Y. Shimasaki et al. / Tetrahedron 62 (2006) 9628–9634
9633
piperonal (408 mg, 2.72 mmol) in a yield of 89% based on
2$2HCl, as a pale yellow oil; Rf 0.79 (CHCl3/EtOH/28%
THF, and stirred for 15 min at room temperature. To the sus-
pension was added Na-piperonylhistamine 19c (555 mg,
1.58 mmol), warmed up to 50 ꢁC, and the mixture was stirred
for 1 h. The reaction mixture was filtrated through a CeliteÒ
pad, added water, and extracted with EtOAc. The combined
organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was chromatographed on
silica gel. Elution with CHCl3/EtOH (20:1) gave 19c (MW:
507.27, 550 mg, 0.922 mmol, 71% based on 14) as a yellow
oil; Rf 0.57 (CHCl3/EtOH¼30:1), [a]2D4 ꢀ0.703 (c 1.28,
CHCl3). 1H NMR (300 MHz, CDCl3): d¼7.47 (s, 1H,
NCH]N), 7.40–7.25 (m, 10H), 6.75–6.65 (m, 4H), 5.91 (s,
2H, OCH2O), 5.64–5.36 (m, 3H), 5.22–5.00 (m, 4H), 4.54–
4.45 (m, 1H, H-2), 3.47 (d, 2H, NCH2Ar), 2.98 (d, 2H,
J¼5.4 Hz, NCH2C]), 2.78–2.40 (m, 6H). 13C NMR
(75 MHz, CDCl3): d¼171.79, 155.91, 147.76, 146.66,
136.19, 135.19, 134.30, 132.84, 131.73, 128.67, 128.56,
128.36, 128.23, 128.05, 127.07, 121.97, 109.19, 107.93,
100.86, 67.20, 66.93, 57.85, 54.78, 53.66, 52.56, 35.35,
23.18. IR: n¼3493–2100 (br s), 1717 (s), 1500 (s), 1487 (s),
1454 (m), 1440 (s), 1342 (w), 1244 (s), 1214 (s), 1187 (m),
1093 (w), 1038 (s), 975 (w), 930 (w), 810 (w), 749 (s), 696
(s), 665 (w) cmꢀ1. FABMS: m/z¼597 (M+H)+, 154, 136,
91 (Bn)+, 73. FABHRMS: calcd for C34H37O6N4 (M+H)+
m/z¼597.2713; found, 597.2718.
1
NH3 aq¼3:3:1). H NMR (300 MHz, CDCl3): d¼7.54 (d,
1H, J¼1.2 Hz, NCH]N), 6.82–6.79 (m, 2H), 6.78–6.72
(m, 2H), 5.95 (s, 2H, OCH2O), 3.73 (s, 2H, ArCH2), 2.92
(pseudo t, 2H, J¼5.7 Hz), 2.79 (pseudo t, 2H, J¼5.7 Hz).
13C NMR (125 MHz, CDCl3): d¼147.69, 146.58, 133.62,
121.30, 108.63, 108.11, 100.89, 53.46, 48.41, 26.29. IR:
n¼3500–2400 (br s), 1503 (m), 1489 (s), 1442 (m), 1246
(s), 1215 (m), 1103 (w), 1039 (m), 931 (w), 810 (w), 744
(s), 665 (w), 626 (w) cmꢀ1. FABMS: m/z¼246 (M+H)+,
135 (piperonyl)+. FABHRMS: calcd for C13H16O2N3
(M+H)+ m/z¼246.1242; found, 246.1248.
4.1.10. Na-(3,4-Methoxybenzyl)histamine (18d). In the
same manner as described for 18a, 18d (MW: 245.28,
71.0 mg, 0.289 mmol, 11%) was obtained from 2$2HCl
(500 mg, 2.72 mmol) and 3,4-dimethoxybenzaldehyde
(1.13 g, 6.79 mmol) in a yield of 11% based on 2$2HCl, as
1
a pale yellow oil; H NMR (300 MHz, CDCl3): d¼7.44 (s,
1H, NCH]N), 6.78 (s, 1H), 6.75 (s, 2H), 6.71 (s, 1H),
3.79 [s, 6H, (OMe)2], 3.69 (s, 2H, ArCH2), 2.86 (t, 2H,
J¼6.5 Hz), 2.73 (t, 2H, J¼6.5 Hz).
4.1.11. Benzyl (2S,4EZ)-2-(benzyloxycarbonylamino)-6-
(benzyl)[2-(4-imidazolyl)ethyl]amino-4-hexenoate (19a).
In the similar manner as described for 19c, 19a (MW:
552.66, 671 mg, 1.22 mmol) was obtained from 14 (MW:
411.45, 1.00 g, 2.43 mmol) and Na-benzylhistamine 18a
(587 mg, 2.91 mmol) in a yield of 50% based on 14, as a yel-
low oil; Rf 0.29 (CHCl3/MeOH¼10:1). 1H NMR (300 MHz,
CDCl3): d¼7.45 (s, 1H, NCH]N), 7.40–7.15 (m, 15H),
6.73 (s, 1H, NCH]C), 5.56–5.35 (m, 2H), 5.20–5.00
(m, 4H), 4.55–4.45 (m, 1H, H-2), 3.58 (s, 2H, NCH2Ph),
3.00 (d, 2H, J¼5.7 Hz, H-6), 2.80–2.40 (m, 6H). FABMS:
m/z¼553 (M+H)+, 471, 279, 91 (Bn)+. FABHRMS:
calcd for C33H37O4N4 (M+H)+ m/z¼553.2815; found,
553.2819.
4.1.14. (S)-2-Amino-9-(4-imidazolyl)-7-azanonanoic acid
(gizzerosine, 1). A 30 ml, two-necked round bottomed flask
equipped with a magnetic stirrer bar, an N2 inlet adapter,
and a septum was placed under a hydrogen atmosphere.
The flask was charged with 19c (MW: 596.67, 54.4 mg,
91.1 mmol) and Pd(OH)2/C (110 mg) in 5 ml of EtOH/
THF/H2O (3:1:1). The mixture was stirred for 5 h at room
temperature. Then this was filtrated through a CeliteÒ pad
and the filtrate was concentrated in vacuo. The resulting
solid was purified through SephadexÒ LH-20 column.
Elution with MeOH/H2O (1:1) gave gizzerosine 1 (MW:
240.30, 10.4 mg, 0.433 mmol, 47%) as a white solid. This
solid was dissolved in 1 M HCl aq and stirred for 5 min.
Then this solution was concentrated in vacuo. This resulting
white amorphous solid was used for analysis; Rf 0.09
(CHCl3/MeOH/28% NH3 aq¼3:3:1), mp 250–251 ꢁC (dec)
[lit.6 251–252 ꢁC (dec)]; [a]D22 +9.45 (c 0.555, H2O) {lit.6
4.1.12. Benzyl (2S,4EZ)-2-(benzyloxycarbonylamino)-6-
[2-(4-imidazolyl)ethyl](p-methoxybenzyl)amino-4-hexe-
noate (19b). In the similar manner as described for 19c, 19b
(MW: 582.69, 262 mg, 449 mmol) was obtained from 14
(MW: 411.45, 200 mg, 0.486 mmol) and Na-(p-methoxy-
benzyl)histamine 18b (135 mg, 533 mmol) in a yield of
92% based on 14, as a yellow oil; Rf 0.50 (CHCl3/
EtOH¼10:1). 1H NMR (300 MHz, CDCl3): d¼7.46 (s, 1H,
NCH]N), 7.36–7.28 (m, 10H), 7.16 (d, 2H, J¼8.4 Hz),
6.83 (d, 2H, J¼8.7 Hz), 6.74 (s, 1H, NCH]C), 5.58–5.36
(m, 3H), 5.20–5.00 (m, 4H), 4.54–4.45 (m, 1H), 3.78 (s,
3H, OMe), 3.52 (s, 2H), 2.99 (d, 2H, J¼5.4 Hz), 2.68 (dd,
2H, J¼16.5, 5.4 Hz), 2.56 (t, 2H, J¼5.7 Hz), 2.49 (t, 2H,
J¼6.6 Hz). FABMS: m/z¼583 (M+H)+, 501, 230, 121
(PMB)+, 91 (Bn)+. FABHRMS: calcd for C34H39O5N4
(M+H)+ m/z¼583.2921; found, 583.2922.
1
[a]2D2 +10.3 (c 1.28, H2O)}. H NMR (300 MHz, D2O):
d¼8.30 (br s, 1H), 7.26 (br s, 1H), 3.75 (t, 1H, J¼6.0 Hz),
3.37 (pseudo t, 2H, J¼7.2 Hz), 3.11 (pseudo t, 4H,
J¼6.6 Hz), 1.89 (m, pseudo q, 2H, J¼7.4 Hz), 1.74 (quint,
2H, J¼7.5 Hz), 1.60–1.35 (m, 2H). 13C NMR (75 Hz,
D2O): d¼175.08, 135.69, 131.45, 116.93, 54.99, 47.72,
46.86, 30.38, 25.65, 22.91, 22.04. IR: n¼3300–2300 (br s),
3116 (s), 2786 (s), 2450 (m), 1634 (s), 1601 (s), 1522 (s),
1462 (s), 1395 (s), 1348 (m), 1329 (m), 1235 (w), 1052 (w),
957 (w), 839 (w), 794 (w), 719 (w), 623 (m) cmꢀ1. FABMS:
m/z¼241 (M+H)+, 207, 185, 93, 75, 57, 45. FABHRMS:
calcd for C11H21N4O2 (M+H)+ m/z¼241.1665; found,
241.167. These spectral data are in good agreement with
those reported.6
4.1.13. Benzyl (2S,4EZ)-2-(benzyloxycarbonylamino)-6-
[2-(4-imidazolyl)ethyl](piperonyl)amino-4-hexenoate
(19c). A 20 ml, two-necked round bottomed flask equipped
with a magnetic stirrer bar, an N2 inlet adapter, and a septum
was placed under a nitrogen atmosphere. The flask was
chargedwith14(MW:411.45,540 mg,1.31 mmol),Pd2(dba)3
(60.0 mg, 65.6 mmol), and PPh3 (18.2 mg, 69.4 mmol) in dry
Acknowledgements
We thank Prof. Takeshi Sugai (Keio Univ., Japan) for useful
advices and Prof. Hidenori Watanabe (Tokyo Univ., Japan)
for kindly giving us the authentic sample.