Nucleic Acids Research, 2017, Vol. 45, No. 2 529
12.6, 5.1 Hz, 3H); 1.78–1.75 (m, 3H). 13C NMR (151 MHz,
CDCl3) ␦: 152.96, 146.07, 142.13, 139.65, 133.99, 132.59,
132.06, 128.73, 119.46, 117.48, 111.73, 96.09, 89.16, 89.11,
77.37, 77.16, 76.95, 67.74, 61.07, 55.04, 46.25, 46.16, 42.57,
37.11, 29.93, 16.02. IR (ATR, cm−1): 2908, 1605, 1491,
1437, 1368, 1331, 1302, 1231, 1143, 1105, 1066, 1021, 987,
914, 867, 812, 767, 748, 698. ESI-MS: [OC3]+ 1048 m/z.
[␣]D = −88◦ (c = 0.12, CHCl3, 589 nm, 25◦C).
plied Photophysics Chirascan plus qCD spectrometer with
samples being prepared in acetonitrile.
Morphine-C3 (MC3). Morphine (0.573 g, 2.01 mmol)
and potassium carbonate (1.110 g, 8.03 mmol) were sus-
pended in acetonitrile (ACN) (30 ml) and heated to reflux.
2,4,6-Tris-(bromomethyl)-mesitylene (0.268 g, 0.66 mmol)
was added in small aliquots to the reaction mixture and vig-
orously stirred overnight (18 h) under reflux conditions. Af-
ter allowing the reaction mixture to cool to room tempera-
ture (RT), the reaction solvent was removed by rotary evap-
oration and crude product dissolved in dichloromethane
(DCM) (50 ml). The organic layer was washed with d.H2O
(40 ml) and the aqueous layer extracted with DCM (3 × 20
ml). All organic layers were combined, then washed with
d.H2O (3 × 20 ml) and with a saturated brine solution
(20 ml). The organic layer was dried over magnesium sul-
phate, filtered and solvents removed by rotary evaporation.
The crude product was purified by column chromatogra-
phy (SiO2, 95:1:1 to 92:8:1 CH2Cl2:MeOH:NH4OH). The
title compound MC3 was isolated as a white solid in 50%
yield (0.338 g, 0.33 mmol). mp. 187–189◦C. 1H NMR (600
MHz, CDCl3) ␦: 6.80 (d, J = 8.2 Hz, 3H); 6.58 (d, J = 8.2
Hz, 3H); 5.69 (ddt, J = 9.9, 3.2, 1.4 Hz, 3H); 5.30–5.27
(m, 3H); 5.21 (d, J = 10.5 Hz, 3H); 5.05 (d, J = 10.4 Hz,
3H); 4.85 (dd, J = 6.5, 1.1 Hz, 3H); 4.17–4.13 (m, 3H); 3.35
(s, 3H); 3.05 (d, J = 18.7 Hz, 3H); 2.66 (s, 3H); 2.61–2.56
(m, 3H); 2.48 (s, 9H); 2.44 (s, 9H); 2.41 – 2.37 (m, 3H);
2.31 (dd, J = 18.7, 6.2 Hz, 3H); 2.05 (td, J = 12.4, 5.0
Hz, 3H); 1.88 (d, J = 11.3 Hz, 3H). 13C NMR (151 MHz,
CDCl3) ␦: 147.59, 141.43, 139.43, 133.41, 131.82, 131.44,
128.19, 119.61, 116.36, 91.27, 77.22, 77.00, 76.79, 67.32,
66.46, 58.93, 46.47, 43.09, 42.96, 40.81, 35.78, 20.64, 15.98.
IR (ATR, cm−1): 2907, 1632, 1602, 1492, 1443, 1247, 1200,
1157, 1118, 1099, 1034, 983, 940, 833, 784, 766, 731. ESI-
MS: [MC3] 1012 m/z. [␣]D = −85◦ (c = 0.154, CHCl3, 589
nm, 25◦C).
Heterocodeine (33,34). Reaction carried out on parallel
synthesizer. Potassium hydride (4.421 g, 110.23 mmol) was
prepared in the reaction vessel under nitrogen flux and
washed with dry hexane, suspended in dry tetrahydrofuran
(THF) (150 ml) over ice. A solution of morphine (2.862
g, 10.03 mmol) in THF (30 ml) was added slowly over
30 min to the reaction under a nitrogen atmosphere and
the resulting solution was allowed to stir at RT for 16 h.
Methyl iodide (1.710 g, 0.75 ml, 12.05 mmol) was added
to the reaction slowly over 15 min and reaction left stir-
ring for 4 h. The reaction was quenched slowly with a mix-
ture of THF/H2O (10:1) at 0◦C. The solution was neutral-
ized to pH 7.0 with 2 M HCl and volatiles were then re-
moved by rotary evaporation. The pH was adjusted to 8.0
by the addition of 1M NaOH and the aqueous layer ex-
tracted with chloroform/isopropanol (3:1, 3×25 ml). The
resulting organic layer was washed with H2O (4×30 ml) and
a final wash with saturated brine solution (20 ml). The or-
ganic layer was dried over magnesium sulphate, filtered and
solvents removed by rotary evaporation. The crude prod-
uct was purified by column chromatography (SiO2, 95:1:1
to 92:8:1 CH2Cl2:MeOH:NH4OH), heterocodeine was iso-
lated as a white solid in 25% yield (756 mg, 2.53 mmol). 1H
NMR (600 MHz, CDCl3) ␦: 6.57 (d, J = 8.1 Hz, 1H); 6.41
(d, J = 8.1 Hz, 1H); 5.64 (ddt, J = 9.9, 3.2, 1.5 Hz, 1H); 5.26
(dt, J = 9.8, 2.7 Hz, 2H); 4.91 (dd, J = 5.8, 1.3 Hz, 1H); 3.72
(td, J = 5.5, 2.3 Hz, 1H); 3.45 (s, 3H); 3.32 (dd, J = 6.3, 3.2
Hz, 1H); 2.97 (d, J = 18.6 Hz, 1H); 2.63 – 2.49 (m, 2H); 2.43
– 2.31 (m, 4H); 2.23 (dd, J = 18.7, 6.4 Hz, 1H); 1.99 (td, J
= 12.4, 5.1 Hz, 1H); 1.88–1.79 (m, 2H).
Oripavine-C3 (OC3). A flask was charged with oripavine
(0.595 g, 2.00 mmol), tetrabutylammonium hydroxide (40%
aqueous solution, 18 ml) and DCM (6 ml) and stirred under
nitrogen for 30 min. A solution of 2,4,6-tris-(bromomethyl)-
mesitylene (0.269 g, 0.66 mmol) in DCM (4 ml) was added
and the biphasic reaction mixture was stirred for 6 h at
RT. The reaction solution was transferred into d.H2O (150
ml) and washed with DCM (4 × 10 ml). Organic layers
were combined and washed with aqueous NaOH solution
(0.1 M, 2 × 20 ml) followed by d.H2O (3 × 20 ml) then
saturated brine solution (20 ml). The organic layer was
dried over magnesium sulphate, filtered and solvents re-
moved by rotary evaporation. The crude product was pu-
rified by column chromatography (SiO2, 95:1:1 to 92:8:1
CH2Cl2:MeOH:NH4OH). The title compound OC3 was
isolated as a golden yellow solid in 47% yield (0.329 g, 0.31
mmol). mp 174–176◦C. 1H NMR (600 MHz, CDCl3) ␦: 6.73
(d, J = 8.1 Hz, 3H); 6.58 (d, J = 8.1 Hz, 3H); 5.56 (d, J = 6.4
Hz, 3H); 5.28 (s, 3H); 5.25 (d, J = 10.7 Hz, 3H); 5.17 (d, J =
10.7 Hz, 3H); 5.03 (d, J = 6.4 Hz, 3H); 3.62 (d, J = 6.6 Hz,
3H); 3.59 (s, 9H); 3.32 (d, J = 18.0 Hz, 3H); 2.83 (td, J =
12.7, 3.3 Hz, 3H); 2.68 (dd, J = 18.1, 7.0 Hz, 3H); 2.63 (dd,
J = 12.7, 4.6 Hz, 3H); 2.47 (s, 9H); 2.46 (s, 9H); 2.20 (td, J =
Heterocodeine-C3 (HC3). A flask was charged with het-
erocodeine (0.700 g, 2.34 mmol), tetrabutylammonium hy-
droxide (40% aqueous solution, 20 ml) and DCM (8 ml) and
stirred under nitrogen for 30 min. A solution of 2,4,6-tris-
(bromomethyl)-mesitylene (0.269 g, 0.66 mmol) in DCM
(4 ml) was added and the mixture was stirred for 6 h at
RT. The reaction solution was transferred into d.H2O (150
ml) and washed with DCM (4 × 10 ml). Organic lay-
ers were combined and washed with aqueous NaOH so-
lution (0.1 M, 2 × 20 ml) followed by d.H2O (3 × 20
ml) then a saturated brine solution (20 ml). The organic
layer was dried over magnesium sulphate, filtered and sol-
vents removed by rotary evaporation. The crude product
was purified by column chromatography (SiO2, 95:1:1 to
92:8:1 CH2Cl2:MeOH:NH4OH), HC3 was isolated by col-
umn chromatography as a white solid in 13% yield (95 mg
0.09 mmol). mp. 164–166◦C. 1H NMR (400 MHz, CDCl3)
␦: 6.73 (d, J = 8.1 Hz, 3H); 6.49 (d, J = 8.1 Hz, 3H); 5.71
(d, J = 9.9 Hz, 3H); 5.32 (dt, J = 10.0, 2.7 Hz, 3H); 5.27–
5.16 (m, 6H); 5.00 (d, J = 5.1 Hz, 3H); 3.80 (dd, J = 5.4,
2.7 Hz, 3H); 3.51 (s, 9H); 3.36 (dd, J = 5.9, 3.1 Hz, 3H);