Synthesis and evaluation of novel 3,4-epoxypiperidines as efficient DNA alkylating agents

Article abstract of DOI:10.3987/COM-09-S(S)112

3,4-Epoxypiperidine derivatives are novel DNA alkylating agents based on an active site of the antitumor antibiotics azinomycins A and B. A 3,4-epoxypiperidine library was constructed containing derivatives with a variety of functional groups at C5 via Huisgen reaction, and DNA cleavage activity was examined. Results revealed a more active derivative than any 3,4-epoxypiperidines previously reported.

Full text of DOI:10.3987/COM-09-S(S)112

HETEROCYCLES, Vol. 80, No. 2, 2010
1249
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 1249 - 1265. © The Japan Institute of Heterocyclic Chemistry
Received, 15th August, 2009, Accepted, 1st October, 2009, Published online, 1st October, 2009
DOI: 10.3987/COM-09-S(S)112
SYNTHESIS AND EVALUATION OF NOVEL 3,4-EPOXYPIPERIDINES
AS EFFICIENT DNA ALKYLATING AGENTS
Yuji Kawada,a Tetsuya Kodama,a Kazuyuki Miyashita,a,b Takeshi Imanishi,a
and Satoshi Obikaa*
aGraduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka,
b
Suita, Osaka 565-0871, Japan; Faculty of Pharmacy, Osaka Ohtani University,
3-11-1 Nishikiorikita, Tondabayashi, Osaka 584-8540, Japan. aE-mail:
obika@phs.osaka-u.ac.jp
Abstract – 3,4-Epoxypiperidine derivatives are novel DNA alkylating agents
based on an active site of the antitumor antibiotics azinomycins A and B. A
3,4-epoxypiperidine library was constructed containing derivatives with a variety
of functional groups at C5 via Huisgen reaction, and DNA cleavage activity was
examined. Results revealed
a
more active derivative than any
3,4-epoxypiperidines previously reported.
INTRODUCTION
Azinomycins A and B are antitumor antibiotics which
were isolated from Streptomyces griseofuscus S42227 in
1986 (Figure 1).1,2 Azinomycins possess potent in vitro
cell cytotoxicity and greater in vivo antitumor activity than
mitomycin C.3,4 This bioactivity is derived from a
4-hydroxy-1-azabicyclo[3.1.0]hexane structure inherent in
azinomycins.5,6 Therefore, compounds containing the
O
O
O
O
N
X
H
MeO
N
O
N
H
O
AcO
HO
azinomycin A : X = H2
azinomycin B : X = CHOH
Figure 1. Structure of azinomycin A and B
4-hydroxy-1-azabicyclo[3.1.0]hexane structure are predicted to function as a DNA alkylating agents.
However, this structure is unstable, which makes synthesis of 4-hydroxy-1-azabicyclo[3.1.0]hexane
derivatives difficult.7,8,9,10
A previously proposed hypothesis suggests that interconversion between the 4-hydroxy-1-
azabicyclo[3.1.0]hexane structure and the 3,4-epoxypiperidine structure is possible (Figure 2). Based on
this hypothesis, several 3,4-epoxypiperidine derivatives were synthesized, and some possessed significant
DNA cleavage activity.11 A relation between structure and DNA-cleavage activity also confirmed that a

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HETEROCYCLES, Vol. 80, No. 2, 2010
NH
N
HO
O
4-hydroxy-1-aza-
bicyclo[3.1.0]hexane
3,4-epoxypiperidine
Figure 2. Hypothetical interconversion between azabicyclohexane and 3,4-epoxypiperidine
nitrogen atom and epoxide group are essential for DNA cleavage. These results supported the hypothesis
and revealed the utility of 3,4-epoxypiperidine derivatives as DNA alkylating agents.
A previous report clarified that an aromatic substituent group at C5 played a significant role in DNA
cleavage activity.11 Thus, the present study describes the construction of a library of 3,4-epoxypiperidine
derivatives with various functional groups at C5 to determine if a more active compound can be
synthesized.
RESULTS AND DISCUSSION
The Huisgen reaction, a 1,3-dipolar cycloaddition between an azide and alkyne, was chosen for synthesis
of the 3,4-epoxypiperidine derivatives. The Huisgen reaction is a representative reaction of “click
chemistry” as proposed by Sharpless et al.12 As azido and alkynyl groups are insensitive to several
conditions, the Huisgen reaction is suitable for introduction of a functional group in the final stage of
synthesis. In addition, a number of alkynes are commercially available. Therefore, the synthesis of a
3,4-epoxypiperidine derivative containing an azido group was planned for application of the Huisgen
reaction.
Initially, an ethoxycarbonyl group of tetrahydropyridine 1, prepared from pyridine according to a method
previously reported13, was exchanged for a 2-trimethylsilylethoxycarbonyl (Teoc) group, which can be
easily removed under mild conditions. Introduction of an azido group into compound 2 was achieved
using 4-azidobenzyl bromide prepared from 4-iodobenzyl alcohol via two steps.14,15 Finally,
O
NTeoc
HO
c
a, b
HO
N
NCO2Et
NTeoc
3
1
2
N3
O
O
NTeoc
NTeoc
d
+
O
O
trans-4
cis-4
N3
N3
Scheme 1. Synthesis of 3,4-epoxypiperidine derivative 4. Reagents and conditions: a) 5 N KOH, EtOH,
reflux; b) Teoc-OSu, CH2Cl2, rt, 83%; c) NaH, 4-azidobenzyl bromide, DMF, rt; d) MCPBA, CH2Cl2,
trans-4: 40% from 2; cis-4: 15% from 2.

HETEROCYCLES, Vol. 80, No. 2, 2010
1251
O
O
NTeoc
NH
O
NTeoc
a
b
O
O
O
N
N
6a-6o
5a 5o
trans-4
-
N
N
N3
N
N
R
R
Scheme 2. Huisgen reaction and deprotection of Teoc group. Reagents and conditions: a) R-C≡CH,
CuSO4·5H2O, sodium ascorbate, t-BuOH : H2O = 1 : 1, rt; b) TBAF, neat, rt.
Table 1. Construction of a 3,4-epoxypiperidine library using various alkynes.
Huisgen reactiona
removal of Teoc groupb
yield (%)c
product reaction time (h) yield (%)c
product reaction time (h)
entry
R
5a
a
b
c
d
e
f
trimethylsilyl
methoxymethyl
ethoxycarbonyl
cyclopropyl
cyclohexyl
6a
6b
6c
6d
6e
6f
82
27
2
85
72
64
87
quant.
85
85
82
71
75
94
93
58
84
66
5b
quant.
96
2
1
5c
1
2
5d
82
1
1
5e
quant.
76
1
1.5
1
5f
1
phenyl
5g
g
h
i
94
1
1
benzyl
6g
6h
6i
5h
5i
83
2
1
2-phenylethyl
2-pyridyl
quant.
quant.
quant.
quant.
quant.
72
1
2
j
5j
5
1
4-fluorophenyl
1-naphthyl
6j
5k
5l
k
l
4
1
6k
6l
0.5
24
24
24
0.5
1
2-naphthyl
5m
5n
5o
m
n
o
1-anthracenyl
2-anthracenyl
9-anthracenyl
6m
6n
6o
2
95
1.5
aCondition (entries a‒l): alkyne (2 equiv.), CuSO4·5H2O (1 equiv.), sodium ascorbate (2 equiv.),
t-BuOH : H2O = 1 : 1, rt; condition (entries m‒o): alkyne (1.3 equiv.), CuSO4·5H2O (1 equiv.), sodium
ascorbate (2 equiv.), t-BuOH : H2O = 1 : 1, rt. bConditions: TBAF (1.5 equiv.), neat, rt. cYield of isolated
product.
epoxidation with MCPBA and separation of two diastereomers by silica gel column chromatography gave
trans-4 and cis-4 as racemates in 40% and 15% yield, respectively. Determination of relative

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HETEROCYCLES, Vol. 80, No. 2, 2010
1
configuration was accomplished by comparison of H NMR spectra of trans-4 and cis-4 with that of the
compounds previously reported.11
A previous report revealed that the trans isomer was more active than the cis isomer. Therefore, trans-4
was selected for reaction with several alkynes (Scheme 2, Table 1). In general, reactions of trans-4 with
alkynes occurred smoothly with good yields as shown in Table 1. When trimethylsilyl acetylene was
employed, elimination of a trimethylsilyl group was also observed to give the corresponding
non-substituted triazole (Table 1, entry a). Because some aromatic alkynes, such as 1-, 2- and
9-ethynylanthracenes, are not soluble in the reaction media (t-BuOH : H2O = 1 : 1), reaction time was
extended and product yields were moderate (Table 1, entries m, n, and o). The resulting triazoles 5 were
transformed into 3,4-epoxypiperidine derivatives 6 in good yields upon removal of the Teoc group.
DNA cleavage activity of the 3,4-epoxypiperidines was examined using a relaxation assay of supercoiled
plasmid DNA.11 DNA damage transforms a supercoiled plasmid DNA (form I) into an open circular
DNA (form II), which can be analyzed by agarose gel electrophoresis; a change in form alters the
mobility on the agarose gel. The 3,4-epoxypiperidines 6a to 6o possessed several degrees of DNA
cleavage activity. In particular, the derivatives containing aromatic rings at the C5 position showed
significant improvement in DNA cleavage activity. These results indicate that the aromatic rings
d)
Lane
1
-
2
3
a) Lane
1
-
2
3
4
5
6
7
8
9
10 11 12 13
compund
7
7
6a 6a 6b
6b 6c
6c 6d 6d 6e 6e
8
8
compund
(conc./M)
(1) (10) (1) (10) (1) (10) (1) (10) (1) (10) (1) (10)
(conc./M)
(1) (10)
Form II
Form I
Form II
Form I
Lane
1
-
2
3
4
5
6
7
8
9
10 11
b)
e)
O
NH
compund
6f
6f
6g 6g 6h 6h
6i
6i 6j 6j
(conc./M)
(1) (10) (1) (10) (1) (10) (1) (10) (1) (10)
O
Form II
Form I
7
Cl
Cl
Lane
1
-
2
3
4
5
6
7
8
9
10 11
c)
N
CO2H
compund
6k
6k
6l
6l 6m 6m 6n
6n 6o 6o
H NH2
(conc./M)
(1) (10) (1) (10) (1) (10) (1) (10) (1) (10)
Form II
Form I
melphalan (8)
Figure 3. DNA cleavage activity of a) epoxypiperidine 7 and 6a–6e, b) epoxypiperidine 6f–6j, c)
epoxypiperidine 6k–6o and d) melphalan (8) as a positive control. e) Structures of 7 and melphalan (8).

HETEROCYCLES, Vol. 80, No. 2, 2010
1253
functionas intercalators and enhance the affinity toward DNA. Interestingly, DNA cleavage of the benzyl
derivative with the benzene ring connected to the triazole ring via a methylene bridge was not as great as
that of derivatives with aromatic rings connected directly to the triazole ring (6f vs. 6g). This fact was
more dramatic for 6h, i.e., the activity of 6h with an ethylene bridge was much weaker. These results
demonstrate that the relative position of the aromatic ring and triazole structure is important for
expression of activity. In compound 6f, the benzene ring and triazole ring may work cooperatively to
intercalate into the DNA strand. In addition, the size of aromatic ring obviously affected the activity. The
activities of the naphthyl derivatives 6k and 6l were greater than those of the phenyl derivative 6f, which
acts at several M, and melphalan (8), a clinically employed DNA alkylating agent.16
Anthracenyltriazoles 6m, 6n and 6o were less active than naphthyl triazoles 6k and 6l, indicating that the
naphthyltriazolyl group is the best choice as the C5-substituent of the 3,4-epoxypiperidine derivative.
In conclusion, a 3,4-epoxypiperidine library 6a–6o was constructed via a Huisgen reaction and the DNA
alkylating activity of the derivatives was evaluated. Results of relaxation assay of plasmid DNA revealed
that naphthyl triazole derivatives 6k and 6l possessed more potent activity than previously reported
3,4-epoxypiperidine derivative 7 and the DNA alkylating agent, melphalan, used for cancer treatment.
This result indicates that 3,4-epoxypiperidine derivatives show promise as anticancer therapy drugs.
EXPERIMENTAL
Unless otherwise mentioned, all chemicals from commercial sources were used without further
purification. CH2Cl2 and triethylamine were distilled over calcium hydride. All reactions were conducted
under a nitrogen atmosphere. Melting points were measured on a Yanagimoto micro melting point
1
13
apparatus and are uncorrected. The H and C NMR spectra were recorded on JEOL EX-270 (1H, 270
MHz; 13C, 67.8 MHz), AL-300 (1H, 300 MHz; 13C, 75.5 MHz), ECS-400 (1H, 400 MHz; 13C, 100 MHz)
instruments. Values of  are in ppm relative to tetramethylsilane (0.00 ppm) or CDCl3 (7.26 ppm) as
internal standards. The IR spectra were recorded on a JASCO FT/IR-4200 spectrometer. FAB-mass or
EI-mass were measured on a JEOL JMS-600 or JMS-700 mass spectrometer. NALDI-mass was measured
on Bruker Daitonics® Autoflex II TOF/TOF. Column chromatography was conducted using Fuji Silysia
FL-100D, PSQ-100B silica gel.
4-Azidobenzyl bromide: 4-Iodobenzyl alcohol was converted to 4-azidobenzyl alcohol according to a
previously reported method.14 To a solution of 4-iodobenzyl alcohol (5.0 g, 21 mmol) in DMSO (35 mL)
and water (7 mL) was added CuI (410 mg, 2.1 mmol), sodium ascorbate (640 mg, 3.2 mmol), NaN3 (1.7 g,
26 mmol), and N,N-dimethylethylenediamine (94 mg, 120 L, 1.1 mmol) at rt, and the resulting mixture
stirred at the same temperature for 12 h. The reaction mixture was diluted with AcOEt and washed with
water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to

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HETEROCYCLES, Vol. 80, No. 2, 2010
give 4-azidobenzyl alcohol (3.1 g) as a yellow oil. To a stirred solution of 4-azidobenzyl alcohol (3.1 g) in
CH2Cl2 (150 mL) was added phosphorus tribromide (2.8 g, 1.0 mL, 10 mmol) at 0°C, and the reaction
mixture stirred for 20 min at the same temperature. After addition of ice water and extraction twice with
CH2Cl2, the combined organic layers were washed with water and brine, dried over MgSO4, and
concentrated under reduced pressure to afford 4-azidobenzyl bromide (3.7 g) as a brown oil, which was
employed for the next reaction without purification; 1H NMR (400 MHz, CDCl3) : 4.48 (2H, s), 7.00 (2H,
dt, J = 2.0, 8.5 Hz), 7.38 (2H, dt, J = 2.0, 8.5 Hz).15
(5RS)-5-Hydroxy-N-(2-trimethylsilyl)ethoxycarbonyl-1,2,5,6-tetrahydropyridine (2): A solution of
compound 1 (5.0 g, 29.2 mmol) in EtOH (20 mL) and 5 N KOH solution (20 mL) was refluxed for 19 h,
and the reaction solvent concentrated under reduced pressure. CH2Cl2 (30 mL) and
N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (8.3 g, 32.1 mmol) was added to the residue. The
reaction mixture was stirred for 45 min at room temperature, diluted with Et2O, and washed with water
and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography (AcOEt : n-hexane = 1 : 2) to give 2
(4.9 g, 83%) as a pale yellow oil; IR max (KBr): 3414, 2953, 2896, 1700, 1433, 1356, 1234, 1178, 1159,
1
1113, 1063 cm-1; H NMR (300 MHz, CDCl3) : 0.39 (9H, s), 1.01 (2H, t, J = 7.5 Hz), 3.60 (2H, brs),
3.83 (1H, dd, J = 2.0, 16.0 Hz), 4.01–4.23 (2H, m), 4.20 (2H, t, J = 7.5 Hz), 5.85–5.94 (2H, m); 13C NMR
(67.8 MHz, DMSO-d6, 80°C) : ‒1.9, 17.0, 42.4, 47.0, 61.9, 62.2, 124.4, 129.8, 154.5; Mass (FAB) m/z
244 (M+H+); HRMS (FAB) calcd for C11H22N1O3Si: 244.1369. Found: 244.1353.
(5RS)-5-(4-Azidobenzyloxy)-N-(2-trimethylsilyl)ethoxycarbonyl-1,2,5,6-tetrahydropyridine (3): To a
stirred solution of 2 (4.2 g, 17.5 mmol) in DMF (60 mL) was added NaH (60% in oil, 1.40 g, 35 mmol) at
0°C and the mixture was stirred at the same temperature for 20 min. 4-Azidobenzyl bromide (3.7 g, 17.5
mmol) in DMF (60 mL) was added dropwise to the reaction mixture at 0°C, and stirred at rt for 1 h. After
addition of water at 0°C, the resulting mixture was extracted twice with Et2O. The combined organic
layers were washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to
give 3 (6.5 g) as a brown oil, which was used for the next reaction without further purification; 1H NMR
(270 MHz, CDCl3) : 0.05 (9H, s), 1.01 (2H, t, J = 8.0), 3.58 (1H, brs), 3.77 (1H, brs), 3.96 (3H, brs),
4.20 (2H, t, J = 8.0 Hz), 4,51–4.64 (2H, m), 5.90 (2H, s), 7.00 (2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5
Hz); Mass (FAB) m/z 375 (M+H+); HRMS (FAB) calcd for C18H27N4O3Si: 375.1852. Found: 375.1830.
(3RS,4RS,5RS)-5-(4-Azidobenzyloxy)-3,4-epoxy-N-(2-trimethylsilyl)ethoxycarbonylpiperidine
(tnans-4): To a solution of 3 (6.6 g, 17.5 mmol) in CH2Cl2 (170 mL) was added MCPBA (9.1 g, 52.5
mmol) at rt and the resulting mixture stirred at the same temperature for 84 h. After addition of a mixture
of saturated aqueous Na2S2O3 and saturated aqueous NaHCO3 (ca. 120 mL, 1 : 1), the reaction mixture

HETEROCYCLES, Vol. 80, No. 2, 2010
1255
was extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 solution,
water, and brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (AcOEt : n-hexane = 1 : 4) to give trans-4 (2.9 g, 40%
from 2) and cis-4 (1.1 g, 15% from 2) as pale yellow oils; trans-4; IR max (KBr): 2953, 2898, 2112, 1698,
1507, 1462, 1424, 1358, 1284, 1248, 1178, 1126, 1089 cm-1; 1H NMR (270 MHz, CDCl3) : 0.04 (9H, s),
1.01 (2H, t, J = 8.0 Hz), 3.27 (2H, s), 3.44–3.56 (2H, m), 3.86 (3H, brs), 4.18 (2H, t, J = 8 Hz), 4.56 (1H,
13
d, J = 11.0 Hz), 4.70 (1H, d, J = 11.0 Hz), 7.02 (2H, d, J = 8.0 Hz), 7.36 (2H, d, J = 8.0 Hz); C NMR
(67.8 MHz, DMSO-d6, 80 °C) : ‒1.9, 16.8, 41.3, 41.4, 49.3, 51.2, 62.4, 69.6, 69.7, 118.6, 128.9, 134.9,
138.4, 154.9; Mass (FAB) m/z 391 (M+H+); HRMS (FAB) calcd for C18H27N4O4Si: 391.1802. Found:
391.1775.
1-(3-Hydroxy-3-methyl-1-butynyl)anthracene: To a solution of 1-bromoanthracene (500 mg, 1.9
mmol) and 2-methyl-3-butyn-2-ol (330 mg, 0.38 mL, 3.9 mmol) in triethylamine (10 mL) were added
CuI (3.7 mg, 19 mol) and Pd(PPh3)2Cl2 (6.8 mg, 9.7 mol), and the reaction mixture stirred at 80°C for
10 h. After removal of the solvent under reduced pressure, the resulting residue was purified by silica gel
column chromatography (CHCl3 : n-hexane = 1 : 1) to give 1-(3-hydroxy-3-methyl-1-butynyl)anthracene
(380 mg, 75%) as a yellow oil; IR max (KBr): 3347, 3050, 2980, 2928, 1613, 1456, 1373, 1314, 1268,
1
1225, 1163 cm-1; H NMR (400 MHz, CDCl3) : 1.82 (6H, s), 2.19 (1H, s), 7.38 (1H, t, J = 7.0 Hz),
7.49–7.52 (2H, m), 7.67 (1H, d, J = 7.0 Hz), 7.95 (1H, d, J = 8.0 Hz), 7.98–8.01 (1H, m), 8.07–8.09 (1H,
m), 8.40 (1H, s), 8.84 (1H, s); 13C NMR (100 MHz, CDCl3) : 31.7, 65.9, 80.4, 99.1, 120.3, 124.4, 124.8,
125.7, 126.8, 127.9, 128.5, 129.1, 130.2, 130.9, 131.1, 131.8, 132.0; Mass (EI) m/z 260 (M+, 100), 245
(50), 242 (29), 202 (29); HRMS (EI) calcd for C19H16O: 260.1201. Found: 260.1211.
1-Ethynylanthracene: A mixture of 1-(3-hydroxy-3-methyl-1-butynyl)anthracene (380 mg, 1.4 mmol)
and KOH (120 mg, 2.1 mmol) in toluene (15 mL) was heated under reflux for 1 h. After removal of the
solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography
(CHCl3 : n-hexane = 1 : 1) to give 1-ethynylanthracene (225 mg, 78%) as a yellow solid; mp 68–70°C
1
(EtOH); IR max (KBr): 3284, 3051, 1611, 1537, 1452, 1371, 1309 cm-1; H NMR (400 MHz, CDCl3) :
3.60 (1H,s), 7.41 (1H, dd, J = 7.0, 9.0 Hz), 7.49-7.53 (2H, m), 7.76 (1H, d, J = 6.5 Hz), 8.03 (2H, d, J =
9.0 Hz), 8.09–8.11 (1H, m), 8.45 (1H, s), 8.93 (1H, s); 13C NMR (100 MHz, CDCl3) : 82.0, 82.4, 119.8,
124.4, 124.9, 125.9, 125.9, 126.9, 128.0, 128.5, 129.7, 131.0, 131.1, 131.9, 132.2; Mass (EI) m/z 202 (M+,
100); HRMS (EI) calcd for C16H10: 202.0782. Found: 202.0783.
2-(3-Hydroxy-3-methyl-1-butynyl)anthracene: To a solution of 2-bromoanthracene (500 mg, 1.9
mmol) and 2-methyl-3-butyn-2-ol (330 mg, 0.38 mL, 3.9 mmol) in triethylamine (10 mL) were added
CuI (3.7 mg, 19 mol) and Pd(PPh3)2Cl2 (6.8 mg, 9.7 mol), and the reaction mixture was stirred at 80°C

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HETEROCYCLES, Vol. 80, No. 2, 2010
for 10 h. After removal of the solvent under reduced pressure, the resulting residue was purified by silica
gel column chromatography (CHCl3) to give 2-(3-hydroxy-3-methyl-1-butynyl)anthracene (175 mg,
35%) as a yellow solid; mp 188°C (EtOH); IR max (KBr): 3347, 2982, 2929, 1623, 1457, 1362, 1272,
1242, 1165 cm-1; 1H NMR (400 MHz, CDCl3) : 1.67 (6H, s), 2.06 (1H, s), 7.33 (1H, d, J = 9.0 Hz), 7.39
(2H, dd, J = 3.0, 6.5 Hz), 7.84 (1H, d, J = 9.0 Hz), 7.90 (1H, brs), 8.03 (1H, s), 8.28 (2H, d, J = 7.5 Hz);
13C NMR (100 MHz, CDCl3) : 31.5, 65.8, 82.7, 94.5, 119.4, 125.7, 125.8, 126.2, 126.2, 127.6, 128.1,
128.2, 128.2, 130.6, 130.9, 131.9, 132.0, 132.1; Mass (EI) m/z 260 (M+, 100), 245 (69), 202 (56); HRMS
(EI) calcd for C19H16O: 260.1201. Found: 260.1208.
2-Ethynylanthracene: A mixture of 2-(3-hydroxy-3-methyl-1-butynyl)anthracene (135 mg, 0.52 mmol)
and KOH (43 mg, 0.77 mmol) in toluene (5 mL) was heated under reflux for 1 h. After removal of the
solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography
(CHCl3) to give 1-ethynylanthracene (96 mg, 92%) as a yellow solid; mp 175–176°C (EtOH); IR max
1
(KBr): 3290, 3053, 1621, 1456, 1304, 1270, 1155 cm-1; H NMR (300 MHz, CDCl3) : 3.21
13
(1H,s),7.46–7.51 (3H, m), 7.96 (1H, d, J = 9.0 Hz), 8.00 (2H, brs), 8.21 (1H, s), 8.40 (1H, s); C NMR
(100 MHz, CDCl3) : 77.9, 84.2, 118.7, 125.8, 125.9, 126.2, 126.4, 127.5, 128.1, 128.3, 128.3, 130.8,
132.0, 132.2, 132.9;Mass (EI) m/z 202 (M+, 100); HRMS (EI) calcd for C16H10: 202.0782. Found:
202.0785.
Typical procedure for preparation of 5
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(1H-1,2,3-triazol-1-yl)benzyloxy]-N-
(2-trimethylsilyl)ethoxycarbonylpiperidine (5a): To a solution of trans-4 (75 mg, 0.19 mmol) in
t-BuOH (1.0 mL) and water (1.0 mL) were added CuSO4·5H2O (48 mg, 0.19 mmol), sodium ascorbate
(76 mg, 0.38 mmol), and trimethylsilylacetylene (39 mg, 55 L, 0.38 mmol) at rt, and the reaction
mixture stirred at the same temperature for 27 h. The reaction mixture was extracted with AcOEt. The
organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced
pressure. The resulting residue was purified by silica gel column chromatography (AcOEt : n-hexane =
1 : 1) to give 5a (68 mg, 85%) as a white paste; IR max (KBr): 2953, 1696, 1522, 1463, 1420, 1359, 1321,
1
1281, 1250, 1177, 1127, 1092, 1030 cm-1; H NMR (270 MHz, CDCl3) : 0.07 (9H, s), 1.01 (2H, t, J =
8.0 Hz), 3.31 (2H, brs), 3.48–3.60 (2H, m), 3.87 (3H, brs), 4.18 (2H, t, J = 8.0 Hz), 4.64 (1H, d, J = 11.5
Hz), 4.80 (1H, d, J = 11.5 Hz), 7.53 (2H, d, J = 7.5 Hz), 7.74 (2H, d, J = 7.5 Hz), 7.86 (1H, s), 7.99 (1H,
13
s); C NMR (67.8 MHz, DMSO-d6, 80°C) : ‒1.0, 18.0, 42.3, 42.4, 50.3, 52.2, 63.4, 70.5, 70.8, 69.7,
120.8, 123.6, 129.4, 134.7, 136.8, 139.4, 155.8; Mass (FAB) m/z 417 (M+H+); HRMS (FAB) calcd for
C20H29N4O4Si: 417.1958. Found: 417.1960.
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-methoxymethyl-1H-1,2,3-triazol-1-yl)benzyloxy]-

HETEROCYCLES, Vol. 80, No. 2, 2010
1257
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5b): a colorless oil; IR max (KBr): 2952, 1696, 1521,
1463, 1421, 1281, 1249, 1094, 1044, 1024 cm-1; 1H NMR (270 MHz, CDCl3) : 0.04 (9H, s), 1.00 (2H, t,
J = 8.0 Hz), 3.31 (2H, brs), 3.47 (3H, s), 3.47–3.60 (2H, m), 3.87 (3H, brs), 4.18 (2H, t, J = 8.0 Hz), 4.63
(1H, d, J = 11.5 Hz), 4.82 (1H, d, J = 11.5 Hz), 7.52 (2H, d, J = 8.0 Hz), 7.73 (2H, d, J = 8.0 Hz), 7.97
13
(1H, s); C NMR (67.8 MHz, DMSO-d6, 80°C) : ‒1.0, 18.0, 42.3, 42.4, 50.3, 52.2, 58.0, 63.4, 65.7,
70.5, 70.8, 120.6, 122.5, 129.4, 136.7, 139.4, 145.7, 155.9; Mass (FAB) m/z 489 (M+H+); HRMS (FAB)
calcd for C23H33N4O6Si: 489.2169. Found: 489.2168.
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-ethoxycarbonyl-1H-1,2,3-triazol-1-yl)benzyloxy]-
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5c): a yellow oil; IR max (KBr): 2953, 2898, 1733,
1
1697, 1541, 1521, 1463, 1422, 1372, 1339, 1250, 1174, 1149, 1127, 1092 cm-1; H NMR (270 MHz,
CDCl3) : 0.04 (9H, s), 1.01 (2H, t, J = 8.0 Hz), 1.45 (3H, t, J = 7.0 Hz), 3.31 (2H, brs), 3.43–3.65 (2H,
m), 3.87 (3H, brs), 4.18 (2H, t, J = 8.0 Hz), 4.48 (2H, q, J = 7.0 Hz), 4.65 (1H, d, J = 11.0 Hz), 4.83 (1H,
13
d, J = 11.0 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.75 (2H, d, J = 8.0 Hz), 8.50 (1H, s); C NMR (67.8 MHz,
DMSO-d6, 80°C) : ‒1.0, 14.7, 18.0, 42.3, 42.4, 50.3, 52.2, 61.2, 63.5, 70.5, 70.9, 121.2, 127.6, 129.4,
136.1, 140.2, 140.5, 155.9, 160.7; Mass (FAB) m/z 461 (M+H+); HRMS (FAB) calcd for C22H33N4O5Si:
461.2220. Found: 461.2225.
(3RS,4RS,5RS)-5-[4-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)benzyloxy]-3,4-epoxy-
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5d): a colorless oil; IR max (KBr) : 2952, 1695, 1521,
1
1463, 1420, 1338, 1281, 1249, 1126, 1091, 1039 cm-1; H NMR (270 MHz, CDCl3) : 0.04 (9H, s),
0.93–1.03 (6H, m), 1.98–2.08 (1H, m), 3.30 (2H, brs), 3.48–3.63 (2H, m), 3.86 (3H, brs), 4.18 (2H, t, J =
8.0 Hz), 4.62 (1H, d, J = 11.5 Hz), 4.79 (1H, d, J = 11.5 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.66 (1H, s), 7.69
(2H, d, J = 8.0 Hz); 13C NMR (67.8 MHz, DMSO-d6, 80°C) : ‒1.0, 7.0, 8.0, 18.0, 42.3, 42.4, 50.3, 52.2,
63.4, 70.6, 70.8, 119.4, 120.3, 129.3, 136.8, 139.0, 150.7, 156.0; Mass (FAB) m/z 457 (M+H+); HRMS
(FAB) calcd for C23H33N4O4Si: 457.2271. Found: 457.2272.
(3RS,4RS,5RS)-5-[4-(4-Cyclohexyl-1H-1,2,3-triazol-1-yl)benzyloxy]-3,4-epoxy-
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5e)
a colorless oil; IR max (KBr) : 2926, 2853, 1697, 1519, 1449, 1420, 1280, 1249, 1126, 1091, 1047 cm-1;
1H NMR (270 MHz, CDCl3) : 0.04 (9H, s), 1.00 (2H, t, J = 8.0 Hz), 1.37–1.51 (6H, m), 1.74–1.86 (2H,
m), 2.11 (2H, brs), 2.86 (1H, brs), 3.30 (2H, brs), 3.44–3.59 (2H, m), 3.87 (3H, brs), 4.18 (2H, t, J = 8
Hz), 4.62 (1H, d, J = 11.0 Hz), 4.80 (1H, d, J = 11.0 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.68 (2H, d, J = 8.0
Hz), 7.73 (1H, s); 13C NMR (67.8 MHz, DMSO-d6, 80°C) : ‒1.0, 18.0, 26.0, 26.2, 33.0, 35.3, 42.3, 42.4,
50.3, 52.2, 63.4, 70.6, 70.8, 119.3, 120.3, 129.3, 137.0, 139.0, 153.8, 155.9; Mass (FAB) m/z 499
(M+H+); HRMS (FAB) calcd for C26H30N4O4Si: 499.2741. Found: 499.2733.

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(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzyloxy]-
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5f): a white solid; mp 58–60°C (toluene : n-hexane = 1 :
1
3); IR max (KBr): 2953, 1697, 1522, 1460, 1419, 1281, 1250, 1124, 1090, 1042 cm-1; H NMR (270
MHz, CDCl3) : 0.05 (9H, s), 1.01 (2H, t, J = 8.0 Hz), 3.32 (2H, brs), 3.49–3.66 (2H, m), 3.87 (3H, brs),
4.20 (2H, t, J = 8 Hz), 4.65 (1H, d, J = 11.5 Hz), 4.70 (1H, d, J = 11.5 Hz), 7.31–7.56 (5H, m), 7.79 (2H,
13
d, J = 8.0 Hz), 7.92 (2H, d, J = 8.0 Hz), 8.20 (1H, s); C NMR (67.8 MHz, DMSO-d6, 80°C) : ‒1.0,
18.0, 42.4, 42.4, 50.3, 52.2, 63.5, 70.6, 70.8, 120.0, 120.6, 126.1, 128.7, 129.4, 131.0, 136.0, 136.7, 139.5,
148.0, 155.9; Mass (FAB) m/z 493 (M+H+); HRMS (FAB) calcd for C26H33N4O4Si: 493.2271. Found:
493.2261; Anal. Calcd for C26H32N4O4Si: C, 63.39; H, 6.55; N, 11.37. Found: C, 63.16; H, 6.48; N,
11.35.
(3RS,4RS,5RS)-5-[4-(4-Benzyl-1H-1,2,3-triazol-1-yl)benzyloxy]-3,4-epoxy-N-
(2-trimethylsilyl)ethoxycarbonylpiperidine (5g): a white paste; IR max (KBr): 2952, 1697, 1520, 1456,
1419, 1359, 1282, 1250, 1124, 1090, 1043, 1024 cm-1; 1H NMR (400 MHz, CDCl3) : 0.03 (9H, s), 1.00
(2H, t, J = 8.0 Hz), 3.29 (2H, brs), 3.44–3.61 (2H, m), 3.84–3.88 (3H, m), 4.17 (2H, t, J = 8 Hz), 4.18 (2H,
s), 4.61 (1H, d, J = 12.0 Hz), 4.79 (1H, d, J = 12.0 Hz), 7.24–7.28 (1H, m), 7.32–7.34 (4H, m), 7.47 (2H,
13
d, J = 8.0 Hz), 7.58 (1H, s), 7.68 (2H, d, J = 8.0 Hz); C NMR (75.45 MHz, DMSO-d6, 80°C) : ‒2.0,
17.0, 30.9, 41.3, 41.4, 49.3, 51.2, 62.4, 69.6, 69.8, 119.5, 120.2, 125.7, 127.9, 128.1, 128.3, 135.8, 138.2,
138.8, 146.7, 154.9; Mass (FAB) m/z 507 (M+H+); HRMS (FAB) calcd for C27H35N4O4Si: 507.2428.
Found: 507.2426.
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-phenethyl-1H-1,2,3-triazol-1-yl)benzyloxy]-
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5h): a colorless oil; IR max (KBr): 2952, 1696, 1520,
1455, 1420, 1281, 1249, 1126, 1091, 1045 cm-1; 1H NMR (270 MHz, CDCl3) : 0.04 (9H, s), 1.01 (2H, t,
J = 8.0 Hz), 3.09 (2H, t, J = 5.5 Hz), 3.11 (2H, t, J = 5.5 Hz), 3.30 (2H, brs), 3.48–3.63 (2H, m), 3.87 (3H,
brs), 4.18 (2H, t, J = 8.0 Hz), 4.62 (1H, d, J = 11.5 Hz), 4.80 (1H, d, J = 11.5 Hz), 7.21–7.30 (5H, m),
7.49–7.54 (3H, m), 7.67 (2H, d, J = 8.0 Hz); 13C NMR (67.8 MHz, DMSO-d6, 80°C) : ‒1.9, 17.1, 26.5,
34.3, 41.5, 41.5, 549.4, 51.3, 62.6, 69.7, 69.9, 119.5, 119.8, 125.6, 127.9, 127.9, 128.5, 136.0, 138.2,
140.8, 147.1, 155.0; Mass (FAB) m/z 521 (M+H+); HRMS (FAB) calcd for C28H37N4O4Si: 521.1584.
Found: 521.2581.
(3RS, 4RS,5RS)-3,4-Epoxy-5-{4-[4-(2-pyridinyl) -1H-1,2,3-triazol-1-yl]benzyloxy}-
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5i): colorless crystals; mp 110–111°C (toluene :
n-hexane = 1 : 2); IR max (KBr): 2952, 1695, 1602, 1521, 1468, 1412, 1357, 1279, 1249, 1126, 1091,
1
1029 cm-1; H NMR (270 MHz, CDCl3) : 0.07 (9H, s), 1.00 (2H, t, J = 7.5 Hz), 3.30 (2H, brs),
3.43–3.60 (2H, m), 3.87 (3H, brs), 4.18 (2H, t, J = 7.5 Hz), 4.64 (1H, d, J = 10.0 Hz), 4.81 (1H, d, J =

HETEROCYCLES, Vol. 80, No. 2, 2010
1259
10.0 Hz), 7.26 (1H, t, J = 7.0 Hz), 7.54 (2H, d, J = 6.5 Hz), 7.79–7.81 (2H, m), 8.25 (1H, d, J = 7.0 Hz),
13
8.59 (1H, s), 8.61 (1H, d, J = 7.0 Hz); C NMR (67.8 MHz, DMSO-d6, 80°C) : ‒1.0, 17.9, 42.3, 42.4,
50.3, 52.2, 63.4, 70.5, 70.8, 120.4, 120.8, 121.7, 123.7, 129.3, 136.6, 137.6, 139.6, 148.8, 150.1, 150.2,
155.8; Mass (FAB) m/z 494 (M+H+); Anal. Calcd for C25H31N5O4Si : C, 60.83; H, 6.33; N, 14.19. Found:
C, 60.97; H, 6.28; N, 14.13.
(3RS,4RS,5RS)-3,4-Epoxy-5-{4-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]benzyloxy}-
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5j): a white solid; mp 97–99°C (toluene : n-hexane = 1 :
1
2); IR max (KBr): 2953, 1698, 1495, 1465, 1423, 1280, 1250, 1093, 1043 cm-1; H NMR (270 MHz,
CDCl3) : 0.04 (9H, s), 1.01 (2H, t, J = 7.5 Hz), 3.31 (2H, brs), 3.48–3.59 (2H, m), 3.87 (3H, brs), 4.18
(2H, t, J = 7.5 Hz), 4.65 (1H, d, J= 11.5 Hz), 4.84 (1H, d, J = 11.5 Hz), 7.16 (2H, t, J = 8.5 Hz), 7.55 (2H,
d, J = 8.0 Hz), 7.78 (2H, d, J = 8.0 Hz), 7.89 (2H, dd, J = 5.5, 8.5 Hz), 8.14 (1H, s); 13C NMR (67.8 MHz,
DMSO-d6, 80°C) : ‒1.0, 18.0, 42.4, 42.4, 50.3, 52.2, 63.5, 70.6, 70.8, 116.4 (d, J = 22.0 Hz), 112.0,
120.6, 127.6 (d, J = 3.0 Hz), 128.1 (d, J = 8.5 Hz ), 129.4, 136.7, 139.6, 147.1, 155.9, 162.7 (d, J = 245.0
Hz); Mass (FAB) m/z 511 (M+H+); HRMS (FAB) calcd for C26H32FN4O4Si: 511.2177. Found: 511.2171.
(3RS,4RS,5RS)-3,4-Epoxy-5-{4-[4-(1-naphthyl) -1H-1,2,3-triazol-1-yl]benzyloxy}-
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5k): a pale yellow foam; IR max (KBr): 2952, 1695,
1520, 1462, 1423, 1356, 1248, 1126, 1091, 1045 cm-1; 1H NMR (270 MHz, CDCl3) : 0.05 (9H, s), 1.02
(2H, t, J = 8.0 Hz), 3.30 (2H, brs), 3.50–3.65 (2H, m), 3.88 (3H, brs), 4.19 (2H, t, J = 8.0 Hz), 4.67 (1H, d,
J = 12.0 Hz), 4.86 (1H, d, J = 12.0 Hz), 7.51‒7.59 (5H, m), 7.92–7.95 (5H, m), 8.25 (1H, s), 8.44 (1H, t, J
= 5.0 Hz); 13C NMR (67.8 MHz, DMSO-d6, 80 °C) : ‒1.0, 18.0, 42.4, 42.5, 50.3, 52.2, 63.5, 70.6, 70.8,
120.8, 122.6, 126.0, 126.1, 126.6, 127.2, 127.7, 128.2, 128.9, 129.4, 129.4, 131.2, 134.3, 136.8, 139.5,
147.3, 155.9; Mass (FAB) m/z 543 (M+H+); HRMS (FAB) calcd for C30H35N4O4Si: 543.2428. Found:
543.2429.
(3RS,4RS,5RS)-3,4-Epoxy-5-{4-[4-(2-naphthyl) -1H-1,2,3-triazol-1-yl]benzyloxy}-
N-(2-trimethylsilyl)ethoxycarbonylpiperidine (5l) a white solid; mp. 113–114°C (toluene : n-hexane =
1
1 : 3); IR max (KBr): 2953, 1698, 1520, 1464, 1418, 1250, 1117, 1042, 951 cm-1; H NMR (270 MHz,
CDCl3) : 0.05 (9H, s), 1.02 (2H, t, J = 8.0 Hz), 3.31 (2H, brs), 3.45–3.61 (2H, m), 3.88 (3H, brs), 4.20
(2H, t, J = 8.0 Hz), 4.66 (1H, d, J = 11.5 Hz), 4.84 (1H, d, J = 11.5 Hz), 7.49–7.58 (4H, m), 7.81–8.00
(6H, m), 8.31 (1H, s), 8.43 (1H, s); 13C NMR (67.8 MHz, DMSO-d6, 80°C) : ‒1.0, 18.0, 42.4, 42.5, 50.3,
52.2, 63.5, 70.6, 70.9, 120.4, 120.6, 124.4, 124.5, 126.7, 127.1, 128.3, 128.5, 128.5, 129.1, 129.4, 133.4,
133.8, 136.7, 139.5, 148.0, 155.9; Mass (FAB) m/z 543 (M+H+); Anal. Calcd for C30H34N4O4Si : C,
66.39; H, 6.31; N, 10.32. Found: C, 66.11; H, 6.29; N, 10.29.
(3RS,4RS,5RS)-5-{4-[4-(1-Anthracenyl)-1H-1,2,3-triazol-1-yl]benzyloxy}-3,4-epoxy-N-

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(2-trimethylsilyl)ethoxycarbonylpiperidine (5m): a yellow foam; IR max (KBr): 2952, 2898, 2109,
1
1694, 1519, 1462, 1418, 1312, 1281, 1250, 1125, 1092, 1039 cm-1; H NMR (400 MHz, CDCl3) : 0.05
(9H, s), 1.02 (2H, t, J = 8.0 Hz), 3.34 (2H, brs), 3.51–3.67 (2H, m), 3.89–3.97 (3H, m), 4.20 (2H, t, J =
8.0 Hz), 4.71 (1H, d, J = 12.0 Hz), 4.87 (1H, d, J = 12.0 Hz), 7.46–7.62 (5H, m), 7.77 (1H, d, J = 6.5 Hz),
7.90 (2H, d, J = 8.0 Hz), 8.03 (2H, d, J = 8.0 Hz), 8.10 (1H, d, J = 8.0 Hz) 8.34 (1H, s), 8.52 (1H, s), 9.06
13
(1H, s); C NMR (67.8 MHz, DMSO-d6, 80 °C) : ‒1.9, 17.0, 41.4, 41.5, 49.3, 51.3, 62.5, 69.6, 69.8,
119.9, 121.8, 124.0, 124.4, 125.2, 125.5, 126.2, 126.3, 127.3, 127.3, 128.2, 128.4, 128.4, 128.7, 130.8,
131.3, 131.3, 135.8, 138.6, 146.4, 154.9; Mass (FAB) m/z 593 (M+H+); HRMS (FAB) calcd for
C34H37N4O4Si: 593.2584. Found: 593.2584.
(3RS,4RS,5RS)-5-{4-[4-(2-Anthracenyl)-1H-1,2,3-triazol-1-yl]benzyloxy}-3,4-epoxy-N-
(2-trimethylsilyl)ethoxycarbonylpiperidine (5n): a yellow solid; mp 155–156°C (toluene : n-hexane =
1
1 : 3); IR max (KBr): 2954, 1698, 1520, 1464, 1418, 1281, 1251, 1231, 1092, 1036 cm-1; H NMR (300
MHz, CDCl3) : 0.05 (9H, s), 1.02 (2H, t, J = 8.0 Hz), 3.32 (2H, brs), 3.50–3.65 (2H, m), 3.88–3.90 (3H,
m), 4.20 (2H, t, J = 8.0 Hz), 4.63 (1H, d, J = 11.5 Hz), 4.82 (1H, d, J = 11.5 Hz), 7.45–7.55 (4H, m), 7.80
13
(1H, d, J = 7.5 Hz), 7.94–8.09 (4H, m), 8.30 (1H, s), 8.41 (1H, s), 8.46 (1H, s), 8.58 (1H, s); C NMR
(67.8 MHz, DMSO-d6, 80°C) : ‒1.9, 17.0, 41.4, 41.5, 49.3, 51.2, 62.5, 69.6, 69.9, 119.5, 119.6, 123.3,
123.4, 125.2, 125.3, 125.7, 125.9, 126.9, 127.6, 127.6, 128.4, 128.5, 130.5, 130.8, 131.2, 131.4, 135.7,
138.6, 147.0, 154.9; Mass (FAB) m/z 593 (M+H+); HRMS (FAB) calcd for C34H37N4O4Si: 593.2584.
Found: 593.2595.
(3RS,4RS,5RS)-5-{4-[4-(9-Anthracenyl)-1H-1,2,3-triazol-1-yl]benzyloxy}-3,4-epoxy-N-
(2-trimethylsilyl)ethoxycarbonylpiperidine (5o): a white foam; IR max (KBr): 2952, 1694, 1519, 1462,
1421, 1357, 1313, 1279, 1249, 1126, 1091, 1047, 1026 cm-1; 1H NMR (270 MHz, CDCl3) : 0.06 (9H, s),
1.02 (2H, t, J = 8.0 Hz), 3.34 (2H, brs), 3.51–3.62 (2H, m), 3.91 (3H, brs), 4.20 (2H, t, J = 8.0 Hz), 4.69
(1H, d, J = 12.0 Hz), 4.87 (1H, d, J = 12.0 Hz), 7.42–7.52 (4H, m), 7.61 (2H, d, J = 7.5 Hz), 7.92 (2H, d,
J = 8.0 Hz), 7.93 (2H, d, J = 8.0 Hz), 8.07 (2H, d, J = 7.5 Hz), 8.25 (1H, s), 8.59 (1H, s); 13C NMR (67.8
MHz, DMSO-d6, 80°C) : ‒1.9, 17.0, 14.4, 41.5, 49.3, 51.3, 62.5, 69.6, 69.8, 123.7, 124.1, 124.9, 125.4,
125.9, 127.7, 128.0, 128.5, 130.3, 130.6, 135.8, 138.6, 143.1, 154.9; Mass (FAB) m/z 593 (M+H+);
HRMS (FAB) calcd for C34H37N4O4Si: 593.2584. Found: 593.2584.
Typical procedure of preparation of 6
(3RS,4RS,5RS)-3,4-epoxy-5-[4-(1H-1,2,3-triazol-1-yl)benzyloxy]piperidine (6a): Tetra-n-
butylammonium fluoride (1.0 M THF solution, 36 mol, 36 L) was added to 5a (10 mg, 24 mol) and
the solvent was concentrated under reduced pressure. The reaction mixture was left at rt for 2 h and
purified by silica gel column chromatography (CHCl3 : MeOH = 25 : 1) to give 6a (5.3 mg, 82%) as a

HETEROCYCLES, Vol. 80, No. 2, 2010
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1
colorless oil. This compound was immediately dissolved in DMSO to prevent polymerization, H NMR
(270 MHz, CDCl3) : 2.51 (1H, dd, J = 7.5, 13.5 Hz), 3.06 (1H, dd, J = 5.0, 13.5 Hz), 3.14–3.25 (3H, m),
3.29 (1H, d, J = 4.0 Hz), 3.65 (1H, dd, J = 5.5, 7.5 Hz), 4.69 (1H, d, J = 12.0 Hz), 4.75 (1H, d, J = 12.0
Hz), 7.53 (2H, d, J = 8.5 Hz), 7.75 (2H, dt, J = 2.0, 8.5 Hz), 7.85 (1H, d, J = 1.0 Hz), 7.99 (1H, d, J = 1.0
Hz); 13C NMR (100 MHz, CDCl3) : 43.9, 45.2, 50.9, 52.8, 70.6, 70.7, 120.7, 121.7, 128.9, 134.5, 136.5,
138.7.
(3RS,4RS,5RS)-3,4-epoxy-5-[4-(4-methoxymethyl-1H-1,2,3-triazol-1-yl)benzyloxy]piperidine (6b): a
colorless oil; 1H NMR (270 MHz, CDCl3) : 2.51 (1H, dd, J = 7.5, 13.5 Hz), 3.06 (1H, dd, J = 5.5, 13.5
Hz), 3.14–3.25 (3H, m), 3.29 (1H, d, J = 3.5 Hz), 3.48 (3H, s), 3.65 (1H, dd, J = 5.5, 7.5 Hz),4.68 (2H, s),
4.67 (1H, d, J = 12.0 Hz), 4.74 (1H, d, J = 12.0 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.73 (2H, d, J = 8.5 Hz),
13
7.98 (1H, s); C NMR (100 MHz, CDCl3) : 43.8, 45.2, 50.9, 52.8, 58.5, 66.0, 70.6, 70.7, 120.5, 120.6,
128.8, 136.5, 138.7, 145.9.
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-ethoxycarbonyl-1H-1,2,3-triazol-1-yl)benzyloxy]piperidine (6c): a
1
colorless oil; H NMR (270 MHz, CDCl3) : 1.44 (3H, t, J = 7.5 Hz), 2.50 (1H, dd, J = 7.5, 13.5 Hz),
3.06 (1H, dd, J = 5.0, 13.5 Hz), 3.14–3.25 (3H, m), 3.29 (1H, d, J = 4.0 Hz), 3.65 (1H, dd, J = 5.5, 7.0
Hz), 4.47 (2H, q, J = 7.5 Hz), 4.70 (1H, d, J = 12.0 Hz), 4.75 (1H, d, J = 12.0), 7.55 (2H, d, J = 8.5 Hz),
13
7.76 (2H, dt, J = 2.0, 8.5 Hz), 8.50 (1H, s); C NMR (100 MHz, CDCl3) : 14.3, 43.8, 45.2, 50.9, 52.8,
61.5, 70.6, 70.7, 120.9, 125.4, 128.9, 135.8, 139.6, 140.89 160.6.
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)benzyloxy]piperidine (6d):
a
colorless oil; 1H NMR (270 MHz, CDCl3) : 0.90–1.05 (4H, m), 1.98–2.08 (1H, m), 2.50 (1H, dd, J = 7.5,
13.5 Hz), 3.05 (1H, dd, J = 5.0, 13.5 Hz), 3.10–3.21 (3H, m), 3.29 (1H, d, J = 3.5 Hz), 3.64 (1H, t, J = 6.0
Hz), 4.67 (1H, d, J = 12.0 Hz), 4.72 (1H, d, J = 12.0 Hz), 7.49 (2H, d, J = 8.5 Hz), 7.67 (1H, s), 7.71 (2H,
13
d, J = 8.5 Hz); C NMR (100 MHz, CDCl3) : 6.7, 7.9, 43.9, 45.2, 51.0, 52.9, 70.6, 70.8, 117.8, 120.4,
128.8, 136.8, 138.3, 151.0; Mass (NALDI) m/z 413 (M+H+).
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-cyclohexyl-1H-1,2,3-triazol-1-yl)benzyloxy]piperidine (6e):
a
1
colorless oil; H NMR (270 MHz, CDCl3) : 1.20–1.52 (5H, m), 1.69–1.78 (3H, m), 2.08–2.11 (2H, m),
2.47 (1H, dd, J = 7.5, 13.5 Hz), 2.76–2.84 (1H, m), 3.01 (1H, dd, J = 5.0, 13.5 Hz), 3.10–3.21 (3H, m),
3.25 (1H, d, J = 4.0 Hz), 3.60 (1H, dd, J = 5.5, 7.5 Hz), 4.64 (1H, d, J = 12.0 Hz), 4.69 (1H, d, J = 12.0
Hz), 7.46 (2H, d, J = 8.5 Hz), 7.63 (1H, s), 7.75 (2H, dt, J = 2.0, 8.5 Hz); 13C NMR (100 MHz, CDCl3) :
26.0, 26.1, 33.0, 35.3, 43.8, 45.1, 50.9, 52.8, 70.5, 70.8, 117.4, 120.4, 128.8, 136.9, 138.2, 154.5; Mass
(NALDI) m/z 355 (M+H+).
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzyloxy]piperidine (6f): a white
solid; mp 129–131°C (toluene : n-hexane = 2 : 1); 1H NMR (270 MHz, CDCl3) : 2.51 (1H, dd, J = 7.5,

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13.5 Hz), 3.07 (1H, dd, J = 5.0, 13.5 Hz), 3.14-3.25 (3H, m), 3.30 (1H, d, J = 3.5 Hz), 3.65 (1H, dd, J =
5.5, 7.5 Hz), 4.70 (1H, d, J = 12.0 Hz), 4.76 (1H, d, J = 12.0 Hz), 7.37-7.56 (5H, m), 7.81 (2H, d, J = 8.5
Hz), 7.93 (2H, d, J = 8.5 Hz), 8.19 (1H, s); 13C NMR (100 MHz, CDCl3) : 43.8, 45.1, 50.9, 52.8, 70.6,
70.7, 117.5, 120.5, 125.8, 128.4, 128.9, 128.9, 130.1, 136.5, 138.7, 148.4.
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-benzyl-1H-1,2,3-triazol-1-yl)benzyloxy]piperidine (6g): a colorless
oil; 1H NMR (400 MHz, CDCl3) : 2.43 (1H, dd, J = 7.0, 13.5 Hz), 2.97 (1H, dd, J = 4.0, 13.5 Hz), 3.04
(1H, dd, J = 2.0, 15.0 Hz), 3.08–3.10 (1H, m), 3.14 (1H, d, J = 15.0 Hz), 3.21 (1H, d, J = 4.0 Hz), 3.56
(1H, dd, J = 5.0, 7.0 Hz), 4.11 (2H, s), 4.60 (1H, d, J = 12.5 Hz), 4.64 (1H, d, J = 12.5 Hz), 7.17–7.21
(1H, m), 7.26–7.27 (4H, m), 7.41 (2H, d, J = 8.0 Hz), 7.52 (1H, s), 7.62 (2H, d, J = 8.0 Hz); 13C NMR
(100 MHz, CDCl3) : 32.3, 43.8, 45.2, 50.9, 52.8, 70.5, 70.7, 119.5, 120.4, 126.6, 128.7, 128.7, 136.6,
138.4, 138.7, 148.5; Mass (NALDI) m/z 363 (M+H+).
(3RS,4RS,5RS)-3,4-Epoxy-5-[4-(4-phenethyl-1H-1,2,3-triazol-1-yl)benzyloxy]piperidine
(6h):
a
colorless oil; 1H NMR (270 MHz, CDCl3) : 2.50 (1H, dd, J = 7.5, 13.5 Hz), 3.02–3.19 (8H, m), 3.29 (1H,
d, J = 4.0 Hz), 3.63 (1H, dd, J = 5.5, 7.5 Hz), 4.67 (1H, d, J = 12.0 Hz), 4.73 (1H, d, J = 12.0 Hz),
7.19-7.33 (5H, m), 7.49 (2H, d, J = 8.5 Hz), 7.54 (1H, s), 7.68 (2H, d, J = 8.5 Hz); 13C NMR (100 MHz,
CDCl3) : 27.5, 35.4, 43.8, 45.2, 50.9, 52.8, 70.5, 70.7, 119.1, 120.4, 126.2, 128.4, 128.5, 128.8, 136.7,
138.3, 141.0, 148.1; Mass (NALDI) m/z 377 (M+H+).
(3RS,4RS,5RS)-3,4-Epoxy-5-{4-[4-(2-pyridinyl)-1H-1,2,3-triazol-1-yl]benzyloxy}piperidine (6i): a
white solid; mp 115–118°C (toluene : n-hexane = 2 : 1); 1H NMR (270 MHz, CDCl3) : 2.51 (1H, dd, J =
7.5, 13.5 Hz), 3.07 (1H, dd, J = 5.5, 13.5 Hz), 3.14-3.24 (3H, m), 3.30 (1H, d, J = 3.5 Hz), 3.66 (1H, dd, J
= 5.5, 7.5 Hz), 4.70 (1H, d, J = 12.0 Hz), 4.75 (1H, d, J = 12.0 Hz), 7.29 (1H, dd, J = 1.0, 5.0 Hz), 7.54
(2H, d, J = 8.5 Hz),7.79–7.85 (3H, m), 8.25 (1H, dt, J = 1.0, 8.0 Hz), 8.61 (2H, m); 13C NMR (100 MHz,
CDCl3) : 43.8, 45.2, 50.9, 52.8, 70.6, 70.7, 119.9, 120.4, 120.5, 123.1, 128.9, 136.5, 137.0, 138.8, 149.0,
149.5, 149.9; Mass (NALDI) m/z 372 (M+Na+).
(3RS,4RS,5RS)-3,4-Epoxy-5-{4-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]benzyloxy}piperidine (6j):
a white solid; mp 179°C (toluene : n-hexane = 2 : 1); 1H NMR (270 MHz, CDCl3) : 2.52 (1H, dd, J = 7.5,
13.5 Hz), 3.07 (1H, dd, J = 5.5, 13.5 Hz), 3.14-3.25 (3H, m), 3.30 (1H, d, J = 3.5 Hz), 3.65 (1H, dd, J =
5.5, 7.5 Hz), 4.70 (1H, d, J = 12.0 Hz), 4.76 (1H, d, J = 12 Hz), 7.16 (2H, t, J = 8.5 Hz), 7.55 (2H, d, J =
8.5 Hz), 7.79 (2H, d, J = 8.5 Hz), 8.89 (2H, dd, J = 5.5, 8.5 Hz), 8.15 (1H, s); 13C NMR (100 MHz,
CDCl3) : 43.9, 45.2, 51.0, 52.8, 70.6, 70.7, 115.9 (d, J = 22.0 Hz), 117.3, 120.6, 126.4 (d, J = 3.0 Hz),
127.6 (d, J = 8.0 Hz ), 128.9, 136.5, 138.8, 147.6, 162.8 (d, J = 247.0 Hz).
(3RS,4RS,5RS)-3,4-Epoxy-5-{4-[4-(1-naphthyl)-1H-1,2,3-triazol-1-yl]benzyloxy}piperidine (6k): a
yellow oil; 1H NMR (270 MHz, CDCl3) : 2.53 (1H, dd, J = 7.5, 13.5 Hz), 3.07 (1H, dd, J = 5.0, 13.5 Hz),

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3.15-3.26 (3H, m), 3.31 (1H, d, J = 3.5 Hz), 3.67 (1H, dd, J = 5.5, 7.5 Hz), 4.72 (1H, d, J = 12.0 Hz), 4.78
(1H, d, J = 12.0 Hz), 7.52–7.65 (5H, m), 7.80 (1H, dd, J = 1.5, 7.5 Hz), 7.86 (2H, dt, J = 2.0, 8.5 Hz),
7.91–8.00 (2H, m), 8.25 (1H, s), 8.42–8.46 (1H, m); 13C NMR (100 MHz, CDCl3) : 43.9, 45.2, 51.0,
52.9, 70.6, 70.8, 120.5, 120.6, 125.4, 126.1, 126.8, 127.4, 127.6, 128.5, 128.9, 129.2, 131.1, 133.9, 136.6,
138.8, 147.6; Mass (NALDI) m/z 399 (M+H+).
(3RS,4RS,5RS)-3,4-Epoxy-5-{4-[4-(2-naphthyl)-1H-1,2,3-triazol-1-yl]benzyloxy}piperidine (6l): a
colorless oil; 1H NMR (270 MHz, CDCl3) : 2.52 (1H, dd, J = 7.5, 13.5 Hz), 3.07 (1H, dd, J = 5.0, 13.5
Hz), 3.14–3.25 (3H, m), 3.31 (1H, d, J = 3.5 Hz), 3.66 (1H, dd, J = 5.5, 7.5 Hz), 4.71 (1H, d, J = 12.0 Hz),
4.76 (1H, d, J = 12.0 Hz),7.47–7.57 (4H, m), 7.81–8.03 (6H, m), 8.31 (1H, s), 8.43 (1H, s); 13C NMR
(100 MHz, CDCl3) : 43.9, 45.2, 51.0, 52.9, 70.6, 70.7, 117.8, 120.6, 123.8, 124.7, 126.3, 126.5, 127.5,
127.8, 128.2, 128.7, 128.9, 133.3, 133.5, 136.6, 138.8, 148.5; Mass (NALDI) m/z 399 (M+H+).
(3RS,4RS,5RS)-5-{4-[4-(1-Anthracenyl)-1H-1,2,3-triazol-1-yl]benzyloxy}-3,4-epoxypiperidine (6m):
1
a yellow oil; H NMR (400 MHz, CDCl3) : 2.55 (1H, dd, J = 7.5, 13.5 Hz), 3.09 (1H, dd, J = 5.0, 13.5
Hz), 3.14 (1H, dd, J = 1.5, 15.0 Hz), 3.18–3.19 (1H, m), 3.23 (1H, d, J = 15.0 Hz), 3.33 (1H, d, J = 3.5
Hz), 3.68 (1H, dd, J = 5.0, 7.5 Hz), 4.74 (1H, d, J = 12.0 Hz), 4.78 (1H, d, J = 12.0 Hz), 7.46–7.56 (4H,
m), 7.60 (2H, d, J = 8.0 Hz), 7.77 (1H, d, J = 7.0 Hz), 7.91 (2H, d, J = 8.0 Hz), 8.02–8.04 (2H, m), 8.10
(1H, d, J = 8.0 Hz), 8.35 (1H, s), 8.52 (1H, s); 13C NMR (100 MHz, CDCl3) : 43.8, 45.2, 50.9, 52.8, 70.6,
70.7, 120.6, 120.6, 120.7, 124.5, 124.6, 125.6, 125.8, 126.9, 127.0, 127.8, 128.7, 128.9, 129.4, 129.6,
131.6, 131.9, 132.1, 136.6, 138.8, 147.9; Mass (NALDI) m/z 449 (M+H+).
(3RS,4RS,5RS)-5-{4-[4-(2-Anthracenyl)-1H-1,2,3-triazol-1-yl]benzyloxy}-3,4-epoxypiperidine (6n): a
yellow oil; 1H NMR (400 MHz, CDCl3) : 2.53 (1H, dd, J = 7.0, 13.5 Hz), 3.08 (1H, dd, J = 5.0, 13.5 Hz),
3.13 (1H, dd, J = 1.5, 15.0 Hz), 3.18–3.19 (1H, m), 3.23 (1H, d, J = 15.0 Hz), 3.32 (1H, d, J = 4.0 Hz),
3.67 (1H, dd, J = 5.0, 7.0 Hz), 4.72 (1H, d, J = 12.0 Hz), 4.76 (1H, d, J = 12.0 Hz), 7.48–7.52 (2H, m),
7.57 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 7.97–8.04 (3H, m), 8.11 (1H, d, J = 8.0 Hz), 8.35 (1H,
s), 8.45 (1H, s), 8.50 (1H, s), 8.61 (1H, s); 13C NMR (100 MHz, CDCl3) : 43.9, 45.2, 51.0, 52.9, 70.6,
70.8, 117.8, 120.6, 123.6, 124.7, 125.6, 125.7, 126.3, 126.7, 126.8, 128.2, 128.2, 128.9, 129.1, 131.3,
131.5, 132.0, 132.1, 136.6, 138.8, 148.5, 154.5; Mass (NALDI) m/z 449 (M+H+).
(3RS,4RS,5RS)-5-{4-[4-(9-Anthracenyl)-1H-1,2,3-triazol-1-yl]benzyloxy}-3,4-epoxypiperidine (6o): a
yellow oil; 1H NMR (270 MHz, CDCl3) : 2.49 (1H, dd, J = 7.0, 13.5 Hz), 2.98–3.05 (2H, m), 3.10–3.14
(2H, m), 3.26 (1H, d, J = 3.5 Hz), 3.63 (1H, dd, J = 5.0, 7.0 Hz), 4.69 (2H, s), 7.34–7.45 (4H, m), 7.53
(2H, d, J = 8.0 Hz), 7.82–7.88 (4H, m), 8.00 (2H, d, J = 8.0 Hz), 8.18 (1H, s), 8.35 (1H, s), 8.51 (1H, s);
13C NMR (100 MHz, CDCl3) : 43.8, 45.2, 50.9, 52.8, 70.6, 70.7, 120.5, 122.6, 123.9, 125.3, 125.8,
126.2, 128.5, 128.5, 128.9, 131.3, 136.5, 138.8, 144.7; Mass (NALDI) m/z 449 (M+H+).

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Examination of relaxation assay of supercoiled plasmid DNA: To a solution of supercoiled pBR 322
DNA (0.15 g) in pH 7.0 TE buffer (9 L) was added a DMSO solution of the compounds (1 L, 10 M
and 100 M), and the mixture was incubated for 24 h at 37°C. The resulting DNA analysis was
conducted using electrophoresis (tris-acetate-EDTA buffer, ethidium bromide 1.3 M solution) on 0.7%
native agarose gel at 7.4 v/cm for 30 min.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Science Research from the Japan Society for the
Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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