Synthesis of D- and L-myo-Inositol 1,4,6-Trisphosphate
J . Org. Chem., Vol. 61, No. 25, 1996 8985
(100 mL). The organic layer was dried over magnesium sulfate
and filtered and the solvent evaporated. The remaining syrup
was purified by flash chromatography to give the title com-
The solution was cooled to -78 °C and tert-butyl hydroperoxide
(1 mL, 7 mmol) was added and the mixture was stirred for 30
min. The reaction mixture was partitioned between dichlo-
romethane and a 10% solution of sodium metabisulfite (100
mL), and the organic layer was washed with brine and water
(100 mL of each) and dried over magnesium sulfate. The
remaining syrup was purified by flash chromatography (chlo-
roform-acetone, 10:1), then ethyl acetate-pentane (2:1), to
give 14a b as a syrup (0.465 g, 85%): TLC, Rf ) 0.30
(chloroform-acetone, 10:1); 1H NMR (400 MHz, CDCl3) 3.41
(dd, J ) 2.0, 9.8 Hz, 1H), 3.56 (t, J ) 9.2 Hz, 1H), 4.21 (dt, J
) 2.0, 9.5 Hz, 1H), 4.42 (br s, 1H), 4.44-5.09 (m, 18H), 6.98-
7.41 (m, 45H); 13C NMR (100 MHz, CDCl3) 68.89, 69.21,
69.41, 69.77, 72.10, 73.53, 75.02, 74.57, 76.32, 77.49, 78.04,
78.78, 79.53, 127.05, 127.47, 127.66, 127.89, 127.96, 128.05,
128.18, 128.47, 128.57, 135.51, 135.77, 135.90, 137.10, 137.85,
137.98 ppm; 31P NMR (162 MHz, CDCl3) -1.56, -1.86, -1.99
ppm; MS (FAB+, NBA) m/z (relative intensity) 1231 (M + H,
1
pound 11a b (2.20 g, 85%): mp 53-54 °C (from hexane); H
NMR (270 MHz, CDCl3) 3.22 (dd, J ) 2.2, 9.7 Hz, 1H), 3.29
(dd, J ) 2.2, 9.9 Hz, 1H), 3.38 (t, J ) 9.3 Hz, 1H), 3.77 (s, 3H),
3.92 (t, J ) 9.5 Hz, 1H), 3.97 (t, J ) 9.5 Hz, 1H), 3.99 (t, J )
2.2 Hz, 1H), 4.08-4.10 (m, 2H), 4.27-4.43 (m, 2H), 4.57-4.85
(m, 8H), 5.11-5.34 (m, 4H), 5.84-6.04 (m, 2H), 6.83 (d, J )
8.6 Hz, 2H), 7.22-7.42 (m, 17H); 13C NMR (68 MHz, CDCl3)
55.20, 71.58, 72.82, 73.95, 74.53, 75.44, 75.83, 74.27, 80.60,
80.73, 81.25, 81.38, 83.58, 113.68, 116.57, 127.24, 127.44,
127.50, 127.73, 127.83, 128.05, 128.28, 129.74, 131.07, 134.89,
135.38, 138.49, 138.91, 159.09 ppm; MS (FAB-, NBA) m/z
(relative intensity) 803 (M + NBA, 100), 696 (35), 665 (55),
559 (25), 485 (40), 440 (35), 318 (68), 287 (60), 178 (30), 124
(25). Anal. Calcd for C41H46O7: C, 75.65; H, 7.13. Found: C,
75.9; H, 7.19.
DL-2,3,5-Tr i-O-ben zyl-6-O-(p-m eth oxyben zyl)-1,4-d i-O-
cis-p r op -1-en yl-m yo-in ositol (12). A mixture of DL-1,4-di-
O-allyl-2,3,5-tri-O-benzyl-6-O-(p-methoxybenzyl)-myo-inosi-
tol (11a b) (1.5 g, 2.3 mmol) and freshly sublimed potassium
tert-butoxide (3.66 g, 30 mmol) in dry DMSO (20 mL) was kept
at 50 °C for 5 h under an atmosphere of nitrogen. TLC (ether-
hexane, 1:1) showed conversion of stating material (Rf ) 0.50)
into a single product (Rf ) 0.72). The dark mixture was cooled,
a saturated solution of potassium chloride (50 mL) was added,
and the product was extracted with ether (4 × 50 mL). The
organic layer was dried over magnesium sulfate and evapo-
rated to give a solid. The crude product was purified by flash
chromatography (ether-hexane, 1:2) to give the title compound
80), 1141 (80), 1051 (30), 91 (100). Anal. Calcd for C69H69
O15P3: C, 67.31; H, 5.65. Found: C, 67.6; H, 5.60.
-
DL-m yo-In ositol 1,4,6-Tr isp h osp h a te (4a b). Ammonia
was condensed into a three-neck flask at -78 °C. Small slivers
of freshly cut sodium were added to the liquid ammonia until
the color remained blue. The ammonia was then distilled into
a second flask and kept at -78 °C. Sodium was then added
once again until the solution remained blue. DL-2,3,5-Tri-O-
benzyl-1,4,6-tris[bis(benzyloxy)phospho]-myo-inositol (14a b)
(0.1 g, 81.3 mol), in dry dioxane (1 mL), was then added to
the sodium in liquid ammonia. The solution was stirred
vigorously for 2 min during which time the sodium in liquid
ammonia remained blue. The reaction was quenched with
methanol, and the solvents were evaporated under a stream
of nitrogen. The residue was dissolved in MilliQ water (250
mL) and purified by ion exchange chromatography on Q-
Sepharose Fast Flow, eluting with a gradient of TEAB buffer
(0-1000 mmol) at pH 8.6. The triethylammonium salt of 4a b
eluted at ca. 600 mmol buffer (48.8 mol, 60%): 1H NMR (270
MHz, D2O) 3.61 (t, J ) 9.2 Hz, 1H), 3.72 (dd, J ) 2.4, 9.7
Hz, 1H), 4.07 (t, J ) 9.5 Hz, 1H), 4.20 (br s, 1H), 4.21 (q, J )
9.3 Hz, 1H), 4.33 (q, J ) 9.3 Hz, 1H); 31P NMR (109 MHz,
D2O) 1.01 (d, J ) 9.8 Hz, 1P), 1.44 (d, J ) 9.8 Hz, 1P), 2.02
(d, J ) 9.8 Hz, 1P); MS (FAB-, NBA) m/z (relative intensity)
419 (M - H), (70), 354 (25), 291 (45), 266 (30), 201 (100), 188
(30), 113 (45); HRMS (FAB-, NBA) calcd for C6H14O15P3 (M -
H+) m/z 418.9545, found 418.9534.
1
12 (1.2 g, 80%): mp 89-91 °C (from hexane); H NMR (270
MHz, CDCl3) 1.64 (dd, J ) 1.65, 6.6 Hz, 3H), 1.67 (dd, J )
1.5, 6.4 Hz, 3H), 3.33 (dd, J ) 2.4, 9.7 Hz, 1H), 3.42 (t, J ) 9.3
Hz, 1H), 3.51 (dd, J ) 2.2, 9.9 Hz, 1H), 3.76 (s, 3H), 4.02 (t, J
) 2.2 Hz, 1H), 4.03 (t, J ) 9.9 Hz, 1H), 4.17 (t, J ) 9.3 Hz,
1H), 4.36 (dq, J ) 6.8 Hz, 1H), 4.44 (dq, J ) 6.8 Hz, 1H), 4.53-
4.83 (m, 8H), 6.08 (dd, J ) 1.65, 6.2 Hz, 1H), 6.26 (dd, J )
1.65, 6.4 Hz, 1H), 6.83 (d, J ) 8.6 Hz, 2H), 7.23-7.41 (m, 17H);
13C NMR (68 MHz, CDCl3) 9.27, 9.36, 55.16, 72.57, 74.45,
75.25, 75.69, 75.91, 78.75, 80.34, 82.53, 82.95, 84.36, 98.10,
100.50, 113.67, 127.34, 127.55, 127.78, 128.07, 128.17, 128.21,
128.26, 129.89, 130.81, 138.27, 138.58, 145.70, 147.68, 159.09
ppm; MS (FAB-, NBA) m/z (relative intensity) 803 (M + NBA,
100), 696 (35), 665 (25), 559 (20), 485 (30), 322 (35), 273 (30),
118 (24). Anal. Calcd for C41H46O7: C, 75.65; H, 7.13.
Found: C, 75.6; H, 7.18.
DL-1,4-Di-O-a llyl-5-O-ben zyl-2,3-O-isop r op ylid en e-6-O-
(p-m eth oxyben zyl)-m yo-in ositol (15). A mixture of DL-1,4-
di-O-allyl-2,3-O-isopropylidene-6-O-(p-methoxybenzyl)-myo-
inositol (9) and sodium hydride (1.2 g, 50 mmol) was stirred
in dry DMF (150 mL) at room temperature. Benzyl bromide
(2.37 mL, 20 mmol) was added dropwise and the reaction was
then stirred for 2 h, after which TLC (ether-hexane, 1:1)
showed a product of Rf ) 0.44. The excess sodium hydride
was destroyed with methanol (10 mL), and the solvents were
evaporated in vacuo. The residue was partitioned between
ether (300 mL) and water (200 mL), and the organic layer was
washed with brine and water (200 mL each). The organic layer
was dried over magnesium sulfate, and the solvent was
evaporated. Flash chromatography (ether-hexane, 1:1) of the
crude product provided the title compound 15 as a syrup (7.1
g, 93%): 1H NMR (270 MHz, CDCl3) 1.38, 1.55 (2s, 6H), 3.36
(t, J ) 9.2 Hz, 1H), 3.61 (dd, J ) 3.8, 9.0 Hz, 1H), 3.67 (dd, J
) 7.0, 9.5 Hz, 1H), 3.79 (s, 3H), 3.86 (t, J ) 8.8 Hz, 1H), 4.08
(dd, J ) 5.7, 6.8 Hz, 1H), 4.20-4.37 (m, 4H), 4.38 (dd, J )
3.85, 5.5 Hz, 1H), 4.68-4.83 (m, 4H), 5.15-5.34 (m, 4H), 5.88-
DL-1,2,5-Tr i-O-ben zyl-m yo-in ositol (13a b). DL-2,3,5-Tri-
O-benzyl-6-O-(p-methoxybenzyl)-1,4-di-O-cis-prop-1-enyl-myo-
inositol (12) (0.95 g, 1.46 mmol) was suspended in ethanol-1
M HCl (60 mL, 2:1). The mixture was heated at reflux
temperature for 4 h, after which TLC (ether) showed a product
of Rf ) 0.30. The solvents were evaporated and the solid was
partitioned between water and dichloromethane (100 mL each)
and washed with sodium hydrogen carbonate (100 mL) and
water (100 mL). The organic layer was then dried over
magnesium sulfate and then evaporated. The title compound
13ab was purified by flash chromatography (dichloromethane-
ethyl acetate, 1:1) (0.55 g, 84%): mp 161-162 °C (from ethyl
acetate-hexane); 1H NMR (270 MHz, CDCl3) 1.65-2.65 (br
s, D2O ex, 3H), 3.23 (t, J ) 9.2 Hz, 1H), 3.30 (dd, J ) 2.4, 9.7
Hz, 1H), 3.40 (dd, J ) 2.75, 9.7 Hz, 1H), 3.82 (t, J ) 9.5 Hz,
1H), 4.06 (t, J ) 2.6 Hz, 1H), 4.12 (t, J ) 9.5 Hz, 1H), 4.58-
4.98 (m, 6H), 7.25-7.40 (m, 15H); 13C NMR (68 MHz, CDCl3)
71.51, 74.01, 72.16, 72.42, 72.84, 78.42, 80.43, 84.29, 127.04,
127.14, 127.33, 127.56, 127.98, 128.08, 128.21, 139.20, 139.79,
139.92 ppm; MS (FAB-, NBA) m/z (relative intensity) 603 (M
+ NBA, 100), 379 (M - H, 85), 359 (20), 335 (10), 303 (20),
151 (20), 109 (5). Anal. Calcd for C27H30O6: C, 71.96; H, 6.49.
Found: C, 71.9; H, 6.71.
6.02 (m, 2H), 6.85 (d, J ) 8.8 Hz, 2H), 7.25-7.37 (m, 7H); 13
C
NMR (68 MHz, CDCl3) 25.82, 27.75, 55.25, 72.51, 72.93,
74.91, 75.91, 74.60, 77.08, 77.55, 79.08, 80.52, 82.26, 109.84,
113.80, 116.80, 117.50, 127.58, 128.02, 128.31, 129.68, 130.83,
134.99, 135.21, 138.69, 159.12 ppm; MS (FAB+, NBA) m/z
(relative intensity) 419 (1.2), 389 (3.3), 121 (100), 91 (45). Anal.
Calcd for C30H38O7: C, 70.55; H, 7.51. Found: C, 70.4; H, 7.64.
DL-2,3,5-Tr i-O-ben zyl-1,4,6-tr is[bis(ben zyloxy)ph osph o]-
m yo-in ositol (14a b). A mixture of bis(benzyloxy)(diisopro-
pylamino)phosphine23 (0.69 g, 2 mmol) and 1H-tetrazole (0.21
g, 3 mmol) in dry dichloromethane was stirred for 15 min. DL-
1,2,5-Tri-O-benzyl-myo-inositol (13a b) (0.2 g, 0.44 mmol) was
then added and the reaction was stirred for a further 15 min.
DL-1,4-Di-O-a llyl-5-O-b en zyl-6-O-(p -m et h oxyb en zyl)-
m yo-in ositol (16a b). DL-1,4-Di-O-allyl-5-O-benzyl-2,3-O-iso-
propylidene-6-O-(p-methoxybenzyl)-myo-inositol (15) (6.54 g,