Enantioselective synthesis of putative lipiarmycin aglycon related to fidaxomicin/tiacumicin B

Article abstract of DOI:10.1002/anie.201409475

An enantioselective synthesis of a putative lipiarmycin aglycon was accomplished and features: 1) Brown's enantioselective alkoxyallylboration and allylation of aldehydes, 2) chain elongation by iterative Horner-Wadsworth-Emmons olefination, 3) Evans' aldol reaction and 4) an enediene ring-closing metathesis. A neighboring-group-assisted chemoselective reductive desilylation was uncovered in this study and was instrumental to the realization of the present synthesis.

Full text of DOI:10.1002/anie.201409475

Angewandte
Chemie
DOI: 10.1002/anie.201409475
Total Synthesis
Enantioselective Synthesis of Putative Lipiarmycin Aglycon Related to
Fidaxomicin/Tiacumicin B**
William Erb, Jean-Marie Grassot, David Linder, Luc Neuville, and Jieping Zhu*
Abstract: An enantioselective synthesis of a putative lipiarmy-
cin aglycon was accomplished and features: 1) Brown’s
enantioselective alkoxyallylboration and allylation of alde-
hydes, 2) chain elongation by iterative Horner–Wadsworth–
Emmons olefination, 3) Evansꢀ aldol reaction and 4) an ene-
diene ring-closing metathesis. A neighboring-group-assisted
chemoselective reductive desilylation was uncovered in this
study and was instrumental to the realization of the present
synthesis.
micin B (3) acts as a RNA synthesis inhibitor by docking into
two domains of the closed RNA polymerase, thus preventing
its opening and activation. It has the same cure rate as
vancomycin but with a lower relapse rate for the treatment of
Clostridium difficile infection (CDI). In May 2011, the FDA
approved tiacumicin B (fidaxomicin, Dificidꢀ) as an alterna-
tive to the well-established metronidazole or vancomycin for
the treatment of CDI.[6]
To date, over 40 members of this family of macrolides
have been isolated.[7] Structurally, these natural products
share a common 18-membered macrolactone unit incorpo-
rating five stereogenic centers, two conjugated dienes, one
trisubstituted double bond, and are O-glycosylated at C11 and
C20. While the absolute configuration of the stereogenic
centers in 3 was determined by single-crystal X-ray structural
analysis, the stereochemistry of lipiarmycin aglycon remains
ambiguous, especially with respect to the absolute config-
uration of C19. Shue and co-workers were among the first to
assign the absolute configuration of lipiarmycin A4 (19S) as
depicted in Figure 1.[8] However, a recent paper from the
group of Serra has shown that lipiarmycin A3 and tiacumi-
cin B (19R) might be identical.[9]
Lipiarmycins A3 (1) and A4 (2; Figure 1) were isolated as
a 3:1 mixture from Actinoplanes deccanensis ATCC 21983 by
Parenti and co-workers in 1975.[1] The structure of 1 and 2 was
elucidated in 1987,[2] and was followed by isolation of
lipiarmycins B3 and B4 congeners a year after.[3] Other
microbial metabolites structurally related to the lipiarmycins,
such as clostomicins[4] and tiacumicins,[5] have subsequently
been isolated from Micromonospora echinospora and Dacty-
losporangium aurantiacum hamdenensis, respectively. Tiacu-
Given our interest in the chemistry and bioactivities of the
lipiarmycins, we requested and received a sample of lipiar-
mycin A3 from Biosearch Italia. We started our research by
detailed NMR studies of this natural product and deduced,
independent of Optimer Pharmaceuticalsꢁ work, the stereo-
chemistry of lipiarmycin A3 to be that shown in Figure 1.[10]
A
total synthesis based on this stereochemical assignment was
subsequently initiated.[11,12] We describe herein our synthesis
of presumed lipiarmycin aglycon.[13] The groups of Gademann
and of Altmann have independently accomplished the syn-
thesis of the tiacumycin B aglycon.[14]
Figure 1. Structures of lipiarmycins and tiacumicin B.
Our retrosynthetic analysis of the lipiarmycin aglycon 4 is
outlined in Scheme 1. Cleavage of both the ester function and
the C4–C5 double bond would give the alcohol 5 and
carboxylic acid 6. In a forward sense, intermolecular cross-
metathesis between 5 and 6 followed by macrolactonization
[*] Dr. W. Erb, Dr. J.-M. Grassot, Dr. D. Linder, Dr. L. Neuville
Centre de Recherche de Gif, Laboratoire International Associꢀ,
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products, Institute of Chemical
Sciences and Engineering, Ecole Polytechnique Fꢀdꢀrale de Lau-
sanne, EPFL-SB-ISIC-LSPN
BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
[**] We thank CNRS (France) and EPFL (Switzerland) for financial
support. W.E. thanks the Ministꢁre de l’Enseignement Supꢀrieur et
de la Recherche for a doctoral fellowship. J.M.G. thanks ICSN for
a doctoral fellowship. D.L. thanks the Swiss National Science
Foundation (SNSF) for a post-doctoral grant.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409475.
Scheme 1. Retrosynthesis of lipiarmycin aglycon.
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Scheme 2. a) sBuLi, THF, À788C, 30 min, then (+)-Ipc2BOMe, À788C,
60 min, then BF3·OEt2, À788C, then acetaldehyde, À788C, 3 h, then
H2O2, NaOH, À788C to RT, 18 h, 9a (74%, ee 93%); 9b (80%, ee
92%); b) NaH, DMF, 08C, 1 h, then BnBr, 08C to RT, 18 h, 81%;
c) CAN, MeCN, H2O, 08C, 15 min, 81%; d) TBSCl, Imidazole, DMF,
RT, 18 h, 90%; e) Cy2BH, THF, 08C, 2 h, then H2O2, NaOH, 08C, 4 h,
73%; f) (COCl)2, DMSO, CH2Cl2, À788C, 1 h, then NEt3, À788C to RT,
1 h, 99%; g) 12, NaH, THF, 08C, 20 min, then 11, 08C, 2 h, 92%,
E/Z=7:1; h) DIBAL-H, Toluene, À788C, 1 h, 93%; i) MnO2, THF, RT,
2 h; j) 12, NaH, THF, 08C, 20 min, then 14, 08C, 2 h, 78%, E/Z=4:1;
k) DIBAL-H, toluene, À788C, 1 h, 59%. CAN=cerium ammonium
nitrate, Cy=cyclohexyl, DIBAL-H=diisobutylaluminium hydride,
DMF=N,Ndimethylformamide, DMSO=dimethylsulfoxide, Ipc=iso-
pinocampheyl, MEM=2-methoxyethoxymethyl, PMP=p-methoxy-
phenyl, TBS=tert-butyldimethylsilyl, THF=tetrahydrofuran.
Scheme 3. a) MnO2, THF, RT, 2 h; b) 16, nBu2BOTf, NEt3, CH2Cl2, 08C,
30 min, then 15, À788C to RT, then H2O2, MeOH, Buffer pH 7.0, 108C
to RT, 1 h, 86% over 2 steps; c) TESCl, imidazole, DMF, 08C, 20 min,
73%; d) EtSH, nBuLi, THF, 08C, 5 min, then 17, THF, RT, 10 min,
85%; e) DIBAL-H, CH2Cl2, À788C, 20 min; f) 12, NaH, THF, 08C,
20 min, then 19, 08C, 2 h, 70% over 2 steps, E/Z=4:1; g) DIBAL-H,
toluene, À788C, 1 h, 56%; h) MnO2, THF, RT, 2 h; i) 21, THF, À788C,
1 h, then H2O2, NaOH, À788C to RT, 3 h, 58%, dr=3:1; j) NaH,
nBu4NI, DMF, 08C, 1 h, then BnBr, 08C to RT, 18 h, 40%. TES=tri-
ethylsilyl, Tf=trifluoromethanesulfonyl.
the oxazolidinone 16 to afford, after protection of the
resulting hydroxy group as a TES ether, the compound 17
(Scheme 3). Reaction of 17 with in situ generated lithium
ethanethiolate produced the thioester 18 which was reduced
with DIBAL-H to the aldehyde 19. Two-carbon homologa-
tion of 19 to the allylic alcohol 20 was accomplished by
a standard HWE reaction/reduction sequence. Oxidation of
the alcohol followed by addition of Brownꢁs allylation
reagent, (À)-Ipc2BAllyl (21),[21] afforded, after O benzylation,
the diastereomerically pure allyl ether 22, a key tetraenic
tetrol building block.
The macrolactonization strategy was initially examined
for the synthesis of the lipiarmycin aglycon. Access to 6 and its
elaboration to the cyclization precursor is detailed in
Scheme 4. Methyl 2-(hydroxymethyl)acrylate (23)[22] was
converted into the E-vinylbromide 24 through a sequence of
O-MOM protection, bromination, and stereoseletive b elimi-
nation of HBr.[23] A Liebeskind-modified Stille coupling
between 24 and tributylvinylstannane in the presence of
copper thiophene carboxylate (CuTC) provided the diene 25
in 75% yield.[24] We noted that the Suzuki–Miyaura cross-
coupling between 24 and either vinyl potassium trifluorobo-
rate, vinylpinacolborane, or vinyl boroxine afforded the
desired diene 25 in a low yield (20 to 40%). Saponification
of the methyl ester was best realized using trimethyltin
hydroxide as a nucleophile (dichloroethane, 808C)[25] to
afford 6, which was transformed into the 2-(trimethylsilyl)-
ethoxymethyl (SEM) ester 26[26] and was stable enough to be
or alternatively, esterification of the acid 6 by 5 and
subsequent ring-closing metathesis of the resulting ene-
diene,[15] could be envisaged for the formation of the 18-
membered macrocycle.
We began our synthesis with the preparation of the diene
7 (Scheme 2). An enantioselective Brown alkoxyallylation of
acetaldehyde by the allyl ether 8a in the presence of
(+)-Ipc2BOMe[16] afforded the syn-diol 9a as a single isolable
diastereomer in 74% yield with 93% ee.[17] The absolute
configuration of 9a (2S, 3S) was determined according to
Trostꢁs method[18] and the observed enantioselectivity was in
agreement with the literature precedent. Likewise, reaction of
8b with acetaldehyde under identical reaction conditions
provided 9b (80%, ee 92%), which was converted into 10 by
a sequence of known reactions. It is worthy to note that the
TBS ether 8c failed to react with acetaldehyde under
standard reaction conditions. Hydroboration/oxidation of
the olefin 10 followed by Swern oxidation of the resulting
primary alcohol furnished the aldehyde 11 in 73% overall
yield. Horner–Wadsworth–Emmons (HWE) olefination[19] of
11 with ethyl 2-(diethoxyphosphoryl)propanoate (12) pro-
vided the trans-olefin 13 as a major isomer and was trans-
formed, upon reduction and oxidation, to the a,b-unsaturated
aldehyde 14. Applying the same HWE olefination/reduction
sequence to 14 provided 7 without event.
Oxidation of 7 with MnO2 afforded the unstable dienal 15
which was directly engaged in the Evans aldol reaction[20] with
2
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in which the C17–OTBS ether was chemoselectively
removed. We hypothesized that formation of the five-
membered aluminum chelate 30 is responsible for this
unexpected result[28] based on the fact that the compound 31
failed to undergo the regioselective O desilylation.
This observation allowed development of a successful
synthesis of the putative lipiarmycin aglycon 4 (Scheme 6).
Scheme 4. a) MOMCl, iPr2NEt, CH2Cl2, 08C to RT, 18 h, 26%; b) Br2,
CCl4, Reflux, 30 min, 54%; c) TBAF, HMPA, 08C to RT, 1 h, 73%;
d) tributylvinylstannane, CuTC, NMP, 08C, 10 min, 57%; e) Me3SnOH,
1,2-DCE, 808C, 5 days, 31%; f) SEMCl, Cs2CO3, DMF, RT, 18 h, 87%;
g) 22, Hoveyda-Grubbs II (25 mol%), toluene, 1008C, M.W., 15 min,
38%; DCE=1,2-dichloroethane, HMPA=hexamethylphosphoramide,
MOM=methoxymethyl, M.W.=microwave, NMP=N-methylpyrrolidi-
none, SEM=tri(methylsilyl)ethoxymethyl, TBAF=tetrabutylammonium
fluoride, TC=thiophene carboxylate.
purified by chromatography on silica gel. Cross-metathesis
between 22 and 26 was problematic, thus affording 27 in only
38% yield in the presence of the Hoveyda–Grubbs II
catalyst.[27] Unfortunately, all trials to selectively remove the
C17–OTBS and C1–OSEM ester protective groups led to
a complex reaction mixture or degradation of the starting
material under forcing conditions. The instability of diene
units as well as the tendency of 27 to undergo dehydration to
the conjugated polyene could account for the experimental
observation. Indeed because of the presence of the C1 ester
group, the H on C6 is quite acidic and is prone to induce
a cascade dehydration leading to highly unstable polyenes.
The failure encountered in the deprotection of 27
prompted us to examine an alternative esterification/RCM
strategy (Scheme 5). Acylation of the diol 28 derived from 22
turned out to be nonregioselective even with substoichio-
metric amounts of the acylation agent. Therefore, access to
a substrate with a free C17 hydroxy group was needed. During
the optimization process for the reduction of 18 with DIBAL-
H, we isolated a variable amount of the hydroxy aldehyde 29
Scheme 6. a) DIBAL-H (1.0m in hexane, 2 equiv), toluene, À788C,
20 min; b) 12, NaH, THF, 08C, 2 h, then crude aldehyde 19, 08C, 2 h,
65% over two steps, E/Z=4:1; c) DIBAL-H (1.0m in hexane, 5 equiv),
CH2Cl2, À788C, 1 h, 71%; d) MnO2, THF, RT, 2 h; e) 6, 1,3,5-trichloro-
benzoyl chloride, Et3N, toluene, RT, 1 h, then 34, DMAP, RT, 4 h, 53%
from 33; f) 21, THF, À788C, 1 h, then H2O2, NaOH, À788C to RT, 3 h,
42%; g) Grubbs II (0.2 equiv), toluene, 1008C, 43%, E/Z=2:1.
DMAP=4-(N,N-dimethylamino)pyridine.
Reduction of 18 with DIBAL-H (1.0m in hexane) followed by
a HWE reaction afforded the triene 32. After a rapid
filtration of the crude reaction mixture, a dichloromethane
solution of 32 was treated with an excess of DIBAL-H (1.0m
solution in hexane, 5 equiv, À788C) to afford the diol 33 in
which the C17–OTBS ether was chemoselectively removed.
Chemoselective oxidation of allylic alcohol in the presence of
the secondary alcohol afforded the hydroxy aldehyde 34
which was esterified with 6 under Yamaguchi conditions to
afford the aldehyde 35.[29] Allylation of 35 with 21 afforded
the desired diastereomer 36 in a 42% yield. The final RCM of
ene-diene afforded two separable macrolactones, 4 and 37, in
yields of 28 and 15%, respectively.[30] Detailed NOE studies
allowed us to conclude that the major isomer has the desired
E geometry of the newly formed double bond (see the
Supporting Information).
Scheme 5. Selective deprotection under reductive conditions: a neigh-
boring-group effect.
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In summary, we developed an enantioselective synthesis
of putative lipiarmycin aglycon featuring a key RCM for the
closure of the 18-membered macrocycle. While iterative
HWE reaction was used for chain elongation, the stereogenic
centers of the macrolide were installed and controlled by
Brownꢁs alkoxyallylboration, allylation, and an Evans aldol
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A
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Received: September 25, 2014
Published online: && &&, &&&&
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Keywords: macrocycles · metathesis · natural products ·
protecting groups · total synthesis
.
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[14] a) Accompanying paper: H. Miyatake-Ondozal, E. Kaufmann,
K. Gademann, Angew. Chem. Int. Ed. 2014, DOI: 10.1002/
anie.201409464; Angew. Chem. 2014, DOI: 10.1002/
ange.201409464; b) Accompanying paper: F. Gaus, K.-H. Alt-
mann, Angew. Chem. Int. Ed. 2014, DOI: 10.1002/
anie.201409510; Angew. Chem. 2014, DOI: 10.1002/
ange.201409510.
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Communications
Total Synthesis
W. Erb, J.-M. Grassot, D. Linder,
L. Neuville, J. Zhu*
&&&& — &&&&
Enantioselective Synthesis of Putative
Lipiarmycin Aglycon Related to
Fidaxomicin/Tiacumicin B
Chain gang: The synthesis of the title
compound is reported. The ene-diene
ring-closing metathesis was used for the
formation of the 18-membered macro-
lactone and the stereogenic centers of the
molecule were installed by Brown’s
alkoxyallylboration, allylation, and an
Evans aldol reaction, while iterative
Horner–Wadsworth–Emmons reactions
were used for chain elongation.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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