copies of NMR spectra for important
intermediates. This material is available free of charge
via the Internet at http://pubs.acs.org.
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€
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^
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a CuTC = copper(I)-thiophene-2-carboxylate; MNBA = 2-methyl-
6-nitrobenzoic anhydride; ADDP = azodicarboxylic acid dipiperidide.
ꢁ
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Org. Lett., Vol. 13, No. 15, 2011
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