Total synthesis of chivosazole F

Article abstract of DOI:10.1021/ja107290s

The first synthesis of the highly biologically active chivosazole F is described. It features an intramolecular Stille coupling for the macrolactone formation and thereby circumvents the problem of isomerization associated with the tetraene segment. Additionally, the synthesis confirms the structure which has been proposed based solely on a combination of NMR/computational methods and genetic analysis.

Full text of DOI:10.1021/ja107290s

Published on Web 09/13/2010
Total Synthesis of Chivosazole F
Tobias Brodmann,† Dominic Janssen,‡ and Markus Kalesse*,†,§
Centre for Biomolecular Drug Research (BMWZ), Leibniz UniVersita¨t HannoVer, Schneiderberg 1b,
D-30167 HannoVer, Germany, Centre for Cancer Research & Cell Biology, Queen’s UniVersity Belfast,
97 Lisburn Road, Belfast BT9 7BL, U.K., and Helmholtz Centre for Infection Research, Inhoffenstrasse 7,
D-38124 Braunschweig, Germany
Received August 13, 2010; E-mail: markus.kalesse@oci.uni-hannover.de
of NOE experiments and computational methods.4 The configura-
Abstract: The first synthesis of the highly biologically active
chivosazole F is described. It features an intramolecular Stille
coupling for the macrolactone formation and thereby circumvents
the problem of isomerization associated with the tetraene seg-
ment. Additionally, the synthesis confirms the structure which has
been proposed based solely on a combination of NMR/compu-
tational methods and genetic analysis.
tions at the secondary alcohols were confirmed by genetic analysis
put forward by Reid and Caffrey.4,5 Even with this state of
knowledge total synthesis was required to confirm the configurations
of the 10 stereocenters. As a consequence of the lability of polyenes,
in particular when Z-configured double bonds are involved, we
embarked on a strategy that established the two sensitive polyene
segments in the last steps of the macrolactone formation. Addition-
ally, the recently published synthesis on the southern hemisphere
of chivosazole F by Paterson et al. confirmed the sensitive nature
of the tetraenoate subunit.6 We proposed the final connections to
The family of the chivosazoles contains seven 31-membered
macrolides which possess a remarkable biological profile.1 They
be made between C25 and C26 by a Wittig olefination and between
exhibit antifungal and cytotoxic activity against mouse fibroblasts
(L-929) and HeLa cells (IC50 9 ng/mL for both cell lines)1a and
reduce actin polymerization.2 In these studies it became apparent
that the chivosazoles act on F-actin differently than proposed for
cytochalasin D, chondramide, or rhizopodin.3 Structurally, chi-
vosazole F differs from the other members of this family by lacking
the 6-deoxyglucose derivative (chivose) at C11.
C7 and C8 by an intramolecular Stille coupling. During our studies
on the synthesis of chivotriene we realized that the best selectivities
were observed when segment 2 serves as the Wittig reagent and
segment 3 as the corresponding aldehyde (Scheme 1).7 The
assembly of segment 3 started from unsaturated ester 8.8 Removal
of the PMB group, DiBAl-H reduction, and protection of the
primary alcohol as the TBS ether was followed by esterification
with phosphonate 11.9 Finally, olefination of 6 with aldehyde 710
provided triene 10 in 80% yield as a 1:1 mixture of the Z and E
isomers (Scheme 2). Gratifyingly, the mixture of isomers could be
separated by simple column chromatography and the desired olefin
was used for the subsequent transformations.
Scheme 1
Scheme 2a
a Reagents and conditions: (a) DDQ, CH2Cl2/H2O, 70%; (b) DiBAl-H;
(c) TBSCl, imidazole, 78% (over 2 steps); (d) 11, DMAP, Et3N, 2,4,6-
trichlorobenzoyl chloride, toluene, 87%; (e) 7, NaH, THF, 80%, Z/E )
1:1; (f) HF-pyridine, pyridine, 51%; (g) MnO2, CH2Cl2, 85%.
For the construction of the western hemisphere, we aimed to
establish the anti relationship in segment 5 through a Marshall-
Tamaru reaction. In order to circumvent the modest selectivities
of the Marshall reaction in transformations with unsaturated
aldehydes,11 we employed aldehyde 12 with a triethyl silyl group
in the R-position to enhance the diastereoselectivity in this reaction.
At the outset of our investigations we proposed the unknown
configurations of the 10 stereogenic centers through a combination
† Leibniz Universita¨t Hannover.
‡ Queen’s University Belfast.
§ Helmholtz Centre for Infection Research.
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13610 J. AM. CHEM. SOC. 2010, 132, 13610–13611
10.1021/ja107290s  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 5a
Using the indium protocol developed by Marshall et al.11a and
S-configured propargylic mesylate 17, the reaction was performed
with high selectivities (anti/syn > 10:1) and provided 13 in good
yields (68%) (Scheme 3). The subsequent standard transformations
established allyl bromide 16.
Scheme 3a
a Reagents and conditions: (a) 17, Pd(OAc)2, ·PPh3, InI, THF-HMPA,
68%; (b) TBAF (5% H2O), 83%; (c) TBSOTf, 2,6-lutidine, 99%; (d) PPTS,
MeOH, 65%; (e) CBr4, PPh3, 99%.
Aldehyde 4 was derived from acid 18 through a sequence of
esterification and standard oxazole formation.12 DiBAl-H reduction
established the aldehyde functionality required for the Wittig
olefination with 5.13 The subsequent olefination installed the new
double bond with high selectivity (E/Z > 10:1). At that stage it
proved beneficial to remove the PMB protecting group prior to the
functionalization of the alkyne. For this transformation the pal-
ladium-catalyzed hydrostannylation provided the highest yields and
regioselectivities. Finally, the allylic alcohol was converted to the
corresponding allyl bromide 20 (Scheme 4).
a Reagents and conditions: (a) PBu3, MeCN; (b) KOtBu, toluene, 48%
(over 2 steps); (c) PdCl2(PhCN)2, DMF; (d) HF-pyridine, pyridine, 18%
(over 2 steps).
mischen Industrie for a FONDS-fellowship for T.B. is gratefully
acknowledged. We thank R. Jansen (HZI) for providing an authentic
sample and S. Eichner for HPLC assistance.
Scheme 4a
Supporting Information Available: Spectroscopic and analytical
data as well as experimental procedures for all compounds described
herein. This material is available free of charge via the Internet at http://
pubs.acs.org.
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E-configured double bond between C25 and C26 using a Wittig
reaction. Without further functional group transformations the
intramolecular Stille14 reaction followed to establish the carbon
framework of chivosazole. The final global deprotection using
buffered HF then completed the total synthesis of chivosazole F
(Scheme 5). The spectroscopic data (1H NMR, 13C NMR, HRMS,
optical rotation) were in all respect identical to the data originally
reported by Ho¨fle and co-workers thus confirming the previously
made configurational assignment.
In summary, the first total synthesis of (-)-chivosazole F has
been achieved through a strategy that establishes the delicate
polyene systems using late-stage Wittig reactions and an intramo-
lecular Stille coupling as the pivotal transformations for their
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Acknowledgment. Generous financial support by the Deutsche
Forschungsgemeinschaft (KA 913/14-1) and the Fonds der Che-
JA107290S
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