N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]amino acids: Their synthesis, anti-inflammatory evaluation and QSAR analysis

Article abstract of DOI:10.1016/j.ejmech.2007.03.015

Developing novel anti-inflammatory drugs is increasingly important in modern pharmaceutical industry. In this work, the reactions of both amino acids and their methylesters with 3-(5,5-dimethyl-1,3-dioxane-2-yl)propanal (2) were performed to either direct

Full text of DOI:10.1016/j.ejmech.2007.03.015

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 8e18
http://www.elsevier.com/locate/ejmech
Original article
N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]amino acids:
Their synthesis, anti-inflammatory evaluation and QSAR analysis
c
, Yu-Rong Tang , Chao Wang , Ziding Zhang
Shiqi Peng
a
c,
b,***
*
,
Xiangmin Li a, Ming Zhao
b,**
a College of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
b College of Pharmaceutical Sciences, Capital Medical University, Beijing 100054, PR China
c College of Biological Sciences, China Agricultural University, Beijing 100094, PR China
Received 16 November 2006; received in revised form 2 March 2007; accepted 8 March 2007
Available online 4 April 2007
Abstract
Developing novel anti-inflammatory drugs is increasingly important in modern pharmaceutical industry. In this work, the reactions of both
amino acids and their methylesters with 3-(5,5-dimethyl-1,3-dioxane-2-yl)propanal (2) were performed to either directly provide the goal
products N-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]amino acids (4aes) in 9e65% yields or provide the intermediates N-[2-(5,5-dimethyl-
1,3-dioxane-2-yl)ethyl]amino acid methylesters (3aes) in 78e87% yields. The saponification of 3aes provided 4aes in 80e89% yields. Using
a xylene-induced ear edema model, the anti-inflammatory activities of these newly synthesized anti-inflammatory agents were evaluated. The
results indicated that comparing to the vehicle control 17 out of 4aes significantly inhibited the development of inflammation in mice
( p < 0.01). In particular, eight out of 4aes exhibited an even higher anti-inflammatory activity than the standard reference drug aspirin
( p < 0.05e0.01). A QSAR analysis was performed by use of the molecular descriptors generated from e-dragon software. The predictive
accuracy of the established QSAR model implies that it may be promising for screening the new derivatives of 2-position amino acid substituted
1,3-dioxanes as potential anti-inflammatory agents.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Anti-inflammatory drug; Chemical synthesis; Amino acid; 1,3-Dioxane; QSAR
1. Introduction
the structure modifications and SAR analysis of the reported
1,3-dioxane anti-inflammatory agents explored the importance
for both 2- and 5-position substitutions, the diversity was still
poor. For instance, the 2-position substituents were mainly al-
kyls, and the 5-position substituents were mainly alkylaminos
and amidos, which were inherently resulted from the simplic-
ity of the aldehyde and the 1,3-diol commonly used in the syn-
thetic reactions [10,13,14].
It is well known that amino acids are usually used as phar-
macokinetic group in drug development. To increase the sub-
stitution diversity and improve pharmacokinetics, in the
present paper a synthetic route of new 1,3-dioxanes, N-[2-
(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]amino acids, was estab-
lished and 19 new compounds were accordingly prepared
(see Scheme 1). Moreover, the anti-inflammatory activities
Inflammation is known not only as a symptom of great deal
of common diseases but also as an early phase of some serious
diseases such as cancer [1e3], heart vascular diseases [4e6]
and Alzheimer’s dementia [7e9]. Thus the discovery of novel
anti-inflammatory drugs has been attracting a lot of interests.
As promising anti-inflammatory agents substituted 1,3-diox-
anes were prepared in some laboratories [10e14]. Though
* Corresponding author. Tel.: þ86 10 6273 4376; fax: þ86 10 6273 1332.
** Corresponding author. Tel./fax: þ86 10 8391 1528.
***Corresponding author. Tel.: þ86 10 8391 1535.
E-mail addresses: mingzhao@mail.bjmu.edu.cn (M. Zhao), zidingzhang@
cau.edu.cn (Z. Zhang), sqpeng@mail.bjum.edu.cn (S. Peng).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.03.015

X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
9
O
C
Table 1
Yields (%) of 3aes (from 2) and 4aes (directly from 2 or from 3aes via 2)
CH
R
N
H
OCH3
iii
O
O
3a-s
OCH3
OCH3
ii
O
O
From 2
From 2
From 3aes
From 3aes via 2
H
3a
3b
3c
3d
3e
3f
80
82
87
79
78
85
79
78
82
83
80
81
79
79
82
85
80
80
80
4a
4b
4c
4d
4e
4f
61
13
37
40
48
65
60
27
12
12
30
42
9
4a
4b
4c
4d
4e
4f
88
89
87
88
88
80
80
87
82
82
84
85
79
81
85
86
87
85
85
4a
4b
4c
4d
4e
4f
70
73
76
70
69
68
63
68
67
68
67
69
62
64
70
73
70
68
68
OCH
3 i
H3CO
O
O
v
O
OCH3OCH3
O
1
2
N
H
CH C OH
iv
O
O
R
4a-s
3g
3h
3i
4g
4h
4i
4g
4h
4i
4g
4h
4i
Scheme 1. The synthetic route of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]-
amino acids. Wherein 3a and 4a R ¼ H, 3b and 4b R ¼ CH3, 3c and 4c
R ¼ CH(CH3)2, 3d and 4d R ¼ CH2CH(CH3)2, 3e and 4e R ¼ CH(CH3)
CH2CH3, 3f and 4f R ¼ CH2C6H5, 3g and 4g R ¼ CH2C6H4-OH-p, 3h and
4h R ¼ CH2OH, 3i and 4i R ¼ CH(OH)CH3, 3j R ¼ CH2CO2CH3, 4j R ¼ CH2
CO2H, 3k R ¼ CH2CH2CO2CH3, 4k R ¼ CH2CH2CO2H, 3l and 4l R ¼ indole-
5-yl-CH2, 3m and 4m R ¼ CH2CH2SCH3, 3n and 4n R ¼ CH2CH2CH2NHC
(NH)NH2, 3o and 4o R1 ¼ CH2CONH2, 3p and 4p R ¼ CH2CH2CONH2, 3q
and 4q R ¼ imidazole-4-yl-CH2, 3r R ¼ CH2CH2CH2CH2NHCBz, 4r R ¼ CH2
CH2CH2CH2NH2, 3s and 4s R ¼ cyclobutylamine-2-yl. (i) 2,2-Dimethyl-1,3-
propanediol, dichloromethane and trifluoroacetic acid; (ii) H3PO4 (6 N), aque-
ous CH3CN (90%, v/v); (iii) amino acid methylester, NaOH, NaCNBH3 and
methanol; (iv) amino acid, NaOH, NaCNBH3 and methanol; (v) NaOH and
methanol.
3j
4j
4j
4j
3k
3l
4k
4l
4k
4l
4k
4l
3m
3n
3o
3p
3q
3r
3s
4m
4n
4o
4p
4q
4r
4s
4m
4n
4o
4p
4q
4r
4s
4m
4n
4o
4p
4q
4r
4s
16
17
15
65
65
10
6 N, 2 N), five solvents, three temperatures (45 ꢀC, 22 ꢀC,
5 ꢀC) and three times (10 h, 30 h, 48 h) were used in the pres-
ent study. The related data are listed in Table 2. The data in-
dicate that when the reaction was carried out in CH2Cl2 at
5 ꢀC for 48 h and 6 N trifluoroacetic acid was used as the cat-
alyst, the highest ratio of 1/10 (8:1) was observed. If the reac-
tion was carried out in CH2Cl2 at 45 ꢀC for 10 h and
concentrated H2SO4 was used as the catalyst, the lowest ratio
of 1/10 (1:9) was observed.
of 19 N-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]amino acids
were evaluated using xylene-induced ear edema. Finally, the
QSAR analysis was also performed.
2. Results and discussion
2.1. Chemical synthesis
In our previous paper 2 was obtained via a partial hydrolysis
of 1, in which the mixture of oxalic acid and silica gel was used
as the catalyst, a 1:1 mixture of 1,2-dichloroethane and tetrahy-
drofuran was used as the solvent, and the reaction was carried
out at 60e100 ꢀC for 6e60 h [15]. In order to lower the temper-
ature of the partial hydrolysis of 1 (cf. Scheme 2), here four acids
(oxalic acid, HCl, H3PO4, F3CCO2H) of two concentrations
(6 N, 2 N), three temperatures (45 ꢀC, 22 ꢀC, 5 ꢀC), four sol-
vents (water, 1,2-dichloroethane, tetrahydrofuran, aqueous
CH3CN), and three times (6 h, 8 h, 10 h) were used. The related
data are listed in Table 3. The data indicate that when the partial
hydrolysis was carried out in aqueous CH3CN (90%, v/v), with
H3PO4 (6 N) as the catalyst and at 5 ꢀC for 6 h, 1 was converted
into 2 in the highest yield (90%). If the partial hydrolysis was
carried out in tetrahydrofuran, with 6 N HCl as the catalyst
and at 45 ꢀC for 6 h, the yield of 2 was the lowest (40%).
As illustrated in Scheme 1, both amino acids and their
methylesters were used to react with 3-(5,5-dimethyl-1,3-diox-
ane-2-yl)propanal (2). In the presence of sodium hydroxide and
anhydrous magnesium sulfate, HCl$L-Gly-OCH3 was succes-
sively treated with half-fold excess of 2 and one-fold excess of
NaCNBH3 to provide N-[2-(5,5-dimethyl-1,3-dioxane-2-yl)
ethyl]amino acid methylesters (3aes) in 78e87% yields. At
0 ꢀC, 3aes were treated by a solution of sodium hydroxide in
a 1:1 mixture of methanol and water (2 mol/L), N-[2-(5,5-di-
methyl-1,3-dioxane-2-yl)ethyl]amino acids (4aes) were
smoothly formed in 80e89% yields. Though 4aes can be di-
rectly formed via the reactions of amino acids, 2 and NaCNBH3,
two-fold excess of 2 and one-and-a-half-fold excess of
NaCNBH3 had to be used, only yields less than 65% were ob-
tained, which were significantly lower than the total yields
through 3aes to 4aes. The data are listed in Table 1.
As we knew, the transacetalization of 1,1,3,3-tetramethox-
ypropane and 2,2-dimethyl-1,3-propanediol depicted in
Scheme 2 usually gave both monocyclic derivative 2-(2,2-
dimethoxylethyl)-5,5-dimethyl-1,3-dioxane (1) and dicyclic
derivative bis(5,5-dimethyl-1,3-dioxane-2-yl)-methane (10),
and 10 was the preferential product [15]. However, the ratio
of 1/10 can be regulated through optimizing the procedure by
appropriately selecting the reaction solvent, catalyst, tempera-
ture and time. To optimize the procedure, four acids (H2SO4,
HCl, H3PO4, F3CCO2H) of three concentrations (concentrated,
O
O
O
1'
H3CO
OH
OH
OCH3
+
O
O
i
+
O
O
OCH3OCH3
ii
O
O
OCH3
2
1
H
OCH3
Scheme 2. Compound 1 was firstly formed via the transacetalization of
1,1,3,3-tetramethoxypropane and 2,2-dimethyl-1,3-propanediol, and then par-
tially hydrolyzed to 2. (i) Dichloromethane and hydrochloric acid; (ii) H3PO4
(6 N), aqueous CH3CN (90%, v/v).

10
X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
O
Table 2
Effect of procedure on the ratio of 1/10
OH
O
O
O
H
N
H
CH C OR'
N
CH C OR'
N
H
CH C OR'
Solvent
Catalyst
Temp. (ꢀC) Time (h) Ratio of 1/10
O
O
O
O
R
ii
-H2O
i
O
O
R
O
O
R
iii
[H]
THF
CHCl3
Ether
HCl (6 mol/L)
HCl (6 mol/L)
HCl (6 mol/L)
22
22
22
22
22
22
22
5
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
30
48
1:5
1:3
1:6
1:4
1.5:2
1:2
1:2
1:1
2:1
1:4
1:5
1:4
1:5
1:9
1:4
1:4
1:4
3:1
2:1
2:1
3:2
5:1
6:1
8:1
2
3'a-s or 4'a-s
3"a-s or 4"a-s
3a-s or 4a-s
Ethyl acetate HCl (6 mol/L)
Scheme 3. The steps included in the formation of 3aes or 4aes from 2 and
amino acids or their methylesters. (i) Trifluoroacetic acid, amino acids or their
methylesters; (ii) anhydrous MgSO4; (iii) NaOH, NaCNBH3 and methanol.
For 30aes, 300aes and 3aes R0 ¼ CH3 and the definition of R is the same as
that in Scheme 1; for 40aes, 400aes and 4aes R0 ¼ H and the definition of
R is the same as that in Scheme 1.
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
HCl (6 mol/L)
HCl (2 mol/L)
HCl (concentrated)
HCl (6 mol/L)
HCl (6 mol/L)
45
22
22
22
5
H2SO4 (6 mol/L)
H2SO4 (2 mol/L)
H2SO4 (concentrated)
H2SO4 (concentrated)
H2SO4 (concentrated)
H3PO4 (6 mol/L)
H3PO4 (2 mol/L)
H3PO4 (concentrated)
F3CCO2H (6 mol/L)
F3CCO2H (2 mol/L)
the dehydrating agent. In the optimization of the elimination
procedure, the condensation of 2 and glycine methylester was
selected as the model reaction and carried out at three temper-
atures (22 ꢀC, 35 ꢀC, 45 ꢀC), for which anhydrous MgSO4,
Na2SO4, Na2CO3 and molecular sieve were used as dehydrating
agents, and the total yield of 3a was examined as comparing cri-
terion. The related data are listed in Table 4. The data indicated
that when the elimination was carried out at 22 ꢀC in methanol
and anhydrous MgSO4 was used as the dehydrating agent, 3a
was obtained in 80% total yield. If the elimination was carried
out at 35 ꢀC in methanol and anhydrous Na2CO3 was used as
the dehydrating agent, the yield of 3a was only 40%. Thus all
eliminations were carried out at 22 ꢀC in methanol and with an-
hydrous MgSO4 as the dehydrating agent.
To determine if any racemization of the preexisting stereo-
genic center had occurred during the course of the synthesis,
the HPLC analysis was used for determining the optical purity
of 4aes. In the determination a Waters 600E instrument with
UV detector (190e600 nm, at 275 nm) was used. The column
Daicel Chiralpak AD-H (2.1 ꢁ 150 mm, 5 mm), the mobile
phase consisted of isopropanol (A) and hexane (B), and
0.5 mL/min of LC flow rate were used. After 20 mL of the so-
lution of 4aes in isopropanol (1.5 mM/L) was loaded, the col-
umn was eluted with the mobile phase. The gradient program
was that after 2 min A was increased to 4% in 5 min, increased
to 10% in 6 min and held for another 10 min. All the determi-
nations gave only a single peak. These observations imply that
no racemization of the preexisting stereogenic center occurred
during the course of the synthesis.
45
22
22
22
22
22
F3CCO2H (concentrated) 22
F3CCO2H (6 mol/L)
F3CCO2H (6 mol/L)
F3CCO2H (6 mol/L)
F3CCO2H (6 mol/L)
5
45
45
45
As depicted in Scheme 3, in the formation of both 3aes and
4aes from 2, the key intermediate Schiff bases 300aes or 400aes
resulted from the amino alcohols 30aes or 40aes via elimina-
tion of water were involved, which significantly depends on
Table 3
Effect of procedure on the yield of the partial hydrolysis of 1
Solvent
Catalyst
(mol/L)
Temp.
(ꢀC)
Time
(h)
Yield
(%)
Water
CH2ClCH2Cl
THF
Oxalic acid (6)
Oxalic acid (6)
Oxalic acid (6)
Oxalic acid (6)
Oxalic acid (6)
Oxalic acid (6)
Oxalic acid (2)
HCl (6)
22
22
22
22
45
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
8
10
43
45
50
65
50
70
45
45
43
50
45
45
40
42
60
62
55
55
50
66
60
62
50
90
80
76
Aqueous CH3CN (90%, v/v)
Aqueous CH3CN (90%, v/v)
Aqueous CH3CN (90%, v/v)
Aqueous CH3CN (90%, v/v)
Water
22
22
22
22
22
22
45
5
CH2ClCH2Cl
THF
HCl (6)
HCl (6)
Aqueous CH3CN (90%, v/v)
THF
THF
HCl (6)
HCl (2)
Table 4
Effect of dehydrating agent on the yield of model compound 3a
HCl (6)
HCl (6)
Dehydrating agent
Temp. (ꢀC)
Yield (%)
THF
Water
F3CCO2H (6)
F3CCO2H (6)
F3CCO2H (6)
F3CCO2H (6)
F3CCO2H (6)
H3PO4 (6)
22
22
22
22
22
22
22
22
22
45
45
45
Na2CO3
Na2CO3
22
35
45
22
35
45
22
35
45
22
35
45
56
40
50
70
55
60
80
73
70
60
55
45
CH2ClCH2Cl
THF
Na2CO3
Na2SO4
Aqueous CH3CN (90%, v/v)
Aqueous CH3CN (90%, v/v)
Water
Na2SO4
Na2SO4
CH2ClCH2Cl
THF
H3PO4 (6)
H3PO4 (6)
MgSO4
MgSO4
MgSO4
Aqueous CH3CN (90%, v/v)
Aqueous CH3CN (90%, v/v)
Aqueous CH3CN (90%, v/v)
Aqueous CH3CN (90%, v/v)
H3PO4 (2)
H3PO4 (6)
Molecular sieve
Molecular sieve
Molecular sieve
H3PO4 (6)
H3PO4 (6)

X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
11
100
80
2.2. Xylene-induced ear edema
By use of a xylene-induced ear edema model the anti-in-
flammatory activities of 4aes were evaluated. The in vivo as-
say involves the test compounds being administrated orally by
gavage in 0.5% carboxymethyl cellulose (CMC) suspension.
Each compound was initially tested at a dose of 20 mg/kg.
The observation explored that 17 compounds from 4aes
showed significant inhibition against xylene-induced inflam-
mation in mice as compared with the vehicle control (CMC
alone, p < 0.01), suggesting that these compounds possess po-
tent anti-inflammatory activity. It was especially noted that
among 4aes, eight compounds exhibited an even higher
anti-inflammatory activity than the standard reference drug as-
pirin ( p < 0.05e0.01, cf. Fig. 1) (Fig. 2).
60
40
20
0
C
A
2 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s
-20
-40
Group
Fig. 2. Inflammatory inhibition of 4aes against xylene-induced ear edema in
mice; n ¼ 11, C ¼ CMC, A ¼ aspirin.
%Inhibition¼339:3ꢂ27:8ꢁnCpꢂ80:6ꢁMor25eꢂ28:2
ꢁRDF040pþ8:7ꢁRDF100u
ð1Þ
2.3. Dose-dependent anti-inflammatory activity
Where the regression coefficient (R) is 0.97. The nCp represents
the number of terminal primary C(sp3) within a molecule. The
other three are 3D-descriptors. The Mor25e is group into the
3D-MoRSE descriptors [16], which are based on the idea of
obtaining information from the 3D atomic coordinates by the
transform used in electron diffraction studies for preparing the-
oretical scattering curves. Mor25e corresponds to signal 25,
weighted by atomic Sanderson electronegativities. The
RDF040p and RDF100u are classified into the RDF molecular
descriptors, which were obtained by radial distribution func-
Three compounds (4h, 4n, 4o) with significant activity
were administrated in a series of lower doses to obtain a de-
tailed pharmacological activity profile. It was observed that
the anti-inflammatory activity of 4h, 4n and 4o was following
dose-dependent manners (Figs. 3e5).
2.4. QSAR analysis
To perform a QSAR analysis on the anti-inflammatory ac-
tivities of 4aes, 1664 different molecular parameters for each
compound were generated from e-dragon webserver (http://
www.vcclab.org/lab/edragon/). Then, the multiple linear re-
gression method was employed to derive the QSAR equation
of 4aes. In this study, the percentage of inhibition (%Inhibi-
tion) was considered as the anti-inflammatory activity of a mol-
ecule. As the number of compounds 4aes is 19, generally the
optimum number of molecular descriptors used in the QSAR
analysis should be not larger than four. To obtain an optimal
QSAR equation, therefore, a genetic algorithm assisted de-
scriptor selection procedure was applied to choose four param-
eters from all the obtained e-dragon descriptors. Finally, the
following optimal QSAR equation in describing the anti-in-
flammatory effects of 4aes was determined:
˚
tions centered on different interatomic distances (from 0.5 A
˚
to 15.5 A) [17]. The RDF molecular descriptors can be inter-
preted as the probability distribution of finding an atom in
a spherical volume of certain radius. For RDF040p, the sphere
˚
radius is of 4.0 A and atomic polarizability weights are used.
˚
For RDF100u, the sphere radius is of 10.0 A and atomic weights
are not used during its calculation.
To validate the established Eq. (1), the resubstitution,
Leave-One-Out (LOO) and Leave-Two-Out (LTO) tests were
carried out. To illustrate the predictive accuracy of the current
QSAR model more explicitly, a parameter named absolute av-
erage error ðeÞ is defined as follows:
ꢀ
ꢀ
P
19
i¼1
ꢀ
ꢀ
% Inhibitioni;measured ꢂ % Inhibitioni;predicted
19
e ¼
ð2Þ
12
10
8
9
8
7
6
5
4
3
2
1
0
a
a
a
a
a
a
a
6
4
a
a
a
b
a
b
b
b
b
b
b
c
c
c
2
0
-1
C
A
2
4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s
0.0mg/kg
0.8mg/kg
4.0mg/kg
20.0mg/kg
-2
Group
Dosage (mg/kg)
Fig. 1. Anti-inflammatory activity of 4aes against xylene-induced ear edema
in mice; n ¼ 11, C ¼ CMC, A ¼ aspirin. (a) Comparing with CMC group,
p < 0.01; (b) comparing with CMC group, p < 0.01, and with aspirin group,
p < 0.05; (c) comparing with CMC and aspirin groups, p < 0.01.
Fig. 3. Anti-inflammatory activity of 4h at different doses against xylene-in-
duced ear edema in mice; n ¼ 11. (a) Comparing with 0.0 mg/kg (CMC)
group, p < 0.05; (b) comparing with 0.8 mg/kg group, p < 0.05; (c) comparing
with 4 mg/kg group, p < 0.05.

12
X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
9
8
7
6
5
4
3
2
1
0
100
a
80
b
c
60
40
0.0mg/kg
0.8mg/kg
4.0mg/kg
20.0mg/kg
Dosage (mg/kg)
20
0
Fig. 4. Anti-inflammatory activity of 4n at different doses against xylene-in-
duced ear edema in mice. n ¼ 11; (a) Comparing with 0.0 mg/kg (CMC)
group, p < 0.05; (b) comparing with 0.8 mg/kg group, p < 0.05; (c) comparing
with 4 mg/kg group, p < 0.05.
-20
-40
Where %Inhibitioni,measured and %Inhibitioni,predicted represent
the measured and predicted values of inhibition effect for com-
pound i, respectively. The resubstitution analysis gave an e
value of 5.0, whereas the e values for the LOO and LTO tests
were 6.8 and 7.0, implying a high predictive accuracy in the
QSAR Eq. (1). The detailed results of the LOO test are further
illustrated in Fig. 6.
-40
-20
0
20
40
Measured Inhibition (%)
60
80
100
Fig. 6. Comparison of the predicted anti-inflammatory activities with the mea-
sured activities in the LOO test.
Due to the physicochemical information embedded in the
Mor25e, RDF040p and RDF100u descriptors is not intuitive,
the established QSAR model may not be very informative to
explain the molecular mechanism of anti-inflammatory effects
of 4aes, although it has reached a high predictive accuracy.
Further investigation is required to explore the possibility of
the current QSAR model to screen the new derivatives of
N-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]amino acid as
potential anti-inflammatory agents.
VG-ZAB-MS and TOF-MS was recorded on MDS SCIEX
QSTAR. Optical rotations were determined on a Schmidt
and Haensch Polartronic D instrument at 20 ꢀC. All L-amino
acids were purchased from China Biochemical Corp. TLC
was made with Qingdao silica gel GF254. Chromatography
was performed with Qingdao silica gel H60 or Sephadex-
LH20. All solvents were distilled and dried before use by ref-
erence to literature procedures.
3. Experimental section
3.1.2. 2-(2,2-Dimethoxylethyl)-5,5-dimethyl-1,3-dioxane (1)
To the solution of 4.92 g (30.0 mmol) of 1,1,3,3-tetrame-
thoxypropane, 0.78 g (7.5 mmol) of 2,2-dimethyl-1,3-pro-
panediol in 25 mL of dichloromethane and 0.1 mL of
trifluoroacetic acid (6 N) were added dropwise. The reaction
mixture was stirred at 5 ꢀC for 24 h and then additional
0.78 g (7.5 mmol) of 2,2-dimethyl-1,3-propanediol was added.
The reaction mixture was stirred at 5 ꢀC for another 24 h and
TLC (petroleum ether/ethyl acetate, 15:1) indicated the com-
plete disappearance of 2,2-dimethyl-1,3-propanediol. To the
reaction mixture, 4.0 g of anhydrous sodium carbonate was
added and stirred at room temperature for 2 h. After filtration
and evaporation under reduced pressure, purification by chro-
matography (petroleum ether/ethyl acetate, 15:1) provided
4.89 g (80%) of the title compound as a colorless powder.
1H NMR (CDCl3): d/ppm ¼ 4.537 (t, J ¼ 6.0 Hz, 1H), 4.488
(t, J ¼ 6.0 Hz, 1H), 3.569 (d, J ¼ 11.1 Hz, 2H), 3.405 (d, J
¼ 11.1 Hz, 2H), 3.304 (s, 6H), 1.939 (m, J ¼ 6.0 Hz, 2H),
1.161 (s, 3H), 1.089 (s, 3H).
3.1. Chemical synthesis
3.1.1. General
All the reactions were carried out under nitrogen (1 bar). 1H
(300 MHz and 500 MHz) and 13C (75 MHz and 125 MHz)
NMR spectra were recorded on Bruker AMX-300 and
AMX-500 spectrometers for solution in CDCl3 with tetrame-
thylsilane as internal standard. FAB/MS was determined on
9
8
7
a
6
5
b
c
4
3
2
1
0
0.0mg/kg
0.8mg/kg
4.0mg/kg
20.0mg/kg
3.1.3. 3-(5,5-Dimethyl-1,3-dioxane-2-yl)propanal (2)
Dosage (mg/kg)
The solution of 2.04 g (10.0 mmol) of 2-(2,2-dimethy-
lethyl)-5,5-dimethyl-1,3-dioxane, 2 mL of H3PO4 (6 N),
50 mL of CH3CN and 5 mL of water were stirred at 5 ꢀC
for 8 h, and TLC (petroleum ether/ethyl acetate, 15:1)
Fig. 5. Anti-inflammatory activity of 4o at different doses against xylene-in-
duced ear edema in mice. n ¼ 11; a) Comparing with 0.0 mg/kg (CMC) group,
p < 0.05; b) Comparing with 0.8 mg/kg group, p < 0.05; c) Comparing with
4 mg/kg group, p < 0.05.

X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
13
indicated the complete disappearance of 2-(2,2-dimethy-
lethyl)-5,5-dimethyl-1,3-dioxane. The temperature of the reac-
tion mixture was raised to 25 ꢀC, diluted with 200 mL of water
and extracted with dichloromethane (50 mL ꢁ 6). The col-
lected dichloromethane phase was dried with anhydrous so-
dium sulfate. After filtration and evaporation under reduced
pressure, purification by chromatography (petroleum ether/
ether, 4:1) provided 1.43 g (90%) of the title compound as
3.68 (d, J ¼ 10.4 Hz, 2H), 3.70 (s, 3H), 3.48 (m, J ¼ 7.1 Hz,
1H), 3.47 (d, J ¼ 10.4 Hz, 2H), 2.66 (t, J ¼ 6.1 Hz, 2H), 2.38
(m, J ¼ 7.1 Hz, 1H), 2.22 (s, 1H), 1.86 (t, J ¼ 6.1 Hz, 2H),
1.01 (d, J ¼ 7.1 Hz, 3H), 1.00 (d, J ¼ 7.1 Hz, 3H), 0.99 (s,
3H), 0.62 (s, 3H). 13C NMR (D2O): d/ppm ¼ 171.73, 101.51,
79.40, 68.43, 39.33, 38.21, 33.22, 27.55, 24.57, 23.19,
17.40, 17.32. ESI-MS (m/e): 274 [M þ H]þ. Anal. calcd for
C14H27NO4: C 61.51, H 9.96, N 5.12; found: C 61.66, H
9.83, N 5.31.
1
a colorless syrup. ESI-MS (m/e): 159 [M þ H]þ. H NMR
(CDCl3): d/ppm ¼ 9.831 (s, 1H), 4.890 (t, J ¼ 4.5 Hz, 1H),
3.683 (d, J ¼ 11.1 Hz, 2H), 3.471 (d, J ¼ 11.1 Hz, 2H),
2.717 (d, J ¼ 4.5 Hz, 2H), 1.197 (s, 3H), 1.047 (s, 3H).
3.1.4.4. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-leucine
methylester (3d). Yield: 227 mg (79%). 1H NMR (BHSC-
300, DMSO-d6): d/ppm ¼ 4.87 (t, J ¼ 4.5 Hz, 1H), 3.69 (d,
J ¼ 10.6 Hz, 2H), 3.67 (s, 3H), 3.49 (t, J ¼ 7.0 Hz, 1H), 3.47
(d, J ¼ 10.6 Hz, 2H), 2.66 (t, J ¼ 6.0 Hz, 2H), 2.11 (s, 1H),
1.86 (t, J ¼ 6.0 Hz, 2H), 1.79 (m, J ¼ 7.0 Hz, 1H), 1.62 (m,
J ¼ 7.0 Hz, 2H), 1.01 (d, J ¼ 7.0 Hz, 3H), 1.01 (d,
J ¼ 7.0 Hz, 3H), 0.98 (s, 3H), 0.65 (s, 3H). 13C NMR (D2O):
d/ppm ¼ 171.80, 102.11, 79.42, 59.69, 50.61, 41.22, 39.34,
38.84, 33.21, 27.10, 26.47, 26.46, 23.91, 23.32. ESI-MS (m/
e): 288 [M þ H]þ. Anal. calcd for C15H29NO4: C 62.69, H
10.17, N 4.87; found: C 62.82, H 10.29, N 4.73.
3.1.4. General procedure for the preparation of N-[2-(5,5-
dimethyl-1,3-dioxane-2-yl)ethyl]amino acid methylesters
(3aes)
The suspension of 1.0 mmol of amino acid methylester,
22 mg (0.55 mmol) of NaOH and 5 mL of methanol was
stirred at room temperature for 10 min to form clean solution.
After addition of 300 mg of anhydrous magnesium sulfate to
the solution, 240 mg (1.52 mmol) of 3-(5,5-dimethyl-1,3-diox-
ane-2-yl)propanal (2) was added dropwise. After stirring at
room temperature for 20 min, to the reaction mixture
126 mg (2.0 mmol) of NaCNBH3 was added, stirred at room
temperature for additional 6 h and TLC (petroleum/ether,
4:1) indicated complete disappearance of 2. The reaction mix-
ture was filtered and the filtrate was evaporated under vacuum
to remove the solvent. The residue was purified by silica gel
chromatography to give the title compound as a colorless
powder.
3.1.4.5. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-isoleu-
cine methylester (3e). Yield: 224 mg (78%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 4.87 (t, J ¼ 4.6 Hz, 1H),
3.69 (d, J ¼ 10.5 Hz, 2H), 3.63 (s, 3H), 3.49 (t, J ¼ 7.1 Hz,
1H), 3.47 (d, J ¼ 10.5 Hz, 2H), 2.67 (t, J ¼ 6.2 Hz, 2H), 2.31
(m, J ¼ 7.1 Hz, 1H), 2.21 (s, 1H), 1.86 (t, J ¼ 6.2 Hz, 2H),
1.32 (m, J ¼ 7.1 Hz, 2H), 1.02 (d, J ¼ 7.1 Hz, 3H), 1.01 (t,
J ¼ 7.1 Hz, 3H), 1.00 (s, 3H), 0.95 (s, 3H). 13C NMR (D2O):
d/ppm ¼ 172.43, 102.31, 79.41, 69.55, 50.15, 41.20, 40.10,
33.38, 33.21, 27.29, 23.86, 23.32, 20.10, 17.36. ESI-MS (m/
e): 288 [M þ H]þ. Anal. calcd for C15H29NO4: C 62.69, H
10.17, N 4.87; found: C 62.56, H 10.09, N 5.02.
3.1.4.1.
N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]glycine
methylesters (3a). Yield: 185 mg (80%). 1H NMR (BHSC-
300, DMSO-d6): d/ppm ¼ 4.86 (t, J ¼ 4.8 Hz, 1H), 3.68 (d,
J ¼ 11.2 Hz, 2H), 3.67 (s, 3H), 3.49 (s, 2H), 3.47 (d,
J ¼ 11.2 Hz, 2H), 2.66 (t, J ¼ 6.5 Hz, 2H), 2.13 (s, 1H), 1.90
(t, J ¼ 6.5 Hz, 2H), 0.99 (s, 3H), 0.59 (s, 3H). 13C NMR
(D2O): d/ppm ¼ 170.97, 102.32, 79.42, 52.47, 51.66, 38.94,
37.61, 32.87, 24.56, 23.19. EI/MS: 232 [M þ H]þ. Anal. calcd
for C11H21NO4: C 57.12, H 9.15, N 6.06; found: C 57.00, H
9.25, N 6.21.
3.1.4.6. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-phenyl-
alanine methylester (3f). Yield: 273 mg (85%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 7.23 (t, J ¼ 7.5 Hz, 2H),
7.20 (d, J ¼ 7.5 Hz, 2H), 7.01 (t, J ¼ 7.5 Hz, 1H), 4.72 (t,
J ¼ 3.9 Hz, 1H), 3.92 (t, J ¼ 6.5 Hz, 1H), 3.64 (s, 3H), 3.49
(d, J ¼ 6.5 Hz, 2H), 3.33 (d, J ¼ 6.5 Hz, 2H), 2.94 (m,
J ¼ 6.6 Hz, 2H), 2.75 (m, J ¼ 4.2 Hz, 2H), 2.21 (s, 1H), 1.76
(m, J ¼ 4.2 Hz, 2H), 0.99 (s, 3H), 0.95 (s, 3H). 13C NMR
(CDCl3): d/ppm ¼ 171.85, 137.33, 129.15, 128.35, 126.60,
100.89, 79.33, 63.15, 51.60, 40.07, 39.50, 38.25, 33.50,
22.85, 22.77. ESI-MS (m/e): 322 [M þ H]þ. Anal. calcd for
C18H27NO4: C 67.26, H, 8.47, N 4.36; found: C 67.13, H
8.39, N 4.52.
3.1.4.2. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-alanine
methylester (3b). Yield: 201 mg (82%). 1H NMR (BHSC-
300, DMSO-d6): d/ppm ¼ 4.85 (t, J ¼ 4.9 Hz, 1H), 3.67 (d,
J ¼ 11.1 Hz, 2H), 3.66 (s, 3H), 3.48 (q, J ¼ 6.6 Hz, 1H),
3.46 (d, J ¼ 11.1 Hz, 2H), 2.76 (t, J ¼ 6.6 Hz, 2H), 2.13 (s,
1H), 1.66 (t, J ¼ 6.6 Hz, 2H), 1.22 (d, J ¼ 6.6 Hz, 3H), 0.99
(s, 3H), 0.59 (s, 3H). 13C NMR (D2O): d/ppm ¼ 170.96,
100.33, 79.42, 58.44, 51.66, 37.97, 36.51, 32.99, 24.56,
23.18, 22.11. ESI-MS (m/e): 246 [M þ H]þ. Anal. calcd for
C12H23NO4: C 58.75, H 9.45, N 5.71; found: C 58.88, H
9.54, N 5.93.
3.1.4.7. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-tyrosine
methylester (3g). Yield: 284 mg (79%). 1H NMR (BHSC-
300, DMSO-d6): d/ppm ¼ 7.20 (d, J ¼ 7.2 Hz, 2H), 7.00 (d,
J ¼ 7.2 Hz, 2H), 5.18 (s, 1H), 4.78 (t, J ¼ 4.1 Hz, 1H), 3.93
(t, J ¼ 6.3 Hz, 1H), 3.69 (d, J ¼ 10.2 Hz, 2H), 3.65 (s, 3H),
3.47 (d, J ¼ 10.2 Hz, 2H), 2.95 (d, J ¼ 6.3 Hz, 2H), 2.58 (t,
J ¼ 4.1 Hz, 2H), 2.21 (s, 1H), 1.76 (t, J ¼ 4.1 Hz, 2H), 0.99
3.1.4.3. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-valine
methylester (3c). Yield: 238 mg (87%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 4.87 (t, J ¼ 6.1 Hz, 1H),

14
X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
(s, 3H), 0.95 (s, 3H). 13C NMR (CDCl3): d/ppm ¼ 172.65,
155.33, 135.34, 128.56, 116.82, 101.24, 79.29, 65.22, 50.39,
40.11, 39.55, 38.21, 33.52, 23.11, 22.87. ESI-MS (m/e): 361
[M þ H]þ. Anal. calcd for C20H28N2O4: C 66.64, H 7.83, N
7.77; found: C 66.52, H 7.72, N 7.91.
3.1.4.12. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-trypto-
phan methylester (3l). Yield: 292 mg (81%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 8.91 (s, 1H), 7.20 (d,
J ¼ 7.2 Hz, 1H), 7.16 (t, J ¼ 7.2 Hz, 1H), 7.10 (d,
J ¼ 7.2 Hz, 1H), 7.03 (t, J ¼ 7.2 Hz, 1H), 6.94 (s, 1H), 4.61
(t, J ¼ 4.6 Hz, 1H), 3.91 (t, J ¼ 5.8 Hz, 1H), 3.69 (d,
J ¼ 10.0 Hz, 2H), 3.66 (s, 3H), 3.49 (d, J ¼ 10.0 Hz, 2H),
2.91 (d, J ¼ 5.8 Hz, 2H), 2.64 (t, J ¼ 4.6 Hz, 2H), 2.13 (s,
1H), 1.86 (t, J ¼ 4.6 Hz, 2H), 0.97 (s, 3H), 0.92 (s, 3H). 13C
NMR (D2O): d/ppm ¼ 172.31, 136.35, 131.66, 122.51,
121.78, 120.45, 119.60, 112.09, 111.01, 101.51, 79.43,
65.72, 50.58, 40.24, 39.63, 33.79, 31.10, 24.52, 23.45. ESI-
MS (m/e): 361 [M þ H]þ. Anal. calcd for C20H28N2O4: C
66.64, H 7.83, N 7.77; found: C 66.79, H 7.74, N 7.59.
3.1.4.8. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-serine
methylester (3h). Yield: 204 mg (78%). 1H NMR (BHSC-
300, DMSO-d6): d/ppm ¼ 4.55 (t, J ¼ 4.6 Hz, 1H), 3.81 (d,
J ¼ 6.6 Hz, 2H), 3.69 (d, J ¼ 10.4 Hz, 2H), 3.65 (s, 3H),
3.47 (d, J ¼ 10.4 Hz, 2H), 3.56 (t, J ¼ 6.6 Hz, 1H), 2.68 (t,
J ¼ 4.6 Hz, 2H), 2.16 (s, 1H), 2.13 (s, 1H), 1.91 (t,
J ¼ 4.6 Hz, 2H), 0.97 (s, 3H), 0.95 (s, 3H). 13C NMR (D2O):
d/ppm ¼ 172.30, 102.30, 79.40, 66.87, 64.33, 50.60, 40.95,
38.70, 33.60, 24.58, 23.18. ESI-MS (m/e): 262 [M þ H]þ.
Anal. calcd for C12H23NO5: C 55.16, H 8.87, N 5.36; found:
C 55.31, H 8.93, N 5.51.
3.1.4.13. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-methio-
nine methylester (3m). Yield: 241 mg (79%). ESI-MS (m/e):
306 [M þ H]þ. 1H NMR (BHSC-300, DMSO-d6): d/
ppm ¼ 4.65 (t, J ¼ 4.5 Hz, 1H), 3.70 (d, J ¼ 10.0 Hz, 2H),
3.65 (s, 3H), 3.57 (t, J ¼ 5.8 Hz, 1H), 3.50 (d, J ¼ 10.0 Hz,
2H), 2.66 (t, J ¼ 4.5 Hz, 2H), 2.47 (t, J ¼ 5.8 Hz, 2H), 2.12
(s, 1H), 2.01 (t, J ¼ 5.8 Hz, 2H), 2.11 (s, 3H), 1.87 (t,
J ¼ 4.5 Hz, 2H), 0.96 (s, 3H), 0.93 (s, 3H). 13C NMR (D2O):
d/ppm ¼ 172.12, 101.00, 79.37, 63.08, 50.40, 40.28, 39.50,
33.81, 33.16, 30.49, 24.48, 23.52, 17.50. ESI-MS (m/e): 306
[M þ H]þ. Anal. calcd for C14H27NO4S: C 55.05, H 8.91, N
4.59; found: C 55.22, H 8.80, N 4.73.
3.1.4.9.
N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-threonine
methylester (3i). Yield: 226 mg (82%). 1H NMR (BHSC-
300, DMSO-d6): d/ppm ¼ 4.64 (t, J ¼ 4.7 Hz, 1H), 3.86 (m,
J ¼ 5.6 Hz, 1H), 3.69 (d, J ¼ 10.0 Hz, 2H), 3.66 (s, 3H),
3.49 (d, J ¼ 10.0 Hz, 2H), 3.47 (d, J ¼ 5.6 Hz, 1H), 2.68 (t,
J ¼ 4.7 Hz, 2H), 2.16 (s, 1H), 2.13 (s, 1H), 1.93 (t,
J ¼ 4.7 Hz, 2H), 1.17 (d, J ¼ 5.6 Hz, 3H), 0.99 (s, 3H), 0.97
(s, 3H). 13C NMR (D2O): d/ppm ¼ 172.41, 102.61, 79.42,
71.62, 68.76, 50.59, 40.78, 39.26, 32.25, 24.61, 23.15,
22.20. ESI-MS (m/e): 276 [M þ H]þ. Anal. calcd for
C13H25NO5: C 56.71, H 9.15, N 5.09; found: C 56.86, H
9.24, N 5.27.
3.1.4.14. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-argi-
nine methylester (3n). Yield: 261 mg (79%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 8.74 (s, 2H), 8.71 (s, 1H),
6.51 (s, 1H), 4.64 (t, J ¼ 4.8 Hz, 1H), 3.70 (d, J ¼ 10.0 Hz,
2H), 3.66 (s, 3H), 3.56 (t, J ¼ 5.6 Hz, 1H), 3.51 (d,
J ¼ 10.0 Hz, 2H), 2.82 (t, J ¼ 5.6 Hz, 2H), 2.64 (t,
J ¼ 4.8 Hz, 2H), 2.14 s, 1H), 1.63 (m, J ¼ 5.6 Hz, 2H), 1.88
(t, J ¼ 4.8 Hz, 2H), 1.53 (m, J ¼ 5.6 Hz, 2H), 0.90 (s, 3H),
0.89 (s, 3H). 13C NMR (D2O): d/ppm ¼ 172.07, 162.60,
101.11, 78.83, 63.75, 50.44, 41.48, 40.32, 39.54, 33.68,
29.24, 27.12, 24.42, 23.55. ESI-MS (m/e): 331 [M þ H]þ.
Anal. calcd for C15H30N4O4: C 54.52, H 9.15, N 16.96; found:
C 54.37, H 9.07, N 17.11.
3.1.4.10.
N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-aspartic
acid dimethylester (3j). Yield: 252 mg (83%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 4.70 (t, J ¼ 4.7 Hz, 1H),
3.82 (t, J ¼ 6.1 Hz, 1H), 3.69 (d, J ¼ 10.1 Hz, 2H), 3.66
(s, 3H), 3.66 (s, 3H), 3.49 (d, J ¼ 10.1 Hz, 2H), 2.58 (d,
J ¼ 6.1 Hz, 2H), 2.58 (t, J ¼ 4.7 Hz, 2H), 2.16 (s, 1H),
1.93 (t, J ¼ 4.7 Hz, 2H), 0.96 (s, 3H), 0.94 (s, 3H). 13C
NMR (D2O): d/ppm ¼ 176.71, 176.21, 102.48, 79.32,
58.75, 50.58, 50.49, 41.12, 40.00, 39.64, 33.55, 24.53,
23.33. ESI-MS (m/e): 304 [M þ H]þ. Anal. calcd for
C14H25NO6: C 55.43, H 8.31, N 4.62; found: C 55.58, H
8.20, N 4.77.
3.1.4.15. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-aspara-
gine methylester (3o). Yield: 236 mg (82%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 6.22 (s, 2H), 4.65 (t,
J ¼ 4.5 Hz, 1H), 3.78 (t, J ¼ 5.7 Hz, 1H), 3.62 (s, 3H), 3.50
(d, J ¼ 10.0 Hz, 2H), 3.48 (d, J ¼ 10.0 Hz, 2H), 2.80 (t,
J ¼ 4.5 Hz, 2H), 2.74 (d, J ¼ 5.7 Hz, 2H), 2.14 (s, 1H), 1.89
(t, J ¼ 4.5 Hz, 2H), 0.98 (s, 3H), 0.97 (s, 3H). 13C NMR
(D2O): d/ppm ¼ 176.71, 172.60, 102.68, 79.37, 61.48, 50.37,
41.18, 40.27, 36.34, 32.11, 24.33, 23.28. ESI-MS (m/e): 289
[M þ H]þ. Anal. calcd for C13H24N2O5: C 54.15, H 8.39, N
9.72; found: C 54.30, H 8.27, N 9.56.
3.1.4.11. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-glutamic
acid dimethylester (3k). Yield: 254 mg (80%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 4.52 (t, J ¼ 4.3 Hz, 1H),
3.69 (d, J ¼ 10.1 Hz, 2H), 3.66 (s, 3H), 3.64 (s, 3H), 3.49
(d, J ¼ 10.1 Hz, 2H), 3.44 (t, J ¼ 5.6 Hz, 1H), 2.88 (t,
J ¼ 4.3 Hz, 2H), 2.34 (t, J ¼ 5.6 Hz, 2H), 2.13 (s, 1H),
1.92 (t, J ¼ 5.6 Hz, 2H), 1.82 (t, J ¼ 4.3 Hz, 2H), 0.97
(s, 3H), 0.94 (s, 3H). 13C NMR (D2O): d/ppm ¼ 172.77,
172.32, 99.56, 79.31, 63.58, 50.61, 50.34, 40.22, 39.65,
33.85, 30.36, 29.10, 24.50, 23.47. ESI-MS (m/e): 318
[M þ H]þ. Anal. calcd for C15H27NO6: C 56.77, H 8.57,
N 4.41; found: C 56.89, H 8.66, N 4.58.
3.1.4.16. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-gluta-
mine methylester (3p). Yield: 257 mg (85%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 6.22 (s, 2H), 4.67

X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
15
(t, J ¼ 4.7 Hz, 1H), 3.64 (s, 3H), 3.60 (t, J ¼ 5.6 Hz, 1H), 3.51
(d, J ¼ 10.0 Hz, 2H), 3.48 (d, J ¼ 10.0 Hz, 2H), 2.79 (t,
J ¼ 4.7 Hz, 2H), 2.23 (d, J ¼ 5.6 Hz, 2H), 2.14 (s, 1H), 1.89
(d, J ¼ 5.6 Hz, 2H), 1.89 (t, J ¼ 4.7 Hz, 2H), 0.98 (s, 3H),
0.93 (s, 3H). 13C NMR (D2O): d/ppm ¼ 175.48, 172.10,
102.31, 79.07, 62.98, 50.37, 41.22, 40.36, 33.01, 31.49,
27.20, 24.39, 23.31. ESI-MS (m/e): 303 [M þ H]þ. Anal. calcd
for C14H26N2O5: C 55.61, H 8.67, N 9.26; found: C 55.45, H
8.55, N 9.10.
was added. The reaction mixture was stirred at 0 ꢀC for
100 min and TLC (chloroform/methanol, 30:1) indicated the
completion of the reaction. The reaction mixture was adjusted
to pH 2 with hydrochloric acid (2 mol/L). Upon evaporation,
the residue was dissolved in 50 mL of chloroform. The organic
phase was washed with saturated aqueous sodium chloride and
then dried over anhydrous sodium sulfate. After filtration, the
title compounds were obtained as colorless powder upon evap-
oration under reduced pressure and purified with flash chroma-
tography (CHCl3/CH3OH, 30:1).
3.1.4.17. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-hiati-
dine methylester (3q). Yield: 249 mg (80%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 12.31 (s, 1H), 8.65 (s,
1H), 7.37 (s, 1H), 4.67 (t, J ¼ 4.6 Hz, 1H), 3.86 (t,
J ¼ 4.3 Hz, 1H), 3.62 (s, 3H), 3.55 (d, J ¼ 10.0 Hz, 2H),
3.50 (d, J ¼ 10.0 Hz, 2H), 3.25 (t, J ¼ 4.3 Hz, 2H), 2.29 (d,
J ¼ 5.3 Hz, 2H), 2.14 (s, 1H), 1.92 (d, J ¼ 5.3 Hz, 2H), 0.98
(s, 3H), 0.93 (s, 3H). 13C NMR (D2O): d/ppm ¼ 172.30,
135.59, 134.64, 122.47, 101.02, 79.34, 64.93, 50.39, 41.36,
40.40, 33.33, 31.47, 24.57, 23.19. ESI-MS (m/e): 312
[M þ H]þ. Anal. calcd for C15H25N3O4: C 57.86, H 8.09, N
13.49; found: C 58.01, H 8.20, N 13.33.
3.1.5.1.
N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]glycine
1
(4a). Yield: 191 mg (88%). H NMR (BHSC-300, DMSO-
d6): d/ppm ¼ 10.87 (s, 1H), 4.87 (t, J ¼ 4.7 Hz, 1H), 3.68 (d,
J ¼ 11.0 Hz, 2H), 3.49 (s, 2H), 3.47 (d, J ¼ 11.0 Hz, 2H),
2.67 (t, J ¼ 6.6 Hz, 2H), 2.51 (s, 1H), 1.90 (t, J ¼ 6.6 Hz,
2H), 0.99 (s, 3H), 0.59 (s, 3H). 13C NMR (D2O): d/
ppm ¼ 174.50, 102.33, 79.38, 55.10, 39.00, 37.63, 32.74,
24.56, 23.19. EI/MS (m/e): 218 [M þ H]þ. [a]D20 ¼ ꢂ41.4
(c ¼ 0.1, DMSO). Anal. calcd for C10H19NO4: C 55.28, H
8.81, N 6.45; found: C 55.39, H 8.90, N 6.30.
3.1.5.2. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-alanine
(4b). Yield: 206 mg (89%). 1H NMR (BHSC-300, DMSO-
d6): d/ppm ¼ 10.86 (s, 1H), 4.87 (t, J ¼ 4.6 Hz, 1H), 3.68 (d,
J ¼ 11.0 Hz, 2H), 3.66 (q, J ¼ 7.2 Hz, 1H), 3.47 (d,
J ¼ 11.0 Hz, 2H), 2.79 (t, J ¼ 6.0 Hz, 2H), 2.13 (s, 1H), 1.69
(t, J ¼ 6.0 Hz, 2H), 1.13 (d, J ¼ 7.2 Hz, 3H), 1.00 (s, 3H),
0.60 (s, 3H). 13C NMR (BHSC-300, DMSO-d6): d/
ppm ¼ 177.37, 100.56, 79.44, 60.50, 38.37, 37.26, 33.00,
24.58, 23.19, 22.47. ESI-MS (m/e): 232 [M þ H]þ.
[a]2D0 ¼ ꢂ72.0 (c ¼ 0.1, CH3Cl). Anal. calcd for C11H21NO4:
C 57.12, H 9.15, N 6.06; found: C 57.00, H 9.07, N 6.21.
3.1.4.18. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-benzyl-
lysine methylester (3r). Yield: 349 mg (80%). 1H NMR
(BHSC-300, DMSO-d6): d/ppm ¼ 10.71 (s, 1H), 8.45 (s,
2H), 7.87 (d, J ¼ 7.0 Hz, 2H), 7.34 (t, J ¼ 7.0 Hz, 2H), 6.95
(t, J ¼ 7.0 Hz, 1H), 4.671 (t, J ¼ 4.6 Hz, 1H), 3.62 (t,
J ¼ 5.5 Hz, 1H), 3.62 (s, 3H), 3.54 (d, J ¼ 10.0 Hz, 2H),
3.49 (d, J ¼ 10.0 Hz, 2H), 2.86 (t, J ¼ 4.8 Hz, 2H), 2.76 (t,
J ¼ 4.6 Hz, 2H), 2.14 (s, 1H), 1.96 (t, J ¼ 4.8 Hz, 2H), 1.86
(m, J ¼ 4.8 Hz, 2H), 1.89 (t, J ¼ 4.6 Hz, 2H), 1.60 (m,
J ¼ 4.8 Hz, 2H), 0.98 (s, 3H), 0.94 (s, 3H). 13C NMR (D2O):
d/ppm ¼ 172.25, 158.35, 141.07, 129.02, 127.50, 126.97,
101.76, 79.00, 70.11, 63.77, 50.33, 49.11, 41.44, 40.27,
34.57, 33.22, 31.49, 22.55, 24.30, 23.46. ESI-MS (m/e): 437
[M þ H]þ. Anal. calcd for C23H36N2O6: C 63.28, H 8.31, N
6.42; found: C 63.44, H 8.43, N 6.59.
3.1.5.3. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-valine
(4c). Yield: 225 mg (87%). 1H NMR (BHSC-300, DMSO-
d6): d/ppm ¼ 10.73 (s, 1H), 4.87 (t, J ¼ 6.0 Hz, 1H), 3.69 (d,
J ¼ 10.9 Hz, 2H), 3.49 (m, J ¼ 7.0 Hz, 1H), 3.47 (d,
J ¼ 10.9 Hz, 2H), 2.66 (t, J ¼ 6.0 Hz, 2H), 2.38 (m,
J ¼ 7.0 Hz, 1H), 2.23 (s, 1H), 1.87 (t, J ¼ 6.0 Hz, 2H), 1.01
(d, J ¼ 7.0 Hz, 3H), 1.01 (d, J ¼ 7.0 Hz, 3H), 1.00 (s, 3H),
0.63 (s, 3H). 13C NMR (D2O): d/ppm ¼ 177.37, 102.36,
79.41, 70.61, 39.36, 38.85, 37.22, 27.57, 24.57, 23.19,
17.40, 17.32. ESI-MS (m/e): 260 [M þ H]þ. [a]D20 ¼ 4.0
(c ¼ 0.1, CH3Cl). Anal. calcd for C13H25NO4: C 60.21, H
9.72, N 5.40; found: C 60.07, H 9.60, N 5.57.
3.1.4.19. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-proline
methylester (3s). Yield: 349 mg (80%). 1H NMR (BHSC-
300, DMSO-d6): d/ppm ¼ 4.86 (t, J ¼ 4.6 Hz, 1H), 3.67 (d,
J ¼ 11.1 Hz, 2H), 3.62 (s, 3H), 3.46 (d, J ¼ 11.1 Hz, 2H),
3.42 (t, J ¼ 5.5 Hz, 1H), 2.65 (t, J ¼ 4.6 Hz, 2H), 2.31 (t,
J ¼ 5.5 Hz, 2H), 1.87 (q, J ¼ 4.6 Hz, 2H), 1.82 (q,
J ¼ 5.5 Hz, 2H), 1.65 (m, J ¼ 5.5 Hz, 2H), 0.98 (s, 3H), 0.96
(s, 3H). 13C NMR (D2O): d/ppm ¼ 172.42, 102.30, 79.36,
67.13, 50.38, 49.11, 39.88, 37.61, 32.72, 27.89, 25.63,
24.55, 23.19. ESI-MS (m/e): 272 [M þ H]þ. Anal. calcd for
C14H25NO4: C 61.97, H 9.29, N 5.16; found: C 62.13, H
9.41, N 5.33.
3.1.5.4. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-leucine
1
(4d). Yield: 240 mg (88%). H NMR (BHSC-300, DMSO-
d6): d/ppm ¼ 10.70 (s, 1H), 4.88 (t, J ¼ 4.6 Hz, 1H), 3.70 (d,
J ¼ 10.7 Hz, 2H), 3.49 (t, J ¼ 7.2 Hz, 1H), 3.48 (d,
J ¼ 10.7 Hz, 2H), 2.67 (t, J ¼ 6.2 Hz, 2H), 2.11 (s, 1H), 1.87
(t, J ¼ 6.2 Hz, 2H), 1.79 (m, J ¼ 7.2 Hz, 1H), 1.62 (m,
J ¼ 7.2 Hz, 2H), 1.02 (d, J ¼ 7.2 Hz, 3H), 1.01 (d,
J ¼ 7.2 Hz, 3H), 0.99 (s, 3H), 0.65 (s, 3H). 13C NMR (D2O):
d/ppm ¼ 177.41, 102.37, 79.42, 60.62, 41.23, 39.36, 38.86,
33.22, 27.11, 26.50, 26.47, 23.92, 23.33. ESI-MS (m/e): 274
3.1.5. General procedure for the preparation of N-[2-(5,5-
dimethyl-1,3-dioxane-2-yl)ethyl]-amino acids (4aes) via
the saponification of 3aes
At 0 ꢀC, to the solution of 1.00 mmol of 3aes in 4 mL of
methanol and 4 mL of water, 180 mg (4.54 mmol) of NaOH

16
X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
[M þ H]þ. [a]D20 ¼ ꢂ53.0 (c ¼ 0.1, CH3Cl). Anal. calcd for
C14H27NO4: C 61.51, H 9.96, N 5.12; found: C 61.38, H
9.82, N 5.29.
3.1.5.9. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-threo-
nine (4i). Yield: 214 mg (82%). 1H NMR (BHSC-300,
DMSO-d6): d/ppm ¼ 10.67 (s, 1H), 4.64 (t, J ¼ 4.8 Hz, 1H),
3.86 (m, J ¼ 5.8 Hz, 1H), 3.69 (d, J ¼ 10.2 Hz, 2H), 3.50 (d,
J ¼ 10.2 Hz, 2H), 3.47 (d, J ¼ 5.8 Hz, 1H), 2.68 (t,
J ¼ 4.8 Hz, 2H), 2.16 (s, 1H), 2.13 (s, 1H), 1.94 (t,
J ¼ 4.8 Hz, 2H), 1.18 (d, J ¼ 5.8 Hz, 3H), 1.00 (s, 3H), 0.98
(s, 3H). 13C NMR (D2O): d/ppm ¼ 176.01, 102.63, 79.43,
71.63, 68.77, 40.79, 39.27, 32.26, 24.62, 23.16, 22.20. ESI-
MS (m/e): 262 [M þ H]þ. [a]2D0 ¼ ꢂ77.3 (c ¼ 0.1, DMSO).
Anal. calcd for C12H23NO5: C 55.16, H 8.87, N 5.36; found:
C 55.30, H 8.98, N 5.51.
3.1.5.5. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-isoleu-
cine (4e). Yield: 240 mg (88%). 1H NMR (BHSC-300,
DMSO-d6): d/ppm ¼ 10.71 (s, 1H), 4.87 (t, J ¼ 4.5 Hz, 1H),
3.70 (d, J ¼ 10.9 Hz, 2H), 3.49 (t, J ¼ 7.0 Hz, 1H), 3.48 (d,
J ¼ 10.9 Hz, 2H), 2.671 (t, J ¼ 6.0 Hz, 2H), 2.315 (m,
J ¼ 7.0 Hz, 1H), 2.210 (s, 1H), 1.864 (t, J ¼ 6.0 Hz, 2H),
1.325 (m, J ¼ 7.0 Hz, 2H), 1.02 (d, J ¼ 7.0 Hz, 3H), 1.02 (t,
J ¼ 7.0 Hz, 3H), 1.00 (s, 3H), 0.95 (s, 3H). 13C NMR (D2O):
d/ppm ¼ 177.42, 102.35, 79.41, 69.56, 41.21, 40.11, 33.40,
33.21, 27.30, 23.87, 23.32, 20.11, 17.37. ESI-MS (m/e): 274
[M þ H]þ. [a]D20 ¼ ꢂ47.0 (c ¼ 0.1, CH3Cl). Anal. calcd for
C14H27NO4: C 61.51, H 9.96, N 5.12; found: C 61.64, H
10.05, N 5.01.
3.1.5.10.
N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-as-
partic acid (4j). Yield: 226 mg (82%). 1H NMR (BHSC-
300, DMSO-d6): d/ppm ¼ 10.88 (s, 1H), 10.82 (s, 1H), 4.71
(t, J ¼ 4.6 Hz, 1H), 3.83 (t, J ¼ 6.0 Hz, 1H), 3.70 (d,
J ¼ 10.0 Hz, 2H), 3.50 (d, J ¼ 10.0 Hz, 2H), 2.59 (d,
J ¼ 6.0 Hz, 2H), 2.58 (t, J ¼ 4.6 Hz, 2H), 2.17 (s, 1H), 1.94
(t, J ¼ 4.6 Hz, 2H), 1.00 (s, 3H), 0.96 (s, 3H). 13C NMR
(D2O): d/ppm ¼ 176.78, 176.24, 102.51, 79.34, 58.79, 41.12,
40.02, 39.64, 33.56, 24.55, 23.35. ESI-MS (m/e): 276
[M þ H]þ. [a]D20 ¼ ꢂ78.3 (c ¼ 0.1, CH3Cl). Anal. calcd for
C12H21NO6: C 52.35, H 7.69, N 5.09; found: C 52.21, H
7.58, N 5.26.
3.1.5.6. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-phenyl-
alanine (4f). Yield: 255 mg (80%). 1H NMR (BHSC-300,
DMSO-d6): d/ppm ¼ 10.70 (s, 1H), 7.24 (t, J ¼ 7.6 Hz, 2H),
7.20 (d, J ¼ 7.6 Hz, 2H), 7.01 (t, J ¼ 7.6 Hz, 1H), 4.82 (t,
J ¼ 4.2 Hz, 1H), 3.93 (t, J ¼ 6.6 Hz, 1H), 3.70 (d,
J ¼ 10.9 Hz, 2H), 3.48 (d, J ¼ 10.9 Hz, 2H), 2.98 (d,
J ¼ 6.6 Hz, 2H), 2.75 (t, J ¼ 4.2 Hz, 2H), 2.21 (s, 1H), 1.76
(t, J ¼ 4.2 Hz, 2H), 1.00 (s, 3H), 0.95 (s, 3H). 13C NMR
(CDCl3): d/ppm ¼ 176.85, 137.33, 129.15, 128.35, 126.60,
100.89, 79.33, 63.15, 40.07, 39.50, 38.25, 33.50, 22.85,
22.77. ESI-MS (m/e): 308 [M þ H]þ. [a]D20 ¼ ꢂ8.3 (c ¼ 0.1,
DMSO). Anal. calcd for C17H25NO4: C 66.43, H 8.20, N
4.56; found: C 66.29, H 8.13, N 4.72.
3.1.5.11. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-gluta-
1
mic acid (4k). Yield: 243 mg (84%). H NMR (BHSC-300,
DMSO-d6): d/ppm ¼ 10.77 (s, 1H), 10.70 (s, 1H), 4.53 (t,
J ¼ 4.2 Hz, 1H), 3.69 (d, J ¼ 10.0 Hz, 2H), 3.49 (d,
J ¼ 10.0 Hz, 2H), 3.44 (t, J ¼ 5.7 Hz, 1H), 2.89 (t,
J ¼ 4.2 Hz, 2H), 2.34 (t, J ¼ 5.7 Hz, 2H), 2.13 (s, 1H), 1.93
(t, J ¼ 5.7 Hz, 2H), 1.83 (t, J ¼ 4.2 Hz, 2H), 0.97 (s, 3H),
0.94 (s, 3H). 13C NMR (D2O): d/ppm ¼ 176.77, 176.32,
99.57, 79.32, 63.60, 40.22, 39.65, 33.86, 30.41, 27.11,
24.51, 23.47. ESI-MS (m/e): 290 [M þ H]þ. [a]D20 ¼ 62.7
(c ¼ 0.1, CH3Cl). Anal. calcd for C13H23NO6: C 53.97, H
8.08, N 4.84; found: C 53.83, H 8.00, N 4.99.
3.1.5.7. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-tyrosine
(4g). Yield: 258 mg (80%). 1H NMR (BHSC-300, DMSO-
d6): d/ppm ¼ 10.76 (s, 1H), 7.21 (d, J ¼ 7.2 Hz, 2H), 7.00
(d, J ¼ 7.2 Hz, 2H), 5.18 (s, 1H), 4.78 (t, J ¼ 4.0 Hz, 1H),
3.93 (t, J ¼ 6.4 Hz, 1H), 3.70 (d, J ¼ 10.7 Hz, 2H), 3.48 (d,
J ¼ 10.7 Hz, 2H), 2.96 (d, J ¼ 6.4 Hz, 2H), 2.58 (t,
J ¼ 4.0 Hz, 2H), 2.22 (s, 1H), 1.77 (t, J ¼ 4.0 Hz, 2H), 0.99
(s, 3H), 0.96 (s, 3H). 13C NMR (CDCl3): d/ppm ¼ 176.65,
155.34, 135.34, 128.56, 116.83, 101.25, 79.30, 65.23, 40.11,
39.56, 38.21, 33.52, 23.12, 22.88. ESI-MS (m/e): 324
[M þ H]þ. [a]2D0 ¼ ꢂ50.6 (c ¼ 0.2, DMSO). Anal. calcd for
C17H25NO5: C 63.14, H 7.79, N 4.33; found: C 63.01, H
7.68, N 4.50.
3.1.5.12. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-trypto-
phan (4l). Yield: 295 mg (85%). 1H NMR (BHSC-300,
DMSO-d6): d/ppm ¼ 10.74 (s, 1H), 8.92 (s, 1H), 7.22 (d,
J ¼ 7.2 Hz, 1H), 7.20 (t, J ¼ 7.2 Hz, 1H), 7.15 (d,
J ¼ 7.2 Hz, 1H), 7.10 (t, J ¼ 7.2 Hz, 1H), 6.96 (s, 1H), 4.62
(t, J ¼ 4.5 Hz, 1H), 3.92 (t, J ¼ 5.9 Hz, 1H), 3.69 (d,
J ¼ 10.2 Hz, 2H), 3.50 (d, J ¼ 10.2 Hz, 2H), 2.92 (d,
J ¼ 5.9 Hz, 2H), 2.64 (t, J ¼ 4.5 Hz, 2H), 2.14 (s, 1H), 1.86
(t, J ¼ 4.5 Hz, 2H), 0.97 (s, 3H), 0.93 (s, 3H). 13C NMR
(D2O): d/ppm ¼ 176.112, 136.35, 131.70, 122.52, 121.80,
120.50, 119.610, 112.10, 111.02, 101.53, 79.44, 65.72,
40.25, 39.64, 33.80, 31.11, 24.52, 23.45. ESI-MS (m/e): 347
[M þ H]þ. [a]2D0 ¼ 26.3 (c ¼ 0.1, DMSO). Anal. calcd for
C19H26N2O4: C 65.87, H 7.56, N 8.09; found: C 65.73, H
7.44, N 8.23.
3.1.5.8. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-serine
1
(4h). Yield: 215 mg (87%). H NMR (BHSC-300, DMSO-
d6): d/ppm ¼ 10.71 (s, 1H), 4.55 (t, J ¼ 4.5 Hz, 1H), 3.81 (d,
J ¼ 6.5 Hz, 2H), 3.69 (d, J ¼ 10.8 Hz, 2H), 3.47 (d,
J ¼ 10.8 Hz, 2H), 3.56 (t, J ¼ 6.5 Hz, 1H), 2.69 (t,
J ¼ 4.5 Hz, 2H), 2.17 (s, 1H), 2.14 (s, 1H), 1.92 (t,
J ¼ 4.5 Hz, 2H), 0.98 (s, 3H), 0.96 (s, 3H). 13C NMR (D2O):
d/ppm ¼ 174.16, 102.526, 79.42, 66.91, 64.34, 40.96, 38.72,
33.61, 24.59, 23.18. ESI-MS (m/e): 248 [M þ H]þ.
[a]2D0 ¼ 14.3 (c ¼ 0.1, DMSO). Anal. calcd for C11H21NO5:
C 53.43, H 8.56, N 5.66; found: C 53.30, H 8.44, N 5.79.
3.1.5.13. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-methio-
nine (4m). Yield: 230 mg (79%). 1H NMR (BHSC-300,

X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
17
DMSO-d6): d/ppm ¼ 10.67 (s, 1H), 4.65 (t, J ¼ 4.6 Hz, 1H),
3.70 (d, J ¼ 10.1 Hz, 2H), 3.57 (t, J ¼ 5.9 Hz, 1H), 3.51 (d,
J ¼ 10.1 Hz, 2H), 2.67 (t, J ¼ 4.6 Hz, 2H), 2.48 (t,
J ¼ 5.9 Hz, 2H), 2.13 (s, 1H), 2.02 (t, J ¼ 5.9 Hz, 2H), 2.11
(s, 3H), 1.87 (t, J ¼ 4.6 Hz, 2H), 0.97 (s, 3H), 0.93 (s, 3H).
13C NMR (D2O): d/ppm ¼ 177.01, 101.07, 79.38, 63.10,
40.30, 39.51, 33.83, 33.16, 30.51, 24.48, 23.53, 17.51. ESI-
MS (m/e): 292 [M þ H]þ. [a]D20 ¼ ꢂ77.3 (c ¼ 0.1, CH3Cl).
Anal. calcd for C13H25NO4S: C 53.58, H 8.65, N 4.81; found:
C 53.44, H 8.57, N 4.96.
(D2O): d/ppm ¼ 177.40, 135.60, 134.65, 122.48, 101.03,
79.34, 64.94, 41.36, 40.40, 33.34, 31.48, 24.58, 23.19. ESI-
MS (m/e): 298 [M þ H]þ. [a]2D0 ¼ 53.1 (c ¼ 0.1, DMSO).
Anal. calcd for C14H23N3O4: C 56.55, H 7.80, N 14.13; found:
C 56.41, H 7.71, N 14.29.
3.1.5.18. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-proline
(4s). Yield: 218 mg (85%). 1H NMR (BHSC-300, DMSO-
d6): d/ppm ¼ 10.85 (s, 1H), 4.86 (t, J ¼ 4.7 Hz, 1H), 3.68 (d,
J ¼ 11.0 Hz, 2H), 3.46 (d, J ¼ 11.0 Hz, 2H), 3.43 (t,
J ¼ 5.6 Hz, 1H), 2.66 (t, J ¼ 4.7 Hz, 2H), 2.32 (t, J ¼ 5.6 Hz,
2H), 1.87 (q, J ¼ 4.7 Hz, 2H), 1.83 (q, J ¼ 5.6 Hz, 2H), 1.65
(m, J ¼ 5.6 Hz, 2H), 0.99 (s, 3H), 0.96 (s, 3H). 13C NMR
(D2O): d/ppm ¼ 177.43, 102.32, 79.37, 67.13, 49.12, 39.88,
37.61, 32.73, 27.90, 25.64, 24.56, 23.19. ESI-MS (m/e): 258
[M þ H]þ. [a]D20 ¼ ꢂ16.0 (c ¼ 0.1, CH3Cl). Anal. calcd for
C13H23NO4:C 60.68, H 9.01, N 5.44; found: C 60.52, H
9.10, N 5.30.
3.1.5.14. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-argi-
nine (4n). Yield: 256 mg (81%). 1H NMR (BHSC-300,
DMSO-d6): d/ppm ¼ 10.68 (s, 1H), 8.76 (s, 2H), 8.72 (s, 1H),
6.52 (s, 1H), 4.65 (t, J ¼ 4.7 Hz, 1H), 3.71 (d, J ¼ 10.2 Hz,
2H), 3.56 (t, J ¼ 5.7 Hz, 1H), 3.52 (d, J ¼ 10.2 Hz, 2H), 2.82
(t, J ¼ 5.7 Hz, 2H), 2.65 (t, J ¼ 4.7 Hz, 2H), 2.15 (s, 1H),
1.64 (m, J ¼ 5.7 Hz, 2H), 1.88 (t, J ¼ 4.7 Hz, 2H), 1.54 (m,
J ¼ 5.7 Hz, 2H), 0.91 (s, 3H), 0.89 (s, 3H). 13C NMR (D2O):
d/ppm ¼ 176.14, 162.85, 101.13, 78.85, 63.78, 41.51, 40.34,
39.56, 33.69, 29.24, 27.13, 24.43, 23.56. ESI-MS (m/e): 317
[M þ H]þ. [a]2D0 ¼ ꢂ106.0 (c ¼ 0.1, DMSO). Anal. calcd for
C14H28N4O4: C 53.15, H 8.92, N 17.71; found: C 53.34, H
9.03, N 17.57.
3.1.6. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)
ethyl]-L-lysine (4r)
To the solution of 436 mg (1.00 mmol) of N-[2-(5,5-di-
methyl-1,3-dioxane-2-yl)ethyl]-L-benzyllysine methylester in
10 mL of trifluoroacetic acid, 4 mL of CF3COOHeCF3SO3H
and 4 mL of phenyl methyl ether were added. The reaction
mixture was stirred at 0 ꢀC for 2 h and evaporation under re-
duced pressure. The residue was treated with 100 mL of ether,
the formed powder was purified by Sephadex G10 column
(distilled water) and 246 mg (yield 85%) of the title compound
was obtained as colorless powder. 1H NMR (BHSC-300,
DMSO-d6): d/ppm ¼ 10.71 (s, 1H), 8.45 (s, 2H), 4.68 (t,
J ¼ 4.7 Hz, 1H), 3.63 (t, J ¼ 5.6 Hz, 1H), 3.55 (d,
J ¼ 10.1 Hz, 2H), 3.50 (d, J ¼ 10.1 Hz, 2H), 2.87 (t,
J ¼ 4.9 Hz, 2H), 2.77 (t, J ¼ 4.7 Hz, 2H), 2.15 (s, 1H), 1.96
(t, J ¼ 4.9 Hz, 2H), 1.86 (m, J ¼ 4.9 Hz, 2H), 1.89 (t,
J ¼ 4.7 Hz, 2H), 1.61 (m, J ¼ 4.9 Hz, 2H), 0.99 (s, 3H), 0.94
(s, 3H). 13C NMR (D2O): d/ppm ¼ 177.11, 101.78, 79.14,
63.78, 49.91, 41.45, 40.27, 34.58, 33.23, 31.49, 22.55,
24.31, 23.46. ESI-MS (m/e): 289 [M þ H]þ. [a]D20 ¼ ꢂ132.0
(c ¼ 0.1, DMSO). Anal. calcd for C14H28N2O4: C 58.31, H
9.79, N 9.71; found: C 58.48, H 9.90, N 9.56.
3.1.5.15. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-aspara-
gine (4o). Yield: 233 mg (85%). 1H NMR (BHSC-300, DMSO-
d6): d/ppm ¼ 10.74 (s, 1H), 6.22 (s, 2H), 4.66 (t, J ¼ 4.6 Hz,
1H), 3.78 (t, J ¼ 5.6 Hz, 1H), 3.50 (d, J ¼ 10.2 Hz, 2H), 3.49
(d, J ¼ 10.2 Hz, 2H), 2.81 (t, J ¼ 4.6 Hz, 2H), 2.75
(d, J ¼ 5.6 Hz, 2H), 2.14 (s, 1H), 1.90 (t, J ¼ 4.6 Hz, 2H), 0.99
(s, 3H), 0.98 (s, 3H). 13C NMR (D2O): d/ppm ¼ 177.02,
175.54, 102.69, 79.38, 61.49, 41.19, 40.28, 36.35, 32.12,
24.34, 23.29. ESI-MS (m/e): 275 [M þ H]þ. [a]D20 ¼ ꢂ60.6
(c ¼ 0.1, CH3Cl). Anal. calcd for C12H22N2O5: C 52.54, H
8.08, N 10.21; found: C 52.71, H 8.19, N 10.38.
3.1.5.16. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-gluta-
mine (4p). Yield: 248 mg (86%). 1H NMR (BHSC-300,
DMSO-d6): d/ppm ¼ 10.72 (s, 1H), 6.23 (s, 2H), 4.67 (t,
J ¼ 4.8 Hz, 1H), 3.60 (t, J ¼ 5.5 Hz, 1H), 3.52 (d,
J ¼ 10.2 Hz, 2H), 3.49 (d, J ¼ 10.2 Hz, 2H), 2.80 (t,
J ¼ 4.8 Hz, 2H), 2.23 (d, J ¼ 5.5 Hz, 2H), 2.15 (s, 1H), 1.90
(d, J ¼ 5.5 Hz, 2H), 1.90 (t, J ¼ 4.8 Hz, 2H), 0.98 (s, 3H),
0.94 (s, 3H). 13C NMR (D2O): d/ppm ¼ 177.35, 175.49,
102.34, 79.08, 62.98, 41.22, 40.37, 33.02, 31.50, 27.21,
24.40, 23.32. ESI-MS (m/e): 289 [M þ H]þ. [a]D20 ¼ ꢂ123.3
(c ¼ 0.1, CH3Cl). Anal. calcd for C13H24N2O5: C 54.15, H
8.39, N 9.72; found: C 54.00, H 8.31, N 9.58.
3.1.7. General procedure for the preparation of 4aes via
the condensation of 2 and amino acids
The mixture of 1.0 mmol of amino acid and 1.1 mmol of
NaOH was dissolved in 5 mL of methanol by stirring at
room temperature for 10 min and then 300 mg of anhydrous
magnesium sulfate was added. To the suspension, 3.0 mmol
of 2 was added dropwise. After stirring at room temperature
for 20 min, to the reaction mixture 2.5 mmol of NaCNBH3
was added, stirred at room temperature for additional 8 h
and TLC (petroleum/ether, 4:1) indicated complete disappear-
ance of 2. The reaction mixture was filtered and the filtrate was
evaporated under vacuum to remove the solvent. The residue
was purified by silica gel chromatography to provide the title
compound as a colorless powder.
3.1.5.17. N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]-L-histi-
dine (4q). Yield: 259 mg (87%). 1H NMR (BHSC-300,
DMSO-d6): d/ppm ¼ 12.34 (s, 1H), 10.77 (s, 1H), 8.66 (s,
1H), 7.38 (s, 1H), 4.67 (t, J ¼ 4.5 Hz, 1H), 3.87 (t, J ¼ 4.2 Hz,
1H), 3.56 (d, J ¼ 10.2 Hz, 2H), 3.50 (d, J ¼ 10.2 Hz, 2H), 3.25
(t, J ¼ 4.2 Hz, 2H), 2.30 (d, J ¼ 5.2 Hz, 2H), 2.14 (s, 1H), 1.92
(d, J ¼ 5.2 Hz, 2H), 0.99 (s, 3H), 0.94 (s, 3H). 13C NMR

18
X. Li et al. / European Journal of Medicinal Chemistry 43 (2008) 8e18
3.2. Xylene-induced ear edema
(2006CB708501). Z.Z. was supported by Program for New
Century Excellent Talents in University (NCET).
Male ICR mice were randomly divided into three groups of
11 mice, namely the test group, vehicle control group, and
positive control group. The mice in vehicle control group
were administrated orally CMC, the mice in positive control
group were administrated orally a suspension of aspirin in
CMC at a dosage of 20 mg/kg, and a concentration of
0.3 mg/mL, while the mice in the test group were adminis-
trated orally a suspension of 4aes in CMC at a dosage of
20 mg/kg, 4.0 mg/kg, 0.8 mg/kg, and a concentration of
2.0 mg/mL, 0.4 mg/mL, 0.08 mg/mL. Thirty minutes later,
0.03 mL of xylene was applied to both the anterior and poste-
rior surfaces of the right ear. The left ear was considered as
control. Two hours after xylene application, the mice were
killed and both ears were removed. Using a cork borer with
a diameter of 7 mm, several circular sections were taken and
weighed. The increase in weight caused by the irritant was
measured through subtracting the weight of the untreated
left ear section from that of the treated right ear section. The
statistical analysis of the data was carried out by use of AN-
OVA test, p < 0.05 is considered significant.
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