Total Synthesis of Tiacumicin B: Implementing Hydrogen Bond Directed Acceptor Delivery for Highly Selective β-Glycosylations

Article abstract of DOI:10.1002/anie.202000231

A total synthesis of tiacumicin B, a natural macrolide whose remarkable antibiotic properties are used to treat severe intestinal infections, is reported. The strategy is in part based on the prior synthesis of the tiacumicin B aglycone, and on the decisive use of sulfoxides as anomeric leaving groups in hydrogen-bond-mediated aglycone delivery (HAD). This new HAD variant permitted highly β-selective rhamnosylation and noviosylation. To increase convergence, the rhamnosylated C1–C3 fragment thus obtained was anchored to the C4–C19 aglycone fragment by adapting the Suzuki–Miyaura cross-coupling used for the aglycone synthesis. Ring-size-selective macrolactonization provided a compound engaged directly in the noviolysation step with virtually total β selectivity. The final efficient removal of all the protecting groups provided synthetic tiacumicin B.

Full text of DOI:10.1002/anie.202000231

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Accepted Article
Title: Total Synthesis of Tiacumicin B: Implementing H-bond-Directed
Acceptor Delivery for Highly Selective β-Glycosylations
Authors: Stéphanie Norsikian, Cedric Tresse, Marc François-Eude,
Louis Jeanne-Julien, Guillaume Masson, Vincent Servajean,
Grégory Genta-Jouve, Jean-Marie Beau, and Emmanuel
Roulland
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000231
Angew. Chem. 10.1002/ange.202000231
Link to VoR: http://dx.doi.org/10.1002/anie.202000231
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10.1002/anie.202000231
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Total Synthesis of Tiacumicin B: Implementing H-bond-Directed
Acceptor Delivery for Highly Selective -Glycosylations
Stéphanie Norsikian,*[a] Cedric Tresse,[a] Marc François-Eude,[a] Louis Jeanne-Julien,[b] Guillaume
Masson,[b] Vincent Servajean,[a] Grégory Genta-Jouve,[b] Jean-Marie Beau,[a][c] and Emmanuel
Roulland*[b]
Dedicated to Professor Henri-Philippe Husson
Abstract: We report a total synthesis of tiacumicin B, a natural
macrolide whose remarkable antibiotic properties are used to treat
severe intestinal infections. The strategy is in part based on our
experience of the synthesis of the tiacumicin B aglycone, and on the
decisive use of sulfoxides as anomeric leaving-groups in H-bond-
the aglycone of Tcn-B, and Zhu[10] the synthesis of a diastereomer.
mediated Aglycone Delivery (HAD). This new HAD variant permitted
the setting of reliable total synthesis pathways. The daunting
structure of Tcn-B has inspired several renowned research groups
to embark in the adventure of its total synthesis.[ 7 ] In 2015
Gademann[8] and Altmann,[9] published the two firsts syntheses of
Nonetheless, only Gademann was capable of completing the total
highly -selective rhamnosylation and noviosylation. To increase
convergence, the rhamnosylated C1-C3 fragment thus obtained was
anchored to the C4-C19 aglycone fragment by adapting the reliable
Suzuki-Miyaura cross-coupling used for the aglycone synthesis.
synthesis of Tcn-B, bringing the following answers to the -
11
, 12 ]
glycosylations problem:[
a) The Helferich’s protocol
[13]
(activating agent: HgO(excess)/HgBr2(cat)
)
was used to noviosylate
the C4-C13 aglycone fragment (α/β: 1/3,  : 54%), as the cyclic
aglycone gave only adducts whatever the conditions. b) The
rhamnosylation was carried out on the macrolide, using an imidate
donor (α/β: 1/4,  : 62%). Following similar strategies, Gademann
also synthesized three congeners of Tcn-B: tiacumicin A,[12] and
mangrolide A[14] and D.[15] In 2019, de Brabander also reported a
total synthesis of mangrolide D.[16] As to our contribution, we
reported two related synthetic pathways leading to the aglycone.[17]
The original strategy we designed for the synthesis of its C12-C15
diene region resulted in the discovery that Pd-nanoparticles
catalyze the Kumada-Corriu reaction of vinylsulfides,[18] and led us
to study the Grigg’s allene/alkyne cross-coupling and proposing a
mechanism based on DFT calculations.[19]
Ring-size selective macrolactonization provided
a compound
engaged directly in the noviolysation step with a virtually total -
selectivity. The final efficient removal of all the protective groups
(PGs) provided synthetic tiacumicin B.
Tiacumicin B (Tcn-B, 1) – also known as clostomicin B1,
fidaxomicin or lipiarmycin A3 – (Scheme 1), is a molecule isolated
for the first time in 1975 from Dactylosporangium aurantiacum, an
actinobacterium.[1] Consisting of an 18-membered macrolactonic
core decorated by two rare sugars (D-noviose and D-rhamnose)
attached through  glycosidic bonds, displaying 14 stereogenic
centers and several polysubstituted alkenes, Tcn-B is therefore one
of the most complex antibiotic-macrolides known. A high degree
of synthetic difficulty arises from such a structural complexity,
whose the thorny problem of the 1,2-cis glycosylations.[ 2 ]
Resistance to antibiotics has become a serious biomedical risk and
a major threat to public health with sever impacts on the economy.
In this context the finding of new antibiotics with new biological
targets is essential. Tcn-B being one of them it received a fast-track
FDA approval in 2011 for the treatment of frequently nosocomial
and fatal gut infections associated with Clostridium difficile.[3] Tcn-
B eradicates bacteria by inhibiting the RNA polymerase, targeting
the “switch-region”.[ 4 ] Cross-resistance with other antibiotics is
very unlikely,[5] even with rifamycin because, although close, the
domains targeted do not overlap so that rifamycin-resistant forms
of Mycobacterium tuberculosis remain highly sensitive to Tcn-B.[6]
The demand for Tcn-B analogues is therefore strong and calls for
[a]
[b]
[c]
Dr. C. Tresse, Dr. M. François-Eude, V. Servajean, Prof. J.-M. Beau,
Dr. S. Norsikian, Institut de Chimie des Substances Naturelles
ICSN-CNRS, Centre de Recherche de Gif,
Avenue de la Terrasse, 91198, Gif-sur-Yvette (France).
Dr. L. Jeanne-Julien, Dr. G. Masson, Dr. G. Genta-Jouve, Dr. E.
Roulland, C-TAC, CitCom, UMR 8038, CNRS-Université de Paris,
Faculté de Pharmacie, 4, avenue de l’Observatoire,
75006, Paris (France).
Prof. J.-M. Beau, Laboratoire de Synthèse de Biomolécules,
ICMMO, UMR 8182, Univ. Paris-Sud and CNRS, Université Paris-
Saclay, F-91405 Orsay, France
E-mail : emmanuel.roulland@parisdescartes.fr
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Tiacumicin B (1) and our retrosynthetic analysis
The new total synthesis of tiacumicin B (1) we depict here is based
on strategic and methodological innovations that allowed an
original and selective assemblage of the three main regions of the
molecule (Scheme 1). It naturally relies on our synthesis of the
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Tcn-B aglycone, whose strategy had been designed with an eye to
the total synthesis. Originally, we had imagined glycosylating our
aglycone sequentially, a possible viable pathway. However, we
attack on the glycosyl donor. We started with the synthesis of the
homodichloro orsellinate attached to the rhamnoside.
Commercially available orcellinate 3 was dichlorinated, and both
phenols were TBS-protected providing 4. The benzylic methyl
group was deprotonated with LDA then methylated giving 5.
Acidic hydrolysis led to deprotected carboxylic acid 6 that upon
treatment with acetone and Tf2O in trifluoroacetic acid furnished
cyclic ester 7. The remaining free phenol of 7 was protected,
supplying 2-naphthalene-methyl (Nap) ether 8.
finally opted for
a less traditional but more convergent
retrosynthetic plan in which Tcn-B was disconnected into
fragments A, B and the known 2,[17a] equivalent in size and
complexity. We chose as first move to assemble fragment A
together with fragment 2, then close the macrolactone, and install
fragment B at the very end. The Suzuki coupling developed during
our aglycone synthesis[17a] was considered robust enough to allow
assembling fragments 2 with fragment A, instead of the small
silylated C1-C3 fragment formerly involved,[17a] thus adding
convergence. This approach reduces risks of failure since
rhamnosylation conditions needed for the synthesis of A can be
developed using the structurally simple C1-C3 fragment as the
acceptor. Complete ring-size selectivity had been previously
observed during the aglycone macrolactonization. Applied to this
total synthesis, this step should provide a monoglycosylated
macrolactone bearing at C11 an unprotected OH directly ready for
the -noviosylation step. This scenario was nonetheless uncertain
for at least three reasons: a) noviosylation is a very late step, b) a
high -selectivity is required, and c) this macrolactone has been
described as a reluctant glycosylation acceptor.[12]
We then addressed the rhamnosyl donor synthesis starting from
phenyl-2,3,4,6-tetra-O-acetyl-1-thio--D-manopyranoside
9
(Scheme 2). Diol 10 was obtained through Zemplén deacetylation
and 4,6-benzylidene formation. Then 10 was selectively TBS-
protected at O-3, methylated at O-2 and deprotected furnishing
triol 11. Selective tosylation in 2,6-lutidine gave 12, whose
reduction with LAH provided the desired rhamnose derivative 13.
Gademann’s conditions allowed assembling ester 8 together with
diol 13 giving selectively 14.[11] The free phenol of 14 was
protected as the Nap ether 15, and the rhamnoside O-3 position
was esterified with picolinic acid. This led to the expected donor
16 ready for the glycosylation of alcohol 18[21] (Scheme 3).
To prepare fragment A we considered using a -selective
glycosylation of acceptor 18 (Scheme 3) by the phenylthio-
rhamnosyl donor 16 that bears a picoloyl group (Pico) at O-3
(Scheme 2).
Scheme 3. Glycosylation conditions and synthesis of fragment A. NIS: N-
iodosuccinimide, DTBMP: 2,6-di-terbutyl-4-methylpiridine, ADMB: 4-allyl-1,2-
dimethoxybenzene.
Initial glycosylation attempts carried out in 1,2-dichloroethane with
dimethyl(methylthio)sulfonium triflate, a classical promoter of H-
bond-mediated Aglycone Delivery (HAD),[20] were disappointingly
unsuccessful. First promising results for the coupling of donor 16
with acceptor 18 were obtained using N-iodosuccinimide (1
equiv/donor) and triflic acid (0.92 equiv/donor)[22] in CH2Cl2 at –
40 °C to rt and produced 19 (76%, /: 1/4),[23] whose anomers
were separated by prep-HPLC. Seeking much higher -selectivity,
we shifted to sulfoxide 17 featuring an anomeric leaving-group
never used before in HAD. In this case, donor 17 (1.7 eq.) was
activated using Tf2O in CH2Cl2 at –70 °C in the presence of
Scheme 2. Syntheses of rhamnopyranosyl donors 16 and 17. TFA:
trifluoroacetic acid, NapBr: 2-naphthalene-methyl-bromide, LDA: lithium di-iso-
propylamide, CSA: camphorsulfonic acid, PTSA: paratoluene sulfonic acid,
DCC: dicyclohexylcarbodiimide, DMAP: 4-dimethylaminopyridine, m-CPBA: 3-
chloroperoxybenzoic acid.
As described by Demchenko,[20] a remotely positioned Pico group
can direct, through intermolecular H-bonding, a selective facial
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acceptor 18, DTBMP and ADMB,[ 24 , 25 ] which resulted in the
formation of desired glycosylated compound 19 with high facial
selectivity (/ : 1/20) and in 64% yield. To verify that this
To secure good -selectivity, we originally programmed to anchor
the noviose using a silicon tether delivery.[30] This strategy failed,
so we decided to again implement a HAD approach by installing a
directing picoloyl group at O-3 of the sugar. The required noviosyl
donor was prepared from D-arabinose 25 (Scheme 5) which was
transformed into lactone 26 through selective acetonide protection,
oxidation of the lactal, and silylation of the remaining OH group.
Lactone 26 was treated with MeMgBr, then oxidized into lactone
27. Dibal-H reduction of 27 led to the corresponding lactol whose
acetonide protection was removed under mild acidic conditions
leading to 28. A thiophenyl group was then installed at the
anomeric position giving diol 29, which was protected as bis-
dichloroacetyl ester 30. Treatment by (iPrCO)2O and a catalytic
amount of Sc(OTf)3 in MeCN allowed the direct replacement of
the TBS group by an isobutyrate leading to 31.[ 31 ] The two
dichloroacetates of 31 were then selectively removed with sym-
collidine giving diol 32. Through the intermediate stannylene of 32,
and a NapBr/CsF treatment, a Nap PG was introduced at the O-2
position leading to alcohol 33 with an unexpectedly high
regioselectivity.[32]
glycosylation took place through HAD, we did
a control
experiment using donor 17’, an analog of 17 whose picoloyl was
replaced by a benzoyl. Product 19’ was the only one formed and its
configuration indicated that the picoloyl group on donor 17 could
remotely direct the nucleophilic attack to the -face by forming an
H-bond. The picoloyl was easily removed from 19 with Cu(OAc)2,
and replaced by a TBS leading to the key fragment A (21).
Our synthesis of aglycone fragment 2 was robust enough to be
scaled up. The cross-coupling of 2 with rhamnoside 21 proceeded
cleanly requiring only slight modifications of the previously used
conditions.[17a] This convergent step provided ester 22 in a 79%
yield (Scheme 4).
Scheme 4. Assemblage of fragments 2 and A, and macrolactonization. MPM:
4-Methoxyphenylmethyl.
Scheme 5. Noviosyl donor synthesis. TEMPO: 2,2,6,6-Tetramethyl-1-
piperidinyloxy, TCCA: trichloroisocyanuric acid.
A critically important selectivity was needed to convert 22 into
seco-acid 23 since a second ester function was present on the
rhamnoside moiety. This was achieved by using Me3SnOH in
toluene at 120 °C giving 23 with yields of 70 to 93%.[26] With
seco-acid 23 in hand, we focused on the macrolactonization
expecting again ring-size selectivity. However, the strict
transposition of the Yamaguchi conditions[27] we had used before,
led to the desired hemi-glycosylated tiacumicin B 24 with only
23% yield. The Boden-Keck’s protocol[28] allowed reaching a 58%
yield but 24 proved to be a mixture of two products resulting from
the isomerization of the C4-C5 alkene. Finally, the Shiina’s
Alcohol 33 was esterified with picolinic acid using DCC to give
sulfide 34, the desired noviosyl donor. Preliminary trials using (+)-
menthol as acceptor led predominantly to the -adduct (/: 1/5) in
a 72 % yield demonstrating the feasibility of this approach.
Unfortunately, the glycosylation of macrolactonic acceptor 24 was
unsuccessful as no adduct was detected.[12] The success of the
above-mentioned rhamnosylation led us to consider that sulfoxide
35 could be a superiorly reactive donor. Under our activation
conditions (Tf2O activation of 35 in the presence of 24, DTBMP,
ADMB/CH2Cl2, –70 °C) we were pleased to isolate the desired
noviosylated product 33 in 68% yield, with a virtually total facial
selectivity (/ > 1/20).[33]
29
]
conditions[
allowed
a
far cleaner and reproducible
macrolactonization into 24 with 72% yield, and an isomerization
minimized at 15%. Our strategy allowed keeping the OH at C11
free of protective-group throughout this synthesis so that 24 could
be directly engaged in the noviosylation step.
The very last steps of this total synthesis consisted in removing
seven PGs from compound 36: 2 MPMs, 3 Naps, 1 Pico and 1 TBS.
First, the TBS group located on the rhamnoside moiety was
cleaved using HF.NEt3 giving alcohol 37 (Scheme 6). The 2 MPMs
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Exploiting this we developed Pd-catalyzed conditions
(Pd2(dba)3/4.PPh3, 1,3-dimethylbarbituric acid, pyridine/DMF,
80 °C) that ultimately provided tiacumicin B (1) cleanly in a good
yield. The 4-steps removal of the 7 PGs took place with 55.5%
overall yield (91.9% per PG). The physicochemical data of our
synthetic Tcn-B are strictly identical to those of the naturally
occurring compound; []23D = –5.6 deg cm3 g–1dm–1 (c= 0.41 g/100
cm3, MeOH), lit.:[1b] ([]23 = –5.5 deg cm3 g–1dm–1 (c=1.98 g/100
D
cm3, MeOH).
In summary, the total synthesis of tiacumicin B (1) was achieved,
with as key steps a highly -selective rhamnosylation, a Suzuki
cross-coupling that allowed assembling the rhamnoside 21 with
aglycone fragment 2, a ring-size selective macrolactonization, a
final and virtually totally selective -noviosylation of the cyclic
aglycone, and the successful removal of all PGs. The remarkable
facial selectivity of both glycosylations relied on an H–bond-
directed effect of a remote 3-O-picoloyl group set on the incoming
glycosyl acceptors, and the conjoint use of a phenylsulfoxide
leaving-group. We believe that this new variant of the Demchenko
procedure will prove useful in addressing the biological relevance
of the carbohydrate moieties of tiacumicin B or other sensitive
aglycones through the preparation of a set of glycosylated
analogues.
Acknowledgements
We gratefully acknowledge financial supports from the French
Agence Nationale pour la Recherche (ANR-14-CE16-0019-02,
SYNTIA project), the CNRS, and the Université de Paris. We
thank Vincent Steinmetz for HPLC support, Karim Hammad for
NMR support, and Dr. Rosemary Green Beau for her editing
comments on the manuscript.
Keywords: antibiotics • natural products • total synthesis •
catalysis • enantioselective synthesis • glycosylation
Scheme 6. Noviosylation and PGs removal. DDQ: 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone.
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as well as the Nap located at O-2 on the novioside, were readily
oxidized by DDQ at 0 °C leading to tetraol 38 in 3 hours. However,
the two Naps on the phenol functions of the rhamnoside proved
resistant to these smooth conditions and an extended reaction time
at r.t. produced an intractable mixture of products. The removal of
the Pico was cleanly carried out (Cu(OAc)2/methanol-CH2Cl2,
0 °C) giving 39. Importantly, this Pico group had to be removed
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had previously observed that Suzuki cross-coupling conditions
used to create the C3-C4 bond of the aglycone led, when conducted
at 80 °C, to a partial loss of the Nap groups of these phenols.
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[32]
A
3J1,2 coupling constant of 9.5 Hz in the 1H NMR spectrum of diol 32
H-1/H-2a trans diaxial orientation. Therefore, the
indicates
a
conformation of the starting diol is not a conventional 4C1 chair but
rather a 1C4 chair certainly imposed by the presence of the gem-
dimethyl group. The equatorial OH is more accessible, which accounts
for the selectivity of this protection.
[33] The  anomer could not be detected in 1H NMR spectrum.
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10.1002/anie.202000231
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
Stéphanie Norsikian,* Cedric Tresse,
Marc François-Eude, Louis Jeanne-
Julien, Guillaume Masson, Vincent
Servajean, Grégory Genta-Jouve, Jean-
Marie Beau, and Emmanuel Roulland*
Page No. – Page No.
Text for Table of Contents
Total Synthesis of Tiacumicin B:
Implementing H-bond-Directed
Acceptor Delivery for Highly Selective
-Glycosylations
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