Synthesis of the C15-C35 northern hemisphere subunit of the chivosazoles

Article abstract of DOI:10.1021/ol102425n

An advanced C15-C35 subunit of the chivosazole polyene macrolides was prepared in a convergent manner, exploiting boron-mediated aldol reactions for the stereocontrolled construction of the C15-C26 and C27-C35 segments, followed by their Pd/Cu-promoted St

Full text of DOI:10.1021/ol102425n

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5530-5533
Synthesis of the C15-C35 Northern
Hemisphere Subunit of the Chivosazoles
Ian Paterson,* Lisa J. Gibson, and S. B. Jennifer Kan
UniVersity Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, U.K.
ip100@cam.ac.uk
Received October 7, 2010
ABSTRACT
An advanced C15-C35 subunit of the chivosazole polyene macrolides was prepared in a convergent manner, exploiting boron-mediated aldol
reactions for the stereocontrolled construction of the C15-C26 and C27-C35 segments, followed by their Pd/Cu-promoted Stille coupling to
configure the signature (23E,25E,27Z)-triene motif. Correlation with a known C28-C35 degradation fragment of chivosazole A was also achieved.
Myxobacteria represent prolific sources of molecular diver-
sity and produce a wide range of unique polyketide-derived
scaffolds, which generally are associated with significant
biological activities and therapeutic potential.1 The chivosa-
zole family of polyene macrolides, isolated from the myxo-
bacterium Sorangium cellulosum,2 displays potent antipro-
liferative activity against a range of human cancer cell lines
(e.g., leukemia K-562, IC50 ) 2.9 nM, and cervical carcinoma
KB-3-1, IC50 ) 3.5 nM, for chivosazole A), as well as
activity against yeasts and filamentous fungi. This antimitotic
activity has recently been shown to derive from selective
inhibition of actin polymerization, leading to disruption of
cytoskeletal dynamics in vitro.3 However, the chivosazoles’
exact mode of action appears to be distinct from other actin-
binding antimicrofilament compounds, making them useful
new tools for the study of the actin cytoskeleton, as well as
promising leads for the development of potential chemo-
therapeutic agents.
From a structural perspective, these architecturally com-
plex macrolides display a remarkable range of functionality,
with some 10 stereocenters and nine alkenes associated with
the aglycon. As the principal congener, chivosazole A (1,
Scheme 1) is a 31-membered macrolactone featuring three
conjugated polyene regions, with alternating E/Z alkene
geometry, an oxazole ring, and three polyol sequences,
together with a 6-desoxyglucopyranoside sugar at C11. A
full configurational assignment for chivosazole A was
proposed in 2007 by Kalesse and co-workers, which de-
pended inter alia on detailed NMR and genetic analysis,
combined with chemical degradation studies.4 Recently, the
Kalesse group validated this assignment by the first total
synthesis of the aglycon, chivosazole F (2),5a with installation
of most of the polyene regions using Wittig olefinations.5b,c
As part of our interest in bioactive polyketide metabolites
isolated from myxobacteria,6 we have also embarked on the
total synthesis of the chivosazoles. Recently, we described
the expedient construction of the C1-C13 tetraenoate subunit
3, corresponding to the southern hemisphere region, termi-
(1) (a) Weissman, K. J.; Mu¨ller, R. Nat. Prod. Rep. 2010, 27, 1276. (b)
Wenzel, S. C.; Mu¨ller, R. Mol. Biosyst. 2009, 5, 567. (c) Wenzel, S. C.;
Mu¨ller, R. Nat. Prod. Rep. 2007, 24, 1211.
(4) Jansen, D.; Albert, D.; Jansen, R.; Mu¨ller, R.; Kalesse, M. Angew.
Chem., Int. Ed. 2007, 46, 4898.
(2) (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) Rho, J.-R.; Shin, J.; Kim, J.-C.;
Ahn, J.-W. J. Korean Magn. Reson. 2001, 5, 91.
(5) (a) Brodmann, T.; Janssen, D.; Kalesse, M. J. Am. Chem. Soc. 2010,
132, 13610. (b) Janssen, D.; Kalesse, M. Synlett 2007, 2667. (c) This Wittig
olefination strategy has also been implemented in the synthesis of chivot-
riene. See: Brodmann, T.; Janssen, D.; Sasse, F.; Irschik, H.; Jansen, R.;
Mu¨ller, R.; Kalesse, M. Eur. J. Org. Chem. 2010, 5155.
(3) Diestel, R.; Irschik, H.; Jansen, R.; Khalil, M. W.; Reichenbach,
H.; Sasse, F. ChemBioChem. 2009, 10, 2900.
10.1021/ol102425n  2010 American Chemical Society
Published on Web 11/02/2010

Scheme 1. Retrosynthetic Analysis
nating in a (Z)-vinyl bromide for planned cross-coupling to
a suitable upper segment.7 Herein, we report the stereocon-
trolled construction of the corresponding C15-C35 subunit
4 using our versatile boron aldol methodology and a Stille
coupling reaction to efficiently introduce the signature
(23E,25E,27Z)-triene.
Guided by the sensitivity of the chivosazole polyene
regions, we targeted the preparation of three key subunits
from which the aglycon could be assembled in a flexible
and convergent manner using suitably mild cross-coupling
protocols. As outlined in Scheme 1, the macrolactone was
envisaged to arise from the cross-coupling/esterification of
a suitable northern hemisphere segment 4 with the pentaene
subunit 3.7 In turn, 4 might arise from a Stille coupling
reaction between (E,E)-dienyl stannane 5 and (Z)-vinyl iodide
6. On the basis of this key bond scission, the requisite
C19-C22 and C29-C32 stereochemistry would be gener-
ated by the boron-mediated aldol coupling of ketones 7 and
8 with aldehydes 9 and 10 and subsequent elaboration to
give coupling partners 5 and 6, respectively.
aldehyde 10.10 Accordingly, enolization of ketone 8 with
c-Hex2BCl and Et3N, followed by addition of aldehyde 10,
afforded the desired aldol adduct 11 with a typically high
level of diastereoselectivity (92%, >95:5 dr).8
Subsequent 1,3-anti reduction of ꢀ-hydroxy ketone 11
under Evans-Tishchenko conditions11 also proceeded with
high diastereoselectivity (>95:5 dr); methanolysis of the
ensuing esters12 then provided diol 12 (72% over 2 steps).13
Diol differentiation by PMP acetal formation (DDQ, 4 Å
MS)14 provided alcohol 13.15 This key intermediate allowed
us to independently verify the relative and absolute config-
uration of the C28-C35 fragment 14 of chivosazole A, as
previously prepared by Kalesse.4 Accordingly, TBS protec-
tion of the C32 hydroxyl in 13 and subsequent hydrogenoly-
sis of the PMP acetal provided diol 14, which correlated by
NMR and specific rotation, [R]D +7.8 (c 0.32, CHCl3) cf.
+8.3 (c 0.29, CHCl3),4 with the data reported for the
authentic degradation fragment.
To facilitate the planned esterification onto the C30
hydroxyl, alcohol 13 was converted into acetonide 15 through
desilylation (TBAF) and acetalization (Me2C(OMe)2, PPTS).
As shown in Scheme 2, preparation of the C27-C35
iodide 6 commenced with the 1,4-syn boron aldol reaction8
of (S)-Roche ester-derived ethyl ketone 89 with ꢀ-silyloxy
(10) (a) Paterson, I.; Britton, R.; Ashton, K.; Knust, H.; Stafford, J. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 11986. (b) Kitamura, M.; Tokunaga,
M.; Ohkuma, T.; Noyori, R. Tetrahedron Lett. 1991, 32, 4163. (c)
Duplantier, A. J.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7079.
(11) Evans, D. A.; Hoveyda, A. J. Am. Chem. Soc. 1990, 112, 6447.
(12) Due to partial transesterification of the kinetic product, a regioi-
someric hydroxy ester was sometimes formed which also gave 12 on
methanolysis.
(6) (a) Paterson, I.; Findlay, A. D.; Anderson, E. A. Angew. Chem., Int.
Ed. 2007, 46, 6699. (b) Paterson, I.; Findlay, A. D.; Noti, C. Chem. Asian
J. 2009, 4, 594. (c) Paterson, I.; Findlay, A. D. Aust. J. Chem. 2009, 62,
624.
(7) Paterson, I.; Kan, S. B. J.; Gibson, L. J. Org. Lett. 2010, 12, 3724.
(8) For recent applications, see: (a) Paterson, I.; Paquet, T. Org. Lett.
2010, 12, 2158. (b) Paterson, I.; Burton, P. M.; Cordier, C. J.; Housden,
M. P.; Mu¨hlthau, F. A.; Loiseleur, O. Org. Lett. 2009, 11, 693. (c) Paterson,
I.; Ashton, K.; Britton, R.; Cecere, G.; Chouraqui, G.; Florence, G. J.;
Stafford, J. Angew. Chem., Int. Ed. 2007, 46, 6167.
(13) The stereochemistry of this intermediate was unambiguously
assigned by 13C NMR analysis of the corresponding acetonide. See the
Supporting Information for details.
(14) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 889.
(9) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.
J. Am. Chem. Soc. 2001, 123, 9535.
(15) Formation of the corresponding orthoester proved problematic with
prolonged reaction times.
Org. Lett., Vol. 12, No. 23, 2010
5531

Scheme 2
.
Synthesis of the C27-C35 Iodide
Scheme 3. Synthesis of the C15-C26 Stannane
To circumvent problems encountered from competing ac-
etonide cleavage, regioselective DIBAL opening of the PMP
acetal in 15 was best performed in TBME.16,17 Dess-Martin
oxidation18 of the resulting primary alcohol then provided
the corresponding R-chiral aldehyde, whose sensitivity to
epimerization necessitated direct submission to Stork-Wittig
olefination.19 This afforded Z-vinyl iodide 16, obtained as
essentially a single geometric isomer (90%, Z:E > 20:1).
Finally, DDQ-mediated oxidative cleavage of the PMB ether
provided the targeted C27-C35 iodide 6 in 25% yield over
the 10 steps from ketone 8.
°C to the resulting enolate, afforded the desired 1,4-syn aldol
adduct 17 with high diastereoselectivity (87%, >95:5 dr).
Subsequent Evans-Tishchenko reduction11 (SmI2, EtCHO)
proceeded smoothly to provide 18 (>95:5 dr),13 which was
advanced to 19 through a sequence of O-methylation, ester
cleavage, and silylation of the ensuing alcohol.
Preparation of the accompanying C15-C26 stannane 5
(Scheme 3) commenced with a second boron aldol reaction, in
this case involving iodo dienal 920 and methyl ketone 7.21 Under
ligand-enhanced conditions,22 treatment of ketone 7 with (-)-
Ipc2BCl and Et3N, followed by addition of aldehyde 9 at -78
With the full stereochemistry of the required C15-C26
subunit now in place, our attention turned to installation of
the requisite oxazole ring. Accordingly, DDQ-mediated
cleavage of the DMB ether in 19 provided alcohol 20, which
was oxidized to the carboxylic acid 21 in high yield (98%)
using TEMPO/PhI(OAc)2 in aqueous MeCN.23 EDC-medi-
(16) Paterson, I.; Ashton, K.; Britton, R.; Cecere, G.; Chouraqui, G.;
Florence, G. J.; Knust, H.; Stafford, J. Chem. Asian J. 2008, 3, 367
(17) Reaction in DCM resulted in competitive opening of the acetonide
at C32 in addition to PMB acetal opening at C28.
(18) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(19) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
(20) (a) Becher, J. Org. Synth. 1980, 59, 79. (b) Paterson, I.; Davies,
R. D. M.; Marquez, R. Angew. Chem., Int. Ed. 2001, 40, 603.
.
(21) (a) Paterson, I.; Findlay, A. D.; Florence, G. J. Org. Lett. 2006, 8,
2131. (b) Paterson, I.; Findlay, A. D.; Florence, G. J. Tetrahedron 2007,
63, 5806.
(22) (a) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663. (b) Paterson,
I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989, 30, 7121.
5532
Org. Lett., Vol. 12, No. 23, 2010

ated coupling24 of 21 with serine methyl ester provided the
corresponding amide, which was smoothly advanced to
oxazole 22 (81%, 2 steps) via the DAST/BrCCl3/DBU
method of Williams and Wipf.25 Reduction of the ester
(DIBAL, 95%) and stannylation under Wulff-Stille condi-
tions26 ((Me3Sn)2, Pd(PPh3)4, 72%) then provided the
C15-C26 stannane 5 with complete retention of the (E,E)-
diene geometry.27
Scheme 4. Completion of the C15-C35 Northern Hemisphere
Having established effective and scalable routes to the
northern hemisphere subunits, dienyl stannane 5, and vinyl
iodide 6, their union to form the sensitive C23-C28 triene
and the complete C15-C35 sequence of chivosazoles A and
F could be investigated. Gratifyingly, after a degree of
optimization, it was found that exposure of a slight excess
of stannane 5 (1.3 equiv) and iodide 6 to a combination of
Pd(PPh3)4, CuTC, and Ph2PO2NBu4 in DMF (0 °C, 1 h)28
resulted in the efficient union of the two coupling partners,
providing the targeted northern hemisphere subunit 4 in
excellent yield (83%) (Scheme 4). Comparison of the NMR
data obtained for 4 with that reported for chivosazoles A4
and F2c,5a allowed confirmation of the (23E,25E,27Z)-triene
geometry.
efficient introduction of the characteristic (23E,25E,27Z)-
triene region. Studies are now ongoing to establish the most
effective means of fragment coupling with the C1-C13
tetraenoate subunit 3, with a view to completing a convergent
synthesis of the chivosazole macrolides.
In summary, by using a combination of our boron-
mediated aldol methodology and a mild Pd/Cu-promoted
Stille coupling reaction, we have prepared the full C15-C35
northern hemisphere subunit 4 of the chivosazoles with the
(23) These conditions proved critical, with degradation and/or alkene
isomerization observed under other oxidation protocols examined. (a) Epp,
J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293. (b) de Nooy, A. E. J.;
Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153.
(24) Downing, S. V.; Aguilar, E.; Meyers, A. I. J. Org. Chem. 1999,
64, 826.
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.
(25) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R.
Org. Lett. 2000, 2, 1165.
(26) (a) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J.
Org. Chem. 1986, 51, 277. (b) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc.
1986, 108, 3033.
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.
(27) Vanderwal, C. D.; Vosburg, D. A.; Sorensen, E. J. Org. Lett. 2001,
3, 4307.
(28) Fu¨rstner, A.; Funel, J.-A.; Tremblay, M.; Bouchez, L. C.; Nevado,
C.; Waser, M.; Ackerstaff, J.; Stimson, C. C. Chem. Commun. 2008, 2873.
OL102425N
Org. Lett., Vol. 12, No. 23, 2010
5533