N-Alkyl derivatives of diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside; synthesis and antimicrobial activity

Article abstract of DOI:10.3762/bjoc.11.97

Diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside is a synthetic saponin exhibiting attractive pharmacological properties. Different pathways tested by us to obtain this glycoside are summarized here. Moreover, the synthesis of N-alkyl and N,N-dialkyl derivat

Full text of DOI:10.3762/bjoc.11.97

N-Alkyl derivatives of diosgenyl 2-amino-2-deoxy-β-D-gluco-
pyranoside; synthesis and antimicrobial activity
Agata Walczewska1, Daria Grzywacz1, Dorota Bednarczyk1, Małgorzata Dawgul2,
Andrzej Nowacki1, Wojciech Kamysz2, Beata Liberek*1,§ and Henryk Myszka1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 869–874.
1Department of Chemistry, University of Gdańsk, Wita Stwosza 63,
80-308 Gdańsk, Poland and 2Department of Pharmacy, Medical
University of Gdańsk, Hallera 107, 80-416 Gdańsk, Poland
doi:10.3762/bjoc.11.97
Received: 19 December 2014
Accepted: 17 April 2015
Published: 22 May 2015
Email:
Beata Liberek* - beata.liberek@ug.edu.pl
Associate Editor: N. Sewald
* Corresponding author
§ Tel.: + 48 58 5235071; Fax: + 48-58-5235012
© 2015 Walczewska et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
antimicrobial activities; D-glucosamine; diosgenin glycosylation;
N-alkylation
Abstract
Diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside is a synthetic saponin exhibiting attractive pharmacological properties. Different
pathways tested by us to obtain this glycoside are summarized here. Moreover, the synthesis of N-alkyl and N,N-dialkyl derivatives
of the glucopyranoside is presented. Evaluation of antibacterial and antifungal activities of these derivatives indicates that they have
no inhibitory activity against Gram-negative bacteria, whereas many of the tested N-alkyl saponins were found to inhibit the growth
of Gram-positive bacteria and human pathogenic fungi.
Introduction
Saponins are a group of steroid or triterpenoid glycosides, yields of homogenous saponins isolated from natural sources
widely distributed in the plant kingdom [1]. Saponins are char- are rather low. Therefore, chemical synthesis of saponins have
acteristic by their foaming properties in aqueous solution, been investigated [12-22] as well as the evaluation of their anti-
causing them to be used as detergents, surfactants and emulsi- tumor activities [23-27].
fiers. Moreover, they display a wide range of pharmacological
activities, including antifungal, antiparasitic, antiinflammatory, Naturally-occurring diosgenyl glycosides are the most abun-
antibacterial, and antitumor activities [2-5]. No wonder, dant steroidal saponins. They have been continuously synthe-
saponins have been evaluated as vaccine adjuvants [6]. Despite sized [28-32] and their cardiovascular, antifungal, anticancer
the fact that thousands of homogeneous saponins have been [33-36] and antithrombotic activities [37] have been investi-
characterized, new types of saponins are regularly isolated from gated. Gelation ability of the pentose derivatized diosgenyl
nature and their biological activities are evaluated [7-11]. The saponins have also been reported [38]. In the family of
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Beilstein J. Org. Chem. 2015, 11, 869–874.
Results and Discussion
diosgenyl β-glycosides D-glucopyranose is the first sugar at-
tached to the diosgenin. Very often this D-glucopyranose is Chemistry
substituted with α-L-rhamnopyranose at 2-OH and other sugars To synthesize the parent diosgenyl 2-amino-2-deoxy-β-D-
at 4-OH. The change of D-glucopyranose into 2-amino-2- glucopyranoside (7), the O-acetylated bromides 2a–d, chlo-
deoxy-D-glucopyranose provides diosgenyl 2-amino-2-deoxy- rides 3a–d and (N-phenyl)trifluoroacetimidates 5a–d, α or β
β-D-glucopyranoside (7), a synthetic saponin, first reported by anomers, were examined (Scheme 1). These glycosyl donors
us [39]. It was also demonstrated that diosgenyl 2-amino-2- were N-protected with trifluoroacetyl (TFA, a), 2,2,2-
deoxy-β-D-glucopyranoside hydrochloride increases the trichloroethoxycarbonyl (Troc, b), phthaloyl (Phth, c), and
number of apoptotic B cells, in combination with cladribine tetrachlorophthaloyl (TCP, d) groups, respectively. Applica-
(2-CdA), which were isolated from chronic lymphotic leukemia tions of bromides 2a and 2d [40] and chlorides 3a–d [45] were
(B-CLL) patients [40]. The presence of the amine group in this previously reported. Here, applications of the two remaining
promising antitumor compound creates the opportunity to bromides 2b and 2c as well as (N-phenyl)trifluoroacetimidates
synthesize new analogues with an enhanced activity. In this 5a–d are demonstrated. To synthesize bromide 2b we used a
way, many of the N-acyl [41-43] as well as urea and thiosemi- procedure described by Ellervik and Magnusson for other
carbazone [44] analogues of 7 have been obtained and evalu- glycosylations [46]. However, the bromide obtained by them
ated. Their characteristic feature is that their amine group is was a mixture of α and β anomers whereas 2b is a pure α
bound with the carbonyl or thiocarbonyl group. Such analogues anomer (J1,2 4,0 Hz). Bromide 2b, identified as the α anomer,
are much more lipophilic, but also less basic than the parent was also synthesized by Higashi et al., but in a slightly different
saponin 7. In this paper, for the first time, the synthesis and manner [47]. Bromide 2c (α + β) was synthesized analogously
antimicrobial activity of the N-alkyl derivatives of diosgenyl to 2b. Synthesis of (N-phenyl)trifluoroacetimidates 5a–d
2-amino-2-deoxy-β-D-glucopyranoside (7) are presented. From demands removal of the acetyl groups from the anomeric
the chemical point of view, the alkyl group has quite different hydroxy groups in 1a–d. It was done with ethylenediamine in a
properties than the acyl group. First, alkylation does not change mixture with acetic acid in THF, a procedure adopted from
significantly the basicity of the parent amine group. Thus, the Zhang and Kováč [48]. This selective 1-O-deacetylation turned
ability to bind protons by the parent compound and its analogue out to be very effective for 1a, 1b, and 1c (97%, 84%, and 90%,
should be comparable. Second, the N-alkylamine group, simi- respectively). However, this was quite ineffective for 1d (36%).
larly to the amine group, is able to work as a hydrogen bond Therefore, 1-O-deacetylation of the latter was carried out via
acceptor. On the other hand, alkylation improves lipophilicity of hydrolysis (Ag2CO3, acetone/H2O 2:1) of bromide 2d (73%
the compound, which may be crucial for its biological activity.
yield) or chloride 3d (72% yield). (N-Phenyl)trifluoroacetimi-
dates 5a–d were synthesized in reaction of the respective
At the beginning, our experiences concerning the synthesis of N-protected 3,4,6-tri-O-acetyl-D-glucosamines 4a–d with
the parent diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7) N-phenyltrifluoroacetimidoyl chloride, according to a proce-
are summarized and presented. We have studied different dure proposed by Yu and Tao for 1-hydroxy derivatives of
glycosyl donors, different amine group protections, different D-glucose and L-rhamnose [49].
solvents and promoters to find the best way to obtain 7. The
presented compilation is informative for all those interested in Glycosylation of diosgenin with twelve different derivatives of
the glycosidation of 2-amino-2-deoxy sugars.
D-glucosamine (2a–d, 3a–d, and 5a–d), was examined using
Scheme 1: Reagents used for the synthesis of diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7).
870

Beilstein J. Org. Chem. 2015, 11, 869–874.
“normal” and “reverse” procedures [50] (Table 1). In the remaining bromides react similarly. The same refers to chlo-
“normal” procedure, the promoter (silver triflate or trimethyl- rides 3a–d. In the case of (N-phenyl)trifluoroacetimidates 4a–d,
silyl triflate) was added to the solution of diosgenin and the the least efficient is 4d with the tetrachlorophthaloyl protection
respective glycosyl donor. In the “reverse” procedure, the of the amine group; the remaining (N-phenyl)trifluoroacetimi-
respective glycosyl donor was added to the solution of dios- dates react similarly. In the experimental section (see
genin and the promoter. Diosgenin glycosylations were carried Supporting Information File 1), the best procedures for each
out in dichloromethane or/and in a mixture of dichloromethane glycosyl donor are presented. Finally, diosgenyl 2-amino-2-
and diethyl ether. The results summarized in Table 1 indicate deoxy-β-D-glucopyranose (7) was obtained by complete depro-
that the “reverse” procedure is much more effective than the tections of 6a–d, as previously reported [45].
“normal” procedure. Running of the diosgenin glycosylation
also depends on the kind of the solvent used. It is particularly To obtain N-alkyl derivatives of diosgenyl 2-amino-2-deoxy-β-
important when bromide 2a is used as a glycosyl donor. Reac- D-glucopyranoside (7), a method called “reductive alkylation of
tion of 2a with diosgenin conducted by the “reverse” procedure amines” was chosen. This method was previously successfully
in the CH2Cl2/Et2O mixture leads to glycoside 6a in 77% yield. used to prepare N-alkyl derivatives of 1,3,4,6-tetra-O-acetyl-2-
The same procedure applied in CH2Cl2 gives no glycoside. amino-2-deoxy-D-glucose [51,52]. Thus, reductive alkylation of
Similarly, reaction of 2b with diosgenin conducted by the 7 with a 1.2 molar excess of the appropriate aldehyde and a
“reverse” procedure in the CH2Cl2/Et2O mixture gives glyco- twofold molar excess of NaBH3CN provided mono- (9, 11, 15,
side 6b in an excellent 98% yield. In turn, bromides with the 16) and dialkylated products (8, 10, 12–14, 17), solely or as
phthaloyl protections of the amine group (2c and 2d) react more mixtures (Scheme 2). The respective mixtures of mono- and
effectively with diosgenin when the reagents are dissolved dialkylated products were separated. Structures of the N-alky-
solely in CH2Cl2. A comparison of the efficiency of the lated derivatives of 7 were confirmed by the NMR (1H and 13C)
glycosyl donors indicates that the yields of diosgenin glycosyl- spectroscopy and mass spectrometry (see Supporting Informa-
ation with bromides 2a, 2b and 2d are higher than those with tion File 1). All of them, similarly to the parent diosgenyl
analogous chlorides 3a, 3b and 3d. However, reactivity of chlo- glycoside (7), adopt the 4C1 conformation, as demonstrated by
ride 3c is stronger than that of analogous bromide 2c. (N-Phe- the J1,2 ≈ 8 Hz, J2,3 ≈ J3,4 ≈ J4,5 ≈ 9–10 Hz coupling constants.
nyl)trifluoroacetimidates (5a–d) seem to be quite effective
glycosyl donors. However their comparison with halogens 2a–d Evaluation of antimicrobial activity
and 3a–d is encumbered since the glycosylation conditions The N-alkyl derivatives of diosgenyl 2-amino-2-deoxy-β-D-
were different for 5a–d. The N-trifluoroacetyl-protected bro- glucopyranosides 8–15 and 17 were tested for their antibacte-
mide 2a is the less reactive among the bromides 2a–d; the rial and antifungal in vitro activity against 5 strains of Gram-
Table 1: Procedures and results concerning diosgenin glycosylation.
Entry
Procedure
Glycosyl donor
Solvent
Promoter
Product
Yield (%)
1
2
normal
reverse
reverse
reverse
normal
reverse
reverse
normal
reverse
reverse
reverse
reverse
reverse
normal
normal
normal
normal
2a (α)
2a (α)
CH2Cl2/Et2O
CH2Cl2/Et2O
CH2Cl2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
6a
6a
―
30
77
―
3
2a (α)
4
2b (α)
CH2Cl2/Et2O
CH2Cl2/Et2O
CH2Cl2/Et2O
CH2Cl2
6b
6c
6c
6c
6d
6d
6a
6b
6c
6d
6a
6b
6c
6d
98
51
55
90
73
93
69
86
99
87
85
81
83
52
5
2c (α + β)
2c (α + β)
2c (α + β)
2d (α + β)
2d (α + β)
3a (α)
6
7
8
CH2Cl2/Et2O
CH2Cl2
9
10
11
12
13
14
15
16
17
CH2Cl2/Et2O
CH2Cl2/Et2O
CH2Cl2
3b (α)
3c (β)
3d (β)
CH2Cl2
5a (α + β)
5b (α + β)
5c (β)
CH2Cl2
CH2Cl2
CH2Cl2
5d (β)
CH2Cl2
871

Beilstein J. Org. Chem. 2015, 11, 869–874.
Scheme 2: N-Alkylation of diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7).
negative bacteria, 5 strains of Gram-positive bacteria, and Staphylococcus epidermidis, and Staphylococcus aureus with
3 strains of human pathogenic fungi. Respective minimum MIC of 1, 1, and 8 μg/mL, respectively. Importantly, both 9 and
inhibitory concentration (MIC) values determined by a serial 11 exhibit a stronger inhibitory effectivity than diosgenyl
dilution microplate method according to the guidelines of the 2-deoxy-2-amino-β-D-glucopyranoside hydrochloride (7·HCl),
Clinical and Laboratory Standards Institute (CLSI) for 8–15 and which was found to be very active alone and in combination
17 as well as for 7 hydrochloride are summarized in Table 2 and with daptomycin and vancomycin against Gram-positive cocci
Table 3. The latter was added as the reference since its high in [53]. The N,N-dialkyl derivatives 12, 13 and 14 act against the
vitro activities and in vivo efficacy were proved [53].
Gram-positive bacteria more efficiently or similarly to 7
hydrochloride. In turn, N-pentyl (15) and N,N-dihexyl (17)
The determined MIC values indicate that compounds explored compounds are completely inactive with respect to all the tested
have rather poor if any inhibitory activity against the Gram- strains of the Gram-positive bacteria. The results presented indi-
negative bacteria, such as Escherichia coli, Klebsiella pneumo- cate that both elongation of the alkyl group as well as addition
niae, Proteus mirabilis, Proteus vulgaris and Pseudomonas of another alkyl group are rather ineffective from the stand-
aeruginosa. In contrast, almost all the tested N-alkyl saponins point of the inhibitory activity towards the Gram-positive
were found to inhibit the growth of the Gram-positive bacteria bacteria. Such findings are probably due to the lower solubility
(Table 2). Among the tested compounds the most active was of the compounds with longer N-alkyl groups or to the micelle
diosgenyl 2-deoxy-2-ethylamino-β-D-glucopyranoside (9) with formation.
MIC of 0.5, 1, 2, and 8 μg/mL against Staphylococcus epider-
midis, Enterococcus faecalis, Staphylococcus aureus, and Studies on the activity of the synthesized N-alkyl derivatives of
Rhodococcus equi, respectively. Also the N-propyl derivative diosgenyl 2-deoxy-2-amino-β-D-glucopyranoside (8–15 and
11 was found to be active against Enterococcus faecalis, 17) against 3 strains of the human pathogenic fungi (Table 3)
Table 2: Minimum inhibitory concentration (MIC) [μg/mL] for 8–15 and 17 against the Gram-positive bacteria.
Comp. Bacillus subtilis Enterococcus faecalis Rhodococcus equi Staphylococcus aureus Staphylococcus epidermidis
7·HCl
8
8
16
16
64
8
16
32
2
16
64
0.5
32
1
8
32
9
64
32
64
16
16
32
>1024
64
1
10
11
12
13
14
15
17
32
16
32
16
16
8
32
8
1
8
8
32
8
8
8
4
16
1024
128
32
1024
256
>1024
64
512
512
872

Beilstein J. Org. Chem. 2015, 11, 869–874.
Table 3: Minimum inhibitory concentration (MIC) [μg/mL] for 8–15 and
17 against human pathogenic fungi.
Supporting Information
Supporting Information File 1
Candida
tropicalis
Candida
albicans
Aspergillus
niger
Experimental details for the preparation of compounds 2b,
2c, 4a–d, 5a–d, 6a–d, 8–17, corresponding characterization
data and information on the way of determination of
minimum inhibitory concentration.
Comp.
7·HCl
8
0.5
2
2
64
64
8
2
9
—a
1
16
2
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-97-S1.pdf]
10
11
12
13
14
15
17
128
8
—a
4
8
4
64
16
256
128
128
128
32
64
128
8
Acknowledgements
16
128
64
This research was financed by the European Union within the
European Regional Development Fund - Grant UDA-
POIG.01.01.02-14-102/09 and by the Ministry of Science and
Higher Education - grant DS/530-8457-D603-15.
aNot determined.
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