Novel macrocyclic molecules based on 12a-N substituted 16-membered azalides and azalactams as potential antifungal agents

Article abstract of DOI:10.1016/j.ejmech.2013.11.032

Novel macrocyclic molecules comprising sulfonyl and acyl moiety at the position N-12a of 16-membered azalides (6a-n) and azalactams (10a-r) scaffold were synthesized from cyclododecanone 1 as starting material via 5 steps and 4 steps, respectively. The an

Full text of DOI:10.1016/j.ejmech.2013.11.032

European Journal of Medicinal Chemistry 73 (2014) 286e294
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Novel macrocyclic molecules based on 12a-N substituted
16-membered azalides and azalactams as potential antifungal agents
Xiaolei Wang, Shun Zhang, Yanlong Pang, Huihui Yuan, Xiaomei Liang, Jianjun Zhang,
*
Daoquan Wang, Mingan Wang, Yanhong Dong
Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel macrocyclic molecules comprising sulfonyl and acyl moiety at the position N-12a of 16-membered
azalides (6aen) and azalactams (10aer) scaffold were synthesized from cyclododecanone 1 as starting
material via 5 steps and 4 steps, respectively. The antifungal activity of these compounds against Scle-
rotinia sclerotiorum, Pyricularia oryzae, Botrytis cinerea, Rhizoctonia solani and Phytophthora capsici were
evaluated and found that compounds possessing a-exomethylene (6c, 6d, 6e and 6g) showed antifungal
activity comparable to commercial fungicide Chlorothalonil against P. oryzae and compounds possessing
p-chlorobenzoyl exhibited enhanced antifungal activity than those with other substituents against
Received 2 August 2013
Received in revised form
19 November 2013
Accepted 24 November 2013
Available online 11 December 2013
Keywords:
Macrocyclic molecules
Azalides
S. sclerotiorum, P. oryzae, and B. cinerea. These findings suggested that the
a-exomethylene and p-
chlorobenzoyl may be two potential pharmacological active groups with antifungal activities.
Ó 2013 Elsevier Masson SAS. All rights reserved.
Azalactams
Synthesis
Antifungal activity
1. Introduction
14-membered lactone antibiotics with double bonds. Avermectins
[11], currently the most widely used insecticide in agriculture, have
Macrolide antibiotics are a class of safe and effective drugs
widely used in the treatment of infectious diseases in clinical
subjects. Azithromycin (AZ) [1e3] is a semisynthetic azalide anti-
biotic with 15-membered macrolide ring having an N-methyl
inserted into the erythromycin aglycone. It has become a “heavy
bomb” drug owing to its wide spectrum of activity and superior
pharmacokinetic and safety properties. These properties prompt
the exploration of synthesis of new antibacterial compounds with
outstanding pharmacokinetics by using azalide scaffold in recent
years [4,5]. Thus, azithromycin derivatives, 48 and 55 [6], were
reported to exhibit excellent antibacterial activity against a wide
range of clinically relevant macrolide-resistant organisms. The
thiourea derivative 7a and urea 9b [7] have shown substantially
improved activity compared to AZ when tested against efflux-
mediated resistant Streptococcus pneumoniae. The novel amino-
quinoline derivative 12 [8] exhibits high in vitro activity and
selectivity against Plasmodium falciparum parasites.
three double bonds in its lactone ring. Cladospolide B [12] with 12-
membered unsaturated lactone was found to have a role in regu-
lating plant growth. The unsaturated sex attractant lactones [13]
have been isolated from secretions of the stored-grain pests Cryp-
tolestes pusillus. Six pheromones containing unsaturated macrolide
structure [14] have also been identified from the secretions of
Cryptolestes ferrugineus.
The exocyclic double bond, mainly referred to as
methylene, is present in many natural products with biological
activities. The simplest lactone containing -exomethylene is
a-exo-
a
Tulipalin A, which could control Fusarium oxysporum [15] and
Botrytis cinerea [16] efficiently. Alantolactone [17] shows bacteri-
cidal activity [18] and antifeedant activity against Tribolium con-
fusum with potential application in pest control. Some studies
suggest that Alantolactone also inhibits the proliferation of tumor
cells [19,20]. Cedarmycin A [21,22] exhibits potent activity against
Candida glabrata IFO 0622 with the MIC of 0.40 mg/mL.
Many natural macrolides bearing double bonds in the ring have
multiple physiological activities and wide range of applications in
the pharmaceuticals and pesticides. Pikromycin [9,10] is one of the
It has been our goal to simplify structures and develop new
potential pesticides via biomimetic synthesis of natural macrolides.
We have synthesized cyclododecanone derivatives [23e25] and
macrolactam/macrolactone derivatives [26e29], and all of them
have shown moderate antifungal activities. For example, the satu-
rated azalide (Fig. 1), 12a-aza-pentadecanelactone tetra-
fluoroborate, possesses excellent antifungal activity against
* Corresponding author. Tel.: þ86 10 62732944; fax: þ86 10 62732507.
E-mail address: dongyh@cau.edu.cn (Y. Dong).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.11.032

X. Wang et al. / European Journal of Medicinal Chemistry 73 (2014) 286e294
287
Rhizoctonia solani [30]. To further promote the research program
aiming to discover novel bioactive wide-spectrum macrocyclic
compounds, the novel azalactams and azalides containing the
endocyclic or exocyclic double bond were designed and synthe-
sized from cyclododecanone and their biological activities were
reported here.
against a panel of agriculturally important pathogens in China
including Sclerotinia sclerotiorum, Pyricularia oryzae, B. cinerea, R.
solani and Phytophthora capsici. Commercial fungicide Chlor-
othalonil was used as a positive control. As shown in Table 1, 32
compounds showed fair to high levels of antifungal activity against
the five fungi. Notably, compound 6g has shown excellent activity
for S. sclerotiorum and P. oryzae and compound 10o for B. cinerea
and R. solani. Importantly, comparison of the inhibitory activity of
azalides and azalactams demonstrated that azalide compounds had
better activity than that of azalactams bearing the same N-
substituted groups (e.g., 6a and 6h vs 10b) against S. sclerotiorum, P.
oryzae, R. solani and P. capsici. For S. sclerotiorum and P. oryzae, the
inhibition rates of the azalides 6g were 75.39% and 67.28%,
respectively, whereas that of 6n was 84.68% and 64.26%, respec-
tively. These activities were higher than the azalactams 10o having
the same p-chlorobenzoyl with the rates of 61.35% and 42.17%,
respectively. Among all test compounds, the compounds containing
p-chlorobenzoyl (6g, 6n and 10o) exhibited the best antifungal
activities against the most of the tested fungi. The inhibition rates of
2. Results and discussion
2.1. Chemistry
Scheme 1 shows the synthetic route of novel 12a-N substituted
16-membered azalides and azalactams. Compound 2 [30] was ob-
tained in high yield from cyclododecanone 1 and 2-azidoethanol in
the presence of Lewis acid boron trifluoride etherate (BF3$OEt2).
This fluoroborate was hydrolyzed with saturated sodium carbonate
(Na2CO3) solution, and the free amino group was protected with di-
tert-butyl pyrocarbonate ((Boc)2O) to give intermediate 3 [31]. tert-
Butyloxycarbonyl-2-methylene-12a-aza-pentadecanelactone (4a)
[32] was synthesized via the condensation reaction of formalde-
hyde and lactone 3 mediated with lithium diisopropylamide (LDA)
in anhydrous tetrahydrofuran (THF) at ꢀ78 ꢁC for 2 h. This is the
first time to use such a method to introduce 2-methylene into
macrolide.
the compounds with
a-exomethylene (6c, 6d, 6e and 6g) were
comparable to that of commercial fungicide Chlorothalonil against
P. oryzae, whereas endocyclic compounds (6j, 6k, 6l and 6n) were
less active than Chlorothalonil. In addition, the compounds 6ceg
showed higher inhibition activity than 6jen against S. sclerotiorum,
P. oryzae, and B. cinerea. The results indicated that p-chlorobenzoyl
The lactone carbanion firstly reacted with bromoselenobenzene
(PhSeBr) to form tert-butyloxycarbonyl-2-phenylselanyl-12a-aza-
pentadecanelactone, which was then oxidized with hydrogen
peroxide (H2O2) to yield tert-butyloxycarbonyl-12a-aza-2E-penta-
decenelactone (4b) [33]. To separate tert-butyloxycarbonyl-2-
phenylselanyl-12a-aza-pentadecanelactone from the reaction
mixture by flash column, toluene/ethyl acetate were used as the
eluent instead of petroleum ether/ethyl acetate to yield better
separation resolution and high recovery yield of 4b. Then, the Boc
group of 4a and 4b was removed using trifluoroacetic acid
(CF3COOH) to yield 5a and 5b [34] in quantitative yield, which
reacted with corresponding aryl chlorides to give compound 6aeg
and 6hen.
To prepare 12a-N substituted 16-membered azalactams, cyclo-
dodecanone 1 reacted with 2-azidoethanol in the presence of Lewis
acid BF3$OEt2 via Boyer reaction [35,36] to give iminium ether,
which reacted with sodium azide (NaN3) in N,N-dimethylforma-
mide (DMF) to yield compound 7. Then, compound 7 reacted with
triphenylphosphine (PPh3) followed by hydrolysis to give com-
pound 8 [37,38]. Compound 8 was treated with 4-toluene sulfonic
acid (TsOH) at reflux under Argon condition to give bicyclic ami-
dine, which was then hydrolyzed with potassium hydroxide (KOH)
to generate compound 9 [39]. Compound 9 reacted with alkyl
chlorides in dry methylene chloride (DCM) in the presence of po-
tassium carbonate (K2CO3) to afford compounds 10aer in moderate
to high yields.
and a-exomethylene may be two active groups conferring potential
antifungal activities.
To understand whether the electric charge distribution of these
compounds may contribute their biological activities, the 3D
structure of each compound was constructed using the Sketch
Molecule module in SYBYL 7.3 software [40] and their energy
minimizations were performed using Tripos force field with a
distance dependent dielectric function and a Powell method with a
convergence criterion of 0.001 kcal/mol. Also, partial atomic
charges were calculated by the Merck molecular force field 94
(MMFF94) [41], which made significant approximations in the
treatment of some important physical interactions and calculated
the potential energy more accurately. Based on the atomic charges
labeled by SYBYL 7.3, two important conclusions were given as
follows: Firstly,
a-exomethylene compound 6g (75.39%), 6e
(55.76%) and 6f (67.80%) have much better antifungal activity
against S. sclerotiorum than the corresponding unsaturated com-
pound 6n (67.28%), 6l (38.22%) and 6m (36.39%) with the same O-
substituted group, respectively. As shown in Table 1, this difference
was because of the higher electropositivity (0.168) of CH2]CeCH2
group compared to CH]CH group (0.084). Secondly, the electrical
property of benzene was analyzed and it indicated that higher
electropositivity in benzene might be unfavorable to the com-
pounds activity. For example, compound 10o (0.187, 61.35% of in-
hibition rate) and 10f (0.239, 28.29% of inhibition rate) are better
than 10r (0.238, 53.78% of inhibition rate) and 10i (0.286, 5.58% of
inhibition rate) against S. sclerotiorum respectively.
2.2. Biological activity
3. Conclusions
Using mycelium growth assay [29], we evaluated antifungal
activities of compounds azalides (6aen) and azalactams (10aer)
We have, for the first time designed and synthesized a novel
double bond-containing azalides, 12a-N-substituted-2-methylene-
12a-aza-pentadecane-lactones (6aef) and 12a-N-substituted-12a-
aza-2E-pentadecenelactones (6gel), as well as new azalactams,
12a-N-substituted-12a-aza-pentadecanelactam (10aer). All of
them showed promising antifungal activities against several agri-
cultural pathogens. Among them, the remarkable inhibitory activity
of compounds possessing p-chlorobenzoyl or a-exomethylene (6c,
6d, 6e, 6n, 6g and 10o) warrant further structural optimization to
Fig. 1. The saturated azalide 12a-aza-pentadecanelactone tetrafluoroborate.
identify more potent antifungal agents.

288
X. Wang et al. / European Journal of Medicinal Chemistry 73 (2014) 286e294
Scheme 1. Synthesis of novel 12a-N substituted 16-membered azalides and azalactams. Reagents and conditions: (a) i) 2-Azidoethanol, BF3$OEt2, reflux, 12h, 85%; ii) NaHCO3; (b) i)
Na2CO3; ii) (Boc)2O, H2O, 98%; (c) 4a: i) LDA, THF, ꢀ78 ꢁC for 3 h; ii) (CH2O)n, 40%; 4b: i) LDA, THF, ꢀ78 ꢁC for 2 h; ii) PhSeBr, 63%; iii) H2O2, Py, 84%; (d) i) CF3COOH, r.t. for 3 h; ii)
NaHCO3; iii) HCl$OEt2, 5a, 87%; 5b, 77%; (e) RCl, K2CO3, Dry DCM; (f) i) 2-Azidoethanol, BF3$OEt2, reflux, 12h, 94%; ii) NaN3, DMF, 16h, 85%; (g) i) PPh3; ii) H2O, 86%; (h) i) TsOH,
Xylene, reflux, 50h; ii) Acetone, KOH, 69%; (i) RCl, K2CO3, Dry DCM.
4. Experimental section
4.4. tert-Butyloxycarbonyl-2-methylene-12a-aza-
pentadecanelactone (4a)
4.1. General
A solution of compound 3 (13.6 g, 40 mmol) in THF (100 mL) was
added dropwise slowly into a solution of LDA (20 mL, 40 mmol) in
THF (100 mL) at ꢀ78 ꢁC under Ar in 2 h. Another 200 mL of
anhydrous THF was added to the mixture under low temperature in
1 h. The formaldehyde gas, depolymerized from 6.00 g (200 mmol)
of paraformaldehyde at 180 ꢁC, was bubbled into the reaction
mixture at ꢀ10 ꢁC by Ar. The mixture was stirred at ꢀ10 ꢁC for 1 h
and then kept at room temperature overnight. After quenching the
reaction by aqueous solution of saturated ammonium chloride
(NH4Cl) (100 mL) at ꢀ5 ꢁC, the reaction mixture was poured into
separatory funnel and separated. The aqueous layer was extracted
with DCM (150 mL ꢂ 3). The combined organic layers were dried
over anhydrous Na2SO4 and then evaporated under reduced pres-
sure, the crude product was purified by flash column chromatog-
raphy (200e300 mesh of silica gel, petroleum ether/ethyl acetate,
30:1) to afford the compound 4a (5.81 g, 40%) as a colorless liquid.
Infrared spectra were recorded in potassium bromide disks on a
PerkinElmer Spectrum 100 Ft-IR spectrophotometer; the 1H NMR
and 13C NMR spectra were recorded on a Bruker DPX 300 MHz NMR
spectrometer, chemical shift values were given in
d relative to TMS
in CDCl3; TLC was performed on precoated silica gel GF254; column
chromatography was performed on silica gel (Merck, 200e
300 mesh); mass spectra (MS) was performed on a Agilent 1100
LCeMS instrument with the electrospray ionization (ESI) mode;
high-resolution mass spectra (HRMS) were obtained on an Agilent
TOF (G1969A) mass spectrometer; elemental analysis was per-
formed on Elementar Vario EL (Germany); melting points were
measured on a ColeeParmer melting-point apparatus and were
uncorrected. Unless otherwise indicated, all the materials were
obtained from commercially available sources and were used
without further purification.
IR
n
(KBr, cmꢀ1): 2930, 2860, 1718, 1700, 1629, 1156; 1H NMR
1.28e1.32 (br, 12H), 1.46e1.55 (m, 13H), 2.36 (t,
(300 MHz, CDCl3):
d
4.2. 12a-Aza-pentadecanelactone tetrafluoroborate (2)
J ¼ 6.8 Hz, 2H), 3.22 (s, 2H), 3.49 (s, 2H), 4.30 (s, 2H), 5.56 (d,
J ¼ 1.2 Hz, 1H), 6.21 (d, J ¼ 1.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
Compound 2 was synthesized in 85% yield according to the
procedure reported in Ref. [30].
d
24.97, 25.61, 25.71, 25.90, 26.07, 26.23, 27.05, 27.42, 27.64, 27.78,
28.04, 28.31, 28.57, 31.09, 47.07, 48.57, 64.49, 79.39, 79.44, 125.65,
140.45, 155.14, 155.52, 167.11; MS (ESI, m/z): 376.2 [M þ Na]þ.
4.3. tert-Butyloxycarbonyl-12a-aza-pentadecanelactone (3)
4.5. tert-Butyloxycarbonyl-12a-aza-2E-pentadecenelactone (4b)
(Boc)2O (1.20 g, 5.5 mmol) was added dropwise into a solution of
1-oxa-4-azacyclo-hexadecan-16-one (1.20 g, 5 mmol) in water
(H2O,10 mL), which was obtained from compound 2 by hydrolyzing
with saturated Na2CO3 solution. The mixture was stirred at room
temperature until the reaction was complete, and then extracted
with DCM (10 mL ꢂ 3). The organic layers were combined and dried
over anhydrous sodium sulfate (Na2SO4). After the solution was
removed by rotary evaporation, the crude mixture was purified by
flash column chromatography (200e300 mesh of silica gel, petro-
leum ether/ethyl acetate, 10:1) to afford the desired compound 3
A solution of compound 3 (6.8 g, 20 mmol) in THF (20 mL) was
added dropwise slowly into a solution of LDA (10 mL, 20 mmol) in
THF (20 mL) at ꢀ78 ꢁC under Ar in 1 h. A solution of PhSeBr (4.7 g,
20 mmol) in THF (20 mL) was added dropwise into the mixture in
1 h after the mixture was stirred at ꢀ78 ꢁC for 1 h. The mixture was
stirred at ꢀ10 ꢁC for 0.5 h and then kept at room temperature
overnight. After quenching the reaction by aqueous solution of
saturated NH4Cl (100 mL) at ꢀ5 ꢁC, the reaction mixture was
poured into separatory funnel and separated. The aqueous layer
was extracted with DCM (50 mL ꢂ 3). The combined organic layers
were dried over anhydrous Na2SO4 and then evaporated under
reduced pressure, the crude product was purified by flash column
chromatography (200e300 mesh of silica gel, toluene/ethyl acetate,
60:1) to afford the compound tert-butyl 16-oxo-15-(phenyl-
selanyl)-1-oxa-4-azacyclohexadecane-4-carboxylate (6.30 g, 63%)
(1.68 g, 98%) as a colorless liquid. IR
1696, 1459, 1409, 1366, 1158, 774; 1H NMR (300 MHz, CDCl3):
1.30e1.39 (m, 14H), 1.46 (s, 9H), 1.53e1.58 (m, 2H), 1.64e1.71 (m,
n
(KBr, cmꢀ1): 2931, 2860, 1739,
d
2H), 2.34 (t, J ¼ 7.1 Hz, 2H), 3.23e3.24 (m, 2H), 3.45 (s, 2H), 4.22 (t,
J ¼ 4.9 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 23.95, 25.02, 26.11,
26.14, 26.21, 26.55, 27.28, 28.44, 33.91, 47.05, 48.64, 64.13, 79.59,
173.69; Anal. Calcd. for C19H35NO4: C 66.83, H 10.33, N 4.10. Found:
C 66.73, H 10.28, N 4.14.
as a colorless liquid. IR
n
(KBr, cmꢀ1): 2929, 2858, 1731, 1696, 1578,
1.28e1.31 (br, 12H), 1.37e1.51
1159; 1H NMR (300 MHz, CDCl3):
d

X. Wang et al. / European Journal of Medicinal Chemistry 73 (2014) 286e294
289
Table 1
Structures, inhibition rate and log P values of the compounds 6aen and 10aer against S. sclerotiorum, P. oryzae, B. cinerea, R. solani and P. capsici (50
m
g/mL).
Comp.
XeY
A
R
Inhibit. rate (%)
Log Pa
S. sclerotiorum
P. oryzae
B. cinerea
R. solani
P. capsici
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
CH2]CeCH2
CH2]CeCH2
CH2]CeCH2
CH2]CeCH2
CH2]CeCH2
CH2]CeCH2
CH2]CeCH2
CH]CH
CH]CH
CH]CH
CH]CH
CH]CH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
C6H5SO2
39.01
32.46
65.45
55.24
55.76
67.80
75.39
45.81
46.86
44.24
26.71
38.22
36.39
67.28
26.29
14.74
21.12
43.03
22.71
28.29
20.72
11.16
5.58
35.46
23.90
39.04
38.65
54.98
61.35
48.61
51.39
53.78
96.07
42.13
37.88
84.68
82.55
81.28
78.30
84.68
54.90
44.26
47.24
41.28
40.43
37.88
64.26
2.61
22.55
15.17
39.35
45.91
36.48
34.84
44.27
17.63
15.17
17.63
16.81
12.71
30.33
31.15
31.58
30.41
32.16
20.47
29.82
43.27
39.77
35.09
34.50
54.39
45.61
44.44
56.14
63.16
64.33
56.14
53.80
47.37
87.81
22.32
18.08
4.47
5.81
8.49
32.13
27.66
42.74
41.62
45.53
46.37
37.43
44.70
27.10
42.46
32.13
37.99
24.31
52.80
5.47
7.03
3.52
14.84
3.13
4.30
0.78
3.91
0.39
2.34
5.63
6.04
5.69
5.53
5.57
5.59
5.97
5.30
5.75
5.36
5.20
5.24
5.26
5.64
3.27
4.80
5.25
5.43
5.46
5.48
5.61
4.74
4.76
3.25
4.46
4.90
5.09
5.11
5.13
5.26
4.39
4.41
p-CH3C6H4SO2
p-CH3OC6H4SO2
p-CH3COC6H4SO2
m-NO2C6H4SO2
p-NO2C6H4SO2
p-ClC6H4CO
C6H5SO2
p-CH3C6H4SO2
p-CH3OC6H4SO2
p-CH3COC6H4SO2
m-NO2C6H4SO2
p-NO2C6H4SO2
p-ClC6H4CO
CH3SO2
11.61
35.49
33.71
36.39
23.22
22.77
16.97
26.79
46.65
15.18
15.95
37.74
38.52
8.95
CH]CH
CH]CH
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
Chlorothalonil
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
CH2eCH2
C6H5SO2
5.22
p-CH3C6H4SO2
o-ClC6H4SO2
m-ClC6H4SO2
p-ClC6H4SO2
p-BrC6H4SO2
m-NO2C6H4SO2
p-NO2C6H4SO2
CH3CO
C6H5CO
p-CH3C6H4CO
o-ClC6H4CO
m-ClC6H4CO
p-ClC6H4CO
p-BrC6H4CO
m-NO2C6H4CO
p-NO2C6H4CO
16.09
29.13
3.91
13.48
3.04
3.91
5.22
9.57
21.30
14.35
24.35
31.30
42.17
24.35
42.17
56.09
84.68
35.80
1.56
4.67
3.89
24.12
61.09
51.36
3.50
66.93
78.21
65.37
35.02
46.69
85.71
9.38
10.16
38.28
41.02
41.80
32.03
17.58
22.66
85.48
a
Log P, calculated on http://www.molinspiration.com.
(m, 13H), 1.77e1.81 (m, 1H), 1.96e2.04 (m, 1H), 3.04 (br, 1H), 3.33
(br, 3H), 3.45 (s, 2H), 4.22 (s, 2H), 3.66 (m, 1H), 3.96 (t, J ¼ 5.4 Hz,
2H), 4.29 (s, 2H), 7.27e7.37 (m, 3H), 7.58e7.61 (m, 2H); 13C NMR
122.04, 149.45, 155.19, 155.41, 165.77; MS (ESI, m/z): 362.2
[M þ Na]þ, HRMS (m/z) calcd for C19H34NO4 [M þ H]þ 340.24824,
found 340.24774.
(75 MHz, CDCl3):
d 25.89, 26.07, 26.36, 26.61, 28.31, 28.88, 29.36,
31.00, 31.74, 33.98, 38.83, 46.85, 48.22, 64.55, 79.43, 127.71, 128.44,
128.86, 135.67, 155.02, 172.82; MS (ESI, m/z): 496.2 [M ꢀ H]ꢀ.
A solution of H2O2 (2.4 g, 21 mmol, 30%) was added dropwise
into a solution of tert-butyl 16-oxo-15-(phenylselanyl)-1-oxa-4-
azacyclohexadecane-4-carboxylate (2.09 g, 4.2 mmol) and pyri-
dine (0.66 g, 8.4 mmol) in DCM (15 mL) at 0 ꢁC. The mixture was
stirred at room temperature for 3 h. After quenching the reaction by
H2O (10 mL), the reaction mixture was poured into separatory
funnel and separated. The aqueous layer was extracted with DCM
(10 mL ꢂ 3). The combined organic layers were dried over anhy-
drous Na2SO4 and then evaporated under reduced pressure, the
crude product was purified by flash column chromatography (200e
300 mesh of silica gel, petroleum ether/ethyl acetate, 20:1) to afford
the compound 4b (1.20 g, 84%) as a colorless solid. M.p. 38e40 ꢁC;
4.6. 2-Methylene-12a-aza-pentadecanelactone hydrochloride (5a)
CF3COOH (8.80 g, 77 mmol) was added dropwise into a solution
of compound 4a (5.40 g, 15 mmol) in DCM (30 mL) at room tem-
perature. After the mixture was stirred for 3 h, a solution of satu-
rated sodium bicarbonate (NaHCO3) was added into the reaction
mixture to make the solution to be basic after evaporating of
CF3COOH in vacuum. The aqueous layer was extracted with DCM
(50 mL ꢂ 3). The combined organic layers were dried over anhy-
drous Na2SO4 and then evaporated under reduced pressure to give
15-methylene-1-oxa-4-azacyclohexadecan-16-one (3.70 g, 95%) as
a light yellow solid. The ethereal hydrogen chloride (3 mL) was
added
into
a
solution
of
15-methylene-1-oxa-4-
azacyclohexadecan-16-one (0.40 g, 1.7 mmol) in anhydrous
diethyl ether (Et2O, 10 mL) at room temperature. The precipitate
was dried to give compound 5a (0.41 g, 89%) as a white solid. M.p.
IR
(300 MHz, CDCl3):
(m, 2H), 3.20 (s, 2H), 3.47e3.53 (m, 2H), 4.30 (s, 2H), 5.84e5.90 (m,
1H), 6.89e6.99 (m, 1H); 13C NMR (75 MHz, CDCl3):
25.08, 25.29,
25.46, 26.40, 26.48, 27.80, 28.24, 30.70, 47.17, 49.49, 64.71, 79.27,
n
(KBr, cmꢀ1): 2931, 2858, 1724, 1697, 1655, 1159; 1H NMR
1.30 (br, 10H), 1.44e1.56 (m, 13H), 2.24e2.31
d
135e136 ꢁC. IR
(300 MHz, CDCl3):
1.91 (m, 2H), 2.38 (t, J ¼ 7.0 Hz, 2H), 3.05 (s, 2H), 3.39 (s, 2H), 4.58 (t,
n
(KBr, cmꢀ1): 2932, 2858, 1701, 1626, 1146; 1H NMR
d
d 1.30e1.33 (m, 10H), 1.46e1.52 (m, 4H), 1.86e

290
X. Wang et al. / European Journal of Medicinal Chemistry 73 (2014) 286e294
J ¼ 4.2 Hz, 2H), 5.62 (d, J ¼ 1.0 Hz, 1H), 6.35 (br, s, 1H), 9.80 (s, 2H);
13C NMR (75 MHz, CDCl3):
24.51, 24.72, 25.52, 25.58, 25.74, 25.82,
25.87, 26.42, 31.05, 44.89, 46.17, 59.81, 126.93, 139.49, 166.59; MS
(ESI, m/z): 254.1 [M ꢀ Cl]þ; HRMS (m/z) calcd for C15H28NO2
[M ꢀ Cl]þ 254.21146, found 254.21133.
4.8.3. 12a-N-((4-Methoxyphenyl)sulfonyl)-2-methylene-12a-aza-
d
pentadecanelactone (6c)
White solid (67% yield); m.p.: 73e74 ꢁC; IR (KBr, cmꢀ1): 2928,
n
2859, 1715, 1636, 1598, 1338, 1160; 1H NMR (300 MHz, CDCl3):
1.27e1.31 (br, 12H), 1.46e1.57 (m, 4H), 2.31e2.36 (m, 2H), 3.11 (t,
d
J ¼ 7.5 Hz, 2H), 3.39 (t, J ¼ 5.1 Hz, 2H), 3.87 (s, 3H), 4.34 (t, J ¼ 4.9 Hz,
4.7. 12a-Aza-2E-pentadecenelactone hydrochloride (5b)
2H), 5.56 (d, J ¼ 1.4 Hz, 1H), 6.19 (d, J ¼ 1.4 Hz, 1H), 6.95e7.00 (m,
2H), 7.72e7.77 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 24.75, 25.57,
CF3COOH (2.00 g, 18 mmol) was added dropwise into a solution
of compound 4b (1.20 g, 3.5 mmol) in DCM (5 mL) at room tem-
perature. After the mixture was stirred for 3 h, a saturated aqueous
solution of NaHCO3 was added into the reaction mixture to make
the solution to be basic. The aqueous layer was extracted with DCM
(15 mL ꢂ 3). The combined organic layers were dried over anhy-
drous Na2SO4 and then evaporated under reduced pressure to give
12a-aza-2E-pentadecenelactone (0.75 g, 90%) as a light yellow
viscous liquid. The ethereal hydrogen chloride (3 mL) was added
25.60, 25.68, 25.93, 26.54, 26.58, 27.81, 29.46, 31.03, 47.76, 49.75,
55.40, 63.95, 114.07, 125.83, 129.03, 130.66, 140.22, 162.64, 166.92;
MS (ESI, m/z): 424.2 [M þ H]þ; HRMS (m/z) calcd for C22H34NO5S
[M þ H]þ 424.21522, found 424.21457.
4.8.4. 12a-N-((4-Acetylphenyl)sulfonyl)-2-methylene-12a-aza-
pentadecanelactone (6d)
Light yellow liquid (59% yield); IR
n
(KBr, cmꢀ1): 2930, 2859,
1716, 1693, 1629, 1596, 1345, 1163; 1H NMR (300 MHz, CDCl3):
into
a solution of 12a-aza-2E-pentadecenelactone (0.40 g,
d
1.27e1.31 (br, 12H), 1.46e1.58 (m, 4H), 2.33 (t, J ¼ 6.7 Hz, 2H), 2.66
1.7 mmol) in anhydrous Et2O (10 mL) at room temperature. The
(s, 3H), 3.17 (t, J ¼ 7.5 Hz, 2H), 3.45 (t, J ¼ 5.0 Hz, 2H), 4.35 (t,
J ¼ 4.8 Hz, 2H), 5.57 (d, J ¼ 1.4 Hz, 1H), 6.18 (d, J ¼ 1.4 Hz, 1H), 7.90e
precipitate was dried to give compound 5b (0.39 g, 89%) as a white
solid. M.p. 168e169 ꢁC. IR
n
(KBr, cmꢀ1): 2936, 2858, 1719, 1642,
7.93 (m, 2H), 8.06e8.10 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 24.67,
1250; 1H NMR (300 MHz, CDCl3):
d 1.25e1.44 (m, 10H), 1.51e1.59
25.50, 25.55, 25.62, 25.83, 26.45, 26.49, 26.63, 27.79, 30.95, 47.80,
49.82, 63.70, 125.98, 127.15, 128.79, 139.69, 140.08, 143.03, 166.84,
196.48; MS (ESI, m/z): 436.2 [M þ H]þ; HRMS (m/z) calcd for
(m, 2H), 1.79e1.89 (m, 2H), 2.26e2.32 (m, 2H), 3.11e3.13 (m, 2H),
3.37 (s, 2H), 4.61 (t, J ¼ 4.3 Hz, 2H), 5.86 (d, J ¼ 15.7 Hz, 1H), 7.02e
7.12 (m, 1H), 9.80 (s, 2H); 13C NMR (75 MHz, CDCl3):
d 24.64, 24.74,
C
23H34NO5S [M þ H]þ 436.21522, found 436.21457.
24.89, 25.18, 25.40, 25.99, 30.98, 44.39, 46.53, 59.58, 121.21, 151.36,
164.74; MS (ESI, m/z): 240.1 [M ꢀ Cl]þ; HRMS (m/z) calcd for
C
14H27NO2 [M ꢀ Cl]þ 240.19581, found 240.19574.
4.8.5. 12a-N-((3-Nitrophenyl)sulfonyl)-2-methylene-12a-aza-
pentadecanelactone (6e)
4.8. General procedure for the preparation of title compounds 6aen
White solid (69% yield); m.p.: 67e68 ꢁC; IR (KBr, cmꢀ1): 2928,
n
2858, 1717, 1630, 1536, 1349, 1168; 1H NMR (300 MHz, CDCl3):
Substituted sulfonyl chlorides/acyl chlorides (0.8 mmol) were
d
1.28e1.33 (br, 12H), 1.46e1.60 (m, 4H), 2.34 (t, J ¼ 6.2 Hz, 2H), 3.22
added dropwise into
a
suspension of compound 5a or 5b
(t, J ¼ 7.6 Hz, 2H), 3.49 (t, J ¼ 5.1 Hz, 2H), 4.37 (t, J ¼ 4.9 Hz, 2H), 5.57
(d, J ¼ 1.4 Hz, 1H), 6.19 (d, J ¼ 1.4 Hz, 1H), 7.74 (t, J ¼ 8.0 Hz, 1H),
8.14e8.17 (m, 1H), 8.42e8.46 (m, 1H), 8.64e8.66 (m, 1H); 13C NMR
(0.4 mmol), K2CO3 (0.12 g, 0.8 mmol) and DCM (10 mL) at room
temperature. The mixture was stirred and monitored by TLC till TLC
(petroleum ether/ethyl acetate, 5:1) showed the reaction was
complete. After removal of the insoluble solid by filter, the solvent
was purified by flash column chromatography (200e300 mesh of
silica gel, petroleum ether/ethyl acetate, 5:1) to yield the title
compounds 6aen.
(75 MHz, CDCl3):
d 24.90, 24.99, 25.16, 25.24, 26.60, 26.83, 29.00,
30.60, 47.77, 50.45, 64.71, 121.51, 122.10, 126.97, 130.54, 132.48,
141.83,148.32,150.40,165.66; MS (ESI, m/z): 439.2 [M þ H]þ; HRMS
(m/z) calcd for C21H31N2O6S [M þ H]þ 439.18973, found 439.18900.
4.8.6. 12a-N-((4-Nitrophenyl)sulfonyl)-2-methylene-12a-aza-
4.8.1. 12a-N-(Phenylsulfonyl)-2-methylene-12a-aza-
pentadecanelactone (6f)
pentadecanelactone (6a)
White solid (80% yield); m.p.: 62e63 ꢁC; IR (KBr, cmꢀ1): 2928,
n
Light yellow liquid (80% yield); IR
n
(KBr, cmꢀ1): 2930, 2859,
1.28e1.32
2860, 1707, 1623, 1530, 1348, 1168; 1H NMR (300 MHz, CDCl3):
1.29e1.31 (br, 12H), 1.46e1.62 (m, 4H), 2.31e2.36 (m, 2H), 3.20 (t,
1716,1628,1600,1343,1170; 1H NMR (300 MHz, CDCl3):
d
d
(br, 12H), 1.47e1.64 (m, 4H), 2.32e2.36 (m, 2H), 3.15 (t, J ¼ 7.6 Hz,
2H), 3.43 (t, J ¼ 5.1 Hz, 2H), 4.35 (t, J ¼ 4.9 Hz, 2H), 5.56 (d, J ¼ 1.4 Hz,
1H), 6.19 (d, J ¼ 1.4 Hz, 1H), 7.49e7.62 (m, 3H), 7.81e7.84 (m, 2H);
J ¼ 7.5 Hz, 2H), 3.48 (t, J ¼ 5.1 Hz, 2H), 4.36 (t, J ¼ 4.9 Hz, 2H), 5.58 (d,
J ¼ 1.4 Hz, 1H), 6.19 (d, J ¼ 1.4 Hz, 1H), 8.00e8.03 (m, 2H), 8.35e8.38
(m, 2H); 13C NMR (75 MHz, CDCl3):
d 24.78, 25.62, 25.67, 25.75,
13C NMR (75 MHz, CDCl3):
d 24.87, 25.70, 25.79, 26.06, 26.68, 26.70,
25.93, 26.53, 26.64, 27.89, 31.06, 47.97, 50.01, 63.67, 124.34, 126.23,
128.22, 140.16, 145.26, 149.90, 166.95; MS (ESI, m/z): 437.1
[M ꢀ H]ꢀ; HRMS (m/z) calcd for C21H31N2O6S [M þ H]þ 439.18973,
found 439.18918.
27.94, 31.18, 47.93, 49.96, 64.06, 126.13, 127.09, 129.09, 132.53,
139.27, 140.30, 167.17; MS (ESI, m/z): 392.2 [M ꢀ H]ꢀ; HRMS (m/z)
calcd for C21H32NO4S [M þ H]þ 394.20466, found 394.20395.
4.8.2. 12a-N-((4-Methylphenyl)sulfonyl)-2-methylene-12a-aza-
pentadecanelactone (6b)
4.8.7. 12a-N-(4-Chlorobenzoyl)-2-methylene-12a-aza-
Light yellow liquid (79% yield); IR
n
(KBr, cmꢀ1): 2930, 2859,
1.26e1.30
pentadecanelactone (6g)
1718, 1628, 1598, 1341, 1170; 1H NMR (300 MHz, CDCl3):
d
Light yellow liquid (78% yield); IR
n
(KBr, cmꢀ1): 2930, 2859,
1.26e1.32 (br,
(br, 12H), 1.4e1.54 (m, 4H), 2.32 (t, J ¼ 6.7 Hz, 2H), 2.41 (s, 3H), 3.11
(t, J ¼ 7.5 Hz, 2H), 3.38 (t, J ¼ 5.1 Hz, 2H), 4.33 (t, J ¼ 4.9 Hz, 2H), 5.54
(d, J ¼ 1.4 Hz, 1H), 6.17 (d, J ¼ 1.4 Hz, 1H), 7.29 (d, J ¼ 8.0 Hz, 2H),
1718, 1638, 1597, 1165; 1H NMR (300 MHz, CDCl3):
d
14H), 1.46e1.56 (m, 4H), 2.38 (t, J ¼ 6.7 Hz, 2H), 3.22e3.75 (m, 4H),
4.20e4.51 (m, 2H), 5.58 (d, J ¼ 1.1 Hz,1H), 6.20 (s,1H), 7.30e7.40 (m,
7.67e7.70 (m, 2H); 13C NMR (75 MHz, CDCl3):
d
21.36, 24.81, 25.63,
4H); 13C NMR (75 MHz, CDCl3):
d 24.82, 25.43, 25.66, 25.69, 25.88,
25.65, 25.73, 25.99, 26.61, 26.64, 27.89, 31.11, 47.86, 49.87, 64.02,
125.97, 127.07, 129.61, 136.17, 140.27, 143.21, 167.06; MS (ESI, m/z):
408.2 [M þ H]þ; HRMS (m/z) calcd for C22H34NO4S [M þ H]þ
408.22031, found 408.21970.
26.06, 26.26, 26.92, 27.25, 31.10, 45.56, 50.54, 63.53, 125.71, 127.88,
128.34, 134.88, 135.27, 140.28, 166.91, 170.73; MS (ESI, m/z): 392.2
[M þ H]þ; HRMS (m/z) calcd for C22H31ClNO3 [M þ H]þ 392.19870,
found 392.19855.

X. Wang et al. / European Journal of Medicinal Chemistry 73 (2014) 286e294
291
4.8.8. 12a-N-(Phenylsulfonyl)-12a-aza-2E-pentadecenelactone
(6h)
White solid (86% yield); m.p.: 64e65 ꢁC; IR
2861, 1725, 1657, 1600, 1338, 1162; 1H NMR (300 MHz, CDCl3):
1.18e1.26 (br, 10H), 1.46e1.60 (m, 4H), 2.24e2.30 (m, 2H), 3.15e
4.8.13. 12a-N-4-((4-Nitrophenyl)sulfonyl)-12a-aza-2E-
pentadecenelactone (6m)
n
(KBr, cmꢀ1): 2936,
White solid (83% yield); m.p.: 120e122 ꢁC; IR
n
(KBr, cmꢀ1):
2938, 2859, 1703, 1653, 1605, 1531, 1347, 1162; 1H NMR (300 MHz,
d
CDCl3): d 1.18e1.26 (br, 10H), 1.46e1.60 (m, 4H), 2.25e2.31 (m, 2H),
3.20 (m, 2H), 3.44e3.46 (m, 2H), 4.33e4.36 (m, 2H), 5.80e5.87 (m,
3.23 (t, J ¼ 8.1 Hz, 2H), 3.50 (t, J ¼ 4.4 Hz, 2H), 4.36 (t, J ¼ 4.3 Hz, 2H),
1H), 6.87e6.95 (m, 1H), 7.49e7.59 (m, 3H), 7.80e7.83 (m, 2H); 13C
5.84 (d, J ¼ 15.7 Hz, 1H), 6.89e6.99 (m, 1H), 7.98e8.02 (m, 2H),
NMR (75 MHz, CDCl3):
d
24.93, 25.06, 25.19, 25.25, 26.61, 26.93,
8.36e8.39 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 24.91, 25.01, 25.15,
29.05, 30.56, 47.66, 50.27, 64.97, 121.68, 126.97, 129.03, 132.46,
139.33, 149.97, 165.74; MS (ESI, m/z): 378.1 [M ꢀ H]ꢀ; HRMS (m/z)
calcd for C20H30NO4S [M þ H]þ 380.18901, found 380.18884.
25.25, 26.61, 26.83, 28.92, 30.58, 47.70, 50.35, 64.76, 121.53, 124.37,
128.19,145.41,149.93,150.37,165.63; MS (ESI, m/z): 425.1 [M þ H]þ;
HRMS (m/z) calcd for C20H29N2O6S [M þ H]þ 425.17408, found
425.17399.
4.8.9. 12a-N-((4-Methylphenyl)sulfonyl)-12a-aza-2E-
4.8.14. 12a-N-4-(4-Chlorobenzoyl)-12a-aza-2E-
pentadecenelactone (6i)
pentadecenelactone (6n)
White solid (82% yield); m.p.: 91e92 ꢁC; IR
n
(KBr, cmꢀ1): 2931,
White solid (39% yield); m.p.: 67e68 ꢁC; IR
n
(KBr, cmꢀ1): 2934,
1.09e
2855, 1721, 1654, 1600, 1336, 1157; 1H NMR (300 MHz, CDCl3):
1.17e1.26 (br, 10H), 1.45e1.59 (m, 4H), 2.24e2.30 (m, 2H), 2.43 (s,
2857, 1726, 1660, 1630, 1600; 1H NMR (300 MHz, CDCl3):
d
d
1.27 (br, 10H), 1.54 (br, 4H), 2.28 (br, 2H), 3.25e3.79 (br, 4H), 4.22e
4.52 (br, 2H), 5.88 (d, J ¼ 15.6 Hz, 1H), 6.91e7.01 (m, 1H), 7.32e7.40
3H), 3.15 (t, J ¼ 8.0 Hz, 2H), 3.42 (t, J ¼ 4.4 Hz, 2H), 4.34 (t, J ¼ 4.3 Hz,
2H), 5.84 (d, J ¼ 15.7 Hz, 1H), 6.88e6.98 (m, 1H), 7.31 (d, J ¼ 8.0 Hz,
(m, 4H); 13C NMR (75 MHz, CDCl3):
d 13.97, 20.78, 24.56, 25.10,
2H), 7.69 (d, J ¼ 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 21.43,
25.28, 26.42, 28.15, 30.48, 44.78, 44.81, 50.55, 63.81, 121.84, 127.76,
128.50, 134.92, 135.16, 149.94, 165.57, 170.64, 170.77; MS (ESI, m/z):
378.1 [M þ H]þ; HRMS (m/z) calcd for C21H29ClNO3 [M þ H]þ
378.18305, found 378.18289.
24.98, 25.13, 25.26, 25.30, 26.66, 26.99, 29.12, 30.63, 47.69, 50.31,
65.07, 121.76, 127.09, 129.68, 136.41, 143.25, 150.01, 165.85; MS (ESI,
m/z): 394.2 [M þ H]þ; HRMS (m/z) calcd for C21H32NO4S [M þ H]þ
394.20466, found 394.20407.
4.9. N-(2-Azidoethyl)laurolactam (7)
4.8.10. 12a-N-4-((4-Methoxyphenyl)sulfonyl)-12a-aza-2E-
pentadecenelactone (6j)
2-Azidoethanol (10.4 g, 120 mmol) was added dropwise to a
solution of BF3$Et2O (31.8 g, 220 mmol, 47%) and cyclododecanone
(18.2 g, 100 mmol) in 250 mL three-necked flask under stirring at
35 ꢁC for 1 h. The solution was then heated up to 65 ꢁC in 1 h and
stirred for 12 h. After cooling to room temperature, the reaction
mixture was washed with anhydrous Et2O (50 mL ꢂ 3) and the
lower light yellow viscous liquid was separated. After DCM (50 mL)
was added, the mixture was washed with distilled H2O (30 mL ꢂ 3).
The organic layer was dried over anhydrous Na2SO4 and then
separated and evaporated to dryness to give the intermediate,
iminium ether fluoroborate (29.1 g, 94%) as a yellow viscous liquid.
White solid (45% yield); m.p.: 79e80 ꢁC; IR (KBr, cmꢀ1): 2927,
n
2863, 1717, 1651, 1597, 1336, 1150; 1H NMR (300 MHz, CDCl3):
1.18e1.26 (br, 10H), 1.45e1.57 (m, 4H), 2.24e2.30 (m, 2H), 2.66 (s,
d
3H), 3.20 (t, J ¼ 8.0 Hz, 2H), 3.47 (t, J ¼ 4.4 Hz, 2H), 4.34e4.36 (m,
2H), 5.81e5.87 (m, 1H), 6.88e6.98 (m, 1H), 7.88e7.92 (m, 2H),
8.07e8.10 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 24.92, 25.07, 25.22,
25.24, 26.61, 26.96, 29.09, 30.58, 47.62, 50.25, 55.51, 65.01, 114.17,
121.70, 129.11, 130.92, 149.97, 162.72, 165.82; MS (ESI, m/z): 410.1
[M þ H]þ; HRMS (m/z) calcd for C21H32NO5S [M þ H]þ 410.19957,
found 410.19928.
1H NMR (300 MHz, CDCl3):
d 1.34e1.39 (br, 14H), 1.83e1.85 (br, 4H),
2.81 (t, J ¼ 7.0 Hz, 2H), 3.79 (t, J ¼ 6.5 Hz, 2H), 4.24 (t, J ¼ 10.0 Hz,
4.8.11. 12a-N-4-((4-Acetylphenyl)sulfonyl)-12a-aza-2E-
2H), 5.02 (t, J ¼ 10.2 Hz, 2H).
pentadecenelactone (6k)
NaN3 (12.1 g, 190 mmol) was added in portion to a solution of
iminium ether fluoroborate (51.8 g, 170 mmol) in anhydrous DMF
(200 mL). The reaction mixture was stirred at room temperature for
0.5 h and then kept at 70 ꢁC for 16 h. After cooling to room tem-
perature, the reaction solution was diluted with H2O (150 mL), then
extracted with Et2O (100 mL ꢂ 4). The combined organic layers
were dried over anhydrous Na2SO4. After the solution was removed
by rotary evaporation, the crude mixture was purified by flash
column chromatography (200e300 mesh of silica gel, petroleum
ether/ethyl acetate, 2:1) to afford the desired compound 7 (37.8 g,
White solid (57% yield); m.p.: 95e96 ꢁC; IR (KBr, cmꢀ1): 2932,
n
2858, 1710, 1691, 1653, 1596, 1346, 1159; 1H NMR (300 MHz, CDCl3):
1.18e1.26 (br, 10H), 1.45e1.57 (m, 4H), 2.24e2.30 (m, 2H), 2.66 (s,
d
3H), 3.20 (t, J ¼ 8.0 Hz, 2H), 3.47 (t, J ¼ 4.4 Hz, 2H), 4.34e4.37 (m,
2H), 5.82e5.87 (m, 1H), 6.88e6.98 (m, 1H), 7.88e7.92 (m, 2H),
8.07e8.10 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 24.94, 25.06, 25.19,
25.28, 26.63, 26.75, 26.89, 28.97, 30.59, 47.67, 50.30, 64.90, 121.63,
127.27, 128.92, 139.87, 143.41, 150.19, 165.71, 196.59; MS (ESI, m/z):
422.2 [M þ H]þ; HRMS (m/z) calcd for C22H32NO5S [M þ H]þ
422.19957, found 422.19919.
85%) as a light yellow liquid. 1H NMR (300 MHz, CDCl3):
d 1.32e1.43
(br, 16H), 1.65e1.80 (m, 4H), 2.31e2.36 (m, 2H), 3.32e3.38 (m, 2H),
3.43e3.51 (m, 4H).
4.8.12. 12a-N-4-((3-Nitrophenyl)sulfonyl)-12a-aza-2E-
pentadecenelactone (6l)
White solid (84% yield); m.p.: 88e89 ꢁC; IR
n
(KBr, cmꢀ1): 2934,
4.10. N-(2-Aminoethyl)laurolactam (8)
2859, 1718,1656, 1608, 1536, 1354, 1166; 1H NMR (300 MHz, CDCl3):
1.22e1.26 (br, 10H), 1.53e1.59 (m, 4H), 2.27e2.29 (m, 2H), 3.21e
d
PPh3 (8.0 g, 31 mmol) was added in portions to a solution of the
compound 7 (7.9 g, 30 mmol) in anhydrous THF (20 mL). The re-
action mixture was stirred at room temperature for 5 h. H2O
(10 mL) was added into the reaction mixture, then stirred at room
temperature for 5 h. Et2O (10 mL) was added and the insoluble solid
was filtered. The filter was dried over anhydrous Na2CO3. The so-
lution was removed by rotary evaporation to afford the desired
compound 8 (6.5 g, 90%) as a light yellow liquid. 1H NMR (300 MHz,
3.27 (m, 2H), 3.49e3.52 (m, 2H), 4.36e4.39 (m, 2H), 5.82e5.87 (m,
1H), 6.92e6.97 (m, 1H), 7.76 (t, J ¼ 7.9 Hz, 1H), 8.13e8.16 (m, 1H),
8.42e8.46 (m, 1H), 8.64e8.66 (m, 1H); 13C NMR (75 MHz, CDCl3):
d
24.90, 24.99, 25.16, 25.24, 26.60, 26.83, 29.00, 30.60, 47.77, 50.45,
64.71, 121.51, 122.09, 126.97, 130.54, 132.48, 141.83, 148.32, 150.39,
165.66; MS (ESI, m/z): 425.1 [M þ H]þ; HRMS (m/z) calcd for
C
20H29N2O6S [M þ H]þ 425.17408, found 425.17346.

292
X. Wang et al. / European Journal of Medicinal Chemistry 73 (2014) 286e294
CDCl3):
d
1.22e1.44 (br, 14H), 1.64e1.80 (m, 4H), 2.31e2.36 (m, 2H),
(m, 2H), 6.32 (s, 1H), 7.33 (d, J ¼ 8.0 Hz, 2H), 7.66e7.69 (m, 2H); 13
C
2.83e2.89 (m, 2H), 3.35e3.42 (m, 2H), 3.63e3.73 (m, 2H).
NMR (75 MHz, CDCl3): d 21.49, 24.54, 25.12, 25.90, 26.00, 26.36,
26.41, 26.82, 27.08, 28.98, 35.93, 39.16, 48.90, 51.30, 127.29, 129.84,
134.83,143.71,173.59; Anal. Calcd. for C21H34N2O3S: C 63.92, H 8.69,
N 7.10. Found: C 63.84, H 8.69, N 7.14.
4.11. 12a-Aza-pentadecanelactam (9)
TsOH (0.09 g, 0.5 mmol) was added into a solution of the com-
pound 8 (6.5 g, 27 mmol) in xylene (30 mL), and the mixture was
stirred for 50 h under refluxing and Argon conditions. After
removal of xylene by evaporation, a brown liquid was obtained and
then dissolved in acetone (15 mL). After KOH solution (20 mL,
2 mol/L) was added, the mixture was stirred at room temperature
for 7 h. The acetone was stripped by rotary evaporation, and the
aqueous layer was extracted with DCM (20 mL). The organic layers
were dried over anhydrous Na2SO4. After the solution was removed
by rotary evaporation, the crude mixture was purified by flash
column chromatography (200e300 mesh of silica gel, CHCl3/
CH3OH/NH4OH, 9:1:1) to afford the desired compound 9 (4.1 g,
4.12.4. 12a-N-((2-Chlorophenyl)sulfonyl)-12a-aza-
pentadecanelactam (10d)
Light yellow liquid (71% yield); IR
2858, 1650, 1538, 1455, 1336, 1158, 760; 1H NMR (300 MHz, CDCl3):
1.26e1.34 (br, 15H), 1.55e1.71 (m, 4H), 2.22e2.27 (m, 2H), 3.33e
n
(KBr, cmꢀ1): 3300, 2931,
d
3.38 (m, 4H), 3.43e3.48 (m, 2H), 6.38 (s, 1H), 7.39e7.45 (m, 1H),
7.48e7.56 (m, 2H), 8.05e8.09 (m, 1H); 13C NMR (75 MHz, CDCl3):
d
24.32, 24.66, 25.74, 25.89, 26.12, 26.33, 26.69, 26.89, 28.25, 35.59,
38.69, 47.71, 49.99, 126.95, 131.71, 131.87, 132.00, 133.57,
136.81,173.44; HRMS (m/z) calcd for C20H31ClN2O3S [M þ H]þ
415.18167, found 415.18207.
69%) as a light yellow solid. M.p.: 78e81 ꢁC; IR
3288, 2926, 2858, 1631, 1553, 1461; 1H NMR (300 MHz, CDCl3):
1.24e1.50 (br, 16H), 1.62e1.69 (m, 2H), 2.22 (t, J ¼ 6.6 Hz, 2H), 2.62
(t, J ¼ 5.5 Hz, 2H), 2.76 (t, J ¼ 5.6 Hz, 2H), 3.32e3.38 (m, 2H), 6.33
(br, 1H); 13C NMR (75 MHz, CDCl3):
25.10, 25.18, 25.96, 26.12,
n
(KBr, cmꢀ1): 3327,
4.12.5. 12a-N-((3-Chlorophenyl)sulfonyl)-12a-aza-
d
pentadecanelactam (10e)
White solid (87% yield); m.p.: 126e127 ꢁC; IR
n
(KBr, cmꢀ1):
d
3332, 2931, 2858, 1644, 1543, 1464, 1340, 1165, 875, 689; 1H NMR
(300 MHz, CDCl3): 1.34 (br, 14H), 1.58e1.71 (m, 4H), 2.26 (t,
26.39, 26.63, 26.71, 27.32, 28.74, 36.17, 38.57, 47.58, 48.01, 173.24.
MS (ESI, m/z): 241.0 [M þ H]þ, HRMS (m/z) calcd for C14H28N2O
[M þ H]þ 241.22744, found 241.22723.
d
J ¼ 6.3 Hz, 2H), 3.10e3.19 (m, 4H), 3.47e3.52 (m, 2H), 6.23 (br, 1H),
7.26e7.49 (m, 1H), 7.51e7.61 (m, 1H), 7.66e7.70 (m, 1H), 7.78e7.79
(m, 1H); 13C NMR (75 MHz, CDCl3):
d 24.48, 25.08, 25.95, 26.07,
4.12. General procedure for the preparation of title compounds
10aer
26.31, 26.41, 26.84, 27.10, 28.86, 35.87, 39.18, 48.94, 51.28, 125.31,
127.29, 130.53, 132.99, 135.58, 139.82, 173.63; Anal. Calcd. for
C
6.77.
20H31ClN2O3S: C 57.88, H 7.53, N 6.75. Found: C 57.89, H 7.55, N
The sulfonyl chlorides/acyl chlorides (1.2 mmol) was added
dropwise into a suspension of compound 9 (0.9 mmol) and K2CO3
(0.27 g, 2.0 mmol) in DCM (10 mL) at room temperature. The
mixture was stirred until TLC (CHCl3/CH3OH, 9:1) showed the re-
action was complete. After removal of the insoluble solid through
filtering, the residue was purified by flash column chromatography
(200e300 mesh of silica gel, petroleum ether/ethyl acetate, 1:2) to
yield the title compounds 10aer.
4.12.6. 12a-N-((4-Chlorophenyl)sulfonyl)-12a-aza-
pentadecanelactam (10f)
White solid (42% yield); m.p.: 162e163 ꢁC; IR
n
(KBr, cmꢀ1):
3320, 2933, 2859, 1620, 1551, 1473, 1341, 1156, 1090, 828; 1H NMR
(300 MHz, CDCl3): d 1.34 (br, 14H), 1.56e1.63 (m, 2H) 1.66e1.70 (m,
2H), 2.26 (t, J ¼ 6.2 Hz, 2H), 3.07e3.16 (m, 4H), 3.46e3.52 (m, 2H),
6.25 (s, 1H), 7.50e7.55 (m, 2H), 7.71e7.76 (m, 2H); 13C NMR
4.12.1. 12a-N-(Methylsulfonyl)-12a-aza-pentadecanelactam (10a)
(75 MHz, CDCl3):
d 24.48, 25.09, 25.94, 26.04, 26.30, 26.40, 26.83,
White solid (86% yield); m.p.: 127e128 ꢁC; IR
n
(KBr, cmꢀ1):
27.10, 28.86, 35.89, 39.16, 48.93, 51.28, 128.66, 129.57, 136.46,
139.50, 173.58; Anal. Calcd. for C20H31ClN2O3S: C 57.88, H 7.53, N
6.75. Found: C 57.70, H 7.56, N 6.76.
3337, 2928, 2859, 1645, 1532, 1459, 1367, 1329, 1140; 1H NMR
(300 MHz, CDCl3): 1.26e1.38 (br, 16H), 1.59e1.69 (m, 4H), 2.23 (t,
d
J ¼ 6.4 Hz, 2H), 2.84 (s, 3H), 3.19 (t, J ¼ 7.0 Hz, 2H), 3.28e3.34 (m,
2H), 3.46e3.52 (m, 2H), 6.22 (s, 1H); 13C NMR (75 MHz, CDCl3):
4.12.7. 12a-N-((4-Bromophenyl)sulfonyl)-12a-aza-
pentadecanelactam (10g)
d
24.52, 24.90, 25.89, 26.10, 26.29, 26.46, 26.73, 27.10, 28.79, 35.81,
39.53, 48.70, 50.80, 173.96; Anal. Calcd. for C15H30N2O3S: C 56.57, H
9.49, N 8.80. Found: C 56.55, H 9.49, N 8.86.
White solid (77% yield); m.p.: 165e165 ꢁC; IR
n
(KBr, cmꢀ1):
3318, 2933, 2858, 1650, 1573, 1551, 1467, 1341, 1150, 1087, 824; 1H
NMR (300 MHz, CDCl3): 1.34 (br, 14H), 1.57e1.60 (m, 2H), 1.64e
d
4.12.2. 12a-N-(Phenylsulfonyl)-12a-aza-pentadecanelactam (10b)
White solid (63% yield); m.p.: 117e118 ꢁC; IR (KBr, cmꢀ1): 3375,
n
1.70 (m, 2H), 2.25 (t, J ¼ 6.4 Hz, 2H), 3.07e3.16 (m, 4H), 3.46e3.52
(m, 2H), 6.21 (s, 1H), 7.64e7.71 (m, 4H); 13C NMR (75 MHz, CDCl3):
2933, 2855, 1640, 1530, 1463, 1331, 1156, 730, 694; 1H NMR
(300 MHz, CDCl3): 1.34e1.38 (br, 14H), 1.56e1.61 (m, 2H), 1.66e
d
24.48, 25.09, 25.94, 26.04, 26.30, 26.40, 26.83, 27.10, 28.85, 35.89,
d
39.16, 48.93, 51.27, 127.94, 128.75. 132.56, 136.99, 173.58; Anal.
Calcd. for C20H31BrN2O3S: C 52.28, H 6.80, N 6.10. Found: C 52.23, H
6.80, N 6.11.
1.71 (m, 2H), 2.26 (t, J ¼ 6.3 Hz, 2H), 3.08e3.16 (m, 4H), 3.46e3.51
(m, 2H), 6.33 (s, 1H), 7.52e7.62 (m, 3H), 7.78e7.81 (m, 2H); 13C NMR
(75 MHz, CDCl3):
d 24.31, 24.85, 25.63, 25.74, 26.08, 26.15, 26.58,
26.82, 28.69, 35.69, 38.95, 48.63, 51.05, 127.02, 129.05, 132.68,
137.55, 173.43; Anal. Calcd. for C20H32N2O3S: C 63.12, H 8.48, N 7.36.
Found: C 63.14, H 8.47, N 7.40.
4.12.8. 12a-N-((3-Nitrophenyl)sulfonyl)-12a-aza-
pentadecanelactam (10h)
White solid (81% yield); m.p.: 140e141 ꢁC; IR
n
(KBr, cmꢀ1):
4.12.3. 12a-N-((4-Methylphenyl)sulfonyl)-12a-aza-
3297, 2931, 2862, 1636, 1563, 1537, 1467, 1340, 1173, 1071, 738; 1H
NMR (300 MHz, CDCl3): 1.35 (br, 14H), 1.59e1.71 (m, 4H), 2.27 (t,
pentadecanelactam (10c)
d
White solid (61% yield); m.p.: 118e119 ꢁC; IR
n
(KBr, cmꢀ1): 3341,
J ¼ 6.2 Hz, 2H), 3.15e3.24 (m, 4H), 3.50e3.55 (m, 2H), 6.21 (s, 1H),
2927, 2862, 1641, 1533, 1458, 1342, 1160, 807; 1H NMR (300 MHz,
CDCl3): 1.34e1.38 (br, 14H), 1.56e1.58 (m, 2H), 1.64e1.70 (m, 2H),
2.25 (t, J ¼ 7.5 Hz, 2H), 2.44 (s, 3H), 3.06e3.13 (m, 4H), 3.45e3.49
7.79 (t, J ¼ 8.0 Hz,1H), 8.13 (d, J ¼ 7.8 Hz,1H), 8.48 (d, J ¼ 8.2 Hz, 1H),
d
8.64 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 24.35, 24.95, 25.92, 26.03,
26.16, 26.34, 26.80, 27.05, 28.57, 35.79, 39.13, 48.87, 51.12, 122.30,

X. Wang et al. / European Journal of Medicinal Chemistry 73 (2014) 286e294
293
127.27, 130.66, 132.65, 140.47, 148.46, 173.62; Anal. Calcd. for
20H31N3O5S: C 56.45, H 7.34, N 9.87. Found: C 56.43, H 7.32, N 9.96.
167.59, 173.62; HRMS (m/z) calcd for C21H32ClN2O2 [M þ H]þ
C
379.21468, found 379.21436.
4.12.9. 12a-N-((4-Nitrophenyl)sulfonyl)-12a-aza-
pentadecanelactam (10i)
4.12.15. 12a-N-(4-Chlorobenzoyl)-12a-aza-pentadecanelactam
(10o)
White solid (81% yield); m.p.: 176e177 ꢁC; IR
n
(KBr, cmꢀ1):
White solid (48% yield); m.p.: 144e145 ꢁC; IR
n
(KBr, cmꢀ1):
3315, 2935, 2860, 1639, 1560, 1457, 1346, 1157, 1087, 856; 1H NMR
(300 MHz, CDCl3): d 1.22 (br, 14H), 1.47e1.51 (m, 4H), 2.06e2.10 (m,
3279, 2933, 2857, 1620, 1543, 1448, 698; 1H NMR (300 MHz, CDCl3):
1.25e1.33 (br, 14H), 1.53 (br, 2H), 1.68 (br, 2H), 2.17e2.21 (m, 2H),
3.34e3.63 (br, 6H), 6.69 (br, 1H), 7.27e7.42 (m, 4H); 13C NMR
(75 MHz, CDCl3): 24.60, 24.68, 26.01, 26.11, 26.60, 26.73, 27.20,
d
2H), 3.13e3.22 (m, 6H), 8.00 (s, 1H), 8.10 (d, J ¼ 8.8 Hz, 2H), 8.41 (d,
J ¼ 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 23.85, 24.16, 25.54,
d
25.72, 26.00, 26.16, 26.52, 26.63, 26.73, 34.60, 38.44, 47.66, 48.70,
124.84, 128.69, 144.53, 149.94, 172.69; Anal. Calcd. for C20H31N3O5S:
C 56.45, H 7.34, N 9.87. Found: C 56.01, H 7.34, N 9.73.
27.98, 36.05, 39.21, 46.60, 50.94, 128.19, 128.76, 134.83, 135.69,
172.15, 173.68; Anal. Calcd. for C21H31ClN2O2: C 66.56, H 8.25, N
7.39. Found: C 66.44, H 8.23, N 7.40.
4.12.10. 12a-N-Acetyl-12a-aza-pentadecanelactam (10j)
4.12.16. 12a-N-(4-Bromobenzoyl)-12a-aza-pentadecanelactam
Light yellow liquid (78% yield); IR
2858, 1633, 1545, 1443, 1371, 1264; 1H NMR (300 MHz, CDCl3):
1.25e1.35 (br, 15H), 1.56e1.67 (m, 4H), 2.14 (s, 3H), 2.17e2.21 (m,
2H), 3.34e3.39 (m, 2H), 3.45e3.51 (m, 4H), 6.63 (s, 1H); 13C NMR
(75 MHz, CDCl3): 21.26, 24.33, 24.54. 25.92, 26.06, 26.36, 26.46,
n
(KBr, cmꢀ1): 3296, 2930,
(10p)
White solid (85% yield); m.p.: 146e147 ꢁC; IR
n
(KBr, cmꢀ1):
d
3284, 2936, 2857, 1645, 1615, 1555, 1440, 833; 1H NMR (300 MHz,
CDCl3): 1.25e1.32 (br, 14H), 1.52 (br, 2H), 1.67 (br, 2H), 2.17e2.20
d
d
(br, 2H), 3.33 (br, 2H), 3.56e3.62 (br, 4H), 6.72 (br, 1H), 7.26 (d,
27.04, 27.77, 35.58, 38.81, 46.42, 49.87, 171.45, 173.51; HRMS (m/z)
calcd for C16H31N2O2 [M þ H]þ 283.23800, found 283.23801.
J ¼ 7.2 Hz, 2H), 7.56 (d, J ¼ 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d
24.23, 24.34, 25.73, 25.77, 26.28, 26.40, 26.42, 26.89, 27.49, 35.60,
38.60, 46.12, 50.48, 123.54, 128.04, 131.39, 135.03, 171.71, 173.45;
Anal. Calcd. for C21H31BrN2O2: C 59.57, H 7.38, N 6.62. Found: C
59.40, H 7.35, N 6.64.
4.12.11. 12a-N-Benzoyl-12a-aza-pentadecanelactam (10k)
White solid (48% yield); m.p.: 100e101 ꢁC; IR
n
(KBr, cmꢀ1):
3279, 2933, 2857, 1620, 1543, 1448, 698; 1H NMR (300 MHz, CDCl3):
1.24e1.33 (br, 14H), 1.51 (br, 2H), 1.68 (br, 2H), 2.20e2.21 (br, 2H),
3.35e3.67 (br, 6H), 6.80 (br, 1H), 7.37e7.44 (m, 5H); 13C NMR
(75 MHz, CDCl3): 24.59, 24.73, 25.93, 26.06, 26.58, 26.70, 27.15,
d
4.12.17. 12a-N-(3-Nitrobenzoyl)-12a-aza-pentadecanelactam (10q)
White solid (69% yield); m.p.: 109e110 ꢁC; IR (KBr, cmꢀ1): 3351,
n
d
2934, 2860, 1640, 1533, 1429, 1348, 810, 730; 1H NMR (300 MHz,
CDCl3): 1.25e1.34 (br, 14H), 1.56 (br, 2H), 1.69 (br, 2H), 2.21e2.25
28.05, 36.07, 39.38, 46.38, 50.95, 126.62, 128.44, 129.56, 136.43,
173.68; Anal. Calcd. for C21H32N2O2: C 73.22, H 9.36, N 8.13. Found:
C 72.94, H 9.31, N 8.12.
d
(br, 2H), 3.32 (br, 2H), 3.61e3.66 (br, 4H), 6.54 (br, 1H), 7.61e7.67
(m, 2H), 7.73e7.76 (m, 1H), 8.28e8.31 (m, 2H); 13C NMR (75 MHz,
CDCl3):
d 24.22, 24.25, 24.40, 25.08, 25.72, 26.21, 26.32, 26.38,
4.12.12. 12a-N-(4-Methylbenzoyl)-12a-aza-pentadecanelactam
26.93, 27.46, 30.52, 33.09, 35.56, 38.35, 46.27, 50.60, 121.52, 123.98,
129.51, 132.33, 137.83, 147.68, 169.88, 173.42; Anal. Calcd. for
(10l)
White solid (35% yield); m.p.: 115e116 ꢁC; IR
n
(KBr, cmꢀ1):
C21H31N3O4: C 64.76, H 8.02, N 10.79. Found: C 64.70, H 8.05, N
3284, 2936, 2857, 1645, 1615, 1555, 1440, 833; 1H NMR (300 MHz,
CDCl3): 1.24e1.33 (br, 14H), 1.52 (br, 2H), 1.68 (br, 2H), 2.17e2.24
(m, 2H), 2.38 (s, 3H), 3.39e3.63 (br, 6H), 6.83 (br, 1H), 7.19e7.22 (m,
2H), 7.27e7.29 (m, 2H); 13C NMR (75 MHz, CDCl3):
21.29, 24.60,
10.57.
d
4.12.18. 12a-N-(4-Nitrobenzoyl)-12a-aza-pentadecanelactam (10r)
d
White solid (56% yield); m.p.: 158e159 ꢁC; IR
n
(KBr, cmꢀ1):
24.70, 25.98, 26.11, 26.58, 26.72, 27.00, 27.15, 27.89, 35.97, 39.30,
46.56, 50.86, 126.68, 128.99, 133.53, 139.63, 173.36, 173.66; Anal.
Calcd. for C22H34N2O2: C 73.70, H 9.56, N 7.81. Found: C 73.58, H
9.53, N 7.84.
3270, 2933, 2858, 1626, 1601, 1522, 1443, 1352, 871; 1H NMR
(300 MHz, CDCl3): 1.16e1.34 (br, 14H), 1.51e1.56 (br, 2H), 1.65e
d
1.69 (br, 4H), 2.21e2.23 (br, 2H), 3.26e3.31 (br, 2H), 3.61e3.67 (br,
4H), 6.33 (br, 1H), 7.56 (d, J ¼ 8.4 Hz, 2H), 8.30 (d, J ¼ 8.7 Hz, 2H); 13
C
NMR (75 MHz, CDCl3):
d 24.14, 24.23, 24.29, 25.74, 26.30, 26.40,
4.12.13. 12a-N-(2-Chlorobenzoyl)-12a-aza-pentadecanelactam
26.93, 27.44, 27.49, 35.70, 38.51, 46.06, 46.09, 46.10, 46.16, 50.41,
123.55, 127.30, 127.40, 142.33, 147.97, 170.39, 173.38; Anal. Calcd. for
(10m)
Light yellow liquid (82% yield); IR
n
(KBr, cmꢀ1): 3307, 2930,
1.23e1.48
2858, 1633, 1540, 1434, 730; 1H NMR (300 MHz, CDCl3):
d
C21H31N3O4: C 64.76, H 8.02, N 10.79. Found: C 64.67, H 7.99, N
10.82.
(br, 18H), 1.68 (br, 2H), 2.18e2.23 (m, 2H), 3.14e3.27 (br, 2H), 3.60e
3.61 (br, 2H), 6.49 (br, 1H), 7.27e7.40 (m, 4H); 13C NMR (75 MHz,
CDCl3):
d
24.21, 24.41, 25.67, 25.96, 26.06, 26.17, 26.41, 26.53, 27.23,
4.13. Evaluation of biological activity
35.71, 38.56, 45.42, 49.79, 126.90, 127.57, 129.50, 130.00, 130.05,
135.90, 169.24, 173.63; HRMS (m/z) calcd for
[M þ H]þ 379.21468, found 379.21466.
C
21H32ClN2O2
Antifungal activity of compounds 6aen and 10aer against
S. sclerotiorum, P. oryzae, B. cinerea, R. solani and P. capsici was
evaluated using the mycelium growth rate assay. Commercial
fungicide Chlorothalonil was used as a positive control. The culture
media with various concentrations of test compounds were pre-
pared by mixing DMSO or DMSO solutions of compounds 6aen and
10aer with potato dextrose agar (PDA). Then, fungus cakes were
placed in the media. The inoculated plates were kept at 25 ꢁC. Each
experiment was performed in triplicates. When the mycelia grew
completely in DMSO treatment, the diameter of the mycelia was
measured and the inhibition rate was calculated by the following
formula and averaged.
4.12.14. 12a-N-(3-Chlorobenzoyl)-12a-aza-pentadecanelactam
(10n)
Light yellow liquid (75% yield); IR
2858, 1726, 1634, 1541, 1459, 1276, 800, 733; 1H NMR (300 MHz,
CDCl3): 1.25e1.34 (br, 14H), 1.53 (br, 2H), 1.66e1.75 (br, 4H), 2.21
n
(KBr, cmꢀ1): 3309, 2930,
d
(t, J ¼ 5.8 Hz, 2H), 3.33 (br, 2H), 3.58e3.64 (br, 4H), 6.60 (br, 1H),
7.24e7.27 (m, 1H), 7.31e7.43 (m, 3H); 13C NMR (75 MHz, CDCl3):
d
24.46, 24.51, 25.91, 26.47, 26.59, 26.60, 27.11, 27.71, 28.77, 35.79,
38.70, 46.17, 51.28, 124.53, 126.74, 129.76, 130.76, 134.42, 138, 12,

294
X. Wang et al. / European Journal of Medicinal Chemistry 73 (2014) 286e294
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D1 ꢀ D0
(1995) 1443e1446.
I ¼
ꢂ 100%
D1
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Acknowledgments
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We acknowledge financial support of this investigation by the
National Natural Science Foundation of China (31272075) and the
Science Foundation of China Agricultural University (No. 2007035).
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Appendix A. Supplementary data
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files and InChiKeys of the most important compounds described in
this article.
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