PAPER
6-O-Glycosylation of Morphine Derivatives Using Thioglycosides as Glycosyl Donors
1245
Table 3 13C NMR Data for Compounds 3a-h and 9
Product
13C NMR (400 MHz, CDCl3), d
C-1’
C-5
Others
3a
3b
118.9
99.0
169.9, 169.1, 168.5, 167.2, 149.9, 132.2, 131.5, 131.3, 130.1, 128.7, 121.7, 89.3, 73.2, 72.6, 71.9,
71.1, 69.2, 58.6, 52.7, 46.2, 43.4, 42.9, 40.9, 35.6, 20.8, 20.5, 20.4, 20.3
118.9
98.1
168.6, 167.8, 165.4, 165.0, 164.8, 151.2, 133.2, 133.05, 133.0, 131.9,131.6, 131.0, 130.3, 129.7,
129.6, 129.4, 128.9, 128.6, 128.2, 128.1, 121.8, 89.4, 72.6, 72.4, 71.7, 71.6, 69.2, 58.7, 58.6, 46.2,
43.4, 42.8, 40.8, 23.3, 20.9, 20.3
3c
3d
3e
3f
118.9
119.0
118.9
119.0
119.0
98.9
98.0
98.8
98.4
98.1
175.8, 175.1, 175.0, 168.6, 167.3, 150.0, 132.2, 131.4, 130.2, 128.7, 121.6, 89.6, 73.0, 72.7, 71.5,
70.8, 69.0, 58.6, 52.6, 46.1, 43.6, 43.0, 41.0, 35.6, 33.7, 20.8, 20.6, 18.8, 18.75, 18.7, 18.6
169.8, 169.5, 169.3, 154.5, 150.3, 132.6, 132.1, 131.7, 130.0, 128.7, 121.4, 89.1, 89.0, 72.7, 72.6,
72.2, 72.1, 71.9, 71.0, 69.4, 58.6, 58.5, 55.4, 53.1, 46.1, 43.6, 42.9, 41.0, 40.9, 35.6, 20.8, 20.5, 20.4
175.8, 175.1, 175.0, 168.6, 167.3, 150.0, 132.2, 131.1, 130.2, 128.7, 121.6, 89.6, 73.0, 72.7, 71.5,
70.8, 69.0, 58.5, 52.6, 46.1, 43.6, 42.9, 41.0, 35.6, 33.7, 20.8, 20.6, 18.9, 18.8, 18.7, 18.6
175.8, 175.2, 175.1, 170.2, 167.3, 152.3, 133.4, 132.4, 131.3, 130.4, 130.3, 129.4, 128.9, 128.5,
121.9, 89.7, 71.5, 70.8, 69.3, 58.6, 52.7, 46.2, 44.0, 43.1, 41.2, 35.8, 33.8, 33.6, 21.0, 18.8, 18.5
3g
167.8, 165.3, 165.0, 164.3, 164.0, 150.2, 133.2, 133.1, 132.8, 132.2, 131.7, 131.6, 130.4, 130.2,
129.75, 129.7, 129.6, 129.2, 129.16, 128.9,128.85, 128.2, 128.1, 128.0, 121.9, 90.1, 72.9, 72.4,
71.6, 71.4, 69.2, 58.7, 52.6, 46.2, 43.8, 43.0, 41.1, 35.5, 20.9
3h
9
118.9
118.7
98.7
97.8
176.8, 176.1, 175.9, 167.1, 164.2, 151.0, 133.3, 132.3, 131.5, 130.4, 129.5, 128.9, 128.4, 121.9,
89.9, 73.3, 72.9, 71.6, 70.9, 69.4, 58.6, 52.7, 46.2, 44.2, 43.1, 41.4, 38.6, 35.9, 27.1, 27.0, 26.9, 21.1
175.5, 175.0, 174.9, 167.3, 164.1, 149.6, 133.3, 132.2, 131.2, 130.5, 130.2, 129.2, 128.4, 122.1,
89.3, 72.4, 71.9, 71.7, 71.1, 69.1, 59.3, 52.5, 46.1, 43.1, 42.8, 38.4, 37.2, 33.6, 33.4, 29.5, 29.2, 23.5,
20.5, 19.7, 18.7, 18.6, 18.4
3-O-(Methoxycarbonyl)morphine (2b):
Compound 2b was prepared from morphine hydrochloride trihy-
drate (7.52 g, 20 mmol) and methyl chloroformate (2.50 g,
Sodium (0.80 g., 35 mmol) was dissolved in anhyd MeOH
(100 mL) under Ar and while stirring at r.t. thiophenol (4.53 mL,
40 mmol) was added dropwise and the solution was stirred for an
additional 20 min. Then the above crude product was added in one
portion and resulting suspension was stirred to completion of the re-
action (monitored by TLC, mobile phase was hexane/EtOAc, 4:1).
MeOH was evaporated under reduced pressure and the red-violet
solid was dissolved in the mixture of CH2Cl2 (100 mL) and H2O
(100 mL). The phases were separated, the aqueous layer was
washed with CH2Cl2 (50 mL) and the combined organics were
washed with sat. aq KHSO4 solution (2 × 80 mL), dried (Na2SO4),
filtered, and the solvent was removed under vacuo. The crude prod-
uct was crystallized from EtOH or i-PrOH to give 1d or 1f in 85-
95% yield.
20
26 mmol) as a white solid in 85% yield; [a]D -193.0 (c = 1,
CHCl3), mp 118-119 ºC (dec.) [Lit.23 mp 116-120 ºC (dec)].
1H NMR (CDCl3): d = 6.84, 6.62 (2 d, 2 H, J = 8.2 Hz, Harom), 5.78,
5.24 (2 d, 2 H, J = 10.0 Hz, 8-H, 7-H), 4.98 (d, 1 H, J = 6.4 Hz),
4.18 (m, 1 H,), 3.90 (s, 3 H, C-3 OCO2CH3), 3.62 (m, 1 H), 3.03 (d,
1 H, J = 18.9 Hz), 2.66 (m, 1 H), 2.55 (dd, 1H, J = 3.8, 11.6 Hz),
2.40 (s, 3 H, NCH3), 2.34 (m, 2 H), 2.12 (m, 2 H), 1.90 (m, 1 H).
13C NMR (CDCl3): d = 153.5, 144.8, 134.0, 133.0, 132.5, 132.3,
127.7, 120.7, 119.7, 92.4, 65.8, 58.8, 55.6, 46.3, 42.9, 42.6, 40.3,
35.1, 20.7.
MS (CI): m/z = 344 (M+ + 1).
Methyl (Phenyl 2,3,4-tri-O-isobutyryl-1-thio-b-D-glucopyra-
nosid)uronate (1d)
Anal. calcd for C19H21NO5 (343.4): C 66.46; H 6.16; N 4.08. Found:
C 66.82; H 6.52; N 3.87.
[a]D20 -17.2 (c = 1, CHCl3); mp 132.4-135.6 ºC.
1H NMR (CDCl3): d = 7.45 (m, 2 H, SPh), 7.29 (m, 3 H, SPh), 5.30
(t, 1 H, J = 9.4 Hz, 3-H), 5.16 (dd, 1 H, J = 9.6, 9.4 Hz, 4-H), 4.99
(dd, 1 H, J = 9.8, 9.4 Hz, 2-H), 4.71 (d, 1 H, J = 9.8 Hz, 1-H), 4.03
(d, 1 H, J = 9.6 Hz, 5-H), 3.71 (s, 3 H, CO2CH3), 2.40-2.53 [m, 3
H, 3 CH(CH3)3], 1.16, 1.10 [2 d, 6 H, J = 7.2 Hz, CH(CH3)3], 1.02-
1.07 [m, 12 H, 2 CH(CH3)3].
13C NMR (CDCl3): d = 175.7, 175.1, 174.8, 166.8, 133.1, 131.5,
128.9, 128.4, 86.5, 72.7, 69.0, 68,9, 52.7, 33.9, 33.8, 18.8, 18.7.
MS (CI): m/z = 511 (M+ + 1).
Thioglycosydes 1d and 1f; General Procedure
Methyl 1,2,3,4-tetra-O-acyl-D-glucopyranuronate24 (28 mmol) was
added in one portion to a precooled (-5 ∞C) 38% wt solution of HBr
in AcOH (100 mL) and the resulting brown-red mixture was stirred
for 1 h at 0∞C and for 10 h at r.t. HBr and AcOH were removed un-
der reduced pressure and the residue was partitioned between
CH2Cl2 (100 mL) and sat. aq NaHCO3 solution (60 mL). The phases
were separated, the aqueous layer was washed with CH2Cl2 (50 mL)
and the combined organic layers were washed with H2O and brine,
dried (Na2SO4), filtered, and the solvent was removed under vacuo.
The crude methyl 2,3,4-tri-O-acyl-D-glucopyranosyl bromide ob-
tained was used in the next step without further purification.
Anal. calcd for C25H34O9S (510.6): C 58.81; H 6.71; S 6.28. Found:
C 59.19; H 6.32; S 6.73.
Synthesis 2000, No. 9, 1241–1246 ISSN 0039-7881 © Thieme Stuttgart · New York