Toward the development of chemoprevention agents. Part 1: Design, synthesis, and anti-inflammatory activities of a new class of 2,5-disubstituted-dioxacycloalkanes

Article abstract of DOI:10.1016/j.bmc.2007.05.013

A new class of 2,5-disubstituted-dioxacycloalkanes were designed and synthesized via stereoselective synthetic method as cancer chemoprevention agents. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse ear edema model. Some of these compounds exhibited comparable or better anti-inflammatory activities than that of aspirin suggesting that they can be further developed as potential anti-inflammatory drug lead compounds. In addition, treatment of these anti-inflammatory agents did not prolong tail bleeding time in mice. The structure/activity relationships were also analyzed among these compounds.

Full text of DOI:10.1016/j.bmc.2007.05.013

Bioorganic & Medicinal Chemistry 15 (2007) 4775–4799
Toward the development of chemoprevention agents. Part 1:
Design, synthesis, and anti-inflammatory activities of a new class
of 2,5-disubstituted-dioxacycloalkanes
b
c,
a,
Keli Gu,a Lanrong Bi,a Ming Zhao,a,* Chao Wang, Jingfang Ju and Shiqi Peng
*
*
aCollege of Pharmaceutical Sciences, Capital University of Medical Sciences, Beijing 100054, PR China
bCollege of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
cUSA-Mitchell Cancer Institute, 307 N. University Boulevard, Mobile AL 36688-0002, USA
Received 19 March 2007; revised 20 April 2007; accepted 1 May 2007
Available online 6 May 2007
Abstract—A new class of 2,5-disubstituted-dioxacycloalkanes were designed and synthesized via stereoselective synthetic method as
cancer chemoprevention agents. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse
ear edema model. Some of these compounds exhibited comparable or better anti-inflammatory activities than that of aspirin sug-
gesting that they can be further developed as potential anti-inflammatory drug lead compounds. In addition, treatment of these anti-
inflammatory agents did not prolong tail bleeding time in mice. The structure/activity relationships were also analyzed among these
compounds.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
A strong interest has been focused on using NSAIDs as
a chemopreventive strategy for colorectal cancer. NSA-
IDs possess several anti-cancer properties that confer a
broad spectrum of chemo-preventive effects during dif-
ferent stages of colorectal tumorigenesis, inducing apop-
tosis, reducing angiogenesis, and inducing cell cycle
arrest.5 Traditional NSAIDs, such as aspirin, target
both COX-1 and COX-2 and exhibit chemopreventive
properties in epidemiological studies. However, the use
of NSAIDs is often associated with side effects such as
gastric bleeding. The chemoprevention agents are
designed to give to huge numbers of people over long
period of time, therefore, these agents must be of low
toxicity, effective at low doses, and devoid of side ef-
fects.5–8
Chemoprevention is a critical area of research in oncol-
ogy. Chemoprevention refers to the use of non-toxic
substances to delay, reverse or suppress multistage carci-
nogenesis.1,2 Chemoprevention offers a unique scope
to intervene in each stage of carcinogenesis by a wide
variety of substances of either natural or synthetic origin.
As inflammation is closely associated with tumorigenesis
in many tumor types, substances with potent anti-
inflammatory activities are anticipated to exert chemo-
preventive effects. Overwhelming evidence from
non-experimental studies supports an association
between long-term use of nonsteroidal anti-inflammatory
drugs (NSAIDs), including aspirin, and a substantially
reduced risk for colorectal and other cancers.3 NSAIDs
could influence carcinogenesis through their cyclooxy-
genase inhibition, which seems to play an important role
in cell transformation, tumor growth, and metastasis,
but other mechanisms have been proposed.4
1,3-Dioxane derivatives have been reported recently
having anti-inflammatory, anti-cancer, and reperfusion
injury protection effects through their anti-proliferative
and anti-inflammatory activities in human neutrophils
and tumor cells.9–12 Our laboratory has been investigat-
ing a new class of 2,5-disubstituted-1,3-dioxanes, some
of which have shown to have anti-inflammatory proper-
ties greater than those of aspirin.13–16 In contrast to clas-
sical, acidic NSAIDs, the new analogues of 1,3-dioxane
are basic. To further improve the pharmacokinetic/phar-
macodynamic and the therapeutic index of these 1,3-
Keywords: Chemoprevention agents; Stereoselective synthesis; 2,5-Di-
substituted-dioxacycloalkanes; Anti-inflammatory activity; Structure–
activity relationship study.
*
Corresponding authors. Tel.: +1 251 460 7393; fax: +1 251 460 6994
(J.J); tel.: +86 10 8391 1528; fax: +86 10 8391 1528 (S.P.); e-mail
addresses: jju@usouthal.edu; sqpeng@bjmu.edu.cn
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.05.013

4776
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
dioxane derivatives and, in this study, a new series of
2,5-disubstituted-dioxacycloalkanes were constructed
using stereoselective synthesis. Chemoprevention trials
require large numbers of subjects followed over many
years and are therefore very expensive and difficult. In
this study, we choose xylene-induced mouse ear edema
model to evaluate the in vivo anti-inflammatory activi-
ties of these compounds. In addition, the cutaneous tail
bleeding time in the rat was used for evaluation of
the hemostatic effects of these newly synthetic
compounds.
(trans)-(2-substitutedphenyl-1,3-dioxan-5-yl)benzoylace-
tamides, 5a–j, 50a–j, (cis)- and (trans)-(2-substitutedphe-
nyl-1,3-dioxan-5-yl)phenylacetamides, 6a–j, 60a–j, were
obtained in good yield. Under this condition, the
(cis)-N-(2-substitutedphenyl-1,3-dioxan-5-yl)amides were
main products (Scheme 2).
Under the same condition, the acetalization of (E)-phe-
nylvinyl aldehyde 4f with 2-phenylacetamido-1,3-diols
30a,b or 2-benzoylacetamido-1,3-diols 300a,b stereoselec-
tively provided a series of (cis)- and (trans)-isomers,
namely, 7a,b, 70a,b, 8a,b, 80a,b (Scheme 3).
2. Results and discussion
2.1. Synthesis
To investigate the impact of ring size on the stereoselec-
tivity and the biological activity of 2,5-disubstituted-
dioxacycloalkanes, the original 1,3-dioxane ring was
expanded to seven- and eight- member ring (Scheme 4).
Among the acetalization of benzaldehyde 4a–e and
2-phenylacetamido-1,4-diol 30c or 2-benzoylacetamido-
1,4-diol 300c only 4c–e stereoselectively provided a series
of isomers containing 7-membered dioxacycloalkanes,
that is, (cis)- and (trans)-(2-substitutedphenyl-1,3-dioxa-
cycloheptan-5-yl)phenylacetylamides 9c–e, 90c–e and
(cis)- and (trans)-(2-substitutedphenyl-1,3-dioxacyclo-
heptan-5-yl)benzoylacetylamides 10c–e and 100c–e.
Under similar condition, among the acetalization of
benzaldehyde 4a–e and 2-phenylacetamido-1,5-diol 30d
or 2-benzoylacetamido-1,5-diol 300d, only 4c–e stereoselec-
tively provided a series of isomers containing 8-membered
dioxacycloalkanes [(cis)- and (trans)-(2-substitutedphe-
nyl-1,3-dioxacyclooctan-5-yl)benzoylacetylamides 11c–e,
110c–e, and (cis)- and (trans)-(2-substitutedphenyl-1,3-
dioxacyclooctan-5-yl)phenylacetylamides 12c–e and 120c–e]
(Scheme 4).
We previously prepared 1,3-dioxacycle derivatives
through the transacetalization of 1,1,3,3-tetramethoxy-
propane and aminodiols.13–16 The main finding was
the stereochemistry of ring formation is dependent on
the structure of the aminodiol compounds. Based on
this, new series of 2,5-disubstituted-dioxacycloalkanes
were prepared, in this study, our strategy was to engage
the pre-existing stereocenter of the chiral amino acids to
direct the subsequent substituted benzaldehydes’ acetal-
ization reaction.
Using optically active amino acids as starting material,
the chiral amino acids 1a–d were easily converted to
the corresponding methyl esters 2a–d in the presence
of thionyl chloride and methanol with high yields. After
treating 2a–d with phenylacetyl chloride or benzoyl
chloride, followed by KBH4 reduction, the correspond-
ing phenylacetamidodiols 30a–d or benzoylacetamidodi-
ols 300a–d were obtained in good yields. As a result,
compounds 30b–d and 300b–d were enantiomerically pure
(Scheme 1).
An interesting feature of the new synthesis route is the
stereoselectivity mediated through the substitutions on
the ring. It is also worth noticing that the ratio between
cis- and trans- products was dependent on the ring size
formed during the acetalizations. These results suggest
that the optically active amino acids may act as chiral
auxiliaries for controlling the stereoselectivity during
acetalization step.
Subsequently, using p-toluenesulfonic acid as catalyst,
2-phenylacetamido-1,3-diols 30a,b or 2-benzoylacetami-
do-1,3-diols 300a,b were subjected to acetalization
with benzaldehydes 4a–e. As a result, (cis)- and
R
H
R
H
iv
iv
C6H5CH2CONH
CO2CH3
C6H5CH2CONH
CH2OH
ii
R
R
H
3'a-d
2'a-d
i
H2N
CO2CH3
H2N
CO2H
R
H
R
C6H5CONH
H
H
iii
C6H5CONH
CO2CH3
CH2OH
2a-d
1a-d
2''a-d
3''a-d
Scheme 1. Synthetic route to compounds 30a–d and 300a–d. Reagents and conditions: (i) SOCl2/MEOH, 0 ꢁC–rt; (ii) C6H5CH2COCl/THF; (iii)
C6H5COCl/THF; (iv) KBH4/THF.

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4777
NHCOC6H5
NHCOC6H5
R''
R''
+
3''a,b
3'a,b
O
O
H
H
H
H
O
R'
O
H
H
R'
5'a-j
5a-j
CHO
R
NHCH2COC6H5
R''
NHCH2COC6H5
R''
4a-e
+
O
O
O
R'
O
H
H
R'
6'a-j
6a-j
Scheme 2. Synthetic route to compounds 5a–j, 50a–j, 6a–j, and 60a–j. Reagents and condition: CHCl3/THF, rt, p-toluenesulfonic acid (catalyst),
anhydrous Na2SO4. In 4a: R = H; 4b: R = 4-CH3, 4c: R = 4-Cl, 4d: R = 4-NO2, 4e: R = 3-NO2.
NHCOC6H5
R
NHCOC6H5
R
H
O
H
O
+
H
3''a,b
3'a,b
H
O
O
C
C
H
C6H5
H
C
H
C C6H5
H
H
C
7'a,b
7a,b
C
H
CHO
NHCOCH2C6H5
NHCOCH2C6H5
R
R
H
4f
O
O
H
H
+
H
O
C
C
H
C6H5
O
H
H
C
H
C C6H5
8a,b
8'a,b
Scheme 3. Synthetic route to compounds 7a,b, 70a,b, 8a,b, 80a,b. Reagents and condition: CHCl3, rt, 12 h, p-toluenesulfonic acid (catalyst),
anhydrous Na2SO4.
2.2. Stereochemical assignment
gen proton at the 5-position and the phenyl proton at
the 2-position for each of these compounds (5a–e, 6a–
e, 7a, 8a, 9c–e, 10c–e, 11c–e, and 12c–e). This further
indicated that the substitutions at both the 2- and
5-positions of these compounds are in a cis-configuration.
Two positive NOE signals were observed between the
To ensure correct structural assignment to these newly
synthesized 2,5-disubstituted-dioxacycloalkanes, nuclear
Overhauser effect (NOE) experiments were performed.
The positive NOE effect was observed between the nitro-

4778
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
NHCOC6H5
NHCOC6H5
3''c
3'c
O
O
O
O
+
H
H
H
H
H
H
H
R
R
H
9c-e
9'c-e
NHCOCH2C6H5
O
NHCOCH2C6H5
O
H
O
R
O
+
+
+
R
H
10c-e
10'c-e
CHO
R'
NHCOC6H5
O
NHCOC6H5
O
3''d
3'd
4c-e
H
O
R
O
H
H
R
11c-e
11'c-e
NHCOCH2C6H5
O
NHCOCH2C6H5
O
H
O
R
O
H
H
R
12c-e
12'c-e
Scheme 4. Synthetic route to compounds 9c–e, 10c–e, 11c–e, 12c–e and 90c–e, 100c–e, 110c–e, 120c–e. Reagents and condition: CHCl3, rt,
p-toluenesulfonic acid (catalyst), anhydrous Na2SO4.
CH3 at the 4-position, the phenyl proton at the 2-posi-
tion, and the NH at the 5-position on the substitutions
at 2-, 4-, and 5-positions of 5f–j, 6f–j, 7b, and 8b, respec-
tively, indicating cis–configuration. In contrast, no posi-
tive NOE effect was observed between the substitutions
at the 2- and 5-positions of compounds 50a–e, 60a–e, 70a,
80a, 90c–e, 100c–e, 110c–e, and 120c–e, indicating that the
configuration of these compounds is a trans-configura-
tion. The NOE difference experiment indicates that the
substitutions at 2-, 4-, and 5-positions of 50f–j, 60f–j,
70b, 80b are in a trans-arrangement due to the absence
of NOE signal.
ically stable products. This is a good example of demon-
strating the possibility of isomer conversion from less
thermodynamically stable compounds to more stable
ones. This allows us to fine tune the desired stereospec-
ificity by changing the experimental conditions such as
reaction time, temperature, and catalyst.
2.4. In vivo anti-inflammatory activity and structure–
activity relationship study15,16
The anti-inflammatory activities of newly synthesized
compounds were evaluated using a xylene-induced ear
edema model assay. Briefly, test compounds were
administered orally in 0.5% carboxymethyl cellulose
(CMC) suspension at a concentration of 20 mg/kg.
2.3. Configuration conversion experiment
To further confirm the stereochemical nature of these
compounds, configuration conversion experiment was
carried out. When concentrated hydrochloric acid was
employed as catalyst at 70 ꢁC for 12 h, 50a–j, 60a–j,
70a,b, 80a,b, 90c–e, 100c–e, 110c–e, 120c–e were converted
to 5a–j, 6a–j, 7a,b, 8a,b, 9c–e, 10c–e, 11c–e, 12c–e,
respectively. With these conversions, 50a–j, 60a–j, 70a,b,
80a,b, 90c–e, 100c–e, 110c–e, 120c–e were confirmed to
be kinetically controlled products, whereas 5a–j, 6a–j,
7a,b, 8a,b, 9c–e, 10c–e, 11c–e, 12c–e were thermodynam-
The starting compounds, N-substituted aminodiols,
were first evaluated to confirm the necessity of 1,3-diox-
ane ring for anti-inflammatory activity (Table 1). Both
compounds were ineffective suggesting that the rigid
1,3-dioxacycle ring is critical, consistent with our previ-
ously reported results.15,16
Next, we initiated the structure–activity relationship
study using 1,3-dioxacycloalkane ring as a template

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4779
Table 1. Anti-inflammatory activities of N-substituted aminodiols
30a–d, 300a–d and aldehydes 4a–f against xylene-induced ear edema in
mice
may express various biological activities. Nevertheless,
in the case of 2,5-disubstituted-dioxacycloalkanes, only
a few pair of the stereoisomers displayed distinguishable
anti-inflammatory activities (5b: 48.0% vs 50b: 39.1%; 5c:
28.5% vs 50c: 47.4%; 5h: 56.4% vs 50h: 47.1%). Most of
the cis- and trans- isomers exhibited the comparable
anti-inflammatory activities (5d: 44.2% vs 50d: 48.7%;
5e: 42.9% vs 50e: 45.2%; 5f: 43.9% vs 50f: 43.9%; 5g:
46.1% vs 50g: 44.9%; 5i: 57.4% vs 50i: 55.4%; 5j: 42.0%
vs 50j: 46.8%; 6c: 43.6% vs 60c: 42.0%; 6d: 43.3% vs
60d: 44.6%; 6e: 41.3% vs 60e: 42.6%; 6f: 40.0% vs 60f:
41.3%; 6h: 46.4% vs 60h: 46.1%; 6i: 55.8% vs 60i:
55.1%; 6j: 47.1% vs 60j: 46.5%). It seemed the stereo-
chemical feature of these 2,5-disubstituted-diox-
acycloalkanes has minimal impact on their biological
activities.
Agents
Edema weight (X SD mg)
CMC
30a
3.23 0.74
3.88 1.25
3.35 0.87
3.44 0.89
3.53 0.82
30b
30c
30d
Aspirin
300a
1.85 0.72
3.25 0.73
3.32 0.79
4.01 1.35
3.38 0.79
300b
300c
300d
4a
4b
4c
4d
4e
4f
3.45 0.67
3.72 0.81
3.80 0.89
3.39 0.82
3.50 0.77
3.40 0.92
In general, the ring size is an important parameter in the
biological activity of cyclic compounds. In particular, it
affects their transport, physicochemical, and biological
properties. The efficacy of the 7-membered ring in a
variety of drugs, for example, benzodiazapenes, is be-
lieved to be due to its modest degree of structural flexi-
bility that permits receptor-induced fit, which might lead
to improved biological profiles.18 However, the anti-
inflammatory activities of the compounds containing
7-, 8-membered dioxacycloalkanes were decreased over
those of their corresponding 6-membered compounds
(5d: 44.2% vs 10d: 19.2%; 11d: 20.5%; 5e: 42.9% vs
10e: 20.8%; 11e: 19.9%; 50d: 48.7% vs 100d: 20.2%;
110d: 20.5%; 6c: 43.6% vs 9c: 23.7%; 12c: 23.1%; 6d:
43.3% vs 9d: 18.9%; 12d: 19.9%; 6e: 41.3% vs 9e:
20.1%; 12e: 19.2%; 60e: 42.6% vs 90e: 21.2%; 120e:
19.9%). It appears that the stereochemical constraints
of these compounds do not play important role in the
biological profiles. We speculate that 7-, 8-membered
dioxacycloalkanes may have unfavorable physicochemi-
cal properties (chemical stability, size, hydrophilicity,
conformation) which needs further investigation.
Dose of N-substituted aminodiols and aldehydes = 20mg/kg; dose of
aspirin = 30 mg/kg; n = 11.
while exploring the influence of different modifications
at 2-, 5-position and ring size. As evaluated using mice
xylene-induced ear edema model, most of 2,5-disubsti-
tuted-1,3-dioxacycloalkanes exhibited well to moderate
anti-inflammatory activities 2 h after administration at
20 mg/kg. As listed in Table 2, it was observed that most
of compounds in the 6-membered ring series exhibited
comparable or better potency (41–56% inhibition of
inflammation) than the reference drug aspirin (aspirin:
41% inhibition of inflammation). Among these, com-
pounds 5h, 5i, 6i, 50i, 60i were the most potent anti-
inflammatory agents in this series, achieving 55–57%
inhibition of inflammation after 2-h treatment.
Upon comparing the anti-inflammatory effect of the
benzoylamide series and the phenylacetamide ones, we
noticed that the former exhibited better anti-inflamma-
tory activity (i.e., 5b: 48.0% vs 6b: 36.5%; 5h: 56.4% vs
6h: 46.4%). It was also worthy noticing that the substitu-
tion on the phenyl ring is important for anti-inflamma-
tory activity. It seemed the electron-withdrawing
groups on the phenyl ring endowed the 2,5-disubsti-
tuted-dioxacycloalkanes with slightly better anti-inflam-
matory profiles (i.e., 5d: 44.2%; 5e: 42.9%; 5i: 57.4%; 5j:
42.0%; 50d: 48.7%; 50e: 45.2%; 50h: 47.1%; 50i: 55.4%; 50j:
46.8%; 6d: 43.3%; 6e: 41.3%; 6i: 55.8%; 6j: 47.1%; 60d:
44.6%; 60e: 42.6%; 60i: 55.1%; 60j: 46.5%). However,
the chlorine substitution on the phenyl ring induced an
ambiguous anti-inflammatory effect (5c: 28.5%; 6c:
43.6%; 5h: 56.4%; 6h: 46.4%). In addition, carbon–car-
bon double bond insertion also decreased the anti-
inflammatory profile (5a: 39.7%; 5f: 43.9% vs 7a:
35.6%; 7b: 38.5%; 70a: 35.0%; 70b: 37.5%; 6a: 38.5%;
6f: 40.0% vs 8a: 27.2%; 8b: 32.1%; 80a: 29.5%; 80b:
33.3%).
2.5. Tail bleeding time measurements
The use of conventional NSAIDs is associated with a
number of significant adverse events, including gas-
trointestinal (GI) bleeding, impaired platelet function,
and prolonged bleeding time.19,20 The clinical effects
of NSAID-induced platelet dysfunction consist of an
increased bleeding, prolonged surgical bleeding, and
additive risk of significant or life-threatening bleeding
in patients taking anticoagulants.21 Both surgical and
non-surgical studies have shown that conventional
NSAIDs increase bleeding time and blood loss. To
develop the safer anti-inflammatory agents, it is crit-
ical to evaluate if these newly synthetic agents have
deleterious effect on normal hemostasis leading to
bleeding complications. The cutaneous bleeding time
model is the most common method used in animal
experiments to investigate bleeding potential in hu-
mans.19–27
To examine the importance of the spatial disposition,
the anti-inflammatory activities of the cis- and trans- iso-
mers were compared. The isomers of chiral compounds
To evaluate the bleeding risk of the new anti-inflamma-
tory agents, the tail bleeding time assays were performed
on mice using previously reported method.28 Male mice

4780
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
Table 2. Anti-inflammatory activities of 2,5-disubstituted-dioxacycloalkanes against xylene-induced ear edema in mice
Chemical structure
Edema weight
(X SD mg)
Inhibition
(%)
Agents
Aspirin
Chemical structure
Edema weight
(X SD mg)
Inhibition
(%)
CMC
3.12 0.55
1.85 0.72b
40.7
NHCOC6H5
NHCOCH2C6H5
O
O
H
O
H
O
5a
1.88 0.57b
39.7
48.0
28.5
44.2
42.9
43.9
46.1
56.4
57.4
42.0
41.3
6a
6b
6c
6d
6e
6f
1.92 0.71b
38.5
H
H
NHCOCH2C6H5
NHCOC6H5
O
H
O
H
O
5b
5c
5d
5e
5f
1.62 0.59b
2.23 0.65b
1.74 0.70b
1.78 0.68b
1.75 0.58b
1.68 0.59b
1.36 0.61b
1.33 0.63b
1.81 0.55b
1.83 0.59b
1.98 0.78b
1.76 0.75b
1.77 0.71a
1.83 0.69b
1.87 0.65b
1.84 0.66b
1.67 0.61b
1.38 0.63b
1.65 0.59b
1.94 0.76b
36.5
43.6
43.3
41.3
40.0
41.0
46.4
55.8
47.1
37.8
O
CH3
CH3
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
H
H
O
Cl
Cl
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
H
H
H
O
NO2
NO2
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
H
O
H
H
NO2
NO2
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
H
H
H
H
H
H
H
H
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
5g
5h
5i
6g
6h
6i
CH3
CH3
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
Cl
Cl
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
NO2
NO2
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
H
H
H
H
5j
6j
H
H
NO2
NO2
NHCOC6H5
O
NHCOCH2C6H5
O
O
H
O
H
50a
60a

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4781
Table 2 (continued)
Chemical structure
Edema weight
(X SD mg)
Inhibition
(%)
Agents
Chemical structure
Edema weight
(X SD mg)
Inhibition
(%)
NHCOC6H5
O
NHCOCH2C6H5
O
H
H
H
O
H
O
50b
1.90 0.60b
39.1
60b
2.01 0.75b
35.6
CH3
CH3
NHCOC6H5
O
NHCOCH2C6H5
O
H
H
O
H
O
H
50c
1.64 0.59b
47.4
60c
1.81 0.78b
42.0
Cl
Cl
NHCOC6H5
O
NHCOCH2C6H5
O
H
H
O
H
O
H
50d
1.60 0.57b
48.7
60d
1.73 0.74a
44.6
NO2
NO2
NHCOCH2C6H5
O
NHCOC6H5
O
H
H
O
H
O
H
50e
1.71 0.69b
45.2
43.9
60e
1.79 0.70b
42.6
41.3
NO2
NO2
NHCOC6H5
O
NHCOCH2C6H5
O
H
H
O
H
O
H
50f
1.75 0.67b
60f
1.83 0.63b
NHCOC6H5
O
NHCOCH2C6H5
O
H
H
O
H
O
H
50g
50h
50i
1.72 0.65b
1.65 0.58b
1.39 0.60b
1.66 0.58b
44.9
47.1
55.4
46.8
60g
60h
60i
1.80 0.69b
1.68 0.54b
1.40 0.67b
1.67 0.57b
42.3
46.1
55.1
46.5
CH3
CH3
NHCOC6H5
O
NHCOCH2C6H5
O
H
H
O
H
O
H
Cl
Cl
NHCOC6H5
O
NHCOCH2C6H5
O
H
H
O
H
O
H
NO2
NO2
NHCOCH2C6H5
O
NHCOC6H5
O
H
H
O
H
O
H
50j
60j
NO2
NO2
(continued on next page)

4782
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
Table 2 (continued)
Chemical structure
Edema weight
(X SD mg)
Inhibition
(%)
Agents
Chemical structure
Edema weight
(X SD mg)
Inhibition
(%)
NHCOCH2C6H5
H
NHCOC6H5
H
O
C6H5
O
C6H5
H
H
7a
7b
2.01 0.53b
35.6
38.5
8a
H
H
2.27 0.65b
27.2
32.1
C
C
O
C C
O
H
H
H
H
NHCOCH2C6H5
O
NHCOC6H5
H
C
1.92 0.54b
8b
2.12 0.56b
O
C6H5
H
O
H
C
O
H
H
H
C6H5
NHCOC6H5
O
NHCOCH2C6H5
O
H
H
H
H
70a
2.03 0.50b
35.0
80a
2.20 0.62b
29.5
H
H
O
O
H
H
H
C6H5
H
C6H5
NHCOC6H5
O
NHCOCH2C6H5
O
70b
9c
1.95 0.58b
2.20 0.55b
2.52 0.51b
37.5
29.5
19.2
80b
10c
10d
2.08 0.53b
2.38 0.61b
2.53 0.62a
33.3
23.7
18.9
H
H
O
O
H
H
H
C6H5
H
C6H5
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
H
H
H
H
Cl
Cl
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
9d
NO2
NO2
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
H
H
H
H
9e
2.47 0.56a
20.8
28.2
10e
2.49 0.58a
20.1
24.4
H
H
NO2
NO2
NHCOC6H5
NHCOCH2C6H5
O
O
O
H
H
O
90c
2.24 0.56b
100c
2.36 0.58b
Cl
Cl
NHCOC6H5
NHCOCH2C6H5
O
H
O
O
H
H
H
O
90d
2.49 0.53a
20.2
100d
2.51 0.60a
19.6
NO2
NO2
NHCOC6H5
NHCOCH2C6H5
O
H
O
H
H
H
O
O
90e
2.44 0.55b
2.24 0.53b
2.48 0.52a
21.8
28.2
20.5
100e
12c
12d
2.46 0.56a
2.40 0.55b
2.50 0.52a
21.2
23.1
19.9
NO2
NO2
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
H
H
H
H
11c
11d
Cl
Cl
H
H
NHCOC6H5
NHCOCH2C6H5
O
O
O
O
NO2
NO2
H
H

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4783
Table 2 (continued)
Chemical structure
Edema weight
(X SD mg)
Inhibition
(%)
Agents
Chemical structure
Edema weight
(X SD mg)
Inhibition
(%)
NHCOC6H5
NHCOCH2C6H5
O
O
O
H
H
H
H
2.50 0.55a
19.9
12e
2.52 0.56a
19.2
O
11e
H
H
NO2
NO2
NHCOC6H5
NHCOCH2C6H5
O
O
O
H
O
H
110c
2.27 0.55b
27.2
120c
2.38 0.54b
23.7
Cl
Cl
NHCOC6H5
NHCOCH2C6H5
O
H
O
O
H
H
O
H
110d
2.44 0.54b
21.8
120d
2.47 0.55a
20.8
NO2
NO2
NHCOCH2C6H5
O
H
NHCOC6H5
O
O
H
O
H
H
110e
2.47 0.54a
20.8
120e
2.50 0.53a
19.9
NO2
NO2
Dose of 2,5-disubstituted-1,3-dioxacycloalkanes = 20 mg/kg, dose of aspirin = 30 mg/kg; n = 11.
a Compare to control, P < 0.05.
b Compare to control, P < 0.01.
(18–22 g) were orally administered with the new anti-
inflammatory agents. After the administration of 30,
45, 60 and 90 min, a mouse was placed in a tube holder
with its tail protruding, and a 2 mm cut was made on the
tail. Flowing blood was gently wiped away with a tissue
every 30 s until bleeding ceased and the time was re-
corded. Baseline bleeding times were similar between
treatment groups with an average of 113–121 s. Treat-
ment with the new anti-inflammatory agents (5a–j,
50a–j, 6a–j, 60a–j) at the high doses (200 mg/kg) did
not significantly prolong bleeding time at any time point
(30, 45, 60, 90 min) compared with NS (115–120 s)
(Table 3).
chemoprevention. The molecular and cellular mechanism
study of these new compounds is currently under way.
4. Materials and methods
4.1. Experimental
All reactions were carried out under the inert atmo-
sphere using nitrogen (1 bar) unless stated otherwise.
The agents used in this work were purchased from
Sigma Chemical Co. (USA). Chromatography was
performed on Qingdao silica gel H (Qingdao of Chi-
na). The purities of the intermediates and the products
were confirmed by TLC (Merck silica gel plates of
type 60 F254, 0.25 mm layer thickness, Germany)
and HPLC (Waters, C18 column 4.6 · 150 mm,
USA). NMR spectra were recorded at 300 MHz on
a VXR-300 instrument or at 500 MHz on an Bruker
Am-500 instrument in CDCl3 with tetramethylsilane
as internal standard. EI-MS was determined by Trace
MS System (Thermo Finnigan, USA). Optical rota-
tions were determined with a Schmidt + Haensch
Polartromic D instrument (Germany). Statistical anal-
ysis was performed using One way ANOVA test with
p < 0.05 as significant.
3. Conclusion
The structure–activity relationship (SAR) data indicate
that (i) the 1,3-dioxane ring is a suitable template to de-
sign a new class of anti-inflammatory compounds; (ii)
good anti-inflammatory activity can be achieved by
varying the electronic and steric properties at the 2-
and 5- position substitution pattern.
In conclusion, although cancer chemoprevention is possi-
ble for certain cancer types, drugs that have more accept-
able side-effect profiles are desired compared to currently
availableNSAIDs. COX-2-specific inhibitors, which have
an improved safety profile, as compared to traditional
NSAIDs that inhibit both the COX-1 and COX-2 en-
zymes, seem to be well-suited drug candidates for cancer
4.1.1. HClÆL-Ser-OCH3 (2a). At 0 ꢁC, thinly chloride
was added dropwise to 50 ml of anhydrous methanol
3.75 ml (47.5 mmol). The solution was stirred at 0 ꢁC
for 30 min and 5.0 g (47.6 mmol) of L-Ser was added.

4784
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
Table 3. Effect of 1,3-dioxacycloalkanes on the tail bleeding time (X SDs) of mice
Compound
Before drug administration
Post-drug administration
30 min
45 min
60 min
90 min
NS
5a
5b
5c
118.0 9.0
114.4 8.4
115.2 7.9
115.3 8.5
122.3 8.6
117.6 7.9
113.4 8.2
117.9 8.7
117.3 7.6
118.2 7.8
118.8 7.9
119.1 8.2
118.2 8.0
120.3 8.4
113.5 8.3
115.5 7.4
116.1 8.4
114.8 8.0
116.9 7.6
113.0 8.0
115.2 7.8
116.5 7.9
117.6 7.7
119.5 8.3
114.9 8.0
118.2 8.5
116.5 7.7
119.7 7.5
116.7 7.5
120.5 8.8
117.2 7.8
119.5 7.9
116.6 7.7
119.5 8.3
117.9 8.0
119.2 8.5
117.5 7.7
118.7 7.5
116.7 7.5
120.5 8.8
119.8 8.0
119.2 8.5
118.3 8.1
118.5 8.4
119.4 8.7
119.3 8.7
120.9 9.0
118.3 7.9
118.4 8.6
118.9 7.6
119.3 8.1
118.5 8.0
119.0 8.3
119.5 8.7
118.8 8.4
118.7 8.2
120.4 8.5
119.6 8.7
117.8 8.0
118.9 8.3
118.5 8.0
117.2 7.8
117.9 8.0
120.7 8.9
117.7 7.9
118.5 8.1
117.9 7.8
118.4 7.6
117.8 8.0
120.1 8.5
118.5 8.0
117.2 7.8
117.9 8.0
120.7 8.9
117.7 7.9
118.5 8.1
117.9 7.8
118.4 7.6
117.8 8.0
120.1 8.5
119.7 7.9
118.8 7.6
119.0 8.7
118.9 7.9
118.7 8.6
118.2 8.4
121.0 9.2
118.9 8.0
119.2 8.3
119.2 8.0
119.2 8.5
119.2 8.7
118.9 8.5
117.7 8.2
118.0 7.7
118.9 7.8
118.5 8.2
118.6 8.3
118.1 8.1
118.2 8.1
119.3 8.5
118.6 8.2
119.2 8.4
120.2 9.2
118.5 8.1
119.0 8.4
118.6 8.1
119.6 8.4
118.5 7.9
118.7 8.1
119.3 8.5
118.6 8.2
119.2 8.4
120.2 9.2
118.5 8.1
119.0 8.4
118.6 8.1
119.6 8.4
118.5 7.9
118.7 8.1
119.2 8.1
117.6 8.0
118.7 7.9
120.9 8.6
120.6 8.7
119.1 8.6
119.8 8.7
118.5 8.1
117.2 8.0
117.4 8.5
119.7 8.8
119.5 8.9
118.7 8.2
118.6 8.0
118.4 8.2
118.6 8.2
118.9 8.6
118.7 8.2
118.8 8.3
119.5 8.6
117.8 8.0
118.4 8.1
119.5 8.3
117.6 8.3
119.2 8.8
118.6 8.1
119.0 8.4
118.6 8.4
117.9 7.6
118.5 8.3
117.8 8.0
118.4 8.1
119.5 8.3
117.6 8.3
119.2 8.8
118.6 8.1
119.0 8.4
118.6 8.4
117.9 7.6
118.5 8.3
118.9 8.6
118.7 8.8
118.4 8.0
119.4 8.3
119.4 8.1
120.2 8.8
118.7 8.5
118.7 8.3
118.9 8.5
118.3 8.6
119.6 8.0
117.8 8.2
119.6 8.7
118.9 8.5
118.7 8.6
118.9 8.4
117.7 7.6
118.6 8.5
119.0 8.7
118.2 8.1
118.9 7.9
119.2 8.2
118.4 8.1
117.7 7.9
118.6 8.6
117.9 7.9
118.5 8.7
119.0 8.7
117.2 7.8
118.6 7.9
118.9 7.9
119.2 8.2
118.4 8.1
117.7 7.9
118.6 8.6
117.9 7.9
118.5 8.7
119.0 8.7
117.2 7.8
118.6 7.9
5d
5e
5g
5h
5i
5j
50a
50b
50c
50d
50e
50f
50g
50h
50i
50j
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
60a
60b
60c
60d
60e
60f
60g
60h
60i
60j
Dose = 200 mg/kg, n = 10.
The reaction mixture was stirred at room temperature
for 24 h until TLC (CH3Cl/CH3OH, 9:1) indicated com-
plete disappearance of L-Ser. The reaction mixture was
evaporated under reduced pressure and the residue
was triturated with petroleum ether repeatedly to pro-
vide 7304 mg (99%) of HClÆL-Ser-OCH3 as a colorless
powder (mp 161–162 ꢁC) that was directly used for the
next reaction.
4.1.4. L-Glu-(OCH3)2 (2d). Using the same procedure
for the preparation of 2a, starting from 6.983 g
(47.5 mmol) of L-Glu, 8146 mg (98%) of HClÆL-Glu-
(OCH3)2 was obtained as a colorless powder (mp 136–
138 ꢁC).
4.1.5. N-Phenyl-L-Ser-OCH3 (20a). At 0 ꢁC, 25 ml of
saturated aqueous of sodium carbonate was added to
the suspension of 1.0 g (6.4 mmol) of HClÆL-Ser-OCH3
in 30 ml of THF. 1.106 ml (8.3 mmol) of phenylacetyl
chloride was added upon stirring with pH adjustment
to 8–9 by adding saturated aqueous of sodium
carbonate. The reaction mixture was stirred at room
temperature for 3 h until complete disappearance of
L-Ser-OCH3 as indicated by TLC (CH3Cl/CH3OH,
19:1). The reaction mixture was evaporated under
reduced pressure and the residue was dissolved in
50 ml of ethyl acetate and washed with saturated aque-
ous of sodium bicarbonate (10 ml · 3), saturated aque-
4.1.2. HClÆL-Thr-OCH3 (2b). Using the same procedure
for the preparation of 2a, starting from 4.998 g (47.5 mmol)
of L-Thr, 7867 mg (98%) of HClÆL-Thr-OCH3 was
obtained as a colorless powder (mp 140–142 ꢁC).
4.1.3. HClÆL-Asp-(OCH3)2 (2c). Using the same proce-
dure for the preparation of 2a, starting from 6.332 g
(47.5 mmol) of L-Asp, 7.495 mg (98%) of HClÆL-Asp-
(OCH3)2 was obtained as a colorless powder (mp 149–
151 ꢁC).

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4785
ous of KHSO4 (10 ml · 3), and saturated aqueous of
NaCl (10 ml · 3). The solution was evaporated under
reduced pressure and the residue was purified using
chromatography (petroleum ether/ethyl acetate, 5:1).
C6H5CH2CO-L-Ser-OCH3 (1140 mg with 75% yield)
was obtained as a colorless powder (mp 77–79 ꢁC).
t (cmꢀ1) = 3452, 3343, 3028, 3004, 2962, 2834, 1638,
1604, 1573, 1505, 1452, 721, 662. H NMR (DMSO-
d6) d (ppm) = 8.11 (d, J = 7.6 Hz, 1H), 7.64 (d,
J = 7.5 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.14 (t,
J = 7.2 Hz, 1H), 4.64 (broad, 2H), 3.95 (m, J = 6.0 Hz,
1H), 3.62 (s, 2H), 3.53 (d, J = 5.7 Hz, 4H). FAB-MS
(m/z) 210 [M+H]+.
1
4.1.6. N-Phenyl-L-Thr-OCH3 (20b). Using the same pro-
cedure for the preparation of 20a, starting from 1010 mg
(6.0 mmol) of HClÆL-Thr-OCH3, 1171 mg (77%) of N-
phenyl-L-Thr-OCH3 was obtained as a colorless powder
(mp 90–92 ꢁC).
4.1.14.
(1S,2R)-N-[2-Hydroxy-1-(hydroxymethyl)pro-
pyl]phenylacetamide (30b). Using the same procedure
for the preparation of 30a, the title compound (203 mg
with 91% yield) was obtained from 252 mg (1.0 mmol)
of phenylacetyl-L-Thr-OCH3 as a colorless powder.
Mp 125–127 ꢁC, IR (KBr) t (cmꢀ1) = 3451, 3362,
3033, 3005, 2965, 2862, 1643, 1608, 1592, 1505, 1482,
712, 651. 1H NMR (DMSO-d6) d (ppm) = 8.04 (d,
J = 7.5 Hz, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.35 (t,
J = 7.6 Hz, 2H), 7.19 (d, J = 7.8 Hz, 1H), 4.24 (q,
J = 6.0 Hz, 1H), 3.96 (m, J = 6.4 Hz, 1H), 3.85 (d,
J = 6.6 Hz, 2H), 3.64 (s, 2H), 3.53 (s, 2H), 1.22 (d,
4.1.7. N-Phenyl-L-Asp-(OCH3) (20c). Using the same
procedure for the preparation of 20a, starting from
1182 mg (6.0 mmol) of HClÆL-Asp-(OCH3)2, 1345 mg
(80%) of N-phenyl-L-Asp-(OCH3)2 was obtained as a
colorless powder (mp 90–92 ꢁC).
J = 6.9 Hz, 3H). FAB-MS (m/z) 224 [M+H]+.
4.1.8. N-Phenyl-L-Glu-(OCH3) (20d). Using the same
procedure for the preparation of 20a, starting from
1274 mg (6.0 mmol) of HClÆL-Glu-(OCH3)2, 1433 mg
(81%) of N-phenyl-L-Glu-(OCH3)2 was obtained as a
colorless powder (mp 111–113 ꢁC).
20
D
½aꢁ ꢀ 32:5 (c 0.02, CH3OH).
4.1.15. (1S)-N-[3-Hydroxy-1-(hydroxymethyl)propyl]-
phenylacetamide (30c). Using the same procedure for
the preparation of 30a, the title compound (207 mg with
93% yield) was obtained from 252 mg (1.0 mmol) of
phenylacetyl-L-Asp-(OCH3)2 as a colorless powder.
Mp 132–134 ꢁC. IR (KBr) t (cmꢀ1) = 3415, 3344,
3023, 3006, 2964, 2833, 1632, 1602, 1585, 1506, 1463,
715, 651. 1H NMR (DMSO-d6) d (ppm) = 8.03 (d,
J = 5.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 2H), 7.32 (t,
J = 7.5 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 4.75 (t,
J = 3.9 Hz, 1H), 4.44 (t, J = 3.9 Hz, 1H), 4.06 (dq,
J = 3.7 Hz, J = 2.5 Hz, 1H), 3.66 (s, 2H), 3.49 (s, 2H),
3.43 (t, J = 3.9 Hz, 1H), 3.40 (t, J = 3.9 Hz, 1H), 1.76
(dt, J = 4.7 Hz, J = 2.7 Hz,1H), 1.63 (dt, J = 5.6 Hz,
4.1.9. N-Benzoyl-L-Ser-OCH3 (200a). Using the same
procedure for the preparation of 20a, starting from
992 mg (6.4 mmol) of HClÆL-Ser-OCH3 and 1162 mg
(8.3 mmol) of benzoyl chloride, 1170 mg (82%) of N-
benzoyl-L-Ser-OCH3 was obtained as a colorless powder
(mp 75–77 ꢁC).
4.1.10. N-Benzoyl-L-Thr-OCH3 (200b). Using the same
procedure for the preparation of 20a, starting from
1082 mg (6.4 mmol) of HClÆL-Thr-OCH3, 1229 mg
(81%) of N-benzoyl-L-Thr-OCH3 was obtained as a col-
orless powder (mp 85–87 ꢁC).
J = 3.3 Hz, 1H) FAB-MS (m/z) 224 [M+H]+.
20
D
½aꢁ ꢀ 28:4 (c 0.02, CH3OH).
4.1.11. N-Benzoyl-L-Asp-(OCH3) (200c). Using the same
procedure for the preparation of 20a, starting from
1261 mg (6.4 mmol) of HClÆL-Asp-(OCH3)2,1357 mg
(80%) of N-benzoyl-L-Asp-(OCH3)2 was obtained as a
colorless powder (mp 91–93 ꢁC).
4.1.16. (1S)-N-[4-Hydroxy-1-(hydroxymethyl)butyl]-
phenylacetamide (30d). Using the same procedure for
the preparation of 30a, the title compound (220 mg,
93% yield) was obtained from 266 mg (1.0 mmol) of
phenylacetyl-L-Glu-(OCH3)2 as a colorless powder.
Mp 102–104 ꢁC, IR (KBr) t (cmꢀ1) = 3425, 3345,
3033, 3004, 2952, 2841, 1636, 1604, 1587, 1505, 1442,
723, 662. 1H NMR (DMSO-d6) d (ppm) = 8.06 (d,
J = 4.9 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.31 (t,
J = 7.4 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), 4.67 (t,
J = 3.9 Hz, 1H), 4.41 (t, J = 3.8 Hz, 1H), 3.96 (dq,
J = 3.9 Hz, J = 2.4 Hz, 1H), 3.66 (s, 2H), 3.43 (t,
J = 6.7 Hz, 1H), 3.38 (s, 2H), 3.35 (t, J = 6.6Hz, 1H),
1.68 (m, J = 4.8 Hz, 1H), 1.49 (m, J = 4.5 Hz, 1H),
4.1.12. N-Benzoyl-L-Glu-(OCH3) (200d). Using the same
procedure for the preparation of 20a, starting from
1350 mg (6.4 mmol) of HClÆL-Glu-(OCH3)2, 1446 mg
(81%) of N-phenyl-L-Glu-(OCH3)2 was obtained as a
colorless powder (mp 92–94 ꢁC).
4.1.13. N-[2-Hydroxy-1-(hydroxymethyl)ethyl]phenylace-
tamide (30a). To the suspension of 200 mg (5.6 mmol) of
KBH4 in 10 ml of THF the solution of 238 mg
(1.0 mmol) of N-Phenyl-L-Ser-OCH3 in 20 ml of THF
was added. The reaction mixture was stirred at room
temperature for 24 h and TLC (C2H5OH/H2O, 7/1) indi-
cated complete disappearance of 20a. The reaction mix-
ture was adjusted to pH 10 with hydrochloric acid
(2 mol/L) and evaporated under reduced pressure. The
residue was purified by chromatography (CH3Cl/
CH3OH, 19:1) to provide 190 mg (91%) of the title com-
pound as a colorless powder. Mp 135–136 ꢁC. IR (KBr)
1.45 (q, J = 3.6 Hz, 2H). FAB-MS (m/z) 238 [M+H]+.
20
D
½aꢁ ꢀ 23:3 (c 0.02, CH3OH).
4.1.17. N-[2-Hydroxy-1-(hydroxymethyl)ethyl]benzoamide
(300a). Using the same procedure for the preparation of
30a, the title compound (189 mg, 97% yield) was ob-
tained from 224 mg (1.0 mmol) of benzoyl-L-Ser-
OCH3 as a colorless powder. Mp 69–70 ꢁC. IR (KBr)
t (cmꢀ1) = 3450, 3341, 3026, 3005, 2960, 2830, 1632,

4786
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
1
1601, 1570, 1500, 1451, 723, 665. H NMR (DMSO-d6)
d (ppm) = 8.105 (s, 1H), 7.900 (d, J = 7.61 Hz, 2H),
7.514 (d, J = 7.53 Hz, 1H), 7.427 (t, J = 7.44 Hz, 2H),
3.853 (m, J = 6.21 Hz, 1H), 3.736 (d, J = 6.21 Hz, 2H),
C12H17NO3: C, 64.55; H, 7.67; N 6.27. Found: C,
64.37; H, 7.80; N 6.40.
4.1.21. (cis)- and (trans)-(2-Phenyl-1,3-dioxan-5-yl)benz-
amide (5a and 50a). The suspension of 418 mg
(2.0 mmol) of 2-benzoylacetamido-1,3-diol (300a),
276 mg (2.6 mmol) of benzaldehyde, 30 mg of tolylsulf-
onylic acid, 100 mg of anhydrous Na2SO4, 50 ml of
chloroform, and 4 ml of THF was stirred at room tem-
perature overnight until the complete disappearance of
300a indicated by TLC (CHCl3/CH3OH, 20:1). The reac-
tion mixture was adjusted to pH 7 with sodium carbon-
ate. The reaction mixture was filtered and the filtrate
was concentrated under reduced pressure. The residue
was purified by chromatography on silica gel to provide
166 mg (69%) of 5a and 17 mg (7%) of 50a.
2.006
(s,
2H).
13C
NMR
(DMSO-d6)
d
(ppm) = 166.950, 133.552, 130.994, 128.578, 127.227,
65.110, 54.592. FAB-MS (m/z) 196 [M+H]+. Anal.
Calcd for C10H13NO3: C, 61.53; H, 6.71; N 7.18. Found:
C, 61.32; H, 6.56; N 7.30.
4.1.18.
(1S,2R)-N-[2-Hydroxy-1-(hydroxymethyl)pro-
pyl]benzoamide (300b). Using the same procedure for the
preparation of 30a, the title compound (197 mg, 94%
yield) was obtained from 238 mg (1.0 mmol) of ben-
zoyl-L-Thr-OCH3 as a colorless powder. Mp 75–77 ꢁC,
IR (KBr) t (cmꢀ1) = 3448, 3355, 3031, 3007, 2962,
1
2860, 1645, 1606, 1590, 1503, 1480, 710, 653. H NMR
(DMSO-d6)
Compound 5a. Colorless powder. Mp 133–135 ꢁC. IR
(KBr): t (cmꢀ1) = 3235, 1637, 1600, 1582, 1499, 1446,
763, 697. 1H NMR (CDCl3) d (ppm) = 7.896 (d,
J = 7.66 Hz, 2H), 7.804 (s, 1H), 7.623 (d, J = 7.00 Hz,
2H), 7.526 (t, J = 7.66 Hz, 1H), 7.512 (t, J = 7.00 Hz,
1H), 7.464 (t, J = 7.66 Hz, 2H), 7.440 (t, J = 7.00 Hz,
2H), 5.597 (s, 1H), 4.253 (d, J = 11.00 Hz, 2H), 4.234
(d, J = 10.04 Hz, 2H), 2.814 (m, J = 10.03 Hz, 1H). In
the NOE experiment, a positive NOE was observed
between the NH-functionality at the 5-position and the
proton of the phenyl at the 2-position. 13C NMR
d
(ppm) = 8.012 (s, 1H), 7.946 (d,
J = 7.51 Hz, 2H), 7.509 (t, J = 7.82 Hz, 1H), 7.435 (t,
J = 7.60 Hz, 2H), 4.009 (m, J = 6.01 Hz, 1H), 3.792 (d,
J = 6.27 Hz, 2H), 3.743 (q, J = 6.60 Hz, 1H), 2.113 (s,
2H), 1.222 (d, J = 6.01 Hz, 3H). 13C NMR (DMSO-d6)
d (ppm) = 167.561, 133.423, 131.850, 128.602, 127.284,
68.119, 62.613, 59.212, 17.873. FAB-MS (m/z) 210
20
[M+H]+. ½aꢁ ꢀ 30:0 (c 0.02, CH3OH). Anal. Calcd
D
for C11H15NO3: C, 63.14; H, 7.23; N 6.69. Found: C,
63.25; H, 7.41; N 6.52.
(DMSO-d6):
d (ppm) = 168.724, 138.614, 134.233,
4.1.19. (1S)-N-[3-Hydroxy-1-(hydroxymethyl)propyl]benz-
amide (300c). Using the same procedure for the preparation
of 30a, the title compound (192 mg, 92% yield) was ob-
tained from 238 mg (1.0 mmol) of benzoyl-L-Asp-
(OCH3)2 as a colorless powder. Mp 80–81 ꢁC. IR (KBr)
t (cmꢀ1) = 3413, 3340, 3021, 3008, 2960, 2830, 1631,
132.755, 129.867, 128.987, 128.734, 127.937, 126.323,
102.452, 73.967, 46.403. EI-MS (m/e): 283 [M]+. Anal.
Calcd for C17H17NO3: C, 72.07; H, 6.05; N 4.94. Found:
C, 72.20; H, 6.13; N 5.06.
Compound 50a. Colorless powder. Mp 146–148 ꢁC. IR
(KBr): t (cmꢀ1) = 3236, 1635, 1603, 1580, 1501, 1443,
765, 695. 1H NMR (CDCl3) d (ppm) = 7.994 (d,
J = 7.63 Hz, 2H), 7.833 (s, 1H), 7.651 (d,
J = 7.06 Hz, 2H), 7.554 (t, J = 7.63 Hz, 1H), 7.561 (t,
J = 7.04 Hz, 1H), 7.634 (t, J = 7.63 Hz, 2H), 7.602 (t,
J = 7.04 Hz, 2H), 5.711 (s, 1H), 4.512 (d,
J = 10.47 Hz, 2H), 4.450 (d, J = 9.57 Hz, 2H), 2.986
(m, J = 9.55 Hz, 1H). In the NOE experiment no
1
1600, 1582, 1502, 1460, 712, 654. H NMR (DMSO-d6)
d (ppm) = 8.008 (s, 1H), 7.942 (d, J = 7.52 Hz, 2H),
7.505 (t, J = 7.46 Hz, 1H), 7.438 (t, J = 7.24 Hz, 2H),
3.794 (t, J = 3.93 Hz, 2H), 3.670 (t, J = 3.98 Hz, 1H),
3.525 (t, J = 3.73 Hz, 2H), 1.762 (dt, J = 4.73 Hz,
J = 2.75 Hz, 2H), 2.007 (s, 2H). 13C NMR (DMSO-d6)
d (ppm) = 167.101, 133.498, 131.882, 128.597, 127.220,
69.003, 57.881, 47.692, 35.291. FAB-MS (m/z) 210
20
D
[M+H]+. ½aꢁ ꢀ 26:0 (c 0.02, CH3OH). Anal. Calcd for
NOE was observed. 13C NMR (DMSO-d6):
d
C11H15NO3: C, 63.14; H, 7.23; N 6.69. Found: C, 63.01;
H, 7.06; N 6.75.
(ppm) = 168.989, 138.920, 134.566, 133.011, 130.230,
129.314, 129.008, 128.122, 126.523, 102.624, 74.168,
47.033. EI-MS (m/e): 283 [M]+. Anal. Calcd for
C17H17NO3: C, 72.07; H, 6.05; N 4.94. Found: C,
72.16; H, 6.09; N 5.10.
4.1.20. (1S)-N-[4-Hydroxy-1-(hydroxymethyl)butyl]benz-
amide (300d). Using the same procedure for the prepara-
tion of 30a, the title compound (201 mg, 90% yield) was
obtained from 252 mg (1.0 mmol) of benzoyl-L-Glu-
(OCH3)2 as a colorless powder. Mp 92–94 ꢁC. IR
(KBr) t (cmꢀ1) = 3422, 3343, 3035, 3008, 2950, 2843,
1634, 1602, 1585, 1503, 1446, 725, 660. 1H NMR
4.1.22. (cis)- and (trans)-2-[40-Methylphenyl]-1,3-dioxan-
5-yl]benzamide (5b and 50b). Using the same procedure
for the preparation of 5a and 50a, from 166 (0.85 mmol)
of 300a and 102 mg (0.85 mmol) of 4-methylbenzalde-
hyde, 164 mg (65%) of 5b and 20 mg (8%) of 50b were
obtained.
(DMSO-d6)
d
(ppm) = 8.007 (s, 1H), 7.943 (d,
J = 7.42 Hz, 2H), 7.505 (d, J = 7.62 Hz, 1H), 7.428 (t,
J = 7.43 Hz, 2H), 3.783 (d, J = 4.55 Hz, 2H), 3.679 (m,
J = 4.55 Hz, 1H), 3.540 (t, J = 4.12 Hz, 2H), 2.008 (s,
2H), 1.674 (m, J = 4.50 Hz, 2H), 1.601 (t, J = 4.50 Hz,
Compound 5b. Colorless powder. Mp 134–136 ꢁC. IR
(KBr): t (cmꢀ1) = 3238, 1652, 1603, 1580, 1501, 1452,
2H). 13C NMR (DMSO-d6)
d (ppm) = 165.681,
133.489, 131.886, 128.591, 127.282, 69.005, 63.291,
1382, 822, 763, 695. 1H NMR (CDCl3)
d
(ppm) = 7.964 (d, J = 7.55 Hz, 2H), 7.804 (s, 1H),
7.526 (t, J = 7.55 Hz, 1H), 7.453 (t, J = 7.55 Hz,
2H), 7.472 (d, J = 7.80 Hz, 2H), 7.248 (d,
51.676, 28.391, 28.088. FAB-MS (m/z) 224 [M+H]+.
20
D
½aꢁ ꢀ 21:0 (c 0.02, CH3OH). Anal. Calcd for

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4787
J = 7.80 Hz, 2H), 5.611 (s, 1H), 4.251 (d, J = 4.42 Hz,
2H), 4.114 (d, J = 4.36 Hz, 2H), 2.975 (m,
J = 4.43 Hz, 1H), 2.365 (s, 3H). In the NOE experi-
ment, a positive NOE was observed between the
NH-functionality at the 5-position and the proton
of the phenyl at the 2-position. 13C NMR (DMSO-
d6): d (ppm) = 168.722, 136.601, 133.482, 132.101,
130.112, 128.593, 127.224, 126.870, 103.115, 74.136,
46.131, 22.071. EI-MS (m/e): 297 [M]+. Anal. Calcd
for C18H19NO3: C, 72.71; H, 6.44; N 4.71. Found:
C, 72.83; H, 6.52; N 4.85.
317 [M]+. Anal. Calcd for C17H16ClNO3: C, 64.26; H,
5.08; N 4.41. Found: C, 64.38; H, 5.21; N 4.27.
4.1.24. (cis)- and (trans)-2-[40-Nitrophenyl]-1,3-dioxan-5-
yl]benzamide (5d and 50d). Using the same procedure for
the preparation of 5a and 50a, from 166 (0.85 mmol) of
300a and 128 mg (0.85 mmol) of 4-nitrobenzaldehyde,
195 mg (70%) of 5d and 28 mg (10%) of 50d were
obtained.
Compound 5d. Colorless powder, mp 220–224 ꢁC. IR
(KBr):
t
(cmꢀ1) = 3278, 3015, 2920, 2860, 1656,
1620, 1605, 1580, 1525, 1450, 1352, 1192, 1070, 800,
Compound 50b. Colorless powder. Mp 146–148 ꢁC. IR
(KBr): t (cmꢀ1) = 3242, 1651, 1602, 1581, 1502, 1454,
1
1381, 821, 761, 695. 1H NMR (CDCl3)
d
719, 690. H NMR (DMSO-d6) d (ppm) = 8.249 (d,
J = 8.72 Hz, 2H), 7.869 (t, J = 6.9o Hz, 2H), 7.752
(d, J = 8.72 Hz, 2H), 7.557 (t, J = 6.64 Hz, 1H),
7.482 (t, J = 6.64 Hz, 2H), 7.110 (s, 1H), 5.667 (s,
1H), 4.310 (d, J = 7.01 Hz, 2H), 4.249 (d,
J = 7.01 Hz, 2H), 3.679 (m, J = 6.88 Hz, 1H). In the
NOE experiment, a positive NOE was observed be-
tween the NH-functionality at the 5-position and the
proton of the phenyl at the 2-position. 13C NMR
(ppm) = 7.982 (d, J = 7.54 Hz, 2H), 7.831 (s, 1H),
7.548 (t, J = 7.54 Hz, 1H), 7.475 (t, J = 7.54 Hz,
2H), 7.503 (d, J = 7.82 Hz, 2H), 7.271 (d,
J = 7.82 Hz, 2H), 5.635 (s, 1H), 4.276 (d,
J = 4.43 Hz, 2H), 4.127 (d, J = 4.37 Hz, 2H), 2.998
(m, J = 4.43 Hz, 1H), 2.382 (s, 3H). In the NOE
experiment no NOE was observed. 13C NMR
(DMSO-d6):
d (ppm) = 169.121, 136.690, 133.520,
(DMSO-d6):
d (ppm) = 170.547, 147.440, 143.302,
132.152, 130.320, 128.704, 127.430, 127.113, 103.368,
74.316, 46.321, 22.314. EI-MS (m/e): 297 [M]+. Anal.
Calcd for C18H19NO3: C, 72.71; H, 6.44; N 4.71.
Found: C, 72.83; H, 6.52; N 4.85.
135.223, 129.784, 128.684, 128.500, 127.392, 123.424,
106.330, 73.906, 51.889. EI-MS (m/e) 328 [M]+. Anal.
Calcd for C17H16N2O5: C, 62.18; H, 4.91; N, 8.53.
Found: C, 62.30; H, 5.01; N, 8.48.
4.1.23. (cis)- and (trans)-2-[40-Chlorophenyl]-1,3-dioxan-
5-yl]benzamide (5c and 50c). Using the same procedure
for the preparation of 5a and 50a, from 166 (0.85 mmol)
of 300a and 119 mg (0.85 mmol) of 4-chlorobenzalde-
hyde, 189 mg (70%) of 5c and 33 mg (12%) of 50c were
obtained.
Compound 50d. Colorless powder, mp 120–122 ꢁC. IR
(KBr): t (cmꢀ1) = 3275, 3020, 2905, 2858, 1649, 1625,
1600, 1590, 1528, 1435, 1354, 1188, 1075, 719, 690. H
1
NMR (DMSO-d6) d (ppm) = 8.258 (d, J = 9.3 Hz, 2H),
7.818 (d, J = 6.9 Hz, 2H), 7.694 (d, J = 9.0 Hz, 2H),
7.507 (t, J = 8.1 Hz, 1H), 7.458 (t, J = 7.5 Hz, 2H),
7.085 (s, 1H), 5.712 (s, 1H), 4.318 (t, J = 7.1 Hz, 2H),
4.262 (d, J = 7.2 Hz, 2H), 3.692 (t, J = 7.6 Hz, 1H). In
the NOE experiment no NOE was observed. 13C
NMR (DMSO-d6): d (ppm) = =40.101, 51.901, 73.954,
106.441, 123.004, 127.112, 128.440, 128.796, 129.112,
135.003, 143.101, 147.105, 170.120. EI-MS (m/e) 328
[M]+. Anal. Calcd for C17H16N2O5: C, 62.18; H, 4.91;
N, 8.53. Found: C, 62.05; H, 4.79; N, 8.70.
Compound 5c. Colorless powder, mp 168–170 ꢁC. IR
(KBr): t (cmꢀ1) = 3240, 3019, 1654, 1629, 1600, 1582,
1500, 1454, 820, 769, 698. 1H NMR (CDCl3) d
(ppm) = 7.984 (d, J = 7.56 Hz, 2H), 7.762 (s, 1H),
7.631 (t, J = 7.56 Hz, 1H), 7.516 (d, J = 7.12 Hz, 2H),
7.438 (t, J = 7.56 Hz, 2H), 7.290 (d, J = 7.12 Hz, 2H),
5.611 (s, 1H), 4.304 (d, J = 3.76 Hz, 2H), 4.152 (d,
J = 6.43 Hz, 2H), 2.923 (s, 1H). In the NOE experiment,
a positive NOE was observed between the NH-function-
ality at the 5-position and the proton of the phenyl
at the 2-position. 13C NMR (DMSO-d6): d (ppm) =
169.352, 137.691, 135.497, 133.252, 132.438, 129.524,
128.761, 128.487, 127.347, 102.194, 74.451, 46.867.
EI-MS (m/e): 317 [M]+. Anal. Calcd for C17H16ClNO3:
C, 64.26; H, 5.08; N 4.41. Found: C, 64.40; H, 5.15;
N 4.30.
4.1.25. (cis)- and (trans)-2-[30-Nitrophenyl]-1,3-dioxan-5-
yl]benzamide (5e and 50e). Using the same procedure for
the preparation of 5a and 50a, from 166 mg (0.85 mmol)
of 300a and 128 mg (0.85 mmol) of 30-nitrobenzaldehyde,
195 mg (69%) of 5e and 28 mg (10%) of 50e were
obtained.
Compound 5e. Mp 144–146 ꢁC. IR (KBr):
t
(cmꢀ1) = 3280, 3019, 2922, 2864, 1658, 1622, 1600,
1582, 1522, 1450, 1350, 1192, 1070, 860, 769, 742, 698.
1H NMR (CDCl3) d (ppm) = 8.303 (s, 1H), 8.292 (d,
J = 9.01 Hz, 1H), 8.011 (d, J = 7.53 Hz, 2H), 7.796 (s,
1H), 7.790 (d, J = 9.01 Hz, 1H), 7.626 (t, J = 7.53 Hz,
1H), 7.562 (t, J = 9.01 Hz, 1H), 7.531 (t, J = 7.53 Hz,
2H), 5.681 (s, 1H), 4.304 (d, J = 6.55 Hz, 2H), 4.220
(d, J = 6.34 Hz, 2H), 3.625 (m, J = 6.33 Hz, 1H). In
the NOE experiment, a positive NOE was observed be-
tween the NH-functionality at the 5-position and the
proton of the phenyl at the 2-position. 13C NMR
Compound 50c. Colorless powder, mp 133–135 ꢁC. IR
(KBr): t (cmꢀ1) = 3242, 3017, 1656, 1627, 1603, 1580,
1504, 1452, 822, 771, 699. 1H NMR (CDCl3) d
(ppm) = 7.997 (d, J = 7.55 Hz, 2H), 7.783 (s, 1H), 7.662
(t, J = 7.55 Hz, 1H), 7.540 (d, J = 7.14 Hz, 2H), 7.462 (t,
J = 7.55 Hz, 2H), 7.320 (d, J = 7.14 Hz, 2H), 5.668 (s,
1H), 4.331 (d, J = 3.79 Hz, 2H), 4.176 (d, J = 6.40 Hz,
2H), 2.953 (s, 1H). In the NOE experiment no NOE was
observed. 13C NMR (DMSO-d6): d (ppm) = 169.564,
137.718, 135.734, 133.533, 132.682, 129.668, 128.876,
128.749, 127.743, 102.496, 74.868, 47.225. EI-MS (m/e):

4788
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
(DMSO-d6):
d
(ppm) = 168.921, 148.964, 145.550,
4.1.27. (2S,4S,5R)- and (2R,4S,5R)-[2-(40-Methylphe-
nyl)-4-methyl-1,3-dioxan-5-yl]benzamide (5g and 50g).
Using the same procedure for the preparation of 5a
and 50a, from 100 mg (0.48 mmol) of 300b and 102 mg
(0.85 mmol) of 4-methylbenzaldehyde, 96 mg (65%) of
5g and 11 mg (7%) of 50g were obtained.
133.435, 131.207, 128.684, 128.024, 127.241, 124.306,
101.124, 74.413, 46.323. EI-MS (m/e) 328 [M]+. Anal.
Calcd for C17H16N2O5: C, 62.18; H, 4.91; N, 8.53.
Found: C, 62.11; H, 4.80; N, 8.44.
Compound 50e. Mp 130–132 ꢁC. IR (KBr):
t
(cmꢀ1) = 3282, 3017, 2920, 2866, 1655, 1620, 1603,
1580, 1524, 1451, 1352, 1194, 1072, 861, 767, 745, 696.
1H NMR (CDCl3) d (ppm) = 8.326 (s, 1H), 8.315 (d,
J = 9.03 Hz, 1H), 8.046 (d, J = 7.55 Hz, 2H), 7.818 (s,
1H), 7.805 (d, J = 9.03 Hz, 1H), 7.647 (t, J = 7.55 Hz,
1H), 7.585 (t, J = 9.03 Hz, 1H), 7.553 (t, J = 7.55 Hz,
2H), 5.704 (s, 1H), 4.328 (d, J = 6.57 Hz, 2H), 4.251
(d, J = 6.36 Hz, 2H), 3.651 (m, J = 6.35 Hz, 1H). In
the NOE experiment no NOE was observed. 13C
Compound 5g. Colorless powder. Mp 152–154 ꢁC. IR
(KBr): t (cmꢀ1) = 3278, 3022, 2902, 2856, 1645, 1622,
1602, 1593, 1436, 1384, 1186, 1072, 822, 739, 696. H
1
NMR (CDCl3) d (ppm) = 8.014 (s, 1H), 7.969 (d,
J = 7.46 Hz, 2H), 7.540 (t, J = 7.46 Hz, 1H), 7.472 (d,
J = 7.40 Hz, 2H), 7.435 (t, J = 7.46 Hz, 2H), 7.258 (d,
J = 7.40 Hz, 2H), 5.612 (s, 1H), 4.240 (d, J = 4.50 Hz,
1H), 4.207 (d, J = 4.26 Hz, 1H), 4.138 (m, J = 6.00 Hz,
1H), 2.710 (m, J = 4.26 Hz, 1H), 2.403 (s, 3H), 1.313
(d, J = 6.00 Hz, 3H). In NOESY experiment, NOEs be-
tween the CH3 at the 4-position and the proton of phe-
nyl at the 2-position, and between the CH3 at the 4-
position and the NH at the 5-position were observed.
13C NMR (DMSO-d6): d (ppm) = 168.147, 138.656,
135.466, 135.160, 134.132, 129.403, 129.004, 128.914,
NMR (DMSO-d6):
d
(ppm) = 169.503, 149.536,
145.672, 133.864, 131.722, 129.006, 128.753, 127.823,
124.766, 101.843, 75.036, 46.975. EI-MS (m/e) 328
[M]+. Anal. Calcd for C17H16N2O5: C, 62.18; H, 4.91;
N, 8.53. Found: C, 62.11; H, 4.80; N, 8.44.
4.1.26. (2S,4S,5R)- and (2R,4S,5R)-(2-Phenyl-4-methyl-
1,3-dioxan-5-yl)benzamide (5f and 50f). Using the same
procedure for the preparation of 5a and 50a, from
100 mg (0.48 mmol) of 300b and 51 mg (0.85 mmol) of
benzaldehyde, 98 mg (69%) of 5f and 11 mg (8%) of
50f were obtained.
127.912, 102.783, 76.867, 75.112, 50.224, 22.121,
20
18.659. EI-MS (m/e) 309 [M]+. ½aꢁ ꢀ 14:2 (c 1.00,
D
CHCl3). Anal. Calcd for C19H21NO3: C, 73.29; H,
6.80; N, 4.50. Found: C, 73.47; H, 6.93; N, 4.32.
Compound 50g. Colorless powder. Mp 144–146 ꢁC. IR
(KBr): t (cmꢀ1) = 3276, 3021, 2900, 2857, 1648, 1620,
1600, 1595, 1434, 1381, 1185, 1070, 820, 737, 698. H
1
Compound 5f. Colorless powder. Mp 125–127 ꢁC. IR
(KBr): t (cmꢀ1) = 3285, 3013, 2925, 2864, 1652, 1622,
1601, 1582, 1382, 1192, 1070, 821. H NMR (CDCl3)
NMR (CDCl3) d (ppm) = 8.124 (s, 1H), 8.010 (d,
J = 7.52 Hz, 2H), 7.644 (t, J = 7.52 Hz, 1H), 7.621 (d,
J = 7.50 Hz, 2H), 7.538 (t, J = 7.50 Hz, 2H), 7.412 (d,
J = 7.50 Hz, 2H), 5.733 (s, 1H), 4.420 (d, J = 4.53 Hz,
1H), 4.318 (d, J = 4.30 Hz, 1H), 4.245 (m, J = 6.02 Hz,
1H), 2.844 (m, J = 4.30 Hz, 1H), 2.516 (s, 3H), 1.422
(d, J = 6.02 Hz, 3H). In the NOE experiment no NOE
1
d (ppm) = 8.014 (s, 1H), 7.943 (d, J = 7.55 Hz, 2H),
7.660 (t, J = 7.55 Hz, 1H), 7.578 (t, J = 7.55 Hz, 2H),
7.572 (d, J = 6.72 Hz, 2H), 7.430 (t, J = 6.68 Hz, 1H),
7.396 (t, J = 6.67 Hz, 2H), 5.573 (s, 1H), 4.281 (m,
J = 6.61 Hz, 1H), 4.220 (d, J = 4.52 Hz, 2H), 2.687 (t,
J = 4.52 Hz, 1H), 1.337 (d, J = 4.50 Hz, 3H). In NOESY
experiment, NOEs between the CH3 at the 4-position
and the proton of phenyl at the 2-position, and between
the CH3 at the 4-position and the NH at the 5-position
was
observed.
13C
NMR
(DMSO-d6):
d
(ppm) = 168.714, 139.121, 136.003, 135.542, 134.473,
129.922, 129.436, 129.114, 128.123, 103.535, 77.275,
75.536, 50.617, 22.685, 19.267. EI-MS (m/e) 309 [M]+.
20
D
were
(ppm) = 168.546, 137.153, 133.517, 132.106, 128.757,
observed.
13C
NMR
(DMSO-d6):
d
½aꢁ 12:7 (c 1.00, CHCl3). Anal. Calcd for C19H21NO3:
C, 73.29; H, 6.80; N, 4.50. Found: C, 73.11; H, 6.64;
N, 4.68.
128.523, 127.472, 127.259, 126.865, 102.560, 74.868,
20
58.764, 18.611. EI-MS (m/e) 295 [M]+. ½aꢁ ꢀ 13:5 (c
D
1.00, CHCl3). Anal. Calcd for C18H19NO3: C, 72.71;
H, 6.44; N, 4.71. Found: C, 72.53; H, 6.30; N, 4.90.
4.1.28. (2S,4S,5R)- and (2R,4S,5R)-[2-(40-Chlorophenyl)-
4-methyl-1,3-dioxan-5-yl]benzamide (5h and 50h). Using
the same procedure for the preparation of 5a and 50a
from 100 mg (0.48 mmol) of 300b and 102 mg
(0.85 mmol) of 4-chlorobenzaldehyde, 126 mg (85%) of
5h and 22 mg (15%) of 50h were obtained.
Compound 50f. Colorless powder. Mp 133–135 ꢁC. IR
(KBr): t (cmꢀ1) = 3283, 3011, 2927, 2862, 1650, 1620,
1
1603, 1580, 1381, 1190, 1072, 824. H NMR (CDCl3) d
(ppm) = 8.232 (s, 1H), 8.024 (d, J = 7.60 Hz, 2H), 7.769
(t, J = 7.60 Hz, 1H), 7.728 (t, J = 7.60 Hz, 2H), 7.680 (d,
J = 7.00 Hz, 2H), 7.593 (t, J = 7.00 Hz, 1H), 7.516 (t,
J = 7.00 Hz, 2H), 5.734 (s, 1H), 4.441 (m, J = 6.70 Hz,
1H), 4.361 (d, J = 4.60 Hz, 2H), 2.867 (t, J = 4.60 Hz,
1H), 1.473 (d, J = 4.60 Hz, 3H). In the NOE experiment
no NOE was observed. 13C NMR (DMSO-d6): d
(ppm) = 169.151, 137.936, 134.172, 132.915, 129.567,
Compound 5h. Colorless powder. Mp 125–127 ꢁC. IR
(KBr): t (cmꢀ1) = 3242, 3017, 1656, 1627, 1602, 1580,
1502, 1456, 823, 767, 699. 1H NMR (CDCl3) d
(ppm) = 8.104 (d, J = 7.46 Hz, 2H), 8.003 (s, 1H),
7.662 (t, J = 7.46 Hz, 1H), 7.501 (t, J = 7.46 Hz, 2H),
7.435 (t, J = 7.60 Hz, 2H), 7.414 (t, J = 7.60 Hz, 2H),
5.634 (s, 1H), 4.235 (m, J = 6.61 Hz, 1H), 4.217 (d,
J = 5.44 Hz, 2H), 2.752 (m, J = 4.62 Hz, 1H), 1.371 (d,
J = 6.61 Hz, 3H). In NOESY experiment, NOEs
between the CH3 at the 4-position and the proton of
phenyl at the 2-position, and between the CH3 at the
129.223, 128.117, 127.961, 127.546, 103.156, 75.286,
20
59.431, 19.161. EI-MS (m/e) 295 [M]+. ½aꢁ 14:7 (c 1.00,
D
CHCl3). Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44;
N, 4.71. Found: C, 72.89; H, 6.57; N, 4.52.

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4789
20
D
4-position and the NH at the 5-position were observed.
13C NMR (DMSO-d6): d (ppm) = 168.367, 137.876,
135.223, 135.138, 133.114, 132.403, 129.664, 128.700,
103.402, 73.581, 57.156, 19.226. ½aꢁ 28:5 (c 0.02,
CHCl3). EI-MS (m/e) 342 [M]+. Anal. Calcd for
C18H18N2O5: C, 63.15; H, 5.30; N, 8.18. Found: C,
63.21; H, 5.41; N, 8.09.
127.488, 102.136, 77.103, 74.615, 50.155, 18.347. EI-
20
MS (m/e) 330 [M]+. ½aꢁ ꢀ 13:1 (c 1.00, CHCl3). Anal.
D
Calcd for C18H18ClNO3: C, 65.16; H, 5.47; N, 4.22.
Found: C, 65.00; H, 5.61; N, 4.04.
4.1.30. (2S,4S,5R)- and (2R,4S,5R)-[2-(30-Nitrophenyl)-
4-methyl-1,3-dioxan-5-yl]benzamide (5j and 50j). Using
the same procedure for the preparation of 5a and 50a,
from 100 mg (0.48 mmol) of 300b and 73 mg (0.85 mmol)
of 3-nitrobenzaldehyde, 137 mg (84%) of 5j and 18 mg
(11%) of 50j were obtained.
Compound 50h. Colorless powder. Mp 120–122 ꢁC. IR
(KBr): t (cmꢀ1) = 3240, 3015, 1655, 1625, 1600, 1582,
1505, 1454, 821, 768, 697. 1H NMR (CDCl3) d
(ppm) = 8.198 (d, J = 7.48 Hz, 2H), 8.114 (s, 1H),
7.826 (t, J = 7.48 Hz, 1H), 7.595 (t, J = 7.48 Hz, 2H),
7.566 (t, J = 7.62 Hz, 2H), 7.523 (t, J = 7.62 Hz, 2H),
5.810 (s, 1H), 4.456 (m, J = 6.60 Hz, 1H), 4.373 (d,
J = 5.46 Hz, 2H), 2.912 (m, J = 4.64 Hz, 1H), 1.450 (d,
J = 6.60 Hz, 3H). In the NOE experiment no NOE
Compound 5j. Colorless powder. Mp 140–142 ꢁC. IR
(KBr): t (cmꢀ1) = 3281, 3017, 2925, 2862, 1656, 1620,
1602, 1580, 1525, 1453, 1381, 1352, 1190, 1071, 862,
1
767, 745, 699. H NMR (CDCl3) d (ppm) = 8.281 (d,
J = 8.40 Hz, 1H), 8.031 (s, 1H), 8.004 (s, 1H), 7.958 (d,
J = 7.52 Hz, 2H), 7.914 (d, J = 7.86 Hz, 1H), 7.672 (t,
J = 8.00 Hz, 1H), 7.543 (t, J = 7.52 Hz, 1H), 7.461 (t,
J = 7.52 Hz, 2H), 5.713 (s, 1H), 4.235 (m, J = 4.32 Hz,
1H), 4.217 (d, J = 2.76 Hz, 2H), 2.744 (m, J = 3.14 Hz,
1H), 1.397 (d, J = 4.67 Hz, 3H). In NOESY experiment,
NOEs between the CH3 at the 4-position and the proton
of phenyl at the 2-position, and between the CH3 at the
4-position and the NH at the 5-position were observed.
13C NMR (DMSO-d6): d (ppm) = 168.334, 149.271,
141.204, 133.652, 133.372, 132.151, 130.522, 128.773,
was
observed.
13C
NMR
(DMSO-d6):
d
(ppm) = 168.763, 138.165, 135.721, 135.524, 133.642,
132.933, 130.465, 129.535, 127.896, 102.643, 77.634,
75.155, 51.515, 19.432. EI-MS (m/e) 330 [M]+.
20
D
½aꢁ 10:9 (c 1.00, CHCl3). Anal. Calcd for
C18H18ClNO3: C, 65.16; H, 5.47; N, 4.22. Found: C,
65.34; H, 5.59; N, 4.39.
4.1.29. (2S,4S,5R)- and (2R,4S,5R)-[2-(40-Nitrophenyl)-
4-methyl-1,3-dioxan-5-yl]benzamide (5i and 50i). Using
the same procedure for the preparation of 5a and 50a,
from 100 mg (0.48 mmol) of 300b and 73 mg (0.85 mmol)
of 4-nitrobenzaldehyde, 139 mg (85%) of 5i and 20 mg
(12%) of 50i were obtained.
127.346, 124.827, 122.814, 100.178, 77.513, 75.276,
20
49.912, 18.864. EI-MS (m/e) 342 [M]+. ½aꢁ ꢀ 14:9 (c
D
1.00, CHCl3). Anal. Calcd for C18H18N2O5: C, 63.15;
H, 5.30; N, 8.18. Found: C, 63.27; H, 5.41; N, 8.27.
Compound 5i. Colorless powder, mp 90–92 ꢁC. IR
(KBr): t (cmꢀ1) = 3450, 3045, 2975, 2940, 2970, 1655,
1600, 1576, 1520, 1480, 1400, 1370, 1176, 1070, 741,
Compound 50j. Colorless powder. Mp 130–132 ꢁC. IR
(KBr): t (cmꢀ1) = 3283, 3016, 2924, 2864, 1653, 1622,
1600, 1585, 1526, 1450, 1383, 1354, 1192, 1072, 863,
1
694. 1H NMR (CDCl3)
d
(ppm) = 8.243 (d,
765, 747, 697. H NMR (CDCl3) d (ppm) = 8.370 (d,
J = 8.40 Hz, 2H), 7.939 (s, 1H), 7.848 (d, J = 7.40 Hz,
2H), 7.685 (t, J = 7.40 Hz, 1H), 7.486 (d, J = 8.40 Hz,
2H), 7.435 (t, J = 7.40 Hz, 2H), 5.787 (s, 1H), 4.639
(m, J = 3.94 Hz, 1H), 4.124 (d, J = 3.95 Hz, 2H), 3.697
(m, J = 4.02 Hz, 1H), 1.332 (d, J = 6.22 Hz, 3H). In
NOESY experiment, NOEs between the CH3 at the 4-
position and the proton of phenyl at the 2-position,
and between the CH3 at the 4-position and the NH at
the 5-position were observed. 13C NMR (DMSO-d6): d
(ppm) = 167.595, 147.511, 143.330, 133.484, 131.807,
J = 8.36 Hz, 1H), 8.133 (s, 1H), 8.012 (s, 1H), 7.987 (d,
J = 7.50 Hz, 2H), 7.967 (d, J = 7.82 Hz, 1H), 7.782 (t,
J = 7.92 Hz, 1H), 7.634 (t, J = 7.50 Hz, 1H), 7.516 (t,
J = 7.50 Hz, 2H), 5.831 (s, 1H), 4.354 (m, J = 4.34 Hz,
1H), 4.318 (d, J = 2.78 Hz, 2H), 2.802 (m, J = 3.16 Hz,
1H), 1.415 (d, J = 4.65 Hz, 3H). In the NOE experiment
no NOE was observed. 13C NMR (DMSO-d6): d
(ppm) = 168.878, 149.712, 141.625, 134.126, 133.743,
132.516, 131.121, 129.367, 127.863, 125.278, 123.418,
100.875, 78.135, 75.764, 50.988, 19.685. EI-MS (m/e)
20
342 [M]+. ½aꢁ 12:7 (c 1.00, CHCl3). Anal. Calcd for
128.669, 128.474, 127.344, 123.433, 103.212, 73.355,
D
20
D
56.898, 19.023. ½aꢁ ꢀ 15:4 (c 0.02, CHCl3). EI-MS
C18H18N2O5: C, 63.15; H, 5.30; N, 8.18. Found: C,
63.05; H, 5.24; N, 8.06.
(m/e) 342 [M]+. Anal. Calcd for C18H18N2O5: C, 63.15;
H, 5.30; N, 8.18. Found: C, 63.04; H, 5.23; N, 8.31.
4.1.31. (cis)- and (trans)-(2-Phenyl-1,3-dioxan-5-yl)pheny-
lacetamide (6a and 60a). The suspension of 418 mg
(2.0 mmol) of 2-phenylacetylaminopropane-1,3-diol(30a),
276 mg (2.6 mmol) of benzaldehyde, 30 mg of tolylsulf-
onylic acid, 100 mg of anhydrous Na2SO4, 50 ml of
chloroform, and 4 ml of THF was stirred at room
temperature overnight until the complete disappearance
of 300a indicated by TLC (CHCl3/CH3OH, 20:1). The
reaction mixture was adjusted to pH 7 with sodium
carbonate. The reaction mixture was filtered and the
filtrate was concentrated under reduced pressure. The
residue was purified by chromatography on silica gel to
provide 268 mg (45%) of 6a and 48 mg (8%) of 60a.
Compound 50i. Colorless powder, mp 112–114 ꢁC. IR
(KBr): t (cmꢀ1) = 3446, 3034, 2980, 2950, 2860, 1655,
1607, 1580, 1525, 1520, 1482, 1406, 1376, 1180, 1068,
1
790, 745, 690. H NMR (CDCl3) d (ppm) = 8.295 (d,
J = 8.52 Hz, 2H), 8.014 (s, 1H), 7.856 (t, J = 7.31 Hz,
2H), 7.695 (d, J = 8.52 Hz, 2H), 7.525 (t, J = 7.31 Hz,
1H), 7.481 (t, J = 7.31 Hz, 2H), 6.151 (s, 1H), 4.460
(m, J = 3.62 Hz, 1H), 4.260 (d, J = 2.75 Hz, 2H), 3.934
(m, J = 6.35 Hz, 1H), 1.368 (d, J = 6.3 Hz, 3H). In the
NOE experiment no NOE was observed. 13C NMR
(DMSO-d6): d (ppm) = 168.114, 147.603, 143.514,
133.506, 132.002, 128.876, 128.555, 127.801, 123.565,

4790
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
Compound 6a. Colorless powder, mp 150–152 ꢁC. IR
(KBr):
(cmꢀ1) = 3239, 1631, 1602, 1581, 1498,
1449, 761,699. 1H NMR (500 MHz, CDCl3):
J = 11.10 Hz, 1H), 3.581 (s, 2H), 2.322 (s, 3H). In the
t
NOE experiment no NOE was observed. 13C NMR
d
(DMSO-d6)
d
(ppm) = 167.737, 137.012, 136.021,
(ppm) = 8.001 (s, 1H), 7.232 (d, J = 7.52 Hz, 2H),
7.221 (t, J = 7.47 Hz, 1H), 7.189 (t, J = 7.52 Hz, 2H),
7.171 (t, J = 7.37 Hz, 2H), 7.103 (t, J = 7.39 Hz, 1H),
7.083 (d, J = 7.37 Hz, 2H), 5.898 (s, 1H,), 4.070 (d,
J = 4.41 Hz, 4H), 3.770 (d, J = 4.41 Hz, 1H), 3.644
(s, 2H). In the NOE experiment, a positive NOE
was observed between the NH-functionality at the
5-position and the proton of the phenyl at the 2-posi-
134.137, 129.820, 129.150, 129.027, 127.626, 127.415,
106.747, 74.631, 52.007, 40.100. EI-MS (m/e): 311
[M]+. Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80;
N 4.50. Found: C, 73.37; H, 6.92; N 4.68.
4.1.33. (cis)- and (trans)-[2-(40-Chlorophenyl)-1,3-dioxan-
5-yl]phenylacetamide (6c and 60c). Using the same proce-
dure for the preparation of 6a and 60a, from 365 mg
(2.6 mmol) of 4-chlorobenzaldehyde, 331 mg (50%) of
6c and 66 mg (10%) of 60c were obtained.
tion. 13C NMR (DMSO-d6)
d
(ppm) = 167.626,
136.967, 135.850, 129.841, 129.111, 128.393, 127.690,
127.644, 127.384, 105.978, 73.889, 51.867, 40.089.
EI-MS (m/e): 297 [M]+. Anal. Calcd for C18H19NO3:
C, 72.71; H, 6.44; N 4.71. Found: C, 72.57; H, 6.58;
N 4.75.
Compound 6c. Colorless powder, mp 170–172 ꢁC. IR
(KBr):
t
(cmꢀ1) = 3245,
3062,
1631,
1551,
1494,14571092, 829,705, 749. 1H NMR (500 MHz,
CDCl3): d (ppm) = 8.003 (s, 1H), 7.351 (d, J = 7.31 Hz,
2H), 7.153 (d, J = 7.22 Hz, 2H), 7.124 (d, J = 7.31 Hz,
2H), 7.071 (d, J = 7.22 Hz, 1H), 7.063 (d, J = 7.22 Hz,
2H), 5.457 (s, 1H), 4.061 (d, J = 4.61 Hz, 4H), 3.779
(m, J = 4.61 Hz, 1H), 3.449 (s, 2H). In the NOE
experiment, a positive NOE was observed between the
NH-functionality at the 5-position and the proton of
the phenyl at the 2-position. 13C NMR (DMSO-d6): d
(ppm) = 167.568, 135.879, 135.296, 132.897, 129.786,
129.203, 129.024, 128.792, 127.385, 105.994, 73.878,
51.882, 40.123. EI-MS (m/e): 345 [M]+. Anal. Calcd
for C19H20ClNO3: C, 65.99; H, 5.83; N 4.05. Found:
C, 66.17; H, 5.96; N 3.88.
Compound 60a. Colorless powder, mp 194–195 ꢁC. IR
(KBr): t (cmꢀ1) = 3237, 1651, 1603, 1581, 1500, 1452,
761, 699. 1H NMR (500 MHz, CDCl3):
d
(ppm) = 8.004 (s, 1H), 7.302 (d, J = 7.54 Hz, 2H),
7.225 (t, J = 7.49 Hz, 1H), 7.192 (t, J = 7.54 Hz, 2H),
7.176 (t, J = 7.40 Hz, 2H), 7.110 (t, J = 7.41 Hz, 1H),
7.088 (d, J = 7.39 Hz, 2H), 5.902 (s, 1H,), 4.075 (d,
J = 4.43 Hz, 4H), 3.774 (d, J = 4.43 Hz, 1H), 3.648 (s,
2H). In the NOE experiment no NOE was observed.
13C NMR (DMSO-d6) d (ppm) = 167.932, 137.079,
136.165, 130.221, 129.323, 128.681, 127.897, 127.718,
127.431, 106.124, 74.132, 52.213, 40.304. EI-MS (m/e):
297 [M]+. Anal. Calcd for C18H19NO3: C, 72.71; H,
6.44; N 4.71. Found: C, 72.87; H, 6.54; N 4.83.
Compound 60c. Colorless powder, mp 256–258 ꢁC. IR
(KBr): t (cmꢀ1) = 3275, 3062, 1647, 1543, 1494, 1455,
1
4.1.32. (cis)- and (trans)-[2-(40-Methylphenyl)-1,3-dioxan-
5-yl]phenylacetamide (6b and 60b). Using the same proce-
dure for the preparation of 6a and 60a, starting from
312 mg (2.6 mmol) of 4-methylbenzaldehyde, 261 mg
(42%) of 6b and 44 mg (7%) of 60b were obtained.
1099, 814, 766,705. H NMR (300 MHz, DMSO-d6): d
(ppm) = 8.113 (s, 1H), 7.430 (d, J = 7.31 Hz, 2H),
7.381 (d, J = 7.22 Hz, 2H), 7.312 (d, J = 7.31 Hz, 2H),
7.285 (d, J = 7.22 Hz, 1H), 7.270 (d, J = 7.22 Hz, 2H),
5.489 (s, 1H), 4.121 (d, J = 4.61 Hz, 4H), 3.620 (m,
J = 4.61 Hz, 1H), 3.369 (s, 2H). In the NOE experiment
no NOE was observed. 13C NMR (DMSO-d6): d
(ppm) = 167.730, 136.357, 135.631, 133.112, 130.124,
129.657, 129.586, 129.132, 127.771, 106.021, 74.105,
52.044, 40.346. EI-MS (m/e): 345 [M]+. Anal. Calcd
for C19H20ClNO3: C, 65.99; H, 5.83; N 4.05. Found:
C, 65.80; H, 5.71; N 3.89.
Compound 6b. Colorless powder, mp 185–187 ꢁC. IR
(KBr): t (cmꢀ1) = 3240, 1650, 1601, 1583, 1505, 1450,
1
1380, 820, 761,699. H NMR (500 MHz, DMSO-d6): d
(ppm) = 8.073 (s, 1H), 7.373 (d, J = 8.01 Hz, 2H),
7.281 (t, J = 7.81 Hz, 2H), 7.183 (d, J = 8.01 Hz, 2H),
7.081 (t, J = 7.81 Hz, 1H), 7.065 (t, J = 7.81 Hz, 2H),
5.981 (s, 1H), 4.108 (d, J = 11.05 Hz, 4H), 3.953 (d,
J = 11.05 Hz, 1H), 3.572 (s, 2H), 2.314 (s, 3H). In the
NOE experiment, a positive NOE was observed between
the NH-functionality at the 5-position and the proton of
the phenyl at the 2-position. 13C NMR (DMSO-d6) d
(ppm) = 167.564, 136.785, 135.901, 134.117, 129.794,
129.092, 128.976, 127.530, 127.407, 106.641, 73.882,
51.903, 40.080. EI-MS (m/e): 311 [M]+. Anal. Calcd
for C19H21NO3: C, 73.29; H, 6.80; N 4.50. Found: C,
73.15; H, 6.66; N 4.39.
4.1.34. (cis)- and (trans)-2-[40-Nitrophenyl]-1,3-dioxan-5-
yl]phenylacetamide (6d and 60d). Using the same proce-
dure for the preparation of 6a and 60a, from 302 mg
(2.0 mmol) of 4-nitrobenzaldehyde, 321 mg (47%) of
6d and 58 mg (8%) of 60d were obtained.
Compound 6d. Colorless powder, mp 201–203 ꢁC. IR
(KBr) 3266, 3018, 2917, 2854, 1659, 1617, 1602, 1575,
1
1543, 1457, 1191, 1065, 802, 724, 693 cmꢀ1. H NMR
(DMSO-d6) d (ppm) = 8.123 (d, J = 9.21 Hz, 2H),
7.956 (s, 1H), 7.486 (t, J = 9.21 Hz, 2H), 7.142 (t,
J = 6.91 Hz, 2H), 7.105 (t, J = 6.91 Hz, 1H), 7.057 (t,
J = 6.91 Hz, 2H), 5.816 (s, 1H), 4.027 (d, J = 5.31 Hz,
4H), 3.768 (t, J = 5.37 Hz, 1H), 3.385 (s, 2H). In the
NOE experiment, a positive NOE was observed between
the NH-functionality at the 5-position and the proton of
the phenyl at the 2-position. 13C NMR (DMSO-d6): d
Compound 60b. Colorless powder, mp 181–183 ꢁC. IR
(KBr):t (cmꢀ1) = 3242, 1651, 1600, 1580, 1502, 1451,
1382, 822, 760, 695. H NMR (500 MHz, DMSO-d6):
d (ppm) = 8.203 (s, 1H), 7.376 (d, J = 8.12 Hz, 2H),
7.287 (t, J = 7.83 Hz, 2H), 7.188 (d, J = 8.12 Hz, 2H),
7.086 (t, J = 7.83 Hz, 1H), 7.069 (t, J = 7.83 Hz, 2H),
5.985 (s, 1H), 4.114 (d, J = 11.10 Hz, 4H), 3.960 (d,
1

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4791
(ppm) = 167.541, 147.304, 142.982, 135.874, 129.784,
128.889, 128.422, 127.215, 105.813, 73.728, 51.869,
40.088. EI-MS (m/e): 342 [M]+. Anal. Calcd for
C18H18N2O5: C, 63.15; H, 5.30; N 8.18. Found: C,
63.27; H, 5.41; N 8.07.
same procedure for the preparation of 6a and 60a, from
448 mg (2.0 mmol) of 30b and 212 mg (0.85 mmol) of
benzaldehyde, 218 mg (35%) of 6f and 37 mg (6%) of
60f were obtained.
Compound 6f. Colorless powder. IR (KBr)
(cmꢀ1) = 3273, 3030,, 1653, 1622, 1550, 1545, 1541,
t
Compound 60d. Colorless powder, mp 107–109 ꢁC. IR
(KBr) 3271, 3023, 2920, 2856, 1654, 1622, 1558, 1546,
1
1430, 1382, 1066, 739, 696. Mp 144–146 ꢁC. H NMR
1
1542, 1437, 1186, 1071, 798, 715, 691 cmꢀ1. H NMR
(CDCl3)
d
(ppm) = 8.123 (s, 1H), 8.343 (d,
(DMSO-d6) d (ppm) = 8.126 (d, J = 9.32 Hz, 2H),
7.959 (s, 1H), 7.490 (t, J = 9.32 Hz, 2H), 7.149 (t,
J = 6.95 Hz, 2H), 7.111 (t, J = 6.95 Hz, 1H), 7.063 (t,
J = 6.95 Hz, 2H), 5.822 (s, 1H), 4.033 (d, J = 5.25 Hz,
4H), 3.791 (t, J = 5.27 Hz, 1H), 3.391 (s, 2H). In the
NOE experiment no NOE was observed. 13C NMR
J = 7.56 Hz, 2H), 7.925 (t, J = 7.56 Hz, 1H), 7.856 (t,
J = 7.56 Hz, 2H), 7.768 (d, J = 6.70 Hz, 2H), 7.685 (t,
J = 6.66 Hz, 1H), 7.598 (t, J = 6.66 Hz, 2H), 5.936 (s,
1H), 4.726 (m, J = 6.64 Hz, 1H), 4.603 (d, J = 4.54 Hz,
2H), 3.392 (s, 2H), 2.989 (t, J = 4.54 Hz, 1H), 1.574 (d,
J = 4.50 Hz, 3H). In NOESY experiment, NOEs
between the CH3 at the 4-position and the proton of
phenyl at the 2-position, and between the CH3 at the
4-position and the NH at the 5-position were observed.
13C NMR (DMSO-d6): d (ppm) = 169.645, 138.351,
134.176, 133.363, 129.574, 129.328, 128.731, 128.196,
(DMSO-d6):
d (ppm) = 167.721, 147.661, 143.143,
136.252, 130.004, 128.949, 128.615, 127.333, 106.036,
74.024, 52.362, 40.237. EI-MS (m/e): 342 [M]+. Anal.
Calcd for C18H18N2O5: C, 63.15; H, 5.30; N 8.18.
Found: C, 63.02; H, 5.18; N 8.32.
127.659, 103.607, 75.966, 59.653, 40.214, 19.540. EI-
20
MS (m/e) 311 [M]+. ½aꢁ ꢀ 14:7 (c 1.00, CHCl3). Anal.
4.1.35. (cis)- and (trans)-2-[30-Nitrophenyl]-1,3-dioxan-5-
yl]phenylacetamide (6e and 60e). Using the same proce-
dure for the preparation of 6a and 60a, from 302 mg
(2.0 mmol) of 3-nitrobenzaldehyde, 195 mg (45%) of 6e
and 28 mg (8%) of 60e were obtained.
D
Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50.
Found: C, 73.40; H, 6.69; N, 4.64.
Compound 60f. Colorless powder. IR (KBr)
t
(cmꢀ1) = 3274, 3032,, 1655, 1620, 1552, 1546, 1540,
1
Compound 6e. Mp 128–132 ꢁC. IR (KBr)
t
1432, 1380, 1064, 735, 693. Mp 156–158 ꢁC. H NMR
(cmꢀ1) = 3270, 3025, 2922, 2853, 1651, 1620, 1554,
1543, 1540, 1435, 1182, 1070, 860, 780, 715, 700, 691.
1H NMR (CDCl3) d (ppm) = 8.360 (s, 1H), 8.611 (d,
J = 9.00 Hz, 1H), 8.404 (d, J = 7.55 Hz, 2H), 8.216 (s,
1H), 7.928 (d, J = 9.00 Hz, 1H), 7.862 (t, J = 7.55 Hz,
1H), 7.764 (t, J = 9.00 Hz, 1H), 7.739 (t, J = 7.55 Hz,
2H), 5.818 (s, 1H), 4.740 (d, J = 6.58 Hz, 2H), 4.602
(d, J = 6.36 Hz, 2H), 3.952 (m, J = 6.35 Hz, 1H), 3.402
(s, 2H). In the NOE experiment, a positive NOE was ob-
served between the NH-functionality at the 5-position
and the proton of the phenyl at the 2-position. 13C
(CDCl3)
d
(ppm) = 8.350 (s, 1H), 8.401 (d,
J = 7.62 Hz, 2H), 7.964 (t, J = 7.62 Hz, 1H), 7.924 (t,
J = 7.62 Hz, 2H), 7.882 (d, J = 7.02 Hz, 2H), 7.759 (t,
J = 7.02 Hz, 1H), 7.718 (t, J = 7.02 Hz, 2H), 5.964 (s,
1H), 4.746 (m, J = 6.72 Hz, 1H), 4.675 (d, J = 4.62 Hz,
2H), 3.406 (s, 2H), 3.008 (t, J = 4.62 Hz, 1H), 1.638 (d,
J = 4.62 Hz, 3H). In the NOE experiment no NOE
was
(ppm) = 170.050, 138.954, 135.218, 133.862, 130.246,
observed.
13C
NMR
(DMSO-d6):
d
129.876, 129.535, 128.627, 128.152, 103.755, 76.168,
60.134, 40.567, 19.784. EI-MS (m/e) 311 [M]+.
20
D
NMR (DMSO-d6):
d
(ppm) = 169.812, 149.787,
½aꢁ 12:3 (c 1.00, CHCl3). Anal. Calcd for C19H21NO3:
146.605, 134.542, 132.323, 129.845, 128.943, 128.144,
125.363, 102.241, 75.530, 47.406, 40.138. EI-MS (m/e):
342 [M]+. Anal. Calcd for C18H18N2O5: C, 63.15; H,
5.30; N 8.18. Found: C, 63.22; H, 5.39; N 8.07.
C, 73.29; H, 6.80; N, 4.50. Found: C, 73.17; H, 6.89;
N, 4.61.
4.1.37. (2S,4S,5R)- and (2R,4S,5R)-[2-(40-Methylphe-
nyl)-4-methyl-1,3-dioxan-5-yl]phenyl-acetamide (6g and
60g). Using the same procedure for the preparation of
6a and 60a from 448 mg (2.0 mmol) of 30b and 240 mg
(2.0 mmol) of 4-methylbenzaldehyde, 208 mg (32%) of
6g and 33 mg (5%) of 60g were obtained.
Compound 60e. Mp 141–143 ꢁC. IR (KBr)
t
(cmꢀ1) = 3273, 3027, 2920, 2855, 1650, 1624, 1550,
1546, 1540, 1433, 1180, 1072, 862, 783, 712, 703, 690.
1H NMR (CDCl3) d (ppm) = 8.460 (s, 1H), 8.702 (d,
J = 9.00 Hz, 1H), 8.450 (d, J = 7.50 Hz, 2H), 8.304 (s,
1H), 7.985 (d, J = 9.00 Hz, 1H), 7.941 (t, J = 7.50 Hz,
1H), 7.856 (t, J = 9.00 Hz, 1H), 7.823 (t, J = 7.50 Hz,
2H), 5.920 (s, 1H), 4.882 (d, J = 6.55 Hz, 2H), 4.643
(d, J = 6.34 Hz, 2H), 3.967 (m, J = 6.33 Hz, 1H), 3.440
(s, 2H). In the NOE experiment no NOE was observed.
13C NMR (DMSO-d6): d (ppm) = 169.933, 149.864,
146.927, 134.747, 132.651, 130.160, 129.351, 128.730,
125.646, 102.448, 75.967, 47.568, 40.561. EI-MS (m/e):
342 [M]+. Anal. Calcd for C18H18N2O5: C, 63.15; H,
5.30; N 8.18. Found: C, 63.22; H, 5.41; N 8.07.
Compound 6g. Colorless powder. Mp 159–161 ꢁC. IR
(KBr) t (cmꢀ1) = 3271, 3032, 1650, 1621, 1552, 1543,
1540, 1432, 1385, 1064, 820, 738, 694. 1H NMR (CDCl3)
d (ppm) = 8.302 (s, 1H), 8.154 (d, J = 7.44 Hz, 2H), 7.891
(t, J = 7.44 Hz, 1H), 7.778 (d, J = 7.42 Hz, 2H), 7.717 (t,
J = 7.44 Hz, 2H), 7.681 (d, J = 7.42 Hz, 2H), 5.864 (s,
1H), 4.631 (d, J = 4.52 Hz, 1H), 4.426 (d, J = 4.28 Hz,
1H), 4.386 (m, J = 5.84 Hz, 1H), 3.434 (s, 2H), 2.996
(m, J = 4.28 Hz, 1H), 2.567 (s, 3H), 1.502 (d,
J = 5.84 Hz, 3H). In NOESY experiment, NOEs be-
tween the CH3 at the 4-position and the proton of phenyl
at the 2-position, and between the CH3 at the 4-position
and the NH at the 5-position were observed. 13C NMR
4.1.36. (2S,4S,5R)- and (2R,4S,5R)-(2-Phenyl-4-methyl-
1,3-dioxan-5-yl)phenyl-acetamide (6f and 60f). Using the

4792
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
(DMSO-d6):
135.908, 135.122, 130.310, 129.849, 129.635, 128.825,
d
(ppm) = 169.274, 139.523, 136.412,
133.872, 130.981, 130.150, 128.957, 103.638, 78.654,
75.817, 52.007, 40.560, 19.748. EI-MS (m/e) 345 [M]+.
20
D
103.694, 77.759, 76.122, 51.341, 40.483, 23.812, 19.502.
½aꢁ 12:3 (c 1.00, CHCl3). Anal. Calcd for
20
D
EI-MS (m/e) 325 [M]+. ½aꢁ ꢀ 13:6 (c 1.00, CHCl3).
C19H20ClNO3: C, 65.99; H, 5.83; N, 4.05. Found: C,
65.87; H, 5.74; N, 4.15.
Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30.
Found: C, 73.74; H, 7.01; N, 4.18.
4.1.39. (2S,4S,5R)- and (2R,4S,5R)-[2-(40-Nitrophenyl)-
4-methyl-1,3-dioxan-5-yl]phenyl-acetamide (6i and 60i).
Using the same procedure for the preparation of 6a and
60a, from 448 mg (2.0 mmol) of 30b and 302 mg
(2.0 mmol) of 4-nitrobenzaldehyde, 299 mg (42%) of 6i
and 50 mg (7%) of 60i were obtained.
Compound 60g. Colorless powder. Mp 125–127 ꢁC. IR
(KBr) t (cmꢀ1) = 3272, 3028,, 1654, 1620, 1552, 1546,
1543, 1431, 1380, 1068, 821, 737, 694. 1H NMR (CDCl3)
d (ppm) = 8.344 (s, 1H), 8.179 (d, J = 7.50 Hz, 2H),
7.962 (t, J = 7.50 Hz, 1H), 7.868 (d, J = 7.52 Hz, 2H),
7.757 (t, J = 7.52 Hz, 2H), 7.708 (d, J = 7.52 Hz, 2H),
5.902 (s, 1H), 4.664 (d, J = 4.55 Hz, 1H), 4.601 (d,
J = 4.34 Hz, 1H), 4.517 (m, J = 6.00 Hz, 1H), 3.505 (s,
2H), 3.014 (m, J = 4.32 Hz, 1H), 2.630 (s, 3H), 1.604
(d, J = 6.00 Hz, 3H). In the NOE experiment no NOE
Compound 6i. Colorless powder, mp 127–129 ꢁC. IR
(KBr) t (cmꢀ1) = 3450, 3045, 2975, 2940, 2970, 1655,
1600, 1576, 1520, 1480, 1400, 1370, 1176, 1070, 741,
694. 1H NMR (CDCl3)
d
(ppm) = 8.354 (d,
was
observed.
13C
NMR
(DMSO-d6):
d
J = 8.22 Hz, 2H), 8.196 (s, 1H), 8.025 (d, J = 7.46 Hz,
2H), 7.956 (t, J = 7.46 Hz, 1H), 7.795 (d, J = 8.22 Hz,
2H), 7.752 (t, J = 7.46 Hz, 2H), 5.873 (s, 1H), 4.831
(m, J = 3.96 Hz, 1H), 4.412 (d, J = 3.96 Hz, 2H), 3.905
(m, J = 4.10 Hz, 1H), 3.438 (s, 2H), 1.503 (d,
J = 6.20 Hz, 3H). In NOESY experiment, NOEs
between the CH3 at the 4-position and the proton of
phenyl at the 2-position, and between the CH3 at the
4-position and the NH at the 5-position were observed.
13C NMR (DMSO-d6): d (ppm) = 168.604, 148.537,
144.402, 134.510, 132.811, 129.591, 129.446, 128.429,
(ppm) = 169.740, 139.880, 136.912, 136.341, 135.720,
130.843, 130.265, 130.772, 129.100, 104.213, 77.968,
76.633, 51.761, 40.807, 23.576, 19.784. EI-MS (m/e)
20
325 [M]+. ½aꢁ 13:3 (c 1.00, CHCl3). Anal. Calcd for
D
C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C,
73.94; H, 7.20; N, 4.41.
4.1.38. (2S,4S,5R)- and (2R,4S,5R)-[2-(40-Chlorophenyl)-
4-methyl-1,3-dioxan-5-yl]phenyl-acetamide (6h and 60h).
Using the same procedure for the preparation of 6a and
60a, from 448 mg (2.0 mmol) of 30b and 280 mg
(2.0 mmol) of 4-chlorobenzaldehyde, 276 mg (40%) of
6h and 55 mg (8%) of 60h were obtained.
124.500, 104.304, 74.424, 57.887, 40.203, 19.346.
20
D
½aꢁ ꢀ 13:8 (c 0.02, CHCl3). EI-MS (m/e) 356 [M]+.
Anal. Calcd for C19H20N2O5: C, 64.04; H, 5.66; N,
7.86. Found: C, 64.11; H, 5.56; N, 7.78.
Compound 6h. Colorless powder. IR (KBr)
t
(cmꢀ1) = 3275, 3033, 1654, 1621, 1552, 1546, 1540,
1432, 1380, 1068, 822, 737, 694. Mp 137–139 ꢁC. 1H
NMR (CDCl3) d (ppm) = 8.303 (d, J = 7.50 Hz, 2H),
8.211 (s, 1H), 7.997 (t, J = 7.50 Hz, 1H), 7.879 (t,
J = 7.50 Hz, 2H), 7.750 (t, J = 7.62 Hz, 2H), 7.711 (t,
J = 7.62 Hz, 2H), 5.841 (s, 1H), 4.530 (m, J = 6.60 Hz,
1H), 4.510 (d, J = 5.46 Hz, 2H), 3.451 (s, 2H), 2.976
(m, J = 4.64 Hz, 1H), 1.517 (d, J = 6.40 Hz, 3H). In
NOESY experiment, NOEs between the CH3 at the 4-
position and the proton of phenyl at the 2-position,
and between the CH3 at the 4-position and the NH at
the 5-position were observed. 13C NMR (DMSO-d6): d
(ppm) = 169.471, 138.795, 136.312, 136.181, 134.315,
133.320, 130.545, 129.614, 128.503, 103.224, 78.231,
Compound 60i. Colorless powder, mp 120–122 ꢁC. IR
(KBr) t (cmꢀ1) = 3446, 3034, 2980, 2950, 2860, 1655,
1607, 1580, 1525, 1520, 1482, 1406, 1376, 1180, 1068,
1
790, 745, 690. H NMR (CDCl3) d (ppm) = 8.395 (d,
J = 8.24 Hz, 2H), 8.230 (s, 1H), 8.150 (t, J = 7.34 Hz,
2H), 7.995 (d, J = 8.24 Hz, 2H), 7.853 (t, J = 7.34 Hz,
1H), 7.787 (t, J = 7.34 Hz, 2H), 5.963 (s, 1H), 4.866
(m, J = 3.65 Hz, 1H), 4.672 (d, J = 2.78 Hz, 2H), 3.987
(m, J = 6.32 Hz, 1H), 3.515 (s, 2H), 1.567 (d,
J = 6.34 Hz, 3H). In the NOE experiment no NOE
was
observed.
13C
NMR
(DMSO-d6):
d
(ppm) = 169.122, 148.637, 144.564, 134.750, 133.127,
129.868, 129.651, 128.821, 124.671, 104.523, 74.586,
20
58.120, 40.601, 19.664. ½aꢁ 18:3 (c 0.02, CHCl3). EI-
D
75.526, 51.204, 40.097, 19.425. EI-MS (m/e) 345 [M]+.
MS (m/e) 356 [M]+. Anal. Calcd for C19H20N2O5: C,
64.04; H, 5.66; N, 7.86. Found: C, 63.94; H, 5.72; N,
7.90.
20
D
½aꢁ ꢀ 10:6 (c 1.00, CHCl3). Anal. Calcd for
C19H20ClNO3: C, 65.99; H, 5.83; N, 4.05. Found: C,
66.08; H, 5.72; N, 4.12.
4.1.40. (2S,4S,5R)- and (2R,4S,5R)-[2-(30-Nitrophenyl)-
4-methyl-1,3-dioxan-5-yl]phenylacetamide (6j and 60j).
Using the same procedure as that for preparation
of 6a and 60a, from 448 mg (2.0 mmol) of 30b
and 302 mg (2.0 mmol) of 3-nitrobenzaldehyde,
315 mg (46%) of 6j and 55 mg (8%) of 60j were
obtained.
Compound 60h. Colorless powder. Mp 129–131 ꢁC. IR
(KBr) t (cmꢀ1) = 3271, 3032, 1654, 1625, 1551, 1546,
1540, 1432, 1383, 1064, 823, 738, 697. 1H NMR (CDCl3)
d (ppm) = 8.387 (d, J = 7.50 Hz, 2H), 8.305 (s, 1H),
8.031 (t, J = 7.50 Hz, 1H), 7.899 (t, J = 7.50 Hz, 2H),
7.820 (t, J = 7.60 Hz, 2H), 7.806 (t, J = 7.60 Hz, 2H),
5.892 (s, 1H), 4.764 (m, J = 6.59 Hz, 1H), 4.631 (d,
J = 5.48 Hz, 2H), 3.601 (s, 2H), 3.008 (m, J = 4.66 Hz,
1H), 1.785 (d, J = 6.45 Hz, 3H). In the NOE experiment
no NOE was observed. 13C NMR (DMSO-d6): d
(ppm) = 169.676, 139.615, 136.748, 136.558, 134.753,
Compound 6j. Colorless powder. Mp 147–149 ꢁC. IR
(KBr) t (cmꢀ1) = 3273, 3027, 2925, 2854, 1653, 1622,
1550, 1545, 1540, 1432, 1382, 1185, 1072, 862, 781,
1
713, 702, 695. H NMR (CDCl3) d (ppm) = 8.324 (d,

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4793
J = 8.42 Hz, 1H), 8.213 (s, 1H), 8.200 (d, J = 7.50 Hz,
2H), 8.112 (d, J = 8.01 Hz, 1H), 7.927 (t, J = 8.01 Hz,
2H), 7.831 (t, J = 7.54 Hz, 1H), 7.715 (t, J = 7.50 Hz,
2H), 5.764 (s, 1H), 4.530 (m, J = 4.34 Hz, 1H), 4.465
(d, J = 2.78 Hz, 2H), 3.427 (s, 2H), 2.913 (m,
J = 3.16 Hz, 1H), 1.424 (d, J = 4.65 Hz, 3H). In NOESY
experiment, NOEs between the CH3 at the 4-position
and the proton of phenyl at the 2-position, and between
the CH3 at the 4-position and the NH at the 5-position
131.769, 128.586, 128.268, 127.653, 127.307, 126.941,
124.589, 74.365, 52.437. EI-MS (m/e) 309 [M]+. Anal.
Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53.
Found: C, 73.64; H, 6.06; N, 4.61.
Compound 70a. Colorless powder, mp 115–117 ꢁC. IR
(KBr):
t
(cmꢀ1) = 3251, 3190, 3032, 1675, 1645,
1637, 1456, 1044, 742, 697. 1H NMR (500 MHz,
CDCl3): (ppm) = 8.01 (s, 1H), 7.772 (d,
d
were
observed.
13C
NMR
(DMSO-d6):
d
J = 7.51 Hz, 2H), 7.510 (t, J = 6.90 Hz, 1H), 7.451 (t,
J = 8.70 Hz, 2H), 7.434 (d, J = 6.90 Hz, 2H), 7.338
(t, J = 6.00 Hz, 2H), 7.299 (d, J = 6.00 Hz, 1H),
6.823 (d, J = 16.20 Hz, 1H), 6.134 (d, J = 16.20 Hz,
1H), 5.124 (d, J = 4.32 Hz, 1H), 4.134 (d,
J = 6.91 Hz, 4H), 3.688 (m, J = 6.51 Hz, 1H). In the
NOE experiment no NOE was observed. 13C NMR
(ppm) = 169.432, 150.126, 142.149, 134.726, 134.325,
133.144, 131.500, 129.745, 128.633, 125.782, 123.840,
101.226, 76.533, 76.163, 50.129, 40.113, 19.648. EI-MS
20
(m/e) 356 [M]+. ½aꢁ ꢀ 12:8 (c 1.00, CHCl3). Anal.
D
Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86.
Found: C, 63.96; H, 5.56; N, 7.95.
(CDCl3):
d
(ppm) = 167.304, 134.501, 133.120,
Compound 60j. Colorless powder. Mp 140–142 ꢁC. IR
(KBr) t (cmꢀ1) = 3271, 3025, 2928, 2852, 1655, 1621,
1552, 1546, 1541, 1434, 1381, 1187, 1070, 861, 782,
131.204, 128.316, 128.009, 127.312, 127.101, 126.515,
124.234, 74.073, 52.130. EI-MS (m/e) 309 [M]+. Anal.
Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53.
Found: C, 73.86; H, 6.28; N, 4.65.
1
715, 704, 697. H NMR (CDCl3) d (ppm) = 8.347 (d,
J = 8.30 Hz, 1H), 8.221 (s, 1H), 8.219 (d, J = 7.52 Hz,
2H), 8.148 (d, J = 7.80 Hz, 1H), 7.984 (t, J = 7.90 Hz,
2H), 7.884 (t, J = 7.52 Hz, 1H), 7.761 (t, J = 7.52 Hz,
2H), 5.897 (s, 1H), 4.627 (m, J = 4.36 Hz, 1H), 4.582
(d, J = 2.76 Hz, 2H), 3.560 (s, 2H), 2.960 (m,
J = 3.18 Hz, 1H), 1.466 (d, J = 4.64 Hz, 3H). In the
NOE experiment no NOE was observed. 13C NMR
4.1.42. (2S,4S,5R)- and (2R,4S,5R)-[2-(E-Phenylvinyl)-4-
methyl-1,3-dioxan-5-yl]benzamide (7b and 70b). Using the
same procedure for the preparing 7a and 70a, from
418 mg (2.0 mmol) of 2-benzoylamino-3-methyl-1,3-dib-
utanol (300b), 517 mg (80%) of 7b and 65 mg (10%) of 70b
were obtained.
(DMSO-d6):
135.160, 134.758, 133.559, 131.967, 130.335, 128.826,
d (ppm) = 169.887, 150.723, 142.653,
Compound 7b. Colorless powder, mp 123–125 ꢁC. IR
(KBr): t (cmꢀ1) = 3252, 3190, 3031, 1675, 1646, 1637,
1454, 1381, 1049, 740, 696. 1H NMR (500 MHz,
CDCl3): d (ppm) = 8.006 (s, 1H), 7.364 (d, J = 6.91 Hz,
2H), 7.297 (t, J = 6.00 Hz, 2H), 7.244 (t, J = 6.91 Hz,
1H), 7.238 (d, J = 6.91 Hz, 2H), 7.186 (t, J = 6.00 Hz,
2H), 7.015 (d, J = 6.00 Hz, 1H), 6.575 (d,
J = 15.90 Hz, 1H), 6.366 (d, J = 15.90 Hz, 1H), 5.313
(d, J = 5.28 Hz, 1H), 4.346 (d, J = 5.71 Hz, 1H), 4.334
(d, J = 6.91 Hz, 2H), 3.878 (m, J = 6.61 Hz, 1H), 1.218
(d, J = 6.10 Hz, 3H). In NOESY experiment, NOEs
between the CH3 at the 4-position and the proton of
phenyl at the 2-position, and between the CH3 at the
4-position and the NH at the 5-position were observed.
126.186, 124.146, 101.857, 77.152, 76.745, 50.868,
20
40.691, 20.547. EI-MS (m/e) 356 [M]+. ½aꢁ 13:1 (c
D
1.00, CHCl3). Anal. Calcd for C19H20N2O5: C, 64.04;
H, 5.66; N, 7.86. Found: C, 64.13; H, 5.75; N, 7.95.
4.1.41. (cis)- and (trans)-[2-(E-Phenylvinyl)-1,3-dioxan-5-
yl]benzamide (7a and 70a). The suspension of 390 mg
(2.0 mmol) of 300a, 343 mg (2.6 mmol) of E-phenylvinyl
aldehyde, 30 mg of tolylsulfonylic acid, 100 mg of anhy-
drous NaSO4, and 50 ml of chloroform was stirred at
room temperature for 12 h until the complete disappear-
ance of 300a indicated by TLC (CHCl3/CH3OH, 20:1).
The reaction mixture was then adjusted to pH 7 with
NaHCO3. The reaction mixture was filtered and the fil-
trate was concentrated under reduced pressure. The res-
idue was purified by chromatography on silica gel
(CHCl3/CH3OH, 30:1) to provide 439 mg (71%) of 7a
and 62 mg (10%) of 70a.
13C NMR (CDCl3):
d (ppm) = 167.513, 134.768,
133.491, 131.842, 128.527, 128.183, 127.517, 127.047,
126.848, 126.207, 124.483, 105.438, 73.892, 73.751,
20
D
57.004, 18.625. ½aꢁ 24:1 (c 0.02, CHCl3). EI-MS (m/e)
323 [M]+. Anal. Calcd for C20H21NO3: C, 74.28; H,
6.55; N, 4.33. Found: C, 74.40; H, 6.68; N, 4.19.
Compound 7a. Colorless powder, mp 119–121 ꢁC. IR
(KBr):
t
(cmꢀ1) = 3250, 3191, 3030, 1673, 1646,
Compound 70b. Colorless powder. Mp.116–118 ꢁC. IR
(KBr): t (cmꢀ1) = 3250, 3188, 3032, 1673, 1645, 1636,
1453, 1380, 1048, 741, 694. 1H NMR (500 MHz,
CDCl3): d (ppm) = 8.009 (s, 1H), 7.833 (d, J = 6.30 Hz,
2H), 7.507 (d, J = 6.60 Hz, 2H), 7.412 (t, J = 6.30 Hz,
2H), 7.295 (d, J = 6.60 Hz, 2H), 7.191 (t, J = 6.60 Hz,
1H), 7.024 (d, J = 6.30 Hz, 1H), 6.840 (d,
J = 16.40 Hz, 1H), 6.242 (d, J = 16.40 Hz, 1H), 5.298
(d, J = 5.20 Hz, 1H), 4.305 (d, J = 6.50 Hz, 1H), 4.119
(m, J = 9.60 Hz, 2H), 3.641 (m, J = 6.30 Hz, 1H),
1.220 (d, J = 6.00 Hz, 3H). In the NOE experiment no
1639, 1455, 1047, 740, 695. 1H NMR (500 MHz,
CDCl3): (ppm) = 8.024 (s, 1H), 7.844 (d,
d
J = 6.66 Hz, 2H), 7.466 (t, J = 5.46 Hz, 1H), 7.409
(d, J = 6.66 Hz, 2H), 7.336 (t, J = 7.52 Hz, 2H),
7.287 (t, J = 6.081 Hz, 1H), 7.185 (d, J = 6.58 Hz,
2H), 6.814 (d, J = 16.20 Hz, 1H), 6.204 (d,
J = 16.20 Hz, 1H), 5.526 (d, J = 3.32 Hz, 1H), 4.175
(d, J = 6.41 Hz, 4H), 4.032 (m, J = 6.51 Hz, 1H). In
the NOE experiment, a positive NOE was observed
between the NH-functionality at the 5-position and
the proton of the phenyl at the 2-position. 13C
NMR (CDCl3): d (ppm) = 167.584, 134.722, 133.387,
NOE was observed. 13C NMR (CDCl3):
(ppm) = 167.307, 134.381, 133.207, 131.502, 128.214,
d

4794
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
128.001, 127.303, 126.988, 126.453, 126.003, 124.136,
1456, 1382, 1048, 742, 695. 1H NMR (300 MHz,
CDCl3): d (ppm) = 7.88 (s, 1H), 7.29 (d, J = 7.47 Hz,
2H), 7.24 (t, J = 7.47 Hz, 2H), 7.16 (t, J = 7.33 Hz,
2H), 7.14 (t, J = 7.47 Hz, 1H), 7.08 (t, J = 7.33 Hz,
1H), 7.05 (d, J = 7.33 Hz, 2H), 6.63 (d, J = 12.12 Hz,
1H), 6.25 (dd, J = 12.12 Hz, J = 6.00 Hz, 1H), 5.23 (d,
J = 6.00 Hz, 1H), 4.42 (m, J = 4.65 Hz, 1H), 4.02 (d,
J = 4.65 Hz, 2H), 3.72 (m, J = 4.65 Hz, 1H), 3.421 (s,
2H), 1.22 (d, J = 4.88 Hz, 3H). In NOESY experiment,
NOEs between the CH3 at the 4-position and the proton
of phenyl at the 2-position, and between the CH3 at the
4-position and the NH at the 5-position were observed.
20
105.143, 73.287, 73.175, 56.791, 18.256. ½aꢁ ꢀ 18:2 (c
D
0.02, CHCl3). EI-MS (m/e) 323 [M]+. Anal. Calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C,
74.18; H, 6.39; N, 4.45.
4.1.43. (cis)- and (trans)-[2-(E-Phenylvinyl)-1,3-dioxan-5-
yl]phenylacetamide (8a and 80a). The suspension of
418 mg (2.0 mmol) of 30a, 343 mg (2.6 mmol) of E-phe-
nylvinyl aldehyde, 30 mg of tolylsulfonylic acid, 100 mg
of anhydrous NaSO4, and 50 ml of chloroform was stir-
red at room temperature for overnight until the com-
plete disappearance of 30a indicated by TLC (CHCl3/
CH3OH, 20:1). The reaction mixture then adjusted to
pH 7 with NaHCO3. The reaction mixture was filtered
and the filtrate was concentrated under reduced pres-
sure. The residue was purified by chromatography on
silica gel (CHCl3/CH3OH, 30:1) to provide 262 mg
(40%) of 8a and 52 mg (8%) of 80a.
13C NMR (CDCl3):
d (ppm) = 169.874, 135.462,
134.847, 129.661, 128.973, 128.214, 127.651, 127.332,
126.957, 124.351, 104.979, 73.910, 73.801, 56.517,
18.769. EI-MS (m/e): 337 [M]. Anal. Calcd for
C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C,
74.61; H, 6.71; N, 4.28.
Compound 80b. Colorless powder, mp 141–143 ꢁC. IR
(KBr): t (cmꢀ1) = 3251, 3190, 3031, 1675, 1642, 1633,
1457, 1381, 1049, 740, 696. 1H NMR (300 MHz,
Compound 8a. Colorless powder, mp 135–136 ꢁC. IR
(KBr): t (cmꢀ1) = 3248, 3189, 3032, 1675, 1644, 1637,
1
1458, 1049, 741, 694. H NMR (300 MHz, CDCl3): d
CDCl3):
d
(ppm) = 7.86 (s, 1H), 7.26 (d,
(ppm) = 8.02 (s, 1H), 7.33 (d, J = 7.66 Hz, 2H), 7.22 (t,
J = 7.66 Hz, 2H), 7.16 (t, J = 7.66 Hz, 1H), 7.14 (t,
J = 7.38 Hz, 2H), 7.10 (t, J = 7.38 Hz, 1H), 7.07 (d,
J = 7.38 Hz, 2H), 6.73 (d, J = 16.20 Hz, 1H), 6.48 (dd,
J = 16.20 Hz, J = 4.82 Hz, 1H), 5.14 (d, J = 4.82 Hz,
1H), 4.02 (d, J = 5.01 Hz, 4H), 3.78 (m, J = 5.01 Hz,
1H), 3.620 (s, 2H). In the NOE experiment, a positive
NOE was observed between the NH-functionality at
the 5-position and the proton of the phenyl at the 2-posi-
tion. 13C NMR (CDCl3):d (ppm) = 169.884, 135.458,
134.820, 129.713, 128.794, 128.230, 127.524, 127.030,
126.883, 124.341, 105.927, 74.329, 52.007, 39.968. EI-
MS (m/e) 323 [M]+. Anal. Calcd for C20H21NO3: C,
74.28; H, 6.55; N, 4.33. Found: C, 74.16; H, 6.68; N, 4.17.
J = 7.45 Hz, 2H), 7.20 (t, J = 7.45 Hz, 2H), 7.12 (t,
J = 7.31 Hz, 2H), 7.10 (t, J = 7.45 Hz, 1H), 7.06 (t,
J = 7.31 Hz, 1H), 7.02 (d, J = 7.31 Hz, 2H), 6.61 (d,
J = 12.38 Hz, 1H), 6.22 (dd, J = 12.38 Hz, J = 6.12
Hz, 1H), 5.27 (d, J = 6.12 Hz, 1H), 4.46 (m,
J = 4.88 Hz, 1H), 4.06 (d, J = 4.88 Hz, 2H), 3.78 (m,
J = 4.61 Hz, 1H), 3.460 (s, 2H), 1.24 (d, J = 4.88 Hz,
3H). In the NOE experiment no NOE was observed.
13C NMR (CDCl3):
d (ppm) = 169.212, 135.170,
134.230, 129.241, 128.537, 128.009, 127.307, 127.112,
126.535, 124.107, 104.651, 73.682, 73.531, 56.304,
18.447. EI-MS (m/e): 337 [M]. Anal. Calcd for
C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C,
74.87; H, 6.96; N, 4.05.
Compound 80a. Colorless powder, mp 150–152 ꢁC. IR
(KBr): t (cmꢀ1) = 3247, 3188, 3030, 1673, 1645, 1638,
1456, 1047, 743, 695. H NMR (300 MHz, CDCl3): d
4.1.45. (2S,5S)- and (2R,5S)-2-(40-Chlorophenyl-1,3-
dioxaheptan-5-yl)phenyl-acetamide (9c and 90c). Using
the same procedure for preparing 8a and 80a, from
161 mg (0.72 mmol) of 30c and 105 mg (0.72 mmol) of
4-chlorobenzaldehyde, 77 mg (30%) of 9c and 36 mg
(14%) of 90c were obtained.
1
(ppm) = 8.00 (s, 1H), 7.28 (d, J = 7.42 Hz, 2H), 7.18 (t,
J = 7.42 Hz, 2H), 7.12 (t, J = 7.42 Hz, 1H), 7.10 (t,
J = 7.34 Hz, 2H), 7.08 (t, J = 7.34 Hz, 1H), 7.04 (d,
J = 7.34 Hz, 2H), 6.76 (d, J = 11.54 Hz, 1H), 5.72 (dd,
J = 11.54 Hz, J = 7.32 Hz, 1H), 5.24 (d, J = 4.82 Hz,
1H), 3.96 (d, J = 5.01 Hz, 4H), 3.88 (m, J = 5.01 Hz,
1H), 3.660 (s, 2H). In the NOE experiment no NOE
was observed. 13C NMR (CDCl3): d (ppm) = 169.267,
135.124, 134.463, 129.506, 128.373, 128.007, 127.307,
126.994, 126.356, 124.107, 105.612, 74.007, 51.981,
39.634. EI-MS (m/e) 323 [M]+. Anal. Calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C,
74.32; H, 6.70; N, 4.20.
Compound 9c. Colorless powder, mp 132–134 ꢁC. IR
(KBr): t (cmꢀ1) = 3325, 3042, 2963, 2918, 2841, 1640,
1600, 1555, 1460, 1372, 1172, 1050, 822, 745, 693. H
1
NMR (CDCl3) d (ppm) = 7.376 (s, 1H), 7.199 (d,
J = 7.50 Hz, 2H), 7.138 (t, J = 7.54 Hz, 2H), 7.127 (d,
J = 7.50 Hz, 2H), 7.068 (d, J = 7.50 Hz, 1H), 7.045 (d,
J = 7.50 Hz, 2H), 5.542 (s, 1H), 4.017 (m, J = 4.34 Hz,
1H), 3.588 (d, J = 4.34 Hz, 2H), 3.468 (s, 2H), 3.371 (t,
J = 4.34 Hz, 2H), 1.671 (m, J = 4.34 Hz, 2H). In the
NOE experiment, a positive NOE was observed between
the NH-functionality at the 5-position and the proton of
the phenyl at the 2-position. 13C NMR (CDCl3): d
(ppm) = 169.778, 135.879, 135.346, 132.884, 129.901,
129.008, 128.976, 128.796, 127.572, 104.724, 69.329,
4.1.44. (2S,4S,5R)- and (2R,4S,5R)-[2-(E-phenylvinyl)-4-
methyl-1,3-dioxan-5-yl] phenylacetyl amide (8b and 80b).
Using the same procedure for preparing 8a and 80a,
from 446 mg (2.0 mmol) of 30b, 270 mg (40%) of 8b
and 52 mg (8%) of 80b were obtained.
58.271, 45.078, 33.073. EI-MS (m/e) 345 [M]+.
20
D
½aꢁ 13:7 (c 0.02, CHCl3). Anal. Calcd for
Compound 8b. Colorless powder, mp 125–127 ꢁC. IR
(KBr): t (cmꢀ1) = 3249, 3187, 3034, 1673, 1645, 1635,
C19H20ClNO3: C, 65.99; H, 5.83; N, 4.05. Found: C,
65.87; H, 5.69; N, 4.12.

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4795
Compound 90c. Colorless powder, mp 139–141 ꢁC. IR
(KBr): t (cmꢀ1) = 3322, 3041, 2966, 2916, 2843, 1641,
1602, 1552, 1450, 1376, 1162, 1053, 820, 742, 694. H
161 mg (0.72 mmol) of 30c and 108 mg (0.72 mmol) of
3-nitrobenzaldehyde, 67 mg (26%) of 9e and 36 mg
(14%) of 90e were obtained.
1
NMR (CDCl3) d (ppm) = 7.763 (s, 1H), 7.343 (d,
J = 7.52 Hz, 2H), 7.218 (t, J = 7.56 Hz, 2H), 7.271 (d,
J = 7.52 Hz, 2H), 7.186 (d, J = 7.52 Hz, 1H), 7.097 (d,
J = 7.52 Hz, 2H), 5.597 (s, 1H), 4.265 (m, J = 4.36 Hz,
1H), 3.659 (d, J = 4.36 Hz, 2H), 3.497 (s, 2H), 3.412 (t,
J = 4.36 Hz, 2H), 1.761 (m, J = 4.36 Hz, 2H). In the
NOE experiment no NOE was observed. 13C NMR
(CDCl3): d (ppm) = 169.957, 135.998, 135.634, 133.017,
129.986, 129.367, 129.048, 128.967, 127.891, 105.034,
Compound 9e. Colorless powder, mp 127–129 ꢁC. IR
(KBr):
t
(cmꢀ1) = 3316, 3032, 2967, 2922, 2852,
1646, 1610, 1560, 1525, 1465, 1369, 1351, 1164, 1048,
861, 776, 745, 692. 1H NMR (CDCl3)
d
(ppm) = 8.119 (s, 1H), 8.114 (d, J = 9.10 Hz, 1H),
8.004 (s, 1H), 7.577 (t, J = 9.10 Hz, 1H), 7.427 (d,
J = 9.10 Hz, 1H), 7.147 (t, J = 7.52 Hz, 2H), 7.074 (t,
J = 7.52 Hz, 1H), 7.059 (t, J = 7.52 Hz, 2H), 5.481 (s,
1H), 3.911 (m, J = 3.74 Hz, 1H), 3.561 (d,
J = 3.74 Hz, 2H), 3.464 (s, 2H), 3.337 (t, J = 3.65 Hz,
2H), 1.681 (m, J = 3.65 Hz, 2H). 13C NMR (CDCl3):
69.591, 58.720, 45.565, 33.472.EI-MS (m/e) 345 [M]+.
20
D
½aꢁ ꢀ 15:0 (c 0.02, CHCl3). Anal. Calcd for
C19H20ClNO3: C, 65.99; H, 5.83; N, 4.05. Found: C,
65.89; H, 5.79; N, 4.02.
d (ppm) = 170.512, 148.367, 138.087, 135.873,
133.654, 129.768, 129.314, 129.104, 128.961, 127.472,
4.1.46. (2S,5S)- and (2R,5S)-2-(40-Nitrophenyl-1,3-dioxa-
heptan-5-yl)phenylacetamide (9d and 90d). Using the
same procedure for preparing 8a and 80a, from 161 mg
(0.72 mmol) of 30c and 108 mg (0.72 mmol) of 4-nitro-
benzaldehyde, 56 mg (22%) of 9d and 28 mg (11%) of
90d were obtained.
122.647, 103.167, 69.394, 58.271, 45.137, 40.807,
20
D
33.096. ½aꢁ 13:7 (c 0.02, CHCl3). EI-MS (m/e) 356
[M]+. Anal. Calcd for C19H20N2O5: C, 64.04; H,
5.66; N, 7.86. Found: C, 63.90; H, 5.56; N, 7.95.
Compound 90e. Colorless powder, mp 135–137 ꢁC. IR
(KBr): t (cmꢀ1) = 3328, 3030, 2961, 2914, 2842, 1642,
1603, 1554, 1456, 1375, 1166, 1049, 861, 772, 741, 694.
1H NMR (CDCl3) d (ppm) = 8.327 (s, 1H), 8.241 (d,
J = 9.12 Hz, 1H), 8.009 (s, 1H), 7.752 (t, J = 9.12 Hz,
1H), 7.724 (d, J = 9.12 Hz, 1H), 7.471 (t, J = 7.54 Hz,
2H), 7.145 (t, J = 7.54 Hz, 1H), 7.097 (t, J = 7.54 Hz,
2H), 5.520 (s, 1H), 3.957 (m, J = 3.76 Hz, 1H), 3.607
(d, J = 3.76 Hz, 2H), 3.471 (s, 2H), 3.473 (t,
J = 3.66 Hz, 2H), 1.773 (m, J = 3.66 Hz, 2H). In the
NOE experiment no NOE was observed. 13C NMR
(CDCl3): d (ppm) = 170.769, 148.673, 138.768, 136.386,
133.892, 130.127, 129.761, 129.567, 129.154, 127.768,
Compound 9d. Colorless powder, mp 125–127 ꢁC. IR
(KBr): t (cmꢀ1) = 3315, 3046, 2973, 2915, 2854, 1646,
1603, 1564, 1521, 1464, 1370, 1351, 1175, 1051, 821,
742, 695. 1H NMR (CDCl3) d (ppm) = 8.141 (d,
J = 9.21 Hz, 2H), 7.803 (s, 1H), 7.454 (d, J = 9.21 Hz,
2H), 7.137 (t, J = 7.52 Hz, 2H), 7.072 (t, J = 7.52 Hz,
1H), 7.062 (t, J = 7.52 Hz, 2H), 5.477 (s, 1H), 3.908
(m, J = 3.64 Hz, 1H), 3.587 (d, J = 3.64 Hz, 2H), 3.471
(s, 2H), 3.377 (t, J = 3.67 Hz, 2H), 1.678 (m,
J = 3.66 Hz, 2H). In the NOE experiment, a positive
NOE was observed between the NH-functionality at
the 5-position and the proton of the phenyl at the 2-po-
sition. 13C NMR (CDCl3): d (ppm) = 169.898, 147.452,
143.268, 135.945, 130.121, 129.017, 128.422, 127.376,
122.957, 103.761, 69.834, 58.726, 45.738, 41.087,
20
D
33.692. ½aꢁ ꢀ 12:8 (c 0.02, CHCl3). EI-MS (m/e) 356
[M]+. Anal. Calcd for C19H20N2O5: C, 64.04; H, 5.66;
N, 7.86. Found: C, 64.00; H, 5.69; N, 8.00.
123.521, 104.153, 69.310, 58.212, 45.016, 33.063.
20
D
½aꢁ 16:8 (c 0.02, CHCl3). EI-MS (m/e) 356 [M]+. Anal.
Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86.
Found: C, 64.17; H, 5.54; N, 7.73.
4.1.48. (2S,5S)- and (2R,5S)-2-(4-Chlorophenyl-1,3-
dioxaheptan-5-yl)benzamide (10c and 100c). Using the
same procedure for the preparation of 8a and 80a, from
150 mg (0.72 mmol) of 300c and 101 mg (0.72 mmol) of 4-
chlorobenzaldehyde, 57 mg (25%) of 10c and 30 mg
(13%) of 100c were obtained.
Compound 90d. Colorless powder, mp 129–131 ꢁC. IR
(KBr): t (cmꢀ1) = 3310, 3051, 2960, 2910, 2845, 1640,
1602, 1520, 1456, 1370, 1351, 1165, 1050, 820, 738, 695
cmꢀ1
.
1H NMR (CDCl3)
d
(ppm) = 8.305 (d,
J = 9.24 Hz, 2H), 7.875 (s, 1H), 7.674 (d, J = 9.24 Hz,
2H), 7.378 (t, J = 7.55 Hz, 2H), 7.279 (t, J = 7.55 Hz,
1H), 7.260 (t, J = 7.55 Hz, 2H), 5.774 (s, 1H), 3.957
(m, J = 3.65 Hz, 1H), 3.875 (d, J = 3.65 Hz, 2H), 3.737
(t, J = 3.65 Hz, 2H), 3.490 (s, 2H), 1.892 (m,
J = 3.68 Hz, 2H). In the NOE experiment no NOE
was observed. 13C NMR (CDCl3): d (ppm) = 170.235,
147.824, 143.863, 136.007, 130.652, 129.712, 128.837,
Compound 10c. Colorless powder, mp 129–131 ꢁC. IR
(KBr): t (cmꢀ1) = 3315, 3046, 2967, 2915, 2844, 1642,
1603, 1560, 1528, 1462, 1375, 1174, 1052, 821, 743,
694. 1H NMR (CDCl3)
d
(ppm) = 7.949 (d,
J = 8.72 Hz, 2H), 7.514 (t, J = 8.72 Hz, 1H), 7.437 (d,
J = 8.72 Hz, 2H), 7.379 (s, 1H), 7.212 (d, J = 7.51 Hz,
2H), 7.127 (d, J = 7.51 Hz, 2H), 5.794 (s, 1H), 4.112
(d, J = 4.32 Hz, 4H), 3.764 (d, J = 4.32 Hz, 1H). In the
NOE experiment, a positive NOE was observed between
the NH-functionality at the 5-position and the proton of
the phenyl at the 2-position. 13C NMR (CDCl3): d
(ppm) = 166.712, 135.432, 135.301, 132.878, 131.907,
127.736, 124.007, 104.637, 69.727, 58.807, 45.612,
20
D
33.715. ½aꢁ ꢀ 15:6 (c 0.02, CHCl3). EI-MS (m/e) 356
[M]+. Anal. Calcd for C19H20N2O5: C, 64.04; H, 5.66;
N, 7.86. Found: C, 64.15; H, 5.70; N, 7.93.
129.072, 128.768, 128.569, 127.257, 105.642, 73.878,
20
D
4.1.47. (2S,5S)- and (2R,5S)-2-(30-Nitrophenyl-1,3-dioxa-
heptan-5-yl)phenylacetamide (9e and 90e). Using the same
procedure for the preparation of 8a and 80a, from
52.341. ½aꢁ 19:2 (c 0.02, CHCl3). EI-MS (m/e)
331[M]+. Anal. Calcd for C18H18ClNO3: C, 65.16; H,
5.47; N, 4.22. Found: C, 64.98; H, 5.32; N, 4.40.

4796
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
Compound 100c. Colorless powder, mp 134–136 ꢁC. IR
(KBr): t (cmꢀ1) = 3318, 3050, 2964, 2912, 2840, 1644,
1600, 1525, 1452, 1373, 1160, 1050, 822, 744, 695. H
3-nitrobenzaldehyde, 69 mg (28%) of 10e and 37 mg
(15%) of 100e were obtained.
1
NMR (CDCl3) d (ppm) = 7.981 (d, J = 8.74 Hz, 2H),
7.589 (t, J = 8.74 Hz, 1H), 7.472 (d, J = 8.74 Hz,
2H), 7.431 (s, 1H), 7.522 (d, J = 7.53 Hz, 2H), 7.353
(d, J = 7.53 Hz, 2H), 5.806 (s, 1H), 4.221 (d,
J = 4.36 Hz, 4H), 3.946 (d, J = 4.36 Hz, 1H). In the
NOE experiment no NOE was observed. 13C NMR
Compound 10e. Colorless powder, mp 114–116 ꢁC. IR
(KBr): t (cmꢀ1) = 3300, 3037, 2963, 2927, 2854, 1648,
1612, 1564, 1522, 1463, 1356, 1167, 1051, 860, 741,
1
695. H NMR (CDCl3) d (ppm) = 8.124 (s, 1H), 8.117
(d, J = 9.12 Hz, 1H), 8.007 (s, 1H), 7.907 (d,
J = 7.54 Hz, 2H), 7.572 (t, J = 9.07 Hz, 1H), 7.504 (t,
J = 7.54 Hz, 1H), 7.454 (d, J = 9.07 Hz, 1H), 7.437 (t,
J = 7.54 Hz, 2H), 5.478 (s, 1H), 3.907 (m, J = 3.72 Hz,
1H), 3.644 (d, J = 3.72 Hz, 2H), 3.364 (t, J = 3.60 Hz,
2H), 1.718 (m, J = 3.62 Hz, 2H). In the NOE experi-
ment, a positive NOE was observed between the NH-
functionality at the 5-position and the proton of the phe-
(CDCl3):
133.172, 132.314, 129.642, 129.140, 128.895, 127.735,
d
(ppm) = 167.013, 135.868, 135.912,
20
106.117, 74.115, 52.517. ½aꢁ ꢀ 16:4 (c 0.02, CHCl3).
D
EI-MS (m/e) 331 [M]+. Anal. Calcd for C18H18ClNO3:
C, 65.16; H, 5.47; N, 4.22. Found: C, 65.33; H, 5.59;
N, 4.04.
nyl at the 2-position. 13C NMR (CDCl3):
d
(ppm) = 167.521, 148.402, 138.004, 133.687, 133.515,
131.811, 129.278, 128.542, 127.274, 122.348, 103.146,
4.1.49. (2S,5S)- and (2R,5S)-2-(4-Nitrophenyl-1,3-dioxa-
heptan-5-yl)benzamide (10d and 100d). Using the same
procedure for the preparation of 8a and 80a, from
150 mg (0.72 mmol) of 300c and 108 mg (0.72 mmol) of
4-nitrobenzaldehyde, 62 mg (25%) of 10d and 32 mg
(13%) of 100d were obtained.
20
69.343, 58.107, 45.371, 33.004. ½aꢁ 17:9 (c 0.02, CHCl3).
D
EI-MS (m/e) 342 [M]+. Anal. Calcd for C18H18N2O5: C,
63.15; H, 5.30; N, 8.18. Found: C, 63.07; H, 5.19; N,
8.30.
Compound 10d. Colorless powder, mp 121–123 ꢁC. IR
(KBr): t (cmꢀ1) = 3301, 3040, 2970, 2920, 2850, 1645,
1609, 1562, 1525, 1460, 1372, 1351, 1170, 1048, 823,
740, 692. 1H NMR (CDCl3) d (ppm) = 8.223 (d,
J = 9.0 Hz, 2H), 7.892 (d, J = 7.5 Hz, 2H), 7.767 (s,
1H), 7.534 (t, J = 7.5 Hz, 1H), 7.465 (d, J = 9.0 Hz,
2H), 7.377 (t, J = 7.5 Hz, 2H), 5.789 (s, 1H), 4.512 (m,
J = 3.2 Hz, 1H), 4.064 (d, J = 3.2 Hz, 2H), 3.360 (t,
J = 3.0 Hz, 2H), 1.740 (m, J = 3.6 Hz, 2H). In the
NOE experiment, a positive NOE was observed between
the NH-functionality at the 5-position and the proton of
the phenyl at the 2-position. 13C NMR (CDCl3): d
(ppm) = 167.608, 145.602, 145.511, 133.499, 131.876,
Compound 100e. Colorless powder, mp 117–119 ꢁC. IR
(KBr): t (cmꢀ1) = 3307, 3034, 2964, 2919, 2849, 1645,
1609, 1557, 1522, 1459, 1351, 1162, 1051, 862, 739,
1
692. H NMR (CDCl3) d (ppm) = 8.301 (s, 1H), 8.245
(d, J = 9.14 Hz, 1H), 8.017 (s, 1H), 7.933 (d,
J = 7.57 Hz, 2H), 7.684 (t, J = 9.14 Hz, 1H), 7.584 (t,
J = 7.57 Hz, 1H), 7.497 (d, J = 9.14 Hz, 1H), 7.460 (t,
J = 7.57 Hz, 2H), 5.521 (s, 1H), 3.967 (m, J = 3.75 Hz,
1H), 3.687 (d, J = 3.75 Hz, 2H), 3.390 (t, J = 3.65 Hz,
2H), 1.731 (m, J = 3.66 Hz, 2H). In the NOE experiment
no NOE was observed. 13C NMR (CDCl3):
d
(ppm) = 168.057, 148.914, 138.537, 134.172, 133.700,
132.113, 129.644, 128.772, 127.901, 122.843, 103.643,
20
129.178, 128.611, 127.302, 123.255, 104.235, 69.001,
69.671, 58.710, 45.713, 33.410. ½aꢁ ꢀ 14:8 (c 0.02,
D
20
58.022, 49.116, 32.336. ½aꢁ 21:0 (c 0.02, CHCl3).
CHCl3). FAB-MS (m/e) 342 [M]+. Anal. Calcd for
C18H18N2O5: C, 63.15; H, 5.30; N, 8.18. Found: C,
63.25; H, 5.41; N, 8.08.
D
FAB-MS (m/e) 342 [M+H]+. Anal. Calcd for
C18H18N2O5: C, 63.15; H, 5.30; N, 8.18. Found: C,
63.26; H, 5.43; N, 8.06.
4.1.51. (2S,5S)- and (2R,5S)-2-(40-Chlorophenyl-1,3-
dioxaoctan-5-yl)benzamide (11c and 110c). Using the
same procedure for the preparation of 8a and 80a from
106 mg (0.47 mmol) of 300d and 66 mg (0.47 mmol) of
4-chlorobenzaldehyde, 55 mg (34%) of 11c and 23 mg
(14%) of 110c were obtained.
Compound 100d. Colorless powder, mp 124–126 ꢁC. IR
(KBr): t (cmꢀ1) = 3310, 3051, 2960, 2910, 2845, 1640,
1602, 1520, 1456, 1370, 1350, 1165, 1050, 822, 739,
1
694. H NMR (CDCl3) d (ppm) = 8.228 (d, J = 8.1 Hz,
2H), 8.003 (s, 1H), 7.815 (d, J = 7.8 Hz, 2H), 7.673 (d,
J = 7.8 Hz, 1H), 7.525 (t, J = 8.1 Hz, 2H), 7.457 (t,
J = 7.8 Hz, 2H), 5.531 (s, 1H), 3.934 (m, J = 3.3 Hz,
1H), 3.697 (d, J = 3.3 Hz, 2H), 3.379 (t, J = 4.1 Hz,
2H), 1.725 (m, J = 4.0 Hz, 2H). In the NOE experiment
Compound 11c. Colorless powder, mp 113–115 ꢁC. IR
(KBr): t (cmꢀ1) = 3316, 3035, 2934, 2853, 1655, 1633,
1600, 1584, 1502, 1454, 1382, 1195, 1050, 821, 741,
no NOE was observed. 13C NMR (CDCl3):
d
(ppm) = 168.331, 146.117, 145.880, 133.781, 132.070,
129.351, 129.006, 127.881, 123.704, 104.221, 68.541,
693 cmꢀ1 1H NMR (CDCl3) d (ppm) = 7.613 (d,
.
J = 7.51 Hz, 2H), 8.010 (s, 1H), 7.241 (t, J = 7.60 Hz,
1H), 7.131 (t, J = 7.60 Hz, 2H), 7.117 (d, J = 7.20 Hz,
2H), 7.044 (t, J = 7.20 Hz, 2H), 5.341 (s, 1H), 3.631
(m, J = 6.21 Hz, 1H), 3.520 (d, J = 6.51 Hz, 2H), 3.223
(t, J = 6.00 Hz, 2H), 1.507 (m, J = 6.01 Hz, 2H), 1.422
(m, J = 6.01 Hz, 2H). In the NOE experiment, a positive
NOE was observed between the NH-functionality at the
5-position and the proton of the phenyl at the 2-posi-
tion. 13C NMR (CDCl3): d (ppm) = 167.103, 135.210,
133.324, 132.767, 131.813, 129.003, 128.732, 128.303,
127.412, 104.251, 69.114, 63.317, 49.251, 28.430,
20
58.308, 49.414, 32.597. ½aꢁ ꢀ 19:3 (c 0.02, CHCl3).
D
FAB-MS (m/e) 342 [M+H]+. Anal. Calcd for
C18H18N2O5: C, 63.15; H, 5.30; N, 8.18. Found: C,
63.07; H, 5.19; N, 8.30.
4.1.50. (2S,5S)- and (2R,5S)-2-(30-Nitrophenyl-1,3-dioxa-
heptan-5-yl)benzamide (10e and 100e). Using the same
procedure for the preparation of 8a and 80a, from
150 mg (0.72 mmol) of 300c and 108 mg (0.72 mmol) of

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4797
20
25.369. EI-MS (m/e) 345 [M]+. ½aꢁ 16:0 (c 1.00, CHCl3).
for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found:
C, 63.87; H, 5.52; N, 7.71.
D
Anal. Calcd for C19H20ClNO3: C, 65.99; H, 5.83; N,
4.05. Found: C, 66.07; H, 5.96; N, 4.17.
4.1.53. (2S,5S)- and (2R,5S)-2-(30-Nitrophenyl-1,3-diox-
aoctan-5-yl)benzamide (11e and 110e). Using the same
procedure for the preparation of 8a and 80a, from
106 mg (0.47 mmol) of 300d and 72 mg (0.47 mmol) of
3-nitrobenzaldehyde, 49 mg (29%) of 11e and 25 mg
(15%) of 110e were obtained.
Compound 110c. Colorless powder, mp 118–120 ꢁC. IR
(KBr): t (cmꢀ1) = 3322, 3041, 2930, 2850, 1654, 1628,
1607, 1584, 1505, 1452, 1380, 1187, 1049, 823, 742,
701. 1H NMR (CDCl3)
d
(ppm) = 7.952 (d,
J = 7.62 Hz, 2H), 8.024 (s, 1H), 7.524 (t, J = 7.62 Hz,
1H), 7.437 (t, J = 7.62 Hz, 2H), 7.207 (d,
J = 7.22 Hz, 2H), 7.130 (t, J = 7.22 Hz, 2H), 5.515 (s,
1H), 3.926 (m, J = 6.32 Hz, 1H), 3.773 (d,
J = 6.91 Hz, 2H), 3.403 (t, J = 6.01 Hz, 2H), 1.796
(m, J = 6.11 Hz, 2H), 1.481 (m, J = 6.11 Hz, 2H). In
the NOE experiment no NOE was observed. 13C
NMR (CDCl3): d (ppm) = 167.848, 135.541, 133.803,
133.114, 132.055, 129.520, 129.132, 128.883, 127.905,
Compound 11e. Colorless powder, mp 124–126 ꢁC. IR
(KBr): t (cmꢀ1) = 3322, 3045, 2921, 2844, 1642, 1621,
1603, 1586, 1524, 1456, 1384, 1349, 1190, 1075, 861,
768, 699. 1H NMR (CDCl3) d (ppm) = 8.127 (s,
1H), 8.121 (d, J = 9.04 Hz, 1H), 8.011 (s, 1H), 7.931
(d, J = 7.49 Hz, 2H), 7.591 (d, J = 9.04 Hz, 1H),
7.523 (t, J = 7.49 Hz, 1H), 7.448 (t, J = 9.04 Hz,
1H), 7.421 (t, J = 7.49 Hz, 2H), 5.479 (s, 1H), 3.917
(m, J = 6.55 Hz, 1H), 3.624 (d, J = 6.55 Hz, 2H),
3.361 (t, J = 6.37 Hz, 2H), 1.549 (m, J = 6.12 Hz,
2H), 1.458 (m, J = 6.12 Hz, 2H). In the NOE exper-
iment, a positive NOE was observed between the
NH-functionality at the 5-position and the proton
of the phenyl at the 2-position. 13C NMR (CDCl3):
104.852, 69.867, 63.880, 49.947, 29.034, 26.143. EI-
20
MS (m/e) 345 [M]+. ½aꢁD ¼ ꢀ13:4 (c 1.00, CHCl3).
Anal. Calcd for C19H20ClNO3: C, 65.99; H, 5.83; N,
4.05. Found: C, 65.86; H, 5.74; N, 4.13.
4.1.52. (2S,5S)- and (2R,5S)-2-(40-Nitrophenyl-1,3-diox-
aoctan-5-yl)benzamide (11d and 110d). Using the same
procedure for the preparation of 8a and 80a, from
106 mg (0.47 mmol) of 300d and 72 mg (0.47 mmol) of
4-nitrobenzaldehyde, 44 mg (26%) of 11d and 23 mg
(14%) of 110d were obtained.
d (ppm) = 167.522, 148.223, 138.014, 133.701,
133.432, 130.994, 129.240, 128.611, 127.320, 122.661,
103.427, 69.708, 63.579, 49.447, 28.694, 25.867.
20
½aꢁ 17:2 (c 1.00, CHCl3). EI-MS (m/e) 356 [M]+.
D
Anal. Calcd for C19H20N2O5: C, 64.04; H, 5.66; N,
7.86. Found: C, 64.17; H, 5.78; N, 7.94.
Compound 11d. Colorless powder, mp 133–135 ꢁC. IR
(KBr): t (cmꢀ1) = 3310, 3050, 2930, 2850, 1650, 1630,
1605, 1580, 1525, 1450, 1386, 1350, 1190, 1050, 821,
Compound 110e. Colorless powder, mp 127–129 ꢁC. IR
(KBr): t (cmꢀ1) = 3315, 3042, 2926, 2847, 1648, 1625,
1601, 1582, 1524, 1453, 1381, 1349, 1194, 1072, 863,
1
738, 690 cmꢀ1. H NMR (CDCl3) d (ppm) = 8.156 (d,
J = 9.02 Hz, 2H), 8.014 (s, 1H), 7.631 (d, J = 9.02 Hz,
2H), 7.601 (t, J = 7.54 Hz, 1H), 7.437 (t, J = 7.54 Hz,
2H), 7.408 (t, J = 7.54 Hz, 2H), 5.834 (s, 1H), 4.303
(m, J = 6.91 Hz, 1H), 3.963 (d, J = 6.91 Hz, 2H), 3.955
(d, J = 6.91 Hz, 2H), 1.821 (m, J = 6.12 Hz, 2H), 1.794
(m, J = 6.12 Hz, 2H). In the NOE experiment, a positive
NOE was observed between the NH-functionality at the
5-position and the proton of the phenyl at the 2-posi-
tion. 13C NMR (CDCl3): d (ppm) = 167.814, 145.506,
145.345, 133.512, 132.237, 129.042, 128.651, 127.342,
1
765, 702. H NMR (CDCl3) d (ppm) = 8.361 (s, 1H),
8.320 (d, J = 9.03 Hz, 1H), 8.014 (s, 1H), 7.967 (d,
J = 7.52 Hz, 2H), 7.633 (d, J = 9.03 Hz, 1H), 7.600 (t,
J = 7.52 Hz, 1H), 7.584 (t, J = 9.03 Hz, 1H), 7.488 (t,
J = 7.52 Hz, 2H), 5.694 (s, 1H), 3.973 (m, J = 6.54 Hz,
1H), 3.647 (d, J = 6.54 Hz, 2H), 3.450 (t, J = 6.35 Hz,
2H), 1.598 (m, J = 6.10 Hz, 2H), 1.466 (m,
J = 6.10 Hz, 2H). In the NOE experiment no NOE
was observed. 13C NMR (CDCl3): d (ppm) = 167.940,
148.653, 138.824, 133.789, 133.661, 131.073, 129.547,
123.401, 105.061, 69.371, 63.501, 29.320, 25.4533. EI-
20
MS (m/e) 356 [M]+. ½aꢁ 20:0 (c 0.02, CHCl3). Anal.
129.034, 127.651, 123.046, 103.763, 70.124, 63.795,
D
20
Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86.
Found: C, 64.17; H, 5.76; N, 7.77.
50.106, 29.323, 26.401. ½aꢁ ꢀ 13:7 (c 1.00, CHCl3).
D
EI-MS (m/e) 356 [M]+. Anal. Calcd for C19H20N2O5:
C, 64.04; H, 5.66; N, 7.86. Found: C, 64.17; H, 5.78;
N, 7.94.
Compound 110d. Colorless powder, mp 116–118 ꢁC.
IR (KBr): t (cmꢀ1) = 3318, 3060, 2950, 2860, 1660,
1625, 1610, 1590, 1520, 1460, 1383, 1351, 1119,
4.1.54. (2S,5S)- and (2R,5S)-2-(40-Chlorophenyl-1,3-
dioxaoctan-5-yl)phenylacetamide (12c and 120c). Using
the same procedure for the preparation of 8a and 80a,
from 111 mg (0.47 mmol) of 30d and 66 mg (0.47 mmol)
of 4-chlorobenzaldehyde, 54 mg (32%) of 12c and 22 mg
(13%) of 120c were obtained.
1090, 819, 738, 692. 1H NMR (CDCl3)
d
(ppm) = 8.193 (d, J = 8.7 Hz, 2H), 8.022 (s, 1H),
7.906 (d, J = 7.2 Hz, 2H), 7.517 (t, J = 7.5 Hz, 1H),
7.450 (t, J = 8.7 Hz, 2H), 7.435 (t, J = 7.2 Hz, 2H),
5.520 (s, 1H), 3.902 (m, J = 6.3 Hz, 1H), 3.771 (d,
J = 6.9 Hz, 2H), 3.316 (t, J = 6.7 Hz, 2H), 1.498 (m,
J = 6.1 Hz, 2H), 1.403 (m, J = 6.1 Hz, 2H). In the
NOE experiment no NOE was observed. 13C NMR
Compound 12c. Colorless powder, mp 120–122 ꢁC. IR
(KBr): t (cmꢀ1) = 3324, 3030, 2931, 2850, 1651, 1630,
1602, 1581, 1504, 1450, 1385, 1191, 1048, 818, 743,
692. 1H NMR (CDCl3) d (ppm) = 8.004 (s, 1H),
7.127 (d, J = 7.50 Hz, 2H), 7.057 (t, J = 7.20 Hz,
2H), 7.030 (d, J = 7.50 Hz, 2H), 7.011 (d,
(CDCl3):
133.220, 132.001, 128.885, 128.201, 127.040, 123.111,
d
(ppm) = 167.222, 145.343, 145.126,
20
D
104.890, 69.105, 63.212, 28.881, 25.003. ½aꢁ ꢀ 18:0
(c 0.02, CHCl3). EI-MS (m/e) 356 [M]+. Anal. Calcd

4798
K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
J = 7.20 Hz, 1H), 7.005 (d, J = 7.20 Hz, 2H), 5.412 (s,
1H), 3.613 (m, J = 6.01 Hz, 1H), 3.470 (s, 2H), 3.302
(d, J = 6.00 Hz, 2H), 3.113 (t, J = 6.00 Hz, 2H), 1.500
(m, J = 6.00 Hz, 2H), 1.422 (m, J = 6.00 Hz, 2H). In
the NOE experiment, a positive NOE was observed
between the NH-functionality at the 5-position and
the proton of the phenyl at the 2-position. 13C
NMR (CDCl3): d (ppm) = 170.102, 135.623, 134.801,
132.644, 129.157, 129.002, 128.637, 128.305, 127.502,
J = 7.51 Hz, 2H), 5.726 (s, 1H), 3.981 (m, J = 5.44 Hz,
1H), 3.713 (d, J = 5.44 Hz, 2H), 3.561 (t, J = 5.26 Hz,
2H), 3.469 (s, 2H), 1.570 (m, J = 5.14 Hz, 2H), 1.487
(m, J = 5.14 Hz, 2H). In the NOE experiment no NOE
was observed. 13C NMR (CDCl3): d (ppm) = 171.142,
147.901, 143.561, 136.304, 130.104, 129.215, 129.003,
128.104, 123.781, 104.671, 70.121, 64.114, 40.557,
20
29.146, 26.371. EI-MS (m/e) 370 [M]+. ½aꢁ ꢀ 15:1 (c
D
0.02, CHCl3). Anal. Calcd for C20H22N2O5: C, 64.85;
H, 5.99; N, 7.56. Found: C, 65.04; H, 6.03; N, 7.42.
104.163, 69.337, 63.654, 49.104, 28.307, 25.424. EI-
20
MS (m/e) 359 [M]+. ½aꢁ 17:6 (c 1.00, CHCl3). Anal.
D
Calcd for C20H22ClNO3: C, 66.75; H, 6.16; N, 3.89.
Found: C, 66.63; H, 6.07; N, 4.01.
4.1.56. (2S,5S)- and (2R,5S)-2-(30-Nitrophenyl-1,3-diox-
aoctan-5-yl)phenylacetamide (12e and 120e). Using the
same procedure for the preparation of 8a and 80a, from
111 mg (0.47 mmol) of 30d and 72 mg (0.47 mmol) of 3-
nitrobenzaldehyde, 49 mg (28%) of 12e and 23 mg (13%)
of 120e were obtained.
Compound 120c. Colorless powder, mp 130–132 ꢁC. IR
(KBr): t (cmꢀ1) = 3314, 3035, 2937, 2854, 1651, 1622,
1600, 1584, 1507, 1458, 1377, 1182, 1047, 820, 744, 692.
1H NMR (CDCl3) d (ppm) = 8.019 (s, 1H), 7.295 (d,
J = 7.51 Hz, 2H), 7.167 (t, J = 7.32 Hz, 2H), 7.131 (d,
J = 7.51 Hz, 2H), 7.087 (d, J = 7.32 Hz, 1H), 7.069 (d,
J = 7.32 Hz, 2H), 5.531 (s, 1H), 3.937 (m, J = 6.20 Hz,
1H), 3.668 (d, J = 6.01 Hz, 2H), 3.476 (s, 2H), 3.434 (t,
J = 6.01 Hz, 2H), 1.686 (m, J = 6.00 Hz, 2H), 1.487 (m,
J = 6.00 Hz, 2H). In the NOE experiment no NOE was
observed. 13C NMR (CDCl3): d (ppm) = 170.887,
136.324, 135.479, 133.160, 130.057, 129.561, 129.323,
Compound 12e. Colorless powder, mp 131–133 ꢁC. IR
(KBr): t (cmꢀ1) = 3335, 3032, 2915, 2836, 1647, 1611,
1600, 1582, 1524, 1452, 1388, 1352, 1194, 1052, 860,
1
773, 699. H NMR (CDCl3) d (ppm) = 8.114 (s, 1H),
8.105 (d, J = 8.91 Hz, 1H), 8.012 (s, 1H), 7.563 (d,
J = 8.91 Hz, 1H), 7.463 (d, J = 8.90 Hz, 1H), 7.138 (t,
J = 7.32 Hz, 2H), 7.058 (t, J = 7.32 Hz, 1H), 7.046 (t,
J = 7.32 Hz, 2H), 5.473 (s, 1H), 3.912 (m, J = 6.20 Hz,
1H), 3.582 (d, J = 6.20 Hz, 2H), 3.459 (s, 2H), 3.364 (t,
J = 6.20 Hz, 2H), 1.610 (m, J = 6.20 Hz, 2H), 1.461
(m, J = 6.15 Hz, 2H). In the NOE experiment, a positive
NOE was observed between the NH-functionality at the
5-position and the proton of the phenyl at the 2-posi-
tion. 13C NMR (CDCl3): d (ppm) = 170.452, 148.305,
138.087, 135.892, 133.614, 130.025, 129.303, 128.964,
127.432, 122.686, 103.489, 69.760, 63.599, 49.103,
129.045, 127.802, 104.791, 70.112, 64.030, 49.637,
20
29.121, 26.332. EI-MS (m/e) 359 [M]+. ½aꢁ ꢀ 14:3 (c
D
1.00, CHCl3). Anal. Calcd for C20H22ClNO3: C, 66.75;
H, 6.16; N, 3.89. Found: C, 66.67; H, 6.22; N, 3.78.
4.1.55. (2S,5S)- and (2R,5S)-2-(40-Nitrophenyl-1,3-diox-
aoctan-5-yl)phenylacetamide (12d and 120d). Using the
same procedure for the preparation of 8a and 80a, from
111 mg (0.47 mmol) of 30d and 72 mg (0.47 mmol) of 4-
nitrobenzaldehyde, 42 mg (24%) of 12d and 21 mg (12%)
of 120d were obtained.
40.085, 28.682, 25.968. EI-MS (m/e) 370 [M]+.
20
D
½aꢁ 15:3 (c 1.00, CHCl3). Anal. Calcd for
C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C,
64.76; H, 6.11; N, 7.67.
Compound 12d. Colorless powder, mp 136–138 ꢁC. IR
(KBr): t (cmꢀ1) = 3321, 3043, 2919, 2837, 1644, 1627,
1600, 1575, 1520, 1456, 1351, 1194, 1048, 821, 742, 693.
1H NMR (CDCl3) d (ppm) = 8.120 (d, J = 8.94 Hz,
2H), 8.010 (s, 1H), 7.443 (d, J = 8.94 Hz, 2H), 7.130 (t,
J = 7.30 Hz, 2H), 7.069 (t, J = 7.30 Hz, 1H), 7.059 (d,
J = 7.30 Hz, 2H), 5.397 (s, 1H), 3.914 (m, J = 5.39 Hz,
1H), 3.585 (d, J = 5.42 Hz, 2H), 3.464 (s, 2H), 3.364 (t,
J = 5.24 Hz, 2H), 1.505 (m, J = 5.12 Hz, 2H), 1.454 (m,
J = 5.12 Hz, 2H). In the NOE experiment, a positive
NOE was observed between the NH-functionality at
the 5-position and the proton of the phenyl at the 2-posi-
tion. 13C NMR (CDCl3): d (ppm) = 170.671, 147.413,
143.112, 135.903, 129.812, 128.914, 128.701, 127.516,
Compound 120e. Colorless powder, mp 138–140 ꢁC. IR
(KBr): t (cmꢀ1) = 3331, 3037, 2915, 2835, 1639, 1622,
1600, 1576, 1524, 1446, 1385, 1351, 1196, 1051, 859,
1
771, 701. H NMR (CDCl3) d (ppm) = 8.162 (s, 1H),
8.210 (d, J = 8.93 Hz, 1H), 8.021 (s, 1H), 7.661 (d,
J = 8.93 Hz, 1H), 7.593 (d, J = 8.93 Hz, 1H), 7.380 (t,
J = 7.34 Hz, 2H), 7.254 (t, J = 7.34 Hz, 1H), 7.163 (t,
J = 7.34 Hz, 2H), 5.741 (s, 1H), 3.974 (m, J = 6.22 Hz,
1H), 3.825 (d, J = 6.22 Hz, 2H), 3.630 (t, J = 6.22 Hz,
2H), 3.472 (s, 2H), 1.676 (m, J = 6.22 Hz, 2H), 1.516
(m, J = 6.13 Hz, 2H). In the NOE experiment no NOE
was observed. 13C NMR (CDCl3): d (ppm) = 171.234,
148.956, 138.706, 136.289, 134.015, 130.657, 129.813,
129.464, 127.861, 123.045, 103.947, 70.013, 64.131,
123.482, 104.316, 69.727, 63.591, 40.007, 28.767,
20
25.989. EI-MS (m/e) 370 [M]+. ½aꢁ 18:2 (c 0.02, CHCl3).
49.738, 40.812, 29.134, 26.320. EI-MS (m/e) 370 [M]+.
D
20
D
Anal. Calcd for C20H22N2O5: C, 64.85; H, 5.99; N, 7.56.
Found: C, 64.78; H, 5.81; N, 7.77.
½aꢁ ꢀ 11:7 (c 1.00, CHCl3). Anal. Calcd for
C20H22N2O5: C, 64.85; H, 5.99; N, 7.56. Found: C,
64.74; H, 5.87; N, 7.71.
Compound 120d. Colorless powder, mp 150–152 ꢁC. IR
(KBr): t (cmꢀ1) = 3326, 3047, 2939, 2845, 1665, 1629,
1613, 1581, 1522, 1462, 1347, 1190, 1050, 822, 739, 694.
1H NMR (CDCl3) d (ppm) = 8.181 (d, J = 9.00 Hz,
2H), 8.015 (s, 1H), 7.953 (d, J = 9.00 Hz, 2H), 7.543 (t,
J = 7.51 Hz, 2H), 7.457 (t, J = 7.51 Hz, 1H), 7.212 (d,
4.2. In vivo anti-inflammatory assay
4.2.1. Animals. Male Kunming mice (about 25 g) were
inbred and grown in the animal laboratory at the college
of Pharmacy, Peking University. The animal facility was

K. Gu et al. / Bioorg. Med. Chem. 15 (2007) 4775–4799
4799
3. Heavey, P. M.; kenna, D. Mc.; Rowland, I. R. Nutr.
Cancer 2004, 48, 124–141.
4. Asano, T. K.; Leod, R. S. Mc. Dis. Colon Rectum 2004,
47, 665–673.
maintained at 23 2 ꢁC with a 12 h light/dark cycle. The
ethical guidelines described in the NIH guide for care
and use of Laboratory Animals were followed.
5. Kune, G. A. Aust. N. Z. J. Surg. 2000, 70, 452–455.
6. Huls, G.; Koornstra, J. J.; Kleibeuker, J. H. Lancet 2003,
362, 230–232.
7. Tarnawski, A. S.; Jmes, M. K. J. Mol. Med. 2003, 81, 627–
636.
8. Grosch, S.; Tegeder, I.; Niederberger, E.; Brautigam, L.;
Geisslinger, G. FASEB J. 2001, 15, 2742–2744.
9. Jiang, J. B.; Johnson, M. G.; Nichols, J. US Patent
5,360,818, 1994.
10. (a) Shi, R. X.; Ong, C. N.; Shen, H. M. Cancer Res. 2005,
65, 7815; (b) Pan, Q.; Bao, L. W.; Kleer, C. G.; Sable, M.
S.; Griffith, K. A.; Teknos, T. N.; Merajver, S. D. Cancer
Res. 2005, 65, 8366.
4.2.2. Xylene-induced ear edema.15–18 Male Kunming
mice were randomly divided into three groups of 12
mice, namely the test group, vehicle control group,
and positive control group. The mice in vehicle control
group were administered orally with a suspension of
Aspirin in CMC at a dosage of 20 mg/kg, and a concen-
tration of 0.3 mg/ml, and the mice in the test group were
administered orally a suspension of 1,3-dioxacycloal-
kane in CMC at a dosage of 20 mg/kg. Thirty minutes
later, 0.03 ml of xylene was applied to both the anterior
and posterior surfaces of the right ear. The left ear was
used as control. Two hours after xylene application, the
mice were sacrificed 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 ANOVA test,
p < 0.05 is considered significant.
11. Aksoy, E.; Goldman, M.; Willems, F. Int. J. Biochem. Cell
Biol. 2004, 36, 183.
12. (a) Hanlon, P. R.; Fy, P.; Wright, G. L.; Steenbergen, C.;
Arcasoy, M. O.; Murphy, E. FASEB J. 2005, 19, 1323; (b)
Churchill, E. N.; Murrile, C. L.; Chen, C. L.; Mochly-
Rosen, D.; Szweda, L. I. Circ. Res. 2005, 97, 78.
13. Bi, L.; Zhao, M.; Wang, C.; Peng, S. Eur. J. Org. Chem.
2000, 2669–2676.
14. Bi, L.; Zhao, M.; Wang, C.; Peng, S.; Winterfeldt, E.
J. Org. Chem. 2002, 67, 22–26.
15. Bi, L.; Zhang, Y.; Zhao, M.; Wang, C.; Tok, J.; Peng, S.
Bioorg. Med. Chem. 2005, 13, 5640.
4.3. Tail bleeding time measurement
16. Gu, K.; Bi, L.; Zhao, M.; Wang, C.; Kao, M.; Tok, J.;
Peng, S. Bioorg. Med. Chem. 2006, 14, 1339.
17. Romay, C.; Armesto, J.; Remirez, D.; Gonzalez, R.;
Ledon, N.; Garcia, I. Inflamm. Res. 1998, 47, 334.
18. Smith, A. B.; Cho, Y. S.; Zawacki, L. E.; Hirschmann, R.;
Pettit, G. R. Org. Lett. 2001, 3, 4063.
19. Moore, R. A.; Derry, S.; Phillips, C. J.; Mcquay, H. J.
BMC Musculoskelet. Disord. 2006, 20, 79.
20. Garcia-Rodriguez, L. A.; Jick, H. Lancet 1994, 343, 769–
772.
The new anti-inflammatory agents were orally adminis-
tered to male mice (body weight 18–22 g). After the
administration of 30, 45, 60, and 90 min, a mouse was
placed in a tube holder with its tail protruding, and a
2 mm cut was made on the tail. Flowing blood until it
stopped was gently wiped away with a tissue every 30 s
until bleeding ceased and the time recorded.
21. Zhang, K.; Young, C.; Berger, J. J. Manag. Care Pharm.
2006, 12, 640–648.
Acknowledgment
22. Kargman, S.; Charleson, S.; Cartwright, M., et al. Gas-
troenterology 1996, 111, 445–454.
23. Grossman, C. J.; Wiseman, J.; Lucas, F. S. Inflamm. Res.
1995, 44, 253–257.
24. Funk, C. D.; Funk, L. B.; Kennedy, M. E., et al. FASEB
J. 1991, 5, 2304–2312.
This work was supported by Beijing Area Major
Laboratory of Peptide and Small Molecular Drugs, the
973 Project of China (2006CB708501), and Beijing Muni-
cipal Commission of Education (KZ 200510025015).
25. Gallagher, J. E.; Blauth, J.; Fornadley, J. A. Laryngoscope
1995, 105, 606–609.
References and notes
26. Conrad, K.; Fagan, T.; Mackie, M., et al. Clin. Pharma-
col. Ther. 1988, 43, 542–546.
27. Spowart, K.; Greer, A.; McLaren, M., et al. Thromb.
Haemost. 1988, 60, 382–386.
1. Arber, N.; Levin, B. Recent Results Cancer Res. 2005, 166,
213–230.
28. Dejana, F.; Villa, S.; Dc Gaetano, G. Thromb. Haemost.
1982, 48, 108–110.
2. Lippman, S. M.; Lee, J. J.; Sabichi, A. L. J. Natl. Cancer
Inst. 1998, 90, 1514–1528.