Skeletal Analogues of Saxitoxin Derivatives
FULL PAPER
(CD3CO2D)). Mass spectra were recorded using a JEOL JMS-T100X
spectrometer in ESI-MS mode with methanol as solvent.
1H), 3.92 (d, J=10.9 Hz, 1H), 3.89 (dd, J=6.3, 6.9 Hz, 1H), 3.77 (s, 3H),
3.59 (dt, J=8.0, 10.9 Hz, 1H), 3.50 (m, 2H), 3.31 (dd, J=6.9, 9.7 Hz,
1H), 2.35 (m, 1H), 1.96 (dd, J=6.9, 13.8 Hz, 1H), 1.49 (s, 9H), 1.43 (s,
9H), 0.97 ppm (m, 21H); 13C NMR (125 MHz, CDCl3): d=161.3, 159.1,
157.6, 156.5, 150.2, 136.4, 130.2, 129.6, 128.4, 128.0, 127.9, 113.6, 82.3,
79.5, 73.0, 72.5, 69.8, 66.8, 55.2, 53.0, 46.8, 32.1, 28.1, 28.0, 17.8, 12.0 ppm;
HRMS (ESI): m/z calcd for C43H68N4O10SiNa: 851.4569 [M+Na+];
found: 851.4602.
Isoxazolidine 8: A mixture of nitrone (+)-5 (10.4 g, 40.5 mmol) and
nitro-olefin 6 (9.49 g, 42.5 mmol) was stirred for 30 min at 408C without
any solvents. The reaction mixture was diluted with CH2Cl2 (150 mL) and
cooled to À408C. DBU (6.28 mL, 44.6 mmol) was added to the solution,
and the resulting mixture was stirred for 1 h at the same temperature.
AcOH (11.6 mL, 203 mmol) and Zn powder (freshly activated with dilut-
ed aqueous HCl, 10.6 g, 162 mmol) were added to the reaction mixture,
and the resulting mixture was warmed to 08C over 5 h. The reaction mix-
ture was then filtered through a pad of Celite, and the filtrates were di-
luted with CH2Cl2 (150 mL) and washed with H2O and brine. The com-
bined organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography on silica gel
(hexane/EtOAc=15:1 to 5:1) to give hydroxylamine 8 (13.5 g, 72%).
Spectral data for 8: [a]D16 = +1.3 (c=2.3 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.25 (d, J=8.2 Hz, 2H), 6.86 (d, J=8.2 Hz, 2H), 5.47 (br,
1H), 4.48 (s, 2H), 4.23 (dt, J=2.3, 5.0 Hz, 1H), 4.12 (q, J=6.0 Hz, 1H),
3.79 (s, 3H), 3.72 (m, 2H), 3.58 (m, 2H), 3.3, (m, 2H), 2.06 (m, 1H), 1.73
(m, 1H), 1.04 ppm (m, 21H); 13C NMR (100 MHz, CDCl3) : d=159.3,
129.6, 129.5, 113.8, 77.9, 77.8, 77.4, 73.4, 71.9, 67.9, 55.8, 55.2, 34.4, 17.9,
12.0 ppm; HRMS (ESI): m/z calcd for C24H42N2O5SiNa: 489.2761
[M+Na+]; found: 489.2758.
Cyclic guanidine 12: Chloromethanesulfonyl chloride (5.72 mL,
47.6 mmol) was added to a solution of guanidine 11 (9.90 g, 11.9 mmol)
and iPr2NEt (12.3 mL, 71.4 mmol) in CH2Cl2 (60 mL) at 08C under an N2
atmosphere. After stirring for 12 h, the reaction was quenched with satu-
rated aqueous NaHCO3, and the organic layer was extracted with
CH2Cl2. The combined organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatogra-
phy on silica gel (hexane/EtOAc=10:1 to 8:1) to give cyclic guanidine 12
(8.35 mg, 87%). Spectral data for cyclic guanidine 12: [a]1D8 = +70.9 (c=
2.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.33 (m, 5H), 7.20 (d,
J=8.24 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.09 (d, J=12.2 Hz, 1H), 5.05
(br, 1H), 4.99 (d, J=12.2 Hz, 1H), 4.45 (d, J=10.3 Hz, 1H), 4.42 (m,
1H), 4.29 (d, J=10.3 Hz, 1H), 4.25 (m, 1H), 3.99 (m, 1H), 3.80 (m,1H),
3.78 (s=3H), 3.71 (dd, J=3.7, 10.1 Hz, 1H), 3.58 (m, 1H), 3.38 (dd, J=
7.3, 9.6 Hz, 1H), 3.18 (d, J=11.0 Hz, 1H), 1.76 (m, 2H), 1.49 (s, 9H),
1.48 (s, 9H), 0.98 ppm (m, 21H); 13C NMR (100 MHz, CDCl3): d=159.6,
159.0, 155.6, 151.6, 135.9, 130.4, 129.6, 128.6, 128.3, 128.2, 113.4, 82.6,
78.1, 74.1, 72.9, 71.4, 68.6, 67.2, 59.4, 55.2, 54.5, 46.0, 32.6, 28.5, 28.1, 17.9,
12.0 ppm; HRMS (ESI): m/z calcd for C43H67N4O9Si: 811.4677 [M+H+];
found: 811.4678.
Isoxazolidine 9: CbzCl (4.01 mL, 28.1 mmol) was added to a solution of
5a-hydroxylamine 8 (10.1 g, 21.6 mmol) and K2CO3 (15.0 g, 108 mmol) in
THF/H2O (1:1, 60 mL) at 08C. After stirring for 10 min at 08C, methanol
(150 mL) was added to the solution, and resulting mixture was warmed
to room temperature. The reaction mixture was then concentrated in
vacuo, and the resulting material was diluted with EtOAc/H2O and ex-
tracted with EtOAc. The combined organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/EtOAc=8:1 to 4:1) to give N-Cbz-
Bis(guanidine) 13: TBAF (3.23 g, 12.4 mmol) was added to a solution of
cyclic guanidine 12 (8.35 g, 10.3 mmol) in a solution of THF (50 mL) at
08C. After stirring for 1 h, the reaction mixture was quenched with satu-
rated aqueous NH4Cl and extracted with EtOAc. The organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane/EtOAc; 3:1 to
EtOAc) to give alcohol (6.27 g, 93%). Pd(OH)2/C (5%, 33.3 mg) was
added to a solution of alcohol (665 mg 1.02 mmol) in methanol (15 mL),
and the mixture was vigorously stirred under an H2 atmosphere (balloon)
at room temperature for 3 h. The reaction mixture was filtered through a
pad of Celite, and the filtrates were concentrated in vacuo to give amine
(538 mg). HgCl2 (331 mg, 1.22 mmol), Et3N (425 mL, 3.05 mmol), and 1,3-
hydroxylamine 9 (10.7 g, 83%). Spectral data for isoxazolidine 9: [a]D16
=
+4.5 (c=2.9 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.35 (m, 5H),
7.19 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 5.20 (d, J=12.4 Hz,
1H), 5.15 (d, J=12.4 Hz, 1H), 4.90 (dd, J=4.6, 5.0 Hz, 1H), 4.44 (d, J=
11.0 Hz, 1H), 4.40 (d, J=11.0 Hz, 1H), 4.34 (m, 1H), 4.12 (dt, J=3.2,
6.0 Hz, 1H), 3.97 (dd, J=2.8, 3.2 Hz, 1H), 3.83 (dd, J=5.5, 11.0 Hz, 1H),
3.77 (s, 3H), 3.63 (dd, J=3.2, 11.0 Hz, 1H), 3.40 (ddd, J=6.0, 12.6,
9.6 Hz, 1H), 3.16 (ddd, J=4.1, 6.9, 12.6 Hz, 1H) 2.02 (m, 1H), 1.75 (m,
1H), 1.01 ppm (m, 21H); 13C NMR (100 MHz, CDCl3): d=159.5, 156.0,
136.0, 129.8, 128.5, 128.2, 113.9, 77.4, 76.3, 75.2, 73.9, 67.8, 67.1, 66.7, 55.2,
33.9, 17.9, 17.8, 11.9 ppm; HRMS (ESI): m/z calcd for C32H48N2O7SiNa:
623.3129 [M+Na+]; found: 623.3137.
bisACTHNUTRGNE(NUG Cbz)-2-methyl-2-thiopseudourea (17) (437 mg, 1.22 mmol) were
added to a solution of amine (538 mg) in DMF (10 mL) at room temper-
ature for 2 h. The reaction mixture was diluted with EtOAc, and the re-
sulting solution was filtered through a pad of Celite. The filtrates were
washed with H2O and brine twice, and the organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified by
column chromatography on Chromatorex NH (hexane/EtOAc=3:2 to
1:2) to give bis(guanidine) 13 (718.2 mg, 85%, two steps). Spectral data
for bis(guanidine) 13: [a]2D1 = +122.8 (c=0.46 in MeOH); 1H NMR
(400 MHz, CDCl3): d=11.59 (s, 1H), 8.97 (d, J=6.41 Hz, 1H), 7.35 (m,
10H), 7.22 (d, J=8.42 Hz, 2H), 6.82 (d, J=8.42 Hz, 2H), 5.48 (brs, 1H),
5.16 (dd, J=11.91, 17.40 Hz, 2H), 5.13 (dd, J=12.36, 45.34 Hz, 2H), 4.62
(m, 1H), 4.51 (t, J=5.50, 1H), 4.39 (dd, J=11.45, 27.93 Hz, 2H), 3.90
(dd, J=7.33, 19.00 Hz, 1H), 3.77 (dd, J=4.12, 9.62 Hz, 1H), 3.73 (s, 3H),
3.68 (m, 1H), 3.47 (dd, J=8.24, 9.62 Hz, 1H), 3.17 (dd, J=4.12, 7.79 Hz,
1H), 3.09 (m, 1H), 2.01 (m, 1H), 1.67 (m, 1H), 1.53 (s, 9H), 1.49 ppm (s,
9H); 13C NMR (100 MHz, CDCl3): d=162.73, 159.61, 155.96, 153.58,
136.42, 134.40, 130.17, 129.56, 129.09, 128.83, 128.67, 128.18, 127.87,
113.93, 83.86, 78.85, 74.93, 73.33, 69.34, 68.79, 68.69, 67.43, 55.36, 54.95,
45.17, 30.13, 28.53, 28.06 ppm; HRMS (ESI): m/z calcd for C43H55N6O11:
831.3928 [M+H+]; found: 831.3896.
Guanidine 11: TiCl3/HCl (20% aq, 14.0 mL, 21.5 mmol; Kanto Chemical)
was added to a solution of N-Cbz hydroxylamine 9 (10.7 g, 17.9 mmol),
NaOAc (4.40 g, 53.7 mmol), and freshly activated Zn powder (3.51 g,
53.7 mmol) in CH2Cl2/MeOH (2:1, 100 mL) at À508C under Ar atmos-
phere. After stirring for 24 h, the reaction was neutralized by an excess
amount of Na2CO3 solid at À508C. Then the dark-green suspension was
warmed to room temperature and vigorously stirred under O2 atmos-
phere for 30 min. The light-gray suspension was extracted with EtOAc,
and the extracts were washed with water and brine. The organic layer
was dried over MgSO4, filtered, and concentrated in vacuo to give dia-
mine 10 (10.8 g). HgCl2 (4.37 mg, 16.1 mmol) was added to a solution of
crude diamine 10 (10.3 g), bisACTHUNRTGNEUNG(Boc)-2-methyl-2-thiopseudourea (16)
(4.68 g, 16.1 mmol), and Et3N (7.48 mL, 53.7 mmol) in DMF (40 mL) at
room temperature under Ar atmosphere. After stirring for 1 h, the reac-
tion mixture was diluted with EtOAc (150 mL) and filtered through a
pad of Celite. The filtrates were washed with H2O and brine. The organic
layer was dried over MgSO4, filtered, and concentrated in vacuo. The res-
idue was purified by column chromatography on silica gel (hexane/
EtOAc=15:1 to 6:1) to give guanidine 11 (12.1 g, 82%, two steps). Spec-
tral data for guanidine 11: [a]1D7 = +0.6 (c=2.6 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=10.31 (s, 1H), 7.33 (m, 5H), 7.21 (d, J=8.6 Hz,
2H), 6.83 (d, J=8.6 Hz, 2H), 5.69 (br, 1H), 5.44 (d, J=9.7 Hz, 1H), 5.09
(d, J=12.0 Hz, 1H), 5.04 (d, J=12.0 Hz, 1H), 4.47 (d, J=2.9 Hz, 1H),
4.42 (d, J=12.0 Hz, 1H), 4.39 (d, J=9.7 Hz, 1H), 4.33 (d, J=12.0 Hz,
Mono-Cbz-guanidine 14: NaOMe (9.0 mg, 0.167 mmol) was added to a
solution of bis(guanidine) 13 (139 mg, 0.167 mmol) in THF/MeOH (1:1,
4 mL) at 08C under an N2 atmosphere, and the mixture was stirred for
5 h. Saturated aqueous NH4Cl was added to the reaction mixture, and or-
ganic layer was extracted with EtOAc. The extracts were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on Chromatorex NH (hexane/
Chem. Eur. J. 2011, 17, 12144 – 12152
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12149