Thieme Chemistry Journals Awardees - Where Are They Now? Ribosylation of an Acid-Labile Glycosyl Acceptor as a Potential Key Step for the Synthesis of Nucleoside Antibiotics

Article abstract of DOI:10.1055/s-0036-1591517

Naturally occurring nucleoside antibiotics (e.g., muraymycins and caprazamycins) represent attractive lead structures for the development of urgently needed novel antibacterial agents. One major challenge in the total synthesis of muraymycins, caprazamycins, and their analogues is the efficient construction of the densely functionalized aminoribosylated uridine-derived core unit. In order to avoid tedious protecting-group manipulations, we have aimed to conduct the aminoribosylation step with an acid-labile glycosyl acceptor. Therefore, different glycosylation approaches have been studied, with pentenyl glycosides giving the best results.

Full text of DOI:10.1055/s-0036-1591517

SYNLETT
0
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-
5
2
1
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1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–G
letter
A
en
D. Wiegmann et al.
Letter
Synlett
Thieme Chemistry Journals Awardees – Where Are They Now?
Ribosylation of an Acid-Labile Glycosyl Acceptor as a Potential Key
Step for the Synthesis of Nucleoside Antibiotics
Daniel Wiegmanna
Anatol P. Sporkb
steric
hindrance
N3
O
O
O
Giuliana Niroa
0
0
0
0
0-
0
0
2
6-
8
0
6
6-
2
7
1
N3
O
O
Christian Ducho*a,b
0
0
0
0
0-
0
0
2
0-
6
2
9
9-
9
9
3
NH
NH
O
O
O
O
O
N
O
N
O
6'
5'
O
O
t-BuOOC
OH
a Saarland University, Department of Pharmacy, Pharmaceutical and Medicinal
Chemistry, Campus C2 3, 66123 Saarbrücken, Germany
christian.ducho@uni-saarland.de
b Georg-August-University Göttingen, Department of Chemistry, Institute of
Organic and Biomolecular Chemistry, Tammannstr. 2, 37077 Göttingen,
Germany
6'
CbzHN
O
O
5'
CbzHN
acid-
labile
NIS, TESOTf
TBDMSO
OTBDMS
TBDMSO
OTBDMS
ribosylation
(6'S) or (6'R)
(6'S) or (6'R)
Dedicated to Professor Joachim Thiem on the occasion of his birthday.
Received: 05.10.2017
Accepted after revision: 06.10.2017
Published online: 12.12.2017
DOI: 10.1055/s-0036-1591517; Art ID: st-2017-b0489-l
Abstract Naturally occurring nucleoside antibiotics (e.g., muraymy-
cins and caprazamycins) represent attractive lead structures for the de-
velopment of urgently needed novel antibacterial agents. One major
challenge in the total synthesis of muraymycins, caprazamycins, and
their analogues is the efficient construction of the densely functional-
ized aminoribosylated uridine-derived core unit. In order to avoid te-
dious protecting-group manipulations, we have aimed to conduct the
aminoribosylation step with an acid-labile glycosyl acceptor. Therefore,
different glycosylation approaches have been studied, with pentenyl
glycosides giving the best results.
Key words natural products, antibiotics, nucleosides, glycosylation, ri-
bosylation, pentenyl glycosides
Spreading resistances of bacteria against a variety of
clinically used antibiotics cause an urgent need for new an-
tibacterial drugs.1 In order to avoid the formation of cross
resistances, these substances should address new targets
and display novel modes of action. Since there is no equiva-
lent biochemical process in eukaryotic cells, bacterial cell
wall biosynthesis furnishes valuable drug targets for anti-
bacterial agents, with multiple established antibiotics in-
hibiting the late extracellular steps of peptidoglycan forma-
tion.2 However, the early intracellular steps of this biosyn-
thetic pathway are only scarcely targeted by drugs.2 The
transmembrane enzyme MraY represents such an emerg-
ing intracellular drug target.3 MraY catalyzes the transfer of
the peptidoglycan precursor UDP-MurNAc-pentapeptide
(‘Park’s nucleotide’) to the membrane-bound undecaprenyl
phosphate lipid carrier on the cytosolic side of the bacterial
membrane (not displayed).4 The formation of the resultant
biosynthetic intermediate ‘lipid I’ is inhibited by nucleoside
antibiotics, i.e., a class of uridine-derived natural products
functioning as MraY inhibitors.5 We are particularly inter-
Christian Ducho was born in Hamburg in 1976. He obtained his Diplo-
ma in Chemistry from the University of Hamburg in 2001 and his Ph.D.
under the guidance of Prof. Chris Meier from the same university in
2005, with an award-winning thesis on antivirally active nucleotide pro-
drugs. His studies were supported by fellowships of the Studienstiftung
des deutschen Volkes and the Fonds der Chemischen Industrie. In 2005,
Christian moved to the University of Oxford for a postdoctoral stay un-
der the guidance of Prof. Christopher J. Schofield, working on carbapen-
em biosynthesis and funded by a fellowship of the Deutsche Akademie
der Naturforscher Leopoldina. In 2007, he started his independent re-
search career as an Assistant Professor of Organic Chemistry at the
Georg-August-University Göttingen. Following a six-month period as
Substitute Professor at the University of Hamburg, he accepted an As-
sociate Professor position at the University of Paderborn in 2011. Since
2014, Christian is Full Professor of Pharmaceutical and Medicinal Chem-
istry at Saarland University. His research interests include synthetic and
biological studies on novel antibacterial agents and on modified oligo-
nucleotides. Christian has received the Thieme Chemistry Journals
Award in 2012.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

B
D. Wiegmann et al.
Letter
Synlett
ested in the muraymycin6 and caprazamycin7 subclasses of
naturally occurring nucleoside antibiotics, which share an
identical aminoribosylated glycyluridine (GlyU)8 core motif
(Figure 1).
er, their method furnished a product bearing the 2-O-meth-
ylated aminoribosyl unit (R3 = Me in Figure 1) that is found
in some naturally occurring muraymycins. Hence, it does
not furnish the target structures of this work (vide infra).
Furthermore, Kurosu’s method requires protection of the
uracil nucleobase and the use of toxic heavy metals in the
transformations towards the GlyU core structure.
O
NH
HO
O
Our goal in this work was to establish a mild ribosyla-
tion methodology with glycosyl donors of type 1, which
should be compatible with glycosyl acceptors 2 and 3 con-
taining acid-labile protecting groups (tert-butyl ester,
TBDMS ethers, Scheme 1). This would then furnish ribo-
sylated target structures 4 and 5, which are protected de-
rivatives of the native aminoribosylated (5′S,6′S)-GlyU core
and its non-natural (6′R)-epimer, respectively. Such a mild
ribosylation reaction will facilitate the total synthesis of
muraymycins and their analogues, and it will also generally
contribute to glycosylation methodology with acid-labile
acceptor structures.
O
O
R1
N
O
6'
5'
H
H
N
OR2
O
N
NH
N
H
HO
N
H
O
O
HN
OH OH
HN
N
H
O
NH
muraymycin A1: R1
muraymycin D2: R1
=
R3 = Me
O
N
NH2
H2N
11
OH
O
R3 = H
=
R2
=
OH OR3
Me
MeO
O
O
R4
=
N3
HOOC
O
NH
O
OMe
N
N
O
O
N
OMe
10
O
N
O
N
O
6'
5'
OR2
O
NH
NH
O
O
O
O
O
O
O
O
O
6'
5'
t-BuOOC
OH
6'
OR4
O
CbzHN
1
O
O
OH OH
5'
caprazamycin A: R3 = H
CbzHN
Figure 1 Selected naturally occurring muraymycin and caprazamycin
antibiotics (blue: GlyU unit; red: aminoribosyl moiety)
TBDMSO
OTBDMS
TBDMSO
OTBDMS
(5'S,6'S) 2
(5'S,6'R) 3
(5'S,6'S) 4
(5'S,6'R) 5
N3
O
X
Initial structure–activity relationship (SAR) studies of
muraymycins9 and caprazamycins10 have already been per-
formed. For such investigations, efficient synthetic access to
the complex target structures is indispensable. Hence, dif-
ferent synthetic strategies towards muraymycin5c,9c,11 and
caprazamycin12 nucleoside antibiotics have been devel-
oped. Most of these total syntheses employed acid-labile
protecting groups, which were then cleaved in a final global
acidic deprotection step.
Particular attention has been given to the preparation of
the β-configured aminoribosylated GlyU core struc-
ture.11b,c,12a,13 Establishing the aminoribosylation of GlyU
with high β-selectivity is challenging as the overall protect-
ing-group strategy precluded the use of neighboring-group
participation. Ichikawa, Matsuda, and coworkers provided
an approach using ribosyl fluoride donors which were ster-
ically shielded on the α-face.13a However, such ribosylation
reactions require rather harsh Lewis acidic conditions
which are incompatible, e.g., with the presence of tert-butyl
esters in the glycosyl acceptor, thus requiring subsequent
protecting-group manipulations in the total synthesis of
muraymycins and their analogues.9a,b,11a Kurosu and co-
workers established a different strategy involving a thiori-
boside donor and an uridine-derived propargyl alcohol ac-
ceptor, which was transformed into the GlyU core motif
over several steps after the ribosylation reaction.11c Howev-
O
O
1
Scheme 1 Attempted ribosylation reaction of acid-labile glycosyl
acceptors
Initially, we tested Ichikawa’s and Matsuda’s originally
reported glycosyl fluoride donor 613a (α- and/or β-config-
ured) in transformations with acceptor 2 (see below for its
synthesis) under various conditions (Table 1). Formation of
product 4 was generally only observed in negligible
amounts at best, while byproducts 7 and 8 were obtained in
varying ratios. Compound 7 apparently resulted from cleav-
age of the tert-butyl ester under the Lewis acidic conditions
with subsequent ribosylation of the resultant carboxylic
acid moiety. Compound 8 was obviously formed in a reac-
tion of the nonribosylated acceptor with the solvent di-
chloromethane. The notable exception in this series of ex-
periments was the transformation of 2 and α-6 in the pres-
ence of AgOTf and Cp2HfCl2 at low temperatures, which
afforded the desired product 4 in 25% yield (Table 1, entry
5). However, besides its rather moderate yield, this method
suffered from limited reproducibility. Attempts to repeat
the reaction with a similar outcome failed, although the
quality of all reagents was checked carefully and the previ-
ously employed protocol was strictly followed.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

C
D. Wiegmann et al.
Letter
Synlett
Table 1 Initial Ribosylation Studies with Fluoride Donor 6 and Acid-
Labile Acceptor 2
The aforementioned formation of bisribosylated by-
product 7 with only limited amounts of desired 4 indicated
that the transformations with glycosyl fluoride 6 suffered
from the relatively harsh activation conditions. Therefore, it
has been decided to investigate a range of alternative glyco-
syl donors with milder activators. Acceptor 2 had been ob-
tained by standard Cbz protection of previously reported
amine 99c,11b in 80% yield (Scheme 2, A). Furthermore, 6′-
epimer 3 was also used as an alternative glycosyl acceptor
additionally allowing for investigation of any potential in-
fluence of the stereochemistry in 6′-postion on the ribo-
sylation reaction (see Scheme 1). Isomer 3 was be obtained
from the previously reported readily accessible amine pre-
cursor 1014 in 81% yield (Scheme 2, A). The respective 6′-
epimeric ribosylated product 5 will also be particularly rel-
evant for further SAR studies on muraymycins and capraza-
mycins. As a structurally simplified model glycosyl accep-
tor, tert-butyl ester 12 was obtained from commercially
available N-Cbz-threonine 11 using Eschenmoser’s meth-
od15 (72% yield, Scheme 2, A). Compound 12 represents a
truncated analogue of acceptor 2 lacking the nucleoside
moiety. Our general approach was to first identify a suitable
ribosylation method using acceptor 12 in model reactions.
The thus obtained most promising method was then envi-
sioned to be applied on the transformation of 3 into 5, and
finally also on the transformation of 2 into ribosylated 4.
Compound 4 should then be used for the synthesis of an
aminoribosylated GlyU building block.
N3
O
R =
O
N
O
O
O
NH
O
O
2
activator
CH2Cl2
N3
O
OR
O
CbzHN
F
different
conditions
O
O
TBDMSO
OTBDMS
(5'S,6'S) 4
6
O
N
O
N
R
NH
O
N
Cl
O
O
O
O
O
OR
O
OH
O
CbzHN
CbzHN
TBDMSO
OTBDMS
TBDMSO
OTBDMS
7
8
Entry Donor Activator
Conditions
–45 °C to r.t., 9 h
Product(s)
1
2
3
4
5
6
7
α/β-6
β-6
BF3·Et2Oa
4 (traces)
BF3·Et2Oa
–24 °C to 0 °C, 3 d 4 + 7b
α-6
α-6
α-6
α-6
β-6
BF3·Et2Oa
0 °C, 3 h
decomposition
Bu4NClO4, CsF
AgOTf, Cp2HfCl2
AgOTf, Cp2HfCl2
AgOTf, Cp2HfCl2
r.t., 16 h
8 (36%)
4 (25%)
4 + 7b
–45 °C to r.t., 9 h
r.t., 18 h
Following the synthesis of glycosyl acceptors, a range of
azidoribosyl donors were prepared. Protected 5′-azido-5′-
deoxyribose 1313a was acetylated to give 14 in 96% yield
(Scheme 2, B), which was envisioned to serve as a precursor
for Koenigs–Knorr glycosyl halides. The trichloroacetimi-
date donor 15 was also synthesized from hemiacetal 13 us-
r.t., 18 h
4 + 7b
a With addition of freshly activated molecular sieves (4 Å).
b Nonseparable mixture.
NH
A
B
Cl3CCN
DBU or PS-DBU
CH2Cl2
O
N
Cl
Cl
Ac2O, DMAP
pyridine
N3
N3
N3
OAc
O
NH
O
O
O
O
O
OH
Cl
96%
92% (with DBU)
96% (with PS-DBU)
O
6'
5'
OH
O
O
O
O
O
O
O
R
N
H
15
13
14
TBDMSO
OTBDMS
EtSH, BF3 Et2O
CH2Cl2
N3
N3
S
9: (5'S,6'S), R = H
10: (5'S,6'R), R = H
C
O
O
CbzCl
+
NaHCO3
THF
S
N3
2: (5'S,6'S), R = Cbz 80%
3: (5'S,6'R), R = Cbz 81%
O
O
O
O
O
F
α-16: 30%
β-16: 34%
O
O
R'O
O
17
BF3 Et2O
CH2Cl2
6
OH
N3
N3
CbzHN
O
O
O
+
t-BuOH
DMF-dineo-
pentyl acetal
toluene
11: R' = H
O
O
O
O
O
72%
HO
12: R' = t-Bu
17
α-18: 6%
β-18: 70%
Scheme 2 Synthesis of glycosyl acceptors 2, 3, and 12 (A) as well as of glycosyl donors 14–16 and 18 (B, C) for studies on the ribosylation reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

D
D. Wiegmann et al.
Letter
Synlett
ing trichloroacetonitrile with either DBU16 or polystyrene-
supported DBU (PS-DBU)17 as base (Scheme 2, B). With PS-
DBU, no further purification was necessary, but yields were
high with both forms of DBU (92% and 96%, respectively).
Thioglycoside 16 was obtained from ribosyl fluoride 6 using
BF3-Et2O as activator, with anomers chromatographically
separated to afford β-16 in 34% yield and α-16 in 30% yield
(Scheme 2, C). Finally, the reaction of 6 with 4-pentene-1-ol
17 under similar conditions furnished n-pentenyl glycoside
18 in anomerically pure form after separation (β-18: 70%
yield, α-18: 6% yield, Scheme 2, C). The anomeric purity of
the glycosyl donors was not considered to have significant
impact on the reaction outcome as the ribosylation reac-
tions were expected to largely proceed via an SN1-type
mechanism. For all donors, the respective β-product was fa-
vored due to the steric shielding of the α-face resulting
from the bulky isopentylidene protecting group.13a
In the next set of experiments, we aimed to implement
a modified version of the Koenigs–Knorr ribosylation meth-
od reported by Gravier–Pelletier et al.18 The ribosyl bromide
19 was freshly generated from 14 and then directly reacted
with acceptors 12 or 3, respectively, in a one-pot manner
(Table 2). The conversion of the acetylated precursor 14 into
19 was accomplished using trimethylsilyl bromide (TMSBr),
and the subsequent activation of resultant bromide 19 was
achieved with silver(I) triflate (AgOTf). Under different re-
action conditions, only limited amounts of the desired
products 20 (from 12) or 5 (from 3), respectively, were ob-
tained (Table 2). In several cases, the products still con-
tained major amounts of the unreacted precursor 14.
Therefore, we concluded that the transformation into bro-
mide 19 was problematic, and that the ribosylation of the
sterically hindered alcohols probably proceeded slowly.
Hence, this method was discarded.
Table 2 Ribosylation Studies Using Koenigs–Knorr Glycosylation
TMSBr
CH2Cl2
N3
N3
OAc
O
O
Br
–40 °C to r.t.
different
conditions
O
O
O
O
14
19
O
O
NHCbz
12 or 3
AgOTf
CH2Cl2
O
N3
O
or 5 (from 3)
–20 °C, 1 h
then –10 °C to
r.t., 14 h
O
O
20 (from 12)
Entry Acceptor TMSBr/activationa
14b
Product(s) (yield)
1
2
3
12
12
12
1 × 4 equiv (2 h),
2 × 8 equiv (2 h each)
0.77 equiv 20/14 1.0:2.5
(14% 20 calcd)c
1 × 4 equiv (2 h),
3 × 8 equiv (2 h each)
1.25 equiv 20/14 1.0:1.2
(23% 20 calcd)c
1 × 4 equiv (2 h),
4 × 8 equiv
1.25 equiv 20 (14%)
(2/2/12/2 h)
4
5
12
3
5 × 8 equiv (1 h each)
1.25 equiv 20/14 1.0:3.0
(12% 20 calcd)c
1 × 4 equiv (2 h),
3 × 8 equiv (2 h each)
4.2 equiv
5 (13%)
a Activation step (14 to 19): equivalents of TMSBr (added portionwise) with
respect to precursor 14 as well as (in parentheses) subsequent reaction
time(s) after each addition of TMSBr.
b Glycosylation step (19 to 20 or 5): equivalents of precursor 14 with re-
spect to the acceptor 12 or 3.
c Yield calculated from the NMR spectra of the product mixture.
Table 3 Ribosylation Studies Using Schmidt’s Tricholoracetimidate
Method
The next glycosylation approach to be studied was
Schmidt’s trichloroacetimidate method, for which some
precedent with furanose donors exists.19 Again, threonine-
derived model compound 12 and the protected GlyU epi-
mer 3 were used as acceptors. Glycosyl donor 15 was mildly
activated with catalytic amounts of trimethylsilyl triflate
(TMSOTf) under different reaction conditions (Table 3). This
method gave encouraging initial results for the transforma-
tion of 12 into 20 (Table 3, entries 1 and 2), and it also fur-
nished the ribosylated protected GlyU epimer 5 (from 3) in
44% yield (69% brsm, Table 3, entry 3). Remarkably, all at-
tempts to reproduce the latter synthesis of 5 failed, when
the reaction was performed again under identical condi-
tions. Portionwise addition of the donor was presumed to
avoid unwanted side reactions, but according further varia-
tions of the reaction protocol were not successful either
(Table 3, entries 4–6). It was therefore concluded that this
method also did not furnish robust and reproducible results.
O
NHCbz
NH
O
12 or 3
TMSOTf
CH2Cl2
Cl
Cl
N3
N3
O
O
O
O
or
5
Cl
(from 3)
different
conditions
O
O
O
O
15
20 (from 12)
Entry Acceptor 15
TMSOTf
Conditions
Product(s) (yield)
1
2
3
4
12
12
3
1.0
2 × 0.05
0 °C to r.t., 2 h 20 (44%)
equiv equiva
2.0 0.06
equiv equiv
0 °C, 30 min
0 °C, 1.5 h
–10 °C, 4 h
20 (72%), α-20
(5%)
2.3
2 × 0.07
5 (44%, 69% brsm),
α-5 (<15%)
equiv equiva
3
2.1
4 × 0.06
rsm 3 (34%),
decomposition
equiv equiva
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

E
D. Wiegmann et al.
Letter
Synlett
of acceptor 3. Zhang and Knapp have recently reported an
indium(III) triflate promoted glycosylation of uridine deriv-
atives with thioglycoside donors, which overcame this hur-
dle.23 We have applied identical conditions to the attempt-
ed ribosylation of 3, but poor conversion and decomposi-
tion products were observed (Table 4, entry 12).
Entry Acceptor 15
TMSOTf
Conditions
Product(s) (yield)
5
6
3
3
5.6
4 × 0.17
–10 °C to
35 °C, 31 h
5 (traces),
decomposition
equiv equiva
4.0 2 × 0.2
0 °C, 1.5 h
decomposition
equiv equiva
a TMSOTf added portionwise (n × the listed equivalents).
Following the results using the thioglycoside approach,
Fraser–Reid’s n-pentenyl glycoside method was studied next.24
Thus, pentenyl glycoside β-18 was mildly activated with N-io-
dosuccinimide (NIS) and catalytic amounts of triethylsilyl
triflate (TESOTf) to enable the ribosylation reaction. Conver-
sions were observed both with the threonine-derived model
acceptor 12 as well as with the 6′-epi-GlyU acceptor 3
We then explored ribosylation reactions with the thio-
glycoside 16 as donor.20 In general, thioglycosides can serve
as stable glycosyl donors with different pathways to acti-
vate them for glycosyl transfer. A very mild activation
method is the treatment with dimethyl(methylthio)-sulfo-
nium triflate (DMTST)21a (Table 4, entries 1–8).21b Using the
sterically less hindered threonine-derived model acceptor
12, the product 20 was obtained in yields up to 36% (60%
brsm, entry 2). However, all attempts to apply this method
to the protected GlyU epimer 3 as acceptor gave the respec-
tive product 5 only in very low yields (ca. 5%, Table 4, en-
tries 4–8). Thus, activation with Cu(II) bromide and tetra-
butylammonium bromide was studied as an even milder
option (Table 4, entries 9–11).22 However, this method
turned out to be too mild for the secondary acceptor alco-
hols 12 and 3, respectively. The starting materials were ei-
ther re-isolated or decomposed at elevated temperatures,
which were applied in order to force the reactions to pro-
ceed. In principle, the unwanted glycosylation of the uracil
ring might be a competing side reaction in the ribosylation
12
O
O
NIS, TESOTf
CH2Cl2
O
O
O
26% (41% brsm)
O
O
N3
CbzHN
20
N3
O
O
N3
O
O
O
O
O
NH
3
β-18
O
NIS, TESOTf
CH2Cl2
N
O
t-BuOOC
O
CbzHN
33% (58% brsm)
TBDMSO
OTBDMS
5
Scheme 3 Ribosylation with n-pentenyl glycoside 18
Table 4 Ribosylation Studies Using Thioglycoside Donor 16
O
S
OTf
S
NHCbz
O
DMTST
12 or 3
activator
CH2Cl2
N3
N3
O
O
O
or
5
S
(from 3)
different
conditions
O
O
O
O
16
20 (from 12)
Entry
Acceptor
16
1.25 equiv
Activator
Conditions
Product(s) (yield)
decomposition
1
12
12
12
3
5.0 equiv DMTST
5.7 equiv DMTST
2.7 equiv DMTST
3.75 equiv DMTST
–15 °C, 4 h, then r.t., 1 h
–15 °C, 3.5 h, then 10 °C, 1.5 h
–15 °C, 2 h
2
1.4 equiv
2.0 equiv
2.5 equiv
2.8 equiv
2.1 equiv
2.4 equiv
2.2 equiv
1.2 equiv
2.0 equiv
2.0 equiv
1.5 equiv
20 (36%, 60% brsm), α-20 (traces)
20 (32%, 44% brsm)
5 (5%, 13% brsm)
3
4
–15 °C, 2 h, then 5 °C, 30 min
–15 °C, 2 h, then r.t., 1 h
–15 °C, 2 h, then 0 °C, 1.5 h
0 °C, 3 h
5
3
3 × 2.8 equiv DMTSTa
8 × 0.43 equiv DMTSTa
3.6 equiv DMTSTb
decomposition
6
3
5 (5%, 14% brsm)
7
3
5 (5%, 12% brsm)
8
3
6.7 equiv DMTSTb
10 °C, 5 h
5 (ca. 5%, impure)
rsm 12 (96%)
9
12
12
3
3.4 equiv CuBr2 + 3.2 equiv Bu4NBr
3.4 equiv CuBr2 + 3.2 equiv Bu4NBr
4.0 equiv CuBr2 + 4.0 equiv Bu4NBr
1.5 equiv In(OTf)3 + 1.5 equiv NIS
r.t., 25 h
10
11
12c
r.t. to 150 °C, 4 d
r.t. to 140 °C, 3 d
0 °C to r.t., 14 h
decomposition
rsm 3 (66%)
3
rsm 3 (crude), decomposition
a DMTST added portionwise (n × the listed equivalents).
b DMTST added steadily over the reaction period.
c 1,2-Dichloroethane used as solvent.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G

F
D. Wiegmann et al.
Letter
Synlett
N3
NHBoc
O
N
O
N
O
O
O
1) PPh3, H2O
THF, toluene
2) (Boc)2O, NaHCO3
3) 1,4-cyclohexadiene
Pd black, i-PrOH
O
O
NH
NH
NH
O
β-18
NIS, TESOTf
CH2Cl2
O
O
O
O
O
O
O
N
O
t-BuOOC
t-BuOOC
OH
O
CbzHN
O
O
CbzHN
H2N
52%
(over 3 steps)
36%
(58% brsm)
TBDMSO
OTBDMS
TBDMSO
OTBDMS
TBDMSO
OTBDMS
2
4
21
Scheme 4 Synthesis of the aminoribosylated (5′S,6′S)-GlyU core structure 21 as a building block for the total synthesis of muraymycin antibiotics
(Scheme 3) to furnish products 20 and 5 in isolated yields of
26% and 33%, respectively. While these yields were moder-
ate, the yields based on recovered acceptor starting material
were acceptable (41% yield brsm for 20, 58% yield brsm for
5). Hence, this approach allowed for significant amounts of
both acceptors to be recovered and then converted within a
second transformation with glycosyl donor 18.
trichloroacetimidate donors as well as thioglycosides and n-
pentenyl glycosides revealed the latter to provide the best
results in terms of both reproducibility and yield. These
findings will aid to facilitate the total synthesis of muray-
mycin and caprazamycin nucleoside antibiotics and their
analogues. Furthermore, they are also relevant in a more
general context as precedent for glycosylation reactions
with n-pentenyl furanosides is rather limited, including few
examples of according arabinosylation reactions.26 Our re-
sults therefore complement the toolbox for synthetic ribo-
sylation reactions, in particular for densely functionalized,
sterically hindered, acid-labile glycosyl acceptor moieties.
Attempts to further improve the yields of these ribo-
sylations with pentenyl glycoside 18 by optimization of the
reaction conditions (temperature, time, protocol of addi-
tion) were not successful. However, in contrast to other
methods (vide supra) the reaction could be repeated several
times with identical results. Thus, the reliability and ro-
bustness of this method provide unquestionable advantag-
es over all other ribosylation approaches studied within
this work. The n-pentenyl glycoside strategy was therefore
also applied for the corresponding transformation of pro-
tected (5′S,6′S)-GlyU 2. The reaction worked as for the epi-
meric acceptor 3 and gave the desired azidoribosylated
(5′S,6′S)-GlyU 4 in 36% isolated yield (58% brsm, Scheme
4).25 Again, recovery of significant amounts of the acceptor
allowed for its potential conversion within a subsequent
second transformation with donor 18. Product 4 was then
subjected to a sequence consisting of Staudinger reduction
of the azido group, Boc protection of the resultant amine,
and subsequent Cbz hydrogenolysis to afford 21 in 52%
yield over three steps. The aminoribosylated GlyU deriva-
tive 21 can serve as a valuable building block for the total
synthesis of muraymycin antibiotics and their analogues, as
it shows significant similarity to an according synthetic in-
termediate employed by Ichikawa and Matusda in their
syntheses of muraymycins.9a,b,11a Furthermore, the success-
ful use of silylated nonribosylated GlyU derivatives in the
synthesis of muraymycin analogues has been demonstrated
by us before.9c,14
Funding Information
We thank the Deutsche Forschungsgemeinschaft (DFG, SFB 803 ‘Func-
tionality controlled by organization in and between membranes’ and
grant DU 1095/5-1) and the Fonds der Chemischen Industrie (FCI,
Sachkostenzuschuss) for financial support. D. W. is grateful for a doc-
toral fellowship of the Konrad-Adenauer-Stiftung. G. N. is grateful for
a doctoral fellowship of the FCI.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591517.
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References and Notes
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(25) Synthesis of Protected Ribosylated (5′S,6′S)-GlyU 4
To a solution of the glycosyl donor β-18 (20.1 mg, 64.5 μmol)
and the (5′S,6′S)-GlyU-derived acceptor 2 (35.6 mg, 48.4 μmol)
in CH2Cl2 (3 mL) with freshly activated molecular sieves (4 Å),
NIS (18.9 mg, 83.9 μmol) was added at r.t. under exclusion of
light. Over 10 min, TESOTf (5.8 μL, 26 μmol, 1% solution in
CH2Cl2) was added dropwise. The reaction mixture was stirred
at r.t. for 15 min before ice (5 g) was added and the mixture was
allowed to warm to r.t. again. It was then diluted with CH2Cl2
(70 mL) and the organic layer was washed with 10% Na2S2O3
solution (1 × 70 mL), sat. NaHCO3 solution (1 × 70 mL), and brine
(1 × 70 mL). The organic layer was dried over Na2SO4, and the
solvent was evaporated under reduced pressure. The resultant
crude product was purified by column chromatography (PE–
EtOAc, 75:25 → 70:30) to give 4 (16.6 mg, 36%, 58% brsm) as a
colorless solid; mp 72 °C. TLC: Rf = 0.28 (i-hexane–EtOAc, 7:3).
[α]D20 –7.0 (c 0.7, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.07 (s,
3 H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3), 0.13 (s, 3 H,
SiCH3), 0.83 (t, J = 7.5 Hz, 3 H, 1iv-H), 0.88 (t, J = 7.5 Hz, 3 H, 5iv-
H), 0.90 (s, 9 H, SiC(CH3)3), 0.90 (s, 9 H, SiC(CH3)3), 1.45 (s, 9 H,
OC(CH3)3), 1.53 (q, J = 7.4 Hz, 2 H, 2iv-H), 1.66 (dq, J = 7.4, 1.8 Hz,
2 H, 4iv-H), 3.55 (dd, J = 13.0, 4.0 Hz, 1 H, 5′′′-Ha), 3.72 (dd, J =
13.0, 3.9 Hz, 1 H, 5′′′-Hb), 3.94 (dd, J = 5.7, 4.1 Hz, 1 H, 3′-H), 4.13
(dd, J = 5.7, 2.3 Hz, 1 H, 4′-H), 4.16 (dd, J = 4.1, 3.6 Hz, 1 H, 2′-H),
4.31–4.34 (m, 1 H, 4′′′-H), 4.39 (dd, J = 2.3, 1.9 Hz, 1 H, 5′-H),
4.48 (d, J = 6.3 Hz, 1 H, 2′′′-H), 4.51 (dd, J = 9.2, 1.9 Hz, 1 H, 6′-H),
4.64 (dd, J = 6.3, 1.4 Hz, 1 H, 3′′′-H), 4.97 (d, J = 12.1 Hz, 1 H, 1′′-
Ha), 5.14 (s, 1 H, 1′′′-H), 5.24 (d, J = 12.1 Hz, 1 H, 1′′-Hb), 5.44 (d,
J = 3.6 Hz, 1 H, 1′-H), 5.60 (dd, J = 8.2, 2.1 Hz, 1 H, 5-H), 6.15 (d,
J = 9.2 Hz, 1 H, 6′-NH), 7.24–7.36 (m, 5 H, aryl-H), 7.82 (d, J = 8.2
Hz, 1 H, 6-H), 8.02 (d, J = 2.1 Hz, 1 H, 3-NH). 13C NMR (126 MHz,
CDCl3): δ = –4.9, –4.8, –4.2, –3.9, 7.6, 8.5, 18.1, 18.2, 26.0, 26.0,
28.1, 28.9, 29.4, 53.5, 56.5, 67.0, 71.5, 74.8, 77.8, 81.8, 82.7, 85.3,
86.0, 86.4, 90.6, 101.1, 112.3, 117.9, 128.3, 128.4, 127.7, 136.8,
140.8, 149.9, 156.4, 162.9, 168.8. HRMS (ESI+): m/z calcd for
(15) Brechbühler, H.; Büchi, H.; Hatz, E.; Schreiber, J.; Eschenmoser,
A. Helv. Chim. Acta 1965, 48, 1746.
(16) Naresh, K.; Bharati, B. K.; Avaji, P. G.; Chatterji, D.; Jayaraman, N.
Glycobiology 2011, 21, 1237.
(17) (a) Chiara, J. L.; Encinas, L.; Díaz, B. Tetrahedron Lett. 2005, 46,
2445. (b) Tomoi, M.; Kato, Y.; Kakiuchi, H. Makromol. Chem.
1984, 185, 2117.
C
45H73N6O13Si2: 961.4769 [M + H]+; found: 961.4778. IR (ATR): ν
= 2930, 2857, 2104, 1685, 1457, 1253, 1160, 1059, 835, 775 cm–1
.
UV (MeCN): λmax = 261 nm.
(26) (a) Lu, J.; Fraser-Reid, B. Org. Lett. 2004, 6, 3051. (b) Lu, J.;
Fraser-Reid, B. Chem. Commun. 2005, 862.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–G