Design, synthesis, and fungicidal activity of macrolactones and macrolactams with a sulfonamide side chain

Article abstract of DOI:10.1021/jf800796z

Four series of novel macrolactones and macrolactams-12-alkylsulfonamido-1, 15-pentadecanlactones (5), 12-alkylsulfonamido-15-methyl-1,15-pentadecanlactones (6), 12-alkylsulfonamido-1,15-pentadecanlactams (7), and N- (alkylsulfonamidoethyl)-1,12-dodecanlactams (8) - were designed and synthesized from readily available 2-nitrocyclododecanone or cyclododecanone. Their structures were confirmed by ¹H NMR, IR, and elemental analysis. The bioassay showed that these compounds displayed fair to excellent fungicidal activity against Rhizoctonia solani Kuehn and have a gradual increase of fungicidal activity in the order of 6, 7, 8, and 5. Among them, compounds 5a, 5b, and 5c displayed excellent fungicidal activity against R. solani comparable with the commercial fungicide carbendazim. Above results illustrated that the rule on the relationship between the activity and hydrogen-bonding, namely the macrocyclic compounds with a hydrogen-bonding acceptor and a hydrogen-bonding donor on the ring and having a three methylenes distance between two polarizable groups have the best fungicidal activity against R. solani, has a general suitability to the macrocyclic compounds, and pesticide molecules may combine with a target enzyme by hydrogen-bonding. The facts, which compound 6 has a much lower fungicidal activity against R. solani than compound 5 but their difference in chemical structure is only that there is a methyl group on the C15 for compound 6 and none but hydrogen atom on the C15 for compound 5, indicated that a methyl group plays an inhibitory role to the fungicidal activity. It suggests that the existence of a methyl group with a great volume between two polarizable groups would interfere in the interaction of pesticide molecules and the target enzyme.

Full text of DOI:10.1021/jf800796z

J. Agric. Food Chem. 2008, 56, 6547–6553 6547
Design, Synthesis, and Fungicidal Activity of
Macrolactones and Macrolactams with a Sulfonamide
Side Chain
WEI-JUAN ZHU,† PENG WU,† XIAO-MEI LIANG,† YAN-HONG DONG,†
JIAN-JUN ZHANG,† HUI-ZU YUAN,‡ SHU-HUA QI,‡ XIANG-QING MENG,†
JIN-PING WU,† FU-HENG CHEN,† AND DAO-QUAN WANG*,†
Key Laboratory of Pesticide Chemistry and Application Technology, Department of Applied
Chemistry, China Agricultural University, and Institute of Plant Protection, Chinese Academy of
Agricultural Science Beijing, People’s Republic of China, 100094
Four series of novel macrolactones and macrolactamss12-alkylsulfonamido-1,15-pentadecanlactones
(5), 12-alkylsulfonamido-15-methyl-1,15-pentadecanlactones (6), 12-alkylsulfonamido-1,15-pentadecan-
lactams (7), and N-(alkylsulfonamidoethyl)-1,12-dodecanlactams (8)swere designed and synthesized from
1
readily available 2-nitrocyclododecanone or cyclododecanone. Their structures were confirmed by H
NMR, IR, and elemental analysis. The bioassay showed that these compounds displayed fair to excellent
fungicidal activity against Rhizoctonia solani Ku¨hn and have a gradual increase of fungicidal activity in
the order of 6, 7, 8, and 5. Among them, compounds 5a, 5b, and 5c displayed excellent fungicidal activity
against R. solani comparable with the commercial fungicide carbendazim. Above results illustrated that
the rule on the relationship between the activity and hydrogen-bonding, namely the macrocyclic compounds
with a hydrogen-bonding acceptor and a hydrogen-bonding donor on the ring and having a three
methylenes distance between two polarizable groups have the best fungicidal activity against R. solani,
has a general suitability to the macrocyclic compounds, and pesticide molecules may combine with a
target enzyme by hydrogen-bonding. The facts, which compound 6 has a much lower fungicidal activity
against R. solani than compound 5 but their difference in chemical structure is only that there is a methyl
group on the C15 for compound 6 and none but hydrogen atom on the C15 for compound 5, indicated
that a methyl group plays an inhibitory role to the fungicidal activity. It suggests that the existence of a
methyl group with a great volume between two polarizable groups would interfere in the interaction of
pesticide molecules and the target enzyme.
KEYWORDS: Macrolactone; macrolactam; sulfonamide; synthesis; fungicidal activity; fungicide; pesticide;
Rhizoctonia solani Ku¨hn
INTRODUCTION
an oxime ether side chain to improve fungicidal activity of
general macrocyclic compounds. Bioassay showed that they
have good fungicidal activity against R. solani. Among them,
those with a hydrogen-bonding acceptor (dNsOs) and a
hydrogen-bonding donor (-CONH-) on the ring and having a
three methylenes distance between two polarizable groups have
the best fungicidal activity. Namely, 12-alkyloxyimino-1,15-
pentadecanlactams (1) have the best fungicidal activity. On the
other hand, it is well-known that sulfonamides have a broad
spectrum of biological activities. For example, sulfanilamide
(2) was the first synthetic antibacterial agent active against a
wide range of infection (3), and flusulfamide (3) is used as a
soil fungicide for the control of plasmodiophora brassicae on
Chinese cabbage (4). In addition, we also reported that 2-oxo-
cyclododecyl sulfonamides (4) have some fungicidal activity
and found that those with a hydrogen atom on the nitrogen atom
have better activity than those without a hydrogen atom on the
Cotton soreshin (Rhizoctonia solani Ku¨hn) is an important
agricultural fungus species that causes serious damage to cotton
production in China (1). Several chemical fungicides have been
approved for the control of R. solani on cotton including
carbendazim. Unfortunately, resistance to these fungicides has
been observed, thus, leading to the continuing need of further
research to discover new classes of fungicides, especially those
with novel modes of action. Our strategy for discovering new
fungicides was to imitate the chemistry of biologically active
natural products. In a previous paper (2), we reported the design
and synthesis of macrolactam and macrolactone derivatives with
* To whom correspondence should be addressed. Phone/Fax: 86-
10-62732219. E-mail: wangdq@cau.edu.cn.
† China Agricultural University.
‡ Chinese Academy of Agricultural Science.
10.1021/jf800796z CCC: $40.75  2008 American Chemical Society
Published on Web 07/11/2008

6548 J. Agric. Food Chem., Vol. 56, No. 15, 2008
Zhu et al.
nitrogen atom, showing the importance of a hydrogen-bonding
donor in the molecule to the fungicidal activity (5).
starting from 2-nitrocyclododecanone by Michael addition to
acrolein or methyl vinyl ketone followed by selective reduction
of the carbonyl at the side chain and ring expansion, were
converted into the corresponding amines (10) by transfer
hydrogenation (6) using ammonium formate and palladium on
carbon. The amines 10 were sulfonylated with alkylsulfonyl
chloride to afford target compounds 5 and 6.
The synthetic route of compound 7 is shown in Scheme 2.
Michael addition of 2-nitrocyclododecanone to acrylonitrile
followed by selective reduction of a nitrile group gave 12-
nitropentadecanlactam (11), which was converted into the
corresponding amine (12) followed by sulfonylation with
alkylsulfonyl chloride to afford target compound 7.
Scheme 2
In view of the above-mentioned facts, we introduce a
sulfonamide group into pentadecanlactone, synthesizing a series
of novel 12-alkylsulfonamido-1,15-pentadecanlactones (5), which
retain a hydrogen-bonding acceptor (here, it is -CO-O-) and
a hydrogen-bonding donor (here, it is -NH-SO2-) on the large
ring and still have a three methylenes distance between two
polarizable groups, and expecting that designed compounds have
a better fungicidal activity than compound 1 or comparable
fungicidal activity with compound 1. In order to investigate if
the rule on the relationship between the activity and hydrogen-
bonding has a general suitability to the macrocyclic compounds,
further structural derivation on compound 5 was carried out:
(a) A methyl group was introduced at the C15 position, and
the 12-alkylsulfonamido-15-methyl-1,15-pentadecanlactones (6)
were synthesized. (b) The lactone ring was replaced by a lactam
ring, and the 12-alkylsulfonamido-1,15-pentadecanlactams (7)
were synthesized. (c) The sulfonamide group was transferred
to the terminal of the side chain and still kept a suitable distance
between the two polarizable groups, and the N-(alkylsulfon-
amidoethyl)-1,12-dodecanlactams (8) were synthesized.
The synthetic route of compound 8 is shown in Scheme 3.
Schmidt reaction (7) of cyclododecanone with 2-azidoethanol
followed by treating with sodium azide (8) gave N-(2-azido-
ethyl)dodecanlactam (14), which was reduced and sulfonylated
to afford target compound 8.
Scheme 3
In this paper, we would like to report the design, synthesis,
and fungicidal activity of compounds 5, 6, 7, and 8.
MATERIALS AND METHODS
1
General. H NMR spectra were recorded in CDCl3, with a Bruker
DPX300 spectrometer, using TMS as the internal standard; infrared
spectra were recorded on potassium bromide disks or liquid films on a
Shimadzu IR-435 spectrophotometer; elemental analysis was performed
by the analytical center in Institute of Chemistry (Beijing), Chinese
Academy of Science; melting points were measured on a Yanagimoto
melting-point apparatus and are uncorrected. The solvents and reagents
were used as received or were dried prior to use as needed.
Chemical Synthesis. Synthesis of 12-Nitro-1,15-pentadecanlactone
(9a). Compound 9a was prepared according to the method given in ref
(7).
The synthetic route of compounds 5 and 6 is shown in
Scheme 1. The 12-nitropentadecanlactones (9), synthesized
Scheme 1
Synthesis of 15-Methyl-12-nitro-1,15-pentadecanlactone (9b). Com-
pound 9bwas prepared according to the method given in ref (9) just
using methyl vinyl ketone instead of acrolein. Colorless liquid: yield
(based on 2-nitrocyclododecanone), 68%; 1H NMR δ 1.23(3H, d, J )
6.2 Hz), 1.32-1.37 (14H, m), 1.54-2.03 (8H, m), 2.30-2.35 (2H, m),
4.41-4.60 (1H, m), 4.89-5.10 (1H, m).
General Procedure for the Synthesis of Compounds 10 (6). A mixture
of compound 9 (0.01 mol), ammonium formate (3.18 g, 0.05 mol),
and palladium on carbon (10%, 0.1 g) in methanol was stirred at room

Fungicidal Activity of Macrolactones and Macrolactams
J. Agric. Food Chem., Vol. 56, No. 15, 2008 6549
temperature for 1 h and then filtered, and the filtrate was concentrated
to dryness at reduced pressure to give a viscous liquid, which was
dissolved in diethyl ether. The resulting solution was passed in dry
hydrogen chloride at 0 °C until no precipitate could be observed.
Filtration gave the desired products. 10a: yield, 82%; mp 167-168 °C
(lit.: mp 167-168 °C (10)). 10b: yield, 88%; mp 156-157 °C; 1H
NMR δ 1.24-1.33 (25H, m), 2.04-2.33 (2H, m), 3.10-3.35 (1H, m),
4.91-5.05 (1H, m), 8.04 (3H, s).
ether was added dropwise at 0 °C until no precipitate could be observed.
The filtration gave the desired product 15 (white solid, 4.3 g): yield,
75%; mp 103-106 °C; H NMR δ 1.18-1.38 (14H, m), 1.54-1.85
(4H, m), 2.43 (2H, t, J ) 7.8 Hz), 3.26 (2H, t, J ) 6.1 Hz), 3.40 (2H,
t, J ) 7.6 Hz), 3.71 (2H, t, J ) 6.1 Hz), 8.37 (3H, s).
1
General Procedure for the Synthesis of Compound 8. To a stirred
mixture of compound 15 (0.28 g, 0.001 mol) and sodium carbonate
(0.45 g, 0.004 mol) in 20 mL of THF and water (1/1, v/v) was added
alkylsulfonyl chloride (0.001 mol), and the mixture was stirred at room
temperature for 6 h. Water (10 mL) was added, and the resulting mixture
was extracted with dichloromethane (10 mL × 3). The combined
organic layer was washed with brine, dried over sodium sulfate, and
evaporated under reduced pressure to give a crude product (viscous
liquid). Further purification on silica gel column chromatography with
dichloromethane and methanol gave the desired compound 8. The
physical and elemental data of the target compounds are given in Table
General Procedure for the Synthesis of Compounds 5 and 6. To a
stirred solution of compound 10 (0.005 mol) and pyridine (1.20 g, 0.015
mol) in 50 mL of anhydrous acetonitrile at room temperature under a
nitrogen atmosphere was added alkylsulfonyl chloride (0.01 mol), and
the mixture stirred under reflux for 6 h. Concentration at reduced
pressure gave a viscous liquid, which was dissolved in aqueous sodium
hydroxide solution. The resulting solution was neutralized to pH 2 with
hydrochloric acid and extracted with dichloromethane (30 mL × 3).
The combined organic layer was washed with water and brine, dried
over sodium sulfate, and evaporated under reduced pressure to give a
crude product. Further purification on silica gel column chromatography
with petroleum and ethyl acetate gave the target compounds 5 or 6.
The physical and elemental data of the target compounds are given in
1
1, and the H NMR and IR data are listed in Table 2.
Bioassay of Fungicidal Activity. Method. Fungicidal activity of
compounds 5, 6, 7, and 8 against R. solani were evaluated using the
mycelium growth rate test (12).
Fungicidal ActiVity of Compounds 5, 6, 7, and 8. The inhibition
rates of compounds 5, 6, 7, and 8 against R. solani at the concentrations
of 100, 50, 25, 12.5, and 6.25 µg /mL were determined first. Then,
EC50 values were estimated using logit analysis (13). As a control,
fungicidal activity of the commercial fungicide carbendazim against
the above-mentioned fungi was evaluated at the same condition. The
results are shown in Table 3.
1
Table 1, and the H NMR and IR data are listed in Table 2.
Synthesis of 12-Nitro-1,15-pentadecanlactam (11). Compound 11
was prepared according to the method given in ref (11).
Synthesis of 12-Amino-1,15-pentadecanlactam (12). The reaction was
run similarly to that used to synthesize 10. After the reaction was
completed, catalyst was removed and water added. The aqueous layer
was extracted with ethyl acetate. The combined organic layer was
washed with water and brine, dried over sodium sulfate, and evaporated
under reduced pressure to give the desired product 12: yield, 94%; mp
103-104 °C; 1H NMR δ 0.95-1.61 (24H, m), 2.01-2.07 (2H, m),
2.50-2.65 (1H, m), 2.89-3.01 (1H, m), 3.15-3.21 (1H, m).
General Procedure for the Synthesis of Compound 7. The reaction
was run similarly to that used to synthesize 5 and 6. The crude products
obtained were recrystallized in methanol and water to give the desired
compound 7. The physical and elemental data of the target compounds
are given in Table 1, and the 1H NMR and IR data are listed in Table
2.
Synthesis of Compound 13. To a stirred solution of cyclododecanone
(4.92 g, 0.027 mol) and azidoethanol (3.5 g, 0.040 mol) in 50 mL of
dichloromethane at -5 °C was added 47% boron trifluoride etherate
(14.2 g, 0.1 mol). The mixture was further stirred for 3 h at the same
temperature and then stirred under reflux for 192 h. Concentration at
reduced pressure gave a viscous liquid, which was dissolved in
dichloromethane (20 mL), washed with water (10 mL × 3), dried over
sodium sulfate, and evaporated under reduced pressure to give the
desired product 13 (viscous liquid, 0.76 g): yield, 90%; 1H NMR δ
1.29-1.45 (14H, m), 1.78-1.90 (4H, m), 2.81 (2H, t, J ) 6.9 Hz),
3.79 (2H, t, J ) 6.5 Hz), 4.24 (2H, t, J ) 10.3 Hz), 5.03 (2H, t, J )
10.3 Hz).
RESULTS AND DISCUSSION
Chemistry. Compounds 5, 6, and 8 were purified by silica
gel column chromatography eluting with petroleum ether-ethyl
acetate (compounds 5 and 6) or dichloromethane-methanol
(compound 8). The yields were 30-44% (compound 5),
36-56% (compound 6), and 23-49% (compound 8), respec-
tively (Table 1). Because of good crystallizability, compound
7 was purified by recrystallization from methanol-water to give
higher yields (72-84%) than compounds 5, 6, and 8 (Table
1).
The structures of the target compounds 5, 6, 7, and 8 were
1
characterized by H NMR, IR, and elemental analysis (Table
2).
There are two diastereoisomers for compound 6 containing
two different chiral carbons (C12 and C15). Existence of two
1
isomers can be observed in the H NMR spectrum of several
of compound 6 (e.g., the resonance peak corresponding to the
methyl group at the side chain displayed two singlets at δ 2.97
and 2.98 in the spectrum of 6l (a mixture of two isomers)).
Similarly, the methoxycarbonyl group on the benzene ring
displayed two singlets at δ 3.98 and 3.99 for compound 6i, and
the methylene group of benzyl displayed two singlets at δ 4.25
and 4.26 for compound 6k. (Note: All of these isomers have
not been separated; therefore, the mixture of two diastereoiso-
mers was used in the bioassay.)
Fungicidal Activity. As shown in Table 3, these compounds
displayed fair to excellent fungicidal activity against R. solani
and have a gradual increase of fungicidal activity in the order
of 6, 7, 8, and 5. Compound 5 displayed well to excellent
activity except individual compound 5k. Among them, com-
pounds 5a, 5b, and 5c, the EC50 values of which were 2.4, 3.7,
and 3.3 µg/mL, respectively, displayed excellent fungicidal
activity and were comparable with compound 1 and the
commercial fungicide carbendazim with an EC50 value of 1.5
µg/mL. As mentioned above, the designed idea of compound 5
was originated from compound 1. In view of the hydrogen-
bonding acceptor and hydrogen-bonding donor, compounds 5
and 1 have similar structural characteristics as shown in Figure
Synthesis of Compound 14. To a stirred solution of compound 13
(3.1 g, 0.01 mol) in 20 mL of anhydrous DMF was added sodium azide
(1.3 g, 0.02 mol) portion by portion. The mixture was stirred at 70 °C
for 16 h. Water (25 mL) was poured into the mixture, and the resulting
mixture was extracted with diethyl ether (10 mL × 4). The combined
organic layer was washed with water and brine, dried over sodium
sulfate, and evaporated under reduced pressure to give a crude product.
Further purification on silica gel column chromatography with petro-
leum and ethyl acetate gave the desired compound 14 (viscous liquid,
1
1.9 g): yield, 70%; H NMR δ 1.34-1.44 (14H, m), 1.61-1.70 (4H,
m), 2.40 (2H, t, J ) 7.0 Hz), 2.90 (2H, t, J ) 6.5 Hz), 3.13 (2H, t, J
) 4.6 Hz), 4.32 (2H, t, J ) 4.6 Hz).
Synthesis of Compound 15. A mixture of compound 14 (5.5 g, 0.021
mol) and triphenyl phosphine (11 g, 0.042 mol) in 100 mL of anhydrous
acetonitrile was stirred at room temperature for 13 h; water (20 mL)
was then added, and resulting mixture was stirred at room temperature
for 4 h. After filtration, the filtrate was extracted with diethyl ether
(100 mL × 4). The combined organic layer was washed with brine,
dried over sodium sulfate, and evaporated under reduced pressure to
give a crude product (viscous liquid), which was dissolved in anhydrous
diethyl ether (100 mL), and a solution of hydrogen chloride in diethyl

6550 J. Agric. Food Chem., Vol. 56, No. 15, 2008
Zhu et al.
Table 1. Physical and Elemental Data of Compounds 5, 6, 7, and 8
1, although compound 5 is a macrolactone with a sulfon-
amide side chain and compound 1 is a macrolactam with an
oxime ether side chain. The results showed that the rule on the
relationship between the fungicidal activity and hydrogen-
bonding has a general suitability to the macrocyclic compounds.
Compound 8 has somewhat lower fungicidal activity against
R. solani than that of compound 5. Although the former is a
13-membered lactam derivative and the latter is a 16-membered
lactone derivative, they are similar in chemical structure (the
active moiety is similar and all of the lipophilic moiety
are 10-11 methylenes of large rings). The difference is that
the greater part of the active moiety of compound 8 is out of
the large ring as the skeleton of the side chain, which is flexible
instead of rigid (Figure 1). The flexible characteristic of the

Fungicidal Activity of Macrolactones and Macrolactams
J. Agric. Food Chem., Vol. 56, No. 15, 2008 6551
Table 2. 1H NMR Data of Compounds 5, 6, 7, and 8
Compds No.
1H NMR (CDCl3, δ)
IR
5a
1.10∼1.39 (m, 17H), 1.47∼1.75 (m, 5H), 2.30 (t, 2H, J ) 6.8 Hz), 3.26∼3.31 3300, 2920, 2870, 1730, 1450, 1335, 1165, 1100, 970
(m, 1H), 4.00∼4.04 (m, 2H), 4.84 (d, 1H, J ) 8.5 Hz), 7.48∼7.60 (m, 3H),
7.88∼7.91 (m, 2H)
5b
5c
5d
5e
5f
1.16∼1.38 (m, 17H), 1.51∼1.66 (m, 5H), 2.30 (t, 2H, J ) 6.8 Hz), 2.43 (s,
3H), 3.26∼3.27 (m, 1H), 4.01-4.05 (m, 2H), 4.59 (d, 1H, J ) 8.5 Hz),
7.27∼7.31 (m, 2H), 7.76 (dd, 2H, J ) 1.7 Hz, J ) 6.6 Hz)
3310, 2920, 2870, 1725, 1600, 1440, 1375, 1230, 1155, 1095
3300, 2920, 2870, 1730, 1580, 1450, 1335, 1250, 1090
3250, 2920, 2870, 1720, 1535, 1460, 1360, 1170, 1020, 970
1.13∼1.43 (m, 17H), 1.50∼1.70 (m, 5H), 2.31 (t, 2H, J ) 6.8 Hz, 3.29∼3.31
(m, 1H), 4.04∼4.09 (m, 2H), 4.75 (d, 2H, J ) 8.6 Hz), 7.46∼7.51 (m, 2H),
7.79∼7.84 (m, 2H)
1.13∼1.46 (m, 17H), 1.55∼1.73 (m, 5H), 2.32 (t, 2H, J ) 6.8 Hz, 3.37∼3.43
(m, 1H), 4.06∼4.11 (m, 2H), 4.75 (d, 1H, J ) 8.8 Hz), 7.72-7.78 (m, 1H),
8.19∼8.23 (m, 1H), 8.41∼8.45 (m, 1H), 8.71-8.73 (m, 1H)
1.17∼1.43 (m, 17H), 1.56∼1.72 (m, 5H), 2.31 (t, 2H, J ) 6.8 Hz), 3.34∼3.35 3300, 2920, 2870, 1710, 1435, 1330, 1170
(m, 1H), 4.06∼4.10 (m, 2H), 4.87 (d, 1H, J ) 8.7 Hz), 7.43∼7.50 (m, 2H),
8.09∼8.10 (m, 1H)
1.17∼1.41 (m, 17H), 1.51∼1.72 (m, 5H), 2.31 (t, 2H, J ) 6.8 Hz, 3.26∼3.32
(m, 1H), 4.02∼4.11 (m, 2H), 4.55 (d, 1H, J ) 8.6 Hz), 7.15∼7.22 (m, 2H),
7.86∼7.93 (m, 2H)
3300, 2920, 2870, 1710, 1590, 1490, 1450, 1330, 1150, 1095, 1020
5g
5h
5i
1.12∼1.42 (m, 17H), 1.56∼1.71 (m, 5H), 2.30 (t, 2H, J ) 6.8 Hz, 3.28∼3.33
(m, 1H), 4.01∼4.06 (m, 2H), 4.96 (d, 1H, J ) 8.6 Hz), 7.39∼7.54 (m, 3H),
8.09∼8.12 (m, 1H)
3250, 2920, 2870, 1725, 1550, 1445, 1335, 1170, 1050
3330, 2920, 2870, 1730, 1595, 1525, 1470, 1435, 1365, 1180, 1010
3300, 2920, 2870, 1725, 1435, 1335, 1290, 1170, 1065
3300, 2920, 2870, 1720, 1445, 1335, 1210, 1145, 1020
3310, 2920, 2870, 1710, 1470, 1305, 1150, 1070, 1010
1.14∼1.39 (m, 17H), 1.57∼1.76 (m, 5H), 2.32 (t, 2H, J ) 6.8 Hz, 3.48∼3.53
(m, 1H), 3.99∼4.05 (m, 1H), 4.09∼4.16 (m, 1H), 5.17 (d, 1H, J ) 8.4 Hz),
7.72∼7.77 (m, 2H), 7.84∼7.88 (m, 1H), 8.13∼8.17 (m, 1H)
1.09∼1.42 (m, 17H), 1.55∼1.71 (m, 5H), 2.31 (t, 2H, J ) 6.8 Hz, 3.38∼3.42
(m, 1H), 3.98 (s, 3H), 4.02∼4.07 (m, 2H), 5.81 (d, 1H, J ) 7.9 Hz),
7.59∼7.66 (m, 2H), 7.79∼7.82 (m, 1H), 8.08∼8.11 (m, 1H)
1.21∼1.42(m, 17H), 1.56∼1.72 (m, 5H), 2.23 (t, 2H, J ) 6.8 Hz, 3.35∼3.39
(m, 1H), 4.05∼4.10 (m, 2H), 4.66 (d, 1H, J ) 4.5 Hz), 7.07∼7.10 (m, 1H),
7.57∼7.59 (m, 1H), 7.60∼7.62 (m, 1H)
5j
5k
1.25∼1.58 (m, 17H), 1.59∼1.71 (m, 5H), 2.31 (t, 2H, J ) 6.8 Hz, 3.32∼3.37
(m, 1H), 3.99 (d, 1H, J ) 8.7 Hz), 4.08∼4.13 (m, 2H), 4.24 (s, 2H),
7.35∼7.44 (m, 5H)
5l
1.32∼1.82 (m, 22H), 2.33 (t, 2H, J ) 6.8 Hz), 2.97 (s, 3H), 3.42∼3.48 (m,
1H), 4.10∼4.24 (m, 2H), 4.30 (d, 1H, J ) 8.0 Hz)
3300, 2920, 2870, 1720, 1320, 1260, 1150
6a
1.09∼1.37 (m, 21H), 1.52∼1.67 (m, 4H), 2.24-2.29 (m, 2H), 3.23 (br,
1H),.4.51-4.53 (m, 1H), 4.79∼4.88 (m, 1H), 7.48∼7.61 (m, 3H), 7.88∼7.91
(m, 2H)
3300, 2950, 2870, 1730, 1450, 1330, 1170, 1030
6b
6c
6d
1.09∼1.52 (m, 24H), 1.60∼1.67 (m, 1H), 2.24-2.29 (m, 2H), 2.43 (s, 3H),
3.26∼3.29 (m, 1H), 4.35-4.38 (m, 1H), 4.81∼4.86 (m, 1H), 7.29∼7.32 (m,
2H), 7.74∼7.79 (m, 2H)
3300, 2930, 2870, 1730, 1440, 1330, 1270, 1160, 820
3300, 2930, 2870, 1730, 1330, 1170, 1100
1.14∼1.44 (m, 21H), 1.53∼1.70 (m, 4H), 2.25∼2.30 (m, 2H), 3.18∼3.27 (m,
1H), 4.46∼4.63 (m, 1H), 4.80∼4.89 (m, 1H), 7.46∼7.51 (m, 2H), 7.79∼7.84
(m, 2H)
1.14∼1.43 (m, 21H), 1.51∼1.71 (m, 4H), 2.26-2.31 (m, 2H), 3.29∼3.34 (m,
1H), 4.76∼4.89 (m, 2H), 7.75 (t, 1H, J ) 8.0 Hz), 8.19∼8.23 (m, 1H),
8.42∼8.45 (m, 1H), 8.72∼8.73 (m, 1H)
3300, 2930, 2870, 1730, 1540, 1450, 1350, 1180, 1060
6e
6f
1.15∼1.37 (m, 20H), 1.47∼1.70 (m, 7H), 2.25-2.31 (m, 2H), 3.34∼3.38 (m,
1H), 4.80∼4.92 (m, 2H), 7.43∼7.50 (m, 2H), 8.09∼8.11 (m, 1H)
1.14∼1.37 (m, 21H), 1.53∼1.68 (m, 4H), 2.25-2.30 (m, 2H), 3.19-3.23 (m,
1H), 4.38-4.56 (m, 1H), 4.82∼4.88 (m, 1H), 7.16∼7.22 (m, 2H), 7.86∼7.92
(m, 2H)
3310, 2930, 2870, 1730, 1450, 1380, 1150
3270, 2910, 2850, 1710, 1590, 1490, 1450, 1330, 1170, 1105, 1010
6g
6h
1.11∼1.36 (m, 19H), 1.45∼1.67 (m, 6H), 2.24-2.29 (m, 2H), 3.22∼3.36 (m,
1H), 4.81∼4.91 (m, 2H), 7.40∼7.54 (m, 3H), 8.09∼8.13 (m, 1H)
1.11∼1.47 (m, 21H), 1.55∼1.76 (m, 4H), 2.26-2.31 (m, 2H), 3.41∼3.50 (m,
1H), 4.83∼4.92 (m, 1H), 5.16∼5.19 (m, 1H), 7.71∼7.78 (m, 2H), 7.85∼7.88
(m, 1H), 8.13∼8.16 (m, 1H)
3300, 2930, 2870, 1710, 1470, 1450, 1350, 1170, 1050
3300, 2930, 2870, 1730, 1530, 1440, 1360, 1160
6i
1.08∼1.40 (m, 17H), 1.47∼1.74 (m, 6H), 2.25-2.30 (m, 2H), 3.33∼3.45 (m,
1H), 3.98 (s) + 3.99 (s) (3H), 4.80∼4.90 (m, 1H), 5.76∼5.83 (m, 1H),
7.60∼7.65 (m, 2H), 7.79∼7.82 (m, 1H), 8.07∼8.12 (m, 1H)
1.14∼1.45 (m, 21H), 1.54∼1.69 (m, 4H), 2.25-2.30 (m, 2H), 3.27∼3.33 (m,
1H), 4.43-4.47 (m, 1H), 4.83∼4.90 (m, 1H), 7.07∼7.10 (m, 1H), 7.57∼7.62
(m, 2H)
3310, 2950, 2870, 1730, 1430, 1340, 1280, 1170, 1060, 950
3300, 2950, 2890, 1730, 1330, 1170
6j
6k
1.01∼1.70 (m, 25H), 2.26-2.33 (m, 2H), 3.24∼3.29 (m, 1H), 3.86-3.96 (m,
1H), 4.25 (s) + 4.26 (s) (2H), 4.83∼4.96 (m,1H), 7.36∼7.51 (m, 4H),
7.75∼7.79 (m, 1H)
3300, 2930, 2870, 1730, 1540, 1460, 1130
6l
1.21∼1.79 (m, 25H), 2.28-2.33 (m, 2H), 2.97 (s) + 2.98 (s) (3H), 3.35∼3.38 2930, 2870, 1730, 1480, 1310, 1160
(m, 1H), 4.08∼4.17 (m, 1H), 4.90∼5.04 (m, 1H)
3300, 2900, 2800, 1650, 1550, 1450, 1350, 1150, 1070
7a
1.14∼1.53 (m, 22H), 1.99∼206 (m, 2H), 2.88∼2.98 (m, 3H), 3.94 (s, 1H),
7.51∼7.65 (m, 4H), 7.69∼7.73 (m, 1H), 7.78∼7.81 (m, 2H)

6552 J. Agric. Food Chem., Vol. 56, No. 15, 2008
Table 2. Continued
Zhu et al.
Compds No.
1H NMR (CDCl3, δ)
IR
7b
1.11∼1.50 (m, 22H), 1.99∼2.03 (m, 2H), 2.38 (s, 3H), 2.90∼3.01 (m, 3H), 7.38 (d, 3300, 2900, 2800, 1650, 1550, 1430, 1320, 1150, 1070
(m, 1H)
2H, J ) 8.2 Hz), 7.45 (d, 1H, J ) 7.7 Hz), 7.67 (d, 2H, J ) 8.2 Hz), 7.71-7.75
7c
7d
7e
7f
1.12∼1.52 (m, 22H), 1.99∼2.04 (m, 2H), 2.93∼3.04 (m, 3H), 7.65∼7.70 (m, 3H),
3300, 2900, 2800, 1650, 1550, 1450, 1350, 1150, 1070, 820, 760
7.71∼7.75 (m, 1H), 7.77∼7.82 (m, 2H)
1.19∼1.52 (m, 22H), 1.99∼2.04 (m, 2H), 2.87∼3.14 (m, 3H), 7.66-7.78 (m, 1H),
7.88∼7.95 (m, 2H), 8.21∼8.24 (m, 1H), 8.46∼8.53 (m, 2H)
1.19∼1.52 (m, 22H), 2.00∼2.04 (m, 2H), 2.89∼3.10 (m, 3H), 7.69∼7.76 (m, 3H),
7.93∼7.94 (m, 1H), 8.04 (d, 1H, J ) 8.6 Hz)
3300, 2900, 2800, 1650, 1550, 1450, 1350, 1170, 1120, 680
3300, 2900, 2800, 1650, 1530, 1450, 1350, 1250, 1170, 830
1.21∼1.52 (m, 22H), 1.99∼2.04 (m, 2H), 2.93∼3.04 (m, 3H), 7.38∼7.47 (m, 2H),
7.50-7.60 (m, 1H), 7.70∼7.74 (m, 1H), 7.82∼7.88 (m, 2H)
1.19∼1.52 (m, 22H), 1.99∼2.06 (m, 2H), 2.87∼3.06 (m, 3H), 7.50∼7.55 (m, 1H),
7.60∼7.71 (m, 3H), 7.79 (d, 1H, J ) 8.5 Hz), 7.98∼8.01 (m, 1H)
1.16∼1.52 (m, 22H), 2.00∼2.05 (m, 2H), 2.91∼3.20 (m, 3H), 7.71∼7.76 (m, 1H),
7.82∼8.03 (m, 5H)
3300, 2900, 2800, 1650, 1580, 1550, 1480, 1450, 1320, 1250, 1150, 1070,
820, 650
3300, 2900, 2800, 1650, 1540, 1450, 1350, 1250, 1150, 1040, 760
7g
7h
7i
3300, 2900, 2800, 1650, 1550, 1450, 1350, 1250, 1170, 1070, 750
1.13∼1.52 (m, 22H), 1.99∼2.04 (m, 2H), 2.90∼3.33 (m, 3H), 3.84 (s, 3H), 7.26 (d, 3300, 2900, 2800, 1720, 1650, 1550, 1450, 1350, 1370, 1250, 1120, 1050,
1H, J ) 8.2 Hz), 7.60∼7.63 (m, 1H), 7.70∼7.75 (m, 3H), 7.89∼7.93 (m, 1H)
1.16∼1.55 (m, 23H), 1.99∼2.04 (m, 2H), 2.91∼3.10 (m, 3H), 7.15∼7.18 (m, 1H),
7.54∼7.56 (m, 1H), 7.72∼7.76 (m, 2H), 7.89∼7.91 (m, 1H)
760
3300, 2900, 2800, 1650, 1550, 1440, 1400, 1350, 1250, 1150
7j
7k
7l
1.14∼1.53 (m, 22H), 1.99∼2.06 (m, 2H), 3.02∼3.17 (m, 3H), 4.28 (s, 2H), 6.99 (d, 3300, 2900, 2800, 1650, 1550, 1450, 1350, 1260, 1130,
1H, J ) 8.0 Hz), 7.33∼7.40 (m, 5H), 7.77∼7.81 (m, 1H)
1.19∼1.56 (m, 22H), 2.02∼2.06 (m, 2H), 2.87 (s, 3H), 3.01∼3.05 (m, 1H),
3.12∼3.18 (m, 2H), 6.92 (d, 1H, J ) 8.0 Hz), 7.76∼7.80 (m, 1H)
1.30∼1.40(m, 14H), 1.56∼1.73(m, 4H), 2.26(t,J ) 7.6 Hz,2H), 3.02∼3.21(m, 4H),
3.42(t, J ) 5.8 Hz, 2H), 6.06(t, J ) 5.2 Hz, 1H), 7.46∼7.58(m, 3H),
7.84∼7.87(m, 2H)
3300, 2900, 2800, 1630, 1550, 1450, 1320, 1150
8a
3411, 3146, 2932, 2857, 1678, 1623, 1529, 1447, 1330, 1161, 1091, 980
8b
1.23∼1.40 (m, 14H), 1.56∼1.74 (m, 4H), 2.26 (t, J ) 7.6 Hz, 2H), 2.42 (s, 3H),
3.11∼3.19 (m, 4H), 3.42 (t, J ) 5.4 Hz, 2H), 5.57 (t, J ) 5.0 Hz, 1H), 7.28∼7.34
(m, 2H), 7.71∼7.75(m, 2H)
3172, 2930, 2860, 1621, 1457, 1335, 1186, 1092, 812
8c
8d
1.23∼1.38 (m, 14H), 1.54∼1.70(m, 4H), 2.23∼2.30 (m, 2H), 3.07∼3.21 (m, 4H),
3.41∼3.51 (m, 2H), 6.23 (s, br, 1H), 7.26∼7.54 (m, 2H), 7.71∼7.81 (m, 2H)
1.23∼1.29 (m, 14H), 1.58∼1.75 (m, 4H), 2.30 (t, J ) 7.7 Hz, 2H), 3.17∼3.26 (m,
4H), 3.47(t, J ) 5.5 Hz, 2H), 6.41 (t, J ) 4.8 Hz, 1H), 7.69-7.75 (m, 1H),
8.18∼8.21 (m, 1H), 8.39∼8.43(m, 1H), 8.67-8.69 (m, 1H)
3320, 2933, 2859, 1640, 1550, 1472, 1341, 1156, 1090, 765
3159, 2931, 2958, 1629, 1528, 1456, 1349, 1168, 1093, 881
8e
1.26∼1.43 (m, 14H), 1.57∼1.79 (m, 4H), 2.33 (t, J ) 7.7 Hz, 2H), 3.12∼3.18 (m,
2H), 3.26 (t, J ) 7.6 Hz, 2H), 3.48 (t, J ) 5.6 Hz, 2H), 6.16 (t, J ) 5.0 Hz, 1H),
7.42∼7.61 (m, 2H), 8.05∼8.07 (m, 1H)
3143, 2933, 2858, 1624, 1451, 1374, 1335, 1242, 1162, 1098, 1041, 829
Table 3. Fungicidal Activity of Compounds 5, 6, 7, and 8 against R. solania
Compds No.
EC50 (µg/mL)
Compds No.
EC50 (µg/mL)
Compds No.
EC50 (µg/mL)
Compds No.
EC50 (µg/mL)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
2.4
3.7
3.3
18.7
28.4
4.5
25.0
22.3
20.9
5.1
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
51.3
57.0
69.6
86.0
30.0
25.1
37.9
93.3
53.4
20.3
28.2
56.4
1.5
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
55.3
13.4
19.6
27.6
30.4
36.7
59.5
21.5
12.8
18.3
8.1
8a
8b
8c
8d
8e
11.6
8.8
18.7
10.7
5.3
5k
52.4
12.2
1.5
6k
7k
5l
carbendazim
6l
carbendazim
7l
carbendazim
45.1
1.5
carbendazim
1.5
a Regression equations and correlation coefficients are omitted.
Figure 1. Comparison of structures of compounds 1, 5, 6, 7, and 8. Structures of active moiety of compounds in the square frames are similar.
active moiety reduces the reactivity of the molecule in combina-
tion with the target enzyme. This is the reason why the
fungicidal activity of compound 8 is somewhat lower than that
of compound 5.
Compound 6 has a much lower fungicidal activity against R.
solani (the EC50 values of all compound 6’s are larger than 20
µg/mL) than that of compound 5. However, their difference in
chemical structure is only that there is a methyl group on the
C15 for compound 6 and none but a hydrogen atom on the C15
for compound 5, which indicated that the methyl group plays
an inhibitory role to the fungicidal activity. We postulate that
maybe the existence of a methyl group with a great volume
between two polarizable groups will interfere in the interaction
of pesticide molecules with the target enzyme, as shown in
Figure 2. Further experimental research would be needed to
confirm such a mode of action.
In the molecule of compound 7, the carbonyl of the amide
bond can play the role as hydrogen-bonding acceptor; therefore,
they have good fungicidal activity, but the active hydrogen on
the nitrogen atom adjacent to the carbonyl would interfere in

Fungicidal Activity of Macrolactones and Macrolactams
J. Agric. Food Chem., Vol. 56, No. 15, 2008 6553
(2) Huang, J. X.; Jia, Y. M.; Liang, X. M.; Zhu, W. J.; Zhang, J. J.;
Dong, Y. H.; Yuan, H. Z.; Qi, S. H.; Wu, J. P.; Chen, F. H.;
Wang, D. Q. Synthesis and fungicidal activity of macrolactams
and macrolactones with an oxime ether side chain. J. Agric. Food
Chem. 2007, 55 (26), 10857.
(3) Patrick, G. L. An Introduction to Medicinal Chemistry; Oxford
University Press: Cary, NC, 1995.
(4) (a) Yoshimoto, T.; Umemoto, M.; Igarashi, K.; Kubota, Y.;
Yamazaki, H.; Enomoto, Y.; Yanagita, H. USP 4851445, 1989.
(b) Fujita, T. Agrochem. Jpn. 1994, 65, 17.
(5) Wang, X. P.; Wang, D. Q. Synthesis and antifungal activity of
N-substituted-R-oxocyclododecyl-sulphonamides. Chem. J. Chin.
UniV. 1997, 18 (6), 889.
(6) Barrett, A. G. M.; Spilling, C. D. Transfer hydrogenation: A
stereospecific method for the conversion of nitro alkanes into
amines. Tetrahedron Lett. 1988, 29 (45), 5733.
Figure 2. Sketch map of the interaction of compounds 5, 6, and 7 with
target enzyme. Pesticide molecules combine with target enzyme by
hydrogen-bonding. Interaction of pesticide molecule with target enzyme
is interfered by a methyl group for compound 6 (R′ is methyl group and
X is O), and the interaction is interfered by an active hydrogen on the
nitrogen atom for compound 7 (X is NH and R′ is H).
(7) Li, J. J. Name Reaction, 3rd expanded ed.; Springer-Verlag, Berlin,
Germany, 2006; p 563.
the interaction of pesticide molecules and the target enzyme.
This is the reason why fungicidal activity of compound 7 is
lower than compound 5.
(8) (a) Gracias, V.; Milligan, G. L.; Aube, J. Synthesis of function-
alized N-alkyl heterocycles from ketone by a sequential ring
expansion/nucleophilic addition process. J. Org. Chem. 1996, 61
(1), 10. (b) Gracias, V.; Frank, K. E.; Milligan, G. L.; Aube, J.
Ring expansion by in situ tethering of hydroxyl azides to ketone:
The Boyer reaction. Tetrahedron 1997, 53 (48), 16241.
(9) Zhang, J. J.; Dong, Y. H.; Liang, X. M.; Wang, D. Q. Synthesis
and characterization of 12-acyl-oxyimino-1,15-pentadecanolides.
Chem. J. Chin. UniV. 2003, 24 (9), 1604.
(10) Zhu, W. J.; Liang, X. M.; Chen, W. H.; Wu, J. P.; Wang, D. Q.
Synthesis of sulfonylureas containing 1,15-pentadecanolide ring.
Chin. J. Org. Chem. 2006, 26 (9), 1313.
(11) Hou, C. J.; Liang, X. M.; Wu, J. P.; Tian, M. L.; Wang, D. Q. A
novel synthesis of 12-oxo-1,15-penta-decanlactam. Chin. J. Org.
Chem. 2006, 26 (11), 1597.
In conclusion, all of the above results once again confirmed
our judgment: macrocyclic compounds with a hydrogen-bonding
acceptor and a hydrogen-bonding donor on the ring and having
a three methylenes distance between two polarizable groups have
the best fungicidal activity against R. solani. At the same time,
the results also showed that the existence of any greater group
other than a hydrogen atom or an active hydrogen between two
polarizable groups would reduce their fungicidal activity pos-
sibly due to the interfering with the interaction of pesticides
molecules with the target enzyme. The rule obtained on the
relationship between the activity and hydrogen-bonding can be
very useful for designing new classes of macrocyclic fungicides,
especially those with novel modes of action.
(12) Li, X. H.; Yang, X. L.; Ling, Y.; Fan, Z. J.; Liang, X. M.; Wang,
D. Q.; Chen, F. H.; Li, Z. M. Synthesis and fungicidal activity of
novel 2-oxocycloalkylsulfonylureas. J. Agric. Food Chem. 2005,
53 (6), 2202–2206.
LITERATURE CITED
(13) Berkson, J. A. Statistically and precise and relatively simple
method of estimating the bioassay with quantal response, based
on the logistic function. J. Am. Stat. Assoc. 1953, 48, 565–599.
(1) (a) Chen, S. Q.; Wu, B.; Qin, Z.; Lin, G. Z.; Den, L.; Den, X. M.
A study on the anostomasis group of R. solani in Sichuan
Province. Southwest China J. Agric Sci. 1998, 12 (1), 56. (b)
Gong, S. J.; Li, G. Y.; Ling, G. C. Detection of resistance of
cotton varieties to Rhizoctonia Solani. J. Shihezi UniV., Nat. Sci.
2004, 22 (sup.), 55. (c) Deng, Z. S.; Zhang, B. C.; Sun, Z. H.;
Zhou, M. L. Study on the anastomotic group of Rhizoctonia Solani
isolated from cotton fields and their pathogenicity in Northern
Xinjiang. Plant Prot. 2006, 32 (4), 36.
Received for review March 13, 2008. Revised manuscript received May
14, 2008. Accepted May 16, 2008. We acknowledge financial support
of this investigation by the National Basic Research Program of China
(2003CB114407).
JF800796Z