Total synthesis of naamine C and pyronaamidine, antitumor marine imidazole alkaloids

Article abstract of DOI:10.1039/b200845a

The total synthesis of naamine C and pyronaamidine, antitumor marine imidazole alkaloids was investigated. All melting points were measured with a Yanaco MP micromelting points apparatus without correction. The most important key step in the total synthes

Full text of DOI:10.1039/b200845a

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Total synthesis of naamine C and pyronaamidine,
antitumor marine imidazole alkaloids
Seikou Nakamura, Ikuo Kawasaki, Miki Kunimura, Miyuki Matsui, Yoko Noma,
Masayuki Yamashita and Shunsaku Ohta*
1
Kyoto Pharmaceutical University, Misasagi Yamashinaku, Kyoto 607-8414, Japan.
E-mail: sohta@mb.kyoto-phu.ac.jp
Received (in Cambridge, UK) 23rd January 2002, Accepted 6th March 2002
First published as an Advance Article on the web 19th March 2002
The first total synthesis of naamine C and pyronaamidine, highly substituted and cytotoxic imidazole
marine alkaloids of a certain kind of sponge, was achieved through an eight-step reaction starting from
1-methyl-2-phenylthio-1H-imidazole.
properties such as antitumor and antifungal activities. For
example, it was reported that naamidine A, B and G 5–71a–e
showed antifungal activity against Cryptococcus neoformans,
and, in particular, pyronaamidine 41e was cytotoxic against KB
cells, minimum inhibitory concentration (MIC) = 5 µg mLϪ1. A
structural characteristic of these alkaloids is that one or two
alkoxybenzyl group(s) are located at the 4 and/or 5-position of
the 1-methyl-1H-imidazole ring. So far as the alkaloids 4–8 are
concerned, the 2-position of the ring is substituted with the
(1-methyl-2,5-dioxo-3H-imidazolin-4-yl)amino moiety. Pyrona-
amidine 4 has been considered to be a possible biometabolic
intermediate in the biochemical production of the tricyclic
alkaloids, kealiiquinone 91e and 2-deoxy-2-aminokealiiquinone
10.1f We have investigated the total synthesis of these imidazole
natural products and already reported the first total synthesis
of several marine imidazole alkaloids, 1,2 3,3 5,2 84 and 9.5
The most important key step in the total synthesis of 4 may be
the construction of the (1-methyl-2,5-dioxo-3H-imidazolin-
4-yl)amino side chain. In this paper, we report the first total
synthesis of 4 through naamine C 2.
Introduction
Many imidazole alkaloids containing highly substituted imid-
azole ring(s) have been isolated from a bright yellow sponge,
Leucetta chagosensis, and several of their structures are shown
in Fig 1.1 These alkaloids generally have interesting biological
Results and discussion
First, the preparation of the 1,2,4,5-tetrasubstituted imidazole
derivative 17 was attempted (Scheme 1). 1-Methyl-2-phenylthio-
1H-imidazole 11 was converted to the 5-substituted imidazole
14 according to our previously reported method.5 When the 4-
position of 14 was lithiated by treatment with tert-butyllithium,
followed by quenching with p-anisaldehyde, a diastereomeric
mixture of the alcohol 15 was obtained in 43% yield. The
TBDMS group was removed by treatment with TBAF. The
alcohol 16 was reduced with zinc powder in conc. HCl–acetic
acid at 80 ЊC to give not the desired 1,2,4,5-tetrasubstituted
imidazole 17 but a tricyclic naphthoimidazole 18 as a major
product (yield 75%) along with many minor uncharacterized
1
products. The structure of 18 was supported by a H-NMR
spectroscopic study based on the data obtained in the previous
investigation of the total synthesis of kealiiquinone 9.5 It could
be considered that an intramolecular Friedel–Crafts type cycli-
zation of 16 occurred under such acidic conditions to give 18.
Reduction of 16 with nickel boride,6 which was used in the
previous report,2 resulted unfortunately in formation of a com-
plex mixture of many compounds such as the corresponding
alcohols and deprotected phenols.
To overcome these problems, the Et3SiH reduction method7
was applied to the present system (Scheme 2). The benzyl alco-
hol 20 having a TBDMS group instead of the MOM group of
Fig. 1
DOI: 10.1039/b200845a
J. Chem. Soc., Perkin Trans. 1, 2002, 1061–1066
This journal is © The Royal Society of Chemistry 2002
1061

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Scheme
1
Reagents: (a) lithium 2,2,6,6,-tetramethylpiperidinide
(LTMP), THF, 89%; (b) TBDMSCl, imidazole, DMF, quant; (c) NBS,
THF, 64%; (d) (i) tert-BuLi THF; (ii) p-anisaldehyde, 43%; (e) TBAF,
THF, quant: (f ) Zn, conc. HCl, AcOH, 18: 75%; (g) NaBH4,
NiCl2ؒ6H2O, THF, MeOH, produced complex mixture.
Scheme 2 Reagents: (a) LTMP, THF, 78%; (b) Et3SiH, TFA, DCM,
98%; (c) NBS, THF, 81%; (d) (i) tert-BuLi (2 equiv.), THF; (ii)
p-anisaldehyde (5 equiv.), 15%; (e) tert-BuLi (6 equiv.), p-anisaldehyde
(5 equiv.), THF, 89%; (f ) Et3SiH, TFA, DCM, 26: 79%; (g) NaBH4,
NiCl2ؒ6H2O, THF, MeOH, 25 62%.
12 was prepared starting from 11 and the aldehyde 19b8 (R =
TBDMS) similarly as above. The compound 20 was smoothly
reduced to the 5-benzylimidazole 21 in 98% yield by treatment
with triethylsilane in the presence of trifluoroacetic acid accord-
ing to Kobayashi’s procedure.7 The 5-benzylimidazole 21 was
brominated by NBS to give the 4-bromoimidazole 22 in 81%
yield. When the bromide 22 was subjected to lithiation with
tert-butyllithium at Ϫ78 ЊC for 15 min followed by quenching
with p-anisaldehyde, the required 4-alkylated product 23 was
obtained in only 15% yield along with a mixture of many minor
uncharacterized products. This result might be attributable to
intermediate formation of an equilibrium mixture containing
the kinetic product 27 and the thermodynamic product 28
before addition of p-anisaldehyde (Scheme 3). Thus, tert-
butyllithium was added into a mixed solution of 23 and
p-anisaldehyde in THF at Ϫ78 ЊC in order to avoid the equi-
librium, and the yield of 23 increased as expected, and reached
89%.
Scheme 3 A possible equilibrium after the lithiation of 22.
group of 30 was removed by treatment with TBAF, and the
subsequent hydrogenation over 10% Pd–C gave naamine C 2
in 84% yield from 30 in 2 steps. Naamine C 2 was isolated
as a yellow powder, the physical and spectral data of which
almost agreed with those of the natural product reported1f,10
(Scheme 4).
Reductive removal of the hydroxy group of 23 with Et3SiH in
the presence of TFA unfortunately resulted in formation of the
tricyclic imidazole derivative 26 in 79% yield instead of the
desired reductant 24 because intramolecular Friedel–Crafts
type cyclization of 23 occurred under such acidic conditions.
On the other hand, reduction of 23 with nickel boride6 gave
successfully the 2-unsubstituted 4,5-dibenzylimidazole 25 in
62% yield. The structure of 25 was supported by 1H-NMR
spectra and other analytical data (Scheme 2).
The imidazole 25 was brominated by NBS to give the
2-bromoimidazole 29, which was subjected to lithiation with
tert-butyllithium followed by treatment with trisyl azide9 † to
afford the 2-azido 30 in 46% overall yield from 25. The TBDMS
The final step was construction of the 2-(1-methyl-2,5-dioxo-
3H-imidazolin-4-yl)amino moiety. We have already reported a
method for the regio-selective condensation of arylamine with
1-methylparabanic acid‡ 32 for constructing the side chain, and
its application to the total synthesis of clathridine 8.4 This time,
naamine C 2 was treated with 32 in the presence of TMSCl and
N,N-diisopropylethylamine according to the previous pro-
cedure11 to give successfully pyronaamidine 4 in 28% yield as
yellow needles, the melting point and spectral data of which
were all consistent with those of the natural product reported
by Scheuer1e,12 (Scheme 4).
While pyrronaamidine 4 was isolated at a relatively early
stage among many imidazole alkaloids of sponges, its total
† The IUPAC name for trisyl azide is azidotriphenylsilane.
‡ The IUPAC name for parabanic acid is imidazolidinetrione.
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J. Chem. Soc., Perkin Trans. 1, 2002, 1061–1066

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Scheme 4 Reagents: (a) NBS, THF, 59%; (b) (i) tert-BuLi, THF, (ii) trisyl azide, 78%; (c) TBAF, THF, 87%; (d) H2, 10% Pd–C, EtOH, 97%; (e) N,N-
diisopropylethylamine, TMSCl, CHCl3, 28%.
synthesis had not been reported, and we were fortunately able
to achieve the first total synthesis of 4 through 2.
added dropwise to a solution of 15 (78 mg, 0.12 mmol) in THF
at room temperature. The mixture was stirred for 10 min at
room temperature. Water (0.5 mL) was added, and the mixture
was extracted with AcOEt. The organic layer was dried over
anhydrous sodium sulfate and evaporated to give an oily resi-
due. The crude product was purified by column chrom-
atography (AcOEt) on silica gel to give 16 (57 mg, 88%), a
diastereomeric mixture (ca. 1 : 1), as a pale yellow viscous
Experimental
All melting points were measured with a Yanaco MP micro-
melting points apparatus without correction. IR was taken
1
with a Shimadzu IR-435 spectrometer. H-NMR spectra were
material; νmax (CHCl3) 3384, 2920, 1596, 1450, 1240, 1090 cmϪ1
;
measured on a Varian INOBA 400NB (1H: 400 MHz, 13C:
100.6 MHz) with tetramethylsilane as an internal standard and
δH (CDCl3) 3.37 (s, 3H, NCH3), 3.42 (s, 3H, NCH3), 3.50 (s, 3H,
OCH3), 3.52 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.78 (s, 3H,
OCH3), 3.82 (s, 6H, 2 × OCH3), 3.83 (s, 3H, OCH3), 3.84
(s, 3H, OCH3), 5.137 (d, 1H, J = 5.7 Hz, OCHaHbO), 5.141 (d,
1H, J = 5.9 Hz, OCHaHbO), 5.16 (d, 1H, J = 5.9 Hz,
OCHaHbO), 5.18 (d, 1H, J = 5.0 Hz, OCHaHbO), 5.94 (s, 1H,
ArCH(OH)Ar), 6.00 (s, 1H, ArCH(OH)Ar), 6.19 (s, 2H, 2 ×
ArCH(OH)Ar), 6.36 (d, 1H, J = 8.4 Hz, Ar–H), 6.47 (d, 1H,
J = 8.8 Hz, Ar–H), 6.55 (d, 1H, J = 8.8 Hz, Ar–H), 6.58 (d, 1H,
J = 8.6 Hz, Ar–H), 6.76 (d, 2H, J = 8.8 Hz, Ar–H), 6.82 (d,
2H, J = 8.8 Hz, Ar–H), 7.09–7.41 (m, 14H, Ar–H) [HRMS
m/z Calc. for C29H32N2O7S: M, 552.1930. Found: Mϩ 552.1933].
1
chemical shifts δ are reported in ppm. Abbreviations of H-
NMR signal patterns are as follows: s (singlet); d (doublet);
t (triplet); m (multiplet). Mass spectra (MS) and high-resonance
MS (HRMS) were obtained on a JEOL JMS BU-20 spectro-
meter under EI ionizing conditions. Silica gel (Merck Art. 7734)
was used for column chromatography.
5-[1-(tert-Butyldimethylsiloxy)-1-(3,4-dimethoxy-2-methoxy-
methoxyphenyl)methyl]-4-[1-hydroxy-1-(4-methoxyphenyl)-
methyl]-1-methyl-2-phenylthio-1H-imidazole (15)
A solution of tert-BuLi in n-pentane (1.51 M; 0.44 mL,
0.66 mmol) was added dropwise to a solution of 145 (200 mg,
0.33 mmol) in THF (2 mL) under an N2 atmosphere at Ϫ78 ЊC.
Stirring was continued for 1 h, then a solution of p-anis-
aldehyde (0.20 mL, 1.64 mmol) in THF (0.5 mL) was added
dropwise at Ϫ78 ЊC. Stirring was continued for 3 h at Ϫ78 ЊC,
then water (2 mL) was added, and the mixture was extracted
with AcOEt. The organic layer was dried over anhydrous
sodium sulfate and evaporated to give an oily residue. The
crude product was purified by column chromatography
(AcOEt–n-hexane 1 : 5) on silica gel to give 15 (95 mg, 43%),
a diastereomeric mixture (ca. 1 : 1) as a pale yellow viscous
6,7-Dimethoxy-8-hydroxy-4-(4-methoxyphenyl)-1-methyl-1H-
naphtho[2,3-d]imidazole (18)
Zn powder (114 mg) was added to a mixture of acetic acid
(0.5 mL), conc. HCl (0.05 mL) and 16 (42 mg, 0.08 mmol), and
then the whole was stirred at 80 ЊC for 1 h. The reaction mixture
was filtered through a cotton plug, and the filtrate was evapor-
ated under reduced pressure. After addition of water (0.5 mL),
K2CO3 powder was added to basify, and the whole was
extracted with AcOEt (2 mL). The organic phase was dried over
anhydrous sodium sulfate and evaporated to give an oily resi-
due, which was purified by column chromatography (CHCl3 :
MeOH = 10 : 1) on silica gel to give 18 (27 mg, 75%) as a pale
yellow viscous material; νmax (CHCl3) 3484, 2979, 1655, 1477,
1240, 1096 cmϪ1; δH (CDCl3) 3.75 (s, 3H, NCH3), 3.82 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 6.33 (s, 1H,
ArOH ), 6.97 (s, 1H, Ar–H), 7.08 (d, 2H, J = 8.8 Hz, Ar–H),
7.21–7.36 (m, 5H, Ar–H), 7.59 (d, 2H, J = 8.8 Hz, Ar–H), 7.94
(s, 1H, Ar–H); δ (CDCl3) 31.0, 55.3, 55.5, 61.4, 97.0, 99.1, 113.8,
118.6, 125.9, 127.29, 127.32, 128.8, 129.3, 129.5, 132.1, 132.4,
132.6, 135.2, 141.6, 143.2, 150.3, 150.8, 158.9 [HRMS m/z
Calc. for C27H24N2O4S: M, 472.1457. Found: Mϩ, 472.1458].
material; νmax (CHCl3) 2917, 1473, 1242, 1083, 834 cmϪ1
;
δH (CDCl3) Ϫ0.28 (s, 3H, SiCH3), Ϫ0.11 (s, 3H, SiCH3), Ϫ0.07
(s, 3H, SiCH3), 0.04 (s, 3H, SiCH3), 0.84 [s, 9H, SiC(CH3)3], 0.85
[s, 9H, SiC(CH3)3], 3.29 (s, 3H, NCH3), 3.40 (s, 3H, NCH3), 3.56
(s, 3H, OCH3), 3.62 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.76
(s, 3H, OCH3), 3.78 (s, 6H, 2 × OCH3), 3.85 (s, 3H, OCH3), 3.86
(s, 3H, OCH3), 4.61 (d, 1H, J = 4.9 Hz, OCHaHbO), 4.92 (d, 1H,
J = 5.0 Hz, OCHaHbO), 4.97 (d, 1H, J = 5.1 Hz, OCHaHbO),
5.09 (d, 1H, J = 4.9 Hz, OCHaHbO), 5.78 (d, 1H, J = 7.5 Hz,
ArCH(OH)Ar), 6.00 (d, 1H, J = 7.5 Hz, ArCH(OH)Ar), 6.28
(s, 1H, ArCH(OTBDMS)Ar), 6.37 (s, 1H, ArCH(OTBDMS)-
Ar), 6.67 (d, 2H, J = 8.8 Hz, Ar–H), 6.796 (d, 2H, J = 8.8 Hz,
Ar–H), 6.802 (d, 2H, J = 8.8 Hz, Ar–H), 7.03–7.38 (m, 16H,
Ar–H) [HRMS m/z Calc. for C35H46N2O7SSi: M, 666.2795.
Found: Mϩ, 666.2799].
5-[1-Hydroxy-1-(2-tert-butyldimethylsiloxy-3,4-dimethoxy-
phenyl)methyl]-1-methyl-2-phenylthio-1H-imidazole (20)
A solution of n-BuLi in n-hexane (1.6 M; 12.7 mL, 20.3 mmol)
was added dropwise to a solution of 2,2,6,6-tetramethyl-
piperidine (3.8 mL, 22.3 mmol) in THF (50 mL) under an N2
atmosphere at Ϫ78 ЊC, and the mixture was stirred for 15 min.
A solution of 11 (3.86 g, 20.3 mmol) in THF (6 mL) was added
5-[1-Hydroxy-1-(3,4-dimethoxy-2-methoxymethoxyphenyl)-
methyl]-4-[1-hydroxy-1-(4-methoxyphenyl)methyl]-1-methyl-
2-phenylthio-1H-imidazole (16)
A solution of TBAF in THF (1 M; 0.14 mL, 0.14 mmol) was
J. Chem. Soc., Perkin Trans. 1, 2002, 1061–1066
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dropwise to the mixture, and the mixture was stirred for 1 h at
Ϫ78 ЊC. A solution of 2-tert-butyldimethylsiloxy-3,4-dimeth-
oxybenzaldehyde 198 (6.02 g, 20.3 mmol) in THF (6 mL) was
added dropwise to the mixture and the whole was stirred at the
same temperature for 2 h. Water (20 mL) was added, and the
mixture was extracted with AcOEt (50 mL). The organic layer
was dried over anhydrous sodium sulfate and evaporated to give
a crystalline mass, which was purified by column chromato-
graphy (AcOEt–n-hexane = 1 : 1) on silica gel followed by
recrystallization from n-hexane–AcOEt to afford 20 (7.70 g,
78%), mp 122.3–122.5 ЊC (colorless needles); νmax (CHCl3) 3150,
2928, 1597, 1455, 1277, 1098, 834 cmϪ1; δH (CDCl3) 0.09 (s, 3H,
SiCH3), 0.23 (s, 3H, SiCH3), 0.88 [s, 9H, SiC(CH3)3], 3.63
(s, 3H, NCH3), 3.76 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.09
(s, 1H, ArCH(OH)Im), 6.60 (d, 1H, J = 8.6 Hz, Ar–H), 6.69
(s, 1H, Im–H), 7.01 (d, 1H, J = 8.8 Hz, Ar–H), 7.12–7.26 (m,
5H, Ar–H); δ (CDCl3) Ϫ4.5, Ϫ4.3, 18.6, 25.9, 31.8, 55.9, 60.4,
63.1, 105.2, 122.2, 124.9, 126.5, 128.0, 129.2, 129.5, 134.8,
136.7, 139.0, 139.4, 146.5, 153.4 [Calcd for C25H34N2O4SSi: C,
61.69; H, 7.04; N, 5.76. Found; C, 61.45; H, 7.07; N, 5.99%.
HRMS m/z Calc. for C25H34N2O4SSi: M, 486.2008. Found: Mϩ,
486.2015].
5-[1-(2-tert-Butyldimethylsiloxy-3,4-dimethoxyphenyl)methyl]-
4-[1-hydroxy-1-(4-methoxyphenyl)methyl]-1-methyl-2-phenyl-
thio-1H-imidazole (23)
[Method A]. A solution of tert-BuLi in n-pentane (1.56 M;
0.17 mL, 0.26 mmol) was added dropwise to a solution of 22
(72 mg, 0.13 mmol) in THF (1.0 mL) under an N2 atmosphere
at Ϫ78 ЊC. Stirring was continued for 1 h, then a solution of
p-anisaldehyde (0.08 mL, 0.66 mmol) in THF (0.5 mL) was
added dropwise at Ϫ78 ЊC. Stirring was continued for 3 h at
Ϫ78 ЊC, then water (2 mL) was added, and the mixture was
extracted with AcOEt. The organic layer was dried over
anhydrous sodium sulfate and evaporated to give an oily resi-
due. The crude product was purified by column chromato-
graphy (AcOEt–n-hexane = 1 : 2) on silica gel to give 23 (12 mg,
15%) as a pale yellow viscous material.
[Method B]. A solution of tert-BuLi in n-pentane (1.56 M;
0.23 mL, 0.36 mmol) was added dropwise to a mixed solution
of 22 (100 mg, 0.18 mmol) and p-anisaldehyde (0.11 mL, 0.91
mmol) in THF (1.5 mL) under an N2 atmosphere at Ϫ78 ЊC.
Stirring was continued at Ϫ78 ЊC and a solution of tert-BuLi in
n-pentane [1.56 M; 0.46 mL (0.23 mL × 2), 0.72 mmol] was
added to the reaction mixture every 15 min until TLC of the
reaction mixture indicated disappearance of the starting com-
pound 22. After stirring was continued for 1 h at Ϫ78 ЊC, water
(1 mL) was added to the mixture. The mixture was extracted
with AcOEt, and the organic layer was dried over anhydrous
sodium sulfate and evaporated to give an oily residue. The
crude product was purified by column chromatography
(AcOEt–n-hexane = 1 : 2) on silica gel to give 23 (98 mg, 89%) as
a pale yellow viscous material; νmax (CHCl3) 3400, 2916, 1602,
1457, 1246, 1098, 834 cmϪ1; δH (CDCl3) 0.197 (s, 3H, SiCH3),
0.203 (s, 3H, SiCH3), 0.98 [s, 9H, SiC(CH3)3], 3.29 (s, 3H,
NCH3), 3.61 (br s, 1H, OH ), 3.73 (s, 3H, OCH3), 3.75 (s, 2H,
ArCH2Im), 3.76 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 5.73 (d,
1H, J = 3.7 Hz, ArCH(OH)Im), 6.10 (d, 1H, J = 8.6 Hz, Ar–H),
6.32 (d, 1H, J = 8.6 Hz, Ar–H), 6.79 (d, 2H, J = 8.8 Hz, Ar–H),
7.10–7.35 (m, 7H, Ar–H ); δ (CDCl3) Ϫ4.2, 18.7, 24.0, 26.1,
31.1, 55.2, 55.8, 60.3, 69.7, 104.9, 113.6, 121.4, 122.3, 126.4,
127.4, 127.9, 127.9, 129.2, 135.1, 135.6, 136.0, 139.7, 142.8,
146.8, 152.2, 158.9 [HRMS m/z Calc. for C33H42N2O5SSi: M,
606.2583. Found: Mϩ, 606.2591].
5-[1-(2-tert-Butyldimethylsiloxy-3,4-dimethoxyphenyl)methyl]-
1-methyl-2-phenylthio-1H-imidazole (21)
To a solution of 20 (2.0 g, 4.1 mmol) in 12 ml of CH2Cl2 were
added a solution of triethylsilane (3.3 ml, 20.5 mmol) and a
solution of TFA (1.9 ml, 24.6 mmol). The solution was stirred
for 12 h at rt under N2 and quenched by the addition of satur-
ated aqueous NaHCO3 solution (15 ml). The mixture was
extracted with CHCl3 (15 mL). The organic layer was dried over
anhydrous sodium sulfate and evaporated to give an oily resi-
due, which was purified by column chromatography (AcOEt–n-
hexane = 1 : 2) on silica gel to give 21 (1.90 g, 98%) as a pale
yellow viscous material; νmax (CHCl3) 2916, 1457, 1098, 834
cmϪ1; δH (CDCl3) 0.21 [s, 6H, Si(CH3)2], 0.97 [s, 9H, SiC(CH3)3],
3.40 (s, 3H, NCH3), 3.76 (s, 3H, OCH3), 3.84 (s, 3H, OCH3),
3.86 (s, 2H, ArCH2Im), 6.47 (d, 1H, J = 8.6 Hz, Ar–H), 6.55 (d,
1H, J = 8.6 Hz, Ar–H), 6.90 (s, 1H, Im–H), 7.10–7.26 (m, 5H,
Ar–H); δ (CDCl3) Ϫ4.2, 18.7, 25.4, 26.0, 31.1, 55.8, 60.3, 105.0,
121.4, 123.5, 126.3, 127.6, 129.1, 129.2, 134.3, 135.4, 137.2,
139.8, 147.1, 152.4 [HRMS m/z Calc. for C25H34N2O3SSi:
M, 470.2059. Found: Mϩ, 470.2050].
8-(tert-Butyldimethylsilyloxy)-6,7-dimethoxy-4-(4-methoxy-
phenyl)-1-methyl-2-phenylthio-4,9-dihydro-1H-naphtho[2,3-d]-
imidazole (26)
4-Bromo-5-[1-(2-tert-butyldimethylsiloxy-3,4-dimethoxy-
phenyl)methyl]-1-methyl-2-phenylthio-1H-imidazole (22)
To a solution of 23 (54 mg, 0.09 mmol) in 1.5 ml of CH2Cl2
were added a solution of triethylsilane (0.02 mL, 0.13 mmol)
and a solution of TFA (0.02 mL, 0.27 mmol). The solution was
stirred for 12 h at rt under N2 and quenched by the addition of
saturated aqueous NaHCO3 solution (2 ml). The mixture was
extracted with CHCl3 (2 mL). The organic layer was dried over
anhydrous sodium sulfate and evaporated to give an oily resi-
due, which was purified by column chromatography (AcOEt–n-
hexane = 1 : 1) on silica gel to give 26 (41 mg, 79%) as colorless
NBS (182 mg, 1.02 mmol) was added to a solution of 21
(482 mg, 1.02 mmol) in THF (4 ml) under an N2 atmosphere
at 0 ЊC, and the whole was stirred for 1 h at 0 ЊC. Then water
(1 ml) was added, and the mixture was extracted with AcOEt.
The organic layer was dried over anhydrous sodium sulfate
and evaporated to give an oily residue. The crude product was
purified by column chromatography (AcOEt–n-hexane = 1 : 2)
on silica gel to afford 22 (454 mg, 81%), mp 86.6–88.4 ЊC (color-
less crystals, recrystallized from n-hexane–AcOEt); νmax
(CHCl3) 2915, 1599, 1457, 1253, 1098, 834 cmϪ1; δH (CDCl3)
0.25 [s, 6H, Si(CH3)2], 1.03 [s, 9H, SiC(CH3)3], 3.36 (s, 3H,
NCH3), 3.75 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.92 (s,
2H, ArCH2Im), 6.38 (d, 1H, J = 8.6 Hz, Ar–H), 6.44 (d, 1H, J =
8.6 Hz, Ar–H), 7.16–7.29 (m, 5H, Ar–H); δ (CDCl3) Ϫ4.1,
18.8, 24.3, 26.1, 32.0, 55.8, 60.3, 105.2, 116.1, 120.8, 122.4,
126.8, 128.0, 129.3, 132.1, 134.4, 137.1, 139.8, 146.9, 152.4
[Calc. For C25H33BrN2O3SSi: C, 54.63; H, 6.05; N, 5.10. Found:
C, 54.41; H, 5.99; N, 5.19%. MS m/z (% base): 551 (3), 550 (7),
549 (2), 548 (6), 496 (2), 495 (12), 494 (28), 493 (100), 492 (26),
491 (92), 478 (18), 476 (15), 397 (15), 209 (27), 199 (24). HRMS
m/z Calc. for C25H33BrN2O3SSi: M, 548.1164. Found: Mϩ,
548.1177].
crystals; νmax (CHCl3) 2917, 1603, 1490, 1246, 1126, 834 cmϪ1
;
δH (CDCl3) 0.27 (s, 3H, SiCH3), 0.28 (s, 3H, SiCH3), 1.07 [s, 9H,
SiC(CH3)3], 3.55 (s, 3H, NCH3), 3.746 (s, 3H, OCH3), 3.752 (s,
3H, OCH3), 3.754 (s, 3H, OCH3), 3.83 (d, 1H, J = 3.7 Hz,
ArCHaHbIm), 3.87 (d, 1H, J = 3.5 Hz, ArCHaHbIm), 5.22 (t,
1H, J = 3.4 Hz, ArCH(Ar)Im), 6.40 (s, 1H, Ar–H), 6.78 (d, 2H,
J = 8.6 Hz, Ar–H), 7.02–7.22 (m, 7H, Ar–H) [HRMS m/z Calc.
for C33H40N2O4SSi: M, 588.2478. Found: Mϩ, 588.2470].
5-[1-(2-tert-Butyldimethylsiloxy-3,4-dimethoxyphenyl)methyl]-
4-[1-(4-methoxyphenyl)methyl]-1-methyl-1H-imidazole (25)
Sodium borohydride (1.08 g, 28.51 mmol) was added to a
solution of 23 (412 mg, 0.68 mmol) and nickel() chloride
1064
J. Chem. Soc., Perkin Trans. 1, 2002, 1061–1066

View Article Online
hexahydrate (2.26 g, 9.51 mmol) in MeOH–THF = 1 : 1 (20 mL)
under an N2 atmosphere at 0 ЊC, and the whole was refluxed
for 2 h. The solvent was evaporated off, then water (20 mL)
was added to the residue. The mixture was extracted with
CHCl3. The organic layer was dried over anhydrous sodium
sulfate and evaporated to give an oily residue. The crude
product was purified by column chromatography (CHCl3–
MeOH = 20 : 1) on silica gel to give 25 (202 mg, 62%) as a pale
yellow viscous material; νmax (CHCl3) 2918, 1601, 1457, 1241,
1099, 834 cmϪ1; δH (CDCl3) 0.25 [s, 6H, Si(CH3)2], 1.03 [s, 9H,
SiC(CH3)3], 3.33 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 3.81 (s, 3H, OCH3), 3.82 (s, 2H, ArCH2Im), 3.84
(s, 2H, ArCH2Im), 6.21 (d, 1H, J = 8.6 Hz, Ar–H), 6.36 (d, 1H,
J = 8.6 Hz, Ar–H), 6.77 (d, 2H, J = 8.6 Hz, Ar–H), 7.16 (d,
2H, J = 8.6 Hz, Ar–H), 7.37 (s, 1H, Im–H); δ (CDCl3) Ϫ4.1,
18.8, 23.0, 26.1, 31.4, 33.0, 55.2, 55.8, 60.3, 104.8, 113.7, 122.5,
122.7, 125.1, 129.5, 133.0, 136.6, 139.2, 146.8, 152.1, 157.7
[HRMS m/z Calc. for C27H38N2O4Si: M, 482.2601. Found: Mϩ,
482.2592].
2-Azido-5-[1-(2-hydroxy-3,4-dimethoxyphenyl)methyl]-4-
[1-(4-methoxyphenyl)methyl]-1-methyl-1H-imidazole (31)
A solution of TBAF in THF (1 M; 1.00 mL, 1.00 mmol) was
added dropwise to a solution of 30 (476 mg, 0.91 mmol) in
THF (5 mL) at room temperature. The mixture was stirred for
5 min at room temperature. Water (2 mL) was added, and the
mixture was extracted with AcOEt. The organic layer was dried
over anhydrous sodium sulfate and evaporated to give an oily
residue. The crude product was purified by column chromato-
graphy (CHCl3–MeOH = 50 : 1) on silica gel to give 31, yellow
crystals (322 mg, 87%), mp 140 ЊC dec. (recrystallized from
CHCl3–n-hexane); νmax (CHCl3) 3475, 2924, 2121, 1607, 1500,
1458, 1240, 1169, 1093 cmϪ1; δH (CDCl3) 3.13 (s, 3H, NCH3),
3.76 (s, 3H, OCH3), 3.78 (s, 2H, ArCH2Im), 3.816 (s, 3H,
OCH3), 3.823 (s, 2H, ArCH2Im), 3.89 (s, 3H, OCH3), 6.31 (d,
1H, J = 8.8 Hz, Ar–H), 6.38 (d, 1H, J = 8.6 Hz, Ar–H), 6.78 (d,
2H, J = 8.8 Hz, Ar–H), 7.16 (d, 2H, J = 8.8 Hz, Ar–H);
δ (CDCl3) 22.4, 29.3, 32.6, 55.2, 55.8, 60.9, 103.5, 113.7, 117.1,
123.3, 124.4, 129.4, 132.8, 135.2, 136.2, 138.8, 146.9, 150.9,
157.8 [HRMS m/z Calc. for C21H23N5O4: M, 409.1750. Found:
Mϩ, 409.1749].
2-Bromo-5-[1-(2-tert-butyldimethylsiloxy-3,4-dimethoxyphenyl)-
methyl]-4-[1-(4-methoxyphenyl)methyl]-1-methyl-1H-imidazole
(29)
Naamine C 2
A mixture of 31 (52 mg, 0.13 mmol) and 10% Pd/C (10 mg) in
EtOH (3 mL) was stirred for 24 h under an H2 atmosphere at
room temperature. The catalyst was removed by filtration with
CHCl3 and the filtrate was evaporated to give an oily residue.
The crude product was purified by column chromatography
(CHCl3 : MeOH = 5 : 1) on silica gel to give 2 as a yellow
powder1f,10 (47 mg, 97%); νmax (CHCl3) 3251, 3107, 2932, 1660,
1608, 1504, 1458, 1236, 1093 cmϪ1; δH (CDCl3) 3.25 (s, 3H,
NCH3), 3.736 (br s, 2H, ArCH2Im), 3.742 (s, 3H, OCH3), 3.75
(br s, 2H, ArCH2Im), 3.83 (s, 3H, OCH3), 3.89 (s, 3H, OCH3),
6.35 (d, 1H, J = 8.6 Hz, Ar–H), 6.47 (d, 1H, J = 8.6 Hz, Ar–H),
6.77 (d, 2H, J = 8.8 Hz, Ar–H), 7.10 (d, 2H, J = 8.8 Hz, Ar–H);
δ (CDCl3) 22.1, 29.7, 29.9, 55.2, 55.8, 61.0, 103.7, 114.0, 115.9,
120.9, 123.3, 124.7, 129.5, 130.1, 135.5, 146.7, 147.2, 151.3,
158.2 [HRMS m/z Calc. for C21H25N3O4: M, 383.1845. Found:
Mϩ, 383.1843].
NBS (9 mg, 0.05 mmol) was added to a solution of 25 (25 mg,
0.05 mmol) in THF (0.5 ml) under an N2 atmosphere at 0 ЊC,
and then the whole was stirred for 1 h at 0 ЊC. Then water
(0.5 ml) was added, and the mixture was extracted with AcOEt.
The organic layer was dried over anhydrous sodium sulfate and
evaporated to give an oily residue. The crude product was puri-
fied by column chromatography (AcOEt–n-hexane = 1 : 2) on
silica gel to give 29 (17 mg, 59%) as a pale yellow viscous
material; νmax (CHCl3) 2917, 1602, 1460, 1244, 1098, 834 cmϪ1
;
δH (CDCl3) 0.24 [s, 6H, Si(CH3)2], 1.02 [s, 9H, SiC(CH3)3], 3.27
(s, 3H, NCH3), 3.76 (s, 6H, 2 × OCH3), 3.810 (s, 2H, ArCH2Im),
3.813 (s, 3H, OCH3), 3.83 (s, 2H, ArCH2Im), 6.24 (d, 1H, J =
8.6 Hz, Ar–H), 6.38 (d, 1H, J = 8.6 Hz, Ar–H), 6.77 (d, 2H, J =
8.8 Hz, Ar–H), 7.15 (d, 2H, J = 8.8 Hz, Ar–H); δ (CDCl3) Ϫ4.1,
18.8, 23.9, 26.1, 32.0, 33.0, 55.2, 55.8, 60.3, 104.9, 113.7, 118.3,
121.9, 122.5, 128.3, 129.5, 132.5, 139.7, 139.8, 146.8, 152.2,
157.8 [MS m/z (% base): 562 (2), 560 (2), 507 (2), 506 (8), 505
(28), 504 (8), 503 (26), 383 (10), 381 (10), 279 (6), 209 (6), 121
(100). HRMS m/z Calc. for C27H37BrN2O4Si: M, 560.1705.
Found: Mϩ, 560.1714].
Pyronaamidine 4
A solution of 1-methylparabanic acid 32 (30 mg, 0.24 mmol)
and N,N-diisopropylethylamine (0.11 mL, 0.61 mmol) and tri-
methylsilyl chloride (0.06 mL, 0.49 mmol) in CHCl3 (0.5 mL)
was stirred for 5 min under an N2 atmosphere at 0 ЊC, and then
the stirring was continued for 2 h at room temperature. A
solution of naamine C 2 (90 mg, 0.24 mmol) in CHCl3 (0.5 mL)
was added to the mixture, the whole was refluxed for 48 h.
The solution was evaporated to give an oily residue, which was
purified by column chromatography (CHCl3–MeOH = 5 : 1)
on silica gel to afford 4, yellow crystals (32 mg, 28%), mp
182.3–184.5 ЊC (recrystallized from CHCl3–n-hexane; lit.1e,12
mp 185–187 ЊC); νmax (CHCl3) 3476, 2977, 1783, 1732, 1659,
1609, 1563, 1504, 1457, 1388, 1297, 1240, 1172, 1144, 1094,
1031 cmϪ1; δH (CD2Cl2) 3.09 (s, 3H, NCH3), 3.54 (s, 3H,
–OCH3), 3.75 (s, 3H, –OCH3), 3.80 (s, 3H, –OCH3), 3.87 (s, 3H,
–OCH3), 3.88 (s, 2H, ArCH2Im), 3.90 (s, 2H, ArCH2Im), 6.35
(d, 1H, J = 8.6 Hz, Ar–H), 6.44 (d, 1H, J = 8.6 Hz, Ar–H), 6.79
(d, 2H, J = 8.8 Hz, Ar–H), 7.10 (d, 2H, J = 8.8 Hz, Ar–H);
δ (CD2Cl2) 23.2, 24.7, 30.0, 32.2, 55.5, 56.1, 61.2, 104.0, 114.1,
116.4, 123.7, 126.9, 129.7, 131.9, 135.2, 135.8, 146.5, 146.8,
147.5, 151.6, 156.4, 158.5, 162.7 [Calc. For C25H27N5O6ؒ½H2O:
C, 59.75; H, 5.62; N, 13.94. Found: C, 59.56; H, 5.53; N,
13.81%. HRMS m/z Calc. for C25H27N5O6: M, 493.1961.
Found: Mϩ, 493.1974].
2-Azido-5-[1-(2-tert-butyldimethylsiloxy-3,4-dimethoxyphenyl)-
methyl]-4-[1-(4-methoxyphenyl)methyl]-1-methyl-1H-imidazole
(30)
A solution of tert-BuLi in n-pentane (1.56 M; 0.43 mL,
0.66 mmol) was added dropwise to a solution of 29 (124 mg,
0.22 mmol) under an N2 atmosphere at Ϫ78 ЊC. The mixture
was stirred for 15 min at Ϫ78 ЊC, then trisyl azide (205 mg,
0.66 mmol) was added, and then the whole was stirred for
1 h at Ϫ78 ЊC. Water (1 mL) was added, and the mixture
was extracted with AcOEt. The organic layer was dried over
anhydrous sodium sulfate and evaporated to give an oily resi-
due. The crude product was purified by column chromato-
graphy (AcOEt–n-hexane = 1 : 3) on silica gel to give 30 (90 mg,
78%) as a pale yellow viscous material; νmax (CHCl3) 2916, 2120,
1601, 1499, 1245, 1098, 834 cmϪ1; δH (CDCl3) 0.23 [s, 6H,
Si(CH3)2], 1.01 [s, 9H, SiC(CH3)3], 3.07 (s, 3H, NCH3), 3.746 (s,
3H, OCH3), 3.753 (s, 2H, ArCH2Im), 3.76 (s, 3H, OCH3), 3.79
(s, 2H, ArCH2Im), 3.81 (s, 3H, OCH3), 6.27 (d, 1H, J = 8.6 Hz,
Ar–H), 6.37 (d, 1H, J = 8.6 Hz, Ar–H), 6.78 (d, 2H, J = 8.8 Hz,
Ar–H), 7.16 (d, 2H, J = 8.8 Hz, Ar–H); δ (CDCl3) Ϫ4.1, 18.8,
23.3, 26.1, 29.2, 32.7, 55.2, 55.8, 60.3, 104.9, 113.7, 122.4, 122.5,
124.5, 129.4, 132.7, 136.5, 138.9, 139.7, 146.8, 152.1, 157.8
[HRMS m/z Calc. for C27H37N5O4Si: M, 523.2614. Found: Mϩ,
523.2612].
Acknowledgements
This research was financially supported, in part, by a Grant-
In-Aid for the promotion of the advancement of education and
J. Chem. Soc., Perkin Trans. 1, 2002, 1061–1066
1065

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M. Yamashita and S. Ohta, Chem. Pharm. Bull., 1997, 45, 1393;
(c) S. Nakamura, N. Tsuno, M. Yamashita, I. Kawasaki, S. Ohta and
Y. Ohishi, J. Chem. Soc., Perkin Trans. 1, 2001, 429.
6 T. G. Back, D. L. Baron and K. Yang, J. Org. Chem., 1993, 58,
2407.
7 N. Kawai, Y. Fujibayashi, S. Kuwabara, K. Takao, Y. Ijuin and
S. Kobayashi, Tetrahedron, 2000, 56, 6467.
research in graduate schools in Subsidies for ordinary expenses
of private schools from the Promotion and Mutual Aid
Corporation for Private Schools, and the Frontier Research
Program and a Grant-In-Aid for Encouragement of Young
Scientists (to I. K.) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan.
8 S. B. Singh and G. R. Pettit, J. Org. Chem., 1989, 54, 4105.
9 R. E. Harmon, G. Wellman and S. K. Gupta, J. Org. Chem., 1973,
38, 11.
10 The reported physical data for the natural naamine C (ref. 1f): yellow
powder; δH (500 MHz; CDCl3) 3.26 (s, 3H), 3.72 (s, 3H), 3.73 (br s,
4H), 3.81 (s, 3H), 3.87 (s, 3H), 6.34 (d, 1H, J = 8.7 Hz), 6.46 (d, 1H,
J = 8.7 Hz), 6.76 (d, 2H, J = 8.7 Hz), 7.06 (d, 2H, J = 8.7 Hz); δ (125
MHz; CDCl3) 22.6, 29.3, 29.6, 55.3, 55.8, 61.0, 103.8, 114.2, 115.1,
121.1, 122.7, 123.3, 129.0, 129.5, 135.5, 146.4, 147.1, 151.5, 158.5.
IR was not reported in ref. 1f.
11 At this time N,N-diisopropylethylamine was used instead of Et3N
and imidazole, which were used in ref. 4. Although use of the latter
bases resulted in low yield of 4 (10% yield), use of the former base
somewhat improved the yield of 4 (28% yield).
12 The reported physical data for the natural pyronaamidine (ref. 1e):
mp 185–187 ЊC (yellow feathery crystals); νmax (CHCl3) 3403 (br)
1790, 1732, 1664, 1613, 1567, 1510, 1444, 1392, 1302, 1246, 1178,
1148, 1096, 1034, 968, 752, 606 cmϪ1; δH (500 MHz; CD2Cl2) 3.09
(s, 3H), 3.54 (s, 3H), 3.75 (s, 3H), 3.80 (s, 3H), 3.87 (s, 3H), 3.88 (s,
2H), 3.90 (s, 2H), 6.34 (d, 1H), 6.44 (d, 1H), 6.78 (d, 2H), 7.15
(d, 2H), 8.14 (br s, 1H), 8.14 (br s, 1H); δ (125 MHz; CD2Cl2) 23.2,
24.7, 29.9, 32.1, 55.5, 56.0, 61.1, 104.0, 114.1, 116.4, 123.7, 126.9,
129.7, 131.9, 135.1, 135.8, 146.5, 146.7, 147.5, 151.7, 156.4, 158.5,
162.7.
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