Total synthesis of the antiproliferative macrolide (+)-neopeltolide

Article abstract of DOI:10.1021/ol902047z

A concise total synthesis of the very promising antiproliferative macrolide (+)-neopeltolide (1) has been performed In 16 steps. The main steps of this approach are a Ru^II-catalyzed alkyne-enal coupling, a Pd ⁰-catalyzed desulfurativ

Full text of DOI:10.1021/ol902047z

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4700-4703
Total Synthesis of the Antiproliferative
Macrolide (+)-Neopeltolide
Xavier Guinchard and Emmanuel Roulland*
Centre de Recherche CNRS de Gif-sur-YVette, Institut de Chimie des Substances
Naturelles, AVenue de la Terrasse, 91198, Gif-sur-YVette, France
emmanuel.roulland@icsn.cnrs-gif.fr
Received September 3, 2009
ABSTRACT
A concise total synthesis of the very promising antiproliferative macrolide (+)-neopeltolide (1) has been performed in 16 steps. The main
steps of this approach are a RuII-catalyzed alkyne-enal coupling, a Pd0-catalyzed desulfurative cross-coupling, and a stereoselective InIII-
catalyzed propargylation. Four stereogenic centers out of six have been set thanks to substrate-controlled diastereoselective reactions with
minimal reliance on protecting groups.
(+)-Neopeltolide (1) is a marine macrolide isolated in 2006
by Wright et al.1 from a sponge of the Neopeltidae family.
Beyond the synthetic challenge, (+)-1 has a great intrinsic
value as it is endowed with a nanomolar level of activity
against proliferation of various cancer cell lines (A549 human
lung adenocarcinoma, NCI/ADR-RES ovarian sarcoma, and
P388 murine leukemia with IC50 of 1.2, 5.1, and 0.56 nM,
respectively) as well as on DLD-1 colorectal cell lines or
on the treatmentless PANC-1 pancreatic cell lines.1 (+)-
Neopeltolide (1) also shows effective activity against fungal
pathogens such as Candida albicans.1 One must notice that
(+)-1 shares common biological properties with (+)-leu-
cascandrolide A,2 a structurally homologous marine natural
product. Furthermore, Kozmin3 suggested that both com-
Figure 1. Retrosynthesis.
pounds target cytochrome bc1, resulting in the inhibition of
* To whom correspondence should be addressed. Fax: (+) 33 1 69 07
72 47. Web site: http://www.icsn.cnrs-gif.fr.
mitochondrial ATP synthesis. It is noteworthy that the
relative configuration initially proposed by Wright et al.1 for
(+)-1, which arose from advanced NMR studies, was
(1) (a) Wright, A. E.; Cook Botelho, J.; Guzma´n, E.; Harmody, D.;
Linley, P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat.
Prod. 2007, 70, 412–416. (b) Wright, A. E.; Pomponi, S. A.; McCarthy,
P. J. U.S. Patent 7179828B2, 2007, European Patent 1644380, 2007.
(2) d’Ambrosio, M.; Tato`, M.; Pocsfalvi, G.; Debitus, C.; Pietra, F. HelV.
Chim. Acta 1999, 82, 347–353. Erratum: d’Ambrosio, M.; Tato`, M.;
Pocsfalvi, G.; Debitus, C.; Pietra, F. HelV. Chim. Acta 1999, 82, 1135.
(3) Ulanovskaya, O. A.; Janjic, J.; Suzuki, M.; Sabharwal, S. S.;
Schumacker, P. T.; Kron, S. J.; Kozmin, S. A. Nat. Chem. Biol. 2008, 4,
418–424.
10.1021/ol902047z CCC: $40.75
Published on Web 09/23/2009
 2009 American Chemical Society

Scheme 1. Synthesis of the C16-C5 Fragment 2
corrected thanks to total syntheses by Panek4 and Scheidt.5
They thus established the right relative configurations for
C11 and C13 and accordingly determined the absolute
configuration of (+)-neopeltolide (1). Since then, this
molecule has strongly inspired the organic chemist com-
munity leading to four more total asymmetric syntheses,6
one racemic approach3 and three formal syntheses,7 along
with the synthesis of neopeltolide analogues.6d,8
The main features of the (+)-neopeltolide (1) structure
include six asymmetric centers, a macrolactonic ring fused
with a trisubstituted tetrahydropyran ring to which is attached
an oxazole-containing side chain, which is identical to that
of (+)-leucascandrolide A. This original structure attracted
our attention and teased our imagination leading to the
retrosynthetic plan shown in Figure 1. Inspired by the work
of Trost,9 we imagined performing a rapid and stereoselective
elaboration of the tetrahydropyran ring of (+)-1 in the course
of a [CpRu(MeCN)3]PF6-catalyzed tandem alkyne-enal
coupling/Michael addition sequence. This key step would
allow assemblage of the silylated alkyne 2 with 3-butenal,
an “ene” cross-coupling partner never used in this type of
reaction before. Considering that the use of asymmetric
reagents and catalysts increases the cost of syntheses, we
designed a strategy restricting their use only to control two
centers (C13 and C7) out of six, the four remaining centers
(C3, C5, C9, C11) being set by substrate-controlled diaste-
reoselective reactions. Furthermore, a minimal reliance on
protective groups was targeted, leading to atom economy
and reduced costs. The C18-C28 oxazole-containing side
chain has also attracted our attention, and we thought it
possible to develop a synthesis more straightforward than
those already reported.6b,d,10 For this goal, a Pd0-catalyzed
desulfurative Sonogashira-like cross-coupling would allow
assemblage of the oxazolethione 3 with alkyne 4.11
The route toward the key C5-C16 fragment 2 commenced
(Scheme 1) by the ruthenium-catalyzed asymmetric hydro-
genation of ꢀ-ketoesters developed by Geneˆt et al.12 provid-
ing alcohol 6 from compound 5 with a full control of the
C13 stereogenic center. After transformation into the Weinreb
amide13 7, a reaction with (2-methylallyl)magnesium chloride
led to ꢀ,γ-unsaturated ketone 8. An Evans-Tishchenko
reaction14 on ketone 8 allowed to control the C11 configu-
ration providing the anti 1,3-diol 9 (84% yield) as a sole
detectable diastereoisomer while installing a strategically
useful benzoate ester at C13. The alcohol function that
remained free at C11 was allowed to react with acryloyl
chloride yielding the diene 10. The ring closure metathesis
of the latter using second-generation Grubbs’ catalyst,15 led
to the R,ꢀ-unsaturated lactone 11 in 86% yield. Then, the
C9 stereogenic center was controlled by a simple Pd/C-
catalyzed hydrogenation that turned out to be totally dias-
tereoselective but with solvolysis leading to an equilibrated
mixture of lactone 12 and seco-ester 13 (ratio: 1/2). Lactone
12 could be nevertheless cleanly reconverted into 13 using
(4) Youngsaye, W.; Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S.
Angew. Chem., Int. Ed. 2007, 46, 9211–9214.
(5) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem. Soc.
2008, 130, 804–805.
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Ed. 2008, 47, 4737–4739. (b) Paterson, I.; Miller, N. A. Chem. Commun.
2008, 4708–4710. (c) Woo, S. K.; Kwon, M. S.; Lee, E. Angew. Chem.,
Int. Ed. 2008, 47, 3242–3244. (d) Vintonyak, V. V.; Kunze, B.; Sasse, F.;
Maier, M. E. Chem.sEur. J. 2008, 14, 11132–11140. For a review, see:
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J. Am. Chem. Soc. 2009, 131, 12406–12414.
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P. Org. Lett. 2008, 10, 853–856.
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4764.
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347. (b) Wang, Y.; Janjic, J.; Kozmin, S. A. J. Am. Chem. Soc. 2002, 124,
13670–13671. (c) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am.
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Org. Lett., Vol. 11, No. 20, 2009
4701

smooth acidic conditions that left the benzoyl ester un-
touched. Then, the secondary alcohol functionality at C11
was transformed into a methoxy group using the Meerwein’s
salt16 leading to 14. In the next step, a careful DIBALH
addition on diester 14 at low temperature led to aldehyde
15 in 94% yield while removing the benzoyl group inherited
from the Evans-Tishchenko step. The second (and last)
reaction involving an asymmetric reagent of this total
synthesis was used to control the C7 stereogenic center. This
step consisted of the InIII-catalyzed propargylation reaction17
in the course of which occurred a fully stereoselective transfer
of the trimethylsilylpropynyl group from the asymmetric
allenyl alcohol 1618 on aldehyde 15 leading to key homopro-
pargylic alcohol 2.
the branched product 19 in the course of a fully diastereo-
selective and reproducible (49% to 54% yield) one-pot, three-
step sequence including the now-needed LiBF4·H2O-pro-
moted acetal-hydrolysis/Michael cyclization. Here again, the
use of a catalytic amount of AcOH appeared to be instru-
mental to allow the ene-yne coupling to occur efficiently.
One can notice that the reaction also worked well on 18 using
[Cp*Ru(MeCN)3]PF6 under the same conditions, leading to
19 in 54% yield with a notably shortened reaction time.
The exo-methylene functions of either compounds 17 or
19 was oxidized by OsO4 and NaIO4 leading to ketone 20
(Scheme 3), which was then transformed into the known
With homopropargylic alcohol 2 in hand, we investigated
Ru-catalyzed reaction conditions (Scheme 2) targeting tetra-
Scheme 3. Synthesis of Key Macrolactone 23
Scheme 2.
RuII-Catalyzed Ene-Yne Coupling Trials
hydropyran 17 by reaction with 3-butenal.19 To our delight,
this key step occurred leading to 17 in the course of the
expected Ru-catalyzed tandem alkyne-enal coupling/ste-
reoselective Michael addition sequence. When adding a
catalytic amount of AcOH, tetrahydropyran 17 was obtained
in better yields and as one sole diastereoisomer (creation of
the C3 stereogenic center). Nevertheless, this reaction
suffered from poor reproducibility, with yields of 17 varying
from 28% to 58%, probably because of the unstable nature
of 3-butenal. During the studies on the [CpRu(MeCN)3]PF6-
catalyzed ene-yne cross-coupling reactions, Trost demon-
strated that the presence of a silicon atom on the alkyne
usually strongly favors the formation of branched products,
disfavoring linear ones.20 Nervertheless, there were only
scarce examples of nonsilylated terminal alkynes giving
branched products with good selectivity.21 In spite of this,
we tried the coupling of the readily obtained desilylated
alkyne 18 with 4,4-diethoxybut-1-ene,22 a protected equiva-
lent of 3-butenal. We were delighted to obtain exclusively
carboxylic acid 216b using the Pinnick oxidation.23 The
macrocycle was then closed using classical Yamaguchi
macrolactonization conditions24 affording 22 in high yield.
As described by Scheidt,5 the ketone 22 was reduced by
NaBH4 into the key alcohol 23 with a good diastereoselec-
tivity.
Concerning the synthesis of the oxazole-containing side
chain, we started from oxazolethione derivative 3 (Scheme
4), which was easily accessed by reaction of KSCN25 with
the known R-hydroxyketone 24.26 Using the palladium-
catalyzed copper-induced desulfurative cross-coupling condi-
tions described by Tatiboue¨t,11 we coupled oxazolethione 3
with alkyne 4 yielding oxazole 25, comprising the first use
of this methodology in the natural product synthesis context.
The alkyne functionality of 25 was then partially hydroge-
nated using Lindlar catalyst leading to the Z alkene 26. The
(19) Vugts, D. J.; Veum, L.; al-Mafraji, K.; Lemmens, R.; Schmitz, R. F.;
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Chem. Soc. 2001, 123, 12504–12509.
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9836–9845.
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Org. Lett., Vol. 11, No. 20, 2009

This final step supplied (+)-neopeltolide (1), the chemical
data of which are identical with those reported for the
naturally occurring compound [[R]20D +24.4 (c 0.24, MeOH)
Scheme 4
.
Synthesis of the Oxazole-Containing Side Chain 28
and Final Coupling
(lit.1a [R]20 +24.0 (c 0.24, MeOH)].
D
In conclusion, we have achieved one of the shortest and
most straightforward (16 steps from 5, 6.2% overall yield)
total syntheses of (+)-neopeltolide (1), a novel biologically
highly important cytotoxic marine natural product. In the
course of this synthesis, four stereogenic centers out of six
have been set, thanks to substrate-controlled diastereoselec-
tive reactions, and our strategy also allowed us to minimize
the use of protective groups. We also performed a new and
straightforward synthesis of the oxazole-containing C20-C28
chain also found in other natural products.
Acknowledgment. This work has been financially sup-
ported by the Institut de Chimie des Substances Naturelles
(ICSN) and the Centre National pour la Recherche Scien-
tifique (CNRS).
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL902047Z
benzyl group was then removed leading to known alcohol
27.27 Finally, we obtained acid 28 by following the route
described by Panek27 and Maier.6d
For the end game, we coupled alcohol 23 with acid 28 in
Mitsunobu conditions, following the Scheidt strategy,5 this
reaction setting then the right C5 configuration (Scheme 4).
(24) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
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2006, 301–305.
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2485–2488. (b) Hydroxy ketone 24 was accessed by oxidation of the
corresponding alkene using the procedure described in: Bonini, C.;
Chiummiento, L.; Funicello, M.; Lupattelli, P.; Pullez, M. Eur. J. Org. Chem.
2006, 80–83.
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