A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution

Article abstract of DOI:10.1016/j.tet.2018.07.051

The title compounds were synthesized from the selectively protected N-acylated D-glucosamine derivatives, containing α-halo carboxylic acid moieties, via intramolecular 3-O-alkylation. It was found that if the starting compound contains asymmetric electrophilic center, isomuramic acid derivatives were mainly formed, regardless of the configuration of the electrophilic carbon atom. An explanation for the observed stereochemical results was proposed on the basis of the analysis of steric interactions in the molecules of the starting compounds, as well as using the concept of anchimeric assistance. It was shown that N-acetylation of the obtained lactam derivatives and subsequent methanolysis under mild conditions led to the selective cleavage of δ-lactam ring resulting in the formation of the corresponding ester derivatives of N-acetylmuramic acid or its analogues in high yields.

Full text of DOI:10.1016/j.tet.2018.07.051

Tetrahedron xxx (2018) 1e11
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A new approach to the synthesis of lactams of muramic, isomuramic
and normuramic acids via intramolecular O-alkylation:
Stereochemical features of the intramolecular nucleophilic
substitution
Sergey S. Pertel*, Sergey A. Seryi, Elena S. Kakayan
V.I. Vernadsky Crimean Federal University, 4, Vernadsky Ave., 295007, Simferopol, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
The title compounds were synthesized from the selectively protected N-acylated D-glucosamine de-
rivatives, containing a-halo carboxylic acid moieties, via intramolecular 3-O-alkylation. It was found that
Received 7 June 2018
Received in revised form
24 July 2018
Accepted 27 July 2018
Available online xxx
if the starting compound contains asymmetric electrophilic center, isomuramic acid derivatives were
mainly formed, regardless of the configuration of the electrophilic carbon atom. An explanation for the
observed stereochemical results was proposed on the basis of the analysis of steric interactions in the
molecules of the starting compounds, as well as using the concept of anchimeric assistance. It was shown
that N-acetylation of the obtained lactam derivatives and subsequent methanolysis under mild condi-
Keywords:
tions led to the selective cleavage of
derivatives of N-acetylmuramic acid or its analogues in high yields.
© 2018 Elsevier Ltd. All rights reserved.
d-lactam ring resulting in the formation of the corresponding ester
Intramolecular nucleophilic substitution
Williamson alkylation
Stereoselectivity
Inversion
Retention of configuration
Neighboring group participation
d-lactam
Muramic
Isomuramic and normuramic acid
1. Introduction
muramic acid
spore or spore cortex. If the cortex does not contain the repeating
units of muramic -lactam, the germination of bacterial spores
d-lactam is unique to the peptidoglycan of bacterial
Muramic acid is a naturally occurring sugar amino acid con-
d
taining the residues of (R)-lactic acid which is linked to C-3 of
D-
becomes impossible [5e8].
glucosamine through an ether linkage. N-Acetylmuramic acid is a
constituent of the repeating unit of peptidoglycan of bacterial cell
wall, so-called murein [1]. Three-dimensional structure of murein,
which is composed of the network of linear polysaccharide chains
cross-linked by short peptide bridges via carboxyl groups of the
muramic acid moieties, confers rigidity to the cell wall and resis-
tance to an outer exposure.
The structure of the bacterial peptidoglycan undergoes signifi-
cant changes during sporulation. A substantial part of the peptide
fragments and N-acetyl substituents are cleaved and intra-
molecular N-acylation occurs in muramic acid constituents result-
The low molecular-weight glycopeptide fragments of the bac-
terial peptidoglycan, so-called muramyl peptides, as well as their
numerous synthetic analogues, possess a wide spectrum of bio-
logical activity, including immunomodulatory and somnogenic ef-
fects [9,10]. Certain muramyl peptides have already been approved
for medical applications and are used as drugs for therapies of
cancer and other diseases [10]. In addition to muramyl peptides,
muramic acid derivatives, which are the substrates of the enzymes
involved in the biosynthesis of murein, are of significant interest
[11e17]. Such compounds are necessary for creating the inhibitors
of the bacterial peptidoglycan biosynthesis, which can be used as
new efficient antibacterial agents [18e20].
ing in the formation of d-lactam derivatives [2e4]. The structure of
In addition to muramic acid and its lactam, the epimer of mur-
amic acid at the lactyl residue, so-called isomuramic acid, occurs in
nature. In particular, it was found in O-specific polysaccharides of
* Corresponding author.
E-mail address: sergepertel@yahoo.com (S.S. Pertel).
https://doi.org/10.1016/j.tet.2018.07.051
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051

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S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
Proteus penneri 62 [21] and Providencia alcalifaciens 032 [22]. Syn-
thetic normuramic acid, which contains glycolic acid residue
instead of lactyl moiety, is the constituent of normuramyl peptides
e biologically active analogues of natural muramyl peptides [23].
The preparation of muramic acid, its analogues and derivatives
V-VII is a cumbersome task. The key step of this synthesis consists
crucially depends on their stereochemical purity [40]. However, the
complete inversion of the configuration is not generally achieved
even under relatively mild conditions and when using the enan-
tiomerically pure alkylating reagents [41e43]. It is explained by the
fact that alkylating reagents, which contain carboxyl function
adjacent to an asymmetric electrophilic center, tend to retain the
configuration due to neighboring group participation (anchimeric
in the Williamson O-alkylation at C-3 of the suitably protected
D-
glucosamine derivative I or II with -halo carboxylic acid or its
a
assistance), accompanied by the formation of the intermediary a-
synthetic equivalent, which is accompanied by the inversion of
configuration [13,24e37] (Scheme 1).
lactone [44e46].
We aimed to study the possibility of performing an alternative
and more efficient approach, in terms of stereoselectivity and the
reaction conditions, to the synthesis of the title compounds, which
is based on intramolecular O-alkylation. In this case, the nucleo-
philic and electrophilic centers are spatially close to each other,
which should facilitate their interaction due to the entropy factor,
and are arranged in a certain position relative to each other, which
should affect the stereochemistry of the process.
In order to implement this approach, the electrophilic moiety,
i.e. the residue of
should be first introduced into the
selective N-acylation is suitable for this purpose. Thus, the com-
pounds, which are designed for such an intramolecular O-alkyl-
ation, should correspond to the structure 1 and the reaction should
directly provide the corresponding lactam derivatives (Fig. 1).
The synthesis of muramic acid lactam and its analogues VI re-
quires the removal of N-protecting group in the products III-IV
under rather harsh conditions followed by intramolecular acyla-
tion, which, in contrast to the previous steps, proceeds smoothly
leading to the corresponding lactam derivative [25,38,39].
Several transformations used in this approach to the synthesis of
the derivatives of muramic acid and its analogues proceed under
quite harsh conditions (e.g. Williamson alkylation and N-deacyla-
tion). It is an obvious drawback of the method since it limits
considerably the choice of protecting groups and may facilitate
racemization of the products. A complete separation of the result-
ing mixture of diastereomers is a time-consuming and tedious
process [29]. At the same time, the presence of stereoisomeric
impurities in the target products is highly undesirable since, as it
has been shown, the biological activity of muramic acid derivatives
a
-halo carboxylic acid or its synthetic equivalent
-glucosamine molecule. The
D
Scheme 1. Synthesis of muramic acid, its analogues and derivatives via intermolecular 3-O-alkylation.
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051

S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
3
Fig. 1. The general structure of the protected derivative 1 designed for the synthesis of the derivatives of muramic acid or its analogues via intramolecular O-alkylation.
2. Results and discussion
12e14 were formed readily. These compounds were isolated in
high yields and characterized by 1H NMR, 13C NMR, and HRMS (see
Experimental). Interestingly, when NaH in 1,4-dioxane was used as
a base, the reaction proceeded in the same manner only in the case
of (R)-chloropropionyl and chloroacetyl derivatives 10 and 11,
whereas the intramolecular O-alkylation did not occur in the case
of the (S)-chloropropionyl derivative 9. Since dioxane is an aprotic
solvent with a low dielectric constant and does not promote
dissociation, this fact may indicate that cyclization of compound 9
proceeds via an ionic mechanism.
The known tetraacetate 2 [47] was used as a starting material for
the synthesis of compounds 9e11, the structures of which corre-
spond to the general structure 1 (Scheme 2).
Compound 2 was acylated with (R)-2-chloropropionic, (S)-2-
chloropropionic [48] or chloroacetic acid in the presence of N,N0-
dicyclohexylcarbodiimide, leading to the formation of the corre-
sponding N-acyl derivatives 3e5. NMR and HRMS data are in good
agreement with the structures of compounds 3e5 (see
Experimental).
A characteristic feature of the 13C NMR spectra of lactam de-
rivatives 12e14, as compared to the spectra of precursor acyclic N-
acyl derivatives, is a substantial downfield shift of the signal of
b-Benzyl glycosides 6e8 were synthesized by the reaction of
derivatives 3e5 with benzyl alcohol in the presence of SnCl4. The
1,2-trans configuration of the glycosidic linkage in these com-
pounds is indicated by the coupling constants J1,2 ¼ 8.2e8.4 Hz of
H-1 signals in the 1H NMR spectra. The glycoside derivatives 6e8
were then deacetylated with sodium methoxide in methanol and
the resulting triols were treated with 2,2-dimethoxypropane in the
presence of pyridinium perchlorate providing O-isopropylidene
derivatives 9e11. NMR and HRMS data are in good agreement with
the structures of compounds 9e11 (see Experimental).
carbon atom located at the
a-position to carbonyl group, as well as
the shift of the signal of C-3 of glucopyranose ring, that occurs
apparently due to the formation of d-lactam cycle involving oxygen
atom at C-3. In the 1H NMR spectra of lactams 12e14, a charac-
teristic signal of a proton of NH-group appears as a broad singlet
that is observed also in the 1H NMR spectra of lactam derivatives of
muramic acid obtained via intramolecular N-acylation [38,39].
However, in the spectra of acyclic N-acyl derivatives of D-glucos-
To perform the intramolecular O-alkylation in compounds 9e11,
the deprotonation of the unprotected hydroxyl at C-3 of glucopyr-
anose ring is required, which should lead to the nucleophilic attack
of the highly reactive alkoxide anion at the chloroalkyl moiety.
Derivatives 9e11 were deprotonated by the treatment with sodium
hydride in 1,4-dioxane or with potassium tert-butoxide in tert-butyl
alcohol at room temperature (Scheme 3).
amine, this signal usually appears as a doublet with a coupling
constant JNH,2 ¼ 6e9 Hz (see Experimental for instance). Appar-
ently, the change of the multiplicity of this signal is due to the
decrease of the coupling constant caused by the change of dihedral
angle H-C(2)-N-H as a result of the formation of the lactam ring.
Judging from the NMR data, the product of intramolecular O-
alkylation, which was obtained from both the (R)-derivative 10 and
the (S)-derivative 9 upon their treatment with an excess of t-BuOK
in tert-butyl alcohol under the same conditions, is a mixture of
We found that when compounds 9e11 reacted with t-BuOK in
the medium of tert-butyl alcohol at room temperature d-lactams
Scheme 2. Synthesis of N-acyl derivatives 9e11. Reagents and conditions: a RCOOH, RCOONa, DCC, CH3CN, r.t.; b BzlOH, SnCl4, CHCl3, r.t.; c CH3ONa, CH3OH, r.t.; d (CH3)2C(OCH3)2,
Py$HClO4, CH3CN, 80e82 ꢀC.
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051

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S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
Scheme 3. Synthesis of lactam derivatives 12e14*. Reagents and conditions: a (CH3)3COH, (CH3)3COK, r.t.; b NaH, DO, r.t. * The yields of lactam derivatives 12e14 are listed in
Table 1.
diastereomeric lactams 12 and 13. It was found that the same
diastereomer significantly predominates for both cases, regardless
of configuration of the starting compounds. The most substantial
differences between the NMR spectra of the major and minor di-
astereomers are observed for the chemical shifts of methine carbon
atoms in the lactyl moiety (73.3 ppm and 74.9 ppm, respectively)
and C-3 carbon atoms (70.5 ppm and 75.7 ppm, respectively), as
well as for the chemical shifts of methine protons of the lactyl
moiety (4.49 ppm and 4.29 ppm, respectively) and H-3 protons
(3.69 ppm and 3.59 ppm, respectively) (see Experimental).
peculiarities of stereoelectronic interactions in reactant molecules.
Indeed, due to the rigid planar structure of the amide function [49],
the number of conformations favorable for the intramolecular
interaction, i.e. such conformations in which the frontier orbitals of
the reaction centers are capable of efficient frontal overlap, is
limited. Fig. 4 shows the corresponding conformations of the
reactant molecules, in which the atomic orbital of nucleophilic
oxygen containing a lone pair, lies on the same line as the vacant
orbital of the electrophilic carbon atom (p-orbital in the case of SN1-
like process or s*-orbital in the case of SN2-like process).
To determine the configuration of the asymmetric center of the
lactyl moiety in the major diastereomer, the two-dimensional Nu-
clear Overhauser Effect Spectroscopy was used. In the NOESY
spectrum of this substance, there is a cross-peak between the H-3
of the glucopyranose ring and the methyl group of the lactyl moiety
while there is no cross-peak between the H-3 and the methine
proton of the lactyl moiety (see Fig. 2).
Considering that on the one hand, the glucopyranose cycle in
compounds 12e14 adopts the chair 4C1 conformation, judging from
the values of coupling constants J2,3; J3,4; J4,5 (9.3e10.0 Hz, see
If the (R)-chloropropionic acid derivative 10 reacts, the confor-
mation shown in Fig. 4 is easily achieved and the preferential
inversion of the configuration should take place as a result of the
reaction, regardless of the type of the mechanism of nucleophilic
substitution. If the asymmetric electrophilic center in the reagent
has the (S)-configuration, as in the case of derivative 9, the methyl
group of the lactyl moiety in the required conformation is brought
closer to the axial H-2 atom in the glucopyranose cycle, which
creates steric hindrance and does not promote the interaction.
As we assume, the intramolecular alkylation in the last case can
be performed via the mechanism of nucleophilic substitution with
the neighboring group participation. The neighboring amide
carbonyl, whose nucleophilicity increases significantly when the
amide function is deprotonated with an excess of the base, can
serve as such a group that promotes the cleavage of the nucleofuge
and stabilizes the ionic intermediate. The deprotonated amide
moiety is isoelectronic to carboxylate anion, and like it, appears to
be capable of anchimeric assistance in the nucleophilic substitution
at the neighboring carbon atom, resulting in the formation of a
Experimental), and on the other hand the trans-fused d-lactam
cycle, due to the planar structure of the amide group [49], adopts
the conformation which is intermediary between E3 and 0H3 [38],
the data obtained from the NOESY spectrum indicate the (S)-
configuration of the asymmetric center in the lactyl residue of the
major diastereomer (see Fig. 3).
The obtained lactam derivatives were further N-acylated and
subjected to methanolysis under mild conditions, resulting in the
formation of normuramic acid methyl ester 17 from lactam 14, and
the corresponding methyl ester derivatives of isomuramic and
muramic acids 15 and 16 were prepared from the mixtures of
diastereomeric lactams 12 and 13 (Scheme 4). The ratio between
the ester derivatives 15 and 16 was determined after complete
chromatographic separation and corresponded to the ratio be-
tween the diastereomeric lactams determined previously by 1H
NMR (see Table 1).
cyclic imidoester 19, which is isoelectronic to
a-lactone, arising
from the participation of the carboxylate anion [44e46] (Scheme 5,
path A). The intermediary imidoester 19, in turn, could be attacked
from the rear by the neighboring highly nucleophilic alkoxide
anion, which should result in the formation of d-lactam cycle and
regaining the initial configuration of the asymmetric center, which
is observed in fact.
Thus, cyclization of the (S)-chloropropionic acid derivative 9
occurring in the medium of tert-butyl alcohol in the presence of
potassium tert-butoxide leads to preferential retention of the
configuration in the lactam product, whereas a predominant
inversion of the configuration is observed in the case of the reaction
of the (R)-chloropropionic acid derivative 10 under the same con-
ditions, resulting in the formation of the same isomuramic acid
lactam derivative 12 as a major diastereomer.
It can not be ruled out that the stereochemical result of the
intramolecular nucleophilic substitution in compound
9 is
explained by the fact that the reaction proceeds via the SN1-like
mechanism without the participation of the amide carbonyl.
Indeed, in this case, the intermediary carbenium ion 20 (or loose
ion pair) can be attacked by the nucleophile at the position where
the leaving group was located prior to dissociation (Scheme 5, path
B), which also leads to the retention of the configuration.
In our opinion, these results can be explained considering the
However, it was found that the nucleophilic substitution in
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051

S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
5
Fig. 2. 2D NOESY spectrum for lactam 12 (400.39 MHz, (CD3)2SO). The correlation of CH3CH with H-3 is present and the correlation of CH3CH with H-3 is absent.
dielectric constant of this protic solvent is twice higher than that of
tert-butyl alcohol. This suggests that the “classical” or “limiting”
SN1 mechanism for this transformation is not realized. On the other
hand, the assumption of the required formation of the intermediary
cyclic imidoester 19 is supported by the fact that a large excess of
potassium tert-butoxide is necessary for the successful occurrence
of intramolecular nucleophilic substitution in the derivative 9, in
contrast to compound 10. When 2 equiv. of (CH3)3COK was used,
the reaction proceeded slowly and did not complete within 24 h,
while it was completed within 2 h in the presence of 5 equiv. of
(CH3)3COK, and further increase of the amount of the base does not
lead to a substantial acceleration of the reaction. Complete depro-
tonation of carbohydrate hydroxyls should occur when a much
lower excess of potassium tert-butoxide is used, since the proton
acidity of the secondary hydroxyl group of sugar is much greater
than the acidity of tert-butyl alcohol. However, the formation of
dianion 18, which is the precursor of the imidoester 19, should
occur in the presence of a large excess of a strong base.
Fig. 3. Correlations observed in the NOESY spectrum of compound 12.
compounds 9e11 does not occur at all in methanol in the presence
of the excess of sodium methoxide, despite the fact that the
It is possible to assume, that the mechanism of the stereocontrol
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051

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S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
Scheme 4. The synthesis of ester derivatives of isomuramic, muramic and normuramic acids 15e17 from lactams 12e14. Reagents and conditions: a AcCl, DIPEA, CH2Cl2, r.t.; b
CH3OH, r.t.; c CH3OH, Et3N r.t.
Table 1
The results of intramolecular nucleophilic substitution in derivatives 9e11 in the medium of (CH3)3COH in the presence of (CH3)3COK.
Compound
Overall yield of lactam derivatives
The ratio between diastereomeric lactam derivatives 12 and 13a
9
10
11
96%
98%
97%
14:1 (12:13)
25:1 (12:13)
e
a
It was determined by 1H NMR spectroscopy and corresponds to the ratio between the diastereomers 15 and 16 determined after complete chromatographic separation.
Fig. 4. Conformations providing the possibility of the frontal overlapping of the HOMO of the nucleophilic center and LUMO of the electrophilic center in the reactant molecules.
similar to the described one may occur in other intramolecular
nucleophilic substitution reactions, in particular, in intramolecular
glycosylation processes.
obtained d-lactam derivatives 12e14 were then converted to the
corresponding ester derivatives of these acids 15e17. It was found
that the intramolecular alkylation results mainly in the retention of
configuration if the asymmetric electrophilic center in the starting
compound has the (S)-configuration (compound 9), while in the
case of the (R)-configuration of this center (derivative 10), the
inversion of the configuration is mainly observed. Thus, the lactam
derivative of isomuramic acid 12 is formed predominantly in both
cases. This phenomenon is apparently explained by steric
In conclusion, we developed a new approach for the synthesis of
d
-lactam derivatives of isomuramic, muramic and normuramic
acids 12e14 via intramolecular nucleophilic substitution in N-
acylated -glucosamine derivatives 9e11 containing -halo car-
D
a
boxylic acid moieties. This approach allows preparing the title
compounds in high overall yields and under mild conditions. The
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051

S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
7
Scheme 5. Plausible mechanisms for the formation of isomuramic acid lactam 12 from compound 9 as a result of nucleophilic substitution with participation (A) and without
participation (B) of the neighboring group.
interactions that occur in carbohydrate derivatives in the course of
reaction, as well as the participation of the neighboring amide
group in the intramolecular nucleophilic substitution.
plates up to ~200 ꢀC. Column chromatography was carried out on
Silica Gel 60 (Fluka 220e448 mesh). 1H and 13C NMR spectra were
recorded on a Bruker Avance 500 spectrometer (499.95 and
125.71 MHz, respectively), or a Bruker Avance 400 spectrometer
(400.08 and 100.61 MHz, respectively). Tetramethylsilane (1H
NMR:
d
¼ 0.00 ppm) and CHCl3 (13C NMR:
¼ 77.16 ppm) were used
d
3. Experimental
as internal standards for 1H and 13C NMR spectra. The assignment
of the signals in NMR spectra was carried out using APT, COSY,
NOESY and HETCOR experiments. Optical rotation was measured
using a Polamat A polarimeter (Carl Zeiss, Jena). Melting points
were determined in capillaries and are uncorrected. High-
resolution mass spectra (HRMS) were recorded using a Bruker
micrOTOF II mass spectrometer in the positive mode (electrospray
ionization) at a concentration of 2$10ꢁ5 mol Lꢁ1 in MeCN.
3.1. General
Commercially available reagents were purchased from Sigma-
Aldrich or Fluka and used without further purification unless
otherwise indicated. 1,4-Dioxane and 2,2-dimethoxypropane were
purified by refluxing over metallic sodium followed by distillation.
Methanol and tert-butyl alcohol were dried by refluxing over
magnesium powder and over sodium wire correspondingly until
the metal had dissolved, then distilled. Chloroform, dichloro-
methane and acetonitrile were distilled over P2O5. Benzyl alcohol,
acetyl chloride and tin tetrachloride were distilled immediately
prior to use. (S)-2-Chloropropionic and (R)-2-chloropropionic acids
were synthesized according to the described procedure [48]. So-
3.2. General procedure for N-acylation of 1,3,4,6-tetra-O-acetyl-2-
amino-2-deoxy-b-D-glucopyranose (2)
To 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-
hydrochloride 2 [47] (499 mg, 1.30 mmol) were added anhydrous
CH3CN (5 mL), the corresponding -halo carboxylic acid
b-D-glucopyranose
dium salts of a-halo carboxylic acids were obtained by neutralizing
a 20% aqueous solution of the corresponding acid with an equiva-
lent amount of sodium carbonate; the resulting solution was
concentrated in vacuo and the crystalline precipitate was filtered off
and dried in vacuo over P2O5. Molecular sieves (4 Å) were activated
in vacuo at 320 ꢀC for 3 h. Pyridinium perchlorate was prepared
according to the reported procedure [50] and stored over P2O5.
Pyridinium p-toluenesulfonate was recrystallized from chloroform/
diethyl ether and stored over P2O5. All reactions were monitored by
thin-layer chromatography (TLC) performed on silica gel STH-1A-
coated aluminum foil (Sorbpolimer, Russian Federation). The
compositions of the solvent mixtures are given in volume ratios.
The spots of the separated compounds were detected by exposure
of TLC plates to chlorosulfonic acid vapor for 5 min at room or
slightly elevated temperature (~35e45 ꢀC), followed by heating the
a
(0.13 mmol, 0.1 equiv.) and sodium salt of this acid (1.30 mmol, 1.0
equiv.). Then N,N0-dicyclohexylcarbodiimide (DCC) (322 mg,
1.56 mmol, 1.2 equiv.) was added to the resulting mixture in four
portions (sequential portions of 125 mg, 100 mg, 57 mg, 40 mg) at
30 min intervals. The reaction mixture was then stirred for 8 h. The
reaction progress was monitored by TLC in chloroform-ethanol (10:
0.5). After 16 h, the precipitate was filtered off and washed with
chloroform (3 ꢂ 5 mL). The filtrate and washings were evaporated
in vacuo. The resulting dry residue was dissolved in chloroform-
diethyl ether (2: 1) (6 mL) and the solution was cooled to ~ 4 ꢀC.
After 24 h, the precipitate formed was filtered off and the filtrate
was evaporated in vacuo. The dry residue was chromatographed on
a column of silica gel, eluting with chloroform-ethanol (100:
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
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S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
0 / 100: 1). The products were crystallized from chloroform-
diethyl ether.
chloroform-ethanol (10: 0.5). After completion of the reaction, a
saturated aqueous solution of sodium hydrogencarbonate (7 mL)
was added to the mixture with stirring. After 15 min, the aqueous
layer was separated and washed twice with an equal volume of
chloroform. The combined organic phase was dried over anhydrous
sodium sulfate and evaporated in vacuo. The dry residue was
3.2.1. 1,3,4,6-Tetra-O-acetyl-2-[(S)-2-chloroprpopionylamino]-2-
deoxy-b-D-glucopyranose (3)
Compound 3 was obtained according to the general procedure
using (S)-2-chloropropionic acid as acylating agent. Yield: 398 mg
chromatographed on a column of silica gel, eluting with
chloroform-ethanol 100: 0 / 100: 1. The products were crystal-
lized from chloroform-diethyl ether.
24
(70%). Colorless crystals, mp 173.5e174.5ꢀС. ½
a
ꢃ
þ5.9ꢀ (с 4.0,
546
СHCl3). 1Н NMR (499.95 MHz, CDCl3):
d
6.74 (d, J ¼ 9.3 Hz, 1H, NH),
5.80 (d, J ¼ 8.7 Hz, 1H, H-1), 5.32 (dd, J ¼ 10.5, 9.6 Hz, 1H, H-3), 5.12
(t, J ¼ 9.6 Hz, 1H, H-4), 4.31 (q, J ¼ 7.0 Hz, 1H, CHCH3), 4.29e4.19 (m,
2H, H-6a þ H-2), 4.13 (dd, J ¼ 12.4, 2.0 Hz, 1H, H-6b), 3.86 (ddd,
J ¼ 9.6, 4.7, 2.0 Hz, 1H, H-5), 2.09, 2.08, 2.04, 2.03 (4 ꢂ s, 12H,
4 ꢂ CH3СО), 1.64 (d, J ¼ 7.0 Hz, 3H, CHCH3). 13C NMR (125.71 MHz,
3.3.1. Benzyl 3,4,6-tri-O-acetyl-2-[(S)-2-chloroprpopionylamino]-
2-deoxy-b-D-glucopyranoside (6)
Compound 6 was obtained from tetraacetate 3 according to the
general procedure. Yield: 454 mg (82%). Colorless crystals, mp
22
CDCl3):
d
171.1 (C]O), 170.8 (C]O), 170.2 (C]O), 169.5 (C]O),
177.5e178ꢀС; ½
aꢃ
ꢁ56.0ꢀ (с 4.0, СHCl3). 1Н NMR (499.95 MHz,
546
169.4 (C]O), 92.4 (C-1), 73.1 (C-3), 71.9 (C-4), 68.1 (C-5), 61.8 (C-6),
55.4 (C-2), 53.4 (CHCl), 22.6 (CH3CHCl), 20.9 (CH3CO), 20,8 (CH3CO),
20.7 (2C, CH3CO). HRMS (ESI): m/z calcd for C17H24ClNNaO10
[MþNa]þ, 460.0986, found: m/z 460.0981.
CDCl3):
d
7.39e7.27 (m, 5 H, Ph), 6.52 (d, J ¼ 8.5 Hz, 1H, NH), 5.32 (br
t, J ¼ 9.7 Hz,1H, H-3), 5.10 (t, J ¼ 9.7 Hz, 1H, H-4), 4.89 (d, J ¼ 12.1 Hz,
1H, PhCHa), 4.73 (d, J ¼ 8.2 Hz, 1H, H-1), 4.60 (d, J ¼ 12.1 Hz, 1H,
PhCHb), 4.30 (q, J ¼ 6.9 Hz,1H, CHCH3), 4.29 (dd, J ¼ 12.0, 4.5 Hz,1H,
H-6a), 4.18 (dd, J ¼ 12.0, 1.9 Hz, 1H, H-6b), 3.91 (br q, J ¼ 8.8 Hz, 1H,
H-2), 3.69 (ddd, J ¼ 9.7, 4.5, 1.9 Hz, 1H, H-5), 2.11, 2.02, 2.01 (3 ꢂ s,
9H, 3 ꢂ CH3СО), 1.66 (d, J ¼ 6.9 Hz, 3H, CHCH3). 13C NMR
3.2.2. 1,3,4,6-Tetra-O-acetyl-2-[(R)-2-chloroprpopionylamino]-2-
deoxy-b-D-glucopyranose (4)
Compound 4 was obtained according to the general procedure
(125.71 MHz, CDCl3): d 170.9 (C]O), 170.7 (C]O), 170.0 (C]O),
using (R)-2-chloropropionic acid as acylating agent. Yield: 364 mg
169.6 (C]O), 136.8 (C, Ph), 128.7 (2 ꢂ CH, Ph), 128.3 (CH, Ph), 128.1
(2 ꢂ CH, Ph), 99.2 (C-1), 72.1 (C-3), 71.8 (C-4), 70.9 (PhCH2), 68.7 (C-
5), 62.2 (C-6), 55.8 (C-2), 55.2 (CHCl), 22.8 (CH3CHCl), 20.9 (CH3CO),
20,8 (CH3CO), 20.7 (CH3CO). HRMS (ESI): m/z calcd for
24
(64%). Colorless crystals, mp 183.5e184.5ꢀС. ½
a
ꢃ
þ15.1ꢀ (с 4.0,
546
СHCl3). 1Н NMR (499.95 MHz, CDCl3):
d
6.65 (d, J ¼ 9.3 Hz, 1H, NH),
5.79 (d, J ¼ 8.7 Hz, 1H, H-1), 5.29 (br t, J ¼ 9.6 Hz, 1H, H-3), 5.13 (t,
J ¼ 9.6 Hz, 1H, H-4), 4.33 (q, J ¼ 7.0 Hz, 1H, CHCH3), 4.30e4.21 (m,
2H, H-6a þ H-2), 4.13 (dd, J ¼ 12.4, 2.0 Hz, 1H, H-6b), 3.85 (ddd,
J ¼ 9.6, 4.6, 2.0 Hz, 1H, H-5), 2.11, 2.09, 2.05, 2.03 (4 ꢂ s, 12H,
4 ꢂ CH3СО), 1.64 (d, J ¼ 7.0 Hz, 3H, CHCH3). 13C NMR (125.71 MHz,
C
22H28ClNNaO9 [MþNa]þ, 508.1350, found: m/z 508.1345.
3.3.2. Benzyl 3,4,6-tri-O-acetyl-2-[(R)-2-chloroprpopionylamino]-
2-deoxy- -D-glucopyranoside (7)
b
CDCl3):
d
171.1 (C]O), 170.8 (C]O), 170.1 (C]O), 169.5 (C]O),
Compound 7 was obtained from tetraacetate 4 according to the
169.4 (C]O), 92.2 (C-1), 73.1 (C-3), 72.3 (C-4), 68.0 (C-5), 61.8 (C-6),
55.3 (C-2), 53.4 (CHCl), 22.4 (CH3CHCl), 21.0 (CH3CO), 20,9 (CH3CO),
20.7 (CH3CO), 20.7 (CH3CO). HRMS (ESI): m/z calcd for
general procedure. Yield: 393 mg (71%). Colorless crystals, mp
22
182.5e183ꢀС; ½
aꢃ
ꢁ47.8ꢀ (с 4.0, СHCl3). 1Н NMR (400.08 MHz,
546
CDCl3):
d
7.37e7.26 (m, 5 H, Ph), 6.46 (d, J ¼ 8.9 Hz, 1H, NH), 5.24
C
17H24ClNNaO10 [MþNa]þ, 460.0986, found: m/z 460.0981.
(dd, J ¼ 9.4, 10.5 Hz, 1H, H-3), 5.10 (br t, J ¼ 9.6 Hz, 1H, H-4), 4.89 (d,
J ¼ 12.3 Hz, 1H, PhCHa), 4.67 (d, J ¼ 8.4 Hz, 1H, H-1), 4.62 (d,
J ¼ 12.3 Hz, 1H, PhCHb), 4.35 (q, J ¼ 7.0 Hz, 1H, CHCH3), 4.29 (dd,
J ¼ 12.3, 4.8 Hz, 1H, H-6a), 4.18 (dd, J ¼ 12.3, 2.5 Hz, 1H, H-6b), 3.99
(br dt, J ¼ 8.6, 10.5 Hz, 1H, H-2), 3.67 (ddd, J ¼ 9.8, 4.8, 2.5 Hz, 1H, H-
5), 2.11, 2.01, 2.00 (3 ꢂ s, 9H, 3 ꢂ CH3СО), 1.65 (d, J ¼ 7.0 Hz, 3H,
3.2.3. 1,3,4,6-Tetra-O-acetyl-2-(chloroacetylylamino)-2-deoxy-b-D-
glucopyranose (5)
Compound 5 was obtained according to the general procedure
using chloroacetic acid as acylating agent. Yield: 512 mg (93%).
22
Colorless crystals, mp 170e171ꢀС. ½
a
ꢃ
þ16.4ꢀ (с 4.0, СHCl3) (Lit
CHCH3). 13C NMR (125.71 MHz, CDCl3):
d 170.9 (C]O), 170.8 (C]O),
546
25
[51]. mp 171e172ꢀС. ½a D25
ꢃ
þ12ꢀ, ½
aꢃ
þ23ꢀ (с 0.5, СHCl3)). 1Н NMR
169.9 (C]O), 169.5 (C]O), 136.7 (C, Ph), 128.7 (2 ꢂ CH, Ph), 128.3
(CH, Ph), 128.2 (2 ꢂ CH, Ph), 98.9 (C-1), 72.2 (C-3), 72.1 (C-4), 70.8
(PhCH2), 68.6 (C-5), 62.2 (C-6), 55.7 (C-2), 55.0 (CHCl), 22.6
(CH3CHCl), 20.9 (CH3CO), 20,8 (CH3CO), 20.7 (CH3CO). HRMS (ESI):
m/z calcd for C22H28ClNNaO9 [MþNa]þ, 508.1350, found: m/z
508.1345.
436
(499.95 MHz, CDCl3):
d
6.68 (d, J ¼ 8.9 Hz, 1H, NH), 5.81 (d,
J ¼ 8.6 Hz, 1H, H-1), 5.29 (br t, J ¼ 9.3 Hz, 1H, H-3), 5.13 (t, J ¼ 9.3 Hz,
1H, H-4), 4.28 (dd, J ¼ 12.6, 4.4 Hz, 1H, H-6a), 4.23 (br q, J ¼ 9.1 Hz,
1H, H-2), 4.13 (dd, J ¼ 12.6, 2.1 Hz, 1H, H-6b), 3.98 (br s, 2H, CH2Cl),
3.85 (ddd, J ¼ 9.3, 4.4, 2.1 Hz, 1H, H-5), 2.11, 2.09, 2.05, 2.04 (4 ꢂ s,
12H, 4 ꢂ CH3СО). 13C NMR (125.71 MHz, CDCl3):
d 170.7 (C]O),
170.5 (C]O), 169.1 (C]O), 169.1 (C]O), 166.4 (C]O), 92.3 (C-1),
73.1 (C-3), 72.1 (C-4), 67.9 (C-5), 61.8 (C-6), 53.6 (C-2), 42.5 (CH2Cl),
21.0 (CH3CO), 20,9 (CH3CO), 20.7 (2C, CH3CO); HRMS (ESI): m/z
3.3.3. Benzyl 3,4,6-tri-O-acetyl-2-(chloroacetylylamino)-2-deoxy-
b-D-glucopyranoside (8)
Compound 8 was obtained from tetraacetate 5 according to the
general procedure. Yield: 436 mg (81%). Colorless crystals, mp
calcd for
446.0824.
C
16H22ClNNaO10 [MþNa]þ, 446.0830, found: m/z
22
190e190.5ꢀС. ½
aꢃ
ꢁ55.0ꢀ (с 4.0, СHCl3). 1Н NMR (499.95 MHz,
546
CDCl3):
d
7.38e7.27 (m, 5 H, Ph), 6.55 (d, J ¼ 8.5 Hz, 1H, NH), 5.29 (br
3.3. General procedure for the synthesis of 1,2-trans benzyl
glycoside derivatives 6e8
t, J ¼ 10.0 Hz, 1H, H-3), 5.10 (t, J ¼ 9.5 Hz, 1H, H-4), 4.90 (d,
J ¼ 12.2 Hz, 1H, PhCHa), 4.71 (d, J ¼ 8.2 Hz, 1H, H-1), 4.61 (d,
J ¼ 12.2 Hz,1H, PhCHb), 4.29 (dd, J ¼ 12.1, 4.6 Hz,1H, H-6a), 4.18 (dd,
J ¼ 12.1, 2.0 Hz, 1H, H-6b), 4.02e3.89 (m, 3H, CH2Cl þ H-2), 3.69
(ddd, J ¼ 9.5, 4.6, 2.0 Hz, 1H, H-5), 2.11, 2.02, 2.01 (3 ꢂ s, 9H,
Benzyl alcohol (247 mg, 2.28 mmol, 2 equiv.) was added to the
solution of the corresponding 1,3,4,6-tetra-O-acetyl-2-deoxy-2-
(acylamino)-
b
-D-glucopyranose (1.14 mmol) in anhydrous chloro-
3 ꢂ CH3СО). 13C NMR (125.71 MHz, CDCl3):
d 170.8 (C]O), 170.8
form (28 mL). The resulting solution was concentrated to half its
volume and cooled to room temperature. Then tin tetrachloride
(89 mg, 0.34 mmol) was added and the reaction mixture was stirred
for 2.5 h. The reaction progress was monitored by TLC in
(C]O), 169.5 (C]O), 166.4 (C]O), 144.8 (C, Ph), 128.7 (2 ꢂ CH, Ph),
128.3 (CH, Ph), 128.2 (2 ꢂ CH, Ph), 99.0 (C-1), 72.1 (C-3), 72.0 (C-4),
70.9 (PhCH2), 68.7 (C-5), 62.2 (C-6), 55.1 (C-2), 42.6 (CH2Cl), 20.9
(CH3CO), 20.7 (2 C, 2 ꢂ CH3CO); HRMS (ESI): m/z calcd for
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051

S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
9
C21H26ClNNaO9 [MþNa]þ, 494.1194, found: m/z 494.1188.
1H, NH), 4.87 (d, J ¼ 12.1 Hz, 1H, PhCHa), 4.63 (d, J ¼ 8.3 Hz, 1H, H-
1), 4.59 (d, J ¼ 12.1 Hz, 1H, PhCHb), 4.03 (d, J ¼ 15.5 Hz, 1H, CHaCl),
3.99 (d, J ¼ 15.5 Hz, 1H, CHbCl), 3.96 (dd, J ¼ 10.7, 5.4 Hz, 1H, H-6a),
3.91 (t, J ¼ 9.4 Hz, 1H, H-3), 3.83 (t, J ¼ 10.7 Hz, 1H, H-6b), 3.67e3.58
(m, 2H, H-2 þ H-4), 3.29 (dt, J ¼ 10.0, 5.4 Hz, 1H, H-5), 1.52, 1.43
3.4. General procedure for the synthesis of 4,6-O-isopropylidene
derivatives 9e11
To the solution of the corresponding
b
-benzyl glycoside deriv-
(2 ꢂ s, 6H, 2 ꢂ CH3С). 13C NMR (100.61 MHz, CDCl3):
d 167.2 (C]O),
ative (0.62 mmol) in absolute methanol (16 mL) was added a 1 M
solution of sodium methoxide in methanol until a pH of 8e9 was
reached. The mixture was kept at room temperature and the re-
action progress was monitored by TLC in chloroform-methanol (10:
2). After completion of the reaction (~12 h), the mixture was
neutralized with acetic acid to pH ~ 6 and the solvent was evapo-
rated in vacuo. Then acetonitrile (6 mL), 2,2-dimethoxypropane
(257 mg, 2.47 mmol, 4 equiv.) and pyridinium p-toluenesulfonate
(60 mg, 0.24 mmol) were added to the dry residue. The reaction
mixture was refluxed until the precipitate was completely dis-
solved. The progress of the reaction was monitored by TLC in
chloroform-ethanol (10: 0.5). After completion of the reaction,
triethylamine (30 mg, 0.30 mmol) was added to the mixture and
the solution was evaporated in vacuo. The dry residue was chro-
matographed on a column of silica gel, eluting with chloroform-
ethanol 100: 0 / 100: 2. The products were crystallized from
chloroform-diethyl ether.
136.6 (C, Ph), 128.7 (2 ꢂ CH, Ph), 128.3 (CH, Ph), 128.3 (2 ꢂ CH, Ph),
100.0 (C(CH3)2)), 99.2 (C-1), 74.3 (C-4), 71.6 (C-3), 71.0 (PhCH2), 67.4
(C-5), 62.1 (C-6), 58.9 (C-2), 42.8 (CH2Cl), 29.2 (CH3C), 19.2 (CH3C).
HRMS (ESI): m/z calcd for C18H24ClNNaO6 [MþNa]þ, 408.1190,
found: m/z 408.1184.
3.5. General procedure for the synthesis of d-lactam derivatives
12e14
Mode
derivative (0.75 mmol) in absolute tert-butyl alcohol (14 mL) was
added a 0.5 solution of potassium tert-butoxide (9 mL, 4.5 mmol,
А To a solution of the corresponding 4,6-O-isopropylidene
М
6 equiv.) in tert-butyl alcohol. The reaction mixture was stirred at
room temperature. The progress of the reaction was monitored by
TLC in chloroform-ethanol (10: 0.35). After completion of the re-
action (2.5e3 h),1 a solution of pyridinium perchlorate (673 mg,
3.75 mmol, 5 equiv.) in methanol (7 mL) was added to the reaction
mixture. The precipitate was filtered off and washed on the filter
with tert-butyl alcohol (3 ꢂ 3 mL). The filtrate and washings were
evaporated in vacuo. The dry residue was chromatographed on a
column of silica gel, eluting with chloroform-ethanol 100: 0 / 100:
2.
Mode B To a solution of the corresponding 4,6-O-isopropylidene
derivative (0.75 mmol) in absolute 1,4-dioxane (14 mL) was added
sodium hydride (4.5 mmol, 6 equiv., 180 mg of 60% dispersion in
mineral oil). The reaction mixture was stirred at room temperature.
The progress of the reaction was monitored by TLC in chloroform-
ethanol (10: 0.35). After completion of the reaction (2.5e3 h), the
reaction mixture was quenched with methanol (3 mL) and a solu-
tion of pyridinium perchlorate (673 mg, 3.75 mmol, 5 equiv.) in
methanol (7 mL) was added. The formed precipitate was filtered off
and washed on the filter with 1,4-dioxane (3 ꢂ 3 mL). The filtrate
and washings were evaporated in vacuo. The dry residue was
3.4.1. Benzyl 2-[(S)-2-chloroprpopionylamino]-2-deoxy-4,6-O-
isopropylidene-b-D-glucopyranoside (9)
Compound 9 was obtained from benzyl glycoside 6 according to
the general procedure. Yield: 198 mg (80%). Colorless crystals, mp
28
189e190ꢀС; ½
a
ꢃ
ꢁ108.5ꢀ (с 4.0, СHCl3); 1Н NMR (400.08 MHz,
546
CDCl3):
d
7.40e7.27 (m, 5 H, Ph), 6.73 (br d, J ¼ 6.6 Hz, 1H, NH), 4.87
(d, J ¼ 12.0 Hz, 1H, PhCHa), 4.63 (d, J ¼ 8.3 Hz, 1H, H-1), 4.59 (d,
J ¼ 12.0 Hz, 1H, PhCHb), 4.38 (q, J ¼ 7.0 Hz, 1H, CHCH3), 3.96 (dd,
J ¼ 10.8, 5.4 Hz, 1H, H-6a), 3.88 (t, J ¼ 9.4 Hz, 1H, H-3), 3.83 (br t,
J ¼ 10.6, 1H, H-6b), 3.67e3.58 (m, 2H, H-2 þ H-4), 3.29 (dt, J ¼ 9.9,
5.4 Hz, 1H, H-5), 1.69 (d, J ¼ 7.0 Hz, 3H, CHCH3), 1.52, 1.43 (2 ꢂ s, 6H,
2 ꢂ CH3С). 13C NMR (100.61 MHz, CDCl3):
d 170.7 (C]O), 136.7 (C,
Ph), 128.7 (2 ꢂ CH, Ph), 128.3 (CH, Ph), 128.2 (2 ꢂ CH, Ph), 100.0
(C(CH3)2)), 99.4 (C-1), 74.4 (C-4), 71.7 (C-3), 71.0 (PhCH2), 67.4 (C-5),
62.1 (C-6), 58.8 (C-2), 56.0 (CHCl), 29.2 (CH3C), 22.7 (CH3CH), 19.3
(CH3C). HRMS (ESI): m/z calcd for C19H26ClNNaO6 [MþNa]þ,
422.1346, found: m/z 422.1341.
chromatographed on
a column of silica gel, eluting with
chloroform-ethanol 100: 0 / 100: 2.
3.4.2. Benzyl 2-[(R)-2-chloroprpopionylamino]-2-deoxy-4,6-O-
isopropylidene-b-D-glucopyranoside (10)
Compound 10 was obtained from benzyl glycoside 7 according
to the general procedure. Yield: 206 mg (83%). Colorless crystals,
3.5.1. Benzyl 2-amino-3-O-[(S)-1-carboxyethyl]-2-deoxy-4,6-O-
isopropylidene-b
-D-glucopyranoside 10,2-lactam (12) and benzyl 2-
amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-4,6-O-isopropylidene-b-
D-glucopyranoside 10,2-lactam (13)
Compounds 12 and 13 were obtained from 4,6-O-iso-
propylidene derivatives 9 or 10 according to the mode A of the
general procedure.
28
mp 191e192ꢀС; ½
aꢃ
ꢁ82.3ꢀ (с 4.0, СHCl3). 1Н NMR (400.08 MHz,
546
CDCl3):
d
7.40e7.27 (m, 5 H, Ph), 6.78 (br d, 1H, J ¼ 5.5 Hz, NH), 4.87
(d, 1H, J ¼ 11.7 Hz, PhCHa), 4.63 (d, 1H, J ¼ 8.1 Hz, H-1), 4.60 (d,
J ¼ 11.7 Hz, 1H, PhCHb), 4.40 (q, 1H, J ¼ 6.8 Hz, CHCH3), 4.02e3.90
(m, 2H, H-6a þ H-3), 3.83 (t, 1H, J ¼ 10.3, H-6b), 3.65e3.53 (m, 2H,
H-4 þ H-2), 3.30 (dt, 1H, J ¼ 5.2 Hz, J ¼ 9.7 Hz, H-5), 1.69 (d,
J ¼ 6.8 Hz, 3H, CHCH3), 1.53, 1.43 (2 ꢂ s, 6H, 2 ꢂ CH3С); 13C NMR
When derivative 9 was used, the overall yield of diastereomeric
26
lactams 12 and132 was 262 mg (96%). ½
aꢃ
ꢁ99.8ꢀ (с 1.7, СH3OH).
546
The ratio between lactam derivatives 12 and 13, determined ac-
cording to 1H NMR, was 14:1 (12:13).
(100.61 MHz, CDCl3):
d 170.9 (C]O), 136.6 (C, Ar), 128.7 (2 C, CH,
When derivative 10 was used, the overall yield of diastereomeric
Ar), 128.3 (3 C, CH, Ar), 100.0 (C(CH3)2)), 99.2 (C-1), 74.4 (C-4), 71.6
(C-3), 71.1 (PhCH2), 67.4 (C-5), 62.1 (C-6), 59.0 (C-2), 56.0 (CHCl),
29.2 (CH3C), 22.9 (CH3CH), 19.2 (CH3C); HRMS (ESI): m/z calcd for
25
lactams 12 and 13 was 267 mg (98%); ½
aꢃ
ꢁ109.0ꢀ (с 2.7, СH3OH).
546
The ratio between lactam derivatives 12 and 13, determined ac-
cording to 1H NMR, was 25:1 (12:13).
C
19H26ClNNaO6 [MþNa]þ, 422.1346, found: m/z 422.1341.
3.4.3. Benzyl 2-(chloroacetylamino)-2-deoxy-4,6-O-
isopropylidene- -D-glucopyranoside (11)
1
An increase of the interaction period leads to the change of the ratio between
b
the diastereomeric lactams due to their racemization in the strongly basic medium
in the presence of excess of potassium tert-butoxide. According to the NMR data,
the racemization process was completed approximately for 30 h.
Compound 11 was obtained from benzyl glycoside 8 according
to the general procedure. Yield: 189 mg (79%). Colorless crystals,
28
mp 190e190.5ꢀС.
(400.08 MHz, CDCl3):
½
a
ꢃ
ꢁ108.3ꢀ (с 4.0, СHCl3). 1Н NMR
2
Diastereomers 12 and 13 were not separated by column chromatography used
546
d
7.40e7.27 (m, 5 H, Ph), 6.72 (br d, J ¼ 6.6 Hz,
in this work.
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051

10
S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
The mode B of the general procedure was also used for the
synthesis of compounds 12 and 13 from 4,6-O-isopropylidene de-
rivative 10. The overall yield of diastereomeric lactams 12 and 13
the case of normuramic acid derivative, triethylamine (72 mg,
0.7 mmol) was additionally added to the methanol solution. After
completion of methanolysis (~3 h), the solvent was evaporated in
vacuo. The dry residue was chromatographed on a column of silica
gel, eluting with chloroform-ethanol 100: 0 / 100: 2. The product
was crystallized from diethyl ether.
25
was 215 mg (79%); ½
aꢃ
ꢁ111.5ꢀ (с 2.0, СH3OH).
546
Spectral data of compound 12: 1Н NMR (400.08 MHz, CDCl3):
7.43e7.30 (m, 5 H, Ph), 6.04 (s, 1H, NH), 4.90 (d, J ¼ 11.4 Hz, 1H,
d
PhCHa), 4.57 (d, J ¼ 11.4 Hz, 1H, PhCHb), 4.49 (q, J ¼ 7.2 Hz, 1H,
CHCH3), 4.45 (d, J ¼ 8.2 Hz,1H, H-1), 3.98 (dd, J ¼ 10.8, 5.4 Hz,1H, H-
6a), 3.89 (br t, J ¼ 10.7 Hz, 1H, H-6b), 3.81 (t, J ¼ 9.2 Hz, 1H, H-4),
3.69 (t, J ¼ 9.2 Hz, 1H, H-3), 3.42e3.33 (m, 2H, H-5 þ H-2), 1.55 (s,
3H, CH3С), 1.53 (d, J ¼ 7.2 Hz, 3H, CHCH3), 1.45 (s, 3H, CH3С). 13C
3.6.1. Benzyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-3-O-[(S)-
1-(methoxycarbonyl)ethyl]-
acetamido-2-deoxy-4,6-O-isopropylidene-3-O-[(R)-1-
(methoxycarbonyl)ethyl]- -D-glucopyranoside (16)
b-D-glucopyranoside (15) and benzyl 2-
b
NMR (100.61 MHz, CDCl3):
d
171.5 (C]O), 136.0 (C, Ph), 128.8
Compounds 15 and 16 were obtained from the mixture of dia-
stereomeric lactams 12 and 13 according to the general procedure.
When using the mixture of lactams obtained from isopropylidene
derivative 9 according to the Mode A (see 4.5.1.), the overall yield of
esters 15 and 16 was 219 mg (91%), the diastereomeric ratio was 14:
1 (15: 16). When using the diastereomeric mixture obtained from
the isopropylidene derivative 10 according to the Mode A (see
4.5.1.), the overall yield of esters 15 and 16 was 224 mg (93%), the
diastereomeric ratio was 25: 1 (15: 16).
(2 ꢂ CH, Ph), 128.6 (CH, Ph), 128.4 (2 ꢂ CH, Ph), 100.3 (C(CH3)2)),
99.7 (C-1), 73.3 (CHCH3), 71.5 (PhCH2), 71.2 (C-4), 70.5 (C-3), 69.2
(C-5), 62.1 (C-6), 57.4 (C-2), 29.1 (CH3C), 19.2 (CH3C), 17.4 (CH3CH);
HRMS (ESI): m/z calcd for C19H26NO6 [MþH]þ, 364.1760, found: m/z
364.1755.
Spectral data of compound 13: 1Н NMR (400.08 MHz, CDCl3):
d
7.44e7.29 (m, 5 H, Ph), 6.02 (s, 1H, NH), 4.89 (d, J ¼ 11.3 Hz, 1H,
PhCHa), 4.56 (d, J ¼ 11.3 Hz, 1H, PhCHb), 4.45 (d, J ¼ 8.2 Hz, 1H, H-1),
4.29 (q, J ¼ 6.9 Hz, 1H, CHCH3), 3.97 (dd, J ¼ 10.8, 5.4 Hz, 1H, H-6a),
3.89 (t, J ¼ 10.8 Hz, 1H, H-6b), 3.83 (t, J ¼ 9.3 Hz, 1H, H-4), 3.59 (t,
J ¼ 9.3 Hz, 1H, H-3), 3.41e3.32 (m, 2H, H-5 þ H-2), 1.54 (s, 3H,
CH3С), 1.50 (d, J ¼ 6.9 Hz, 3H, CHCH3), 1.46 (s, 3H, CH3С). 13C NMR
Analytical data for compound 15: Colorless crystals, mp
24
151.5e152ꢀС; ½
aꢃ
ꢁ73.2ꢀ (с 1.5, СHCl3). 1Н NMR (400.08 MHz,
546
CDCl3):
d
7.35e7.27 (m, 5 H, Ph), 5.98 (br d, J ¼ 7.1 Hz, 1H, NH), 5.16
(d, J ¼ 8.2 Hz, 1H, H-1), 4.83 (d, J ¼ 11.8 Hz, 1H, PhCHa), 4.54 (d,
J ¼ 11.8 Hz, 1H, PhCHb), 4.26 (dd, J ¼ 10.1, 8.9 Hz, 1H, H-3), 4.19 (q,
J ¼ 6.9 Hz, 1H, CHCH3), 3.91 (dd, J ¼ 10.6, 5.3 Hz, 1H, H-6a), 3.76 (t,
J ¼ 10.6 Hz,1H, H-6b), 3.69 (s, 3H, CH3O), 3.60 (br t, J ¼ 9.1 Hz,1H, H-
4), 3.32 (br dt, J ¼ 10.0, 5.3 Hz, 1H, H-5), 3.09 (ddd, J ¼ 10.1, 8.2,
7.1 Hz, 1H, H-2), 1.90 (s, 3H, CH3СO), 1.41 (s, 3H, CH3С), 1.31 (s, 3H,
CH3С), 1.27 (d, J ¼ 6.9 Hz, 3H, CHCH3). 13C NMR (100.61 MHz,
(100.61 MHz, CDCl3):
d
171.2 (C]O), 136.0 (C, Ph), 128.8 (2 ꢂ CH,
Ph), 128.6 (CH, Ph), 128.4 (2 ꢂ CH, Ph), 100.3 (C(CH3)2)), 99.8 (C-1),
75.7 (C-3), 74.9 (CHCH3), 71.5 (PhCH2), 71.4 (C-4), 69.1 (C-5), 62.1
(C-6), 57.4 (C-2), 29.2 (CH3C), 19.3 (CH3C), 17.7 (CH3CH); HRMS
(ESI): m/z calcd for C19H26NO6 [MþH]þ, 364.1760, found: m/z
364.1755.
CDCl3):
d
173.9 (C]O),170.5 (C]O),137.3 (C, Ph),128.5 (2 ꢂ CH, Ph),
3.5.2. Benzyl 2-amino-3-O-carboxymethyl-2-deoxy-4,6-O-
isopropylidene-b
-D-glucopyranoside 10,2-lactam (14)
Compound 14 was obtained from 4,6-O-isopropylidene deriva-
tive 11 according to the Mode A or Mode B of the general procedure.
The product was crystallized from diethyl ether-hexane. The yield
of compound 14 was 254 mg (97%), when Mode A was used, and
128.1 (2 ꢂ CH, Ph), 128.0 (CH, Ph), 99.3 (C(CH3)2)), 99.3 (C-1), 77.6
(C-3), 76.5 (CHCH3), 75.1 (C-4), 71.7 (PhCH2), 66.7 (C-5), 62.2 (C-6),
58.4 (C-2), 51.8 (CH3O), 29.2 (CH3C), 23.7 (CH3СO), 19.5 (CH3CH),
18.9 (CH3C). HRMS (ESI): m/z calcd for C22H31NNaO8 [MþNa]þ,
460.1947, found: m/z 460.1942.
Analytical data for compound 16: Colorless crystals, mp
20
202 mg (77%), when Mode B was used.
143.4e143.8ꢀС. ½
a
ꢃ
ꢁ57.0ꢀ (с 1.0, СHCl3). 1Н NMR (400.08 MHz,
546
24
Colorless crystals, mp 183.5e184.5ꢀС. ½
aꢃ
ꢁ85.0ꢀ (с 2.7,
CDCl3):
d
7.35e7.23 (m, 5 H, Ph), 6.34 (br d, J ¼ 6.6 Hz, 1H, NH), 4.88
546
СHCl3). 1Н NMR (400.08 MHz, CDCl3):
d
7.41e7.29 (m, 5 H, Ph), 6.25
(d, J ¼ 12.2 Hz, 1H, PhCHa), 4.65 (d, J ¼ 8.1 Hz, 1H, H-1), 4.57 (d,
J ¼ 12.2 Hz, 1H, PhCHb), 4.44 (q, J ¼ 7.0 Hz, 1H, CHCH3), 3.93 (dd,
J ¼ 10.7, 5.4 Hz, 1H, H-6a), 3.79 (t, J ¼ 10.7 Hz, 1H, H-6b), 3.70 (s, 3H,
CH3O), 3.69 (br t, J ¼ 9.6 Hz,1H, H-3), 3.67e3.56 (m, 2H, H-4 þ H-2),
3.24 (br dt, J ¼ 10.0, 5.4 Hz, 1H, H-5), 1.99 (s, 3H, CH3СO), 1.48 (s, 3H,
CH3С), 1.38 (s, 3H, CH3С), 1.34 (d, J ¼ 7.0 Hz, 3H, CHCH3). 13C NMR
(br s, 1H, NH), 4.90 (d, J ¼ 11.4 Hz, 1H, PhCHa), 4.57 (d, J ¼ 11.4 Hz,
1H, PhCHb), 4.46 (d, J ¼ 8.1 Hz, 1H, H-1), 4.34 (d, J ¼ 17.0 Hz, 1H,
CHaCO), 4.21 (d, J ¼ 17.0 Hz, 1H, CHbCO), 3.98 (dd, J ¼ 10.8, 5.3 Hz,
1H, H-6a), 3.89 (br t, 10.7 Hz, 1H, H-6b), 3.84 (t, J ¼ 9.3 Hz, 1H, H-4),
3.55 (t, J ¼ 9.3 Hz, 1H, H-3), 3.42e3.33 (m, 2H, H-2 þ H-5), 1.54 (s,
3H, CH3С), 1.46 (s, 3H, CH3С). 13C NMR (100.61 MHz, CDCl3):
d
168.1
(100.61 MHz, CDCl3): d 174.7 (C]O), 171.3 (C]O), 137.5 (C, Ph),
(C]O), 135.9 (C, Ph), 128.8 (2 ꢂ CH, Ph), 128.6 (CH, Ph), 128.4
(2 ꢂ CH, Ph), 100.3 (C(CH3)2)), 99.7 (C-1), 75.8 (C-3), 71.5 (PhCH2),
71.3 (C-4), 69.0 (C-5), 68.1 (CH2CO), 62.1 (C-6), 56.8 (C-2), 29.1
(CH3C), 19.2 (CH3C); HRMS (ESI): m/z calcd for C18H24NO6 [MþH]þ,
350.1604, found: m/z 350.1598.
128.4 (2 ꢂ CH, Ph), 127.9 (2 ꢂ CH, Ph), 127.8 (CH, Ph), 101.0 (C-1),
99.4 (C(CH3)2)), 77.4 (C-3), 75.7 (C-4), 75.3 (CHCH3), 70.9 (PhCH2),
67.1 (C-5), 62.4 (C-6), 56.3 (C-2), 52.1 (CH3O), 29.3 (CH3C), 23.7
(CH3СO), 19.3 (CH3CH), 19.0 (CH3C). HRMS (ESI): m/z calcd for
C
22H31NNaO8 [MþNa]þ, 460.1947, found: m/z 460.1942.
3.6. General procedure for the synthesis of ester derivatives of
muramic, normuramic and isomuramic acids 15e17
3.6.2. Benzyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-3-O-
[(methoxycarbonyl)methyl]- -D-glucopyranoside (17)
b
Compound 17 was obtained from lactam 14 according to the
To the corresponding lactam derivative (0.55 mmol) were added
diisopropylethylamine (711 mg, 5.5 mmol, 10 equiv.), dichloro-
methane (1.5 mL) and acetyl chloride (432 mg, 5.5 mmol, 10 equiv.).
The reaction mixture was stirred at room temperature. The prog-
ress of the reaction was monitored by TLC in chloroform-ethanol
(10: 0.35). After completion of the reaction, the resulting solution
was evaporated in vacuo and co-evaporated with toluene
(2 ꢂ 2 mL). The dry residue was dissolved in methanol (3 mL) and
the solution was stirred at room temperature. The progress of the
reaction was monitored by TLC in chloroform-ethanol (10: 0.35). In
general procedure. Yield: 198 mg (85%). Colorless crystals, mp
24
117.5e118ꢀС; ½
aꢃ
ꢁ61.6ꢀ (с 2.0, СHCl3). 1Н NMR (400.08 MHz,
546
CDCl3):
d
7.37e7.23 (m, 5 H, Ph), 6.23 (br d, J ¼ 7.3 Hz, 1H, NH), 4.88
(d, J ¼ 12.2 Hz, 1H, PhCHa), 4.71 (d, J ¼ 8.3 Hz, 1H, H-1), 4.57 (d,
J ¼ 12.2 Hz, 1H, PhCHb), 4.39 (d, J ¼ 17.3 Hz, 1H, CHaCO), 4.28 (d,
J ¼ 17.3 Hz, 1H, CHbCO), 3.93 (dd, J ¼ 10.7, 5.4 Hz, 1H, H-6a), 3.81 (br
t, J ¼ 9.6 Hz, 1H, H-3), 3.80 (t, J ¼ 10.7 Hz, 1H, H-6b), 3.72 (s, 3H,
CH3O), 3.70 (t, J ¼ 9.3 Hz, 1H, H-4), 3.61 (br dt, J ¼ 9.6, 7.7 Hz, 1H, H-
2), 3.26 (br dt, J ¼ 9.9, 5.4 Hz, 1H, H-5), 1.98 (s, 3H, CH3СO), 1.49 (s,
3H, CH3С), 1.38 (s, 3H, CH3С). 13C NMR (100.61 MHz, CDCl3):
d 172.0
Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051

S.S. Pertel et al. / Tetrahedron xxx (2018) 1e11
11
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(C]O), 171.1 (C]O), 137.4 (C, Ph), 128.4 (2 ꢂ CH, Ph), 127.9 (2 ꢂ CH,
Ph), 127.8 (CH, Ph), 100.8 (C-1), 99.5 (C(CH3)2)), 78.1 (C-3), 75.6 (C-
4), 71.0 (PhCH2), 68.5 (CH2CO), 67.0 (C-5), 62.3 (C-6), 56.3 (C-2), 51.9
(CH3O), 29.3 (CH3C), 23.8 (CH3СO), 19.3 (CH3C). HRMS (ESI): m/z
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This work was supported by the Program of Development of the
Federal State Autonomous Educational Institution of Higher Edu-
cation ’’V. I. Vernadsky Crimean Federal University’’ for 2015e2024
in the framework of the project ’’Support of Academic Mobility of
the University Staff on Application Basis'’. The authors are grateful
to Prof. L. O. Kononov and Dr. A. I. Zinin for the fruitful discussions
and Prof. A. V. Turov for performing the NOESY experiments.
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Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.07.051.
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Please cite this article in press as: S.S. Pertel, et al., A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids
via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution, Tetrahedron (2018), https://doi.org/
10.1016/j.tet.2018.07.051