Total synthesis of the Tiacumicin B (lipiarmycin A3/fidaxomicin) aglycone

Article abstract of DOI:10.1002/anie.201409510

Tiacumicin B (lipiarmycin A3, fidaxomicin) is an atypical macrolide antibiotic which is used for the treatment of Clostridium difficile infections. Tiacumicin B is also a potent inhibitor of Mycobacterium tuberculosis, but due to its limited oral bioavailability is unsuitable for systemic therapy. To provide a basis for structure-activity studies that might eventually lead to improved variants of tiacumicin B, we have developed an efficient approach to the synthesis of the tiacumicin B aglycone. The synthesis features a high-yielding intramolecular Suzuki cross-coupling reaction to effect macrocyclic ring closure. Key steps in the synthesis of the macrocyclization precursor were a highly selective, one-pot Corey-Peterson olefination and an ene-diene cross-metathesis reaction. Depending on the reaction conditions, the final deprotection delivered either the fully deprotected tiacumicin B aglycone or partially protected versions thereof.

Full text of DOI:10.1002/anie.201409510

Angewandte
Chemie
DOI: 10.1002/anie.201409510
Natural Product Synthesis
Total Synthesis of the Tiacumicin B (Lipiarmycin A3/Fidaxomicin)
Aglycone**
Florian Glaus and Karl-Heinz Altmann*
Abstract: Tiacumicin B (lipiarmycin A3, fidaxomicin) is an
atypical macrolide antibiotic which is used for the treatment of
Clostridium difficile infections. Tiacumicin B is also a potent
inhibitor of Mycobacterium tuberculosis, but due to its limited
oral bioavailability is unsuitable for systemic therapy. To
provide a basis for structure–activity studies that might
eventually lead to improved variants of tiacumicin B, we
have developed an efficient approach to the synthesis of the
tiacumicin B aglycone. The synthesis features a high-yielding
intramolecular Suzuki cross-coupling reaction to effect macro-
cyclic ring closure. Key steps in the synthesis of the macro-
cyclization precursor were a highly selective, one-pot Corey–
Peterson olefination and an ene–diene cross-metathesis reac-
tion. Depending on the reaction conditions, the final depro-
tection delivered either the fully deprotected tiacumicin B
aglycone or partially protected versions thereof.
reogenic center is present in the short side chain attached to
C17. The aglycone core is connected via glycosidic linkages to
4-O-isobutyryl-5-methyl-b-d-rhamnose (at C11) and to 2-O-
methyl-b-d-rhamnose (at C20), with the latter being esterified
at C4 with dichlorohomoorsellinic acid.
I
n 1987 researchers at Abbott Laboratories described the
isolation of the glycosylated macrolide tiacumicin B (1) as the
major antibacterial constituent of the soil bacterium Dactylo-
sporangium aurantiacum.[1,2] The compound was found to be
identical[1b] to lipiarmycin, which had already been isolated in
1975 from Actinoplanes deccanensis,[3] and to clostomicin B1,
isolated from Micromonospora echinospora in 1986.[4] The
original preparation of lipiarmycin[3] was later discovered to
be a ca. 3:1 mixture of two closely related macrolides,
lipiarmycin A3 and lipiarmycin A4, whose gross chemical
structures were determined in 1987.[5] The complete relative
and absolute configuration of 1 (from Dactylosporangium
aurantiacum) was elucidated in 2005 by X-ray crystallo-
graphic analysis;[6] importantly, most recently, 1 has been
shown to be identical to lipiarmycin A3.[7]
Tiacumicin B (1) is an inhibitor of bacterial RNA
polymerase[8] and it exhibits significant antibacterial activity
against a range of Gram-positive organisms[9] and also against
Mycobacterium tuberculosis.[10] At the same time, the com-
pound is not susceptible to cross-resistance with rifamycin-
type antibiotics,[10] which were the only class of bacterial RNA
polymerase inhibitors of clinical significance before 2011
(vide infra). Notably, 1 shows only minimal oral bioavailabil-
ity,[11] which limits its utility for the treatment of systemic
infections, but renders it highly useful for the elimination of
pathogens confined to the gastrointestinal tract. In 2011,
tiacumicin B (1), under the generic name fidaxomicin (trade
names Dificid (U.S.) and Dificlir (Europe)), was approved for
the treatment of infections with the opportunistic pathogen
Clostridium difficile, which is the most frequent cause of
nosocomial diarrhea infections in the developed world.[12]
Rather surprisingly, despite their intriguing structures and
biological profiles, no total synthesis of any member of the
tiacumicin/lipiarmycin/clostomicin family (or the correspond-
ing aglycones) has been reported in the literature to date. In
the context of our work on new drugs against tuberculosis,[13]
we have thus embarked on the total synthesis of the
tiacumicin B aglycone (2; Scheme 1), in order to provide
a basis for structure–activity relationship (SAR) studies.[14]
Ultimately, this work aims to identify tiacumicin B analogues
with improved biopharmaceutical properties. Alternative
approaches to the synthesis of the tiacumicin B aglycone (2)
and its 18S isomer are described in two concurrent papers in
this issue by the groups of Gademann and Zhu, respec-
tively.[32]
The structure of tiacumicin B (1) features an 18-mem-
bered macrolactone core with four chiral centers and a high
degree of unsaturation; an additional, hydroxy-bearing ste-
[*] M. Sc. F. Glaus, Prof. K.-H. Altmann
Swiss Federal Institute of Technology (ETH) Zꢀrich
Department of Chemistry and Applied Biosciences
Institute of Pharmaceutical Sciences, HCI H405
Vladimir-Prelog-Weg 4, 8093 Zꢀrich (Switzerland)
E-mail: karl-heinz.altmann@pharma.ethz.ch
[**] This work was supported by the European Union as part of the EU
FP7 programme “More Medicines for Tuberculosis” (MM4TB),
grant agreement no. 260872. We are indebted to Dr. Bernhard
Pfeiffer and Leo Betschart for NMR support, to Dr. Michael Wçrle,
Dr. Nils Trapp, and Michael Solar for X-ray crystallographic analysis,
and to Dr. Xiangyang Zhang, Louis Bertschi, Rolf Hꢁfliger, and
Oswald Greter for mass spectra.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409510.
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Scheme 2. a) MnO2, 3 ꢂ molecular sieves, CH2Cl2, RT, 75 min; b) 10,
Bu2BOTf, NEt3, CH2Cl2, ꢀ788C, 2.5 h; then 08C, 1.5 h; then pH 7
buffer, MeOH, H2O2, 08C, 1 h; c) MeONHMe·HCl, AlMe3, THF, 08C,
2 h, 53% (three steps); d) TESCl, imidazole, CH2Cl2, RT, 30 min, 94%;
e) DIBAL-H, THF, ꢀ308C, 1 h; then ꢀ208C, 1 h, 94%; f) 12, sBuLi,
THF, ꢀ208C, 2 h; then PhSH, ꢀ208C, 2 h; then sat. aq. NaH2PO4, RT,
4 h, E/Z 20:1, 81% (ca. 95% pure); g) 14, Sc(OTf)3, CH2Cl2, ꢀ358C to
ꢀ208C, 30 min; then ꢀ208C, 2.5 h; then 1m HCl, RT, 7 min, 83%,
d.r.>20:1; h) TBSCl, imidazole, CH2Cl2, RT, 22 h, 93%. OTf=trifluoro-
methanesulfonate, DIBAL-H=diisobutylaluminum hydride,
THF=tetrahydrofuran.
Scheme 1. Retrosynthesis of the tiacumicin B aglycone (2). TBS=tert-
butyldimethylsilyl, TES=triethylsilyl.
As illustrated in Scheme 1, one of the central elements of
our projected synthesis of 2 was the use of an intramolecular
Suzuki cross-coupling reaction to effect macrocyclic ring
closure. The requisite macrocyclization precursor 3 could be
disconnected into acid 4 and alcohol 5; the former was to be
obtained by ene–diene cross-metathesis between olefin 6 and
diene 7,[15] followed by ester saponification. While olefin–
olefin cross-metathesis has found numerous applications in
organic synthesis, reactions involving conjugated dienes such
as 7 have been investigated only scarcely.[16] The terminal
olefin 6 was envisioned to be synthesized from the known
alcohol 9[17] by a sequence of oxidation, stereoselective aldol
reaction, olefination, and stereoselective allylation. Finally,
protecting groups were chosen such as to allow for stepwise
selective deprotection of the C11 and C20 hydroxy groups, in
order to enable subsequent independent derivatization at
these positions for analogue synthesis (or the synthesis of the
natural product 1).
functionality with DIBAL-H then furnished aldehyde 8.
Aldehyde 8 was then transformed into enal 13 by a newly
developed variant of the Corey–Peterson olefination reac-
tion,[20] which employed thiophenol (rather than the com-
monly used trifluoroacetic acid)[21] to isomerize the E/Z
mixture of aldimines formed upon addition of the anion of a-
silylimine 12 to aldehyde 8. Treatment of the aldimine
mixture (E/Z ca. 1:3) with thiophenol in situ induced rapid
Z to E isomerization, yielding imine mixtures with E/Z ratios
of between 15:1 and 22:1 within two hours;[21] hydrolysis of
the imine moiety then afforded enal 13 in 81% yield and 95%
purity. Allylation of 13 with Leightonꢀs strained silacycle 14[22]
[23]
in the presence of Sc(OTf)3
set the C7 stereocenter
(tiacumicin numbering) with excellent selectivity (d.r. >
20:1) and in high yield (83%).[24] TBS protection of the
secondary hydroxy group then furnished the desired building
block 6.
Based on the above retrosynthetic considerations, the
synthesis commenced with the MnO2-mediated allylic oxida-
tion of 9 (Scheme 2). The resulting volatile aldehyde was not
isolated, but the reaction mixture was filtered through celite
and the concentrated filtrate was treated directly with the
boron enolate of 10;[18] this protocol gave the desired syn-
aldol product with excellent diastereoselectivity (d.r. > 20:1).
Separation of the aldol product from unreacted 10 proved to
be difficult and thus was not attempted for multigram-scale
reactions. Rather, the mixture, after aqueous workup and
filtration through silica, was treated with AlMe3/MeONH-
Me·HCl to provide Weinreb amide 11 in 53% overall yield for
the three-step sequence from 9. The absolute configuration of
11 was secured by X-ray crystallography (see the Supporting
Information for details).[19] TES protection of the secondary
hydroxy group followed by reduction of the Weinreb amide
The synthesis of building block 5 departed from racemic
but-3-en-2-ol (15), which was subjected to Sharpless kinetic
resolution, affording, after in situ protection of the hydroxy
group, 16 in 21% yield (compare to a maximum yield of 45%)
(Scheme 3).[25] The epoxide ring in 16 was then smoothly
opened with the anion of propyne to provide 17 in 75% yield.
CuI-catalyzed formal hydroboration[26,27] then afforded Z-
vinyl boronic ester 5 with superb regio- (> 20:1) and
stereoselectivity (Z/E > 20:1) in 79% yield.
With all fragments in hand, the assembly of the tiacumi-
cin B aglycone (2) was investigated, with the initial focus on
the crucial cross-metathesis step (Scheme 4). These experi-
ments revealed a pronounced tendency of diene 7 towards
rapid homodimerization, regardless of the catalyst used
(Grubbs I, II, and III; Hoveyda–Grubbs I and II, Piers–
Grubbs),[28] solvent (toluene, CH2Cl2, Et2O, EtOAc, THF,
2
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Careful saponification of the ester group in the metathesis
product with LiOH in tBuOH/H2O at slightly elevated
temperature (338C) afforded acid 4 in 69% yield together
with some TES-deprotected material (18); the latter could be
readily converted into 4 by reaction with an excess of
TESCl.[31] Esterification of 4 with alcohol 5 (Scheme 4)
using a Yamaguchi protocol[29] then provided 3, as the
requisite precursor for the projected Suzuki macrocyclization.
Ring closure was effected by treating 3 with [Pd(PPh3)4]
followed by TlOEt in a mixture of THF and water.[30]
Remarkably, under these conditions the reaction was usually
complete in less than 30 min at room temperature and
furnished the desired macrocycle 19 in 73% yield as a 9.5:1
mixture of E/Z isomers at C4–C5.[31]
Scheme 3. a) Ti(OiPr)4, (ꢀ)-DIPT, tBuOOH (0.45 equiv), 3 ꢂ molecular
sieves, CH2Cl2, ꢀ208C, 39 h; then TBSCl, imidazole, CH2Cl2, ꢀ208C to
RT; then RT, 16 h, 21%; b) nBuLi, propyne, BF3·OEt2, THF, ꢀ788C,
3.5 h, 75%, 18% recovered 16; c) bis(pinacolato)diboron, CuCl
(5 mol%), KOtBu (20 mol%), PPh3 (6 mol%), THF/MeOH, RT, 3.5 h,
79%. (ꢀ)-DIPT=(ꢀ)-diisopropyl d-tartrate.
While 19 was not crystalline, a differently protected
version of the compound (i.e. 22, Figure 1) afforded crystals
suitable for X-ray analysis,[19] which confirmed the correct
configurations of all stereocenters and double bonds (for
details see the Supporting Information). Importantly, 22 was
Figure 1. Structural formula and ORTEP representation of 22; thermal
ellipsoids drawn at 50% probability. Disorders were omitted (see the
Supporting Information for details). TBDPS=tert-butyldiphenylsilyl.
obtained from 9 by the same route as 19 (except for the
introduction of protecting groups). Global desilylation of 19
was best achieved with NEt3·3HF, which provided 2 in 47%
yield after purification by preparative HPLC (Scheme 4).[31]
When the reaction temperature was lowered from 558C to
158C or ꢀ158C, it was possible to use the same reagent to
remove the secondary TES group (!20) with reasonable
selectivity, or selectively cleave the TES ether and the
primary TBS ether simultaneously (!21), thus generating
substrates suitable for further functionalization, including the
synthesis of tiacumicin B (1).
Scheme 4. a) Hoveyda–Grubbs II (15 mol%), EtOAc, RT, 3.5 h, 56%,
E/Z 6.7:1 at C4–C5, 27% recovered 6; b) LiOH, tBuOH/H2O 3:1,
338C, 48 h, 69% (4), 16% (18); c) 1. TESCl, imidazole, CH2Cl2, RT,
14 h; 2. K2CO3, MeOH, RT, 10 min, 84% (two steps); d) 5, 2,4,6-
Cl3H2C6COCl, NEt3, DMAP, toluene, RT, 5.5 h, 81%; e) [Pd(PPh3)4]
(20 mol%), TlOEt, THF/H2O 3:1, RT, 25 min, 73%; f) NEt3·3HF,
CH3CN, 08C to RT, 1 h; then RT, 8 h; then 508C, 86 h, 47% after HPLC
purification; g) NEt3·3HF, CH3CN/THF 7:3, ꢀ158C, 4 h; then ꢀ258C,
15 h; then ꢀ15 8C, 7 h, 70% (20), 22% (19); h) NEt3·3HF, CH3CN/
THF 6:4, ꢀ158C to 58C, 2 h; then 58C, 5 h; then 158C, 27 h, 54%.
Bpin=pinacolatoboron, DMAP=4-dimethylaminopyridine.
In conclusion, we have developed an efficient synthesis of
the tiacumicin B aglycone (2). The synthesis comprises 12
linear steps from alcohol 9 to the fully protected aglycone 19.
Key steps are a modified Corey–Peterson olefination, which
allowed for the one-pot formation of E-a-methyl a,b-
unsaturated aldehyde 13, a cross-metathesis reaction between
6 and 7, and a highly efficient intramolecular TlOEt-
promoted Suzuki coupling as the macrocyclization step.
Based on the chemistry presented in this paper, current
work in our laboratory focuses on the synthesis of tiacumicin
analogues and their biological evaluation.
dioxane, and C6F6 were investigated), and temperature (08C
to 808C). In addition, rapid catalyst deactivation was noticed
in all cases. In general, second-generation Grubbs and
Hoveyda–Grubbs catalysts gave better conversions and
higher E/Z ratios for the newly formed C4–C5 double bond
than first- and third-generation catalysts. Best results were
obtained when separate solutions of 7 and Hoveyda–Grubbs
II catalyst in EtOAc were added simultaneously to a solution
of 6 in EtOAc at room temperature (syringe pump addition).
Following this protocol, the desired cross-metathesis product
could be isolated in 56% yield as an inseparable 6.7:1 mixture
of E/Z isomers at C4–C5; at the same time, 27% of the more
valuable fragment 6 could be re-isolated.
Received: September 26, 2014
Published online: && &&, &&&&
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Hu, S. Li, Y. Xiao, L. Ma, G. Zhang, H. Zhang, X. Yang, J. Ju, C.
Zhang, ChemBioChem 2011, 12, 1740 – 1748. See also Ref. [1a].
[15] The synthesis of a TIPS-protected variant of this diene has been
described: A. B. Charette, B. Cꢁtꢂ, S. Monroc, S. Prescott, J. Org.
Chem. 1995, 60, 6888 – 6894, and references therein.
[16] For a review see: A. Wojtkielewicz, Curr. Org. Synth. 2013, 10,
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[17] R. Baker, J. L. Castro, J. Chem. Soc. Perkin Trans. 1 1990, 47 – 65.
[18] D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103,
2127 – 2129.
Keywords: Corey–Peterson olefination · macrolides ·
Suzuki coupling · tiacumicin · total synthesis
.
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Chemie
Communications
Natural Product Synthesis
F. Glaus, K.-H. Altmann*
The crucial ring closure in the title total
synthesis is effected by an intramolecular
Suzuki cross-coupling. Key steps in in the
assembly of the linear macrocyclization
precursor are a highly selective one-pot
Corey–Peterson olefination, which is
based on a new thiophenol-mediated Z!
E isomerization of an a,b-unsaturated
aldimine, and an ene–diene cross-meta-
thesis reaction.
&&&& — &&&&
Total Synthesis of the Tiacumicin B
(Lipiarmycin A3/Fidaxomicin) Aglycone
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