Regioselective synthesis of novel 3-alkoxy (phenyl) thiophosphorylamido-2-(per-O-acetylglycosyl-1′-imino)thiazolidine-4-one derivatives from O-alkyl N4-glycosyl(thiosemicarbazido)phosphonothioates

Article abstract of DOI:10.1016/j.carres.2009.03.027

A series of 3-alkoxy(phenyl)thiophosphorylamido-2-(per-O-acetylglycosyl-1′-imino)thiazolidine-4-one derivatives were prepared by the reaction of 1-alkoxy(phenyl)thiophosphoryl-4-(per-O-acetylglycosyl) thiosemicarbazides with ethyl bromoacetate. ¹

Full text of DOI:10.1016/j.carres.2009.03.027

Carbohydrate Research 344 (2009) 1248–1253
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Regioselective synthesis of novel 3-alkoxy (phenyl) thiophosphorylamido-2-
(per-O-acetylglycosyl-10-imino)thiazolidine-4-one derivatives from
O-alkyl N4-glycosyl(thiosemicarbazido)phosphonothioates
Yu Xin Li, Hao An Wang, Xiao Ping Yang, Hai Ying Cheng, Zhi Hong Wang, Yi Ming Li,
*
Zheng Ming Li , Su Hua Wang, Dong Wen Yan
State Key laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
A series of 3-alkoxy(phenyl)thiophosphorylamido-2-(per-O-acetylglycosyl-10-imino)thiazolidine-4-one
derivatives were prepared by the reaction of 1-alkoxy(phenyl)thiophosphoryl-4-(per-O-acetylglycosyl)
thiosemicarbazides with ethyl bromoacetate. 1H/13C HMBC measurements corroborated by X-ray crystal-
lographic results revealed the exclusive regioselectivity of these ring closures toward the N-2 position of
the thiosemicarbazide moiety. The bioactivity data of 3a–k suggest that the thiazolidine-4-one ring is
critical for the herbicidal and fungicidal activities.
Article history:
Received 22 November 2008
Received in revised form 26 March 2009
Accepted 27 March 2009
Available online 1 April 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
2-Iminothiazolidine-4-ones
Thiosemicarbazidophosphonothioates
1H/13C HMBC correlation spectra
Regioselectivity
Thiazolidine-4-one compounds have been shown to display
antimicrobial,1 antimycobacterial,2 anticonvulsant,3 anti-inflam-
matory,4 anti-HIV-1,5 analgesic,6 antituberculosis,7 immunosup-
pressant,8 and antimalarial9 activities. Recently, it was reported
that thiazolidinones displayed antidegenerative activity on
human chondrocyte cultures.10 Previously, we have described
the synthesis of bioactive 2-arylsulfonylhydrazono-3-(per-O-acet-
ylglycosyl)thiazolidine-4-ones using 1-arylsulfonyl-4-(per-O-acet-
ylglycosyl)thiosemicarbazides as precursor.11 Since organo
phosphorus compounds are known as highly effective agrochem-
roform. Finally, we obtained cyclization products when we used
dichloromethane as solvent. A reaction time of 12 h at reflux in
dichloromethane was maintained since a longer reaction time
did not improve the yield.
Several reports regarding the condensation of thiosemicarbaz-
ides with alkyl halides have pointed out that main products are
of type 30a,16,17 resulting from cyclization at N-4. 2-(Dimethylhyd-
razono)-3-phenylthiazol-4-one was obtained by reflux of
thiosemicarbazide with ethyl bromoacetate for 7 days in dichloro-
methane.18 In the presence of a weak base, Saleh et al. cyclized
substituted thioureas with chloroacetic acid, giving thiazolidine-
4-one compounds substituted at N-4.19 Conversely, the cyclization
at N-2 has been more scarcely reported. Moghaddam and Hojabri20
and Rajanarendar et al.21 have reported cyclizations at N-2 posi-
tion. A detailed study of the condensation of thiosemicarbazides
with ethyl bromoacetate to give N-2 isomers as major products
has been reported.22
icals,12 we planned to prepare
a series of 2-alkoxy(phenyl)
thiophosphorylhydrazono-3-(per-O-acetylglycosyl)thiazolidine-4-
one derivatives.
We started from 1-alkoxy(phenyl)thiophosphoryl-4-(per-O-
acetylglycosyl) thiosemicarbazides 2a–k, obtained from the
reaction of glycosyl isothiocyanates13,14 and thiophosphoryl hydra-
zines.15 Reaction of 2a–k with ethyl bromoacetate was investi-
gated (Scheme 1). We first tried to use chloroform as the
reaction medium. Unfortunately, we failed to obtain any cycliza-
tion product. However, we successfully separated a moderately
stable S-alkylated intermediate in the presence of sodium acetate.
FABMS (m/z 948 [M+H]+ for 2k with ethyl bromoacetate) indicates
that it is an uncyclized product. It is likely that this S-alkylated
intermediate was unstable when the reaction was refluxed in chlo-
It is of interest that the cyclization of thiosemicarbazides 2a–k,
which includes a relatively bulky substituent, with ethyl bromo-
acetate leads to the formation of N-2 isomers 3a–k. When these
reactions were monitored by TLC, we found that the polarity of
3a–k was smaller than that of 2a–k and the polarity of previously
reported
2-arylsulfonylhydrazono-3-(per-O-acetylglycosyl)thia-
zolidine-4-ones was higher than that of 1-arylsulfonyl-4-(per-O-
acetylglycosyl)thiosemicarbazides. 1H and 13C NMR spectra of final
products (after work-up) suggest absence of any trace of the iso-
mers, indicating that the final products are isomerically pure.
* Corresponding author.
E-mail address: nkzml@vip.163.com (Z.M. Li).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.03.027

Y. X. Li et al. / Carbohydrate Research 344 (2009) 1248–1253
1249
R2
R1
O
S
R3
N
AcO
O
R2
OAc
N
R1
NH
P
R5
O
R3
R4
S
R2
R1
AcO
NCS
b
OAc
O
S
NHCSNHNHP R5
R4
R3
1a-e
+
a
3a-k, cyclization at N-2 position
AcO
OAc
R2
S
b
O
R1
R4
P
NHNH2
+
2a-k
O
R3
R5
N
S
AcO
1a, 2a, 3a: R1 = CH2OAc, R2 = H, R3 = OAc, R4 = R5 = OC2H5
OAc
N
1a, 2b, 3b: R1 = CH2OAc, R2 = H, R3 = OAc, R4 = OCH3, R5 = Ph
1a, 2c, 3c: R1 = CH2OAc, R2 = H, R3 = OAc, R4 = OC3H7, R5 = Ph
1b, 2d, 3d: R1 = CH2OAc, R2 = OAc, R3 = H, R4 = R5 = OC2H5
1b, 2e, 3e: R1 = CH2OAc, R2 = OAc, R3 = H, R4 = OCH3, R5 = Ph
1c, 2f, 3f: R1 = H, R2 = H, R3 = OAc, R4 = R5 = OCH3
NH
P
R4
S
R5
3'a, cyclization at N-4 position
1c, 2g, 3g: R1 = H, R2 = H, R3 = OAc, R4 = R5 = OC2H5
1c, 2h, 3h: R1 = H, R2 = H, R3 = OAc, R4 = OCH3, R5 = Ph
1c, 2i, 3i: R1 = H, R2 = H, R3 = OAc, R4 = OC2H5, R5 = Ph
1d, 2j, 3j:
1e, 2k, 3k: R1 = CH2OAc, R2 = H, R4 = R5 = OC2H5
OAc
1d, 2j, 3j: R3
R
1 = CH2OAc, R2 = H, R4 = R5 = OC2H5
OAc
OAc
1e, 2k, 3k: R3
=
AcO
=
O
O
O
AcO
AcO
OAc
OAc
O
Scheme 1. Reagents and conditions: (a) MeCN, rt and (b) CH2Cl2, BrCH2CO2Et, reflux.
Due to the presence of the imino group, the chemical shift value of
H-10 for 3f (4.76 ppm) is smaller than that of H-10 (5.42 ppm), as
we previously reported in the case of 2-phenylsulfonylhydrazon-
1. Experimental
1.1. General methods
o-3-(20,30,40-tri-O-acetyl-b-
D-xylopyranosyl)thiazolidine-4-one, and
the chemical shift value of C-10 for 3f (88.90 ppm) is larger
than that of C-10 (81.63 ppm).11 These differences in chemical
shifts may indicate different types of ring closures. Formation of
the N-4 vs N-2 type closure for the sulfonylhydrazono versus
glycosylimino derivatives has now been proven by HMBC experi-
ments. Figure 1 shows the HMBC spectra of 2-phenylsulfonylhyd-
Melting points were obtained on a Yanaco MP-500 micro-melt-
ing point apparatus. 1H and 13C NMR spectra were recorded on a
Bruker AC-400 instrument using CDCl3 as solvent and Me4Si as
internal standard. Elemental analysis was performed on a Yanaco
CHN Corder MF-3 automatic elemental analyzer. Mass spectra
were recorded with a VG ZAB-HS instrument using the FAB ioniza-
tion mode.
razono-3-(20,30,40-tri-O-acetyl-b-
D-xylopyranosyl)thiazolidine-4-
one11 (Fig. 1A), 3a (Fig. 1C) and 3f (Fig. 1E). Based on the HMBC
correlations in Figure 1, we can unambiguously assign all chemical
shift values of carbon and proton atoms in the sugar ring. On the
other hand, the three-bond connectivity of H-10 at d 5.42 ppm with
C-2 at d 164 ppm and with C-4 at d 172 ppm in the HMBC spectrum
confirmed the cyclization of 1-arylsulfonyl-4-(per-O-acetylglyco-
syl)thiosemicarbazides with ethyl bromoacetate at N-4 (Figure
1B); the three-bond connectivity of H-10 at d 4.76 ppm with C-2
at d 155 ppm in the HMBC spectrum proved the cyclization of 1-
1.2. 1-Alkoxy(phenyl)thiophosphoryl-4-(per-O-acetylglycosyl)-
thiosemicarbazide derivatives (2a–k), general method
To a soln of 1a–e (4 mmol) in MeCN (20 mL), the corresponding
thiophosphoryl hydrazine (6 mmol) was added with stirring. The
mixture was heated at reflux for 2 h and the solvent was removed
under diminished pressure. Concentration resulted in a crude
product which was purified on a silica gel column (1:2 EtOAc–
petroleum ether).
alkoxy(phenyl)thiophosphoryl-4-(per-O-acetyl
glycosyl)thiose-
micarbazides with ethyl bromoacetate at N-2 (Fig. 1F). This type
of ring closure was confirmed by X-ray crystallography.23
Compounds 2a–k and 3a–k were tested in soil treatment
against several herbs such as Brassica campestris, Echinochloa
crus-galli, Amaranthus retroflexus L., and Digitaria sanguinalis(L.)Scop
at 1.5 kg/ha.24 The bioassay results showed that 3a–k have a rather
moderate herbicidal activity. The inhibitory rate of 3b against Bras-
sica campestris was 62.7%. Compounds 2a–k and 3a–k were also
tested for their growth inhibition and fungicidal activity in vitro
against Gibberella zeae, Alternaria solani, Cercospora arachidicola,
Physalospora piricola, Phoma asparagi at 50 ppm. The inhibitory
rates of 3a–k against Physalospora piricola, Phoma asparagi were
between 40% and 50%. Higher inhibitory rate of 3a–k compared
to that of 2a–k indicates that the thiazolidine-4-one ring is critical
for the herbicidal and fungicidal activities.
1.2.1. 1-Diethoxythiophosphoryl-4-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)thiosemicarbazide (2a)
From 1.56 g (4 mmol) of 1a (1.97 g, 87%); white crystals from
EtOAc–petroleum ether; mp 164–165 °C. 1H NMR (CDCl3, ppm): d
7.64 (d, J 8.4 Hz, 1H, NH), 7.60 (br s, 1H, NH), 5.78 (t, 1H, H-10),
5.37 (m, 2H, H-20, H-30), 5.06 (m, 2H, H-40, H-60), 4.31 (dd, J1
4.2 Hz, J2 3.6 Hz, 1H, H-50), 4.13 (m, 5H, H-60, 2 ꢀ POCH2), 3.86 (d,
J 8.4 Hz, 1H, NH), 2.10, 2.06, 2.04, 2.02 (4s, 12H, 4 ꢀ OAc), 1.32 (t,
6H, 2 ꢀ POCH2CH3); 13C NMR (CDCl3, ppm): d 183.67 (C@S),
171.20, 170.83, 169.99, 169.74 (4C, 4 ꢀ CO), 82.28 (C-60), 73.59
(C-30), 72.91 (C-20), 68.30 (C-10), 64.66, 63.89 (2C, 2 ꢀ POCH2),
63.50 (C-50), 61.82 (C-40), 20.82, 20.75, 20.70, 20.67 (4C, 4 ꢀ OAc),

1250
Y. X. Li et al. / Carbohydrate Research 344 (2009) 1248–1253
Figure 1. (A) 1H–13C HMBC spectra of 2-phenylsulfonylhydrazono-3-(20,30,40-tri-O-acetyl-b- -xylopyranosyl)thiazolidine-4-one11; (B) 1H–13C HMBC spectra of H-10/C-2,C-4
D
in 2-phenylsulfonylhydrazono-3-(20,30,40-tri-O-acetyl-b- -xylopyranosyl)thiazolidine-4-one; (C) 1H–13C HMBC spectra 3a; (D) 1H–13C HMBC spectra of H-10 with C-2 in 3a;
D
(E) 1H–13C HMBC spectra 3f; and (F) 1H–13C HMBC spectra of H-10 with C-2 in 3f.
15.83 (2C, 2 ꢀ POCH2CH3); 31P NMR (CDCl3, ppm): d 79.16. Anal.
Calcd for C19H32N3O11PS2: C, 41.78; H, 5.32; N, 5.04. Found: C,
41.58; H, 5.61; N, 4.98.
NH), 5.68–3.75 (m, 9H, OCH2, H-10, H-20, H-30, H-40, H-50, H-60),
2.09, 2.03, 1.97, 1.93 (4s, 12H, 4ꢀOAc), 1.29 (m, 2H, POCH2CH2),
0.91 (t, 3H, CH3); 13C NMR (CDCl3): d 184.08 (C@S), 170.33,
170.13, 170.04, 169.84 (4C, 4 ꢀ CO), 140.33, 132.65, 131.87,
131.29, 129.43, 138.96 (6H, Ar-C), 82.89, 73.79, 69.34, 63.85,
63.52, 63.43, 61.45 (7C, C-10, C-20, C-30, C-40, C-50, C-60, OCH2),
33.68 (POCH2CH2), 20.81, 20.54, 20.36, 20.12 (4C, 4 ꢀ OAc), 16.29
(CH3); 31P NMR (CDCl3, ppm): d 79.27, 79.01. Anal. Calcd for
C24H34N3O10PS2: C, 46.52; H, 5.53; N, 6.78. Found: C, 46.23; H,
5.60; N, 6.95.
1.2.2. 1-Methoxy(phenyl)thiophosphoryl-4-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)thiosemicarbazide (2b)
From 1.56 g (4 mmol) of 1a (1.80 g, 76%); white crystals from
EtOAc–petroleum ether; mp 169–171 °C. 1H NMR (CDCl3, ppm):
d 7.83 (m, 2H, Ar-H), 7.70 (d, J 9.2 Hz, 1H, NH), 7.54–7.46 (m,
4H, Ar-H, NH), 5.89 (br s, 1H, NH), 5.71–3.69 (m, 10H, OCH3,
H-10, H-20, H-30, H-40, H-50, H-60), 2.08, 2.01, 1.98, 1.96, 1.98,
(4s, 12H, 4 ꢀ OAc); 13C NMR (CDCl3, ppm): d 183.65 (C@S),
171.02, 170.89, 170.04, 169.75, 170.04, 170.89, 171.02 (4C,
4 ꢀ CO), 133.34, 131.94, 131.86, 131.74, 129.12, 128.98 (6C, Ar-
C), 82.35, 73.74, 73.00, 70.78, 68.18, 61.75 (6C, C-10, C-20, C-30,
C-40, C-50, C-60) 53.36 (OCH3), 21.01, 20.81 (4C, 4 ꢀ OAc); 31P
1.2.4. 1-Diethoxythiophosphoryl-4-(2,3,4,6-tetra-O-acetyl-b-D-
galactopyranosyl)thiosemicarbazide (2d)
From 1.56 g (4 mmol) of 1b (1.56 g, 68%); white crystals from
EtOAc–petroleum ether; mp 167–168 °C. 1H NMR (CDCl3, ppm): d
7.59 (m, 2H, NHNH), 5.71 (t, 1H, H-10), 5.43 (m, 2H, H-20, H-30),
5.17 (m, 2H, H-40, H-60), 4.01 (m, 7H, H-50, H-60, 2 ꢀ POCH2, NH),
2.14, 2.04, 2.01, 1.97 (4s, 12H, 4 ꢀ OAc), 1.31 (t, 6H,
2 ꢀ POCH2CH3); 13C NMR (CDCl3, ppm): d 183.76 (C=S), 171.41,
170.60, 170.26, 169.95 (4C, 4 ꢀ CO), 82.96 (C-60), 72.63 (C-30),
71.01 (C-20), 68.79 (C-10), 67.38 (C-50), 65.09, 64.92 (2C,
2 ꢀ POCH2), 61.24 (C-40), 21.08, 20.83, 20.73, 20.56 (4C, 4 ꢀ OAc),
16.10, 16.04 (2C, 2 ꢀ POCH2CH3); 31P NMR (CDCl3, ppm): d 79.16.
Anal. Calcd for C19H32N3O11PS2: C, 41.78; H, 5.32; N, 5.04. Found:
C, 41.35; H, 5.11; N, 4.98.
NMR (CDCl3, ppm):
d
81.94, 81.76. Anal. Calcd for
C22H30N3O10PS2: C, 44.67; H, 5.11; N, 7.10. Found: C, 44.38; H,
5.24; N, 7.01.
1.2.3. 1-Phenyl(propoxy)thiophosphoryl-4-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)thiosemicarbazide (2c)
From 1.56 g (4 mmol) of 1a (1.70 g, 69%); white crystals from
EtOAc–petroleum ether; mp 166–167 °C. 1H NMR (CDCl3, ppm): d
7.91 (br s, 1H, NH), 7.79–7.41 (m, 6H, Ar-H, NH), 5.89 (br s, 1H,

Y. X. Li et al. / Carbohydrate Research 344 (2009) 1248–1253
1251
1.2.5. 1-Methoxy(phenyl)thiophosphoryl-4-(2,3,4,6-tetra-O-
acetyl-b- -galactopyranosyl)thiosemicarbazide (2e)
1.2.10. 1-Diethoxythiophosphoryl-4-[2,3,4,6-tetra-O-acetyl-b-
galactopyranosyl-(1?4)-2,3,6-tri-O-acetyl-b- -glucopyranosyl]
thiosemicarbazide (2j)
D-
D
D
From 1.56 g (4 mmol) of 1b (1.7 g, 72%); white crystals from
EtOAc–petroleum ether; mp 178–179 °C. 1H NMR (CDCl3, ppm): d
8.10 (br s, 1H, NH), 7.87 (m, 6H, Ar-H, NH), 5.84 (d, J 8.4 Hz, 1H,
NH), 5.78–3.57 (m, 10H, H-10, H-20, H-30, H-40, H-50, H-60, OCH3),
2.15, 2.04, 1.98, 1.96 (4s, 12H, 4 ꢀ OAc); 13C NMR (CDCl3, ppm):
d 184.98 (C@S), 171.32, 171.03, 170.27, 169.67 (4C, 4 ꢀ CO),
139.76, 134.02, 133.10, 132.68, 130.64, 128.96 (6C, Ar-C), 81.98,
73.85, 72.69, 71.78, 67.56, 61.71, 61.55 (7C, C-10, C-20, C-30, C-40,
C-50, C-60, CH3O), 21.00, 20.89, 20.81, 20.79 (4C, 4 ꢀ OAc); 31P
NMR (CDCl3, ppm): d 79.86, 79.65. Anal. Calcd for C22H30N3O10PS2:
C, 44.67; H, 5.11; N, 7.10. Found: C, 44.34; H, 4.89; N, 7.28.
From 2.7 g (4 mmol) of 1d (2.3 g, 67%); white crystals from
EtOAc–petroleum ether; mp 140–141 °C. 1H NMR (CDCl3, ppm): d
7.88 (br s, 1H, NH), 7.43 (br s, 1H, NH), 5.76–3.56 (m, 18H,
2 ꢀ POCH2, sugar ring), 2.04, 2.01, 1.98, 1.97, 1.95, 1.92, 1.91 (7s,
21H, 7 ꢀ OAc), 1.26 (t, 6H, 2C, 2 ꢀ POCH2CH3); 13C NMR (CDCl3,
ppm): d 184.86 (C@S), 170.96, 170.48, 170.26, 170.12, 169.81,
169.38, 169.27 (7C, 7 ꢀ CO), 89.37, 79.69, 76.33, 74.39, 72.93,
71.76, 70.73, 68.28, 67.83, 62.96, 62.34, 61.97, 61.36, 58.12 (14C,
sugar ring, 2 ꢀ P ꢀ POCH2), 21.32, 21.13, 21.09, 21.03, 21.01,
20.99, 20.94, 20.88 (7C, 7 ꢀ OAc), 15.97, 15.88 (2C, 2 ꢀ POCH2CH3);
31P NMR (CDCl3, ppm): d 79.82. Anal. Calcd for C31H48N3O19PS2: C,
43.20; H, 5.61; N, 4.88. Found: C, 42.90; H, 5.60; N, 5.12.
1.2.6. 1-Dimethoxythiophosphoryl-4-(2,3,4-tri-O-acetyl-b-D-
xylopyranosyl)thiosemicarbazide (2f)
From 1.26 g (4 mmol) of 1c (1.48 g, 78%); white crystals from
EtOAc–petroleum ether; mp 181–182 °C. 1H NMR (CDCl3, ppm): d
8.02 (br s, 1H, NH), 7.84 (d, J 8.4 Hz, 1H, NH), 5.63 (br s, 1H, NH),
5.57–3.54 (m, 12H, H-10, H-20, H-30, H-40, H-50, 2ꢀOCH3), 2.04,
2.03, 1.89 (3s, 9H, 3ꢀOAc); 13C NMR (CDCl3, ppm): d 185.13
(C@S), 170.56, 170.03, 169.84 (3C, 3 ꢀ CO), 80.97, 72.36, 68.72,
67.88, 64.66, 66.68, 59.89 (7C, C-10, C-20, C-30, C-40, C-50, 2ꢀOCH3),
20.98, 20.24, 20.02 (3C, 3 ꢀ OAc); 31P NMR (CDCl3, ppm): d 69.63.
Anal. Calcd for C14H24N3O9PS2: C, 35.52; H, 5.11; N, 8.88. Found:
C, 35.50; H, 5.21; N, 8.39.
1.2.11. 1-Diethoxythiophosphoryl-4-[2,3,4,6-tetra-O-acetyl-
-glucopyranosyl-(1?4)-2,3,6-tri-O-acetyl-b- -glucopyranosyl]-
thiosemicarbazide (2k)
a-
D
D
From 2.7 g (4 mmol) of 1e (1.58 g, 75%); white crystals from
EtOAc–petroleum ether; mp 160–163 °C. 1H NMR (CDCl3, ppm): d
7.59 (br s, 1H, NH), 7.48 (d, J 8.8 Hz, 1H, NH), 5.75 (t, 1H, H-10),
5.38–3.81 (m, 18H, 2 ꢀ POCH2, sugar ring), 2.10, 2.06, 2.03, 2.01,
1.99, 1.98, 1.96 (7s, 21H, 7ꢀOAc), 1.29 (t, 6H, 2C, 2 ꢀ POCH2CH3);
13C NMR (CDCl3, ppm): d 183.84 (C@S), 171.19, 170.85, 170.72,
170.58, 170.00, 169.87, 169.66 (7C, 7 ꢀ CO), 95.78, 82.18, 75.17,
74.20, 72.88, 71.61, 70.23, 68.72, 68.48, 68.15, 65.11, 64.98,
62.79, 61.16 (14C, sugar ring, 2 ꢀ POCH2), 21.06, 20.96, 20.81 (7C,
7 ꢀ OAc), 16.14, 16.02 (2C, 2 ꢀ POCH2CH3); 31P NMR (CDCl3,
ppm): d 69.47. Anal. Calcd for C31H48N3O19PS2: C, 43.20; H, 5.61;
N, 4.88. Found: C, 43.18; H, 5.78; N, 4.67.
1.2.7. 1-Diethoxythiophosphoryl-4-(2,3,4-tri-O-acetyl-b-D-
xylopyranosyl)thiosemicarbazide (2g)
From 1.26 g (4 mmol) of 1c (1.38 g, 69%); white crystals from
EtOAc–petroleum ether; mp 179–181 °C. 1H NMR (CDCl3, ppm): d
8.01 (br s, 1H, NH), 7.72 (d, J 8.4 Hz, 1H, NH), 5.68 (br s, 1H, NH),
5.58–3.44 (m, 10H, H-10, H-20, H-30, H-40, H-50, 2ꢀOCH2), 2.01,
2.00, 1.98 (3s, 9H, 3 ꢀ OAc), 1.25 (t, 6H, 2 ꢀ POCH2CH3); 13C NMR
1.3. 3-Alkoxy(phenyl)thiophosphorylamido-2-(per-O-
acetylglycosyl-10-imino)thiazolidine-4-one derivatives (3a–k),
general method
(CDCl3, ppm):
d 184.56 (C@S), 171.25, 170.32, 169.98 (3C,
3 ꢀ CO), 81.32, 71.67, 68.77, 67.82, 64.65, 63.25, 61.04 (7C, C-10,
C-20, C-30, C-40, C-50, 2 ꢀ OCH2), 21.33, 20.72, 20.54 (3C, 3ꢀOAc),
16.16, 16.11 (2C, 2 ꢀ POCH2CH3); 31P NMR (CDCl3, ppm): d 69.74,
69.61. Anal. Calcd for C16H28N3O9PS2: C, 38.33; H, 5.63; N, 8.38.
Found: C, 38.78; H, 5.38; N, 7.98.
To a soln of 2a–k (2 mmol) in CH2Cl2 (20 mL), ethyl bromoace-
tate (0.5 g, 3 mmol) was added dropwise with stirring. The mixture
was heated at reflux for 12 h and the solvent was removed under
diminished pressure. Concentration resulted in a crude product
which was purified on a silica gel column (1:2 EtOAc–petroleum
ether).
1.2.8. 1-Methoxy(phenyl)thiophosphoryl-4-(2,3,4-tri-O-acetyl-
b-
D
-xylopyranosyl)thiosemicarbazide (2h)
From 1.26 g (4 mmol) of 1c (1.48 g, 72%); white crystals from
1.3.1. 3-Diethoxythiophosphorylamido-2-(20,30,40,60-tetra-O-
EtOAc–petroleum ether; mp 163–164 °C. 1H NMR (CDCl3, ppm): d
7.86 (m, 7H, NHNH, Ar-H), 5.71–3.52 (m, 10H, H-10, H-20, H-30, H-40,
H-50, OCH3, NH), 2.09, 2.04, 1.98 (3s, 9H, 3 ꢀ OAc); 13C NMR (CDCl3,
ppm): d 183.89 (C@S), 171.22, 170.96, 170.38 (3C, 3 ꢀ CO), 140.82,
133.22, 131.97, 130.65, 128.39, 127.56 (6H, Ar-C), 82.80, 72.19,
69.17, 64.12, 63.03, 61.25 (6C, C-10, C-20, C-30, C-40, C-50, OCH3),
20.86, 20.43, 19.87 (3C, 3 ꢀ OAc). Anal. Calcd for C19H26N3O8PS2: C,
43.93; H, 5.04; N, 8.09. Found: C, 43.60; H, 4.69; N, 7.93.
acetyl-b-D
-glucopyranosyl-10-imino)thiazolidine-4-one (3a)
From 1.14 g of 2a (0.59 g, 48%); white crystals from EtOAc–
petroleum ether; mp 140–141 °C; 1H NMR (CDCl3, ppm): d 5.71
(d, J 8.74 Hz, 1H, NH), 5.50 (m, 1H, H-20), 5.32 (d, 1H, J 3.6 Hz, H-
10), 5.13 (m, 1H, H-30), 5.06 (t, 1H, H-40), 4.28 (m, 7H, H-50, H-60,
2 ꢀ POCH2), 3.84 (s, 2H, H-5), 2.06, 2.02, 1.99, 1.98 (4s, 12H,
4ꢀOAc), 1.28 (t, 6H, 2 ꢀ POCH2CH3); 13C NMR (CDCl3, ppm): d
170.71, 170.11, 170.01, 169.53 (4C, 4 ꢀ CO), 168.18 (C-4), 156.70
(C-2), 83.41 (C-60), 71.33 (C-30), 70.68 (C-20), 68.69 (C-10), 64.59,
64.56(2C, 2 ꢀ POCH2), 63.75 (C-50), 61.89(C-40), 29.93 (C-5),
20.84, 20.77, 20.68, 20.59 (4C, 4 ꢀ OAc), 15.90, 15.85 (2C,
2 ꢀ POCH2CH3); 31P NMR (CDCl3, ppm): d 71.17. FABMS: m/z 613
[M+H]+. Anal. Calcd for C21H32N3O12PS2: C, 41.11; H, 5.26; N,
6.85. Found: C, 41.24; H, 5.27; N, 6.76.
1.2.9. 1-Ethoxy(phenyl)thiophosphoryl-4-(2,3,4-tri-O-acetyl-b-
D
-xylopyranosyl)thiosemicarbazide (2i)
From 1.26 g (4 mmol) of 1c (1.56 g, 73%); white crystals from
EtOAc–petroleum ether; mp 163–164 °C. 1H NMR (CDCl3, ppm): d
8.02 (br s, 1H, NH), 7.45 (d, J 8.4 Hz, 1H, NH), 7.86–3.49 (m, 14H,
H-10, H-20, H-30, H-40, H-50, OCH2, NH, Ar-H), 2.11, 2.03, 2.00 (3s,
9H, 3 ꢀ OAc), 1.56 (t, 3H, CH3); 13C NMR (CDCl3, ppm): d 183.66
(C@S), 170.82, 170.49, 170.36 (3C, 3 ꢀ CO), 149.87, 132.65,
131.87, 131.39, 128.34, 126.97 (6C, Ar-C), 83.60, 82.55, 72.16,
69.46, 65.64, 63.56, 63.01 (6C, C-10, C-20, C-30, C-40, C-50, OCH2),
20.96, 20.89, 20.43 (3C, 3ꢀOAc), 16.33 (POCH2CH3). Anal. Calcd
for C20H28N3O8PS2: C, 45.02; H, 5.29; N, 7.88. Found: C, 44.73; H,
5.00; N, 7.66.
1.3.2. 3-Methoxy(phenyl)thiophosphorylamido-2-(20,30,40,60-
tetra-O-acetyl-b-D
-glucopyranosyl-10-imino)thiazolidine-4-one
(3b)
From 1.18 g of 2b (0.79 g, 64%); white crystals from EtOAc–
petroleum ether; mp 87–89 °C; 1H NMR (CDCl3, ppm): d 8.07–
7.36 (m, 5H, Ar-H), 5.70 (d, J 8.4 Hz, 1H, NH), 5.48 (t, 1H, H-20),
5.27 (d, J 4.4 Hz, 1H, H-10), 5.22 (t, 1H, H-30), 5.11 (t, 1H, H-40),

1252
Y. X. Li et al. / Carbohydrate Research 344 (2009) 1248–1253
5.02 (m, 2H, H-60, H-50), 3.90 (s, 3H, CH3O), 3.72 (m, 3H, H-60, H-5),
2.06, 2.02, 2.00, 1.96 (4s, 12H, 4 ꢀ OAc); 13C NMR (CDCl3, ppm): d
170.93, 170.81, 170.30, 169.73 (4C, 4 ꢀ CO), 168.68 (C-4), 157.40
(C-2), 132.74, 131.83, 131.69, 131.57, 128.86, 128.71 (6C, Ar-C),
88.30 (CH3O), 83.73 (C-60), 71.52 (C-30), 70.87 (C-20), 68.92 (C-10),
62.01 (C-50), 53.23 (C-40), 29.98 (C-5), 21.15, 20.99, 20.94, 20.86
(4C, 4 ꢀ OAc); 31P NMR (CDCl3, ppm): d 81.75, 81.69. FABMS: m/z
631 [M+H]+. Anal. Calcd for C24H30N3O11PS2: C, 45.64; H, 4.79; N,
6.65. Found: C, 45.91; H, 4.96; N, 6.92.
3.43 (m, 1H, H-50), 2.07, 2.06, 2.05 (3s, 9H, 3 ꢀ OAc); 13C NMR (CDCl3,
ppm): d 170.30, 169.8, 169.5 (3C, 3 ꢀ CO), 167.76 (C-4), 155.8 (C-2),
89.73 (C-10), 81.67 (C-50), 72.8 (C-30), 72.43 (C-20), 68.97 (C-40), 54.97,
54.76 (2C, 2 ꢀ POCH3), 29.98 (C-5), 21.00, 20.95, 20.84(3C, 3 ꢀ OAc);
31P NMR (CDCl3, ppm): d 70.65. FABMS: m/z 514.2 [M+H)+. Anal.
Calcd for C16H24N3O10PS2: C, 37.43; H, 4.71; N, 8.18. Found: C,
37.35; H, 5.02; N, 8.32.
1.3.7. 3-Diethoxythiophosphorylamido-2-(20,30,40-tri-O-acetyl-
b-D
-xylopyranosyl-10-imino)thiazolidine-4-one (3g)
1.3.3. 3-Phenyl(propoxy)thiophosphorylamido-2-(20,30,40,60-
From 1.02 g of 2g (0.60 g, 58%); white crystals from EtOAc–
tetra-O-acetyl-b-
D
-glucopyranosyl-10-imino)thiazolidine-4-one
petroleum ether; mp 101–103 °C; 1H NMR (CDCl3, ppm): d 7.96–
7.52 (m, 5H, Ar-H), 5.54 (br s, 1H, NH), 5.30 (m, 2H, H-30), 5.01
(m, 1H, H-40), 4.92 (m, 1H, H-20), 4.39 (d, J 8.4 Hz, 1H, H-10), 4.03
(s, 2H, H-50), 3.92 (m, 6H, 2 ꢀ POCH2, 2 ꢀ H-5), 3.70 (m, 1H, H-
50), 2.06, 2.05, 2.03 (3s, 9H, 3 ꢀ OAc), 1.40 (t, 6H, 2 ꢀ POCH2CH3);
13C NMR (CDCl3, ppm): d 170.87, 170.33, 169.42 (3C, 3 ꢀ CO),
168.70 (C-4), 157.11 (C-2), 89.84 (C-10), 82.37 (C-50), 71.99 (C-20),
71.01, 67.45, 60.29, 54.96 (4C, C-30, C-40, 2 ꢀ POCH2), 30.47 (C-5),
21.01, 20.68, 20.43 (3C, 3 ꢀ OAc), 16.23, 16.17 (2C, 2 ꢀ POCH2CH3);
31P NMR (CDCl3, ppm): d 70.66. FABMS: m/z 541 [M+H]+. Anal.
Calcd for C18H28N3O10PS2: C, 39.92; H, 5.21; N, 7.76. Found: C,
39.74; H, 5.30; N, 7.88.
(3c)
From 1.2 g of 2c (0.55 g, 42%); white crystals from EtOAc–petro-
leum ether; mp 107–108 °C; 1H NMR (CDCl3, ppm): d 7.79–7.41
(m, 5H, Ar-H), 5.68 (d, J 8.4 Hz, 1H, NH), 5.50 (t, 1H, H-20), 5.22
(d, J 4.4 Hz, 1H, H-10), 5.11 (t, 1H, H-30), 5.09 (m, 3H, H-40, H-50,
H-60), 3.94 (m, 2H, CH2O), 3.75(m, 3H, H-60, H-5), 2.06, 1.98, 1.97,
1.95 (4s, 12H, 4 ꢀ OAc), 1.28 (t, 2H, CH2), 0.93 (t, 3H, CH3); 13C
NMR (CDCl3, ppm) d 170.27, 169.94, 169.58, 169.20 (4C, 4 ꢀ CO),
168.88 (C-4), 154.92 (C-2), 132.34, 131.65, 131.54, 128.69,
128.54, 128.38 (6C, Ar-C), 86.74, 74.71, 73.66, 68.23, 67.34, 62.79,
62.43 (7C, C-10, C-20, C-30, C-40, C-50, C-6, POCH2), 32.81 (C-5), 23.67
(POCH2CH2), 20.92, 20.79, 20.55 (4C, 4ꢀOAc), 10.45
(POCH2CH2CH3); 31P NMR (CDCl3, ppm): d 82.37, 82.26. FABMS:
m/z 659 [M+H]+. Anal. Calcd for C26H34N3O11PS2: C, 47.34; H,
5.20; N, 6.37. Found: C, 47.58; H, 5.39, N, 5.53.
1.3.8. 3-Methoxy(phenyl)thiophosphorylamido-2-(20,30,40-tri-O-
acetyl-b-D
-xylopyranosyl-10-imino)thiazolidine-4-one (3h)
From 1.03 g of 2h (0.52 g, 47%); white crystals from EtOAc–petro-
leum ether; mp 95–96 °C; 1H NMR (CDCl3, ppm): d 8.06–7.51 (m, 5H,
Ar-H), 5.56 (br s, 1H, NH), 5.29 (m, 2H, H-30, H-40), 5.00 (m, 1H, H-20),
4.36 (d, J 8.4 Hz, 1H, H-10), 4.02 (m, 1H, H-50), 3.91 (m, 5H, CH3O,
2 ꢀ H-5), 3.79 (m, 1H, H-50), 2.07, 2.06, 2.05 (3s, 9H, 3ꢀOAc); 13C
NMR (CDCl3, ppm): d 170.50, 170.46, 169.35 (3C, 3 ꢀ CO), 168.76
(C-4), 156.40 (C-2), 132.82, 131.79, 131.67, 131.50, 128.66, 128.45
(6C, Ar-C), 93.74, 83.46, 73.42, 70.46, 68.82, 62.45, 53.43 (6C, C-10,
C-20, C-30, C-40, C-50, CH3O), 31.54 (C-5), 21.00, 20.89, 20.46 (3C,
3ꢀOAc); 31P NMR (CDCl3, ppm): d 81.70, 81.52. FABMS: m/z 559
[M+H]+. Anal. Calcd for C21H26N3O9PS2: C, 45.08; H, 4.68; N, 7.51.
Found: C, 45.11; H, 4.96; N, 7.22.
1.3.4. 3-Diethoxythiophosphorylamido-2-(20,30,40,60-tetra-O-
acetyl-b-D
-galactopyranosyl-10-imino)thiazolidine-4-one (3d)
From 1.14 g of 2d (0.34 g, 24%); syrup; 1H NMR (CDCl3, ppm): d
5.65 (d, J 8.4 Hz, 1H, NH), 5.41 (t, 1H, H-20), 5.22 (t, 1H, H-30), 5.10
(t, 1H, H-40), 4.70 (d, J 8.8 Hz, 1H, H-10), 4.22–4.10 (m, 6H, H-60, H-
50, 2 ꢀ POCH2), 3.60 (m, 3H, H-60, H-5), 2.13, 2.07, 2.02, 1.98 (4s,
12H, 4 ꢀ OAc), 1.30 (t, 6H, 2 ꢀ POCH2CH3); 13C NMR (CDCl3,
ppm): d 170.61, 170.41, 170.17, 168.54 (4C, 4 ꢀ CO), 167.80 (C-
4), 156.46 (C-2), 84.23 (C-10), 72.01 (C-50), 67.79 (C-30), 66.69 (C-
20), 64.74 (C-40), 64.01, 63.77 (2C, 2 ꢀ POCH2), 61.56(C-60), 33.47
(C-5), 21.16, 20.92, 20.84, 20.77 (4C, 4 ꢀ OAc), 16.17, 16.09 (2C,
2 ꢀ POCH2CH3); 31P NMR (CDCl3, ppm): d 71.74. FABMS: m/z 613
[M+H]+. Anal. Calcd for C21H32N3O12PS2: C, 41.11; H, 5.26; N,
6.85. Found: C, 41.00; H, 5.43; N, 6.78.
1.3.9. 3-Ethoxy(phenyl)thiophosphorylamido-2-(20,30,40-tri-O-
acetyl-b-D
-xylopyranosyl-10-imino)thiazolidine-4-one (3i)
From 1.06 g of 2i (0.71 g, 63%); syrup; 1H NMR (CDCl3, ppm): d
8.01–7.66 (m, 5H, Ar-H), 5.57 (br s, 1H, NH), 5.31 (m, 2H, H-30), 5.12
(m, 1H, H-40), 5.02 (m, 1H, H-20), 4.33 (d, J 8.4 Hz, 1H, H-10), 3.99
(m, 4H, 2 ꢀ H-5, CH2O), 3.83 (m, 1H, H-50), 2.07, 2.04, 2.03 (3s,
9H, 3 ꢀ OAc), 1.36 (t, 3H, CH3); 13C NMR (CDCl3, ppm): d 170.52,
170.12 (3C, 3 ꢀ CO), 168.99 (C-4), 159.52 (C-2), 135.29, 134.36,
134.64, 133.58, 130.66, 129.87 (6C, Ar-C), 89.45, 80.21, 73.26,
69.37, 62.55, 53.60 (6C, C-10, C-20, C-30, C-40, C-50, CH3O), 30.57
(C-5), 20.94, 20.83, 20.32 (3C, 3ꢀOAc), 16.25 (POCH2CH3), 31P
NMR (CDCl3, ppm): d 81.85, 81.70. FABMS: m/z 573 [M+H]+. Anal.
Calcd for C22H28N3O9PS2: C, 46.07; H, 4.92; N, 7.33. Found: C,
46.39; H, 5.18; N, 7.70.
1.3.5. 3-Methoxy(phenyl)thiophosphorylamido-2-(20,30,40,60-
tetra-O-acetyl-b-D
-galactopyranosyl-10-imino)thiazolidine-4-
one (3e)
From 1.18 g of 2e (0.77 g, 61%); white crystals from EtOAc–
petroleum ether; mp 98–100 °C; 1H NMR (CDCl3, ppm): d 7.93–
7.37 (m, 5H, Ar-H), d 5.70 (d, J 8.4 Hz, 1H, NH), 5.44 (t, 1H, H-50),
5.25 (t, 1H, H-30), 5.16 (t, 1H, H-20), 4.82 (d, J 8.8 Hz, 1H, H-10),
4.33–4.19 (m, 5H, H-60, H-40, POCH3), 3.73 (m, 3H, H-60, H-5),
2.05, 2.03, 1.98, 1.95 (4s, 12H, 4 ꢀ OAc); 13C NMR (CDCl3, ppm):
d 170.69, 170.59, 170.32, 170.10 (4C, 4 ꢀ CO), 169.55 (C-4),
156.75 (C-2), 132.56, 131.75, 131.65, 131.52, 128.52, 128.37 (6C,
Ar-C), 95.88 (C-10), 76.37 (C-50), 76.14 (C-30), 70.18 (C-20), 69.49
(C-40), 68.73 (POCH3), 68.22 (C-60), 30.07 (C-5), 30.07, 21.04,
20.84, 20.75 (4C, 4 ꢀ OAc); 31P NMR (CDCl3, ppm): d 83.87, 83.62.
FABMS: m/z 631 [M+H]+. Anal. Calcd for C24H30N3O11PS2: C,
47.59; H, 5.18; N, 4.50. Found: C, 47.44; H, 5.58; N, 4.70.
1.3.10. 3-Diethoxythiophosphorylamido-2-[2,3,4,6-tetra-O-
acetyl-b-
D-galactopyranosyl-(1?4)-2,3,6-tri-O-acetyl-b-D-
glucopyranosyl-10-imino]thiazolidine-4-one (3j)
From 1.72 g of 2j (0.6 g, 35%); white crystals from EtOAc–petro-
leum ether; mp 88–91 °C; 1H NMR (CDCl3, ppm): d 5.53–3.48 (m,
20H, lactosyl ring, 2 ꢀ POCH2, 5-H), 2.14, 2.10, 2.09, 2.04, 2.03,
1.94 (m, 21H, 7 ꢀ OAc), 1.27 (t, 6H, 2 ꢀ POCH2CH3); 13C NMR
(CDCl3, ppm): d 170.55, 170.49, 170.33, 170.27, 169.67 (7C,
7 ꢀ CO), 169.22 (C-4), 156.13 (C-2), 91.36, 88.30, 74.22, 72.77,
71.18, 70.92, 69.23, 66.80, 63.76, 62.04, 61.02 (14C, lactosyl ring,
2 ꢀ CH2O), 33.69 (C-5), 21.08, 20.97, 20.85, 20.72 (7C, 7 ꢀ COCH3),
16.19, 16.11 (2C, 2 ꢀ POCH2CH3); 31P NMR (CDCl3, ppm): d 71.05.
1.3.6. 3-Dimethoxythiophosphorylamido-2-(20,30,40-tri-O-
acetyl-b-D
-xylopyranosyl-10-imino)thiazolidine-4-one (3f)
From 0.84 g of 2f (0.44 g, 43%); white crystals from EtOAc–petro-
leum ether; mp 146–148 °C; 1H NMR (CDCl3, ppm): d 5.53 (br s, 1H,
NH), 5.27(m, 1H, H-30), 5.06(m, 1H, H-40), 5.01(m, 1H, H-20), 4.76(d, J
8.4 Hz, 1H, H-10), 4.20 (m, 1H, H-50), 3.83 (m, 8H, 2 ꢀ CH3O, 2 ꢀ H-5),

Y. X. Li et al. / Carbohydrate Research 344 (2009) 1248–1253
1253
FABMS: m/z 901 [M+H]+. Anal. Calcd for C33H48N3O20PS2: C, 43.95;
H, 5.36; N, 4.66. Found: C, 44.16; H, 5.54; N, 4.97.
4. Ottana, R.; Maccari, R.; Barreca, M. L.; Bruno, G.; Rotondo, A.; Rossi, A.;
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Lee, R. E. Bioorg. Med. Chem. Lett. 2003, 13, 3227–3230.
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Chem. Abstr. 143:59967.
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4795–4798.
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1.3.11. 3-Diethoxythiophosphorylamido-2-[2,3,4,6-tetra-O-
acetyl-
a-D-glucopyranosyl-(1?4)-2,3,6-tri-O-acetyl-b-D-
glucopyranosyl-10-imino] thiazolidine-4-one (3k)
From 0.26 g of 2k (0.56 g, 33%); syrup; 1H NMR (CDCl3, ppm): d
5.58–3.48 (m, 20H, maltosyl ring, 2 ꢀ CH2O, 5-H), 2.19, 2.13, 2.10,
2.07, 2.03, 2.00, 1.97 (s, 21H, COCH3), 1.22 (t, 6H, 2 ꢀ POCH2CH3);
13C NMR (CDCl3, ppm): d 168.17, 168.01, 167.81, 167.56, 167.35,
167.05, 166.40, 165.26 (8C, 7 ꢀ CO, C-4), 160.17 (C-2), 93.09,
85.18, 80.83, 76.47, 73.50, 70.48, 70.43, 69.55, 67.65, 67.01,
66.04, 65.67, 60.57, 59.58 (14C, sugar ring, 2 ꢀ CH2O), 30.57 (C-
5), 18.55, 18.49, 18.30, 18.21 (7C, 7 ꢀ COCH3), 14.26, 13.99 (2C,
2 ꢀ POCH2CH3); 31P NMR (CDCl3, ppm): d 68.99. FABMS: m/z 901
[M+H]+. Anal. Calcd for C33H48N3O20PS2: C, 43.95; H, 5.36; N,
4.66. Found: C, 43.88; H, 5.76; N, 4.38.
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The project was supported by NNSFC #20432010 and the Sci-
ence and Technology Innovation Foundation of Nankai University.
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