A diverted total synthesis of mycolactone analogues: An insight into buruli ulcer toxins

Article abstract of DOI:10.1002/chem.201102542

Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins.

Full text of DOI:10.1002/chem.201102542

FULL PAPER
DOI: 10.1002/chem.201102542
A Diverted Total Synthesis of Mycolactone Analogues: An Insight into
Buruli Ulcer Toxins
Anne-Caroline Chany,[a] Virginie Casarotto,[a] Marjorie Schmitt,[a] Cꢀline Tarnus,[a]
Laure Guenin-Macꢀ,[b] Caroline Demangel,[b] Olivier Mirguet,[c] Jacques Eustache,[a] and
Nicolas Blanchard*[a]
Abstract: Mycolactones are complex
macrolides responsible for a severe ne-
crotizing skin disease called Buruli
ulcer. Deciphering their functional in-
teractions is of fundamental impor-
tance for the understanding, and ulti-
mately, the control of this devastating
mycobacterial infection. We report
herein a diverted total synthesis ap-
proach of mycolactones analogues and
provide the first insights into their
structure–activity relationship based on
cytopathic assays on L929 fibroblasts.
The lowest concentration inducing a
cytopathic effect was determined for
selected analogues, allowing a clear
picture to emerge by comparison with
the natural toxins.
Keywords: Buruli ulcer · metathe-
sis · mycolactones · structure–activi-
ty relationships · total synthesis
Introduction
mycin and rifampicin recommended by the World Health
Organization is effective in early and limited infections[5]
but still needs to be combined with wide surgical excision in
severe cases.[6]
The compelling structures of mycolactones have immedi-
ately triggered considerable interest from the synthetic com-
munity. Seminal studies by Kishi and co-workers have estab-
lished the relative and absolute stereochemistry of mycolac-
tone in 2001.[7]
In the following years, elegant syntheses of almost all the
members of these seducing macrolides have then been dis-
closed by Kishiꢀs group.[8] Besides unveiling highly unusual
features such as stereochemical heterogeneity in mycolac-
tones F,[8g] these studies have recently been extended to the
efficient detection of traces amounts of mycolactones by a
fluorogenic chemosensor.[9] In 2011, the groups of Negishi[10]
and Altmann[11] reported on the second and third stereose-
lective total synthesis of mycolactone A/B. Partial syntheses
have also been disclosed since 2001.[12–14]
Isolation of mycolactones A and B from Mycobacterium ul-
cerans MU1615 by Small and co-workers in 1999[1] led to a
new paradigm in polyketide natural products. These enig-
matic macrolides constitute the first and only examples of
polyketides that are a virulence determinant of a human
pathogen.[2] Indeed, mycolactones are responsible for Buruli
ulcer, a devastating necrotizing skin disease present in more
than thirty countries in the world, located mainly in West
and Central Africa but also in Australia and now in Japan.[3]
In addition, it has been recently proposed that other geneti-
cally related mycolactone-producing mycobacteria such as
Mycobacterium shinshuense, “liflandii” and pseudoshottsii or
marinum (except M. marinum M) that are pathogenic
agents for human, frogs, and fish, respectively, should be
now reclassified as M. ulcerans strains, thus highlighting the
worldwide distribution and broad host range of these myco-
bacteria.[4] To date, progress has been made in the antibio-
therapy of Buruli ulcer; the use of a combination of strepto-
However, the understanding of mycolactones functional
interactions at a molecular level is still missing and would
[a] A.-C. Chany, Dr. V. Casarotto, Dr. M. Schmitt, Prof. Dr. C. Tarnus,
Prof. Dr. J. Eustache, Dr. N. Blanchard
Universitꢁ de Haute-Alsace
Ecole Nationale Supꢁrieure de Chimie de Mulhouse
Laboratoire de Chimie Organique et Bioorganique EA4566
3 rue A. Werner, 68093 Mulhouse Cedex (France)
Fax : (+33)389-33-68-60
E-mail: nicolas.blanchard@uha.fr
[b] Dr. L. Guenin-Macꢁ, Dr. C. Demangel
Institut Pasteur, Immunobiologie de l’Infection
25 rue du Dr. Roux, 75724 Paris Cedex 15 (France)
[c] Dr. O. Mirguet
Lipid Metabolism DPU, GlaxoSmithkline, 25 av. du Quꢁbec
91951 Les Ulis Cedex (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102542.
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certainly pave the way for the control of this dramatic myco-
bacterial infection. For the past years, we have been engag-
ed in a research program at the frontiers of immunology
and cell biology trying to decipher the functional interplay
of mycolactones by use of diverted total synthesis.[15] Herein,
we wish to report a flexible synthetic Scheme that allows for
rapid elaboration of a panel of simplified C8-desmethyl my-
colactones analogues. The cytopathic activity of the various
mycolactones analogues on L929 fibroblasts was determined
and led to the first structure–activity relationship of these
potent toxins. The synthesis of a fluorescent mycolactone
variant is also reported based on this key structural informa-
tion.
cation of extracts of M. ulcerans 1615 (ATCC35840) cultures
at the Institut Pasteur.
The synthesis of the C1–C13 core structure of mycolac-
tone could be efficiently traced back to a single chiral
retron, (S)-Roche ester 1, displaying the required absolute
stereochemistry for the C6- and C12-stereocenters
(Scheme 1). Asymmetric allylboration of aldehyde 3 ob-
tained in three steps from 1 with (À)- or (+)-Ipc2Ballyl[18] af-
forded the corresponding homoallylic alcohols 4-syn[19] and
4-anti as single diastereomers. This diastereoselective allyl-
boration reaction has to be performed at a strictly con-
trolled temperature (À788C) to ensure a high diastereo-
meric ratio.[11,19] The nature of the oxidative work-up was
also found to be crucial: the use of diethanolamine as rec-
ommended[19] required extensive chromatographic separa-
tion and led to low yields,[11] whereas sodium perborate,[20]
an inexpensive oxidant, afforded 4 reproducibly and in high
yields (70–76% over two steps). Starting from 4-syn, four
trivial steps, including an efficient cross-metathesis with
acrylic acid, gave the desired w-iodocarboxylic acid 6. Dis-
placement of the iodo leaving group by a variety of alkenyl
nucleophiles proved to be very difficult. After an extensive
screening, only the iron-catalyzed alkenylation reaction de-
veloped by Cossy[21] led to the desired w-alkenylcarboxylic
acid 7 (Scheme 1). It is worthwhile noticing that this is the
first example of an iron-catalyzed alkenylation reaction of a
free carboxylic acid. Compound 7 was then submitted to an
esterification reaction with alcohol 4-anti using Steglich con-
ditions.
Results and Discussion
The efficiency and logic of a retrosynthetic analysis of myco-
lactones into three fragments, C1–C13, C14–C20, and C1’–
C16’, originally proposed by Kishi, has been widely accepted
by the community.[11,13] We adopted these key disconnec-
tions for the elaboration of mycolactone analogues and de-
veloped distinct synthetic approaches to the C1–C13 (C8-
desmethyl) undecenolide and C1’–C16’ fragments. The syn-
thesis of these fragments has to be flexible thereby allowing
a rapid elaboration of simplified toxin analogues. Three ele-
ments of structural diversity were more specifically targeted:
the northern fragment C14–C20, the trisubstituted alkene
C8–C9, and the C12’,C13’,C15’-stereotriad. Based on investi-
gations by the groups of Small[16] and Leadlay,[17] the latter
appears to be a key structural element for both cytopathic
and immunosuppressive activity. A synthetic access to natu-
ral mycolactones A/B was not the highest priority in this
program because these macrolides were obtained by purifi-
The resulting ester 8 underwent an E-selective ring-clos-
ing metathesis (RCM) using 10 mol% of second-generation
Grubbs catalyst.[11,13] Iodide 9 could then be obtained by
using a Finkelstein reaction. Treatment of iodomacrolactone
9 with Riecke zinc allowed a smooth conversion to the cor-
Scheme 1. Synthesis of the C1–C20 fragment of C8-desmethyl mycolactones.
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A Diverted Total Synthesis of Mycolactone Analogues
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responding organozinc derivative, which could be coupled
with vinyliodide 10 (prepared according to Kishiꢀs route[8])
by a Negishi coupling. The C1–C20 fragment of C8-des-
methyl mycolactones A/B was thus obtained in 63% yield.
This very efficient coupling strategy was previously devel-
oped by the group of Kishi[8] and also used by the groups of
Altmann[11] and Burkart[13] during their synthetic studies on
the mycolactones C1–C20 fragment. Previous disconnec-
tions for the synthesis of the C1–C20 fragment investigated
earlier in our laboratories involved the formation of the
C15–C16 carbon–carbon bond through organometallic cou-
plings. However, all these efforts proved unsuccessful.[22] Fi-
nally, we were able to selectively access the C5-hydroxy
macrolactone 11b or the fully deprotected C1–C20 fragment
11c with HF·pyridine.
A flexible approach to the C1’–C16’ fragment was then
devised based on the highly efficient catalytic asymmetric
oxidation/reduction sequence developed by OꢀDoherty[23]
(Scheme 2). Regio- and enantioselective asymmetric dihy-
droxylation of trienoate 12 (prepared in one step from
trans,trans-2,4-hexadienal) delivered dihydroxyester 13
(70% yield, 86% enantiomeric excess (ee)). Carbonate for-
mation followed by allylic reduction led cleanly to the d-hy-
droxyester 15 with the C15’ absolute configuration matching
that of natural mycolactones A/B. Asymmetric dihydroxyla-
tion then proceeded with complete regio- and diastereose-
lectivity affording ester 16 in good yield after protection of
the diol moiety as a silyl ether. A three-step sequence in-
cluding a chromium-mediated one-carbon homologation of
the a,b-unsaturated aldehyde led to dienylstannane 17.[24]
The latter could be engaged in a highly practical copper
thiophene carboxylate-promoted cross-coupling reaction
with iodotrienoate 18 (prepared in ten steps from diethyl
methylmalonate), at room temperature in only 45 min. The
corresponding sensitive ester was obtained in 48% yield
over two steps thus highlighting the reactivity of Liebeskind
and Sroglꢀs mediator in challenging transformations.[25]
Saponification and photoisomerisation of the pentaenoic
acid 19 (green house bulb, 12 mWcmÀ2) afforded a Z-D4’,5’
/
E-D4’,5’ =60:40 mixture as in natural mycolactones A/B.
Macrolactone 11b and pentaenoic acid 19 were then cou-
pled in 82% yield. As previously noticed by Kishi,[8h] global
deprotection of the resulting pentakis-silylether by tetra-n-
butylammonium fluoride (TBAF) is a very challenging
transformation with dramatic scale-up issues. The
C12’,C13’,C15’-silylethers are readily deprotected with
TBAF at room temperature, contrary to the C17 and C19 si-
lylethers. An anhydrous work-up procedure[26] and the recy-
cling of the partially deprotected material were keys to the
isolation of the C8-desmethyl mycolactones A/B 20a.
Scheme 2. Synthesis of the southern fragment of mycolactones A/B and its assembly with the C8-desmethyl core 11b.
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N. Blanchard et al.
The synthetic strategy presented in Scheme 1 and
Scheme 2 is flexible and allowed the rapid elaboration of a
panel of C8-desmethyl mycolactone variants, eight of which
are represented in Scheme 3.[27] The activity of these simpli-
fied mycolactones analogues was then studied in a cytopath-
ic assay on L929 mouse fibroblasts. These cells are consid-
ered as a standard for the evaluation of the cytopathic activ-
ity (CPA) of lipidic extracts of M. ulcerans strains since
1974.[1]
Figure 1. Cytophatic activity of C8-desmethyl mycolactone analogues on
L929 mouse fibroblasts at 10 and 50 mm.
Overall, these cellular assays provided significant informa-
tion on the structural requirements for cytotoxicity. Neither
the undecenolide core 21 alone nor the unsaturated fatty
acid side chain of mycolactones 23 are sufficient for cytopa-
thicity. Compounds 11c and 22 possessing, respectively, the
northern fragment (C14–C20) or the southern fragment
(C1’–C16’) of the toxin combined with the undecenolide
core showed limited cytopathicity at 10 mm, suggesting that
the combination of the northern, central, and southern frag-
ment of the toxins is required for potency. Particularly note-
worthy is the role of the C12’-hydroxyl: when this functional
group is deleted as in compound 20d, only 49% of cell
rounding is observed, whereas 100% cell rounding is ob-
tained under the same conditions for compound 20a, the
C8-desmethyl mycolactones A/B.[29] Interestingly, the same
phenomenon has been reported for natural mycolactone C:
this macrolide induced 90% of cell rounding at 1.1 mm, a
50 fold decrease compared to natural mycolactones A/B.[30]
In line with these results, the fully epi-stereotriad in 20c led
to a dramatic decrease in cytopathicity (10% at 10 mm). The
stereochemistry at C15’ appeared less important since 100%
of CPA was obtained for 20b at 10 mm.
Scheme 3. A panel of C8-desmethyl mycolactones analogues obtained
through DTS.
The cytopathic activity (determined as the number of
rounded cells compared to the total number of cells) of
these eight variants was first measured at 10 and 50 mm in
serum-free media[28] on L929 mouse fibroblasts. Then, the
lowest concentration inducing a cytopathic effect was deter-
mined for selected analogues, unraveling clear structure–ac-
tivity relationships by comparison with the natural toxins.
The results obtained are summarized in Figure 1. The sim-
plified fragments 21 and 23 induced less than 20% of cell
rounding in 48 h, both at 10 and 50 mm. The C1–C20 frag-
ment 11c and the analogue 22 lacking the C14–C20 north-
ern fragment were also moderately cytopathic at 10 mm, with
less than 30 and 60%, respectively, of cell rounding but
demonstrated 100% of cell rounding at 50 mm. The deoxy-
C12’ derivative 20d induced a cell rounding in the 50%
range at 10 mm, whereas analogues 20a–b and natural myco-
lactones A/B induced 100% of cell rounding within 48 h.
The lowest concentration inducing a cytopathic effect was
then determined for natural mycolactones A/B and for the
structurally closest analogue 20a, lacking the C8-methyl sub-
stituent of the natural toxins. At 40 nm, mycolactones A/B
induce 90% of cell rounding of L929 fibroblasts within 24 h,
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A Diverted Total Synthesis of Mycolactone Analogues
FULL PAPER
which is in agreement with
studies by Small and co-work-
ers.[30] By comparison the mini-
mal concentration for such an
effect for compound 20a is
5 mm. The lack of the C8-methyl
substituent thus reduces the
CPA by a factor 125, stressing
the importance of seemingly
simple structural simplifications
on structure–activity relation-
ships.
Deciphering the functional
interactions of mycolactones is
of fundamental importance for
the understanding and ultimate-
ly the control of Buruli ulcer.
The design of a fluorescent my-
colactone analogue would also
constitute an additional tool
that could allow for the identifi-
cation of the yet unknown cel-
lular target of Buruli ulcer
toxins. Based on the results of
the cytopathic assays presented
above, we chose to substitute
the northern fragment of myco-
lactone with a bodipy fluoro-
phore, thus avoiding the chemi-
cal suppression of the crucial
C12’,C13’,C15’-triol
motif,
which was reported by Small
and Snyder in the design of a
related probe.[16] Compound 28
was synthesized in five steps
from macrolactone 24 through
a
copper-catalyzed
azide–
alkyne cycloaddition between
azide 26 and the w-alkynyl-
ACHTUNGTRENNUNGbodipy 27 (Figure 2). To our de-
light, probe 28 presented a cy-
topathic activity close to 20a
with a minimum concentration
inducing 90% of cell rounding
of 10 mm. As desired, no cell
rounding was measurable at
0.5 mm, the concentration used
in the uptake experiments illus-
trated in Figure 2. Bodipy my-
colactone 28 was detected and
localized in less than two mi-
nutes in the cytoplasm, without
any visible binding with the nu-
cleus, therefore pointing to-
wards
a
cytoplasmic target
Figure 2. Top: Synthesis of bodipy-mycolactone 28. Bottom: L929 fibroblasts incubated for 48 h in serum-free
medium with DTS analogues (10 mm, 0.1% DMSO); a) 21; b) 20a; c) 20c; d) serum-free medium/DMSO
(0.1%); e) uptake of bodipymycolactone variant 28 (0.5 mm) after 2 h of incubation and f) after staining of the
nuclei with 4’,6-diamidino-2-phenylindole (DAPI, magnification ꢃ40).
(Figure 2, e and f). Thus, deriv-
ative 28 is structurally related
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Conclusion
In conclusion, a diverted total synthesis approach of Buruli
ulcer toxins analogues has been designed, featuring a diver-
sity of metal-mediated transformations including Cossyꢀs
iron-catalyzed alkenylation reaction,[21a] a cross-metathesis,
and a ring-closing metathesis for the construction of the C8–
C9 unsaturation. In addition, a modular approach of the
C12’,C13’,C15’ stereotriad has been devised based on the
highly stereoselective catalytic asymmetric oxidation/reduc-
tion sequence developed by OꢀDoherty.[23] A copper-mediat-
ed Liebeskind–Srogl coupling allowed the elaboration of the
sensitive pentaenic moiety, thus completing the synthesis of
the challenging southern fragment of mycolactones. The im-
plementation of this modular strategy allowed a rapid syn-
thesis of a panel of analogues including a fluorescent var-
iant. Their cytopathicities have been measured on L929
mouse fibroblasts, thus providing the first structure–activity
relationship of these potent toxins. In addition, the lowest
concentration inducing a cytopathic effect was determined
for natural mycolactones A/B and for the structurally closest
analogue 20a.
The structural information gathered during these studies,
such as the central role of the C8-methyl substituent and of
the C12’,C13’,C15’ stereotriad, will be central to the under-
standing of the functional interactions of mycolactones and
ultimately to the deciphering of their mode of action.
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We thank the CNRS, the University of Haute-Alsace, GlaxoSmithKline,
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A Diverted Total Synthesis of Mycolactone Analogues
FULL PAPER
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Received: August 16, 2011
Published online: November 30, 2011
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