Synthesis of (+)-Dibromophakellin and (+)-Dibromophakellstatin
1H and 13C NMR spectra were recorded on JEOL JNM-ECA 500, JNM-
ECX 400, or JMTC 300 spectrometers. The spectra were referenced in-
ternally according to residual solvent signals of CDCl3 (1H NMR; d=
7.26 ppm, 13C NMR; d=77.0 ppm), [D6]DMSO (1H NMR; d=2.54 ppm,
(+)-Phakellstatin 5: To a solution of cyclic urea 41 (87 mg, 0.24 mmol) in
MeOH (5 mL) was added a catalytic amount of Pd/C. The suspension
was vigorously stirred for 2 h under a H2 atmosphere (balloon) at room
temperature, after which it was filtered through a pad of Celite. The fil-
trates were concentrated in vacuo, and the residue was purified by
column chromatography on silica gel (ethyl acetate/MeOH=19:1) to
give (+)-phakellstatin (5) (49 mg, 89%). [a]D18 =+104.7 (c 0.3, DMF);
1H NMR (125 MHz, [D6]DMSO) d=8.11 (br s, 1H), 7.77 (br s, 1H), 7.13
(m, 1H), 6.65 (dd, J=4.0, 1.7 Hz, 1H), 6.27 (dd, J=4.0, 2.9 Hz, 1H), 5.75
(s, 1H), 3.52 (m, 1H), 3.43 (m, 1H), 2.23 (m, 1H), 2.10 (m, 2H),
1.97 ppm (m, 1H); 13C NMR (500 MHz, [D6]DMSO) d=160.1, 157.2,
124.3, 123.3, 112.8, 112.2, 80.0, 68.9, 45.6, 39.8, 20.6 ppm; HRMS (ESI,
M+Na+) calcd for C11H12N4NaO2 255.08579, found 255.08323.
13C NMR;
d
=40.45 ppm) and CD3OD (1H NMR; d=3.30 ppm,
13C NMR; d=49.0 ppm). Data for 1H NMR were recorded as follows:
chemical shift (d, ppm), multiplicity (s singlet, d doublet, t triplet, m mul-
tiplet, br broad), integration, coupling constant (Hz). Data for 13C NMR
are reported in terms of chemical shift (d, ppm). Mass spectra were re-
corded on JEOL JMS-T100X spectrometer with ESI-MS mode using
methanol as solvent.
Thiopseudourea 35: Benzyloxycarbonyl isothiocyanate (34; 330 mg,
1.71 mmol) was added to a solution of amine 27 (365 mg, 1.14 mmol) in
CH2Cl2 (20 mL) at 08C under an argon atmosphere. After stirring for
1.5 h at room temperature, the reaction mixture was concentrated in
vacuo. The crude product was recrystallized from CH2Cl2 and hexane to
give the isothiocyanate (546 mg, 93%). Methyliodide (108 mL,
1.74 mmol) and potassium carbonate (482 mg, 3.48 mmol) were added to
a solution of thiourea (449 mg, 0.87 mmol) in THF (10 mL) at room tem-
perature. The reaction mixture was stirred for 3 h at 508C, quenched
with H2O, and extracted with ethyl acetate. The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (hexane/ethyl acetate=1:1) to
give thiopseudourea 35 (450 mg, 98%). [a]D20 =+37.3 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3) d=10.54 (br s, 1H), 7.33 (m, 5H), 6.92 (dd,
J=3.8, 1.7 Hz, 1H), 6.88 (dd, J=2.4, 1.7 Hz, 1H), 6.22 (dd, J=3.8,
2.4 Hz, 1H), 5.54 (s, 1H), 5.10 (d, J=12.4 Hz, 1H), 5.05 (d, J=12.4 Hz,
1H), 4.05 (m, 1H), 3.64 (m, 1H), 2.37 (m, 1H), 2.29 (s, 1H), 2.12 (m,
3H), 1.09 (s, 9H), 0.28 ppm (d, J=7.6 Hz, 6H) ; 13C NMR (75 MHz,
CDCl3) d=161.5, 157.3, 136.8, 128.5, 128.2, 127.8, 123.1, 120.8, 115.1,
110.5, 84.0, 80.2, 77.4, 77.0, 76.6, 67.1, 47.0, 39.2, 25.5, 21.7, 18.0, 14.2,
À4.1, À4.4 ppm; HRMS (ESI, M+Na+) calcd for C26H36N4NaO4SSi
551.21242, found 551.21181.
(+)-Dibromophakellstatin 6: NBS (15.3 mg, 0.086 mmol) was added to a
stirred solution of (+)-phakellin (5) (10 mg, 0.043 mmol) in CH3CN
(1 mL) at room temperature. After 3 h at 408C, the reaction mixture was
concentrated in vacuo. The residue was purified by column chromatogra-
phy on silica gel (CH2Cl2/MeOH=19:1) to give (+)-dibromophakellsta-
tin (6) (15.3 mg, 91%). [a]D17 =+85.1 (c 0.55, MeOH); 1H NMR
(500 MHz, [D6]DMSO) d=8.29 (br s, 1H), 7.98 (br s, 1H), 6.91 (s, 1H),
5.75 (d, J=2.3 Hz, 1H), 3.55 (m, 1H), 3.42 (m, 1H), 2.29 (m, 1H), 2.10
(m, 2H), 1.98 ppm (m, 1H); 13C NMR (125 MHz, [D6]DMSO) d=158.9,
155.1, 126.4, 114.8, 106.6, 102.1, 80.0, 69.6, 45.1, 39.8, 19.8 ppm; HRMS
(ESI, M+Na+) calcd for C11H10Br2N4NaO2 410.90682, found 410.9029.
Acknowledgements
This work was financially supported by a Grant-in-Aid for Scientific Re-
search (B) from JSPS (No. 20310130). T.I. is grateful for financial support
from the JSPS Predoctoral Fellowships for Young Scientists. We are
grateful to Dr. Kei-ichi Noguchi (TUAT) for the X-ray crystallographic
measurements.
Thiopseudourea 40: TBAF (419 mg, 1.60 mmol) was added to a solution
of thiopseudourea 35 (424 mg, 0.80 mmol) and 4 ꢂ M.S. (802 mg) in
CH2Cl2/THF (1:1, 20 mL) at À408C under an argon atmosphere. After
stirring for 10 min at À408C, methanesulfonyl chloride (186 mL,
2.40 mmol) was added to the reaction mixture, which was stirred for a
further 1 h at À408C then allowed to stir at room temperature for
30 min, after which it was quenched with sat. NH4Cl aq., and extracted
with ethyl acetate. The organic layer was separated and washed with sat.
NaHCO3 aq. and brine. The organic layer was dried over MgSO4, fil-
tered, and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel that had been washed with Et3N
(hexane/ethyl acetate=2:1 to 1:2) to give cyclic thiopseudourea 40
(183 mg, 57%) and isourea 37 (34 mg, 11%). [a]D22 =À74.6 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3) d=7.43 (m, 5H), 6.90 (m, 2H),
6.23 (t, J=3.4, 1H), 6.18 (s, 1H), 5.41 (d, J=12.0, 1H), 5.33 (d, J=12.0,
1H), 3.93 (m, 1H), 3.80 (m, 1H), 2.35 (s, 3H), 2.11 ppm (m, 4H);
13C NMR (75 MHz, CDCl3) d=156.0, 150.6, 134.2, 129.1, 128.8, 128.7,
124.4, 122.4, 113.0, 111.9, 89.0, 72.2, 69.3, 44.5, 40.1, 20.3, 15.2 ppm;
HRMS (ESI, M+Na+) calcd for C20H20N4NaO3S 419.11538, found
419.11564.
[1] For phakellins, see: a) P. R. Burkholder, G. M. Sharma, Lloydia
1969, 32, 466–483; b) G. M. Sharma, P. R. Burkholder, J. Chem. Soc.
Poupat, E. Tran Huu Dau, P. Potier, M. Pusset, J. Pusset, P. Laboute,
Tetrahedron 1985, 41, 6019–6033; for phakellstatins, see; e) G. R.
Pettit, J. McNulty, D. L. Herald, D. L. Doubek, J. C. Chapuis, J. M.
[2] A. Al-Mourabit, P. Potier, Eur. J. Org. Chem. 2001, 237–243.
[3] For the original isolation of palau’amine and its related congener,
see: a) Sceptrin: R. P. Walker, D. J. Faulkner, D. Van Engen, J.
Keifer, R. E. Schwartz, M. E. S. Koker, R. G. Hughes, Jr., D. Ritt-
nellamine: S. Urban, P. deAlmeida Leone, A. R. Carroll, G. A. Fech-
731–735; d) Palau’amine: R. B. Kinnel, H. P. Gehrken, P. J. Scheuer,
mura, S. Matsunaga, M. Shibasaki, K. Suzuki, K. Furihata, R. W. M.
synthetic studies of palau’amine and/or its related congener, see:
f) S. G. Koenig, S. M. Miller, K. A. Leonard, R. S. Lçwe, B. C. Chen,
I. B. Seiple, I. S. Young, D. P. OꢃMalley, M. Maue, P. S. Baran,
Urea 41: m-CPBA (126 mg, 0.56 mmol) was added to a stirred solution
of cyclic thiopseudourea 40 (111 mg, 0.28 mmol) in CH2Cl2/sat. NaHCO3
aq. (2:1, 6 mL) at room temperature. After 1.5 h, the reaction mixture
was quenched with sat. Na2S2O3 aq. and extracted with ethyl acetate. The
combined organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by silica gel column chromatography
23
(hexane/ethyl acetate=1:3) to give cyclic urea 41 (87 mg, 85%). [a]D
=
À151.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d=7.41 (m, 5H),
7.00 (dd, J=2.8, 1.7 Hz, 1H), 6.96 (br s, 1H), 6.94 (dd, J=3.8, 1.7 Hz,
1H), 6.25 (dd, J=3.8, 2.8 Hz, 1H), 5.44 (d, J=12.0 Hz, 1H), 5.38 (d, J=
12.0 Hz, 1H), 2.21 ppm (m, 4H); 13C NMR (100 MHz, CDCl3) d=156.4,
152.0, 150.3, 134.7, 128.7, 128.6, 128.2, 123.5, 123.2, 114.2, 112.2, 76.5,
69.6, 69.0, 44.6, 39.8, 19.6 ppm; HRMS (ESI, M+Na+) calcd for
C19H18N4NaO4 389.12257, found 389.125851.
Chem. Asian J. 2010, 5, 1810 – 1816
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1815