Synthesis of the C1-C13 tetraenoate subunit of the chivosazoles

Article abstract of DOI:10.1021/ol101630p

Using a combination of asymmetric vinylogous Mukaiyama aldol and Stille cross-coupling reactions, an advanced polyene fragment of the chivosazoles was prepared in a highly stereocontrolled manner. This key C1-C13 pentaene subunit, featuring the conjugated

Full text of DOI:10.1021/ol101630p

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3724-3727
Synthesis of the C1-C13 Tetraenoate
Subunit of the Chivosazoles
Ian Paterson,* S. B. Jennifer Kan, and Lisa J. Gibson
UniVersity Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, U.K.
ip100@cam.ac.uk
Received July 14, 2010
ABSTRACT
Using a combination of asymmetric vinylogous Mukaiyama aldol and Stille cross-coupling reactions, an advanced polyene fragment of the
chivosazoles was prepared in a highly stereocontrolled manner. This key C1-C13 pentaene subunit, featuring the conjugated (2E,4Z,6E,8Z)-
tetraenoate motif and anti-configured C10 and C11 stereocenters of the chivosazoles, terminates in a (Z)-vinyl bromide for the planned cross-
coupling to a northern hemisphere fragment.
The chivosazoles are a unique family of polyene macrolides,
isolated initially by the Ho¨fle and Reichenbach group from
the myxobacterium Sorangium cellulosum (strain So ce12),1
that show potent antiproliferative activity against a range of
human cancer cell lines, as well as activity against yeasts
and filamentous fungi. The chivosazoles function through
specific binding to G-actin, leading to disruption of cytosk-
eletal dynamics in vitro. Importantly, their exact mode of
action appears to be distinct from other microfilament-
disrupting compounds such as rhizopodin and cytochalasin
D,1c making them promising leads for the development of
new chemotherapeutic agents, as well as tools for study of
the actin cytoskeleton.
arrays (Scheme 1). Members of the chivosazole family
(A-F) are distinguished by variation in the C20 oxygenation
and C11 glycosylation patterns, with chivosazole F (1)
corresponding to the aglycon of chivosazole A (2). The
stereochemistry of chivosazole A has only recently been
elucidated, using a combination of NMR methods, chemical
degradation, partial synthesis, molecular modeling, and
analysis of the ketoreductase domains of the biosynthetic
gene cluster.3
There has been limited synthetic work reported on this
important family of bioactive macrolides, with Kalesse’s
synthesis of a C15-C35 northern segment representing the
only published effort to date.4 As part of our interest in
antimitotic polyketide metabolites from myxobacteria,5,6 we
have also identified the chivosazoles as testing targets for
total synthesis. Herein, we outline our strategy and report
The chivosazoles are also structurally intriguing and
synthetically enticing polyketides2 possessing an elaborate
31-membered macrolactone ring, featuring an oxazole, 10
stereocenters, and, most notably, three distinctive polyene
(3) Jansen, D.; Albert, D.; Jansen, R.; Mu¨ller, R.; Kalesse, M. Angew.
Chem., Int. Ed. 2007, 46, 4898.
(1) (a) Irschik, H.; Jansen, R.; Gerth, K.; Ho¨fle, G.; Reichenbach, H. J.
Antibiot. 1995, 48, 962. (b) Jansen, R.; Irschik, H.; Reichenbach, H.; Ho¨fle,
G. Liebigs Ann. Chem. 1997, 1725. (c) Diestel, R.; Irschik, H.; Jansen, R.;
Mohammed, W. K.; Reichenbach, H.; Sasse, R. ChemBioChem 2009, 10,
2900.
(4) Jansen, D.; Kalesse, M. Synlett 2007, 2667.
(5) (a) Paterson, I.; Findlay, A. D.; Noti, C. Chem. Asian J. 2009, 4,
594. (b) Paterson, I.; Findlay, A. D.; Anderson, E. A. Angew. Chem., Int.
Ed. 2007, 46, 6699
.
(2) For identification and analysis of the chivosazole biosynthetic gene
cluster, see: Perlova, O.; Gerth, K.; Kaiser, O.; Hans, A.; Mu¨ller, R.
J. Biotechnol. 2006, 121, 174.
(6) (a) Wenzel, S. C.; Mu¨ller, R. Nat. Prod. Rep. 2007, 24, 1211. (b)
Weissman, K. J.; Mu¨ller, R. Nat. Prod. Rep. 2010, 27, DOI: 10.1039/
c001260m
.
10.1021/ol101630p  2010 American Chemical Society
Published on Web 07/26/2010

of the bidirectional coupling partner 6. Bishalide linker 6
might then be derived from (Z)-bromoacrolein 8 and silyl
ketene N,O-acetal 9 through an asymmetric vinylogous
Mukaiyama aldol reaction to define the trisubstituted olefin
geometry, and the C10 and C11 stereogenic centers, in a
single operation.
Scheme 1. Retrosynthetic Analysis
Our synthetic efforts commenced with the preparation of
silyl dienolate 9 (Scheme 2).7 Enolization of imide 10 with
Scheme 2
.
Synthesis of the C7-C13 Region via an Asymmetric
Vinylogous Mukaiyama Aldol Reaction
NaHMDS followed by silylation with TBSCl afforded
(E,E)-9 cleanly. Following the Kobayashi protocol,8 reaction
of 9 with aldehyde 89 in the presence of TiCl4 proceeded to
give the anti aldol adduct as a Z/E mixture of vinyl bromides
under all attempted conditions. This is likely due to Lewis
acid-mediated isomerization of the starting (Z)-enal 8 prior
to aldol coupling.10 With a view to performing a selective
trans-debromination at a later stage, we then examined the
use of dibromoacrolein 11.9 Pleasingly, the vinylogous
Mukaiyama aldol reaction with 9 using TiCl4 now afforded
the desired adduct 12 in high yield and diastereoselectivity
(92%, 10:1 anti:syn). The dr could be upgraded to >99:1 by
recrystallization, which also enabled us to obtain the X-ray
crystal structure, confirming the trisubstituted (E)-olefin
geometry and also the requisite 10,11-anti configuration.11
progress toward the synthesis of the chivosazoles, culminat-
ing in the highly stereocontrolled construction of the
advanced C1-C13 pentaene subunit 3 for planned cross-
coupling to a suitable C14-C35 fragment.
The potential sensitivity of the polyene regions of the
chivosazoles, in particular the conjugated (2Z,4E,6Z,8E)-
tetraenoate moiety, should clearly be a prime consideration
for any synthetic approach. Guided by this, and the fact that
the configuration has not yet been assigned with full
confidence, we sought to prepare each stereocluster in
isolation and construct the chivosazole aglycon through the
flexible and convergent assembly of the appropriate frag-
ments. As outlined retrosynthetically in Scheme 1, we
initially anticipated integrating the tetraenoate motif into the
nascent chivosazole macrocycle through the late-stage union
of the key C1-C13 subunit 3 with a suitable northern
hemisphere fragment, arising from the cross-coupling of
stannane 4 and iodide 5.
(7) Nicolaou, K. C.; Sun, Y.-P.; Guduru, R.; Banerji, B.; Chen, D. Y.-
K. J. Am. Chem. Soc. 2008, 130, 3633.
(8) (a) Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126,
13604. (b) Shinoyama, M.; Shirokawa, S.; Nakazaki, A.; Kobayashi, S.
Org. Lett. 2009, 11, 1277.
(9) See the Supporting Information for the synthesis of aldehydes 8 and
11.
(10) The Kobayashi vinylogous aldol reaction using the corresponding
(Z)-iodoacrolein gave only the isomerized (E)-vinyl iodide adduct in low
yield.
(11) CCDC 782548 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
Simplification of tetraenoate 3 to give two (Z,E)-dienes 6
and 7 was planned through a Stille coupling reaction, in
which we aimed to exploit the relative vinyl halide reactivity
Org. Lett., Vol. 12, No. 16, 2010
3725

Notably, this aldol addition provides an expedient and
versatile entry to the C7-C13 region of the chivosazoles,
where, if required, all four C10/C11 stereoisomers could be
prepared selectively, starting with ent-9 and/or followed by
a Mitsunobu inversion at the C11 hydroxyl.7,12
Elaboration of aldol adduct 12 to cross-coupling linker 6
began with TES protection of the newly installed C11
hydroxyl group (TESOTf, 2,6-lutidine, 99%, Scheme 3).
subjected to catalytic Pd(MeCN)2Cl2 in DMF, in the
presence of Ph2PO2NBu4 as a tin halide scavenger,18 cross-
coupled product 18 was obtained as the major product
(42%), which was inseparable from other isomeric prod-
ucts by flash chromatography. Detailed NMR analysis
indicated a (2Z,4E,6E,8E)-tetraenoate had been gener-
ated.19 Although this initial study failed to establish the
required (6Z)-alkene geometry, it succeeded in demon-
strating that electron-deficient stannyldienoate 7 was a
competent coupling partner and that the greater reactivity
of the iodide over the bromide termini in linker 6 permitted
a chemoselective monocoupling reaction.
Scheme 3. Synthesis of C6-C13 Cross-Coupling Linker
The preferential formation of the (6E)-olefin in 18 was
attributed to isomerization of the starting vinyl iodide 6. To
circumvent this problem, the known ability of copper salts
to accelerate Stille cross-coupling reactions might be ex-
ploited to achieve a more rapid fragment union with 6.20
Following this reasoning, a Stille cross-coupling reaction of
6 and 7, using a combination of Pd(PPh3)4, CuTC, and
Ph2PO2NBu4 in DMF, was then performed (Scheme 4).
Scheme 4. Completion of the C1-C13
(2Z,4E,6Z,8E)-Tetraenoate Subunit
Selective (E)-debromination of dibromoalkene 13 was then
achieved, using Bu3SnH and catalytic Pd(PPh3)4,13 to afford
(Z)-vinylbromide 14 in 95% yield. Reductive cleavage of
the imide with NaBH4 and subsequent MnO2-mediated allylic
oxidation of 15 generated aldehyde 16 (91% over 2 steps),
which was submitted to a range of Stork-Wittig olefination
conditions.14 Optimally, addition of 16 to a mixture of
(Ph3PCH3I)+I- and NaHMDS in THF/HMPA (88:1) at -78
°C, followed by slow warming to room temperature, afforded
the requisite (Z,E)-iododiene 6 with excellent selectivity
(97%, >95:5 Z,E:E,E). This delicate building block is light
sensitive and prone to isomerization, requiring careful
handling, and was best used without purification.
At this stage, we required access to the Stille coupling
partner (2Z,4E)-dienoate 7. This was conveniently pre-
pared from known stannylenal 1715 through a Still-Gennari
olefination16 (94%, >95:5 Z,E:E,E),17 setting the stage for
the critical task of generating the full C1-C13 tetraenoate
fragment with the required chivosazole alkene stereo-
chemistry. When iododiene 6 and stannane 7 were
Under these Fu¨rstner-type conditions,21 the reaction pro-
ceeded cleanly even at 0 °C, providing the desired coupled
product 3, isolated as a single (2Z,4E,6Z,8E)-stereoisomer
(12) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem.
Soc. 2007, 129, 6386
.
(18) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997,
119, 12376.
(13) (a) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org.
Chem. 1996, 61, 5716. (b) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji,
J. J. Org. Chem. 1998, 63, 8965.
(19) Interestingly, the congeneric chivosazole A1 is reported to have
this configuration of the tetraenoate, i.e., with the (6E)-geometry.
(20) For leading references, see: (a) Farina, V.; Kapadia, S.; Krishnan,
B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905. (b) Allred,
G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748. (c) Espinet,
P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704. (d) Nicolaou,
K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
(21) Fu¨rstner, A.; Funel, J. A.; Tremblay, M.; Bouchez, L. C.; Nevado,
C.; Waser, M.; Ackerstaff, J.; Stimson, C. C. Chem. Commun. 2008, 2873.
(14) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
(15) (a) Beaudet, I.; Parrain, J.-L.; Quintard, J. P. Tetrahedron Lett. 1991,
32, 6333. (b) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Reuter,
D. C. Tetrahedron Lett. 1989, 30, 2065.
(16) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(17) Franci, X.; Martina, S. L. X.; McGrady, J. E.; Webb, M. R.; Donald,
C.; Taylor, R. J. K. Tetrahedron Lett. 2003, 44, 7735.
3726
Org. Lett., Vol. 12, No. 16, 2010

in 85% yield.22 Gratifyingly, the diagnostic 1H NMR
coupling constants measured for 3 agreed with those reported
for the corresponding tetraenoate region of chivosazole A,3
indicating that the (6Z)-olefin had now been installed
correctly.
union with a suitable northern hemisphere fragment. Studies
toward the remaining C15-C26 and C27-C35 subunits 4
and 5, respectively, and their controlled assembly incorporat-
ing building block 3 to give the chivosazoles are ongoing.
In summary, by using a combination of asymmetric
vinylogous Mukaiyama aldol and Stille cross-coupling reac-
tions, we have prepared the fully elaborated C1-C13
tetraenoate subunit 3 of the chivosazoles with high stereo-
chemical fidelity and efficiency. This key C1-C13 pentaene
subunit, featuring the characteristic conjugated (2E,4Z,6E,8Z)-
tetraenoate motif and anti-configured C10 and C11 stereo-
centers, terminates in a (Z)-vinyl bromide in readiness for
Acknowledgment. We thank the EPSRC (EP/F025734/
1), the EPSRC-Pharma Synthesis Studentships Program and
Pfizer (S.B.J.K.), and the Cambridge Overseas Trust (L.J.G.)
for support and Alan Jessiman (Pfizer, Sandwich) for helpful
discussions.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) This pentaene product was purified on Et3N-washed silica gel and
is stable upon storage at -20 °C under an inert atmosphere with the
exclusion of light.
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