Total synthesis of the protected aglycon of fidaxomicin (tiacumicin B, lipiarmycin A3)

Article abstract of DOI:10.1002/anie.201409464

Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic that is used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have excellent bactericidal activity

Full text of DOI:10.1002/anie.201409464

Angewandte
Chemie
DOI: 10.1002/anie.201409464
Natural Product Synthesis
Hot Paper
Total Synthesis of the Protected Aglycon of Fidaxomicin
(Tiacumicin B, Lipiarmycin A3)**
Hideki Miyatake-Ondozabal, Elias Kaufmann, and Karl Gademann*
Abstract: Fidaxomicin, also known as tiacumicin B or lip-
iarmycin A3, is a novel macrocyclic antibiotic that is used in
hospitals for the treatment of Clostridium difficile infections.
This natural product has also been shown to have excellent
bactericidal activity against multidrug-resistant Mycobacte-
rium tuberculosis. In spite of its attractive biological activity, no
total synthesis has been reported to date. The enantioselective
synthesis of the central 18-membered macrolactone is reported
herein. The key reactions include ring-closing metathesis
between a terminal olefin and a dienoate moiety for macro-
cyclization, a vinylogous Mukaiyama aldol reaction, and
a Stille coupling reaction of sterically demanding substrates.
The retrosynthesis involves three medium-sized fragments,
thus leading to a flexible yet convergent synthetic route.
aglycon fragment with multiple stereogenic centers and two
glycosidic linkages where the eastern glycoside carries a fully
substituted dichlororesorcinol unit. Unfortunately, the low
bioavailability and the instability of the compound under
acidic conditions make it unsuitable for use as a therapeutic
for TB.[5] Structural modification, by either semi- or total
synthesis, could therefore be crucial to improve its pharma-
cokinetic profile.
Currently, fidaxomicin is used in the clinic for the
treatment of a different disease, namely Clostridium difficile
infections, and was introduced to the market by Optimer
pharmaceuticals in 2011.[6] Fidaxomicin has demonstrated
similar clinical cure rates compared to vancomycin, however
it is considered to be superior owing to its favorable adverse
effect profile and decreased rates of disease recurrence.
Given its proven potential as a pharmaceutical, we started to
investigate an efficient and convergent total synthesis of
fidaxomicin (1) to allow access to structurally diverse
analogues with appropriate pharmacokinetics for the treat-
ment of TB. It is remarkable that no total synthesis has been
reported since its first isolation through fermentation of
Actinoplanes deccanensis in 1975, despite its clinical use as
a pharmaceutical agent.[7] To date, synthetic studies of the
core aglycon have been documented in a PhD thesis,[8] and
studies on the carbohydrate[9,10] and resorcinol[11] parts have
been reported. Independent and concomitant syntheses of the
lipiarmycin A3 macrolactone and a putative lipiarmycin
aglycon have been reported by the groups of Altmann and
Zhu, respectively.[12]
A
mong all the treatable diseases, tuberculosis (TB) remains
a major public health concern worldwide.[1] Approximately
nine million new cases of TB and an estimated two million
deaths occur each year.[2] Current therapeutic options, such as
the use of the frontline drugs rifampicin and isoniazid, have
become limited owing to the spread of resistant forms of the
bacterium.[3] Hence, the development of new pharmaceuticals
against Mycobacterium tuberculosis has become an urgent
task in medical research. In this context, we became
interested in fidaxomicin (1, tiacumicin B, lipiarmycin A3),[4]
Herein, we report the successful synthesis of the central
aglycon of fidaxomicin (1) through an approach featuring
a vinylogous Mukaiyama aldol reaction (VMAR), a Stille
coupling reaction, Yamaguchi esterification, and a ring-clos-
ing metathesis (RCM). We established a relatively short and
highly convergent synthetic route to the macrocycle 2, and
our retrosynthetic analysis led to three main building blocks:
which is an inhibitor of bacterial RNA polymerase and shows
promising antibacterial activity against TB.[1] The molecule is
also structurally attractive, owning a complex 18-membered
vinyl iodide 3, vinyl stannane 4, and dienoic acid
5
(Scheme 1).
[*] Dr. H. Miyatake-Ondozabal, E. Kaufmann, Prof. Dr. K. Gademann
Department of Chemistry, University of Basel
The synthesis started with the preparation of silyl ketene
N,O-acetal 7 through g-deprotonation and O-tert-butyldime-
thylsilylation of the known building block 6 (Scheme 2).[13]
Subsequently, anti-selective VMAR[14] was performed
between 7 and freshly prepared (E)-3-iodo-2-methylacrylal-
dehyde in the presence of TiCl4 as a Lewis acid. In searching
for the best reaction conditions, we found that a higher
reaction concentration led to the best yield and diastereose-
lectivity (47%, d.r. > 20:1, 35% recovery of desilylated
starting material 6). To our knowledge, this transformation
represents the first example of a VMAR, developed by
Kobayashi et al.,[14] in which a different substituent (an ethyl
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: karl.gademann@unibas.ch
Homepage: http://www.chemie.unibas.ch/~gademann
[**] We gratefully acknowledge financial support by the Latsis Prize (to
K.G.) and the Novartis Early Career Award (to K.G.). We thank
Christian Fischer for skillful technical support, Priv.-Doz. Dr. D.
Hꢀussinger for assistance with NMR spectroscopy, and Dr. M.
Neuburger for X-ray crystallographic analysis. This publication is
supported by the Swiss National Science Foundation as part of the
NCCR Molecular Systems Engineering.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409464.
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Pd-catalyzed hydrostannylation to give the sec-
ondary alcohol 4 in 46% yield over two steps.
During the course of hydrostannylation, forma-
tion of the undesired regioisomer could not be
suppressed, thus leading to only moderate yield.
Other approaches such as hydrozirconation[21]
and stannyl cupration[22] gave complex mixtures
of products.
Scheme 1. Retrosynthetic analysis for the target macrolactone 2.
The final building block 5 constitutes the
eastern part of the macrolactone and incorpo-
rates the dienoic acid moiety (Scheme 4). First,
commercially available ethyl 3-hydroxypropa-
noate (15) was treated with excess of lithium
diisopropylamide and reacted with acrolein to
furnish the corresponding aldol product. Next,
monoselective
tert-butyldimethylsilylation
mediated by dimethyltin dichloride[23] was fol-
lowed by acetylation and base-induced
E
1cb elimination to give dienoate 16 in 54%
yield over four steps (d.r. = 5.5:1). Finally,
formal hydrolysis (DIBAH reduction, allylic
and Lindgren–Pinnick oxidations) of ester 16
was executed to give the corresponding carbox-
ylic acid 5 in 70% yield over three steps. It is
worth mentioning that the standard hydrolysis
conditions with either lithium hydroxide or
sodium hydroxide led to desilylation as a major
side reaction.
With the three building blocks 3, 4, and 5 in
hand, we focused our attention on the Stille
coupling step. As anticipated, this transforma-
tion was experimentally challenging owing to
the sterically damanding nature of both the vinyl
iodide and stannane fragments. After screening
several sets of reaction conditions, we identified
Scheme 2. Synthesis of vinyl iodide fragment 3. a) NaHMDS, THF, À788C; then
TBSCl, 97%; b) (E)-3-iodo-2-methylacrylaldehyde, TiCl4, CH2Cl2, À788C to À308C,
47%, d.r.>20:1; c) para-nitrobenzoic acid, DEAD, PPh3, THF, 08C, 78%; d) NaBH4,
THF/H2O; e) MnO2, CH2Cl2, 76% (2 steps); f) (À)-Ipc2B(allyl), Et2O, À788C; then aq.
NaBO3, 70%, d.r.=20:1; g) TBSOTf, 2,6-lutidine, CH2Cl2, 93%; h) K2CO3, MeOH/H2O;
i) TESOTf, 2,6-lutidine, CH2Cl2, 95% (2 steps). DEAD=diethyl azodicarboxylate,
HMDS=hexamethyldisilazane, Ipc=isopinocampheyl, PNB=para-nitrobenzyl,
TBS=tert-butyldimethylsilyl, TES=triethylsilyl, THF=tetrahydrofuran.
group in our case) has been utilized as opposed to the
standard methyl group. In order to obtain the desired syn-
configured product, a Mitsunobu inversion was carried out to
give ester 9 in 78% yield.[15] The selective cleavage of Evans
auxiliary[16a] over the PNB ester was achieved under reducing
conditions,[16b] and subsequent allylic oxidation with MnO2
gave the a,b-unsaturated aldehyde 10 in 76% yield over two
steps. The absolute configuration of the product was unam-
biguously confirmed by single crystal X-ray crystallographic
analysis of its vinyl bromide derivative. The next step involved
a diastereoselective Brown allylation of aldehyde 10 with (À)-
allyl-diisopinocampheylborane.[17] A high diastereoselectivity
of 20:1 was observed, along with an acceptable yield of 70%.
TBS protection of the allylic alcohol 11 furnished silyl ether
12 (93%). Subsequent exchange of the protecting groups
from benzoyl esters to silyl ethers (95% over two steps)
turned out to be essential to successfully accomplishing the
cross-coupling reaction.
Scheme 3. Synthesis of vinyl stannane fragment 4. a) TBSCl, Imid,
CH2Cl2, 93%; b) propyne, nBuLi, BF3·Et2O, THF, À788C to 08C, 90%;
c) Pd(OAc)2, PCy3, Bu3SnH, hexane, 51%. Imid=imidazole, Cy=cyclo-
hexyl.
Scheme 4. Synthesis of dienoic acid fragment 5. a) LDA (3.5 equiv),
THF, À788C; then acrolein, À788C; b) Me2SnCl2 (10 mol%), TBSCl,
Et3N, 75% (2 steps); c) Ac2O, Et3N, DMAP, CH2Cl2; d) DBU, CH2Cl2,
72% (2 steps), E:Z=5.5:1; e) DIBAH, CH2Cl2, À108C; f) MnO2,
CH2Cl2; g) NaClO2, KH2PO4, 2-methyl-2-butene, tBuOH/H2O, 70%
(3 steps). LDA=lithium diisopropylamide, DBU=1,8-diazabicycloun-
dec-7-ene, DIBAH=diisobutylaluminum hydride, DMAP=4-dimethyl-
aminopyridine.
The southern building block of the macrolactone was
prepared in three synthetic steps (Scheme 3). The synthesis
began with silyl etherification[18] of the known chiral epoxy
alcohol 13 (93%, e.r. > 99:1), which is accessible through
kinetic resolution of 3-buten-2-ol by using Sharpless epox-
idation.[19] Regioselective epoxide opening[20] with propynyl-
lithium and boron trifluoride diethyl etherate was followed by
2
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the optimal conditions as a combination of copper thiophene-
2-carboxylate (CuTC)[24] and [Pd(PPh3)4] in the presence of
tetrabutylammonium diphenylphosphonate salt.[25] These
conditions give the diene 17 in very high yield of 77%
(Scheme 5). The only significant side reaction was self-
chromatography, which in turn allowed recycling of the
Z isomer to give an 80% yield of E isomer 19 after one cycle.
The final selective deprotection of the primary TBS ether and
secondary TES ether was achieved in 65% yield by using
triethylamine trihydrofluoride. In order to avoid unwanted
over-deprotection, the reaction had to be stopped after
a certain time to allow the isolation of TES-deprotected
intermediate 20 (32%), which could be recycled to give more
of the desired diol 2. The aglycon 2 fulfills the criteria for
a key building block for the completion of the total synthesis
since it has the appropriate free hydroxy groups for the
following glycosylations.
In summary, we report the preparation of the protected
aglycon of fidaxomicin (1). The target macrocycle 2 was
successfully synthesized in 14 steps (longest linear sequence)
via three main fragments, thus allowing a considerable
amount of flexibility in exploring the points of diversity for
analogue synthesis. The highlights of our strategy include
RCM between a terminal olefin and a dienoate moiety for
macrocyclization, a diastereoselective VMAR, and a Stille
coupling reaction of sterically hindered substrates. Currently,
total synthesis of the natural product, including preparation of
the noviose, rhamnose, and resorcinol units, as well as
glycosylation studies, are in progress in our group.
Received: September 25, 2014
Published online: && &&, &&&&
Keywords: antibiotics · cross coupling · natural products ·
.
stereoselective synthesis
Scheme 5. Synthesis of bis(silyl)-protected aglycon 2. a) 4, CuTC, [Pd-
(PPh3)4], [Bu4N]+[Ph2PO2]À, DMF, 77%; b) 5, Cl3C6H2COCl, Et3N,
DMAP, PhMe, 86%; c) Grubbs cat. II (15 mol%), PhMe, 408C (micro-
wave irradiation), 10 min, E/Z=2:3; then 1008C, 18 h, E/Z=2:1,
90%; d) Grubbs cat. II (15 mol%), PhMe, 1008C, 18 h, E/Z=2:1,
92%; e) 3 HF·Et3N, THF/MeCN 1:1, 08C to 238C, 2: 65%, 20: 32%.
CuTC=copper(I) thiophene-2-carboxylate, DMF=dimethylformamide.
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Natural Product Synthesis
H. Miyatake-Ondozabal, E. Kaufmann,
K. Gademann*
&&&& — &&&&
Total Synthesis of the Protected Aglycon
of Fidaxomicin (Tiacumicin B,
Lipiarmycin A3)
Fidaxomicin fix: The core aglycon of the
clinically used antibiotic fidaxomicin was
synthesized by using ring-closing meta-
thesis for macrocyclization. This syn-
thetic route is highly convergent and the
key steps include a diastereoselective
vinylogous Mukaiyama aldol reaction of
a novel substrate, Yamaguchi esterifica-
tion, and a Stille coupling reaction
between two sterically hindered inter-
mediates.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!