Synthesis and antimicrobial activity of novel 3-benzyloxy-4-substituted-2- azetidinones: Formation of a hydrophobic layer via a self-organization effect

Article abstract of DOI:10.1080/10426507.2011.553208

We report the synthesis of new persulfide-spacer N-substituted-2- azetidinone-D-glucosamine in an attempt to potentially provide new antibiotics. The Schiff base ligands considered for this study were derived from D-glucosamine and 2-hydroxybenzaldehyde, 4-methoxy-benzaldehyde, cinnamaldehyde, 4-chlorobenzaldehyde, and 4-hydroxy-3-methoxy-benzaldehyde. Staudinger [2+2] cycloaddition of benzyloxyacetyl chloride to the newly reported per-O-allyl-N-substituted benzylidene-2-deoxy - D-glucosamine provided the sugar-based monocyclic -lactams in moderate yields. Radical addition of 2-mercaptoethanol catalyzed by azobisisobutyronitrile to the per-O-allyl-N-substituted-2-azetidinone-D-glucosamine led to the corresponding persulfide-spacers in good yields. All new compounds were characterized by spectroscopic and spectrometric methods. The scanning electron microscopy image of 1,3,4,6-tetra-O-[3-(hydroxythioethyl)-propyl]-2-deoxy-2-N-[(3-benzyloxy-4-(4- chloropenyl)-2-azetidinone] - D-glucopyranoside, as a representative example, demonstrated a super hydrophobic layer formed via highly organized thioether spacers on gold as the adsorbate system through the formation of sulfur-gold bonds. The reported glucosides showed a moderate antifungal activity against Candida albicans while being slightly to moderately active against gram-positive and gram-negative bacteria used in this investigation at a concentration of 1 mg/mL dissolved in dimethyl sulfoxide. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2011.553208

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Synthesis and Antimicrobial Activity
of Novel 3-Benzyloxy-4-Substituted-2-
Azetidinones: Formation of a
Hydrophobic Layer Via a Self-
Organization Effect
Hammed H. A. M. Hassan a & Raafat Soliman b
a Department of Chemistry, Faculty of Science , Alexandria
University , Alexandria, Egypt
b Department of Pharmaceutical Chemistry, Faculty of Pharmacy ,
Alexandria University , Alexandria, Egypt
Published online: 24 Aug 2011.
To cite this article: Hammed H. A. M. Hassan & Raafat Soliman (2011) Synthesis and Antimicrobial
Activity of Novel 3-Benzyloxy-4-Substituted-2- Azetidinones: Formation of a Hydrophobic Layer Via a
Self-Organization Effect, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:9, 1932-1947,
DOI: 10.1080/10426507.2011.553208
To link to this article: http://dx.doi.org/10.1080/10426507.2011.553208
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Phosphorus, Sulfur, and Silicon, 186:1932–1947, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.553208
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NOVEL
3-BENZYLOXY-4-SUBSTITUTED-2-AZETIDINONES:
FORMATION OF A HYDROPHOBIC LAYER VIA A
SELF-ORGANIZATION EFFECT
Hammed H. A. M. Hassan1 and Raafat Soliman2
1Department of Chemistry, Faculty of Science, Alexandria University,
Alexandria, Egypt
2Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Alexandria University, Alexandria, Egypt
GRAPHICAL ABSTRACT
Abstract We report the synthesis of new persulfide-spacer N-substituted-2-azetidinone-D-
glucosamine in an attempt to potentially provide new antibiotics. The Schiff base ligands
considered for this study were derived from D-glucosamine and 2-hydroxybenzaldehyde,
4-methoxy-benzaldehyde, cinnamaldehyde, 4-chlorobenzaldehyde, and 4-hydroxy-3-
methoxy-benzaldehyde. Staudinger [2+2] cycloaddition of benzyloxyacetyl chloride
to the newly reported per-O-allyl-N-substituted benzylidene-2-deoxy-β-D-glucosamine
provided the sugar-based monocyclic β-lactams in moderate yields. Radical addition of
2-mercaptoethanol catalyzed by azobisisobutyronitrile to the per-O-allyl-N-substituted-2-
azetidinone-D-glucosamine led to the corresponding persulfide-spacers in good yields. All new
compounds were characterized by spectroscopic and spectrometric methods. The scanning
electron microscopy image of 1,3,4,6-tetra-O-[3-(hydroxythioethyl)-propyl]-2-deoxy-2-N-
[(3-benzyloxy-4-(4-chloropenyl)-2-azetidinone]-β-D-glucopyranoside, as
a representative
example, demonstrated a super hydrophobic layer formed via highly organized thioether
spacers on gold as the adsorbate system through the formation of sulfur–gold bonds. The
reported glucosides showed a moderate antifungal activity against Candida albicans while
being slightly to moderately active against gram-positive and gram-negative bacteria used in
this investigation at a concentration of 1 mg/mL dissolved in dimethyl sulfoxide.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords D-Glucosamine; sulfide spacer; antibiotics
Received 23 October 2010; accepted 5 January 2011.
Address correspondence to Hammed H. A. M. Hassan, Department of Chemistry, Faculty of Science,
Alexandria University, P.O. Box-2-Moharram beck, Alexandria 21598, Egypt. E-mail: hassan10@safwait.com
1932

SELF-ASSEMBLED PERSULFIDE MONOCYCLIC β-LACTAMS LAYER
1933
INTRODUCTION
The successful development of any medicinal compound relies on specific and potent
pharmacological activity combined with efficient delivery of the molecule to its target
site. Many potential drugs and medicinal peptides fail to reach the marketplace due to poor
bioavailability and factors such as molecular size, charge, hydrophilicity, hydrogen bonding
potential, and enzymatic lability. Their potential therefore rests on the design of effective
and stable drug delivery systems. Formulation is one means by which the absorption of a
drug can be enhanced, using surfactants, penetration enhancers, or through ion pairing.1,2
Chemical modification is another means, although a compromise between introducing and
modifying structural features of a drug moiety that optimizes biopharmaceutical properties
(e.g., membrane permeability and metabolism) and those that optimize pharmacological
activity (e.g., enzyme or receptor binding) must be sought.
Sugar-based surfactants have been studied as antimicrobial agents.3 Such surface-
active agents are known to disrupt cell membranes because they dissolve in both the
extracellular fluid and the lipid membrane. This lowers the surface tension of the membrane,
allowing water to flow into the cell and ultimately resulting in lysis and bactericidal action.
The primary factors that influence the activity of these molecules are the structure of the
carbohydrates moiety, the presence of the hydrophobic tail, and the length of the alkyl chain
and the latter factor being more important.4 The most frequent types of linkage between the
hydrophilic and hydrophobic moieties are of ester, amine, amide, and glycosidic nature.5
Surprisingly, the basic carbohydrate structures recognized by carbohydrate-binding proteins
are simple, with at best a trisaccharide or tetrasaccharide moiety being deeply involved in
the protein’s active sites,6 unless conformational epitopes are involved. The innate immune
system recognizes the structure of carbohydrate on bacteria through their carbohydrate-
binding protein as the first defense mechanism against this type of infectious agents.7
Alternatively, bacteria possess proteins that also recognize and bind to the carbohydrate of
host human tissues as the premise for bacterial infections.8
[2 + 2] Cycloaddition reactions between ketenes, bearing amino, oxy, or halo groups,
and imines are recognized as being among the most important and direct routes to β-
lactams, and by the virtue of this way, β-lactams with a widely varying substitution pattern
at 1, 3, and 4 positions of the ring are constructed stereoselectively.9 Appropriate sub-
stituents on the monocyclic azetidin-2-one led to the discovery of new biologically active
monocyclic β-lactam compounds displaying either antibiotic or nonantibiotic activities10
and this discovery prompted us to construct new derivatives of such compounds. We
postulated that radical addition of 2-mercaptoethanol, as a spacer arm, to per-O-allyl-
2-amino-2-deoxy-glycoside carrying monocyclic azetidin-2-one with a varying substitu-
tion at position 4 of the β-lactam ring11 could be useful for the construction of potent
lipophilic sulfide-spacer carbohydrates. Such types of spacer arms contain two functional
groups, which can interact with receptors independently. The terminal hydroxyl groups
of these spacers are available for either direct attachment to specific receptors or cova-
lently modify into another functional group for subsequent binding.12 In this report, we
describe the preparation of a new type of symmetrically substituted persulfide-spacer 2-
amino-2-deoxy-glucoside containing 3-hydroxy-4-substituted-2-azetidinone and evaluate
their antimicrobial and antifungal activity against Staphylococcus aureus, Enterococcus
fecalis, Klebsiella pneumonia, Pseudomonas aeruginosa, Escherichia coli, and Candida
albicans.

1934
H. H. A. M. HASSAN AND R. SOLIMAN
RESULTS AND DISCUSSION
The importance of amino sugars as constituents of aminoglycosides antibiotics,
antigenic determinants, glycoproteins, and glycolipids is well recognized. A large num-
ber of imines or Schiff bases have been reported by the reaction of sugar aldehy-
des with amines or by the reaction of amino sugars such as 2-amino-2-deoxy-sugars
with aldehydes.9,11 The Schiff base ligands considered for this study are derived from
2-hydroxybenzaldehyde (salicylaldehyde), 4-methoxybenzaldehyde, cinnamaldehyde, 4-
chlorobenzaldehyde, and 4-hydroxy-3-methoxybenzaldehyde (vanillin). The N-substituted
benzylidene-D-glucosamines 2,13 4,14 6,15 8,16 and 1017 were obtained by refluxing equimo-
lar quantities of D-glucosamine hydrochloride 1, NaOH, and appropriate aldehyde in
MeOH solution for 2 h following the literature procedures18 (Scheme 1). The structures
of the resulted imines were confirmed by mass spectrometry, IR, and elemental analy-
sis. The perallyl-substituted benzylidene β-D-glucosides 3, 5, 7, 9, and 11 were prepared
according to the literature procedures.19 Thus, peracetylation of imines 2, 4, 6, 8, and
10 using Ac2O/HClO4 followed by treatment with red P/Br2 according to a reported
method20 provided the respective α-glucoside bromides. Koenigs–Knorr glycosidation
with allyl alcohol/AgOTf21 followed by O-deacetylation using NH4OH/CH3OH (2:1 v/v)
provided the allyl-β-D-glucosides that were further reacted with NaH/allyl bromide/N,N-
dimethylformamide (DMF) mixture to furnish the target intermediates, i.e., per-O-allyl
β-D-glucosides 3, 5, 7, 9, and 11 in moderate overall yields. The structures of the prepared
per-O-allyl-β-D-glucosides 3, 5, 7, 9, and 11 were fully characterized by spectroscopic
and spectrometric analysis methods. IR spectra (film, NaCl) showed bands around υ 3010
and 1610 cm−1, which correspond to the υstr (C C) of the allyl groups and strong bands
around υ 1650 cm−1 due to the imine υstr (C N) groups. 1H- and 13C-NMR spectroscopic
data for the allylated glucosides were in agreement with the published chemical shifts and
coupling constant values for related analogues.22,23 The anomeric proton (H-1) resonated
around δ 5.20 ppm (J = 6.1 Hz) confirming the indicated β-stereochemistry. The olefinic
protons appeared as two multiplet signals within δ 4.95–6.00 ppm range and the imine
proton (N CH) resonated at δ 10.50 ppm.
The reaction of per-O-allyl-N-substituted benzylidene-2-deoxy-β-D-glucosamines
3, 5, 7, 9, and 11 with benzyloxyacetyl chloride in the presence of triethylamine accord-
ing to the method described by Manhas et al.24 resulted in the respective per-O-allyl-N-
substituted-2-azetidinone-D-glucosamines 12–16 (Scheme 2) in good yields. The structures
of the prepared monocyclic β-lactams 12–16 were fully characterized by spectroscopic and
spectrometric analysis methods. It is noteworthy that the NMR spectra of the crude reaction
products revealed the presence of an inseparable mixture of cis- and trans-stereoisomers in
nearly equal ratios. The synthesis of the targeted persulfide-spacer glycosides 17–21 were
accomplished by the addition of 2-mercaptoethanol to the per-O-allyl-N-substituted-2-
azetidinone-D-glucosamines 12–16 in good yields. Various methods are known to conduct
the free radical addition reactions mostly by exposure to UV radiation or by the addition
of chemical initiators. The first case requires a special apparatus and in this work, adducts
17–21 were obtained by the use of azobisisobutyronitrile (AIBN) as a radical initiator.25
Elongated persulfide-spacer glycosides exhibited similar spectroscopic behaviors. IR spec-
tra (film, NaCl) showed a broad band around υ 3400 cm−1, which correspond to the free
1
terminal OH groups and a strong band at υ 2920 cm−1 due to the alkyl groups. The H-
NMR spectra are characterized by a number of overlapping broad band peaks due to many
magnetically equivalent ( CH2) and ( CH ) groups on each molecule. 1H-NMR spectra

SELF-ASSEMBLED PERSULFIDE MONOCYCLIC β-LACTAMS LAYER
1935
Scheme 1
of either persulfide-spacer glycosides revealed the presence of signals at δ 1.91–1.74 (m,
8H, 4 × CH2), 2.69–2.59 (m, 8H, 4 × CH2S ), 2.81 (m, 8H, 4 × SCH2 ), 3.69–3.57
(m, 10H, 4 × OCH2, 2 × H-6), and 3.77 (m, 8H, 4 × CH2OH), which correspond to
thio-spacer protons, whereas anomeric protons of the carbohydrates resonated at δ 5.62 (d,
1H, J = 7.6 Hz, H-1, β-configuration).

1936
H. H. A. M. HASSAN AND R. SOLIMAN
Scheme 2
We then focused on the role played by the symmetrically arranged thioether spacers
on the morphology of the surface. Figure 1 shows the scanning electron microscopy (SEM)
image of 1,3,4,6-tetra-O-[3-(hydroxylthioethyl)-propyl]-2-deoxy-2-N-[(3-benzyloxy-4-(4-
chloropenyl)-2 azetidinone]-β-D-glucopyranoside 20, as a representative example, demon-
strating a super hydrophobic layer formed via highly organized thioether spacers on gold
as the adsorbate system. Self-assembled monolayers (SAMs) are the simplest form of
self-assembled material. Their construction is driven by the thermodynamically favored

SELF-ASSEMBLED PERSULFIDE MONOCYCLIC β-LACTAMS LAYER
1937
Figure 1 The SEM image of 20 demonstrating a super hydrophobic layer formed via highly organized thioether
spacers on gold as the adsorbate system.
segregation of molecules to a phase boundary, most typically the surface of a solid in
contact with a liquid or other ambient environment. The interest in these materials has
developed greatly in recent years in no small part as a direct response to the needs of
technology.26,27
SAMs are typically formed by small organic molecules, which in some way are
amphiphilic; they are typically limited to dimensions of less than a few nanometers. The
amphiphilic or dual solubility character of a compound implies that it (1) adsorbs at any
polar–apolar interface, reducing the interfacial tension, that is, the amount of work required
to increase the area of the interface at standard conditions and (2) self-organizes in bulk
into aggregates containing many molecules and having well-defined average shape and
size. The main thermodynamic driving force for both adsorption and self-assembly is
the hydrophobic effect.28 The best defined materials currently available for the study are
the SAMs formed by various organosulfur compounds, especially alkanethiols, on metal
surfaces such as those formed by Au, Ag, and to a lesser degree Cu.29 Figure 2 shows
Figure 2 The general schematic structure of an organothiol used in forming firmly anchored SAMs on the gold
substrate via a sulfur–gold bond.

1938
H. H. A. M. HASSAN AND R. SOLIMAN
a generic depiction that captures the essential aspects of the molecular structure of a
thiolate SAM on Au. The organothiol consists of three essential units: the thio function
( S ), employed as the anchor group; a linker unit such as alkyl chains ( CH2
)
30 or
n
oligophenylenes ( C6H4 )n,31 and a functional terminal group ( X). Critically important
for the generation of organic surfaces using SAMs is that the terminal group X of the
corresponding organothiol determines the surface of the organic ultrathin layers.
The generation and fundamental characteristics of these molecular “furs” have been
discussed31 and the precise geometric arrangement at the thiolate–gold interphase was
a topic of an intense debate.32 The production of the monomolecular layers is achieved
by immersing gold substrates in the corresponding organothiol solutions. In most cases,
ethanol is the solvent; however, depending on the organothiol, other solvents (e.g., water,
acetone, and dichloromethane) were employed. As a rule, a highly organized layer will form
on the substrate immersed in the solution in as little as a few hours.30 Several organosulfur
compounds bearing different functionalities and studies of the highly organized thiolate
SAMs on Au as the adsorbate system have been reported.33
The imaging of compound 20 by an SEM involves sputter coating the sample with
gold prior to examination. The thioether-spacer moieties generate sulfur–gold bonds, either
by direct adsorption or by in situ cleavage of a thioether bond,34 and a self-organization
effect that easy surface segregation to form a rough surface nanostructure to exhibit super-
hydrophobicity.27a
Biological Screening: Antimicrobial Activity Tests
There has been a suggestion that the bacteria may utilize a carbohydrate uptake mech-
anism, which allows a better transport of the monocyclic β-lactams across the membrane.
The prepared perallylated and persulfide-spacer glucosides were screened in vitro against
gram-positive bacteria Staphylococcus aureus (S) ATCC6538P and gram-negative bac-
teria Enterococcus fecalis (Ent) ATCC29212, Klebsiella pneumonia (Kl) ATCC10031,
Pseudomonas aeruginosa (Ps) ATCC9027, and Escherichia coli (E) ATCC8739. The
compounds were also screened against Candida albicans (C) ATCC2091 fungi. The an-
tibacterial and antifungal activities of test compounds were performed using the filter
paper disc method.35 Screening results are summarized in Table S1 (supplemental mate-
rials). The antimicrobial screening against test strains showed slight to moderate activity
against the tested bacteria strains for all compounds at a concentration of 1 mg/mL. Inter-
estingly, the reported compounds showed a broad spectrum of antifungal activity against
Candida albicans.
EXPERIMENTAL SECTION
General Procedures
All solvents were dried and distilled using standard procedures prior to use. All
moisture-sensitive reactions were performed under a nitrogen atmosphere using oven-
dried glassware. AIBN was recrystallized in dry methanol before use. Evaporation was
◦
performed under vacuum with a water bath temperature below 40 C. Reactions were
monitored by thin layer chromatography on silica gel 60 F254 plates with detection by
UV at 254 nm and by charring with 5% ethanolic H2SO4. Column chromatography was
performed on silica gel 60 (EM Science, 70–230 mesh). Optical rotations were measured

SELF-ASSEMBLED PERSULFIDE MONOCYCLIC β-LACTAMS LAYER
1939
at 20 ◦C on an Optika polarimeter (WXG-4). IR spectra (film, NaCl) were recorded on a
Perkin-Elmer 781 spectrophotometer. 1H-NMR and 13C-NMR were recorded on JOEL 500
MHz spectrometers equipped with Sun off-line editing workstation. Chemical ionization
mass spectrometry (CIMS) measurements were determined using a Finnigan SSQ 7000
spectrometer attached to digital DEC 300 workstation at the central scientific services unit,
National Research Center, Dokki, Cairo, Egypt. Methane, the ionizing gas, was introduced
directly into the source of the mass spectrometer and the pressure of the gas in the source was
approximately 0.5 torr. Under these conditions, essentially all of the charged ions originate
from methane. Elemental analyses were determined at the Chemistry Department, Faculty
of Science, Cairo University, Egypt. The image of compound 20 was observed by an SEM
(JEOL-JSM5300) at the E-Microscope Unit, Faculty of Science, Alexandria University,
Egypt. The dilute methanolic solution was air-dried on a cover glass and sputter coated
with gold prior to examination. Antimicrobial and antifungal evaluations were determined
by the Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Alexandria
University, Egypt. The supplemental materials contain example spectra of compounds 3,
12, and 17.
Preparation of N-Substituted Benzylidene-D-Glucosamines 2, 4, 6, 8,
and 10 (General Methods)14
Method 114. D-Glucosamine hydrochloride (10 g, 46.5 mmol) was dissolved in
NaOH (55 mL, 1N) and substituted benzaldehyde (48 mmol) was slowly added while
stirring. A yellow solid soon precipitated and after approximately 2 h it was filtered off,
washed carefully with little methanol and water, and dried under vacuum for 2 days.
Method 2. A mixture of equimolar quantities of D-2-glucosamine hydrochloride
in NaOH and respective aldehyde in MeOH solution was refluxed for 2 h according to the
literature procedure.18
N-(2-Hydroxy-Benzylidene)-D-Glucosamine 213. Yield (9 g, 70%), mp = 183
◦C–185 ◦C. FT-IR (KBr, cm−1): υ 3387, 2934, 2888, 2764, 1632, 1493, 1408, 1340, 1279,
1224, 1153, 1098, 1016, 899, 876, 768, 741, 712, 595. CI-MS [m/z (%)]: 283 (M+) (2),
279 (3), 266 (2), 252 (3), 246 (2), 237 (2), 232 (2), 228 (2), 226 (2), 218 (4), 216 (7), 206
(12), 203 (3), 202 (4), 192 (15), 181 (6), 177 (6), 166 (6), 164 (13), 155 (13), 148 (16), 141
(22), 137 (9), 131 (12), 127 (21), 124 (15), 122 (16), 120 (15), 117 (49), 114 (19), 110 (33),
108 (23), 104 (35), 102 (31), 98 (18), 94 (69), 91 (43), 76 (57), 56 (100), 50 (56). Calc.:
C13H17NO6 (283); C: 55.12, H: 6.05, N: 4.94; found: C: 54.77, H: 5.80, N: 4.61.
N-(4-Methoxy-Benzylidene)-D-Glucosamine 414. Following the general
method described, the known imine 4 was obtained: yield (9.5 g, 74%), mp 165 ◦C. Calc.:
C14H19NO6 (297); C: 56.56, H: 6.44, N: 4.71; found: C: 55.94, H: 6.11, N: 4.30.
N-(3-Meth◦oxy-4-Hydroxy-Benzylidene)-D-Glucosamine 615. Yield (9.5 g,
70%), mp = 184 C (decomp.). FT-IR (KBr, cm−1): υ 3218 br, 2850, 1665, 1592, 1519,
1461, 1363, 1304, 1266, 1206, 1174, 1132, 1062, 1018, 862, 824, 731, 679, 613, 599.
CI-MS [m/z (%)]: 306 (2), 298 (2), 253 (2), 249 (2), 243 (3), 232 (3), 230 (2), 228 (2), 225
(3), 217 (4), 213 (5), 206 (2), 203 (5), 202 (4), 192 (7), 188 (6), 179 (6), 166 (6), 164 (8),
155 (3), 148 (14), 141 (9), 137 (14), 131 (7), 127 (7), 124 (12), 122 (31), 117 (6), 112 (8),
110 (20), 108 (37), 104 (23), 97 (35), 94 (27), 91 (14), 76 (19), 56 (64), 54 (49), 45 (100).
Calc.: C14H19NO7 (313); C: 53.67, H: 6.11, N: 4.47; found: C: 52.41, H: 5.60, N: 4.01.
N-(4-Chloro-Benzylidene)-D-Glucosamine 816. Yield (10.5 g, 81%), mp =
◦
133 C. FT-IR (KBr, cm−1): υ 3492, 3302, 3197, 2940, 2885, 2845, 1694, 1646, 1591,

1940
H. H. A. M. HASSAN AND R. SOLIMAN
1491, 1429, 1385, 1321, 1281, 1250, 1207, 1147, 1076, 1031, 896, 884, 829, 708, 638,
579, 541, 505. CI-MS [m/z (%)]: 302 (M+) (3), 287 (3), 266 (3), 246 (5), 229 (10), 227
(26), 217 (8), 203 (16), 192 (45), 181 (6), 177 (12), 166 (10), 164 (28), 155 (26), 148 (18),
140 (38), 137 (94), 130 (20), 127 (28), 124 (34), 117 (29), 114 (21), 110 (50), 104 (24),
102 (43), 98 (16), 95 (100), 91 (63), 88 (26), 76 (43), 57 (78), 54 (62), 50 (74).
N-(3-Phenyl-Allylidene)-D-Glucosamine 1017. Yield (10.5 g, 84%), mp = 137
◦C. FT-IR (KBr, cm−1): υ 3467, 3297, 3197, 2855, 1674, 1629, 1492, 1448, 1384, 1329,
1251, 1204, 1124, 1069, 1025, 976, 883, 750, 689, 644, 609, 580, 508. CI-MS [m/z (%)]:
295 (M+ +2) (4), 294 (M+ +1) (3), 293 (M+) (2), 264 (5), 249 (4), 244 (23), 192 (16),
181 (29), 177 (13), 166 (19), 164 (20), 153 (49), 147 (30), 143 (25), 130 (40), 127 (45),
116 (29), 114 (43), 104 (51), 102 (65), 96 (30), 94 (26), 90 (71), 88 (16), 76 (100), 56 (57),
54 (48), 50 (58). Calc.: C15H19NO5 (293); C: 61.42, H: 6.53, N: 4.78; found: C: 60.90, H:
6.03, N: 4.20.
Preparation of Perallyl-N-Substituted Benzylidene-2-Deoxy-β-D-
Glucosamines 3, 5, 7, 9, and 11 (General Method)
The N-substituted benzylidene-D-glucosamines 2, 4, 6, 8, and 10 (10 mmol) were
converted to the corresponding N-substituted benzylidene-3,4,6-tri-O-acetyl-α-D-glucosyl
bromides according to the literature procedure.19 The allyl β-D-glucosides were prepared
from the respective α-D-glucosyl bromides via AgOTf-catalyzed Koenigs–Knorr glycosi-
dation,21 followed by O-deacetylation using NH4OH/CH3OH (2:1 v/v) to provide the
◦
respective unprotected glucosides. To a cold (0 C) solution of the unprotected allyl β-
D-glucosides dissolved in DMF (25 mL), NaH (1.73 g, 72 mmol, 8 × equivalent based
◦
on crude starting materials) was added portionwise. Stirring was continued at 0 C for
◦
15 min and for 45 min at r.t. and then the salty solution was cooled to 0 C again. Allyl
bromide (8.7 g, 72 mmol, 8 × equivalent) in DMF (10 mL) was added slowly and the clear
mixture was allowed to stir at r.t. for 15 h. The organic solvent and volatiles were removed
under a high vacuum and the crude product was purified on column chromatography (1:2
EtOAc/hexane).
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-(2-Hydroxy-Benzylidene)-β-D-Glucopy
ranoside 3. Yield (overall) = (1.4 g, 33%), Rf = 0.30, [α]D = −4.4 (c 1.0 CHCl3).
FT-IR (NaCl film, cm−1): υ 3415, 3077, 2978, 2918, 2866, 1679, 1642, 1597, 1487, 1452,
1422, 1389, 1287, 1240, 1110, 998, 923, 842, 757, 656, 565. 1H-NMR (CDCl3, 500 MHz):
10.51 (s, 1H, N = CH), 7.98 (s br, 1H, OH), 7.82–7.80 (m, 1H, arom.), 7.52–7.50 (m, 1H,
arom.), 7.35–7.25 (m, 2H, arom.), 5.90–5.70 (m, 4H, 4 = CH), 5.30–4.95 (m, 8H, 4 =
CH2), 5.20 (d, J = 6.1 Hz, 1H, H-1), 4.40–3.94 (m, 8H, 4 × OCH2), 3.80–3.53 (m, 6H,
H-2, H-3, H-4, H-5, 2 × H-6). 13C-NMR (CDCl3, 125 MHz): 190.0 (C N), 161.0 (arom.)
133.4−132.5 (CH CH2), 128.5 (arom.), 128.4 (arom.), 121.2 (arom.), 120.6 (arom.),
118.0 (arom.), 112.6 (CH CH2), 73.9–69.7 (4 × OCH2, C-5), 69.3 (C-6), 69.2 (–OCH2),
68.6 (C-2).
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-(4-Methoxy-Benzylidene)-β-D-Glucopy
ranoside 5. Yield (overall) = (1.6 g, 36%), Rf = 0.33, [α]D = –5.1 (c 1.0 CHCl3).
FT-IR (NaCl film, cm−1): υ 3448, 3078, 3010, 2927, 2857, 1697, 1645, 1602, 1512,
1461, 1424, 1346, 1257, 1216, 1160, 1105, 995, 923, 834, 768, 722, 641, 602, 559, 517.
1H-NMR (CDCl3, 500 MHz): 9.81 (s, 1H, N = CH), 7.77 (d, J = 3.68 Hz, 2H, arom.),
6.94 (d, J = 3.36 Hz, 2H, arom.), 5.90–5.70 (m, 4H, 4 = CH), 5.30–4.95 (m, 8H, 4 =
CH2), 5.20 (d, J = 6.1 Hz, 1H, H-1), 4.40–3.94 (m, 8H, 4 × OCH2), 3.82 (s, 3H, OCH3),

SELF-ASSEMBLED PERSULFIDE MONOCYCLIC β-LACTAMS LAYER
1941
3.80–3.53 (m, 6H, H-2, H-3, H-4, H-5, 2× H-6). 13C-NMR (CDCl3, 125 MHz): 190.9
(C N), 164.6 (arom.), 134.8, 134.7, 134.6 (3× CH CH2), 132.0 (CH CH2, arom.),
129.9, 129.1 (arom.), 116.9, 116.3 (arom.), 114.3 (CH CH2), 76.9 (C-5), 72.2–69.4
(OCH2, C-6), 62.8 (C-2), 55.6 (OMe). CI-MS [m/z (%)]: 457 (2), 449 (7), 422 (2), 409
(5), 379 (87), 364 (8), 346 (7), 337 (28), 326 (7), 320 (7), 309 (7), 293 (8), 287 (5), 278
(11), 269 (4), 261 (17), 251 (16), 245 (6), 231 (9), 223 (20), 209 (9), 179 (38), 175 (36),
160 (12), 152 (94), 148 (53), 134 (56), 120 (32), 81 (100), 78 (39), 54 (71).
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-(3-Methoxy-4-Hydroxy-Benzylidene)-
β-D-Glucopyranoside 7. Yield (overall) = (1.4 g, 30%), Rf = 0.35, [α]D = –4.0 (c 1.0
CHCl3). FT-IR (NaCl film, cm−1): υ 3458, 3078, 2978, 2918, 2867, 1682, 1644, 1590,
1511, 1455, 1420, 1338, 1267, 1131, 1037, 924, 867, 809, 782, 759, 732, 658, 589, 565.
1H-NMR (CDCl3, 500 MHz): 9.81 (s, 1H, N = CH), 7.25 (s, 1H, arom.), 6.94 (d, J =
8.4 Hz, 2H, arom.), 6.07–5.72 (m, 4H, 4 = CH), 5.42–4.97 (m, 9H, 4 = CH2, H-1),
4.67–3.99 (m, 8H, 4 × OCH2), 4.00 (s, 3H, OCH3), 4.11–3.50 (m, 6H, H-2, H-3, H-4,
H-5, 2 × H-6). 13C-NMR (CDCl3, 125 MHz): 191.1 (C N), 153.5, 149.5, 134.7, 134.4,
133.0, 132.3 (4 × CH CH2), 132.1 (arom.), 126.63, 126.1, 125.0 (arom.), 118.8, 117.3,
116.0 (arom.), 112.1 (CH CH2), 111.6 (arom.), 98.6 (C-1), 78.5, 78.3, 73.9, 72.5, 70.4,
70.3, 69.9 (OCH2), 69.8 (OCH2), 69.7 (OCH2), 69.3 (OCH2), 69.2 (C-5), 69.1 (C-6), 56.1
(OMe). CI-MS [m/z (%)]: 474 (M+ +1), 338 (2), 326 (2), 311(3), 286 (2), 269 (3), 253
(2), 246 (2), 243 (2), 232 (14), 227 (2), 225 (3), 217 (24), 208 (3), 203 (14), 200 (4), 196
(4), 190 (61), 182 (5), 178 (14), 177 (40), 164 (38), 155 (7), 150 (41), 144 (28), 137 (17),
131 (15), 127 (28), 124 (8), 122 (7), 117 (24), 112 (7), 110 (17), 108 (21), 104 (33), 97
(18), 94 (26), 91 (100), 76 (44), 56 (36), 54 (44), 50 (33).
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-(4-Chloro-Benzylidene)-β-D-Glucopyra
noside 9. Yield (overall) = (1.5 g, 33%), Rf = 0.25, [α]D = –6.1 (c 1.0 CHCl3).
FT-IR (NaCl film, cm−1): υ 3413 br, 3079, 2979, 2922, 2868, 1725, 1644, 1596, 1489,
1
1412, 1347, 1270, 1092, 1011, 924, 829, 809, 759, 660, 523. H-NMR (CDCl3, 500
MHz): 9.97 (s, 1H, N = CH), 7.98 (d, J = 8.4 Hz, 2H, arom.), 7.81 (d, J = 8.4
Hz, 2H, arom.), 6.06–5.60 (m, 4H, 4 = CH), 5.27–4.90 (m, 8H, 4 = CH2), 5.20 (d,
J = 6.1 Hz, 1H, H-1), 4.47–4.00 (m, 8H, 4 × OCH2), 3.74–3.50 (m, 6H, H-2, H-3, H-4,
H-5, 2 × H-6). 13C-NMR (CDCl3, 125 MHz): 165.5 (arom.), 136.0, 135.4, 134.7, 133.1
(4 × CH CH2), 131.2 (arom.), 129.2–127.9 (arom.), 119.0–116.0 (arom.), 98.8 (C-1),
76.8 (C-4), 72.4 (C-5), 65.8 (OCH2). CI-MS [m/z (%)]: 462.5 (M+ +1) (4), 428 (9), 410
(6), 404 (4), 369 (9), 338 (9), 321 (40), 304 (10), 277 (6), 266 (4), 250 (5), 235 (9), 223
(8), 218 (27), 211 (12), 196 (9), 193 (10), 190 (29), 181 (25), 167 (22), 164 (38), 155 (12),
153 (17), 140 (38), 137 (100), 129 (23), 127 (27), 123 (66), 117 (7), 114 (15), 112 (21),
104 (9), 102 (7), 98 (14), 96 (14), 91 (9), 88 (8), 76 (14), 57 (33), 54 (34), 50 (14). Calc.:
C25H32NClO5 (461.5); C: 65.00, H: 6.98, N: 3.03; found: C: 64.10, H: 6.32, N: 2.91.
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-(3-Phenyl-Allylidene)-β-D-Glucopyra
noside 11. Yield (overall) = (1.3 g, 30%), Rf = 0.42, [α]D = −2.2 (c 1.0 CHCl3). FT-IR
(NaCl film, cm−1): υ 3454, 3075, 3023, 2980, 2919, 1731, 1641, 1601, 1493, 1450, 1335,
1244, 1121, 995, 923, 757, 701, 557. 1H-NMR (CDCl3, 500 MHz): 7.44–7.25 (m, 6H, 4H
arom., CH CH), 5.95–5.60 (m, 4H, 4 = CH), 5.28–5.05 (m, 8H, 4 = CH2), 5.20 (d, J =
6.1 Hz, 1H, H-1), 4.30–4.09 (m, 8H, 4 × OCH2), 4.00–3.50 (m, 6H, H-2, H-3, H-4, H-5,
2× H-6). 13C-NMR (CDCl3, 125 MHz): 171.3 (C N), 134.0−130.0 (CH CH2, arom.),
129.8–127.3 (arom.), 119.0–116.0 (arom.), 98.5 (C-1), 76.8 (C-4), 72.3 (C-5), 68.9 (C-6),
64.6, 64.3, 64.2 (OCH2), 60.5 (C-2). CI-MS [m/z (%)]: 454 (M+ +1) (3), 412 (3), 409 (5),
400 (8), 394 (9), 384 (16), 378 (8), 356 (6), 352 (12), 342 (2), 327 (11), 301 (3), 299 (92),

1942
H. H. A. M. HASSAN AND R. SOLIMAN
257 (28), 251 (25), 229 (20), 223 (29), 215 (17), 211 (83), 198 (22), 192 (41), 172 (26),
169 (24), 166 (17), 164 (13), 154 (18), 151 (37), 140 (34), 143 (23), 130 (45), 127 (100),
116 (39), 114 (61), 109 (22), 104 (44), 102 (42), 96 (11), 94 (9), 91 (56), 88 (5), 76 (22),
55 (23), 50 (8).
Preparation of N-Substituted-2-Azetidinone-D-Glucosamine 12–16
(General Method)23
A solution of the Schiff base (3, 5, 7, 9, and 11; 10 mmol) and triethylamine (15
mmol) in CH2Cl2 (50 mL) was stirred at r.t. while a solution of benzyloxyacetyl chloride
(15 mmol) in CH2Cl2 (25 mL) was added dropwise over a period of 1 h. The mixture was
stirred at r.t. for additional 20 h. Then, the mixture was washed with water, dried, and the
solvent and volatiles were removed under reduced pressure. The residue was purified over
a short column of Florisil using CH2Cl2 as the eluent.
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-[(3-Benzyloxy-4-(2-Hydroxyphenyl)-2-
Azetidinone]-β-D-Glucopyranoside 12. Yield (3.8 g, 65%), clear thick oil. FT-IR
(NaCl film, cm−1): υ 3451 br, 3075, 2978, 2918, 2868, 1755, 1687, 1642, 1598, 1487,
1451, 1390, 1284, 1238, 1121, 998, 924, 842, 753, 703, 656, 614, 573. 1H-NMR (CDCl3,
500 MHz): 7.82–7.25 (m, 9H, arom.), 6.08–5.88 (m, 4H, 4 = CH), 5.46–5.03 (m, 8H,
4 = CH2), 4.88–4.50 (m, 11H, H-1, –CH2Ph, 4 × OCH2), 4.09–3.69 (m, 6H, H-2, H-3,
H-4, H-5, 2× H-6). 13C-NMR (CDCl3, 125 MHz): 170.8 (CO), 164.7 (arom.), 137.0
(arom.), 136.0–134.0 (CH CH2), 132.0 (arom.), 131.4 (arom.), 128.7–127.8 (arom.),
117.2 (arom.), 113.2 (CH CH2), 112.6 (CH CH2), 74.0 (C-4), 73.4 (C-5), 72.9, 69.2
(CH2), 67.1, 61.1 (C-6), 52.1 (C-2), 51.8 (CH). CI-MS [m/z (%)]: 593 (M+ +2) (2), 553
(2), 523 (4), 501 (1), 496 (5), 482 (6), 471 (7), 443 (7), 412 (4), 401 (7), 377 (8), 347 (11),
341 (4), 338 (6), 325 (5), 269 (9), 266 (5), 256 (3), 244 (6), 242 (6), 227 (13), 221 (14),
216 (6), 202 (20), 189 (6), 185 (21), 181 (3), 179 (21), 171 (27), 166 (6), 164 (16), 148
(11), 146 (27), 141 (7), 137 (16), 131 (46), 127 (25), 122 (9), 119 (36), 117 (10), 114 (9),
110 (23), 109 (23), 106 (55), 104 (27), 96 (16), 95 (17), 90 (100), 76 (21), 56 (15), 50 (15).
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-[(3-Benzyloxy-4-(4-Methoxyphenyl)-2-
Azetidinone]-β-D-Glucopyranoside 13. Yield (3.6 g, 62%), clear thick oil. FT-IR
(NaCl film, cm−1): υ 3491, 3078, 3010, 2927, 2858, 1753, 1697, 1645, 1602, 1512, 1456,
1425, 1348, 1257, 1211, 1119, 1033, 996, 924, 834, 741, 700, 641, 604, 560, 517. 1H-NMR
(CDCl3, 500 MHz): 7.81–6.96 (m, 9H, arom.), 5.90–5.60 (m, 4H, 4 = CH), 5.30–4.86
(m, 9H, H-1, 4 = CH2), 4.86 (s, 2H), 4.40–3.97 (m, 8H, 4 × OCH2), 3.85–3.57 (m, 6H,
H-2, H-3, H-4, H-5, 2 × H-6), 3.72 (s, 3H, OCH3). 13C-NMR (CDCl3, 125 MHz): 170.9
(CO), 164.7 (arom.), 137.0 (arom.), 136.0–134.0 (CH CH2), 132.0 (arom.), 128.7, 128.4,
128.3, 128.0, 116.7 (arom.), 114.6 (CH CH2), 73.5 (C-5), 73.1 (C-4), 72.8, 72.4, 72.2
(OCH2), 72.0 (CH2), 67.1 (C-6), 63.0 (CH), 55.9 (OCH3), 52.0 (C-2), 51.8 (CH). CI-MS
[m/z (%)]: 605 (M+, 1), 497 (5), 485 (4), 457 (5), 440 (5), 416 (4), 387 (6), 379 (20), 364
(9), 346 (8), 345 (8), 337 (12), 329 (13), 321 (7), 307 (12), 293 (10), 285 (7), 279 (11),
267 (13), 251 (16), 227 (16), 222 (9), 208 (16), 179 (14), 175 (50), 160 (44), 152 (55), 147
(52), 134 (100), 120 (53), 80 (95), 78 (36), 54 (56).
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-[(3-Benzyloxy-4-(3-Methoxy-4-Hydroxy
phenyl)-2-Azetidinone]-β-D-Glucopyranoside 14. Yield (3.7 g, 60%), clear thick
oil. FT-IR (NaCl film, cm−1): υ 3453 br, 3077, 2978, 2917, 2868, 1755, 1682, 1643,
1590, 1511, 1455, 1422, 1343, 1268, 1129, 1034, 925, 867, 810, 782, 736, 701, 659,
1
617, 567. H-NMR (CDCl3, 500 MHz): 7.34–6.95 (m, 8H, arom.), 6.07–5.60 (m, 4H,

SELF-ASSEMBLED PERSULFIDE MONOCYCLIC β-LACTAMS LAYER
1943
4 = CH), 5.33–4.70 (m, 10H, 2H, 4 = CH2), 4.69–4.09 (m, 8H, 4 × OCH2), 3.95–3.57
(m, 6H, H-2, H-3, H-4, H-5, 2× H-6), 3.72 (s, 3H, OCH3). 13C-NMR (CDCl3, 125 MHz):
170.8 (CO), 153.5 (arom.), 149.9 (arom.), 137.0 (arom.), 135.0, 134.8, 134.2, 133.7, 132.3
(CH CH2), 130.2, 128.7, 128.2, 127.5, 127.0, 126.6, 119.0, 118.6, 117.2 (arom.), 112.5,
112.1, 111.7 (CH CH2), 109.3 (arom.), 98.7 (C-1), 74.0 (C-4), 73.4 (C-5), 73.2, 72.8,
70.5, 70.4 (OCH2), 69.9 (CH2), 67.3 (CH), 56.2 (OCH3), 46.0 (C-2). CI-MS [m/z (%)]:
648 (2), 585 (2), 543 (2), 533 (2), 513 (12), 501 (4), 473 (12), 454 (6), 445 (4), 431 (8),
426 (5), 415 (26), 400 (8), 394 (9), 385 (14), 374 (15), 366 (22), 356 (14), 329 (16), 315
(12), 298 (19), 285 (52), 274 (22), 259 (12), 246 (6), 232 (81), 217 (27), 207 (7), 204 (11),
191 (77), 177 (35), 161 (100), 155 (7), 150 (29), 133 (61), 126 (17), 120 (58), 117 (21),
112 (11), 110 (44), 108 (23), 104 (34), 97 (20), 94 (24), 92 (20), 76 (19), 56 (23), 54 (39),
50 (10).
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-[(3-Benzyloxy-4-(4-Chloropenyl)-2-Aze
tidinone]-β-D-Glucopyranoside 15. Yield (3.6 g, 60%), clear thick oil. FT-IR (NaCl
film, cm−1): υ 3480 br, 3077, 2979, 2926, 2869, 1755, 1729, 1643, 1597, 1490, 1451,
1347, 1271, 1207, 1092, 1013, 924, 830, 740, 700, 611, 524. 1H-NMR (CDCl3, 500 MHz):
8.08, 7.98 (2d, 2H, J = 7.6, 8.4 Hz, arom.), 7.81 (2d, J = 8.4 Hz, 2H, arom.), 7.58–7.16
(m, 5H, arom.), 5.90–5.66 (m, 4H, 4 = CH), 5.29–4.95 (m, 9H, CH, 4 = CH2), 4.86 (d, J
= 17.5 Hz, 1H), 4.79 (d, J = 6.1 Hz, 1H, H-1), 4.69–4.07 (m, 8H, 4 × OCH2), 3.77–3.53
(m, 6H, H-2, H-3, H-4, H-5, 2 × H-6), 3.36 (d, J = 6.9 Hz, 1H), 3.25 (d, J = 6.9 Hz,
1H). 13C-NMR (CDCl3, 125 MHz): 170.8 (CO), 139.5 (arom.), 137.1 (arom.), 134.3,
134.0, 133.6, 133.0 (CH CH2), 131.2, 129.2–127.8, 119.0, 116.9, 116.2 (arom.), 112.2
(CH CH2), 98.9 (C-1), 76.4 (C-5), 73.3 (C-3), 67.1 (OCH2), 60.9 (CH), 52.0 (C-2). Calc.:
C34H40NClO7 (610.5); C: 66.93, H: 6.61, N: 2.30; found: C: 66.21, H: 6.33, N: 1.99.
1,3,4,6-Tetra-O-Allyl-2-Deoxy-2-N-[3-Benzyloxy-4-(3-Phenyl-Vinylidene)-
2-Azetidinone-β-D-Glucopyranoside 16. Yield (3.8 g, 64%), clear thick oil. FT-IR
(NaCl film, cm−1): υ 3488, 3071, 3026, 2979, 2920, 1748, 1731, 1641, 1601, 1493, 1449,
1276, 1206, 1122, 996, 923, 751, 701, 613, 560. 1H-NMR (CDCl3, 500 MHz): 7.39–7.19
(m, 10H, arom.), 5.90–5.66 (m, 6H, 6 = CH), 5.27–4.85 (m, 11H, CH, CH2Ph, 4 =
CH2), 4.22–3.96 (m, 8H, 4 × OCH2), 3.78–3.69 (m, 6H, H-2, H-3, H-4, H-5, 2 × H-6).
13C-NMR (CDCl3, 125 MHz): 170.9 (CO), 139.5 (arom.), 137.0 (arom.), 134.9−133.0
(CH CH2), 128.7–127.8, 119.0, 118.4, 117.7 (arom.), 116.0 (CH CH2), 73.4 (C-5), 67.1
(CH2), 64.3, 64.1, 63.8 (OCH2), 61.1 (C-6), 59.7 (OCH2), 51.8 (CH), 45.6 (C-2). CI-MS
[m/z (%)]: 585 (M+ +16) (2), 567 (1), 557 (2), 536 (1), 485 (3), 453 (2), 412 (2), 409 (2),
400 (4), 395 (3), 385 (4), 379 (3), 371 (8), 356 (2), 351 (4), 342 (6), 325 (8), 300 (9), 279
(13), 258 (4), 244 (12), 238 (16), 227 (16), 223 (13), 215 (8), 211 (28), 204 (28), 195 (31),
183 (19), 171 (43), 166 (16), 164 (17), 154 (20), 152 (30), 148 (4), 140 (31), 130 (61), 128
(78), 116 (38), 114 (54), 109 (8), 104 (70), 102 (48), 96 (11), 94 (10), 91 (100), 88 (7), 76
(39), 66 (17), 50 (13).
General Procedure for Radical Elongations: Preparation of Compounds
17–21
A solution of perallyl N-substituted-2-azetidinone-D-glucosamines 12–16 (3 mmol),
AIBN (0.1–0.2 mmol), and 2-mercaptoethanol (10 mL) in 1,4-dioxane (10 mL) was de-
gassed by bubbling N2 gas in solution before heating at 75 ◦C (preheated oil bath). Stirring
was continued for 10 h and then concentrated to dryness. Coevaporation was carried out
twice with toluene and the residue was purified on silica gel column chromatography
(EtOAc and then 9:4:2 EtOAc/iPrOH/H2O).

1944
H. H. A. M. HASSAN AND R. SOLIMAN
1,3,4,6-Tetra-O-[3-(Hydroxythioethyl)-Propyl]-2-Deoxy-2-N-[(3-Benzyloxy-
4-(2-Hydroxyphenyl)-2-Azetidinone]-β-D-Glucopyranoside 17. Yield (2 g,
75%), clear thick oil. FT-IR (NaCl film, cm−1): υ 3333 br, 2920, 2868, 1755, 1661, 1598,
1487, 1451,1414, 1286, 1243, 1159, 1046, 1010, 935, 819, 757, 658. 1H-NMR (CD3OD,
500 MHz): 7.56–6.93 (m, 9H, arom.), 5.62 (d, 1H, J = 7.6 Hz, H-1), 5.58 (d, J = 13.7 Hz,
1H, –CH2Ph), 5.55 (d, J = 13.7 Hz, 1H, –CH2Ph), 4.60 (s br, 1H), 4.30–3.90 (m, 6H),
3.77 (m, 8H, 4 × CH2OH), 3.69–3.57 (m, 10H, 4 × OCH2, 2 × H-6), 3.29–3.28 (m, 1H,
H-4), 2.81 (m, 8H, 4 × SCH2 ), 2.69–2.59 (m, 8H, CH2S ), 2.13–2.05 (m, 4H, 4 ×
OH), 1.91–1.74 (m, 8H, 4 × CH2). 13C-NMR (CD3OD, 125 MHz): 155.3, 128.7, 128.5,
128.3, 111.7 (arom.), 66.4, 61.3, 61.0, 60.9, 60.8 (CH2), 60.1, 59.9, 59.7, 59.0 (CH2OH),
58.7 (C-2), 40.7 (CH), 34.3–33.5 ( S CH2 ), CH2 S), 29.8–28.0 ( CH2 CH2 ).
Calc.: C42H65NO12S4 (904); S: 14.18; found: S: 14.53.
1,3,4,6-Tetra-O-[3-(Hydroxythioethyl)-Propyl]-2-Deoxy-2-N-[(3-Benzyloxy-
4-(4-Methoxyphenyl)-2-Azetidinone]-β-D-Glucopyranoside 18. Yield (1.7 g,
63%), clear thick oil. FT-IR (NaCl film, cm−1): υ 3454, 2918, 2858, 1753, 1662, 1611,
1
1510, 1416, 1286, 1046, 941, 833, 634. H-NMR (500 MHz, CD3OD): δ 7.36 (d, J =
6.8 Hz, 2H, arom.), 7.10–6.90 (m, 5H, arom.), 6.86 (d, J = 6.8 Hz, 2H, arom.), 5.51 (s
br, 1H, H-1), 5.42 (s br, 1H, CH), 5.10 (s, 2H, CH2Ph), 4.90 (d, J = 5.1 Hz, 1H, CH),
4.60 (s br, 1H, CH), 4.25–4.10 (m, 2H, H-2, H-5), 3.80–3.75 (m, 8H, 4 × CH2OH), 3.75
(s, 3H, OCH3), 3.70–3.65 (m, 8H, 4 × OCH2), 3.60 (m, 1H, H-5), 2.85–2.80 (m, 8H,
4 × SCH2), 2.69–2.64 (m, 8H, 4 × CH2S), 1.88–1.82 (m, 8H, 4 × CH2). 13C-NMR (125
MHz, CD3OD): δ 148.7, 128.8–128.3, 109.1, 98.9, 71.8–70.1 ( OCH2 ), 61.3–61.1
( CH2 OH), 53.5, 53.4, 52.8–51.5, 34.3–32.7 ( S CH2 ), 30.8–30.2 ( CH2 S),
29.5–29.0 ( CH2 CH2 ). Calc.: C43H67NO12S4 (918); S: 13.97; found: S: 14.41.
1,3,4,6-Tetra-O-[3-(Hydroxythioethyl)-Propyl]-2-Deoxy-2-N-[(3-Benzyloxy-
4-(3-Methoxy-4-Hydroxyphenyl)-2-Azetidinone]-β-D-Glucopyranoside
19.
Yield (1.9 g, 69%), clear thick oil. FT-IR (NaCl film, cm−1): υ 3453 br, 2920, 2868, 1755,
1
1641, 1595, 1511, 1453, 1416, 1266, 1229, 1134, 1044, 937, 814, 755, 638. H-NMR
(CD3OD, 500 MHz): 7.56–6.93 (m, 9H, arom.), 5.62 (d, 1H, J = 7.6 Hz, H-1), 5.58 (d, J
= 13.75 Hz, 1H, –CH2Ph), 5.55 (d, J = 13.75 Hz, 1H, –CH2Ph), 4.06 (s br, 1H), 4.30–3.90
(m, 6H), 3.77 (m, 8H, 4 × CH2OH), 3.69–3.57 (m, 10H, 4× OCH2, 2× H-6), 3.29–3.28
(m, 1H, H-4), 2.81 (m, 8H, 4 × SCH2 ), 2.69–2.59 (m, 8H, CH2S ), 2.13–2.05 (m,
4H, 4 × OH), 1.91–1.74 (m, 8H, 4 × CH2). 13C-NMR (CD3OD, 125 MHz): 148.7,
147.3, 146.0, 132.7, 128.0, 127.0, 119.6, 111.9 (arom.), 86.0 (CH, C-5), 66.2 (CH2), 60.7,
60.3, 59.5, 59.1 (OCH2), 52.2 (C-2), 40.1 (CH), 39.9, 39.7, 33.5, 33.3, 33.9 ( SCH2 ),
29.0–27.0 ( CH2 CH2 ). Calc.: C43H67NO13S4 (934); S: 13.73; found: S: 14.02.
1,3,4,6-Tetra-O-[3-(Hydroxythioethyl)-Propyl]-2-Deoxy-2-N-[(3-Benzyloxy-
4-(4-Chloropenyl)-2-Azetidinone]-β-D-Glucopyranoside 20. Yield (1.9 g, 70%),
clear thick oil. FT-IR (NaCl film, cm−1): υ 3353 br, 2920, 2869, 1755, 1644, 1413, 1284,
1220, 1047, 1009, 940, 825, 635. 1H-NMR (CDCl3, 500 MHz): 7.63–6.92 (m, 9H, arom.),
5.62 (d, 1H, J = 7.6 Hz, H-1), 5.58 (d, J = 13.75 Hz, 1H, CH2Ph), 5.55 (d, J = 13.75
Hz, 1H, CH2Ph), 4.60–3.95 (m, 7H), 3.77 (m, 8H, 4 × CH2OH), 3.69–3.57 (m, 10H,
4 × OCH2, 2 × H-6), 3.29–3.28 (m, 1H, H-4), 2.81 (m, 8H, 4 × SCH2 ), 2.70–2.50
(m, 8H, CH2S ), 1.91–1.74 (m, 8H, 4 × CH2). 13C-NMR (CD3OD, 125 MHz): 155.3,
128.7, 128.5, 128.3, 111.7 (arom.), 66.4 (CH2), 61.3, 60.8, 60.1 (C-6), 59.7, 59.0, 58.7
(OCH2), 41.1 (C-2), 40.7 (CH), 34.3–33.5 (SCH2), 29.8–28.0 (CH2 CH2 ). Calc.:
C42H64NClO11S4 (922.5); C: 54.67, H: 6.99, N: 1.52, S: 13.90; found: C: 53.40, H: 6.17,
N: 1.03, S: 13.62.

SELF-ASSEMBLED PERSULFIDE MONOCYCLIC β-LACTAMS LAYER
1945
1,3,4,6-Tetra-O-[3-(Hydroxythioethyl)-Propyl]-2-Deoxy-2-N-[3-Benzyloxy-
4-(3-Phenyl-Vinylidene)-2-Azetidinone]-β-D-Glucopyranoside 21. Yield (1.9
g, 70%), clear thick oil. FT-IR (NaCl film, cm−1): υ 3328 br, 2917, 1728, 1712, 1695,
1665, 1644, 1601, 1554, 1535, 1448, 1414, 1285, 1220, 1044, 940, 819, 761, 703, 660.
1H-NMR (500 MHz, CD3OD): δ 7.50–7.25 (m, 10H, arom.), 6.94 (d, J = 16.4 Hz, 1H,
CH CHtrans), 5.50 (s br, 1H, H-1), 5.42 (s br, 1H, CH), 4.82 (s, 2H, CH2Ph), 4.20–3.90
(m, 4H, H-2, H-5, 2 × CH), 3.80–3.60 (m, 8H, 4 × CH2OH), 3.60–3.40 (m, 8H, 4 ×
OCH2), 2.82–2.80 (m, 8H, 4 × SCH2), 2.64–2.60 (m, 8H, 4 × CH2S), 1.84–1.70 (m, 8H,
4 × CH2). 13C-NMR (CD3OD, 125 MHz): δ 154.1 (arom.), 128.7–127.3 (arom.), 111.7,
71.78–69.95 ( O CH2 ), 61.36–60.90 ( CH2 OH, C-6), 53.53 (CH), 51.83 (C-2),
34.60–32.79 ( SCH2 ), 30.81–30.22 ( CH2 S), 29.46–28.37 ( CH2 CH2 ). Calc.:
C44H67NO11S4 (914); S: 14.03; found: S: 13.97.
CONCLUSIONS
The synthesis of new persulfide-spacer N-substituted-2-azetidinone-D-glucosamine
in the attempt to potentially provide new antibiotics is described. Staudinger [2+2] cy-
cloaddition of benzyloxyacetyl chloride to the newly reported per-O-allyl-N-substituted
benzylidene-2-deoxy-β-D-glucosamines 3, 5, 7, 9, and 11 provided the sugar-based mono-
cyclic β-lactams 12–16 in good yields. Radical addition of 2-mercaptoethanol to per-O-
allyl-N-substituted-2-azetidinone-D-glucosamine led to the persulfide spacers 17–21 in
good yields. All new compounds were characterized by spectroscopic and spectrometric
methods. The reported glucosides showed a moderate antifungal activity against Candida
albicans while being slightly active against gram-positive and gram-negative bacteria used
in this work. The SEM image of 1,3,4,6-tetra-O-[3-(hydroxythioethyl)-propyl]-2-deoxy-2-
N-[(3-benzyloxy-4-(4-chloropenyl)-2-azetidinone]-β-D-glucopyranoside, as a representa-
tive example, demonstrated a super hydrophobic layer formed via highly organized thioether
spacers on gold as the adsorbate system through the formation of sulfur–gold bonds. The
formation of self-assembled hydrophobic layer of carbohydrate-containing thioether spac-
ers on gold with a high degree of structural order is an important class of model substrates
for the mechanistic investigation of biomolecules and they might have potential application
as platforms for studies of cell adhesion due to their flexibility.36,37
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