Gabriel-Cromwell aziridination of amino sugars; chiral ferrocenoyl-aziridinyl sugar synthesis and their biological evaluation

Article abstract of DOI:10.1016/j.carres.2021.108430

N-sugar substituted chiral aziridines were synthesized via Gabriel-Cromwell reaction. Novel pure diastereomers of aziridine derivatives (4 diastereomers) were readily obtained in high yields and their structures were confirmed by means of ¹H NM

Full text of DOI:10.1016/j.carres.2021.108430

Carbohydrate Research 509 (2021) 108430
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Gabriel-Cromwell aziridination of amino sugars; chiral
ferrocenoyl-aziridinyl sugar synthesis and their biological evaluation
a,
1
a,
1
b
a,*
¨
Mustafa Sert , Ozer I s¸ ılar , Ayse Sahin Yaglioglu , Adnan Bulut
a
Department of Chemistry, Kırıkkale University, 71450, Yah s¸ ihan, Kırıkkale, Turkey
b
Department of Chemistry and Chemical Process Technology, Amasya University, 05186, Amasya, Turkey
A R T I C L E I N F O
A B S T R A C T
Keywords:
Amino sugar
Aziridine
Ferrocene
PC3
N-sugar substituted chiral aziridines were synthesized via Gabriel-Cromwell reaction. Novel pure diastereomers
of aziridine derivatives (4 diastereomers) were readily obtained in high yields and their structures were
confirmed by means of 1H NMR, C NMR, FT-IR, Mass and optical rotations. This is, to the best of our
knowledge, the unique example of N-sugar aziridine synthesis. Diastereomeric effects for prostate (PC3) and
cervix (HeLa) cancers were screened and it has been observed that the epimers bearing the same sugars showed
different results against PC3 and HeLa cancer cells. The novel sugar aziridines were investigated as promising
prodrug candidates for prostate cancer (PC3) therapy. Moreover, the drug likeness calculations (Lipinski’s rule,
physicochemical properties, lipophilicity, solubility, pharmacokinetics and bioavailability radar) have indicated
that the sugar aziridines can be good candidates as oral drugs.
13
HeLa
Drug likeness
1
. Introduction
Aziridine is a saturated three-membered heterocyclic amine con-
reaction) [12], Michael type addition [13], 1,2-amino alcohols (intra-
molecular cyclization) [14] and enantioselective catalytic aziridination
[15]. On the other hand, synthesis of aziridinyl sugar is limited due to
the nature of sugars. Despite the numerous transformations of aziridines,
few examples of synthetic methodologies have been described in car-
bohydrate chemistry. In other words, aziridine functionality has not
received the attention it deserves in synthetic carbohydrate chemistry.
taining one nitrogen atom in the ring [1–3]. The discovery of aziridines
dates back to 1888 [4]. Its inherent reactivity, like its analogue epoxide,
arises from the fact that the smallest strained three membered com-
pounds have bond angle distortion and the dipole between carbon and
hetero atom. Therefore, it has been used as a versatile building block in
many organic transformations. They allow convenient access to amines,
amino acids, amino alcohols, diamines, and other useful
nitrogen-containing molecules [5,6]. Moreover, aziridine ring can be
converted to azomethine ylides which can provide biologically impor-
tant heterocyclic compounds with a dipolarophile such as alkene,
alkyne, carbonyls and imines [7]. Although it has an inherent reactivity,
many natural and synthetic compounds containing aziridines are suffi-
ciently stable. Several natural aziridine alkaloids bearing the aziridine
ring exhibit potential biological activity such as mitomycin, azir-
inomycin and madurastatin [8–10].
N
One of the most used methods for aziridinyl sugar synthesis is the S 2
reaction between the vicinal groups such as amino and the leaving group
[16]. Reductive ring closure of azido-sugars by triphenylphosphine gave
aziridine-sugars with inversion of configuration [17]. Keniche et al.
synthesized aziridine-sugars from N-acyl-2-iodo-aziridines by nucleo-
philic displacement of iodine with amino-sugars [18]. Dhavale et al.
synthesized the D-glucose derived aziridine by using Gabriel-Cromwell
reaction from
α
-bromo-
α,β-unsaturated ester sugar and primary benzyl
amine [19] (Fig. 1b). Some sugar-derived aziridines are depicted in
Fig. 1 [20–23].
Cancer is the most abundant and fatal disease in the world, the
prostate and cervix cancer being among the most common for men and
women, respectively. Stereoisomeric drugs that have different structures
in three dimensional space operate differently towards chiral natural
living systems. In this context, many studies have been reported in
The synthesis of enantiomerically pure aziridines is one of the major
areas of organic chemistry. Some of the common synthetic methods used
in aziridine synthesis can be listed as follows; nitrene or nitrenoids
addition to alkene [11], carbene addition to imine (Aza-Darzens
*
Corresponding author.
E-mail address: adnnblt@kku.edu.tr (A. Bulut).
This authors contributed equally.
1
https://doi.org/10.1016/j.carres.2021.108430
Received 1 April 2021; Received in revised form 22 August 2021; Accepted 23 August 2021
Available online 28 August 2021
0
008-6215/© 2021 Elsevier Ltd. All rights reserved.

M. Sert et al.
Carbohydrate Research 509 (2021) 108430
medicinal chemistry [24]. Due to the different activities of enantiomers,
many disasters have occurred in medicinal treatments [25]. Moreover,
we have envisaged that ferrocene unit could improve anti-cancer ac-
tivity of sugar-aziridine diastereomers because many reports have been
published about excellent anti-cancer activities of ferrocene-based
molecules [26].
(the protocol adapted from the Dogan group [36] (Scheme 3).
Finally, two diastereomeric aziridinyl-ferrocenoyl sugars (13, 14, 15
and 16) were obtained readily in high yields (up to 90%). The reaction
mechanism (Gabriel–Cromwell reaction) for the last step is given in
Scheme 4. During the work-up, the flash columns were applied easily
because all the diastereomers (13, 14, 15 and 16) were colorful (Fig. 3).
Consequently, the diastereomers were purified and separated. Unfor-
tunately, single crystallization attempts failed. Therefore, the absolute
configurations of the diastereomers could not be determined. We
numbered the diastereomers in the order they came from the column.
The 1H NMR (see the Experimental section and Supporting Infor-
mation, respectively) of the compound 15 is chosen as a representative
Many synthetic aziridines have been tested for their biological ac-
tivity (Fig. 2). Vega-Peres at al. have synthesized aziridinyl gal-
actopyranoside derivatives from alkenyl β-D-galacto pyranosides using
Sharpless conditions and screened against lung cancer cell line. They
found that some possess high and selective anti-cancer activities [27].
Within this work pure chiral ferrocenoyl-sugar-aziridine stereoisomers
were synthesized and screened against PC3 and HeLa cancer cells.
1
example for verifying the formation aziridinyl sugar. In the H NMR
spectrum of 15, nine hydrogens of mono-substituted ferrocene resonate
at 4.87 (s, 2H), 4.52 (s, 2H) and 4.16 (s, 5H) ppm. The seven hydrogens
on the sugar ring appear at 5.92 (d, J = 3.6 Hz, 1Hanomeric), 4.47 (m,
2
. Results and discussions
2
8
H
2,3), 4.13–4.09 (m, 1H
4
), 4.00 (dd, J = 9.2, 3.2 Hz, 1H ), 3.93 (dd, J =
5
Novel N-sugar aziridines were obtained readily by employing the
.5, 5.8 Hz, 1H6a) and 2.41 ppm (d, J = 3.1 Hz, 1H6b) respectively. In
Gabriel-Cromwell reaction [33]. The synthesis starts with pure chiral
sugars which are cheap and commercially available in large quantities.
In this context, it can be called as “chiral pool asymmetric aziridine
synthesis”. Newly formed chiral center and the preserved absolute
configuration of the sugars (1 and 5) afforded easily separable
ferrocenoyl-aziridinyl-sugar diastereomers.
addition, the methyl hydrogens of isopropylidene groups appear at 1.44,
.36, 1.32 and 1.23 ppm as sharp singlets. On the other hand, H of
) while its
) and 2.15 (d,
1
α
aziridine ring was observed at 2.59 (dd, J = 6.4, 3.3 Hz, 1H
α
diastereotopic hydrogens appear at 2.33 (d, J = 3.2 Hz, 1H
J = 6.6 Hz, 1Hβ’) ppm respectively.
β
2
.1. Chemistry
2.2. Anticancer activity results
The synthetic part might be divided into three sections as follows;
Anticancer activities of the compounds (13, 14, 15 and 16) against
amino sugar synthesis,
α
,β-dibromopropanoylferrocene synthesis and
HeLa and PC3 cells were investigated at four different concentrations
aziridinyl sugar synthesis. In the first part, amino sugars (4 and 8) were
obtained in three steps as we have reported [34] (Scheme 1). Firstly,
commercially available sugars were tosylated with p-toluenesulfonyl
chloride in pyridine at room temperature. Next, the tosylated sugars (2
(100, 50, 25 and 5 M). IC50 values of the compounds 13, 14, 15 and 16
μ
against HeLa and PC3 cells are given in Table 1.
As can be seen from Table 1 all of the sugar aziridines (13, 14, 15 and
16) depicted significant toxic effect with IC50 values of 29.50 ± 0.02
23.55 ± 0.01 M, 27.98 ± 0.05 M and 29.32 ± 0.05 M against PC3 cell
M). Of the
μ
M,
and 6) were reacted with sodium azide, NaN
sugars (3 and 7). Subsequently, azido-sugars (3 and 7) were reduced
with LiAlH , into amino-sugars (4 and 8).
In the second part, acryloylferrocene was obtained from ferrocene
and acryloyl chloride in the presence of an alkyl Lewis acid (EtAlCl or
EtAlCl Al) [35]. Next, it was dibrominated according to the Dogan
–Me
group procedure [36] (Scheme 2).
In the third part,
,β-dibromopropanoylferrocene (12) and either
amino sugar (4 and 8) were reacted for 3 days at ambient temperature
3
, to give azido-deoxy
μ
μ
μ
with respect to the standard drug 5-FU (IC50: 37.40 ± 0.01
μ
4
four aziridines, 14 afforded the best cytotoxicity with IC50 value of
23.55 ± 0.01. On the other hand, these four compounds (13, 14, 15 and
16) showed very poor toxic effect against HeLa cancer with IC50 values
2
2
3
of 39.57 ± 0.01
0.01 M against HeLa cell with respect to the standard drug 5-FU (IC50
2.51 ± 0.01 M).
The anticancer activities of compounds 13, 14, 15, 16 and 5-FU were
μM, 25.88 ± 0.01 μM, 39.25 ± 0.03 μM and 24.98 ±
μ
:
α
μ
Fig. 1. Some selected sugar-derived aziridines.
2

M. Sert et al.
Carbohydrate Research 509 (2021) 108430
Fig. 2. Some selected biologically active aziridines [28–32].
◦
, THF, ꢀ 10 ◦C.
Scheme 1. i) TsCl, Pyridine, rt ii) NaN
3
, DMF, 150 C iii) LiAlH
4
Scheme 2.
α,β-dibromopropanoylferrocene synthesis.
determined to have the dose dependent effects against the PC3 cell lines
Fig. 4-A). Although at all doses, 13, 14, 15 and 16 were investigated to
provide higher activities than 5-FU (standard compound) against PC3
cell, at the lowest dose (5 M) remarkable activities were shown by 13
and 16 (10 times higher and 7 times higher inhibition than the standard
-FU respectively). IC50 results of 13 and 16 also confirm these
activities.
As with PC3, when the sugar aziridines (13, 14, 15 and 16) and 5-FU
were screened with HeLa cells, they exhibited a dose-dependent effect
Fig. 4-B). In contrast to PC3 cancer cell, they afforded poor activities
applications as drugs. Only five drug candidates can reach the stage of
clinical testing as a result of screening of about 10,000 compounds.
Before the discovery and drug development stages, it is necessary to
acquire sufficient knowledge and physicochemical properties about the
diseases and symptoms for which the considered drug can be used. Drug
candidates that fit RO5 rules tend to have an increased chance of
reaching the higher clinical stages. The four chiral azirdinyl-sugars (13,
14, 15 and 16) obey the Lipinski’s rule as explained below. Their
number of hydrogen bond acceptors (HBA) and donors (HBD) are within
the Lipinski’s rules; n-ON <10 and n-OHNH<5. Their calculated logP
are smaller than 5 (logP <10, according to Lipinski’s rules). The mo-
lecular weights of them are 497.36 g/mol which must be smaller than
(
μ
5
(
against HeLa cancer cell than the standard drug at all concentrations.
High IC50 results at HeLa cancer cell support these results (Table 1).
5
00 g/mol according to Lipinski’s rules. In drug design, the blood-brain
barrier (BBB) score is valuable physicochemical information since it
prevents toxic effects of drugs. As can be seen at Table 3, the BBB score of
2
.3. Drug likeness properties
1
3, 14, 15 and 16 ranges from 3.09 to 3.12 (the BBB score should be
One of the aims for synthesis of molecules is related to their
3

M. Sert et al.
Carbohydrate Research 509 (2021) 108430
Scheme 3. Synthesis of Sugar-aziridine-ferrocenoyl diastereomers.
Scheme 4. Gabriel-Cromwell aziridination mechanism.
Table 1
IC50 values of compounds 13, 14, 15, 16 and 5-FU (standard drug).
Compound PC3 ( M) HeLa ( M)
μ
μ
1
1
1
1
5
3
29.50 ± 0.02
23.55 ± 0.01
27.98 ± 0.05
29.32 ± 0.05
37.40 ± 0.01
39.57 ± 0.01
25.88 ± 0.01
39.25 ± 0.03
24.98 ± 0.01
2.51 ± 0.01
4
5
6
-FU
and 16) were investigated as soluble and moderately soluble respec-
tively. In addition, their skin permeations are equal and found as ꢀ 7.32
which implies they have moderately skin permeations. As a result of
Lipinski’s rule of five (RO5) and other physicochemical calculations, 13,
1
4, 15 and 16 might be a new potential anticancer agents according to
the calculated data (see Tables 2 and 3).
Fig. 5 shows the bioavailability radars of 13, 14, 15 and 16. The
pentagonal pink area represents the optimal range for each property
(
lipophilicity: LOGP between ꢀ 0.7 and + 5.0, size: MW between 150
2
and 500 g/mol, polarity: TPSA between 20 and 130 Å , solubility: log S
Fig. 3. Visible flash column for diastereomeric aziridinyl-ferrocenoyl
3
sugar separation.
not higher than 6, saturation: fraction of carbons in the sp hybridization
not less than 0.25, and flexibility: no more than 9 rotatable bonds. Thus,
it can be concluded that the compounds of 13, 14, 15 and 16 can be
orally bioavailable.
between 6-high and 0-low) [37]. The synthetic accessibility scores of the
gluco-aziridine epimers (13 and 14) and galacto-aziridine (15 and 16)
epimers have been found as 6.14 and 6.20 respectively (Table 2). The
acceptable range for the synthetic accessibility is 1 (very easy) to 10
3
. Conclusion
(
difficult). Topological polar surface area (TPSA) values of 13, 14, 15
In summary, the present study reports the successful synthesis,
and 16 were smaller than 70 Å (66.23 Å). Moreover, the solubilities of
the gluco-aziridine derivatives (13 and 14) and galacto-aziridine (15
characterization, cytotoxic, anticancer and drug likeness study of novel
4

M. Sert et al.
Carbohydrate Research 509 (2021) 108430
Fig. 4. Antiproliferative activity of 13, 14, 15, 16 and 5-FU against PC3 (A) and HeLa (B) cells lines *Data are presented as mean ± SD (n = 6). Statistical significant
difference (p < 0.01) was observed between treatments (ANOVA, Duncan).
aziridinyl sugar derivatives. Two different amino-sugars have been
synthesized and reacted with freshly synthesized
,β-dibromo prop-
literatures [34,35] respectively. 3-Amino-3-deoxy-1,2:5,6-di-O--
isoproylidene- -D-glucofuranose (4) and 6-Amino-6-deoxy-1,2:3,
4-di-O-isopropylidene- -D-galactopyranose (8) were prepared according
α
α
anoylferrocene to give four different novel diastereomeric ferrocenoyl-
aziridinyl sugars in high yields (80–90%). Of particular significance is
reporting the first synthesis N-sugar substituted aziridine within this
research. In addition, their separation is quite easy through flash column
chromatography (without need TLC) since they are colorful and visible.
Furthermore, their antiproliferative activity against PC3 and HeLa
cancer cells were tested and found as good prodrug candidates for PC3
cancer cell. As a result of antiproliferative activities at the low dose (5
α
to our previous report [33].
1H and 13C NMR spectra of CDCl
solutions were measured on a
3
Bruker spectrospin Avance DPX-400 Ultra shield instrument at 400 MHz
and 100 MHz respectively (standard TMS). FT-IR spectra were obtained
on Bruker Platinum ATR-IR instrument and reported in reciprocal cen-
ꢀ 1
timeters (cm ). All solvents were dried and distilled prior to use. For
measuring optical rotations, Rudolph Research Analytical Autopol III
Polarimeter was used. Products were separated by flash column chro-
matography on Silica Gel 60 (Merck, 230–400 mesh ASTM). TLC ana-
μ
M), 13 and 16 can be good drug candidates for prostate cancer with
IC50 values of 29.50 ± 0.02 M and 29.32 ± 0.05 M respectively. IC50
μ
μ
results also confirm these activities. Compounds 13, 14 and 15, 16 are
epimers among themselves and have given different anti-cancer activ-
ities. Thus, it can be interpreted that different absolute configurations of
chiral compounds might give different biological evaluations. Finally,
the drug likeness calculations were performed in order to find the ideal
bioavailability. The molecular weight (MW), the number of hydrogen
bond acceptors (HBA), the number of hydrogen bond donors (HBD), the
number of rotatable bonds (RB) and the topological polar surface area
lyses were applied on 250 m Silica Gel 60 F254 plates. Mass spectra
μ
were recorded with GCMS-QP2010 Plus SHIMADZU instrument. The
NMR spectra, FT-IR spectra and Mass spectra are given in Supplemen-
tary data section.
4.1.1. Procedure for aziridination of amino sugars
6-Amino-6-deoxy-1,2:3,4-di-O-isopropylidene-
(8) (0.122 g, 0,4703 mmol) was dissolved in 1 mL of CH
for 30 min. To this solution, 1,2-dibromoprapanoylferrocene (12)
(0.150 g, 0.4703 mmol) and Et N (0.13 mL, 0,9406 mmol) were added.
α
-D-galactopyranose
2
Cl and stirred
2
(
TPSA) for all the compounds are in good agreement with the Lipinski’s
rule of five.
3
The reaction period was monitored via TLC. After mixing 2 days at
◦
ambient temperature (25 C), It was directly added to the column (as
4
. Experimental
eluent system: Hexane-EtOAc (1:1)) for separation and purification
without doing any work-up. The colorful diastereomers (13 and 14)
were readily collected without doing TLC. 0.130 g 13 and 0.081 g 14
were isolated. (90% total yield). The diastereomers were numbered in
the order they came from the column.
4
.1. Chemistry (General methods)
All chemicals including 1,2:5,6-di-O-isopropylidene- -D-allofuranose
α
(
1) and 1,2:3,4-di-O-isopropylidene- -D-galactopyranose (5) were sup-
α
plied from Sigma-Aldrich Company. Acryloyl ferrocene (11) and 1,2-
dibromoprapanoylferrocene (12) were prepared according to the
5

M. Sert et al.
Carbohydrate Research 509 (2021) 108430
Table 2
Physicochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness and medicinal chemistry of 13, 14, 15 and 16 predicted using Swiss ADME.
No
Physicochemical
properties
Lipophilicity
Water solubility
Pharmacokinetics
Drug likeness
Medicinal Chemistry
1
3
Formula:
Log Po/W (iLOGP):
0.00
Log S (ESOL): 4.31
Solubility:2.43e-02 mg/
ml; 4.89e-05 mol/l
Class:Moderately soluble
Log S (Ali): 3.88
GI absorption: High
BBB permeant:Yes
P-gpsubstrate:Yes
Lipinski: Yes
Ghose: No; 1
violation: MW > 480
Veber: Yes
PAINS: = 0 alert
and
C25H31FeNO6
Moleculer weight:
Brenk: 2 alers: Three-
membered_heterocycle,
heavy_metal
1
4
Log Po/W
4
97.36 g/mol
(XLOGP3):2.83
Log Po/W
CYP1A2 inhibitor:No
CYP2C19 inhibitor:No
CYP2C9 inhibitor:No
CYP2D6 inhibitor:No
CYP3A4 inhibitor:No
Log Kp (skin
Num. heavy atoms: 33
Num. arom.heavy
atoms: 0
Egan: Yes
Leadlikeness: No; 1 violation: MW
> 350
(WLOGP):2.54
Log Po/W
Solubility: 6.58e-02 mg/
ml; 1.32e-04 mol/l
Class: Soluble
Muegge: Yes
Bioavailability Score:
0.55
Synthetic accessibility: 6.14
Fraction Csp3:0.64
Num. rotatable
bon4ds: 6
(MLOGP):1.67
Log Po/W (SILICOS-
IT):0.43
Log S(SILICOS-IT): 1.58
Solubility: 1.31e+01 mg/
ml; 2.64e-02 mol/l
Class: Soluble
permeation): 7.32 cm/s
Num. H-bond
acceptors: 7
Consensus Log Po/
W
: 1.49
Num. H-bond donors:
0
Molar Refractivity:
1
20.22
TPSA: 66.23 Å
Formula:
1
5
Log Po/W (iLOGP):
0.00
Log S (ESOL): 4.31
Solubility:2.43e-02 mg/
ml; 4.89e-05 mol/l
Class:Moderately soluble
Log S (Ali): 3.88
GI absorption: High
BBB permeant:Yes
P-gpsubstrate:Yes
Lipinski: Yes
Ghose: No; 1
violation: MW > 480
Veber: Yes
PAINS: = 0 alert
and
C25H31FeNO6
Moleculer weight:
Brenk: 2 alers: Three-
membered_heterocycle, heavy
metal
1
6
Log Po/W
4
97.36 g/mol
(XLOGP3):2.83
Log Po/W
CYP1A2 inhibitor:No
CYP2C19 inhibitor:No
CYP2C9 inhibitor:No
CYP2D6 inhibitor:No
CYP3A4 inhibitor:No
Log Kp (skin
Num. heavy atoms: 33
Num. arom.heavy
atoms: 0
Egan: Yes
Leadlikeness: No; 1 violation: MW
> 350
(WLOGP):2.54
Log Po/W
Solubility: 6.58e-02 mg/
ml; 1.32e-04 mol/l
Class: Soluble
Muegge: Yes
Bioavailability Score:
0.55
Synthetic accessibility: 6.20
Fraction Csp3:0.64
Num. rotatable
bon4ds: 6
(MLOGP):1.67
Log Po/W
Log S(SILICOS-IT): 1.45
Solubility: 1.76e+01 mg/
ml; 3.53e-02 mol/l
Class: Soluble
(SILICOS-IT):0.51
Consensus Log Po/
W: 1.51
permeation): 7.32 cm/s
Num. H-bond
acceptors: 7
Num. H-bond donors:
0
Molar Refractivity:
1
20.22
TPSA: 66.23 Å
Table 3
SMILES, Lipinski rule of five and drug-likeness of 13, 14, 15 and 16 predicted using molsoft programe.
No
SMILES
Molecular properties
Drug likeliness
–
1
3
4
[H][C@@]1(CN1CC1OC2OC(C)(C)OC2C2OC(C)(C)OC12)C(=O)C1=CC
–
CC1
Molecular formula:C25H31FeNO6
Molecular weight: 497.15
Number of HBA: 7
–
–
–
–
CC C1
[
Fe]C1C
–
–
CC1
1
[H][C@]1(CN1CC1OC2OC(C)(C)OC2C2OC(C)(C)OC12)C(=O)C1=CC
–
–
–
–
CC C1
[
Fe]C1C
Number of HBD: 0
MolLogP: 3.72
MolLogS: 3.70 (in Log (moles/L)) 98.27
(
in mg/L)
2
MolPSA: 58.49 A
3
MolVol: 523.23 A
Number of stereo centers: 7
BBB Score: 3.09
Drug-likeness model score: 0.82
1
5
6
[H][C@@]1(CN1C1C(OC2OC(C)(C)OC12)C1COC(C)(C)O1)C(=O)
Molecular formula:C25H31FeNO6
Molecular weight: 497.15
Number of HBA: 7
–
–
– –
CC C1
– –
C1=CC
CC1[Fe]C1C
–
–
1
[H][C@]1(CN1C1C(OC2OC(C)(C)OC12)C1COC(C)(C)O1)C(=O)C1=CC
CC1
–
–
–
–
CC C1
[
Fe]C1C
Number of HBD: 0
MolLogP: 3.99
MolLogS: 4.02 (in Log (moles/L)) 47.37(in
mg/L)
2
MolPSA: 56.08 A
3
MolVol: 525.60 A
Number of stereo centers: 7
BBB Score: 3.12
Drug-likeness model score: 1.41
4
.1.1.1. (2R(or
2S))-1-(6-amino-6-deoxy-1,2:3,4-di-O-isopropylidene-
= 4.9, 2.1 Hz, 1H
7.5 Hz, 1H6a), 2.66 (dd, J = 6.2, 3.0 Hz, 1H
1H6b), 2.30 (s, 1H
4
), 4.17 (s, 5H-Fc), 4.05 (m, 1H
5
), 2.73 (dd, J = 11.7,
2
5
α
2
1
5
1
-D-galactopyranose) aziridin-2-yl)(ferrocenyl)methanone (13). [
α
]
= -
α
), 2.55 (dd, J = 11.7, 5.8 Hz,
D
91.7 (c = 0.0005, CHCl
3
); FT-IR (neat): 2985, 2920, 1665, 1457, 1372,
β
), 1.82 (d, J = 6.4 Hz, 1Hβ’), 1.48 (s, 3Hip), 1.39 (s,
1
13
257, 1213, 1105, 1069, 1016, 841, 484. H NMR (400 MHz, CDCl
3
) δ
.44 (d, J = 4.9 Hz, Hanomeric), 4.85 (s, 1H-Fc), 4.83 (s, 1H-Fc), 4.52 (s,
), 4.48 (d, J = 9.8 Hz, 2H-Fc), 4.25 (d, J = 8.0 Hz, 1H )), 4.22 (dd, J
3Hip), 1.25 (s, 3Hip), 1.22 (s, 3Hip). C NMR (101 MHz, CDCl
3
) δ 200.2,
1
108.9, 108.6, 96.3, 78.6, 72.7, 72.5, 71.2, 70.6, 70.5, 70.1, 69.9, 69.1,
H
2
3
66.9, 59.7, 41.8, 35.6, 26.1, 24.9, 24.4. GC-Mass, m/z calcd. for
6

M. Sert et al.
Carbohydrate Research 509 (2021) 108430
Fig. 5. Drug-likeness of 13, 14, 15 and 16 were predicted using Bioavailability radar. The pink area represents the optimal range for each properties (Lipo: Lip-
ophilicity, Size: Moleculer weight, POLAR: Total Polar Surface Area, INSOLU: Insolubility, INSATU: Insaturation, FLEX: Flexibility). (For interpretation of the ref-
erences to color in this figure legend, the reader is referred to the Web version of this article.)
C
25
H
31FeNO
6
[m/z]: 497.1, found: 497.0.
2R))-1-(6-amino-6-deoxy-1,2:3,4-di-O-isopropylidene-
4.1.1.4. (2S (or 2R)-1-(3-amino-3-deoxy-1,2:5,6-di-O-isopropylidene-
2
5
α
-D-glucofuranose) aziridin-2-yl)(ferrocenyl)methanone (16). [
α
]
=
D
4
.1.1.2. (2S(or
ꢀ 140.0 (c = 0.0027, CHCl
3
); FT-IR (neat): 2924, 2854, 1743, 1650,
2
5
α
8
1
4
2
2
-D-galactopyranose) aziridin-2-yl)(ferrocenyl)methanone (14). [
α
]
= +
1542, 1455, 1374, 1256, 1210, 1116, 1106, 1067, 1002, 860, 821, 484.
D
1
5.4 (c = 0.0005, CHCl
169, 1075, 1015, 824, 509. H NMR (400 MHz, CDCl
.9 Hz, 1Hanomeric), 4.86 (s, 1H-Fc), 4.80 (s, 1H-Fc), 4.54 (dd, J = 7.9,
.0 Hz, 1H ), 4.20 (dd, J = 4.9,
), 4.48 (s, 2H-Fc), 4.30 (d, J = 7.9 Hz, 1H
.2 Hz, 1H ), 2.68
), 4.19–4.15 (m, 5H), 2.75 (dd, J = 11.9, 6.6 Hz, 1H
3
); FT-IR (neat): 2981, 1660, 1460, 1374, 1257,
H NMR (400 MHz, CDCl
(m, 2H-Fc), 4.55 (d, J = 3.6 Hz, 1H-Fc), 4.51 (s, 1H-Fc), 4.46 (d, J = 1.2
Hz, 1H ), 4.14 (s, 5H-Fc), 4.00–3.87 (m, 3H4,5,6a),
), 4.25–4.16 (m, 1H
2.88 (dd, J = 6.5, 3.3 Hz, 1H ), 2.34 (d, J = 3.3 Hz, 1H ), 2.30 (d, J = 1.7
Hz, 1H6b), 1.84 (d, J = 6.6 Hz, 1Hβ’), 1.43 (s, 3Hip), 1.31 (s, 3Hip), 1.26
3
) δ 5.97 (d, J = 3.6 Hz, 1Hanomeric), 4.89–4.83
1
3
) δ 5.43 (d, J =
2
3
2
3
α
β
4
5
1
3
(
dd, J = 6.3, 3.1 Hz, 1H6a), 2.51 (dd, J = 11.9, 6.1 Hz, 1H6b), 2.42 (s,
(s, 3Hip), 0.98 (s, 3Hip). C NMR (101 MHz, CDCl
3
) δ 199.3, 111.5,
1
H
α
), 2.21 (d, J = 14.7 Hz, 1H
ip), 1.39 (s, 3Hip), 1.21 (s, 3Hip), 1.18 (s, 3Hip). C NMR (101 MHz,
) δ δ 199.9, 109.0, 108.6, 96.2, 78.6, 72.5, 71.5, 70.6, 70.3, 70.1,
9.9, 69.1, 7.2, 60.1, 41.4, 36.1, 29.7, 26.1, 26.1, 24.9, 24.3. GC-Mass,
m/z calcd. for C25 31FeNO [m/z]: 497.1, found: 497.0.
-Amino-3-deoxy-1,2:5,6-di-O-isoproylidene- -D-glucofuranose (4)
0.122 g, 0,4703 mmol) was dissolved in 1 mL of CH Cl and mixed for ½
of an hour. To this solution, 1,2-dibromoprapanoylferrocene (12)
0.150 g, 0.4703 mmol) and Et N (0.13 mL, 0,9406 mmol) were added.
β
), 1.82 (d, J = 6.4 Hz, 1Hβ’), 1.41 (s,
109.3, 105.1, 84.9, 81.4, 78.3, 74.9, 72.8, 72.5, 72.4, 71.1, 69.9, 68.6,
1
3
3
H
67.9, 43.8, 33.6, 26.9, 26.8, 26.3, 24.9. GC-Mass, m/z calcd. for
CDCl
3
25 6
C H31FeNO [m/z]: 497.1, found: 497.0.
6
H
6
3
α
Declaration of competing interest
(
2
2
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
(
3
The reaction period was monitored via TLC. After mixing 2 days at
◦
ambient temperature (25 C), It was directly added to the column (as
eluent system: Hexane-EtOAc (1:1)) for separation and purification
without doing any work-up. The colorful diastereomers (13 and 14)
were readily collected without doing TLC. 0.078 g 15 and 0.090 g 16
were isolated. (85% total yield). The diastereomers were numbered in
the order they came from the column.
Acknowledgement
This work was supported by Scientific Research Projects Coordina-
tion Unit of Kırıkkale University. Project number: 2018/032.
Appendix A. Supplementary data
4
.1.1.3. (2R(or
2S))-1-(3-amino-3-deoxy-1,2:5,6-di-O-isopropylidene-
2
5
α
4
1
-D-glucofuranose) aziridin-2-yl)(ferrocenyl)methanone (15). [
α
]
= +
D
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.carres.2021.108430.
5.0 (c = 0.0008, CHCl
210, 1105, 1066, 1001, 802, 484. H NMR (400 MHz, CDCl
3
); FT-IR (neat): 2923, 1646, 1455, 1375, 1257,
1
3
) δ 5.92 (d,
J = 3.6 Hz, 1Hanomeric), 4.87 (s, 2H-Fc), 4.52 (s, 2H-Fc), 4.47 (m, 2H2,3),
.16 (s, 5H-Fc), 4.13–4.09 (m, 1H ), 4.00 (dd, J = 9.2, 3.2 Hz, 1H ), 3.93
dd, J = 8.5, 5.8 Hz, 1H6a), 2.59 (dd, J = 6.4, 3.3 Hz, 1H ), 2.41 (d, J =
.1 Hz, 1H6b), 2.33 (d, J = 3.2 Hz, 1H ), 2.15 (d, J = 6.6 Hz, 1Hβ’), 1.44
s, 3Hip), 1.36 (s, 3Hip), 1.32 (s, 3Hip), 1.23 (s, 3Hip). C NMR (101 MHz,
CDCl
) δ 199.6, 111.7, 109.3, 105.3, 84.9, 81.5, 78.1, 74.9, 72.9, 72.8,
2.6, 69.9, 69.8, 69.5, 68.2, 40.5, 37.8, 26.9, 26.8, 26.3, 25.4. GC-Mass,
m/z calcd. for C25 31FeNO [m/z]: 497.1, found: 497.0.
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