Synthesis of lipid II phosphonate analogues

Article abstract of DOI:10.1016/j.carres.2011.04.024

Simple analogues of lipid II were synthesized from 3,4,6-tri-O-acetyl-2- acetamido-2-deoxy-1-thio-β-d-glucopyranose using conjugate addition onto ethylidene bisphosphonate and subsequent Wadsworth-Horner-Emmons reaction with long chain aliphatic aldehydes.

Full text of DOI:10.1016/j.carres.2011.04.024

Carbohydrate Research 346 (2011) 1628–1632
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Synthesis of lipid II phosphonate analogues
Anikó Borbás a, Pál Herczegh b,
⇑
a Research Group for Carbohydrates of the Hungarian Academy of Sciences, University of Debrecen, PO Box 94, H-4010 Debrecen, Hungary
b Department of Pharmaceutical Chemistry, Center of Medical and Health Sciences, University of Debrecen, PO Box 70, H-4010 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 29 April 2011
Simple analogues of lipid II were synthesized from 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-1-thio-b-D-
glucopyranose using conjugate addition onto ethylidene bisphosphonate and subsequent Wadsworth–
Horner–Emmons reaction with long chain aliphatic aldehydes.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor András Lipták on the
occasion of his 75th birthday
Keywords:
Lipid II analogues
Conjugate addition
Wadsworth–Horner–Emmons reaction
The bacterial cell wall is a resistant exoskeleton based on a
polymeric network of a peptidoglycan consisting of N-acetyl-
In the first step, the conjugate addition of the 1-thio-N-acetyl-
D
-glucosamine derivative 110 to the activated double bond of
D-
glucosaminyl-N-acetylmuramyl (NAcGlu-NAcMur) peptide as the
repeating unit.1 This building block is synthesized within the bac-
terial cell in activated form as an undecaprenyl diphosphate
derivative, which is known as lipid II (Fig. 1). It is anchored
through the lipophilic side chain in the membrane. Lipid II, once
synthesized within the cell, is transported to the external surface
of the cell membrane where it reacts with the reducing end of the
growing peptidoglycan chain. This reaction is catalysed by trans-
glycosylase enzymes. Since these molecules are building up out-
side of the bacterial membrane, possible inhibitors, antibiotics,
targeting this process do not have to cross the membrane to
reach their target, therefore, such inhibitors can be of therapeutic
importance.2–6 Inhibitors of bacterial transglycosylases can be
classified into two types: the substrate binders and the enzyme
binders.4 Glycopeptide-type antibiotics, such as vancomycin and
teicoplanin belong to the first class,6 and the only known natural
product that binds to transglycosylases is moenomycin A. The lat-
ter antibiotic contains a characteristic side chain attached to an
oligosaccharide through a phosphate ester, mimicking the sub-
strate of a transglycosylase. In a systematic, pioneering work of
Welzel7 many structural fragments of this antibiotic have been
prepared and several simple analogues have been synthesized
by Wong8 and also by Vederas.9
diphosphonate 211 afforded the glycosylthio-diphosphonate 3.
Wadsworth–Horner–Emmons reaction of the latter with n-oct-
anal or n-decanal resulted in the formation of mixtures of the Z
and E isomers 4a, 4b and 5a, 5b, respectively. The concomitant
formation of 1 was also observed, due to a concurrent elimination
reaction of the intermediate carbanion. The two diastereoisomers
were formed in a ꢀ1:1 ratio in both cases. Column chromato-
graphic separation of these mixtures afforded the pure 4a, 4b,
5a and 5b, and their structures could be determined on the basis
of three-bond proton-phosphorous couplings along the carbon–
carbon double bond (Table 1). Coupling constants of 22 Hz in
the proton spectra indicated syn relationship between the cou-
pled nuclei (E-isomers, 4b and 5b),12 while anti relationship of
P and H resulted in couplings of 47 Hz (Z-isomers, 4a and 5a).
The two synthetic steps could also be performed in one flask
starting from 1 by means of subsequent addition of sodium hy-
dride, compound 2 and the appropriate aldehyde (Scheme 1, con-
dition c).
Deprotection13 of the diethylphosphonate moieties of interme-
diates 4 and 5 using the classical Rabinowitz-procedure14 followed
by deacetylation afforded the Z isomers 6 and 7 and the E isomers 8
and 9, respectively (Scheme 2).
We also attempted to alkylate the diphosphonate intermediate
3 with 1-bromodecane but, owing to a concurrent elimination
reaction of the 1-thio sugar, its S-alkylated product, the thio glyco-
side 10 could only be isolated (Scheme 3). This case is similar to the
concurrent formation of 1 from 3 during the Wadsworth–Horner–
Emmons reaction (Scheme 1). In this reaction the reactivity of the
intermediate carbanion towards the alkyl halide was lower than
In this paper we report the synthesis of simple, glycosylthio
analogues of lipid II carrying a lipophilic chain and a phosphonate
moiety.
⇑
Corresponding author. Tel.: +36 52512900/22462; fax: +36 52512900/22342.
E-mail address: herczegh.pal@pharm.unideb.hu (P. Herczegh).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.04.024

A. Borbás, P. Herczegh / Carbohydrate Research 346 (2011) 1628–1632
1629
HO
HO
HO
3
HO
O
7
O
O
OH
O
O
P
O
P
OH
NHAc
O
O
O
NHAc
H3C
O
L-Ala
γ
-D-Glu
DAP
A
D-Ala
D-Ala
HO
COOH
O
HO
HO
HO
HO
HO
O
O
OH
O
P
COOH
O
H2N
O
O
O
O
S
O
O
HO
O
N
OH
NHAc
O
OH
O
O
P
NHAc
O
HO
OH
C
OH
O
O
O
HO
HO
N
H
O
O
O
O
HO
OH
O
P
O
COOH
OH
OH
HO
NHAc
B
D
Figure 1. Structures of lipid II and its natural and synthetic analogues. (A) lipid II; (B) moenomycin A; (C) synthetic analogue8 and (D) synthetic analogue.9
determined on a Cole-Palmer hot-stage apparatus and are uncor-
rected. TLC was performed on Kieselgel 60 F254 (Merck) with detec-
tion by immersing into molybdenum blue (6 g ammonium
molybdate dissolved in 100 mL of 5% aq sulfuric acid soln) followed
by heating. Column chromatography was performed on Silica Gel
60 (E. Merck, 0.063–0.200 mm) and reversed phase silica gel C18
Table 1
3
Characteristic JP,H couplings, and chemical shifts of the vinylic protons of the (Z)-
isomers (4a, 5a) and (E)-isomers (4b, 5b)
PO(OEt)2
CH2
PO(OEt)2
H
S
S
(Kieselgel 60 RP-18, 40–63 lm, Merck). The organic solutions were
H
CH2
dried over MgSO4 and concentrated in vacuo. The 1H (200, 400 and
500 MHz) and 13C NMR (50, 100 and 125 MHz) spectra were re-
corded with Bruker WP-200 SY, DRX-400 and DRX-500 Avance
spectrometers. Chemical shifts are referenced to Me4Si (0.00 ppm
for 1H) or to the residual solvent signals (77.00 ppm (CDCl3) or
49.05 ppm (MeOD) for 13C). MALDI-TOF MS analyses of the com-
pounds were carried out in the positive reflectron mode using a BI-
FLEX III mass spectrometer (Bruker, Germany) equipped with
delayed-ion extraction. The 2,4,6-trihydroxy-acetophenone (THAP)
matrix solution was saturated THAP solution in MeCN.
4a or 5a
4b or 5b
3JP,H (Hz) (1H NMR: d)
47 (6.20 ppm)
22.4 (6.54 ppm)
that of the aldehydes in the WHE reaction, therefore, the elimina-
tion of the thiol took place exclusively. A detailed literature search
for similar alkylation of alkylthiomethyl-substituted bisphospho-
nates, phosphonoacetates and malonates gave no results, a mech-
anistic study of such reactions is worth to be done.
We postulated that analogues of lipid II would inhibit the biosyn-
thesis of the bacterial cell wall. Unfortunately, compounds 6–9 did
not show any antibacterial activity in a test against a panel of vari-
ous Gram positive bacteria including methicillin resistant and sen-
sitive Staphylococcus aureus, Streptococcus epidermidis, vancomycin
and teicoplanin resistant Enterococcus faecalis and Bacillus subtilis.
1.1. Tetraethyl 2-(3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-b-D-
glucopyranosyl-1-thio)ethane-1,1-diyldiphosphonate (3)
A solution of 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-1-thio-b-
-glucopyranose10 (1, 2.18 g, 6 mmol), tetraethyl ethene-1,1-
D
diyldiphosphonate11 (2, 1.80 g, 6 mmol) and triethylamine
(840 lL, 6 mmol) was stirred overnight at rt. Then the mixture
1. Experimental
was concentrated and the residue was purified by silica column
chromatography (CH2Cl2/MeOH 95:5) to yield 3 (3.6 g, 90%) as a
Optical rotations were measured at room temperature with a
Perkin–Elmer 241 automatic polarimeter. Melting points were
colourless syrup. [
a
]
D
À37.5 (c 0.10, CHCl3); 1H NMR (500 MHz,

1630
A. Borbás, P. Herczegh / Carbohydrate Research 346 (2011) 1628–1632
OAc
OAc
O
P
O
EtO
EtO
O
O
EtO
S
OEt
OEt
P
P
OEt
OEt
O
a
AcO
AcO
SH
AcO
AcO
+
P
O
EtO
NHAc
NHAc
1
2
3
OAc
OAc
O
O
O
EtO
S
OEt
R
O
EtO
S
OEt
R
P
P
c
AcO
AcO
AcO
b
1
2
+
1
+
+
3
NHAc
AcO
NHAc
4a
5a
R =
R =
CH3
4b
5b
CH3
Scheme 1. Reagents and conditions: (a) abs CH2Cl2, Et3N, rt, 24 h (90%); (b) dioxane, 60% NaH, 30 min, then n-octanal or n-decanal, 1 h (with n-octanal 1: 31%, 4a: 18%, 4b:
15%; with n-decanal 1: 31%, 5a: 19%, 5b: 14%); (c) dioxane, 60% NaH, n-octanal or n-decanal, 2 h (with n-octanal 4a: 20%, 4b: 17%, recovered 1: 21%; with n-decanal 5a: 20%,
5b: 15%, recovered 1: 24%).
NMR (125 MHz, CDCl3): d 170.5, 170.5, 170.1, 169.1 (4 COCH3),
OH
84.7 (C-1), 75.6, 74.0 (C-3, C-5), 68.3 (C-4), 62.9 62.8, 62.8, 62.7,
O
P
2 Et3NH+
O
R
3
62.6 (4d, JC,P 6.6 Hz, 4 OCH2CH3), 62.0 (C-6), 52.6 (C-2), 38.9 (t,
-
-
O
O
1
1C, JC,P 132 Hz, CHP2), 25.91 (SCH2), 22.9, 20.5, 20.0 (4 COCH3),
a
HO
4a
5a
S
or
4
16.2 (d, 4C, JC,P 6.3 Hz, 4 OCH2CH3). MALDI-TOF: m/z 686.24
[M+Na]+ (Calcd [M] 663.19). Anal. Calcd for C24H43NO14P2S: C,
43.44; H, 6.53; N, 2.11. Found: C, 43.12; H, 6.69; N, 2.01.
HO
NHAc
6
7
R = C7H15
R = C9H19
1.2. (Z)-Diethyl 1-(3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-b-
glucopyranosyl-1-thio)dec-2-en-2-ylphosphonate (4a), (E)-
D-
Diethyl 1-(3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-b-
D-
glucopyranosyl-1-thio)dec-2-en-2-ylphosphonate (4b)
OH
2 Et3NH+
O
O
P
-
-
To a stirred solution of 3 (350 mg, 0.52 mmol) in abs dioxane
were successively added 1.2 equiv of NaH (25 mg, 0.62 mmol)
and 1 equiv of n-octanal (83 lL, 0.52 mmol) at rt. TLC showed com-
O
S
O
HO
a
4b
5b
or
plete conversion of the starting material after 1 h, then 50% aq ace-
tic acid was added until neutral and the mixture was evaporated.
The residue was dissolved in CH2Cl2, washed with water, dried
and concentrated. The crude product was purified on silica by
two subsequent chromatographic steps (first eluent CH2Cl2/ace-
tone 9:1–7:3; second eluent n-hexane: CH2Cl2/MeOH 5:5:0.4) to
give 1 (60 mg, 31%), 4a (60 mg 18%) and 4b (50 mg, 15%).
R
HO
NHAc
8
9
R = C7H15
R = C9H19
Scheme 2. Reagents and conditions: (a) CH3CN, pyr, Me3SiBr, 0 °C, 2 h; MeOH/H2O/
Et3N (7:3:1), rt, 24 h, (6: 46%, 7: 42%, 8: 43%, 9: 45%).
Compound 1: mp 168–170 °C, lit.10 173 °C; [
a
]
À14.4 (c 0.86,
D
CHCl3), lit.10
[M] 363.10).
[a
]
D
À16; MALDI-TOF: m/z 386.28 [M+Na]+ (Calcd
OAc
Compound 4a: [
a]
D
À26.6 (c 0.10, CHCl3); 1H NMR (500 MHz,
3
3
O
CDCl3): d 6.87 (d, 1H, J 8.8 Hz, NH), 6.20 (dt, JP,H 47 Hz, JH,CH2
7.5 Hz, PC@CH), 5.19 (t, 1H, J2,3 = J3,4 9.5 Hz, H-3), 5.07 (t, 1H, J4,5
9.5 Hz, H-4), 4.64 (d, 1H, J1,2 10.5 Hz, H-1), 4.21–4.04 (m, 7H),
3.61–3.58 (m, 1H, H-5), 3.53–3.41 (m, 2H, SCH2), 2.43–2.40 (m,
2H, CH2), 2.08, 2.01, 1.93 (3s, 12H, 4 COCH3), 1.42–1.19 (m, 16H, 5
a
3
AcO
AcO
S
CH3
NHAc
3
CH2, 2 OCH2CH3), 0.89 (t, 3H, JH,CH3 6.7 Hz, CH3); 13C NMR
10
(125 MHz, CDCl3): d 170.6, 170.5, 170.4, 169.3 (4 COCH3), 150.5
(d, 1C, JC,P 11.3 Hz, PC@CH), 124.7 (d, 1C, JC,P 181 Hz, PC@CH)
Scheme 3. Reagents and conditions: (a) dioxane, 60% NaH, n-bromodecane, 1 h,
then N,N-DMF, 30 min (85%).
2
1
82.2 (C-1), 75.7, 74.3 (C-3, C-5), 68.6 (C-4), 62.8–61.9 (m, 2C,
3
OCH2CH3, C-6), 61.6 (d, 1C, JC,P 6.2 Hz, OCH2CH3), 52.4 (C-2), 35.2
3
3
CDCl3): d 6.77 (d, 1H, J 9.0 Hz, NH), 5.29 (t, 1H, J2,3 = J3,4 9.5 Hz, H-3),
5.09 (t, 1H, J4,5 9.5 Hz, H-4), 4.85 (d, 1H, J1,2 10.5 Hz, H-1), 4.26–4.12
(m, 11H, 4 OCH2CH3, H-2, H-6a,b), 3.77–3.74 (m, 1H, H-5), 3.29–
3.08 (m, 2H, CH2CHP2), 3.00–2.84 (m, 1H, CH2CHP2), 2.10, 2.01,
1.94 (3s, 12H, 4 COCH3), 1.39–1.34 (m, 12H, 4 OCH2CH3); 13C
(d, 1C, JC,P 13.5 Hz, SCH2), 32.5 (CH2), 30.6 (d, 1C, JC,P 6.3 Hz,
@CHCH2), 29.2, 29.0, 28.7 (3 CH2), 22.9 (COCH3), 22.5 (CH2) 20.7,
20.6, 20.5 (3 COCH3), 16.3 (m, 2C, 2 OCH2CH3) 14.0 (CH3). MALDI-
TOF: m/z 660.26 [M+Na]+ (Calcd [M] 637.27). Anal. Calcd for
C
28H48NO11PS: C, 52.73; H, 7.59; N, 2.20. Found: C, 53.12; H, 6.69.

A. Borbás, P. Herczegh / Carbohydrate Research 346 (2011) 1628–1632
1631
Compound 4b: [
a
]
À23.6 (c 0.20, CHCl3); 1H NMR (200 MHz,
added, then the reaction mixture was evaporated. The residue
was purified by chromatography on reversed phase silica (RP-
18, H2O/MeOH 1:1) to obtain the acetylated phosphonic acid
intermediate. The product was stirred in H2O/MeOH/Et3N (7:3:1,
3 mL) overnight then evaporated and the residue was purified
D
3
3
CDCl3): d 6.87 (d, 1H, J 9.0 Hz, NH), 6.20 (dt, JP,H 22.4 Hz, JH,CH2
7.3 Hz, PC@CH), 5.14–5.07 (m, 2H, H-3, H-4), 4.64 (d, 1H, J1,2
10.6 Hz, H-1), 4.21–4.09 (m, 7H, 2 OCH2CH3, H-2, H-6a,b), 3.74–
3.56 (m, 2H, H-5, SCH2), 3.45 (t, 1H, J 14 Hz, SCH2), 2.44–2.41 (m,
2H, CH2), 2.09, 2.01, 1.92 (3s, 12H, 4 COCH3), 1.36–1.29 (m, 16H,
5 CH2, 2 OCH2CH3), 0.95–0.87 (m, 3H, CH3); 13C NMR (100 MHz,
(RP-18, H2O/MeOH 1:1) to give 6 (70 mg, 62%). [
a
]
À5.41 (c
D
3
0.11, H2O); 1H NMR (500 MHz, D2O + CD3OD): d 6.05 (dt, JP,H
2
3
CDCl3): d 170.6, 170.5, 170.3, 169.2 (4 COCH3), 149.7 (d, 1C, JC,P
8 Hz, PC@CH), 124.7 (d, 1C, JC,P 183.2 Hz, PC@CH) 83.4 (C-1),
42 Hz, JH,CH2 6 Hz, PC@CH), 4.54 (d, 1H, J1,2 10 Hz, H-1), 3.89–
1
3.32 (m, 8H), 2.42–2.38 (m, 2H, CH2), 2.00, (s, 3H, COCH3),
1.42–1.38 (m, 2H, CH2), 1.32–1.24 (m, 8H, 4 CH2), 0.86 (br t,
3H, J 6 Hz, CH3); 13C NMR (125 MHz, D2O + CD3OD): d 175.4
75.7, 74.4 (C-3, C-5), 68.3 (C-4), 62.5–62.2 (m, 2C, 2 OCH2CH3, C-
6), 52.6 (C-2), 31.7 (SCH2), 29.2, 29.0, 28.7 (4 CH2), 26.3 (d, 1C,
3JC,P 13.1 Hz, @CHCH2), 23.0 (COCH3), 22.6 (CH2), 20.7, 20.6 (3
COCH3), 16.3 (2 OCH2CH3) 14.0 (CH3). MALDI-TOF: m/z 660.34
[M+Na]+ MALDI-TOF: m/z 660.34 [M+Na]+ (Calcd [M] 637.27). Anal.
Calcd for C28H48NO11PS: C, 52.73; H, 7.59; N, 2.20. Found: C, 52.47;
H, 7.70; N, 2.02.
1
(COCH3), 147.6 (PC@CH), 130.2 (d, 1C, JC,P 170.9 Hz, PC@CH)
83.1 (C-1), 81.0 (C-5), 76.6 (C-3), 71.0 (C-4), 62.0 (C-6), 55.5 (C-
2
2), 36.0 (d, 1C, JC,P 15 Hz, SCH2), 32.3, 31.4, 29.9, 29.8, 29.5 (5
CH2), 23.3 (COCH3), 23.2 (CH2), 14.8 (CH3). MALDI-TOF: m/z
478.38 [M2À+2H++Na+], 578.2 [MÀ+H++Na+], (Calcd [M2À
]
453.16). Anal. Calcd for C30H64N3O8PS: C, 54.77; H, 9.81; N,
6.39. Found: C, 55.12; H, 9.69, N, 6.15.
1.3. (Z)-Diethyl 1-(3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-b-
glucopyranosyl-1-thio)dodec-2-en-2-ylphosphonate (5a) and
(E)-Diethyl 1-(3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-b-
glucopyranosyl-1-thio)dodec-2-en-2-ylphosphonate (5b)
D-
D
-
1.5. (E)-[Bis(triethylammonium) 1-(2-acetamido-2-deoxy-b-D-
glucopyranosyl-1-thio)dec-2-en-2-ylphosphonate] (7)
Compound 3 (350 mg, 0.52 mmol) was treated with 1.2 equiv of
NaH (25 mg, 0.62 mmol) and 1.2 equiv of n-decanal (120 L,
0.52 mmol) as described for the synthesis of 4 to give 1 (60 mg,
Compound 4b (110 mg, 0.17 mmol) was treated analogously as
l
described for 4a to give 7 (76 mg, 67%); [
a
]
À4.12 (c 0.09, H2O);
D
1H NMR (500 MHz, D2O + CD3OD): d 6.43 (br d, 3JP,H 21 Hz, PC@CH),
4.62 (d, 1H, J1,2 10.0 Hz, H-1), 3.91–3.41 (m, 8H), 2.24–2.12 (m, 2H,
CH2), 2.02, (s, 3H, COCH3),1.42–1.29 (m, 14H, 7 CH2), 0.86 (br s, 3H,
CH3); 13C NMR (100 MHz, D2O + CD3OD): d 175.1 (COCH3), 147.1
31%), 5a (66 mg, 19%) and 5b (50 mg, 14%).
Compound 5a [
a
]
À23.9 (c 0.14, CHCl3); 1H NMR (200 MHz,
D
3
3
CDCl3): d 6.88 (d, 1H, J 8.8 Hz, NH), 6.20 (dt, JP,H 47 Hz, JH,CH2
7.5 Hz, PC@CH), 5.18 (t, 1H, J2,3 = J3,4 9.5 Hz, H-3), 5.05 (t, 1H, J4,5
9.5 Hz, H-4), 4.61 (d, 1H, J1,2 10.5 Hz, H-1), 4.31–4.00 (m, 7H),
3.66–3.41 (m, 3H, H-5, SCH2), 2.42–2.38 (m, 2H, CH2), 2.07, 2.00,
1.91 (3s, 12H, 4 COCH3), 1.37–1.25 (m, 20H, 7 CH2, 2 OCH2CH3),
1
(PC@CH), 129.7 (d, 1C, JC,P 183 Hz, PC@CH), 84.7 (C-1), 80.9, 76.4
(C-3, C-5), 70.8 (C-4), 62.0 (C-6), 55.5 (C-2), 31.0, 28.8, 28.0, 27.8
3
(5 CH2), 26.0 (d, 1C, JC,P 15 Hz, @CHCH2), 22.0 (COCH3), 21.6
(CH2), 13.0 (CH3). MALDI-TOF: m/z 478.40 [M2À+2H++Na+]+,
3
0.86 (t, 3H, JH,CH3 6.6 Hz, CH3); 13C NMR (100 MHz, CDCl3): d
500.40 [M2À+H++2Na+], (Calcd [M2À] 453.16). Anal. Calcd for
2
170.5, 170.4, 170.3, 169.2 (4 COCH3), 150.5 (d, 1C, JC,P 11 Hz,
PC@CH), 124.7 (d, 1C, JC,P 179.2 Hz, PC@CH) 82.1 (C-1), 75.7,
C30H64N3O8PS: C, 54.77; H, 9.81; N, 6.39. Found: C, 55.12; H, 9.69,
N, 6.22.
1
74.3 (C-3, C-5), 68.5 (C-4), 62.2–62.4 (m, 2C, OCH2CH3, C-6), 61.6
3
3
(d, 1C, JC,P 5.3 Hz, OCH2CH3), 52.4 (C-2), 35.3 (d, 1C, JC,P 12 Hz,
1.6. (Z)-[Bis(triethylammonium) 1-(2-acetamido-2-deoxy-b-D-
glucopyranosyl-1-thio)dodec-2-en-2-ylphosphonate] (8)
3
SCH2), 31.8 (CH2), 30.7 (d, 1C, JC,P 4.9 Hz, @CHCH2), 29.7, 29.5,
29.4, 29.3 (5 CH2), 23.0 (COCH3), 22.7 (CH2) 20.8, 20.7, 20.6 (3
COCH3), 16.3 (2 OCH2CH3) 14.0 (CH3). MALDI-TOF: m/z 688.45
[M+Na]+ (Calcd [M] 665.30). Anal. Calcd for C30H52NO11PS: C,
54.12; H, 7.87; N, 2.10. Found: C, 53.62; H, 7.10; N, 2.01.
Compound 5a (160 mg, 0.24 mmol) was treated analogously as
described for 4a to give 8 (85 mg, 52%); [
a
]
D À8.96 (c 0.22, H2O); 1H
3
NMR (500 MHz, D2O + CD3OD): d 6.1 (br d, JP,H 42 Hz, PC@CH),
4.56 (d, 1H, J1,2 10 Hz, H-1), 3.87–3.36 (m, 8H), 2.48–2.38 (m, 2H,
CH2), 2.00, (s, 3H, COCH3), 1.42–1.24 (m, 14H, 7 CH2), 0.86 (br s,
3H, CH3); 13C NMR (125 MHz, D2O + CD3OD): d 175.4 (COCH3),
Compound 5b [
a
]
À23.8 (c 0.11, CHCl3); 1H NMR (200 MHz,
D
3
3
CDCl3): d 6.85 (d, 1H, J 9.0 Hz, NH), 6.56 (dt, JP,H 22.4 Hz, JH,CH2
7.3 Hz, PC@CH), 5.17–5.04 (m, 2H, H-3, H-4), 4.67 (d, 1H, J1,2
10.6 Hz, H-1), 4.27–4.01 (m, 7H, 2 OCH2CH3, H-2, H-6a,b), 3.79–
3.48 (m, 2H, H-5, SCH2), 3.40 (t, 1H, J 13.8 Hz, SCH2), 2.30–2.19
(m, 2H, CH2), 2.09, 2.01, 1.92 (3s, 12H, 4 COCH3), 1.36–1.26 (m,
1
147.6 (PC@CH), 129.7 (d, 1C, JC,P 171 Hz, PC@CH) 83.1 (C-1), 81.0
(C-5), 76.6 (C-3), 70.8 (C-4), 61.9 (C-6), 55.6 (C-2), 36.1 (SCH2),
32.7, 31.6, 30.4, 30.3, 30.2, 30.1 (7 CH2), 23.5 (COCH3), 23.4 (CH2),
14.8 (CH3). Anal. Calcd for C32H68N3O8PS: C, 56.03; H, 9.99; N,
6.13. Found: C, 55.12; H, 9.69, N, 6.04.
20H, 7 CH2, 2 OCH2CH3), 0.88 (t, 3H, JH,CH3 6.7 Hz, CH3); 13C
3
NMR (100 MHz, CDCl3): d 170.6, 170.5, 170.3, 169.2 (4 COCH3),
2
1
149.7 (d, 1C, JC,P 8.3 Hz, PC@CH), 125.7 (d, 1C, JC,P 183.5 Hz,
PC@CH) 83.4 (C-1), 75.8, 74.5 (C-3, C-5), 68.3 (C-4), 62.5–62.3 (m,
2C, 2 OCH2CH3, C-6), 52.6 (C-2), 31.8 (SCH2), 29.4–28.7 (6 CH2),
1.7. (E)-[Bis(triethylammonium) 1-(2-acetamido-2-deoxy-b-D-
glucopyranosyl-1-thio)dodec-2-en-2-ylphosphonate] (9)
3
26.4 (d, 1C, JC,P 12.5 Hz, @CHCH2), 23.1 (COCH3), 22.7 (CH2),
20.7, 20.6 (3 COCH3), 16.4 (2 OCH2CH3) 14.1 (CH3). MALDI-TOF:
Compound 5b (90 mg, 0.13 mmol) was treated analogously as
m/z 688.43 [M+Na]+ (Calcd [M] 665.30). Anal. Calcd for
described for 4a to give 9 (60 mg, 67%). [
a
]
À6.92 (c 0.35,
D
3
C30H52NO11PS: 54.12; H, 7.87; N, 2.10. Found: C, 53.80; H, 7.11,
CHCl3); 1H NMR (500 MHz, D2O + CD3OD): d 6.38 (br t, JP,H
21 Hz, PC@CH), 4.62 (d, 1H, J1,2 10 Hz, H-1), 3.87–3.46 (m, 8H),
2.22–2.09 (m, 2H, CH2), 2.00, (s, 3H, COCH3), 1.42–1.37 (m, 2H,
CH2), 1.32–1.24 (m, 12H, 6 CH2), 0.86 (br s, 3H, CH3); 13C NMR
(125 MHz, D2O+CD3OD): d 175.2 (COCH3), 146.4 (PC@CH), 130.5
N, 2.11.
1.4. (Z)-Bis(triethylammonium) 1-(2-acetamido-2-deoxy-b-D-
glucopyranosyl-1-thio)dec-2-en-2-ylphosphonate (6)
1
(d, 1C, JC,P 170 Hz, PC@CH) 84.9 (C-1), 81.3 (C-5), 76.7 (C-3),
To a solution of 4a (110 mg, 0.17 mmol) in anhydrous CH3CN
(5 mL) pyridine (1.7 mmol, 140 L) was added at 0 °C, followed
by dropwise addition of Me3SiBr (1.7 mmol, 227 L). After stirring
for 2 h at 0 °C, a mixture of water and pyridine (9:1, 200 L) was
71.1 (C-4), 62.3 (C-6), 55.9 (C-2), 33.1, 30.8, 30.7, 30.5, 30.2,
30.1, 29.7, 27.7 (7 CH2, SCH2), 23.9 (COCH3), 23.8 (CH2), 15.2
(CH3). Anal. Calcd for C32H68N3O8PS: C, 56.03; H, 9.99; N, 6.13.
Found: C, 55.12; H, 9.69, N, 6.30.
l
l
l

1632
A. Borbás, P. Herczegh / Carbohydrate Research 346 (2011) 1628–1632
1.8. n-Decyl 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-1-thio-b-D-
Acknowledgements
glucopyranoside (10)
This work was supported by the TÁMOP 4.2.1/B-09/1/KONV-
2010–0007 project. The project was co-financed by the European
Union and the European Social Fund. Financial support of the Hun-
garian Research Fund (K 62802 and K 79126) is also acknowledged.
To a stirred solution of 3 (98 mg, 0.15 mmol) in abs dioxane
(5 mL) 1.2 equiv of NaH (7 mg, 0.17 mmol) and 1.5 equiv of n-decyl
bromide (46 lL, 0.22 mmol) were added at 10 °C. There was no
reaction after 2 h, then 1 mL of DMF was added. TLC showed com-
plete conversion of the starting compound after 20 min. MeOH
(0.5 mL) was added, the reaction mixture was stirred for 15 min,
then the solvents were evaporated. The residue was dissolved in
CH2Cl2, washed with water, dried and concentrated. The crude
product was purified on silica (CH2Cl2/acetone 9:1) to give 10 as
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white needles (63 mg, 85%), mp 148–150 °C, [a] –42.6 (c 0.10,
D
CHCl3). 1H NMR (500 MHz, CDCl3): d 5.75 (br d, 1H, J 10 Hz, NH),
5.19 (t, 1H, J2,3 = J3,4 10 Hz, H-3), 5.09 (t, 1H, J4,5 9.5 Hz, H-4), 4.61
(d, 1H, J1,2 10 Hz, H-1), 4.24 (d, 1H, Jgem 12.5 Hz, J5,6a 5.5 Hz, H-
6a), 4.13 (dd, 1H, J5,6b 2 Hz, H-6b), 4. 09 (dd, 1H, H-2), 3.72–3.69
(m, 1H, H-5), 2.73–2.63 (m, 2H, SCH2), 2.08, 2.03, 2.02, 1.96 (4s,
12H, 4 COCH3), 1.61–1.57 (m, 2H, CH2), 1.36–1.32 (m, 2H, CH2),
1.32–1.25 (m, 12H, 6 CH2), 0.88 (t, 3H, JH,CH3 6.5 Hz, CH3); 13C
NMR (100 MHz, CDCl3): d 170.9, 170.6, 170.0, 169.2 (4 COCH3),
84.4 (C-1), 75.8 (C-5), 73.8 (C-3), 68.4 (C-4), 62.3 (C-6), 53.2 (C-
2), 31.8 (SCH2), 29.9–28.8 (7 CH2), 23.2 (COCH3), 22.6 (CH2), 20.7,
20.6, 20.5 (3 COCH3), 14.0 (CH3). Anal. Calcd for C24H43NO8S: C,
57.01; H, 8.57; N, 2.77. Found: C, 57.12; H, 8.69, N, 2.53.
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