Synthesis of a Tiacumicin B Protected Aglycone

Article abstract of DOI:10.1021/acs.orglett.7b01744

Tiacumicin B is an antibiotic endowed with the remarkable ability to interact with a new biological target, giving it an inestimable potential in the context of the ever-growing and worrisome appearance of resistances of bacteria and mycobacteria to antibiotics. The synthesis of an aglycone of tiacumicin B ready for glycosylation is reported. The key steps of this approach are a [2,3]-Wittig rearrangement, a Pd/Cu-catalyzed allene-alkyne cross-coupling, a E-selective cross-metathesis, and a final ring-size selective macrolactonization.

Full text of DOI:10.1021/acs.orglett.7b01744

Letter
pubs.acs.org/OrgLett
Synthesis of a Tiacumicin B Protected Aglycone
Louis Jeanne-Julien,† Guillaume Masson,† Eloi Astier,† Gregory Genta-Jouve,† Vincent Servajean,‡
́
Jean-Marie Beau,‡,§ Stephanie Norsikian,‡ and Emmanuel Roulland*,†
́
†C-TAC, UMR 8638, CNRS/Universite
́
Parie Descartes, 4, avenue de l’Observatoire, 75006 Paris, France
‡ICSN-CNRS Centre de Recherche de Gif, Univ Paris-Sud, Universite
France
́
Paris-Saclay, Avenue de la Terrasse, F-91198 Gif-sur-Yvette,
§Laboratoire de Synthes
̀
e de Biomolec
ules, ICMMO, Univ.Paris-Sud and CNRS, Universite Paris-Saclay, F-91405 Orsay, France
́ ́
S
* Supporting Information
ABSTRACT: Tiacumicin B is an antibiotic endowed with the
remarkable ability to interact with a new biological target, giving it an
inestimable potential in the context of the ever-growing and
worrisome appearance of resistances of bacteria and mycobacteria
to antibiotics. The synthesis of an aglycone of tiacumicin B ready for
glycosylation is reported. The key steps of this approach are a [2,3]-
Wittig rearrangement, a Pd/Cu-catalyzed allene−alkyne cross-
coupling, a E-selective cross-metathesis, and a final ring-size selective macrolactonization.
esistance to antibiotics is a serious re-emerging biomedical
threat in rapid progression, with negative consequences on
quality of life and significant economic impacts. It has become
urgent to identify new molecules that interact with medicinally
virgin biological targets so as to fight these resistances. Such
molecules are scarce; however, tiacumicin B (1) (Figure 1), also
with improved pharmacokinetic profiles or modified antibacterial
spectra. Actually, chemical synthesis is likely the most efficient
way to reach this goal. For all these reasons, but also because this
complex polyketide/sugar mixed structure represents a beautiful
synthetic challenge, tiacumicin B has already attracted the
attention of the groups of Gademann6 and Altmann,7 who
achieved the synthesis of its adequately protected macrolactonic
core. The group of Zhu8 synthesized the putative adequately
protected macrolactonic core of lipiarmycin, a diastereomer of 1.
Ultimately, Gademannandco-workers recently achievedthetotal
synthesis of tiacumicin B (1).9
R
The complexity of this structure authorizes numerous
alternative approaches and is therefore a source of inspiration
and strategic innovations. Scheme 1 depicts the strategy we
designed for this synthesis. The [2,3]-Wittig rearrangement of
propargyl allyl ethers is a powerful synthetic tool,10 and we
imagined it could allow building of the C4−C13 fragment in a very
straightforward and direct manner. Actually, through this single
operation, a C−C bond would be created, and both the C10 and
Figure 1. Tiacumicin B, a new antibiotic lead.
knownas clostomicin B1, fidaxomicin, orlipiarmycinA3,1 belongs
to this category. Tiacumicin B interacts with the β′-subunit of the
switch regionof theRNApolymerase (β′-sr-RNAP) andblocks it,
which stops RNA synthesis and eventually leads to the death of
bacteria.2 The structure of the bacterial RNAP, and in particular
the switch region, is conserved all across bacterial species but is
different from the one of superior animals; therefore, a broad
spectrum of bacteria could be covered selectively with only
limited toxicity. This naturally occurring antibiotic, produced by
fermentation, received FDA approval in 2011 in the USA for the
treatment of a deadly nosocomial intestinal infection associated
with Clostridium difficile.3 β′-sr-RNAP is a drug target exploited
since 2011, and no cross-resistance with any other antibacterial
agentshasyetappeared. Tuberculosisisanotherinfectionthatcan
potentially be treated by blocking RNAP,4 which is appreciable
considering the emergence of multiresistant Mycobacterium.5
Within this context, exploiting this new drug target is a unique
opportunity that must be grasped by providing analogues of 1
Scheme 1. Retrosynthesis of the Tiacumicin B Aglycone
Received: June 9, 2017
© XXXX American Chemical Society
A
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Letter
C11 stereogenic centers, aswellas theconfiguration oftheC8C9
trisubstituted double bond, would be controlled simultaneously,
thus offering an original access to the most densely functionalized
fragment of our target. Unfortunately, the Wittig rearrangement
of propargylic ethers of tertiary allylic alcohols such as A has been
described only once and moreover with no diastereoselectivity.11
So, albeit very attractive, this strategy appeared to be very risky,
and this led us to carry out DFT calculations to evaluate its
viability. Predictions showed that the transition state leading to
the desired diastereomer laid 2.56 kcal mol−1 lower than the other
possible one so a 99:1 syn/anti ratio was expected at −80 °C,12
which prompted us to implement this Wittig rearrangement. This
reaction providing the C4−C13 fragment as a terminal alkyne, we
imagined using an allene/alkyne cross-coupling13 for the
assemblage with fragment C14−C19 that should therefore bear
an allene function. The transformation of the resulting enyne into
the desired diene seemed easily feasible considering the literature.
To control the configuration of the alkene at C4, we envisioned a
cross-metathesis with a vinylboron derivative, a type of coupling
partner known to give high E selectivity. This would be followed
by a Suzuki−Miyaura cross-coupling to install fragment C1−C3.
For the final step, we expected to perform a Yamaguchi
macrolactonization with ring-size selectivity. Thus, the resulting
aglycone having a nonprotected OH at position C11 would be
glycosylation ready.
was exposed to various strong bases to promote the key [2,3]-
Wittig rearrangement (Table 1). Under conventional conditions:
Table 1. Improvement of the [2.3]-Wittig rearrangement of 8
into 9
a
b
solvent −additive
temp
(°C)
yield
9-syn/9-
c
entry base (equiv)
(equiv)
(%)
anti
1
2
3
4
5
n-BuLi (1.0) THF
−80
−80
−80
−80
38
76/24
71/29
70/30
t-BuLi (1.0)
THF
THF
55
LDA (1.2)
32
n-BuLi (1.0) hexane
trace
nr
d
t-BuONa
(1.0)
THF
−80
6
n-BuLi (1.0) THF−HMPA (3.0)
n-BuLi (3.0) THF−LiCl (9.0)
n-BuLi (3.0) THF−LiCl (9.0)
n-BuLi (3.0) THF−LiCl (9.0)
−80
−80
−100
+20
18
85
80
24
74
90/10
93/7
e
f
7
8
95/5
9
81/19
85/15
10
MeLi·LiBr
THF−Et2O
−80
(2.0)
a
b
c
Concentration of 8 is 0.1 M. Isolated yield. Evaluated by 1H NMR.
d
e
f
Room temperature reached before quench. Quenched at −80 °C. 1
h of reaction before quench at −100 °C.
n-BuLi in THF at −80 °C and no additive (Table 1, entry 1), two
diastereomers 9-syn and 9-anti were obtained in a 76/24 ratio in
low yield. Nonetheless, in this first trial, the major product was of
syn stereochemistry as DFT predicted, and this has encouraged us
to optimize this transformation. There was no improvement
whent-BuLi(entry2) orLDA(entry3)was used, and noreaction
was observed with n-BuLi in hexane (entry 4). Interestingly, the
use of HMPA as an additive (entry 6) led to an important
improvement of the selectivity in favor of 9-syn albeit in low yield.
This result provided an interesting indication: the deaggregation
of polymeric organolithium species has a positive impact on the
selectivity. By forming homoaggregated organolithium species,18
LiCl has similar properties, and actually its addition leads to
spectacular yield and stereoselectivity improvements (85%, 93/7:
syn/anti, entry 7) even reproducible on a 3 g scale. It has been
reported that LiBr suppressed concurrent [1,2]-Wittig rearrange-
ment,19 but the effect of Li+ on syn/anti selectivity has not been
reported before. The use of MeLi·LiBr (entry 10) still led to a
good yield, but with a lower selectivity. However, diastereomers
9-syn and 9-anti remained inseparable even by preparative
HPLC.20 Finally, the TES protective group of 9 was easily
removed using aqueous NaOH affording key intermediate 10
obtainedfrom3ineightscalablestepswithanoverallyieldof27%.
1H and 13C NMR chemical shifts of all possible stereoisomers of 9
were simulated by DFT, indicating that its structure is very likely
theoneexpected.12 Toprovideaunivocalstructuralconfirmation,
alcohol 10 was protected as silyl ether 11 and the alkyne function
of 11 was transformed into the corresponding vinylboronic ester
12 through methyl boration21 and then into vinylic iodide22 13
(Scheme 3). Removing the MPM protective group23 gave 147
that has been used by Altmann for his own synthesis of the
tiacumicin B aglycone.
The construction of fragment C4−C13 commenced with the
multigramscalesynthesisofknownallylicalcohol( )-3(Scheme
2).14 Kinetic resolution through Sharpless catalytic epoxidation15
Scheme 2. Synthesis of the C4−C13 Fragment
led to epoxy alcohol 2 (ee > 98%),16 this step constituting
therefore the sole source of chirality of the three stereogenic
centers of the C4−C13 fragment. Epoxy alcohol 2 was protected as
4-methoxybenzyl ether 4 and hydrolyzed into diol 5 under basic
conditions. A Parikh−Doering oxidation17 led to sensitive
hydroxy aldehyde 6, which albeit non-OH-protected, underwent
WittigolefinationsuccessfullytofurnishZtertiaryallylicalcohol7
(Z/E 14:1, 61% yield of (Z)-7 over two steps). We first met
difficulties in obtaining propargylic ether 8, but finally we found
that the addition of 20 mol % of water to a suspension of NaH in
THF allowed us to reach a yield of 93%. Then propargylic ether 8
We accessed allene 18-anti (C14−C19 fragment) from (R)-2-
methyloxirane (Scheme 4).24 Opening of the latter by
nucleophilic attack of sodium thiophenolate and one-pot
protection as a 4-methoxybenzyl ether led to 15. The thioether
was oxidized into sulfoxide 16, and a Pummerer rearrange-
ment25/acidic hydrolysis/Luche propargylation26 sequence led
to homopropargylic alcohol 17 as a ca. 1/1 syn/anti mixture in
81%.Thesetwodiastereoisomersweredifficulttoseparatesothey
B
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consisted in using the Duboudin reaction on 20.29 However, this
Scheme 3. Structure Confirmation of the Fragment 10
approach failed. The Furtsner’s ruthenium-catalyzed OH-
̈
directed hydrosilylation30 installed the silicium at the wrong
distal position in low yield, and radical OH-directed hydro-
stannylationwithPh3SnH31 ledtodegradation. Finally, regio-and
trans-selective nucleophilicalkynehydrosulfuration32 ofenyne20
yielded vinyl sulfide 21 efficiently. Ni-catalyzed cross-coupling
completely failed to install the missing methyl C24 from vinyl
sulfide 21. An unusual ligand-free Pd-catalyzed Kumada−Corriu
cross-coupling33 finally enabled us to introduce efficiently the
methyl-24 onthe C4−C19 fragment togive key compound 22. It is
noteworthythatnoprotectivegroupwasnecessarytoperformthe
whole coupling/hydrosulfuration/methylation sequence. In
addition, this strategy constitutes an innovative alternative to
those traditionally based on the protocols of Suzuki, Negishi, and
Stille, with the advantage of requiring no preactivation of both
cross-coupling partners under the form of a [halide/organo-
metallic] couple, which is a gain in terms of time, number of steps,
and amount of waste produced. Ultimately, we broached the final
stages of this synthesis. For this we could have follow one of the
previously described pathways based on ring-closure or cross-
metathesis strategies.6−9 However, the various E selectivities at
position 4reportedthere, wereunsatisfactory unless anadditional
isomerization step was used. As planned, we used vinylboronate
23 as cross-metathesis partner,34,35 and 22 was transformed into
boronic ester 24, with as expected a 9/1 E/Z ratio, using only 4
mol % of Grubbs’ second-generation catalyst, and with an 80%
yield (Scheme 5).
ASuzuki−Miyauracross-coupling withbrominatedcompound
2536 using the RuPhos ligand37 led to diene 27 in a good yield
albeit with the loss of the TBS protective group (compound 26).
The latter was selectively reinstalled to give 27 in a high yield. A
saponification gave seco-acid 28. Cases of ring-size-selective
macrolactonizations with the Yamaguchi38 reaction have been
reported,39 and in our case it seemed likely that the desired 18-
membered lactone would prevail over the 12-membered one.40
DFT calculations showed us that the 18-membered ring laid 25.1
kcal mol−1 lower than its concurrent 12-membered ring,12 and
gratifyingly, ring-sizeselectivityoccurred12 asdiol28cyclizedinto
macrolactone 29 in a 64% yield. Advantageously, with its OH
function at C11 remaining nonprotected, aglycone 29 is ready for
the next glycosylation step with D-noviose. We are currently
optimizing a substrate-directed 1,2-cis selective41 noviosylation to
complete our total synthesis of tiacumicin B. The relevance of the
use of MPM groups to protect the OH at C7 and C18 was
confirmed. Their removal step has been planned for the very end
of the total synthesis of tiacumicin B (1) where, in particular, the
oxidizable OH at C11 is engaged in a glycosidic bond with D-
noviose. Therefore, this step was tested on compound 30 which
bears a MOM group on this OH, thus mimicking a glycosidic
linkage. We were pleased to see that under classical oxidative
conditions23 the two MPM groups were cleanly removed to
furnishdiol31witha78%yield,thusindicatingthatourprotective
groups choice will very likely allow the achievement of the total
synthesis of tiacumicin B.
Scheme 4. Synthesis of the C14−C19 Fragment 18-anti
werebothtransformed27 intoHPLC-separableallenes18-synand
18-anti. Allene 18-syn can be recycled and converted into 18-anti
via ketone 19 and selectively reduced.28
The assemblage of fragments C4−C13 (10) and C14−C19 (18-
anti) was then addressed. We used the planned alkyne/allene
cross-coupling13 which led to enyne 20 in good yield (78%, E/Z >
95:5, Scheme 5). To the best of our knowledge, this is the first
implementation of this reaction in total synthesis. We had now to
transform this enyne function into the desired diene and also
install the missing C24-methyl group. The simplest way to do this
Scheme5. AssemblageofFragmentsC4−C13 withC14−C19 and
Final Cyclization Steps
In conclusion, we have achieved the synthesis of an adequately
protected tiacumicin B aglycone. Starting from known alcohol
( )-3, thissynthesiswasperformedwitha3.6%overallyieldin16
steps (longest linear sequence), of which only four dealt with
installation or removal of protective groups. DFT predictions
prompted us to use a strategically risky [2,3]-Wittig rearrange-
ment of the propargyl ether of a tertiary allylic alcohol, allowing us
to synthesize the most densely functionalized fragment of the
C
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
(17) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(18) The Chemistry of Organolithium Compounds; Li, R., Rappoport, Z.,
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Chem. 2015, 80, 6222.
(20) Small amounts of pure 9-syn and 9-anti could be obtained for
characterization after HPLC separation of their corresponding 4-
nitrobenzoyl esters and saponification. The traces of the products
resulting from the transformation of minor isomer 9-anti disappeared
gradually as we moved along in the synthesis.
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01744.
Experimental procedures, characterization data, and DFT
calculations (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: emmanuel.roulland@parisdescartes.fr.
ORCID
(21) Alfaro, R.; Parra, A.; Aleman
Am. Chem. Soc. 2012, 134, 15165.
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, J.; García Ruano, J. L.; Tortosa, M. J.
(22) Wang, C.; Tobrman, T.; Xu, Z.; Negishi, E.-i. Org. Lett. 2009, 11,
4092.
Jean-Marie Beau: 0000-0002-3510-4964
(23) Nakajima, N.; Abe, R.; Yonemitsu, O. Chem. Pharm. Bull. 1988, 36,
4244.
(24) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 1307.
Stephanie Norsikian: 0000-0003-2706-4007
Emmanuel Roulland: 0000-0002-8012-7946
Notes
́
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work was supported by the Agence Nationale pour la
Recherche (ANR-14-CE16-0019-02, SYNTIA project), the
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P.; Fillion, H.; Andre, D.; Luche, J.-L. J. Chem. Soc., Chem.
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