RESEARCH FRONT
Synthesis and Structure Reassessment of Psammopemmin A
865
4
-Amino-2-bromo-5-iodopyrimidine 10
filtrate was then concentrated onto neutral alumina and chro-
matographed (eluting in hexanes). Any brown impurities were
removed by further purification via MPLC (silica; eluting at
-Amino-2-chloro-5-iodopyrimidine[7] (9, 0.73 g, 2.86 mmol)
4
in 33% HBr:AcOH was stirred for 1 h then refluxed for an
additional hour. The mixture was subsequently cooled to room
temperature and the solvent removed under vacuum. Water was
then added to the concentrate, the solid collected via filtration,
and dried under vacuum affording 10 (0.74 g, 2.46 mmol, 86%
5
% EtOAc:Hex) to afford 14 (2.69 g, 5.59 mmol, 78% yield) as
◦
a white crystalline solid, mp = 107–109 C. δH (CDCl3) 0.35
(s, 6H, Si(CH3)2), 1.08 (s, 9H, SiC(CH3)3), 1.14 (d, 18H,
SiCH(CH3)2), 1.65 (sept, 3H, SiH), 6.52 (d, J 7.7 Hz, H5), 6.98
(dd, J 7.7, 8.1 Hz, H6), 7.07 (d, J 8.1 Hz, H7), 7.10 (s, H2). δC
◦
−1
yield), mp = 189–190 C. νmax(neat)/cm 3330, 3168, 3009,
(
1
CDCl3) −3.7 (2C), 13.0 (3C), 18.2 (6C), 18.7, 26.2 (3C), 90.6,
1
633, 1549. δH (CDCl3) 5.78 (brs, 2H, NH2), 8.31 (s, H6). δC
07.7, 109.1, 121.0, 122.8, 129.7, 142.7, 149.5. m/z 482.1905,
(
CDCl3) 75.4, 152.1, 162.8, 163.9. m/z 299.8626, HRMS calc.
+
23 41 2
HRMS calc. for [C H BrNOSi ] 482.1905.
+
for [C4H4BrIN3] 299.8629.
4-Indolol 12
2
-Bromo-5-(4-(tert-butyldimethylsilyloxy)-1-
A stirred mixture of 1,5,6,7-tetrahydro-4H-indol-4-one (2.50 g,
(triisopropylsilyl)-1H-indol-3-yl)pyrimidin-4-amine 17
1
8.4 mmol) and 10% Pd/C (625 mg) in 2,6-dimethyl-4-
To a stirred solution of 14 (470 mg, 0.98 mmol) in dry THF
◦
◦
heptanone (25 mL) was refluxed (190 C) under N2 for 48 h.
The mixture was then cooled to room temperature and filtered
through Celite.The filter cake was washed with DCM and the fil-
trate concentrated under vacuum. Kugel-rohr distillation of the
(5 mL) at −78 C under N2 was added tert-butyllithium (1.6 M
in pentane) dropwise until the solution remained yellow. A
further aliquot (1.3 mL, 2.15 mmol) was then added dropwise
and the solution stirred for 15 min. Neat 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (15, 364 mg, 1.96 mmol,
◦
concentrateaffordeddiscoloured4-indolol(150 C, 4torr)which
was subjected to MPLC (silica; eluting at 30–35% EtOAc:Hex)
to yield 12 (1.19 g, 9.0 mmol, 49% yield) as a white crystalline
solid. δH (d6-DMSO, not stable in CDCl3) 6.31 (d, J 6.1 Hz, H3),
0
.4 mL) was then added dropwise. The resultant mixture was
◦
stirred for 1 h at −78 C and was subsequently quenched with
sat. NH4Cl. The mixture was warmed to room temperature and
was partitioned between Et2O:sat. NH4Cl. The aqueous layer
was extracted 2× with EtO2 and the combined organic layers
were dried (anhyd. MgSO4) and concentrated to afford a crude
borate ester 16 which was used immediately in the next reaction
without further purification.
6
9
1
.43 (m, H5), 6.81 (m, H6), 6.82 (m, H7), 7.10 (d, J 2.4 Hz, H2),
.21 (s, OH), 10.86 (brs, NH), δC (d6-DMSO) 98.5, 102.8 (2C),
17.8, 121.8, 122.9, 137.9, 150.5. m/z 134.0600, HRMS calc.
+
for [C8H8NO] 134.0600.
A stirred mixture of crude 16 (0.98 mmol), tetrakis(triphenyl-
phosphine)palladium (104 mg, 0.09 mmol), and 4-amino-2-
bromo-5-iodopyrimidine (10, 283 mg, 0.98 mmol), benzene
4
-(tert-Butyldimethylsilyloxy)-1H-indole 13
A mixture of 4-indolol (12, 1.05 g, 7.89 mmol), tert-
butyldimethylsilyl chloride (1.43 g, 9.47 mmol), and imidazole
(25 mL, degassed by sparging with N2), methanol (5 mL,
(
1.74 g, 25.3 mmol) was stirred in 25 mL of dry DMF at room
temperature under N2 for 1 h. The mixture was partitioned
EtOAc:water). The organic layer was washed with water then
degassed), and aqueous sodium carbonate (1.25 mL, 2 M,
degassed) was refluxed under N2 for 24 h. The mixture was
allowed to cool to room temperature, diluted with EtOAc
and dried (anhyd. MgSO4). The filtrate then was concen-
trated onto silica and purified via MPLC (silica, eluting at
18% EtOAc:hexane) to afford 17 (252 mg, 0.44 mmol, 45%
(
dried (anhyd. MgSO4), filtered, and concentrated under reduced
pressure onto silica. Purification using MPLC (silica; eluting at
1
8%EtOAC:hexane)afforded 13(1.76 g, 7.14 mmol, 91%yield)
◦
−1
as a white solid, mp = 79–80 C. νmax(neat)/cm 3399, 3056,
◦
−1
yield), mp = 131–133 C. νmax(neat)/cm 3351, 3130, 2951. δH
2
6
7
7
2
961, 2928, 1583. δH (d6-DMSO, not stable in CDCl3) 0.19 (s,
H, Si(CH3)2), 1.02 (s, 9H, SiC(CH3)3), 6.35 (m, H3), 6.41 (d, J
.5 Hz, H5), 6.93 (dd, J 7.5, 8.0 Hz, H6), 7.02 (d, J 8.0 Hz, H7),
.21 (s, H2), 11.0 (brs, NH). δC (d6-DMSO) −4.4 (2C), 18.0,
(
CDCl3) 0.09 (s, 6H, Si(CH3)2), 0.83 (s, 9H, SiC(CH3)3), 1.16
d, 18H, SCH(CH3)2), 1.69 (sept, 3H, SiCH), 5.25 (brs, 2H,
(
NH2), 6.54 (d, J 7.1 Hz, H5), 7.04 (dd, J 7.9, 8.1 Hz, H6), 7.07
ꢀ
(
s, H2), 7.15 (d, J 8.1 Hz, H7), 7.95 (s, H6 ). δC (CDCl3) −4.1
5.7 (3C), 98.3, 105.4, 107.6, 121.2, 121.5, 123.8, 137.9, 148.1.
+
(2C), 13.0 (3C), 18.3 (6C), 18.4, 25.8 (3C), 107.9, 109.0, 109.3,
m/z 248.1468, HRMS calc. for [C14H22NOSi] 248.1465.
1
14.1, 121.7, 123.2, 130.3, 143.9, 149.6, 150.3, 156.2, 163.9.
+
m/z 575.2248, HRMS calc. for [C27H44N4OSi2] 575.2232.
3
1
-Bromo-4-(tert-butyldimethylsilyloxy)-1-(triisopropylsilyl)-
H-indole 14
Psammopemmin A 18
To 13 (1.77 g, 7.14 mmol) in 35 mL dry THF under stirring
and N2 was added dropwise n-butyllithium (1.36 mL, 1.6 M in
To 17 (50 mg, 0.087 mmol) in 1.0 mL acetonitrile (dried over 4 Å
molecular sieves) and 0.1 mL pyridine (dried over 4 Å molecu-
lar sieves) was added 50 μL hydrogen fluoride pyridine (70% as
HF, 30% as pyridine). After 30 min the starting material had
completely dissolved and after 1 h a precipitate had formed.
The mixture was stirred for a further 11 h at room tempera-
ture. The precipitate was collected via filtration and washed
with acetonitrile. Drying the precipitate under high vacuum
resulted in 18 (15 mg, 0.049 mmol, 56%) as a tan powder.
◦
hexanes, 0.85 mL) at −78 C. The mixture was then warmed
◦
to −10 C and stirred for 10 min before being cooled again to
◦
−
78 C. Triisopropylsilyl chloride (1.93 g, 10.0 mmol, 2.14 mL)
was added dropwise and the mixture then warmed to 0 C and
stirred until reaction was complete (via TLC). The mixture
◦
◦
was then cooled to −78 C and N-bromosuccinimide (1.72 g,
9
.64 mmol) dissolved in dry THF (10 mL) was added to the
◦
cooled mixture. After stirring for 2 h at −78 C, the mixture
was warmed to room temperature, diluted with 1% pyridine
in hexane, and filtered through Celite. Any 3-bromo-4-(tert-
butyldimethylsilyloxy)-1H-indole in the mixture will lead to
decomposition of the desired product upon concentration. The
−
1
νmax(neat)/cm 3429, 3313, 3163, 3015. δH (d6-DMSO) 6.38
(d, J 7.1 Hz, H5), 6.88 (d, J 8.3 Hz, H7), 6.93 (dd, J 8.3, 7.1 Hz,
ꢀ
H6), 7.27 (s, H2), 7.79 (s, H6 ), 9.30 (s, OH), 11.29 (brs, NH).
δC (d6-DMSO) 103.2, 103.8, 105.6, 113.0, 115.4, 122.6, 123.6,