Total Synthesis of Tiacumicin B: Study of the Challenging β-Selective Glycosylations**

Article abstract of DOI:10.1002/chem.202005102

We give a full account of the total synthesis of tiacumicin B (Tcn-B), a natural glycosylated macrolide with remarkable antibiotic properties. Our strategy is based on our experience with the synthesis of the tiacumicin B aglycone and on unique 1,2-cis-glycosylation steps. We used sulfoxide anomeric leaving-groups in combination with a remote 3-O-picoloyl group on the donors that allowed highly β-selective rhamnosylation and noviosylation that rely on H-bond-mediated aglycone delivery. The rhamnosylated C1–C3 fragment was anchored to the C4–C19 aglycone fragment by a Suzuki–Miyaura cross-coupling. Ring-size-selective Shiina macrolactonization provided a semiglycosylated aglycone that was engaged directly in the noviolysation step with a virtually total β-selectivity. Finally, a novel deprotection method was devised for the removal of a 2-naphthylmethyl ether on a phenol, and efficient removal of all the protecting groups provided synthetic tiacumicin B.

Full text of DOI:10.1002/chem.202005102

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&
Total Synthesis |Hot Paper|
Total Synthesis of Tiacumicin B: Study of the Challenging
b-Selective Glycosylations**
CØdric Tresse,[a] Marc FranÅois-Heude,[a] Vincent Servajean,[a] Rubal Ravinder,[a]
ClØmence Lesieur,[a] Lucie Geiben,[a] Louis Jeanne-Julien,[b] Vincent Steinmetz,[a]
Pascal Retailleau,[a] Emmanuel Roulland,*[b] Jean-Marie Beau,[a, c] and StØphanie Norsikian*[a]
Abstract: We give a full account of the total synthesis of tia-
cumicin B (Tcn-B), a natural glycosylated macrolide with re-
markable antibiotic properties. Our strategy is based on our
experience with the synthesis of the tiacumicin B aglycone
and on unique 1,2-cis-glycosylation steps. We used sulfoxide
anomeric leaving-groups in combination with a remote 3-O-
picoloyl group on the donors that allowed highly b-selective
rhamnosylation and noviosylation that rely on H-bond-medi-
ated aglycone delivery. The rhamnosylated C1–C3 fragment
was anchored to the C4–C19 aglycone fragment by a
Suzuki–Miyaura cross-coupling. Ring-size-selective Shiina
macrolactonization provided a semiglycosylated aglycone
that was engaged directly in the noviolysation step with a
virtually total b-selectivity. Finally, a novel deprotection
method was devised for the removal of a 2-naphthylmethyl
ether on a phenol, and efficient removal of all the protecting
groups provided synthetic tiacumicin B.
Introduction
one of the tracks consists in developing new antibiotics with
new biological targets.[1] Tiacumicin B (Tcn-B) meets these crite-
ria and, received marketing authorization in 2011 in the United
States for the treatment of Clostridium difficile intestinal infec-
tions, which are often of nosocomial origin and had previously
been fatal in 25% of the cases.[2] Tcn-B interacts with bacterial
RNA polymerase (RNAP)[3] blocking RNA synthesis, a strategy
already used in broad-spectrum antibacterial therapy. As Tcn-B
inhibits bacterial RNAP by binding a site that does not overlap
with other antibiotic binding sites, there is no known cross-re-
sistance with the other antibiotics in use. There is no cross-re-
sistance with rifamycin,[4] so Tcn-B is active on resistant strains
of Mycobacterium tuberculosis, which opens up new therapeu-
tic possibilities.[5] In this context, designing reliable total syn-
theses of Tcn-B that could also lead to analogues proves partic-
ularly relevant.
Nowadays antibiotic resistance is one of the most serious
threats to global health, food security and development, de-
grading the quality of life and heavily impacting the economy
with longer hospital stays, higher medical expenses and higher
mortality. This is a natural phenomenon whose process is ac-
celerated by the excessive use or misuse of these drugs in
humans and animals. An increasing number of infections, such
as pneumonia, tuberculosis or salmonellosis, are becoming
more and more difficult to treat because of the lack of effec-
tiveness of the antibiotics used. To circumvent this resistance,
[a] Dr. C. Tresse, Dr. M. FranÅois-Heude, V. Servajean, R. Ravinder, C. Lesieur,
L. Geiben, V. Steinmetz, Dr. P. Retailleau, Prof. Dr. J.-M. Beau,
Dr. S. Norsikian
Institut de Chimie des Substances Naturelles, UPR 2301
CNRS UniversitØ Paris–Saclay
91198, Gif-sur-Yvette (France)
Tcn-B is representative of a class of antibiotic macrolides and
is also known as clostomicin B1, fidaxomicin or lipiarmycin A3
(Figure 1).[6] This natural product was first isolated in the 70s
from an actinobacterium, Actinoplanes deccanensis, found in
E-mail: stephanie.norsikian@cnrs.fr
[b] Dr. L. Jeanne-Julien, Dr. E. Roulland
C-Tac, CitCom, UMR 8038, FacultØ de Pharmacie
CNRS–UniversitØ de Paris
avenue de l’Observatoire 4,75006, Paris (France)
E-mail: emmanuel.roulland@parisdescartes.fr
[c] Prof. Dr. J.-M. Beau
Institut de Chimie MolØculaire et des MatØriaux d’Orsay (ICMMO), UMR
8182
Univ. Paris-Sud and CNRS, UniversitØ Paris-Saclay
91405 Orsay (France)
[**] A previous version of this manuscript has been deposited on a preprint
server (https://doi.org/10.26434/chemrxiv.13176188.v2).
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202005102.
Figure 1. Tiacumicin B (Tcn-B).
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the soil in India.[7] Its structure was partially elucidated be-
tween 1983 and 1987 by Martinelli,[8] Arnone and Nasini[9] and
recently its biosynthesis could be resolved by the team of
Zhang.[10] Tcn-B is among the most complex and heavier mac-
rolide and its structure can be divided into three main parts:
1) a central core composed of an eighteen-membered macro-
lactone displaying two E,E-conjugated dienes, a trisubstituted
(E)-alkene and featuring five stereogenic centers; 2) an eastern
part with 2-O-methyl-d-rhamnose, linked as the b-anomer and
esterified at the 4-position by an homodichloro-orsellinic acid;
and 3) a western part consisting in a rare sugar, d-noviose, also
linked as the b-anomer and esterified at the 4-position by iso-
butyric acid.
sis of the northern and southern glycosylated fragments of
Tcn-B.[19] The total syntheses of tiacumicin A,[20] mangrolide A[21]
and D,[22] three congeners of tiacumicin B with a slightly simpli-
fied aglycone structure were also achieved.
In this article we wish to report with more details on our
total synthesis of Tcn-B,[23] highlighting the original glycochem-
istry that we had to develop to achieve this goal. Displaying
axial CÀO bonds at C2, d-rhamnose and d-noviose can both
be related to d-mannose derivatives, in which the methylhy-
droxy group in the C5-position has been replaced by a methyl
or a gem-dimethyl group, respectively. For this series, the gly-
cosylation reactions leading to 1,2-cis derivatives are particular-
ly challenging since the a-compound is favored for steric and
thermodynamic (anomeric effect) reasons and its C-2 configu-
ration precludes the application of conventional neighboring
group participation effects.[24]
In 2015, aglycone’s syntheses of Tcn-B were achieved by the
Gademann[11] and Altmann[12] groups while the Zhu[13] group
synthesized the macrolactonic core of a diastereomer of Tcn-B
(OH on C-18). In 2017, we also reported our own syntheses of
the aglycone by designing two closely related pathways.[14]
The development of our strategy led us to discover a Kumada-
Corriu reaction of vinyl sulfides catalyzed by Pd nanoparti-
cles.[15] We also reexplored the Grigg’s allene/alkyne cross-cou-
pling and proposed an unprecedented mechanism.[16] Until
2020, only the Gademann’s team managed to complete the
total synthesis of Tcn-B, providing solutions to the challenging
problem of the 1,2-cis-glycosylations but there was still room
for innovation and improvement of selectivity.[17] For the novio-
sylation step, the cyclic aglycone was found to show low reac-
tivity toward a variety of different glycosyl donors or led exclu-
Results and Discussion
Our total synthesis of Tcn-B relies on our syntheses of the Tcn-
B aglycone,[14] that are based on original and selective assem-
bly of the three main regions of the molecule. We had original-
ly imagined to sequentially glycosylate the aglycone, but final-
ly opted for two more convergent retrosynthetic plans. In
these scenarios, Tcn-B was disconnected into fragments A1,
B1, and C or into fragments A2, B2, and C (Figure 2).[14] Con-
nection of fragment A1 together with fragment B1 would first
be achieved using ruthenium-catalyzed cross metathesis while
sively to the a-glycosylated adduct. The mercury(II) Helferich’s a Suzuki coupling would allow the assembly of vinylbromide
protocol[18] was then used for the glycosylation of an acyclic
triene fragment with a noviosyl bromide giving the corre-
sponding product in 63% yield (a/b: 1:3). After assembly and
cyclization of the aglycone, the rhamnosylation was carried out
on the macrolide with an acetimidate glycosyl donor delivering
the fully protected Tcn-B (a/b: 1:4, 62%). Note that recently De
Brabander used similar glycosylation strategies for the synthe-
B2 with the boronic ester A2. In both cases, following these
steps, a ring-size-selective macrolactonization would deliver a
monoglycosylated aglycone having an unprotected OH at C-11
ready for the noviosylation step with fragment C. Knowing
that the macrolactone has been described as a reluctant glyco-
syl acceptor, this challenging late b-glycosylation carried a high
risk of failure.[17]
Figure 2. Pathways to tiacumicin B (Tcn-B).
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Preparation of the eastern part with 2-O-methyl-d-rhamnose
For the preparation of the rhamnose fragments B1 or B2, we
initially considered using the mannose b-glycosylation method
described by Kahne[25] and Crich.[26] The activation of a manno-
syl donor having a 4,6-benzylidene and an anomeric sulfoxide
or a thioaryl leaving group would allow the selective formation
of the b-mannoside compound through SN2 displacement of
the corresponding a-anomeric triflate. The obtained glycoside
would therefore be later functionalized into a rhamnoside de-
rivative after subsequent C6 deoxygenation. To this aim, thio-
glycosyl donor 1 was prepared[27] and submitted to Crich gly-
cosylation conditions using pre-activation at À608C by 1-ben-
zenesulfinyl piperidine (BSP) in the presence of 2,4,6-tri-tert-bu-
tylpyrimidine (TTBP) and Tf2O (Scheme 1).[28] The intermediate
triflate was then allowed to react with the acceptor 3[14b] lead-
ing to the desired glycosylation product in a good 94% yield
and a good selectivity of 1/6 in favor of the b-adduct. The ste-
Scheme 1. Synthesis of b-mannoside 4. BSP: 1-benzenesulfinyl piperidine,
TTBP: 2,4,6-tri-tert-butylpyrimidine.
we did not succeed in further functionalizing this compound
into the desired rhamnoside.
reochemistry was determined by measuring the C-1/H-1 cou-
We then turned to a glycosylation using the phenylthio-
rhamnosyl donor 12 comprising the homodichloroorsellinate
ester at the 4-position and a picoloyl group (Pico) at O-3
(Scheme 2, Table 1).
1
pling constant (1JC-1 H-1
,
~160 Hz if H-1 is axial and JC-1 H-1
,
~
1
170 Hz if H-1 is equatorial) derived from its H-coupled hetero-
nuclear single quantum correlation spectrum. Unfortunately,
Scheme 2. Synthesis of orsellinate derivative 7 and rhamnopyranosyl donors 12–14. TFA: trifluoroacetic acid, TFAA: trifluoroacetic anhydride, NapBr: 2-naph-
thalene-methyl bromide, LDA: Lithium di-iso-propylamide, DCC: dicyclohexylcarbodiimide, DMAP: 4-dimethylaminopyridine, m-CPBA: 3-chloroperoxybenzoic
acid.
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chlorinated and both phenols protected as tert-butyldimethyl-
silyl ethers provided 8.[23] With this compound, the sequence
of the deprotonation of the benzylic methyl group/methyla-
tion proceeded in an almost quantitative yield to furnish repro-
ducibly the homologated compound. After acidic hydrolysis
with concentrated sulfuric acid to the deprotected carboxylic
acid 9, treatment with acetone and triflic anhydride in trifluoro-
acetic acid furnished the cyclic ester. Note that no reaction
took place using trifluoracetic anhydride instead of Tf2O. The
remaining free phenol was finally protected, supplying Nap
ether 7.
Table 1. Rhamnosylation conditions of different acceptors with donors
12–14.
The synthesis of donor 12 was performed from diol 10 ob-
tained in a few steps from phenyl-2,3,4,6-tetra-O-acetyl-1-thio-
b-d-mannopyranoside (Scheme 2).[23] Esterification of this diol
using homodichloroorsellinate ester 7 and NaH in THF led to
compound 11. As observed by Gademann et al.,[20] the O-3 po-
sition is first esterified and the desired adduct is formed after
ester migration on a prolongated reaction time. The liberated
phenol was then protected as 2-Nap ether and the O-3 posi-
tion of the rhamnoside was esterified with picolinic acid to
give the desired donor 12.
D [equiv.]
A
Conditions[a]
P, Yield [%][b] a/b[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
12 (1.3) 16a DMTST[d]
12 (1.3) 15a DMTST[d]
12 (1.3) 15a NIS, cat. TfOH[e]
–
–
18, 85
18, 86
–
1:6.5
1:4
–
12 (1.3) 17
12 (1.3) 17
12 (1.3) 17
12 (1.3) 17
13 (1.3) 17
13 (1.3) 17
13 (1.7) 17
13 (2.1) 17
13 (1.3) 17
14 (1.7) 17
DMTST[d]
[e]
NIS, cat. TfOH
–
–
BSP, TTBP, Tf2O, À608C[f]
–
–
NIS, TfOH[g]
19, 75–86
19, 52
19, 48
19, 64
19, 70
19, 20
20, 95
1:3–1:4
1:12
1:16
1:20
1:20
1:2
Tf2O, À508C[h]
Tf2O, À708C[h]
Tf2O, À708C[h]
Tf2O, À708C[h]
Tf2O, À708C[i]
Tf2O,-708C[h]
Rhamnosyl donor 12 was first engaged in a glycosylation re-
action with the monoprotected diol 16a as the acceptor
(Table 1, entry 1). This compound was prepared from 2,2-di-
methyl-1,3-dioxan-5-one[32] after a Wittig reaction with bromo-
trimethylphenylphosphonium bromide in the presence of
sodium bis(trimethylsilyl)amide (NaHMDS) in THF (Scheme 3).
This was followed by deprotection of the acetonide and mono-
protection of the resulting diol as TBS ethers 15a and 15b.[33]
A Suzuki cross coupling of a mixture of 15a,b with phenylvi-
nylboronic acid using catalytic Pd(OAc)2 combined with 2-dicy-
20:1
[a] Reaction performed in CH2Cl2 (c 0.01m) with 4 Š MS unless otherwise
stated. [b] After chromatography on silica gel. [c] Ratio and stereochemis-
try determined by 1H NMR analysis of the crude mixture and by measur-
1
ing JC1,H1 coupling, respectively. [d] With 2.6 equiv. of the promotor in
DCE as solvent from 08C to RT. [e] With 1.2 equiv. of NIS and 0.24 equiv.
of TfOH from À408C to RT. [f] With 1.3 equiv. of BSP, 2.5 equiv. of TTBP
and 1.4 equiv. of Tf2O. [g] With 1.2 equiv. of NIS and 1 equiv. of TfOH from
À408C to RT. [h] With 1.3–1.9 equiv. of Tf2O, 3.5–4.6 equiv. of DTBMP and
4.2–6 equiv. of ADMB. [i] Preactivation protocol.
clohexylphosphino-2’,6’-dimethoxybiphenyl
(Sphos)[34]
as
ligand and potassium phosphate in THF/water at room tem-
perature was then carried out giving 16a and 16b that could
be separated using preparative HPLC.
This glycosylation strategy, developed by Demchenko, in-
volves intermolecular H-bonding between the nitrogen of the
picoloyl group and the acceptor, directing the selective facial
attack on the glycosyl donor on the same side as the Pico
group.[29] We started with the synthesis of orsellinate derivative
7 needed for the esterification at the 4-position of S-Phenyl-2-
O-methyl-1-thio-a-d-rhamnopyranoside 10.[23] This compound
can be synthesized in a straightforward manner from commer-
cially available carboxylic acid 5a (Scheme 2). After dichlorina-
tion in acetic acid[30] and formation of the cyclic ester using
acetone and trifluoracetic anhydride (TFAA) in trifluoroacetic
acid (TFA),[31] the resulting phenol was protected as a 2-naph-
thylmethyl ether (Nap) 6. This protecting group was chosen as
it could be removed using the same conditions (2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ)) as for 4-methoxybenzyl
(MPM) ethers, already present on the aglycone. Lithiation of
the benzylic methyl group of 6 with lithium diisopropylamide
(LDA) at À788C followed by trapping the corresponding anion
with methyl iodide allowed the formation of the targeted 7.
Unfortunately, this reaction proved unreproducible giving
yields ranging from 53 to 10% on a larger scale. For this
reason, we chose a longer but reliable sequence starting from
commercially available ethyl orsellinate 5b. The latter was
The glycosylation reaction of 16a was carried out in 1,2-di-
chloroethane (DCE) with dimethyl(methylthio)sulfonium triflate
(DMTST), a classical promoter used in H-bond-mediated agly-
cone delivery (HAD). However, no glycosylation adduct was ob-
tained with donor 12, 16a proving very unstable under these
conditions. Acceptor 15a was then used and with DMTST
(2 equiv.) in DCE at room temperature, we were pleased to
obtain the glycosylation product 18 in 85% yield (Table 1,
entry 2). A good a/b selectivity of 1/6.5 was also achieved sug-
Scheme 3. Synthesis of acceptors 15a and 16a. NaHMDS: sodium bis(tri-
methylsilyl)amide, PTSA: para-toluene sulfonic acid, SPhos: 2-dicyclohexyl-
phosphino-2’,6’-dimethoxybiphenyl.
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Scheme 4. X-ray crystal structure and functionalization of 18. CSA: camphor sulfonic acid.
gesting that HAD might have worked to mediate a b-selective
glycosylation through an intermediate such as 21. Recrystalliza-
tion allowed us to separate both anomers and to unambigu-
ously determine the configuration of the major one through X-
ray crystal diffraction analysis (Scheme 4).[35] The reaction was
also carried out in dichloromethane using N-iodosuccinimide
(NIS, 1.2 equiv.) and a catalytic amount of triflic acid (TfOH,
0.24 equiv.), which gave a good yield (86%) but with a slightly
lower stereoselectivity (a/b=1:4; Table 1, entry 3).
leading to the degradation of the acceptor (Table 1, entry 6).
However, by increasing the amount of TfOH (0.92 equiv./
donor)[36] used in combination with NIS (1 equiv./donor) in
CH2Cl2 at À408C to room temperature produced 19 in a 76%
yield as a mixture of anomers (a/b: 1:4; Table 1, entry 7), that
could be separated by preparative HPLC. Note that in this par-
ticular case, the excess of TfOH could disrupt the HAD pathway
and the glycosylation would follow a different mechanism,
probably involving the protonation of the nitrogen on the pi-
coloyl and formation of a glycosyl triflate.[37] By changing pa-
rameters such as temperature, promoter or donor amount, di-
lution, etc., we were not able to obtain a better selectivity.
Seeking for higher b-selectivity, we decided to explore the re-
action with sulfoxide 13 (Scheme 2), a type of anomeric leav-
ing group never before used in combination with a directing
picoloyl group. Following m-CPBA oxidation of sulfide 12, the
activation of donor 13 (1.3 equiv.) was first examined in CH2Cl2
at À508C with Tf2O in the presence of acceptor 17 using 2,6-
di-tert-butyl-4-methylpiridine (DTBMP) as acid scavenger, and
4-allyl-1,2-dimethoxybenzene (ADMB) (Table 1, entry 8).[38,39] We
were pleased to find that under these conditions the desired
glycosylated compound 19 with an upgraded facial selectivity
(a/b: 1:12) and a yield of 52%. Higher yield (70%) and selectiv-
ity (a/b: 1:20) could be further attained by increasing the
donor amount (2.1 equiv.) and by lowering the temperature of
the activation at À708C (see Table 1, entries 8 to 11 for com-
parison). To verify the influence of the remote picoloyl group
in stereodirecting the nucleophilic attack on the b-face by H-
bonding, we carried out two control experiments. The first
consisted in performing the reaction by pre-activating the
donor using Tf2O at À708C for 15 minutes followed by the ad-
dition of the acceptor (Table 1, entry 12). These conditions led
to the formation of the expected glycoside 19 in only 20%
yield and poor selectivity (a/b: 1:2). The second control experi-
ment was achieved with donor 14 (Scheme 2) having a benzo-
yl group in place of the picoloyl (Table 1, entry 13). This reac-
Before optimizing this glycosylation step, we chose to test
the synthetic sequence leading to the key building block B1
necessitating a terminal carboxylic acid group. Thus, the Pico
group in 18 was smoothly and selectively removed with
Cu(OAc)2 in dichloromethane/methanol (Scheme 4). This was
followed by a Pd-catalyzed Suzuki reaction with phenylvinyl-
boronic acid using catalytic Pd(OAc)2/Sphos and K3PO4 in THF/
water at room temperature for 18 hours. Following these mild
conditions, we noticed the presence of about 20% of products
displaying deprotected phenols on the orsellinate moiety.
Direct treatment of the crude reaction mixture with NapBr in
the presence of K2CO3 in DMF allowed us to reinstall the pro-
tective groups and obtain the targeted diene compound 23 in
73% yield. The 3-OH on the rhamnoside moiety was then pro-
tected as a TBS-ether and the primary alcohol was deprotected
using camphor sulfonic acid (CSA) in methanol/CH2Cl2, provid-
ing 24 in a 75% yield. Unfortunately, we did not succeed in ox-
idizing this compound into the corresponding carboxylic acid
prior to the next Ru-catalyzed cross metathesis with fragment
A1.
We then turned our attention toward the glycosylation of
the alternative acceptor 17 already bearing the carboxylic
function. Contrary to previous results with 15a, activation of
12 with DMTST or NIS/cat. TfOH were disappointingly unsuc-
cessful since no glycosylation adduct was observed (Table 1,
entries 4 and 5). Activation with the BSP/Tf2O method at
À608C in the presence of TTBP was also tried without success
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Scheme 5. Assemblage of A2 and B2 and macrolactonization to monoglycosylated 26. Ruphos: 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl.
tion led to pure a-glycosylation product 20, indicating that the
HAD mechanism may effectively take place only with the pico-
loyl group. The picoloyl of 19 was then removed with
Cu(OAc)2 in CH2Cl2/MeOH, and replaced by a TBS group to
lead to fragment B2 (Scheme 5).
the 2-O position of the noviosyl moiety.[44] The axial configura-
tion of the 2-hydroxy group of the donor being favorable, this
approach would a priori provide a 1,2-cis glycosidic linkage
with complete b-stereocontrol. For the preparation of the re-
quired noviosyl donor, we started from d-arabinose
(Scheme 6). Selective acetonide protection of the cis-diol, oxi-
dation of the hemiacetal with trichloroisocyanuric acid (TCCA)
and catalytic 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) fol-
lowed by silylation of the remaining 2-OH group provided lac-
tone 27. Introduction of the gem-dimethyl groups was achiev-
ed using the reaction of 27 with the methyl Grignard reagent
and the corresponding diol was re-oxidized to lactone 28.
Dibal-H reduction led to the lactol and a mild acidic treatment
with formic acid allowed the selective removal of the aceto-
nide protection, prior to the introduction of a thiophenyl
group at the anomeric position.[45] The resulting diol 29 was
protected as dichloroacetyl esters, which upon treatment by
(iPrCO)2O in MeCN with a catalytic amount of Sc(OTf)3 allowed
the direct replacement of the TBS group by an isobutyrate.[46]
The two dichloroacetates in the obtained compound were
then selectively removed with sym-collidine in MeOH giving
diol 30.
Assemblage of A2 and B2 and macrolactonization
We could easily scale up our synthesis of the aglycone frag-
ment A2. The convergent step of Pd-catalyzed cross-coupling
of boronic ester A2 with rhamnoside B2 proceeded cleanly
with catalytic Pd(OAc)2/Ruphos (2-dicyclohexylphosphino-2’,6’-
diisopropoxybiphenyl)[34] and K3PO4 in a mixture of THF/water
at room temperature, furnishing ester 25 in 79% yield
(Scheme 5). As reported by Nicolaou et al.,[40] the use of
Me3SnOH allowed us to hydrolyze selectively the methyl ester
in the presence of the orsellinate on the rhamnoside moiety.
Performed in toluene at 1208C, the reaction led cleanly to
seco-acid in 70 to 93% yields. With the latter in hand, we then
focused on a ring-size-selective macrolactonization using Ya-
maguchi conditions as described for the synthesis of our agly-
cone.[14] However, the transposition of these conditions on this
substrate led to the desired hemi-glycosylated tiacumicin B 26
in a low 23% yield. With the Boden-Keck’s protocol,[41] the
yield reached 58% yield, but 26 proved to be a mixture of two
products resulting from the E/Z isomerization of the C4=C5
alkene.[42] Finally, a far cleaner and reproducible macrolactoni-
zation was achieved using the Shiina’s conditions[43] with 2-
methyl-6-nitrobenzoic anhydride furnishing 26 in 72% yield,
and an isomerization minimized at 15%. This selective strategy
allowed us to keep the free OH at C-11 so that 26 could be di-
rectly engaged in the next glycosylation step.
The latter was then selectively mono-alkylated (NapBr, CsF)
after the prior formation of the stannylene 31 giving predomi-
nantly the compound 32 with 2-naphthylmethyl ether at O-2
position (2-O-Nap/3-O-Nap=95:5) in 80% yield. This unexpect-
ed selectivity can be rationalized by the preferred conforma-
4
tion of the starting diol 30, which is not the conventional C1
1
chair but the C4 chair, certainly imposed by the presence of
3
the gem-dimethyl group. This was confirmed by the J1,2 cou-
1
pling constant of 9.5 Hz in the H NMR spectrum of diol 30 in-
dicating a H-1/H-2 trans diaxial orientation. The equatorial OH
bond being more accessible, this accounts for the selectivity of
this protection.
Preparation of the western part with d-niovose and novio-
sylation step
We chose to investigate IAD approach with 32, although to
our knowledge, no other example has been described with a
glycosyl acceptor linked to the 3-O position of the donor
(Scheme 7). Starting our study with (À)-menthol 33 as a
For the noviosylation, we had first programmed intramolecular
aglycone delivery (IAD) using a silicon tether anchoring 26 to
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Scheme 6. Preparation of the noviosyl thioglycoside 32 from d-arabinose, conformational preference of diol 30 and likely structure of stannylene 31 with an
equatorial C2ÀO2 bond. TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy, TCCA: trichloroisocyanuric acid.
Scheme 7. Preparation of the silaketals 35–37 and glycosylation. NIS : N-iodosuccinimide; DTBMP: 2,6-di-tert-butyl-4-methylpyridine.
model, the corresponding silaketal 35 could be easily synthe-
sized with the recently reported method of Montgomery.[44c]
After treatment of noviosyl adduct 32 with dimethylchlorosi-
lane, the corresponding alkoxysilane reacted with (À)-menthol
33 in the presence of B(C6F5)3 as catalyst. As indicated by the
1H NMR spectrum, the silylated compound 35 also adopts ex-
(1.3 equiv.) and TMSOTf (1.8 equiv.) in CH2Cl2 in the presence of
DTBMP (3 equiv.) at À408C for 1 h. Treatment of the reaction
mixture with a solution of tetrabutylammonium fluoride (TBAF)
in THF led to the desired glycosylation product 39a (X=H) in
55% yield and as a single b-anomer. In this case, the obtained
4
compound 39a adopted a C1 conformation with a measured
1
clusively a C4 chair conformation. Considering that intermedi-
1JC-1,H-1 of 159 Hz confirming the b-configuration. The moderate
yield obtained here is likely due to the presence of the TBAF
reagent that can cleave the iso-butyrate ester. However, with-
out TBAF treatment, we isolated, after silica gel chromatogra-
phy, two stable glycosylation adducts bearing various silyl
groups (39b, X=Me2SiOH,[47] and 39c, X=Me2SiOTMS[48]) at
ate oxonium 38, resulting from 35, must display a half-chair
conformation (Scheme 7), the alcohol to be transferred must
then occupy a position favorable for the formation of the de-
sired b-derivative. Optimized glycosylation conditions on 35
were obtained when the reaction was carried out with NIS
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the 3-O position of the novioside. To avoid their formation, an
anhydrous HCl solution in methanol was added after comple-
tion of the glycosylation which delivered targeted product 39a
in a 81% yield with complete b-stereocontrol. The reaction
was also carried out with the more complex alcohol 34, a syn-
thetic precursor of the aglycone fragment A2. The formation
of the silaketal was performed as with (À)-menthol which pro-
Table 2. Glycosylation conditions of donors D (41–42) with different ac-
ceptors.
D (equiv.)
A
Conditions[a]
P, Yield [%][b]
a/b[c]
1
2
3
4
5
6
41 (1.3)
41 (1.3)
41 (1.3)
42 (1.3)
42 (2.1)
42 (2.1)
33
34
34
33
34
26
DMTST[d]
43, 83
44, 11
44, 21
43, 66
44, 62
45, 68
1:5
n.d.
n.d.
>1:20
1:20
>1:20
DMTST[d]
NIS, TfOH[e]
Tf2O, À708C[f]
Tf2O, À708C[g]
Tf2O, À708C[g]
1
duced 36 exclusively in a C4 chair conformation and a good
76% yield. Using the glycosylation conditions described previ-
ously and acid treatment, the corresponding adduct 40 was
obtained in 41% yield also as a single b-anomer. As for 39, the
[a] Reaction performed in CH2Cl2 (0.01m) with 4 Š MS unless otherwise
stated. [b] After chromatography on silica gel. [c] Ratio and stereochemis-
try determined by 1H NMR analysis of the crude mixture and by measur-
4
obtained glycosylated compound 40 adopted a C1 conforma-
1
1
ing JC1,H1 coupling. [d] With 2.3 equiv. of the promotor in DCE (0.02m)
tion with a measured JC-1,H-1 of 159 Hz. Despite this unsatisfac-
from 08C to RT. [e] With 1.4 equiv. of NIS and 1.8 equiv. of TfOH from
À408C to RT. [f] With 1.5 equiv. of Tf2O and 3 equiv. of DTBMP. [g] With
1.9 equiv. of Tf2O, 4.7 equiv. of DTBMP and 4.2 equiv. of ADMB.
tory result, we decided to attempt the reaction with the semi-
glycosylated tiacumicin B 26. In this case we failed at preparing
the silaketal using Montgomery’s conditions but good results
were obtained with the preliminary formation of the chloroalk-
oxysilane[44a] that reacted with 26 providing the corresponding
dialkoxysilane 37 in 73% yield. Unfortunately, glycosylation
using NIS and TMSOTf in CH2Cl2 at À408C followed by an HCl
treatment led to degradation of the compound without evi-
dence of the formation of the targeted glycosylated adduct.
We then shifted to another strategy based this time on a
HAD approach involving the use of noviosyl donor 41 bearing
a Pico group at the 3-position (Scheme 8). Following esterifica-
in 66% yield (Table 2, entry 4). With alcohol 34, the use of the
sulfoxide approach proved to be more efficient as well provid-
ing b-glycosylation product 44 in a 62% yield (Table 2, entry 5).
Moreover, these reaction conditions applied to the hemiglyco-
sylated tiacumicin B 26 delightfully furnished the desired nov-
iosylated product 45 in 68% yield, with high facial selectivity
(Table 2, entry 6, a/b>1:20).
Final deprotection stages
The last steps consisting in the removal of all protective
groups (2 MPM, 3 Nap, 1 Pico and 1 TBS) from compound 45
proved unpleasantly more difficult than expected (Scheme 9).
Using HF·NEt3 in THF allowed us to remove first the TBS group
located on the rhamnosyl moiety giving the corresponding al-
cohol. The 2 MPM as well as the Nap located on the novioside
were then oxidized with DDQ in CH2Cl2/H2O. At this stage, the
two Nap groups protecting the phenol functions of the rham-
nosyl moiety resisted these conditions at 08C, and a longer re-
action time at 208C led to an intractable mixture of products.
The removal of the picoloyl was then cleanly carried out using
Cu(OAc)2 in CH2Cl2/MeOH at 08C to produce 46. This deprotec-
tion sequence order was important as the Pico group had to
be removed after its neighboring Nap group to avoid the
DDQ-promoted formation of a 2,3-O-naphthylmethylidene on
the novioside. These three operations were performed with no
intermediate purifications providing an overall yield of 74% of
46. However, the unexpected problem of cleavage of the two
Nap groups located on the two phenol functions remained to
be addressed. Lewis acid-mediated treatment of the Nap led
only to the degradation of the molecule. Pd-catalyzed hydro-
genation (Pd/C, cyclohexene) allowed the phenol deprotection
but along with the reduction of the C4=C5 alkene.[49] As above
mentioned, we observed a partial loss of the Nap groups locat-
ed on the phenol moiety during the Pd-catalyzed Suzuki reac-
tion of 23 with phenyl vinylboronic acid (see Scheme 4 and
text). Exploiting this observation, we finally discover a new and
selective method of deprotection of Nap ether on phenol.
After a few optimizations, we found that using Pd2(dba)3 as a
catalyst in combination with PPh3 along with 1,3-dimethylbar-
Scheme 8. Preparation of the noviosyl donors D (41 and 42) and glycosyla-
tion (structure of R1OH in Scheme 7).
tion of 32 with picolinic acid, the corresponding sulfide 41 was
engaged in a glycosylation reaction with (À)-menthol as the
acceptor (Table 2, entry 1). The reaction was carried out with
DMTST as the promoter and led predominantly to the b-com-
pound 43 (a/b: 1:5) in 83% yield. With elaborated unsaturated
alcohol 34, this approach led to poor yields (11 to 21%) either
with DMTST (Table 2, entry 2) or NIS/TfOH (Table 2, entry 3) and
unfortunately turned out unsuccessful with macrolactonic ac-
ceptor 26 since no glycosylated adduct was detected. The suc-
cess of the above-mentioned rhamnosylation led us to consid-
er that sulfoxide 42 derived from sulfide 41 could be a far
more reactive donor. A first trial with (À)-menthol as acceptor
under Tf2O activation at À708C revealed the potency of this
method, as the b-anomer 43 was obtained as the only adduct
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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 UniversitØ de Paris. We
thank Karim Hammad and Jean-FranÅois Gallard for NMR sup-
port and Rosemary Green Beau for her editing of the manu-
script.
Conflict of Interests
The authors declare no conflict of interests.
Keywords: antibiotics · cis-glycosylation · glycochemistry ·
natural products · total synthesis
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Manuscript received: November 27, 2020
Accepted manuscript online: January 12, 2021
Version of record online: February 18, 2021
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