Synthesis of the macrocyclic core of (-)-pladienolide B

Article abstract of DOI:10.1021/ol800946x

(Chemical Equation Presented) An efficient synthesis of the macrocyclic core of (-)-pladienolide B is disclosed. The concise route relies on a chiral auxiliary-mediated asymmetric aldol addition and an osmium-catalyzed asymmetric dihydroxylation to install the three oxygenated stereocenters of the macrocycle. This purely reagent-controlled and flexible strategy sets the stage for future analogue syntheses and structure-activity relationship plotting of the appealing anticancer lead structure pladienolide B.

Full text of DOI:10.1021/ol800946x

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2821-2824
Synthesis of the Macrocyclic Core of
(-)-Pladienolide B
Philip R. Skaanderup*,†,‡ and Thomas Jensen†
Department of Chemistry, Technical UniVersity of Denmark, Building 201, KemitorVet,
DK-2800 Kgs. Lyngby, Denmark, and NoVartis Institutes for BioMedical Research,
NoVartis AG, CH-4056 Basel, Switzerland
philip.skaanderup@noVartis.com
Received April 24, 2008
ABSTRACT
An efficient synthesis of the macrocyclic core of (-)-pladienolide B is disclosed. The concise route relies on a chiral auxiliary-mediated
asymmetric aldol addition and an osmium-catalyzed asymmetric dihydroxylation to install the three oxygenated stereocenters of the macrocycle.
This purely reagent-controlled and flexible strategy sets the stage for future analogue syntheses and structure-activity relationship plotting
of the appealing anticancer lead structure pladienolide B.
The identification of new targets of clinical relevance is a
cornerstone in improving the level of existing disease
remedies and for developing new therapies for hitherto
untreatable diseases.1 Recently, it has been indicated that
splicing factors are important potential targets for the
development of new cancer therapies.2 The natural product
pladienolide B (1, Figure 1) potently inhibits cancer cell
proliferation, and biological studies aimed at elucidating its
mode of action have led to a proposed mechanism involving
binding to the splicing factor SF3b.3 Pladienolide B was
isolated by Sakai and co-workers in 2004 from the fermenta-
tion broth of Streptomyces platensis Mer-11107 using a
screen designed to identify compounds that inhibit cell
signaling pathways in a tumor-specific microenvironment.4a–c
Significantly, pladienolide B inhibts hypoxia-induced VEGF
expression and proliferation of human cancer cell lines with
low to subnanomolar IC50 values.4a,c Moreover, pladienolide
B displays unchanged inhibitory activity against drug-
resistant cancer cells, as compared to their parental cell lines,
and has demonstrated complete regression of BSY-1 tumors
in xenograft mice models.4c This unique biological profile
has inspired considerable interest from the scientific com-
munity5,6 leading to elucidation of the absolute stereochem-
istry5 (1, Figure 1) and the first total synthesis by Kotake
and co-workers.6a,c Despite these noteworthy efforts, little
is known about the structural basis for pladienolide B’s
modulation of spliceosomal activity and potential interaction
with other targets.
At the outset of our synthetic efforts in April 2005, only
the planar structure of pladienolide B had been reported.4b,7
Interestingly, the 12-membered core and the side chain of
pladienolide B resemble the macrocyclic core of 10-
† Technical University of Denmark.
‡ Novartis Institutes for BioMedical Research.
(1) Fishman, M. C.; Porter, J. A. Nature 2005, 437, 491–493.
(2) (a) Karni, R.; de Stanchina, E.; Lowe, S. W.; Sinha, R.; Mu, D.;
Krainer, A. R. Nature Struc. Mol. Biol. 2007, 14, 185–193. (b) He, X.;
Pool, M.; Darcy, K. M.; Lim, S. B.; Auersperg, N.; Coon, J. S.; Beck,
W. T. Oncogene 2007, 26, 4961–4968.
(4) (a) Sakai, T.; Sameshima, T.; Matsufuji, M.; Kawamura, N.; Dobashi,
K.; Mizui, Y. J. Antibiot. 2004, 57, 173–179. (b) Sakai, T.; Asai, N.; Okuda,
A.; Kawamura, N.; Mizui, Y. J. Antibiot. 2004, 57, 180–187. (c) Mizui,
Y.; Sakai, T.; Iwata, M.; Uenaka, T.; Okamoto, K.; Shimizu, H.; Yamori,
(3) Kotake, Y.; Sagane, K.; Owa, T.; Mimori-Kiyosue, Y.; Shimizu,
H.; Uesugi, M.; Ishihama, Y.; Iwata, M.; Mizui, Y. Nature Chem. Biol.
2007, 3, 570–575.
T.; Yoshimatsu, K.; Asada, M. J. Antibiot. 2004, 57, 188–196
(5) Asai, N.; Kotake, Y.; Niijima, J.; Fukuda, Y.; Uehara, T.; Sakai, T.
J. Antibiot. 2007, 60, 364–369
.
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10.1021/ol800946x CCC: $40.75
Published on Web 05/30/2008
2008 American Chemical Society

Figure 1. Metabolites of the Streptomyces family 1-3 and target structure 4.
deoxymethynolide8 (2, Figure 1) and the side chain of
herboxidiene9 (3). From an evolutionary point of view, it is
conceivable that pladienolide B and other secondary me-
tabolites produced by Streptomyces strains, such as herboxi-
diene and 10-deoxymethynolide, could be synthesized by
polyketide synthases encoded by related gene clusters.10
Consistent with a common biogenesis for these three
polyketides, we projected that the absolute configuration of
1 would correlate to that of 2 and 3. Hence, we focused our
synthetic studies on the asymmetric synthesis of core
structure 4, the enantiomer of the (+)-pladienolide B core
(Figure 1). Herein, we wish to report a convergent synthesis
of 4 and its crystal structure.
be available from commercial (S)-Roche ester and 6 was
anticipated to arrive from sequential olefination and osmium-
catalyzed asymmetric dihydroxylation thereby installing the
vicinal oxygen-substituted stereocenters of the macrocycle.
Finally, key intermediate 7 would result from chiral auxiliary-
mediated asymmetric aldol addition of known acetylthiazo-
lidine-thione 9 and aldehyde 8 (Scheme 1).
Scheme 1. Retrosynthesis of (-)-Pladienolide B Core Structure
Structurally, the core structure 4 consists of a 12-membered
macrolactone bearing four stereocenters with an O-acetylated
secondary alcohol adjacent to a tertiary hydroxyl group. The
macrolactone also contains a disubstituted trans olefin, a
tertiary stereocenter, and a second hydroxyl group stereo-
center. Toward our synthetic target 4 we envisioned a
strategy with maximum flexibility that would provide access
to all sixteen stereoisomers of the core structure. Specifically,
we envisioned an orthoester formation and ring-opening
sequence to selectively acetylate the desired secondary
alcohol and complete the synthesis of 4. Macrolactonization
and (E)-selective cross metathesis between olefins 5 and 6
could construct the 12-membered lactone. 5 would in turn
(6) (a) 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. (b)
Mandel, A. L.; Jones, B. D.; La Clair, J. J.; Burkart, M. D. Bioorg. Med.
Chem. Lett. 2007, 17, 5159–5164. (c) Kanada, R. M.; Itoh, D.; Sakai, T.;
Asai, N.; Kotake, Y.; Niijima, J. Eisai R & D Management Co., Ltd., Japan.
PCT Int. Appl. WO 2007043621.
The synthesis takes advantage of the easily obtainable
building blocks 5 and 8 (Scheme 2). Tritylation of (S)-Roche
ester 10 followed by LAH reduction, Swern oxidation,11 and
Wittig methylenation afforded alkene 5 smoothly over this
four-step sequence (Scheme 2a). Prilezhaev epoxidation12
of commercial acetate 11 and subsequent epoxide cleavage
(7) The Danish Research Council for Technology and Production
Sciences, grant no. 26-04-0143, Synthesis of Novel Pladienolide Analogues:
Structure-Activity Relationship Mapping and Mode of Action Studies.
(8) Lambalot, R. H.; Cane, D. E. J. Antibiot. 1992, 45, 1981–1982.
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Liu, H. J. Am. Chem. Soc. 1999, 121, 9881–9882. (b) Firn, R. D.; Jones,
C. G. Nat. Prod. Rep. 2003, 20, 382–391. (c) Nguyen, T.; Ishida, K.; Jenke-
Kodama, H.; Dittmann, E.; Gurgui, C.; Hocmuth, T.; Taudien, S.; Platzer,
M.; Hertweck, C.; Piel, J. Nat. Biotechnol. 2008, 26, 225–233.
(11) (a) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41,
3329–3331. (b) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem.
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Org. Lett., Vol. 10, No. 13, 2008

Scheme 2
.
Synthesis of Intermediates 5, 8, and 7
Scheme 3. Synthesis of (E)-Olefin 14
formed in equal diastereomeric ratio and is the likely product
of intramolecular acetyl migration. All attempts to convert
13b into 13a were unsuccessful. The key alkene fragment 6
was prepared from 13a in a four-step sequence initially
involving acetonide formation and treatment with K2CO3 in
methanol to concomitantly cleave the acetate and convert
the chiral auxiliary into a methyl ester.17 Parikh-Do¨ering
oxidation18 followed by Wittig methylenation provided
alkene 6 in 71% yield over these four steps. With compound
6 in hand, we set out to identify reaction conditions that
would furnish (E)-alkene 14 efficiently. Initial attempts to
mediate the cross-metathesis between olefins 5 and 6 with
10 mol% of either Grubbs’ second-generation catalyst,19
Hoveyda-Grubbs’ second-generation catalyst,20 or Grubbs’
third-generation catalyst21 gave the desired alkene 14 in less
than 30% yield.22 Interestingly, only the (E)-alkene was
using periodic acid provided aldehyde 8.13 Secondary alcohol
12a was available via an asymmetric aldol reaction of
aldehyde 8 with a chiral acetylthiazolidinethione enolate
generated from 9 using Vilarrasa’s conditions.14 The selec-
tivity of the aldol reaction could be tuned to give either 12a
or 12b as the major product even when the same acetylthi-
azolidinethione was employed. The titanium enolate gener-
ated with titanium tetrachloride and Hu¨nig’s base gave
predominantly the desired isomer 12a in excellent yield. If
the enolate was generated from dichlorophenylborane and
(-)-sparteine, 12b was formed as the major product.15
Additionally, the valine and tert-leucine-derived auxiliaries
gave slightly improved product ratios of 5:1 to 6:1. However,
we chose to use the phenylalanine-derived auxiliary because
all intermediates leading to 9 are crystalline and can be
obtained easily in analytically pure form. The aldol product
was then protected as the TBS ether to give 7 in 92% yield
(Scheme 2b).
1
observed by H NMR. Following optimization the yield of
14 could be improved to 76% using Hoveyda-Grubbs’
second-generation catalyst and by adding 5 in two portions
over the course of the reaction (Scheme 3). Selective
The oxygenated functionality at the northern portion of
the target molecule was installed by Sharpless’s asymmetric
dihydroxylation protocol.16 From the well-defined olefin
geometry of the substrate, which relates back to nerol and
using the (DHQD)2PHAL ligand, diol 13a was produced in
good yield and selectivity greater than 20:1 at the newly
formed stereocenters (Scheme 3). Acetate 13b was also
23
deprotection of the trityl ether using a solution of BCl3
followed by methyl ester hydrolysis successfully gave seco-
acid 15 in 84% yield for this two-step sequence (Scheme
4).
(17) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775–777.
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´
(14) Gonza´lez, A.; Aiguade´, J.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett.
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(20) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
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Schrodi, Y. Org. Lett. 2007, 9, 1589–1592.
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(22) Using the corresponding TBS-ether afforded the desired alkene in
25% yield; however, the TBS-ether was volatile and thus impractical to
employ in the synthesis.
Org. Lett., Vol. 10, No. 13, 2008
2823

Scheme 4. Macrolactonization and Completion of 4
Figure 2.
Structure of 4 in the crystal.28 The ellipsoids are drawn
at the 50% probability level, and the hydrogen atoms are drawn
with an arbitrary radius. For the enantiomer shown, the Flack x
parameter refined to 0.03(4).29
10 and 11 using a total number of 19 steps (longest linear )
15 steps). The achieved synthesis, with full control of all
four stereocenters of the macrocyclic core structure, illustrates
the flexibility of our approach. Through cross metathesis
reactions between olefin 6 and homoallylic alcohols, as a
readily available source of chemical diversity, our method
sets the stage for rapid synthesis of new pladienolide
analogues.30 Our ongoing efforts are focused on using this
strategy to synthesize new side-chain analogues and to study
the structural basis for pladienolide B’s anticancer activity.
Attempts to close the macrocycle under modified Yamagu-
chi conditions24 at room temperature produced 16 in 34%
yield. However, by increasing the reaction temperature to
80 °C and adding the preformed mixed anhydride slowly to
a DMAP-benzene solution,25 the yield improved consider-
ably, and macrocycle 16 could be isolated in 63% yield. The
TBS and acetonide groups were then effectively removed
through the action of aqueous HF in MeCN.26 Finally, the
secondary allylic alcohol was acetylated selectively by
treating the diol with trimethyl orthoacetate and CSA
followed by cleavage of the resulting orthoester with aqueous
AcOH to give the macrocyclic core structure 4 in 86% yield
(Scheme 4).
Acknowledgment. This work was supported by The
Danish Research Council for Technology and Production
Sciences, grant no. 26-04-0143. We gratefully acknowledge
Trixie Wagner (Novartis AG, Switzerland) for the X-ray
structure determination and Professor Robert Madsen (Tech-
nical University of Denmark) for helpful discussions.
The structure and absolute stereochemistry of macrolactone
4 were unambiguously established by single-crystal X-ray
crystallography (Figure 2).27
In summary, the macrocyclic core of (-)-pladienolide B
(4) has been synthesized in 8.1% overall yield starting from
Supporting Information Available: Full experimental
details and spectral data for all new compounds. This material
is availabe free of charge via the Internet at http://pubs.acs.org.
OL800946X
(23) Jones, G. B.; Hynd, G.; Wright, J. M.; Sharme, A. J. Org. Chem.
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(27) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre, deposition no.
CCDC 682897.
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S.; Flack, H. D. Abstracts of the 22nd European Crystallography Meeting,
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Org. Lett., Vol. 10, No. 13, 2008