Total syntheses of naamine A and naamidine A, marine imidazole alkaloids

Article abstract of DOI:10.3987/COM-00-8952

The first total syntheses of naamine A (4) and naamidine A (5), marine imidazole alkaloids, were achieved through twelve and thirteen steps of reactions, respectively, starting from 1-methyl-2-phenylthio-1H-imidazole (17).

Full text of DOI:10.3987/COM-00-8952

HETEROCYCLES, Vol. 53, No.9, 2000, pp. 1939 - 1955, Received, 22nd May, 2000
TOTAL SYNTHESES OF NAAMINE A and NAAMIDINE A, MARINE
IMIDAZOLE ALKALOIDS
Shunsaku Ohta,* Naoki Tsuno, Seikou Nakamura, Norio Taguchi, Masayuki
Yamashita, Ikuo Kawasaki, and Mieko Fujieda
Kyoto Pharmaceutical University, Misasagi Yamashinaku, Kyoto 607-8414,
Japan, e-mail: sohta@mb.kyoto-phu.ac.jp
Abstract － The first total syntheses of naamine A (4) and naamidine A (5),
marine imidazole alkaloids, were achieved through twelve and thirteen steps of
reactions, respectively, starting from 1-methyl-2-phenylthio-1H-imidazole (17).
Recently, many marine imidazole alkaloids such as 1 - 10 in Table 1 have been isolated from sponges,
and their antitumour and antibacterial activities have been also found.1,2 Structural characteristics of
these alkaloids are that one or two alkoxybenzyl group(s) locates at the 1-, 4- and/or 5-positions of the
1H-imidazole ring and the 2-position is substituted with a primary amino group or a
(1-methyl-2,5-dioxo-3-imidazolin-4-yl)amino moiety2 (Table 1).
Hitherto, we have reported the total synthesis of several marine imidazole alkaloids such as nortopsentins
A - D,3 topsentin,4 kealiiquinone (10),5 and clathridine A (2).6
In this paper, we would like to report
the first total syntheses of naamine A (4) and naamidine A (5) starting from 1-methyl-2-phenyl-
thio-1H-imidazole (17).
In previous papers, we reported a procedure for the preparation of 2-aminoimidazoles and preclathridine
A (2) by using a reaction of 2-bromoimidazole with sodium azide or trimethysilyl azide (TMSN3) in the

R4
R5
N
R2
N
R1
Table 1. Several Marine Imidazole Alkaloids2
Name
Dorimidazole
Compd No.
R1
CH3
R2
R4
b
R5
H
1
NH2
NH2
H
Preclathridine A
Isonaamine A
Naamine A
2
3
4
5
6
7
8
9
CH3
c
b
b
c
H
H
b
b
b
e
CH3
CH3
b
NH2
a
Naamidine A
Isonaamidine A
Pyrronaamidine A
Clathridine A
Clathridine B
c
a
b
c
CH3
CH3
CH3
a
a
d
d
H
d
a
OCH3
H
N
N
O
CH2
CH2
OCH3
OH
c :
b :
a :
N
O
O
O
CH3
H
N
CH3O
CH3O
O
N
CH2
e : CH2
HO
d :
OCH3
OCH3
O
CH3
O
10
presence of an appropriate palladium complex followed by catalytic hydrogenation of the intermediate
2-azidoimidazoles.7 However, subsequent investigations indicated that the reported procedure did not
always give good results probably because of the relatively high substrate specificity of the palladium
complex used.
Therefore, we searched for more general methods for the introduction of a primary
amino group into the 2-position of 1-methylbenzimidazole.
First, we examined Curtius rearrangement
to the imidazole system (Route A in Scheme 1).
The hydrazide (13), derived from 12,7 was treated
with nitrous acid followed by heating the intermediate acyl azide in toluene and subsequent hydrolysis
with concentrated hydrochloric acid to give 2-amino-1-methylbenzimidazole (16). However, overall
yield of 16 from 11 via Route A was too low to achieve the total synthesis of 5.

N
Route A
N
N
N
H2NNH2 H2O
COOC2H5
CONHNH2
1) n-C4H9Li / THF
2) ClCOOC2H5
N
N
CH3
CH3
CH3
12 (27.0%)
13 (31.4%)
11
Route C
1) n-C4H9Li / THF
2) TsN3 (90.0%) or
TrsN3 (53.2%)
1) HNO2
2) refl./c-HCl
3) K2CO3
Route B (ref. 8)
56.3%
N
H2 / Pd-C
N
N
XN3 / (n-C4H9)3SnCl
NH2
N
Br
N3
Pd cat. / 60°C
(see Table 2)
N
N
CH3
CH3
CH3
15
16
14
Scheme 1
Next, we also tried the conversion of the bromide (14)8 to the azide (15), in which the bromide (14) was
treated with sodium azide in the presence of tributyltin chloride, 15-crown-5 ether and an appropriate
9
palladium catalyst in tetrahydrofuran (THF) (Route B in Scheme 1).
As shown in Table 2, the
combination of TMSN3 and PdCl2[P(o-tolyl)3]2 was not effective (Entries 3 ~ 5), while that of NaN3,
PdCl2(PPh3)2, and 15-crown-5 ether gave the best result (81.2% yield of 15), though the reaction took 48
h to complete. (Entry 2).
Table 2. Conversion of the Bromide (14) to the Azide (15)
Entry
XN3
NaN3
NaN3
NaN3
NaN3
TMSN3
Pd-Catalyst
PdCl2(PPh3)2
Coadditive
None
15-Crownb
15-Crownb
15-Crownb
None
Reaction Time (h)
Yield of 15 (%)a
73.2
1
2
3
4
5
48
48
48
72
48
PdCl2(PPh3)2
81.2
PdCl2[P(o-tolyl)3]2
PdCl2[P(o-tolyl)3]2
PdCl2(PPh3)2
No Reaction
No Reaction
No Reaction
a: Isolated yields.
b: 15-Crown-5 ether.
Moreover, the preparation of 16 via Route C in Scheme 1 was examined. 2-Lithio-1-methyl-

benzimidazole was quenched with tosyl azide or trisyl azide to give the oily 2-azidobenzimidazole (15) in
90.0 or 53.2% yield, respectively. Thus, we were able to develop several applicable methods for the
introduction of an azide group into the 2-position of the imidazole ring. The azide (15) could be
hydrogenated over palladium-charcoal to 16 in high yield.
The preparation of a naamine A precursor (26) was started from 1-methyl-2-phenylthio-1H-imidazole
(17)10 as shown in Scheme 2.
Reaction of 4-methoxymethoxybenzaldehyde with the 5-lithio derivative
of 17 gave the alcohol (18), which was subjected to protection of the OH group with
tert-butyldimethylsilyl (TBS) group in the usual manner, followed by bromination of the 4-position with
N-bromosuccinimide (NBS) to give the bromide (20) in 74.5% yield from 17. The 4-position in 20
was lithiated by treatment with tert-butyllithium, followed by quenching with 4-methoxybenzaldehyde to
TBSCl/(C2H5)3N
DMAP/DMF
N
N
1) LTMP/DME-THF
N
SPh
SPh
SPh
N
N
MOMO
MOMO
N
MOMO
CHO
2)
CH3
CH3
OH
OTBS
CH3
18 (quant.)
19 (quant.)
17
OH
Br
N
N
H3CO
NBS
TBAF
1) tert-C4H9Li
N
SPh
SPh
MOMO
2)
in THF
N
MOMO
CHO
CH3O
CH3
OTBS
CH3
OTBS
21 (51.1%)
20 (74.5%)
(diastereomeric ratio: 1/1)
OH
OH
OH
X
CH3O
CH3O
CH3O
N
N
NiCl2 6H2O/NaBH4
in THF/CH3OH = 1/3
N
N
SPh
+
MOMO
N
N
MOMO
MOMO
CH3
CH3
CH3
OH
Y
22 (99.0%)
(diastereomeric ratio: 1/1)
23 (31.2%)
(diastereomeric ratio: 1/1)
24 (42.7%):
X=OH, Y=H or X=H, Y=OH
CH3O
CH3O
TBSCl/ImH/DMF
N
Zn/c-HCl/AcOH/80 °C
N
N
N
TBSO
HO
CH3
CH3
26 (87.5%)
25 (71.4% from 23)
(69.4% from 24)
Scheme 2

give the tetrasubstituted imidazole (21), which was desilylated by treatment with tetrabutylammonium
fluoride (TBAF) to afford a diastereomeric mixture (ratio: about 1/1 on the basis of 1H-NMR) of the diol
(22) in 50.6% yield from 20.
Reduction of 22 with nickel boride11 gave a mixture of the
2-unsubstituted diol (23) (31.2% yield) and the 2-unsubstituted monool (24) (42.7% yield); however,
reductive desulfurization of 22 with Raney nickel (W-2) or sodium metal in liquid ammonia did not
proceed at all.
The compounds 23 and 24 were each further treated with zinc powder in conc.-HCl -
acetic acid at 80 ℃ to reduce to 4,5-dibenzylimidazole (25),12 and the phenolic hydroxy group of 25 was
silylated with TBS chloride in the usual manner to give 26.
CH3O
TBSO
CH3O
TBSO
1) tert-C4H9Li/Et2O
N
N
NBS
Br
26
N3
N
2) TrsN3
N
CH3
CH3
27 (72.4%)
28 (45.3%)
[Recovery of 27 (34.4%)]
CH3O
CH3O
N
N
H2/Pd-C
N
TBAF
NH2
NH2
HO
N
TBSO
CH3
CH3
29 (68.2%)
Naamine A (4, 70.0%)
H
O
N
O
N
O
CH3O
HO
30
O
N
N
N
CH3
H
N
N
(C2H5)3N/ImH
DMAP/TMSCl
CH3
CH3
O
Naamidine A (5, 43.5%)
Scheme 3

The next steps were lithiation of the 2-position of the TBS ether (26) with n-butyllithium and subsequent
introduction of an azide group with trisyl azide; however, most of the starting material (26) was recovered.
This result would be attributed to lithiation at the benzyl methylene group of the 5-position rather than the
2-position and difficulty in the subsequent approach of trisyl azide to the relatively hindered lithiated
position. On the other hand, fortunately, bromination of the 2-position in 26 with NBS followed by
lithiation with tert-butyllithium and subsequent treatment with trisyl azide proceeded to afford the azide
(28) in 32.8% yield from 26.
Hydrogenation of the azide (28) over palladium-charcoal gave the amine
(29) in 68.2 % yield, and the TBS group was removed by treatment with TBAF to give naamine A (4)2d,13
in 70.0% yield. Conversion of 4 to naamidine A (5) was achieved by the condensation of 4 with
1-methylparabanic acid (30) in the presence of trimethylsilyl chloride and triethylamine as previously
reported6 to give naamidine A (5) as yellow granules in 43.5% yield. The structure of the synthetic
13
naamidine A (5) was confirmed by comparison of its 1H-NMR, C-NMR, IR and MS spectral data with
those of the natural naamidine A.2d, 14 (Scheme 3)
ACKNOWLEDGMENT
This research was financially supported in part by the Frontier Research Program of the Ministry of
Education, Science, Sports and Culture of Japan.
EXPERIMENTAL
All melting points were measured with a Yanaco MP micro-melting points apparatus and are not
corrected. IR were taken with a Shimadzu IR-435 spectrophotometer.
1H-NMR was measured on a
Varian XL-300 (1H: 300 MHz, 13C: 75.4 MHz) and a Varian UNITY INOVA 400NB (1H: 400 MHz, 13C:
100.6 MHz) with tetramethylsilane as an internal standard, and chemical shifts are reported in ppm.
Low-resolution MS (LRMS) and high-resolution MS (HRMS) were measured on JEOL JMS-SX 102A
QQ and JEOL JMS BU-20 spectrometers.
Silica gel (Merck Art. 7734) and Silica Gel 60PF254
(Nacalai Tesque) were used for column chromatography and preparative TLC (PTLC), respectively.

2-Ethoxycarbonyl-1-methylbenzimidazole (12)7
n-C4H9Li (1.6 M in n-hexane, 0.325 mL, 2.5 mmol)
was added dropwise to a solution of 1-methylbenzimidazole (11; 264 mg, 2.00 mmol) in THF (2 mL) at
–78 ℃ under N2 and the whole was stirred for 30 min at the same temperature. To the reaction mixture,
a solution of ethyl chloroformate (239 mg, 2.20 mmol) in THF (4 mL) was added dropwise at –78 ℃
and the whole was stirred for 30 min. After addition of water (2 mL), the mixture was extracted with
AcOEt. The organic layer was washed with water, dried over anhydrous sodium sulfate.
removal of the solvent under reduced pressure, the residue was purified by column chromatography
(AcOEt / n-hexane = 1 / 3) to give 12. Yield, 110 mg (27.0％). Colorless powder (ethyl acetate -
After
n-hexane), mp 148.8~150.1 ℃. IR (CHCl3): 2965, 1782, 1720, 1687, 1654, 1610, 1522, 1404, 1454,
1229 cm-1. 1H-NMR (300 MHz in CDCl3) δ: 1.50 (t, 3H, J=7.1 Hz, OCH2CH3), 4.17 (s, 3H, N-CH3),
4.52 (q, 2H, J=7.1 Hz, O-CH2-CH3), 7.33~7.45 (m, 4H, Ar-H). HRMS m/z: Calcd for C11H12N2O2,
204.0899. Found, 204.0907 (M+).
1-Methylbenzimidazole-2-carboxylic Acid Hydrazide (13) A mixture of 12 (174 mg, 0.85 mmol),
hydrazine monohydrate (255 mg, 5.10 mmol), and EtOH (1.5 mL) was refluxed overnight.
After
addition of water, the mixture was extracted with AcOEt. The organic phase was washed with water
and dried over sodium sulfate. Evaporation of the solvent gave a solid mass, which was purified by
column chromatography (AcOEt) to give 13. Yield, 51 mg (31.4%). Colorless needles (AcOEt), mp
133.7~134.9 ℃. IR (CHCl3): 3396, 2980, 1674, 1610, 1509, 1462, 1392, 1329, 1257 cm-1. 1H-NMR
(300 MHz in CDCl3) δ: 4.23 (s, 3H, N-CH3), 7.32~7.79 (m, 3H, Ar-H), 7.79 (d, 1H, J=1.2 Hz, Ar-H).
HRMS m/z: Calcd for C9H10N4O, 190.0854. Found, 190.0852 (M+).
2-Azido-1-methylbenzimidazole (15)15
a) From 14 with NaN3 NaN3 (24 mg, 0.36 mmol) and
15-crown-5 ether (79 mg, 0.36 mmol) were added to a solution of tributyltin chloride (117 mg, 0.36
mmol) in THF (1 mL) under N2, and the mixture was stirred for 2 h at rt. A solution of 14 (51 mg,
0.24 mmol) in THF (1 mL) and PdCl2(PPh3)2 (8.0 mg, 0.01 mmol) were added to the mixture, and the
whole was refluxed for 48 h. After addition of aqueous 10% KF solution (1 mL), the mixture was

extracted with AcOEt and the organic phase was dried over anhydrous sodium sulfate. Evaporation of
the solvent gave a crystalline solid, which was purified by column chromatography (AcOEt / n-hexane =
1 / 2) to give 15 as pale yellow needles. Yield, 34 mg (81.2%). IR (CHCl3): 2965, 2167, 1616, 1492,
1445, 1405, 1258 cm-1. 1H-NMR (300 MHz in CDCl3) δ: 3.54 (s, 3H, N-CH3), 7.19~7.26 (m, 3H,
Ar-H), 7.60~7.63 (m, 1H, Ar-H). HRMS m/z: Calcd for C8H7N5, 173.0700. Found, 173.0703 (M+).
b) From 11 with TrsN3 n-C4H9Li (1.6 M in n-hexane, 0.34 mL, 0.55 mmol) was added to a solution of
11 (66 mg, 0.50 mmol) in THF (2 mL) at –78 ℃ under N2, and the mixture was stirred for 30 min.
Trisyl azide (170 mg, 0.55 mmol) in THF (1.0 mL) was added to the mixture, and the whole was stirred
for 30 min.
After dilution with AcOEt (20 mL), the reaction mixture was washed with water (2 mL),
A solid mass, obtained by
and the separated organic phase was dried over anhydrous sodium sulfate.
evaporation of the solvent, was purified by column chromatography (AcOEt / n-hexane = 1 / 2).
Yield,
46 mg (53.2%).
c) From 11 with TsN3 Reaction was carried out in a similar manner as that for b) except for use of TsN3
(108 mg, 0.55 mmol) instead of TrsN3. Yield, 78 mg (90.0%).
2-Amino-1-methylbenzimidazole (16)15,16
a) From 13
A solution of NaNO2 (93 mg, 1.35 mmol)
in water (1.0 mL) was added to an ice-cooled and stirred solution of 13 (52 mg, 0.27 mmol) in conc-HCl
(0.5 mL), and the whole was stirred at rt for 1 h. The reaction mixture was basified with powdered
K2CO3, and extracted with toluene. After evaporation of the solvent, the residual solid was dissolved
in conc-HCl (1.0 mL) and the whole mixture was heated at 80 ℃ for 1 h. The mixture was basified
with powdered K2CO3, and extracted with AcOEt. The organic phase was dried over sodium sulfate
followed by evaporation under reduced pressure to give a solid mass. The residue was purified by
column chromatography (CHCl3 / MeOH = 10 / 1) to give 16. Yield, 22 mg (56.3%). Colorless
needles (AcOEt - n-hexane), mp 196.4~197.3 ℃ (lit., mp 201~202 ℃). IR (CHCl3): 3381, 2928,
1630, 1551, 1456, 1240, 1085 cm-1. 1H-NMR (300 MHz in CDCl3) δ: 3.53 (s, 3H, N-CH3), 7.04~7.16 (m,
3H, Ar-H), 7.38~7.40 (m, 1H, Ar-H). HRMS m/z: Calcd for C8H9N3, 147.0800. Found, 147.0793
(M+).

b) From 15
A mixture of 15 (65 mg, 0.38 mmol), 10% Pd-C (30 mg), and EtOH (3 mL) was stirred
under hydrogen atmosphere of usual pressure at rt for 3 h. After removal of the catalyst by filtration,
the filtrate was evaporated under reduced pressure to give a crystalline solid, which was purified by
column chromatography (CHCl3 / MeOH = 10 / 1) to give 16. Yield 50 mg (89.5%).
5-[1-Hydroxy-1-(4-methoxymethoxyphenyl)methyl]-1-methyl-2-phenylthio-1H-imidazole (18)
n-C4H9Li (1.6 M in n-hexane, 26.6 mL, 42.5 mmol) was added dropwise to a solution of
2,2,6,6-tetramethylpiperidine (4.99 g, 35.4 mmol), DME (12 mL) and THF (4 mL) at –78 ℃ under N2
atmosphere, and the mixture was stirred for 15 min.
A solution of 17 (6.73 g, 35.4 mmol) in THF (5
mL) was added dropwise to the mixture, and the mixture was stirred for 1 h at -78 ℃. A solution of
4-methoxymethoxybenzaldehyde (5.89 g, 35.4 mmol) in THF (5 mL) was added dropwise to the mixture
and the whole was stirred at the same temperature for 2 h. After dilution with AcOEt (50 mL), the
mixture was washed with water (10 mL), and the separated organic phase was dried over anhydrous
sodium sulfate followed by evaporation under reduced pressure to give an oily residue. The crude
product was purified by column chromatography (AcOEt / n-hexane = 1 / 1) to give 18. Yield, 12.6 g
(quant.). Colorless needles (AcOEt - n-hexane), mp 86.4~87.8 ℃. IR (CHCl3): 3547, 3239, 2940,
1718, 1607, 1529, 1221, 1148, 1075 cm-1. 1H-NMR (400 MHz in CDCl3) δ: 3.47 (s, 6H, N-CH3 and
O-CH3), 5.16 (s, 2H, O-CH2-O), 5.76 (s, 1H, Ar-C(OH)H-Ar), 6.72 (s, 1H, C4-H), 6.95~7.01 (m, 2H,
Ar-H), 7.02~7.10 (m, 2H, Ar-H), 7.11~7.22 (m, 3H, Ar-H), 7.24~7.30 (m, 2H, Ar-H).
HRMS m/z:
Calcd for C19H20N2O3S, 356.1194. Found, 356.1199 (M+). Anal. Calcd for C19H20N2O3S: C, 64.02; H,
5.66; N, 7.86. Found: C, 64.42; H, 5.81; N, 7.60.
5-[1-tert-Butyldimethylsiloxy-1-(4-methoxymethoxyphenyl)methyl]-1-methyl-2-phenylthio-1H-
imidazole (19) tert-Butyldimethylsilyl cholide (TBSCl, 29.2 g, 194 mmol) was added to a solution of
18 (12.5 g, 35.1 mmol), and imidazole (18.0 g, 265 mmol) in DMF (100 mL) under N2 atmosphere and
ice-cooling, and the mixture was stirred at 60 ℃ overnight.
mixture was washed with water (40 mL), and the separated organic layer was dried over anhydrous
sodium sulfate. After removal of the solvent, the residue was purified by column chromatography
After dilution with ether (200 mL), the

(AcOEt / n-hexane = 1 / 3) to give 19. Colorless viscous oil.
Yield, 16.5 g (quant.). IR (CHCl3):
2935, 1607, 1581, 1503, 1474, 1454, 1248, 1215, 1164, 1072 cm-1. 1H-NMR (400 MHz in CDCl3) δ:
-0.06 (s, 3H, Si-CH3), 0.19 (s, 3H, Si-CH3), 1.02 (s, 9H, Si-C(CH3)3), 3.43 (s, 3H, N-CH3), 3.59 (s, 3H,
O-CH3), 5.29 (s, 2H, O-CH2-O), 6.00 (s, 1H, Ar-C(OTBS)H-Ar), 7.25 (s, 1H, C4-H), 7.02~7.08 (m, 2H,
Ar-H), 7.09~7.14 (m, 2H, Ar-H), 7.17~7.23 (m, 2H, Ar-H), 7.24~7.32 (m, 3H, Ar-H). HRMS m/z:
Calcd for C25H34N2O3SSi, 470.2059. Found, 470.2055 (M+).
4-Bromo-5-[1-tert-butyldimethylsiloxy-1-(4-methoxymethoxyphenyl)methyl]-1-methyl-2-phenylthio
-1H-imidazole (20) N-Bromosuccimide (18 mg, 0.10 mmol) was added to a solution of 19 (47 mg,
0.10 mmol) in THF (1 mL) at 0 ℃, and the mixture was stirred for 3 h at 0 ℃. The mixture was
diluted with ether, washed with aqueous 5% Na2S2O3 (2 mL), and the separated organic phase was dried
over anhydrous sodium sulfate.
Evaporation of the solvent gave an oily residue, which was purified by
column chromatography (AcOEt/n-hexane = 1 / 5) to give 20 as a pale yellow viscous oil. Yield, 41 mg
(74.5%). IR (CHCl3): 2938, 1723, 1607, 1580, 1503, 1474, 1445, 1250, 1228, 1163, 1073 cm-1.
1H-NMR (400 MHz in CDCl3) δ: -0.06 (s, 3H, Si-CH3), 0.18 (s, 3H, Si-CH3), 0.91 (s, 9H, Si-C(CH3)3),
3.47 (s, 3H, N-CH3), 3.63 (s, 3H, O-CH3), 5.16 (s, 2H, O-CH2-O), 6.07 (s, 1H, Ar-C(OTBS)H-Ar), 6.99
(d, 2H, J=8.8 Hz, Ar-H), 7.08 (d, 2H, J=8.8 Hz, Ar-H) , 7.14~7.33 (m, 5H, Ar-H).
HRMS m/z: Calcd
for C25H33N2O3BrSSi, 548.1164. Found, 548.1156 (M+).
5-[1-tert-Butyldimethylsiloxy-1-(4-methoxymethoxyphenyl)methyl]-4-[1-hydroxy-1-(4-methoxy-
phenyl)methyl]-1-methyl-2-phenylthio-1H-imidazole (21) tert-C4H9Li (1.51 M in n-pentane, 0.26
mL, 0.40 mmol) was added to a solution of 20 (110 mg, 0.20 mmol) in ether (4 mL) at -78 ℃ under N2
atmosphere, and the mixture was stirred for 30 min. p-Anisaldehyde (136 mg, 1.0 mmol) was added,
and the whole was stirred at the same temperature for 3 h. After dilution with AcOEt (10 mL), the
mixture was washed with water (3 mL), and the separated organic phase was dried over anhydrous
sodium sulfate.
Evaporation of the solvent gave an oily residue, which was purified by column
chromatography (AcOEt / n-hexane = 1 / 2) to give a diastereomeric mixture (1:1) of 21 as a pale yellow
viscous oil. Yield, 62 mg (51.1%). IR (CHCl3): 3437, 2936, 1723, 1608, 1581, 1505, 1459, 1240,

1167, 1073, 1000 cm-1. 1H-NMR (400 MHz in CDCl3) δ: -0.30 (s, 3H, Si-CH3), -0.09 (s, 3H, Si-CH3),
-0.04 (s, 3H, Si-CH3), 0.16 (s, 3H, Si-CH3), 0.86 (s, 9H, Si-C(CH3)3), 0.90 (s, 9H, Si-C(CH3)3), 3.26 (s,
3H, N-CH3), 3.33 (s, 3H, N-CH3), 3.44 (s, 3H, O-CH3), 3.47 (s, 3H, O-CH3), 3.78 (s, 3H, O-CH3), 3.79 (s,
3H, O-CH3), 5.11 (s, 2H, O-CH2-O), 5.15 (s, 2H, O-CH2-O), 5.83 (s, 1H, Ar-C(OTBS)H-Ar), 5.90 (s, 1H,
Ar-C(OTBS)H-Ar), 5.97 (s, 1H, Ar-C(OH)H-Ar), 6.09 (s, 1H, Ar-C(OH)H-Ar), 6.82~6.89 (m, 6H, Ar-H),
6.90~6.98 (m, 4H, Ar-H), 7.00~7.29 (m, 12H, Ar-H), 7.36~7.46 (m, 4H, Ar-H). HRMS m/z: Calcd for
C33H42N2O5SSi, 606.2583. Found, 606.2592 (M+).
5-[1-Hydroxy-1-(4-methoxymethoxyphenyl)methyl]-4-[1-hydroxy-1-(4-methoxyphenyl)methyl]-1-
methyl-2-phenylthio-1H-imidazole (22) Tetrabutylammonium fluoride (1.0 M in THF, 0.20 mL, 0.20
mmol) was added to a solution of 21 (121 mg, 0.20 mmol) in THF (1 mL) at rt and the mixture was
stirred for 10 min.
After dilution with AcOEt (10 mL), the mixture was washed with water (1 mL),
Evaporation of the solvent
and the separated organic phase was dried over anhydrous sodium sulfate.
gave an oily residue, which was purified by column chromatography (AcOEt/n-hexane = 1 / 1) to give a
diastereomeric mixture (1:1) of 22 as a pale yellow viscous oil. Yield, 97 mg (99.0%). IR (CHCl3):
3305, 2974, 1724, 1608, 1580, 1505, 1474, 1448, 1235, 1213, 1167 cm-1. 1H-NMR (400 MHz in
CDCl3) δ: 3.23 (s, 3H, N-CH3), 3.28 (s, 3H, N-CH3), 3.44 (s, 3H, O-CH3), 3.45 (s, 3H, O-CH3), 3.72 (s,
3H, O-CH3), 3.73 (s, 3H, O-CH3), 5.10 (s, 2H, O-CH2-O), 5.11 (s, 2H, O-CH2-O), 5.70 (s, 1H,
Ar-C(OH)H-Ar), 5.92 (s, 1H, Ar-C(OH)H-Ar), 5.95 (s, 1H, Ar-C(OH)H-Ar), 6.05 (s, 1H,
Ar-C(OH)H-Ar), 6.70~6.77 (m, 4H, Ar-H), 6.81~6.88 (m, 4H, Ar-H), 6.91~7.02 (m, 8H, Ar-H),
7.03~7.18 (m, 6H, Ar-H), 7.19~7.30 (m, 4H, Ar-H). HRMS m/z: Calcd for C27H28N2O5S, 492.1719.
Found, 492.1718 (M+).
5-[1-Hydroxy-1-(4-methoxymethoxyphenyl)methyl]-4-[1-hydroxy-1-(4-methoxyphenyl)methyl]-1-
methyl-1H-imidazole (23) and 5(4)-[1-Hydroxy-1-(4-methoxymethoxyphenyl)methyl]-4(5)-[1-(4-
methoxyphenyl)methyl]-1-methyl-1H-imidazole (24)
mmol) and NaBH4 (1.23 g, 32.6 mmol) were added to a solution of 22 (642 mg, 1.30 mmol) in MeOH /
THF = 3 / 1 (8 mL), and the mixture was stirred at rt for 1.5 h. The reaction mixture was passed
Nickel(II) chloride hexahydrate (2.17 g, 9.12

through a florisil column to remove Ni colloid. The eluate was diluted with water (20 mL) and
extracted with AcOEt (50 mL). The organic phase was dried over anhydrous sodium sulfate and
evaporated to give an oily residue, which was purified by column chromatography (CHCl3 / MeOH = 20 /
1) to give a diastereomeric mixture (1:1) of 23 and 24. 23: Colorless oil. Yield, 156 mg (31.2%). IR
(CHCl3): 3324, 2980, 1723, 1607, 1505, 1236, 1167, 1074, 1028 cm-1.
1H-NMR (400 MHz in
CDCl3) δ: 3.27 (s, 3H, N-CH3), 3.28 (s, 3H, N-CH3), 3.46 (s, 3H, O-CH3), 3.46 (s, 3H, O-CH3), 3.74 (s,
3H, O-CH3), 3.75 (s, 3H, O-CH3), 5.14 (s, 4H, O-CH2-O), 5.70 (s, 1H, Ar-C(OH)H-Ar), 5.79 (s, 1H,
Ar-C(OH)H-Ar), 5.98 (s, 1H, Ar-C(OH)H-Ar), 5.98 (s, 1H, Ar-C(OH)H-Ar), 6.79 (d, 4H, J=8.6 Hz,
Ar-H), 6.92 (d, 4H, J=8.8 Hz, Ar-H), 7.19 (s, 1H, C2-H), 7.20 (s, 1H, C2-H), 7.07 (dd, 4H, J=8.4, 2.4 Hz,
Ar-H), 7.24 - 7.40 (m, 4H, Ar-H). HRMS m/z: Calcd for C21H24N2O5, 384.1685. Found, 384.1691
(M+).
24: Colorless oil. Yield, 205 mg (42.7%).
IR (CHCl3): 3089, 2981, 2820, 1607, 1581, 1504,
1459, 1234, 1166, 1075, 1002 cm-1. 1H-NMR (400 MHz in CDCl3) δ: 3.28 (s, 3H, N-CH3), 3.47 (s, 3H,
O-CH3), 3.74 (s, 3H, O-CH3), 3.77 (d, 1H, J=15.6 Hz, Ar-CH2-Ar), 3.82 (d, 1H, J=15.6 Hz, Ar-CH2-Ar),
5.15 (s, 2H, O-CH2-O), 6.00 (s, 1H, r-C(OH)H-Ar), 6.75 (d, 2H, J=8.6 Hz, Ar-H), 6.94 (d, 2H, J=8.8 Hz,
Ar-H), 7.09~7.18 (m, 5H, Ar-H). HRMS m/z: Calcd for C21H24N2O4, 368.1736. Found, 368.1732
(M+).
4-[1-(4-Methoxyphenyl)methyl]-5-[1-(4-hydroxyphenyl)methyl]-1-methyl-1H-imidazole (25)
From 24. Zn powder (5.0 g) were added to a mixture of acetic acid (20 mL), conc.-HCl (5 mL) and 24
(598 mg, 1.63 mmol), and the whole was stirred at 80 ℃ for 1 h. The reaction mixture was filtered
a)
through a cotton plug, and the filtrate was evaporated under reduced pressure. After addition of water (5
mL), K2CO3 powder was added to basify, and the whole was extracted with AcOEt. The organic phase
was dried over anhydrous sodium sulfate and evaporated to give an oily residue, which was purified by
column chromatography (CHCl3 / MeOH = 30 / 1) to give 25. Yield, 347 mg (69.4%). Colorless
crystals (AcOEt – MeOH), mp 222.8 - 225.2 ℃.
1080 cm-1. 1H-NMR (400 MHz in CDCl3) δ: 3.33 (s, 3H, N-CH3), 3.75 (s, 3H, O-CH3), 3.86 (s, 2H,
Ar-CH2-Ar), 3.87 (s, 2H, Ar-CH2-Ar), 6.68 (d, 2H, J=8.4 Hz, Ar-H), 6.78 (d, 2H, J=8.6 Hz, Ar-H), 6.83
IR (KBr): 3400, 2900, 1607, 1507, 1450, 1242, 1170,

(d, 2H, J=8.6 Hz, Ar-H), 7.15 (d, 2H, J=8.6 Hz, Ar-H), 7.41 (s, 1H, C2-H). HRMS m/z: Calcd for
C19H20N2O2, 308.1525. Found, 308.1521 (M+). Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N,
9.08. Found: C, 73.76; H, 6.66; N, 8.92.
b) From 23. Reaction was carried out in a similar manner as that for a) except for use of 23 (9 mg, 0.02
mmol) instead of 24. Yield, 5 mg (71.4%).
5-[1-(4-tert-Butyldimethylsiloxyphenyl)methyl]-4-[1-(4-methoxyphenyl)methyl]-1-methyl-1H-
imidazole (26)
This compound was prepared in a similar manner as that used for preparation of 19
The obtained crude product was purified by
except for use of 25 (257 mg, 0.83 mmol) instead of 18.
column chromatography (CHCl3 / MeOH = 30 / 1) to give 26 as a pale yellow viscous oil.
Yield, 306
1H-NMR
mg (87.5%). IR (CHCl3): 2915, 1605, 1505, 1459, 1247, 1223, 1167, 1097, 1032 cm-1.
(400 MHz in CDCl3) δ: 0.17 (s, 6H, Si-CH3), 0.97 (s, 9H, Si-C(CH3)3), 3.31 (s, 3H, N-CH3), 3.76 (s, 3H,
O-CH3), 3.86 (s, 2H, Ar-CH2-Ar), 3.87 (s, 2H, Ar-CH2-Ar), 6.71 (d, 2H, J=8.6 Hz, Ar-H), 6.80 (d, 2H,
J=8.6 Hz, Ar-H), 6.85 (d, 2H, J=8.6 Hz, Ar-H), 7.16 (d, 2H, J=8.6 Hz, Ar-H), 7.26 (s, 1H, C2-H).
HRMS m/z: Calcd for C25H34N2O2Si, 422.2389. Found, 422.2379 (M+).
2-Bromo-5-[1-(4-tert-butyldimethylsiloxyphenyl)methyl]-4-[1-(4-methoxyphenyl)methyl]-1-methyl-
1H-imidazole (27) N-Bromosuccinimide (148 mg, 0.83 mmol) was added to a solution of 26 (352 mg,
0.83 mmol) in THF (5 mL) at 0 ℃ and the mixture was stirred for 1 h at 0 ℃. After dilution with
AcOEt (10 mL), the mixture was washed with aqueous 5% Na2S2O3 (2 mL), and the separated organic
phase was dried over anhydrous sodium sulfate. Evaporation of the solvent gave an oily residue,
which was purified by column chromatography (AcOEt / n-hexane = 1 / 2) to give 27 as a pale yellow
viscous oil. Yield, 301 mg (72.4%). IR (CHCl3): 2932, 1723, 1605, 1504, 1482, 1245, 1170, 1099,
1033 cm-1. 1H-NMR (400 MHz in CDCl3) δ: 0.18 (s, 6H, Si-CH3), 0.97 (s, 9H, Si-C(CH3)3), 3.26 (s, 3H,
N-CH3), 3.76 (s, 3H, O-CH3), 3.84 (s, 2H, Ar-CH2-Ar), 3.86 (s, 2H, Ar-CH2-Ar), 6.71 (d, 2H, J=8.6 Hz,
Ar-H), 6.78 (d, 2H, J=8.8 Hz, Ar-H), 6.84 (d, 2H, J=8.8 Hz, Ar-H), 7.12 (d, 2H, J=8.8 Hz, Ar-H).
13C-NMR (100.6 MHz in CDCl3) δ: 18.1, 25.6, 29.2, 29.7, 32.2, 32.9, 55.2, 113.8, 118.4, 120.2, 128.6,
128.8, 129.4, 130.2, 132.5, 139.5, 154.3, 157.9. HRMS m/z: Calcd for C25H33N2O2BrSi, 500.1495.

Found, 500.1486 (M+).
2-Azido-5-[1-(4-tert-butyldimethylsiloxyphenyl)methyl]-4-[1-(4-methoxyphenyl)methyl]-1-methyl-
1H-imidazole (28)
tert-C4H9Li (1.51 M in n-pentane, 0.44 mL, 0.67 mmol) was added dropwise to a
solution of 27 (160 mg, 0.32 mmol) in ether (1 mL) at –78 ℃, and the mixture was stirred for 30 min.
Trisylazide (109 mg, 0.35 mmol) was added to the mixture at -78 ℃, and the whole was stirred for 1 h.
After dilution with AcOEt (10mL), the mixture was washed with water (2 mL), and the separated organic
phase was dried over sodium sulfate.
Evaporation of the solvent gave an oily residue, which was
purified by column chromatography (AcOEt / n-hexane = 1 / 5) to give 28 as a pale yellow viscous oil
and 27 (55 mg, 34.4%).
Yield, 67 mg (45.3%).
IR (CHCl3): 2912, 2119, 1604, 1503, 1250, 909
cm-1. 1H-NMR (400 MHz in CDCl3) δ: 0.17 (s, 6H, Si-CH3), 0.97 (s, 9H, Si-C(CH3)3), 3.06 (s, 3H,
N-CH3), 3.77 (s, 3H, O-CH3), 3.78 (s, 2H, Ar-CH2-Ar), 3.83 (s, 2H, Ar-CH2-Ar), 6.71 (d, 2H, J=8.4 Hz,
Ar-H), 6.80 (d, 2H, J=8.4 Hz, Ar-H), 6.85 (d, 2H, J=8.4 Hz, Ar-H), 7.12 (d, 2H, J=8.8 Hz, Ar-H).
13C-NMR (100.6 MHz in CDCl3) δ: 18.2, 25.7, 28.7, 29.4, 32.7, 55.2, 113.8, 120.2, 123.7, 124.9, 128.8,
129.4, 130.7, 132.7, 136.2, 138.9, 154.2, 157.9.
Found, 463.2405 (M+).
HRMS m/z: Calcd for C25H33N5O2Si, 463.2403.
2-Amino-5-[1-(4-tert-butyldimethylsiloxyphenyl)methyl]-4-[1-(4-methoxypheny)methyl]-1-methyl-
1H-imidazole (29) This compound was prepared in a similar manner as that used for the preparation
of 16 from 15 except for use of 28 (34 mg, 0.074 mmol) instead of 15. The crude oily product was
purified by column chromatography (CHCl3 / MeOH = 7 / 3) to give 29 as a pale yellow viscous oil.
Yield, 22 mg (68.2%). IR (CHCl3): 3288, 2916, 1723, 1667, 1605, 1505, 1459, 1246, 1220 cm-1.
1H-NMR (400 MHz in CDCl3) δ: 0.18 (s, 6H, Si-CH3), 0.97 (s, 9H, Si-C(CH3)3), 3.05 (s, 3H, N-CH3),
3.76 (s, 3H, O-CH3), 3.76 (s, 2H, Ar-CH2-Ar), 3.78 (s, 2H, Ar-CH2-Ar), 5.23 (br, 2H, NH2), 6.73 (d, 2H,
J=8.8 Hz, Ar-H), 6.79 (d, 2H, J=8.8 Hz, Ar-H), 6.89 (d, 2H, J=8.8 Hz, Ar-H), 7.15 (d, 2H, J=8.4 Hz,
Ar-H). 13C-NMR (100.6 MHz in CDCl3) δ: 18.2, 28.4, 29.1, 31.3, 38.7, 55.2, 113.9, 120.3, 120.8, 128.8,
129.5, 130.5, 130,.9 131.9, 154.3, 158.0.
437.2508 (M+).
HRMS m/z: Calcd for C25H35N3O2Si, 437.2498. Found,

Naamine A (4) TBAF (1.0 M in THF, 0.032 mL, 0.032 mmol) was added to a solution of 29 (14 mg,
0.032 mmol) in THF(1 mL) at rt under N2 atmosphere, and the mixture was stirred for 10 min. After
dilution with CHCl3 (10 mL), the mixture was washed with water (1 mL), and the separated organic
phase was dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave
an oily residue, which was purified by column chromatography (CHCl3 / MeOH = 7 / 3) to give 4 as a
pale yellow powder. Yield, 7 mg (70.0%). mp 202.0 - 204.5 ℃. IR (KBr): 3350, 1668, 1568,
1507, 1417, 1240 cm-1. 1H-NMR (400 MHz in CDCl3) δ: 3.05 (s, 3H, N-CH3), 3.65 (s, 3H, Ar-CH3),
3.72 (s, 2H, Ar-CH2-Ar), 3.73 (s, 2H, Ar-CH2-Ar), 6.72 - 6.82 (m, 6H, Ar-H ), 7.10 (d, 2H, J=8.4 Hz,
Ar-H). HRMS m/z: Calcd for C21H19N3O2, 323.1634. Found, 323.1643 (M+). These data were
almost agreed with those of the natural naamine A.2d, 13
Naamidine A (5) A mixture of 1-methylparabanic acid (30; 7 mg, 0.053 mmol), 4-N,N-dimethyl-
aminopyridine (1 mg), imidazole (4 mg, 0.059 mmol), triethylamine (11 mg, 0.11 mmol), and
trimethylsilyl chloride (12 mg, 0.111 mmol) in CHCl3 (0.5 mL) was stirred for 5 min under ice-cooling
and N2 atmosphere, and then the stirring was continued for 2 h at rt. A solution of naamine A (4; 17
mg, 0.053 mmol) in CHCl3(1 mL) was added to the mixture, and the whole was refluxed for 72 h.
After dilution with CHCl3 (10 mL), the mixture was washed with water (1 mL), and the separated organic
phase was dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced
pressure to give a crystalline residue, which was triturated with CHCl3 followed by filtration to give pure
5 as yellow granules. Yield, 10 mg (43.5%).
mp 186.5 – 190.0 ℃.
IR (CHCl3): 3410, 1725, 1668,
1635, 1608, 1508, 1440, 1240 cm-1. 1H-NMR (400 MHz in CDCl3 + CD3OD) δ: 3.04 (s, 3H, N-CH3),
3.15 (s, 3H, N-CH3), 3.78 (s, 3H, O-CH3), 3.79 (s, 2H, Ar-CH2-Ar), 3.83 (s, 2H, Ar-CH2-Ar), 6.75 (d, 2H,
J=8.4 Hz, Ar-H), 6.82 (d, 2H, J=8.8 Hz, Ar-H), 6.91 (d, 2H, J=8.4 Hz, Ar-H), 7.13 (d, 2H, J=8.4 Hz,
Ar-H).
13C-NMR (75.4 MHz in CDCl3 + CD3OD) δ: 24.9, 27.4, 28.4, 29.7, 54.5, 113.4, 115.0, 127.5,
128.4, 128.8, 129.9, 130.4, 131.8, 146.6, 148.4, 155.3, 157.8, 162.5. HRMS m/z: Calcd for C23H23N5O4,
433.1750. Found, 433.1742 (M+).
naamidine A.2d, 14
These data were almost agreed with those of the natural

REFERENCES AND NOTES
1. J. R. Lewis, Nat. Prod. Rep., 1992, 9, 81; D. J. Faulkner, ibid., 1992, 9, 323.
2. a) P. Ciminiello, E. Fattorusso, S. Magno, and A. Mangoni, Tetrahedron, 1989, 45, 3873; b) K. A.
Alvi, B. M. Peters, L. M. Hunter, and P. Crews, ibid., 1993, 49, 329; c) S. Carmely and Y. Kashman,
ibid., 1987, 28, 3003; d) S. Carmely, M. Ilan, and Y. Kashman, Tetrahedron, 1989, 45, 2193.
3. I. Kawasaki, M. Yamashita, and S. Ohta, J. Chem. Soc., Chem. Commun., 1994, 2085; I. Kawasaki, M.
Yamashita, and S. Ohta, Chem. Pharm. Bull., 1996, 44, 1831.
4. I. Kawasaki, H. Katsuma, Y. Nakayama, M. Yamashita, and S. Ohta, Heterocyclic Commun., 1996, 2,
189; I. Kawasaki, H. Katsuma, Y. Nakayama, M. Yamashita, and S. Ohta, Heterocycles, 1998, 48,
1887.
5. I. Kawasaki, N. Taguchi, T. Yamamoto, M. Yamashita, and S. Ohta, Tetrahedron Lett., 1995, 36,
8251; I. Kawasaki, N. Taguchi, M. Yamashita, and S. Ohta, Chem. Pharm. Bull., 1997, 45, 1393.
6. S. Ohta, N. Tsuno, K. Maeda, S. Nakamura, N. Taguchi, M. Yamashita, and I. Kawasaki, Tetrahedron
Lett., in press.
7. F. H. Pinkerton and S. F. Thamas, J. Heterocycl. Chem., 1972, 9, 67.
8. I. Kawasaki, N. Taguchi, Y. Yoneda, M. Yamashita, and S. Ohta, Heterocycles, 1996, 43, 1375.
9. S. G. Anil and S. L. Buchwald, J. Am. Chem. Soc., 1994, 116, 7901.
10. S. Ohta, T. Yamamoto, I. Kawasaki, M. Yamashita, H. Katsuma, R. Nasako, K. Kobayashi, and K.
Ogawa, Chem. Pharm. Bull., 1992, 40, 2681.
11. T. G. Back, D. L. Baron, and K. Yang, J. Org. Chem., 1993, 58, 2407.
12. Catalytic hydrogenolysis of the benzylic hydroxyl group for 23 and 24 in the presence of 5 or 10%
Pd-C did not proceed at all.
13. The reported data for the natural naamine A (ref. 2d): IR (KBr): 3500 (br), 2920, 1670, 1615 cm-1.
1H-NMR (DMSO-d6) δ: 3.15 (br s, 3H), 3.69 (s, 3H), 3.79 (br s, 2H), 3.84 (br s, 2H), 6.70 (d, 2H,
J=8.6 Hz), 6.83 (d, 2H, J=8.6 Hz), 6.89 (d, 2H, J=8.6 Hz), 7.16 (d, 2H, J=8.6 Hz), 7.60 (br s, 2H).

Mp was not reported in ref. 2d.
14. The reported data for the natural naamidine A (ref. 2d): Yellow foaming oil.
IR (KBr): 3650-3100
(br), 2930, 1707, 1570, 1510, 1440, 1250, 1170, 1025 cm-1. 1H-NMR (CDCl3 + CD3OD) δ: 3.13 (s,
3H), 3.48 (br s, 3H), 3.77 (s, 3H), 3.88 (br s, 2H), 3.91 (br s, 2H), 6.72 (d, 2H J=8.6 Hz), 6.81 (d, 2H
J=8.6 Hz), 6.84 (d, 2H J=8.6 Hz), 7.11 (d, 2H J=8.6 Hz). 13C-NMR (CDCl3 + CD3OD) δ: 24.4, 28.2,
29.6, 31.3, 55.0, 113.9, 115.6, 126.7, 127.4, 128.7, 129.1, 130.7, 132.9, 146.2, 148.4, 155.6, 158.3,
163.3. Mp was not reported in ref. 2d.
15. Y. Shiokawa and S. Ohki, Chem. Pharm. Bull., 1971, 19, 401; N. P. Bednyagina and I. Y. Postovskii,
Zh. Obshch. Khim., 1960, 30, 1431 [CA, 55; 1586h (1961)].
16. Y. Kikugawa, Synthesis, 1981, 124; A. M. Simonov and N. D. Vitkevich, Zh. Obshch. Khim., 1960,
30, 590 [CA, 54; 24677i (1960)].