Synthesis of the Cororubicin Trisaccharide
J . Org. Chem., Vol. 64, No. 17, 1999 6281
Met h yl 4-O-Acet yl-3-(O-b en zylh yd r oxya m in o)-2,3,6-
tr id eoxy-3-C-m eth yl-r/â-L-r ibo-h exop yr a n osyl-(1f4)-3-O-
b en zyl-2,6-d id eoxy-r-L-lyxo-h exop yr a n osid e (19, 20).
Thioglycoside 14 (234 mg, 0.58 mmol) and acceptor 6 (104 mg,
0.41 mmol) were dissolved in dry dichloroethane-ether (1:1,
v/v, 5 mL) under dry nitrogen, and the solution was cooled to
-20 °C. In a separate flask, triflic acid (5.2 mL, 0.058 mmol)
was added to a mixture of N-iodosuccinimide (132 mg, 0.58
mmol) in dry dichloroethane-ether (1:1, 3 mL). The NIS-
triflic acid suspension was added dropwise to the solution of
14 and 6 over 1 min, and the resulting mixture was stirred
for an additional 2 h while being warmed to 10 °C. The reaction
mixture was diluted with dichloromethane (20 mL), washed
with aqueous sodium bisulfite solution (5%, 10 mL) and
saturated sodium chloride solution (10 mL), dried (Na2SO4),
and concentrated under reduced pressure. Purification of the
product by flash chromatography on silica gel with ethyl
acetate-hexanes (1:3) gave syrupy â-disaccharide 20 (127 mg,
0.23 mmol, 57%) and R-disaccharide 19 (70 mg, 0.13 mmol,
31%).
(br s, 1H), 7.38-7.28 (m, 5H), 5.34 (dd, 1H, J ) 2.9, 1.1 Hz),
4.82 (dd, 1H, J ) 1.9, 1.9 Hz), 4.68 (d, 1H, J ) 10.0 Hz), 4.59
(m, 2H), 4.12, (dq, 1H, J ) 10.0, 6.2 Hz), 3.89-3.79 (m, 3H),
3.32 (s, 3H), 2.27 (dd, 1H, J ) 14.8, 1.1 Hz), 2.12 (s, 3H), 1.96-
1.92 (m, 2H), 1.78 (m, 1H), 1.59 (s, 3H), 1.31 (d, 3H, J ) 6.6
Hz), 1.17 (d, 3H, J ) 6.2 Hz); 13C NMR (CDCl3) δ 172.4, 130.8,
128.4, 127.7, 127.5, 98.6, 91.3, 77.1, 72.9, 70.0, 68.3, 68.1, 65.3,
62.7, 54.6, 40.3, 29.8, 23.7, 20.6, 17.4, 16.7.
Meth yl 3-(O-Ben zylh yd r oxya m in o)-2,3,6-tr id eoxy-3-C-
m et h yl-â-L-r ibo-h exop yr a n osyl)-(1f4)-3-O-b en zyl-2,6-
d id eoxy-r-L-lyxo-h exop yr a n osid e (23). To â-disaccharide
20 (60 mg) dissolved in dry methanol (5 mL) was added
dropwise NaOMe (0.1 mL, 1.0 M), and the mixture was stirred
for 15 h. The volume was reduced to half in vacuo, and the
residue was diluted into CH2Cl2, washed with water (5 mL ×
2) and brine (5 mL), and dried (Na2SO4) to give syrupy 23 (51
mg, 92%): Rf 0.56 (ethyl acetate-hexanes, 2:3); [a]22 -49.6°
D
1
(c, 0.92, chloroform); H NMR (CDCl3) δ 7.37-7.19 (m, 10H),
5.42 (br s, 1H), 5.17 (dd, 1H, J ) 9.6, 2.1 Hz, H1′), 4.81 (br d,
1H, J ) 3.7 Hz, H1), 4.54 (s, 2H, OBn), 4.54, 4.49 (2d, 1H each,
J ) 11.4 Hz, OBn), 3.92 (br s, 1H, H4), 3.82 (ddd, 1H, J ) 9.6,
4.9, 2.6 Hz, H3), 3.80 (bq, 1H, J ) 6.6 Hz, H5), 3.66 (dq, 1H,
J ) 9.6, 6.2 Hz, H5′), 3.29 (s, 3H, OCH3), 3.10 (dd, 1H, J )
9.6, 7.3 Hz, H4′), 2.84 (d, 1H, J ) 7.3 Hz, OH), 2.10 (dd, 1H,
J ) 13.9, 2.1 Hz, H2′eq), 2.06 (m, 1H, J ) 12.6, 12.4, 3.7 Hz,
H2ax), 1.91 (br dd, 1H, J ) 12.6, 4.9 Hz, H2), 1.55 (dd, 1H, J
) 13.9, 9.6 Hz, H2′ax), 1.25 (s 3H, CH3), 1.25, 1.24 (2d, 3H each,
H6, H6′); 13C NMR (CDCl3) δ 138.6, 137.0, 128.4-127.2(10C),
98.8 (C1′), 97.9 (C1), 78.7, 76.6, 74.4, 73.4, 70.4, 70.2, 66,2,
58.6, 54.6, 40.9, 30.4, 23.7, 18.3, 17.1.
20: Rf 0.72 (ethyl acetate-hexanes, 2:3); [a]22 -48.3° (c,
D
1.5, chloroform); 1H NMR (CDCl3) δ 7.31-7.15 (m, 10H), 5.42
(dd, 1H, J ) 9.6, 2.1 Hz, H1′), 5.39 (br s, 1H, NH), 4.85 (dd,
1H, J ) 3.5, 1.2 Hz, H1), 4.69 (d, 1H, J ) 9.7 Hz, H4′), 4.54 (s,
2H, OBn), 4.52, 4.37 (2d, 1H each, J ) 11.1 Hz, OBn), 3.96
(m, 1H, J ) 2.6, 1.2, 0.7 Hz, H4), 3.96 (dq, 1H, J ) 9.8, 6.3
Hz, H5′), 3.85 (ddd, 1H, J ) 12.5, 4.9, 2.6, H3), 3.82 (dq, 1H,
J ) 6.5, 0.7 Hz, H5), 3.30 (s, 3H, OCH3), 2.45 (dd, 1H, J )
13.9 Hz, H2′eq), 2.10 (m, 1H, J ) 12.6, 12.5, 3.5 Hz, H2ax), 2.05
(s, 3H, CH3CO), 1.94 (m, 1H, J ) 12.6, 4.9, 1.2 Hz, H2eq), 1.55
(dd, 1H, J ) 13.9, 9.6 Hz, H2′ax), 1.26 (d, 3H, J ) 6.5 Hz, H6),
1.10 (s, 3H, CH3), 1.09 (d, 3H, J ) 6.3 Hz, H6′); 13C NMR
(CDCl3) δ 169.8, 138.5-127.3 (12C), 98.8 (C1′), 98.1 (C1), 78.5,
76.9, 74.5, 73.5, 70.4, 67.7, 66.3, 59.1, 54.6, 39.3, 30.3, 23.2,
20.6, 17.9, 17.1. Anal. Calcd for C30H41NO8: C, 66.28; H, 7.60;
N, 2.58. Found: C, 66.49; H, 7.57; N, 2.44.
Meth yl 3,4-Di-O-a cetyl-2,6-d id eoxy-r-L-lyxo-h exop y-
r a n osyl-(1f4)-3-(O-ben zylh yd r oxya m in o)-2,3,6-tr id eoxy-
3-C-m eth yl-â-L-r ibo-h exopyr an osyl)-(1f4)-3-O-ben zyl-2,6-
d id eoxy-r-L-lyxo-h exop yr a n osid e (24). To â-disaccharide
23 (143 mg, 0.29 mmol) dissolved in dry benzene (5 mL) and
s-collidine (102 mg, 0.84 mmol), containing molecular sieves
(4 Å, 200 mg) and silver triflate (215 mg, 0.84 mmol), at 5 °C
under dry nitrogen was added a solution of 3,4-di-O-acetyl-
2,6-dideoxy-R-L-lyxo-hexopyranosyl bromide 2a (prepared fresh
from HBr(g) and 3,4-di-O-acetyl-L-fucal, 184 mg 0.86 mmol) in
dry benzene (5 mL) over 10 min. After 2 h, the reaction was
allowed to warm to room temperature and stir for 24 h in the
dark. The mixture was filtered through a Celite pad, and the
solids were rinsed with dichloromethane and ethyl acetate (5
mL each). The organic phase was concentrated in vacuo,
diluted with more dichloromethane (25 mL), washed with
water (30 mL × 2) and brine (30 mL), and dried with Na2SO4.
Column chromatography on silica gel (ethyl acetate-hexanes,
1:3) separated unreacted disaccharide and trisaccharide from
other glycosyl bromide remnants. The recovered di- and
trisaccharide mixture was then separated on a second silica
column (methanol-dichloromethane, 1:99) to give unreacted
disaccharide (53 mg, 106 mmol, 37% of original) and trisac-
charide 24 (88 mg, 68% based on consumed disaccharide).
19: Rf 0.61 (ethyl acetate-hexanes, 2:3); [a]22D -161° (c, 1.0,
1
chloroform); H NMR (CDCl3) δ 7.41-7.22 (m, 10H), 6.61 (br
s, 1H, NH), 4.94 (d, 1H, J ) 4.1 Hz, H1′), 4.82, 4.74 (2d, 1H
each, J ) 11.4 Hz, OBn), 4.76 (m, 1H, H1), 4.66 (d, 1H, J )
10.2 Hz, H4′), 4.56 (s, 2H, OBn), 4.38 (dq, 1H, J ) 10.2, 6.0
Hz, H5′), 3.83-3.74 (m, 3H, H3, H4, H5), 3.27 (s, 3H, OCH3),
2.44 (br d, 1H, J ) 14.5 Hz, H2′eq), 2.06 (s, 3H, CH3CO), 1.96
(m, 1H, J ) 13.0, 13.0, 3.6 Hz, H2ax), 1.86 (dd, 1H, J ) 13.0,
4.9 Hz, H2eq), 1.60 (dd, 1H, 14.5, 4.5 Hz, H2′ax), 1.21 (d, 3H, J
) 6.6 Hz, H6), 1.16 (s, 3H, CH3), 0.80 (d, 3H, J ) 6.1 Hz, H6′);
13C NMR (CDCl3) δ 170.4, 138.6, 138.5, 128.4-127.2 (10C),
98.7 (C1′), 97.9 (C1), 76.9, 76.8, 74.6, 72.5, 70.0, 66.6, 62.4,
57.7, 54.5, 37.4, 30.6, 23.2, 20.7, 17.5, 17.5. Anal. Calcd for
C
30H41NO8: C, 66.28; H, 7.60; N, 2.58. Found: C, 65.54; H,
7.41; N, 3.00.
Meth yl 4-O-Acetyl-2,3,6-tr id eoxy-3-C-m eth yl-3-(tr iflu o-
r oa ceta m id o)-r/â-L-r ibo-h exop yr a n osyl)-(1f4)-3-O-ben -
zyl-2,6-d id eoxy-r/â-L-lyxo-h exop yr a n osid e (21, 22). Fol-
lowing the procedure described for the preparation of 19 and
20, thioglycoside 17 (R-anomer, 55 mg, 0.14 mmol) and 6 (25
mg, 0.10 mmol) in 3 mL of dichloroethane-ether (1:1) were
treated with a mixture of NIS (32 mg, 0.14 mmol) and TfOH
(1.3 µL, 0.014 mmol) in 3 mL of dry dichloroethane-ether (1:
1) for 3 h to give a mixture of disaccharides. Column chroma-
tography on silica gel (ethyl acetate-hexanes, 15:85) gave
â-anomer 22 (7 mg, 13%), R-anomer 21 (13 mg, 25%), and 11
mg of methyl 4-O-acetyl-2,3,6-trideoxy-3-C-methyl-3-trifluo-
roacetamido-R-L-hexopyranoside, formed by transglycosylation.
Rf(ethyl
Rf
acetate-hexanes (methanol-CH2Cl2
(2:3))
0.49
0.47
0.32
(5:95))
0.20
0.39
disaccharide
trisaccharide
glycosyl bromide remnant
0.38
Careful column chromatography using 120 mg of silica gel on
a 3.5 × 15 cm column with 2% methanol-dichloromethane
22: [a]22 -49° (c, 0.48, chloroform); 1H NMR (CDCl3) δ
gave a clean separation in a repeated preparation of 24: [a]22
D
D
7.39-7.22 (m, 5H), 6.25 (br s, 1H), 4.93 (dd, 1H, J ) 9.6, 1.8
Hz, H1′), 4.80 (br d, 1H, J ) 2.6 Hz, H1), 4.67 (d, 1H, J ) 9.9
Hz), 4.52 (ABq, 2H, J ) 12.4 Hz, PhCH2), 3.83-3.77 (m, 3H),
3.58 (dq, 1H, J ) 9.9, 6.2 Hz), 3.33 (dd, 1H, J ) 14.4, 1.8 Hz,
H2′eq), 3.28 (s, 3H), 2.16 (s, 3H), 2.05-1.86 (m, 2H), 1.64 (dd,
1H, J ) 14.4, 9.6 Hz, H2′ax), 1.36 (s, 3H), 1.21 (d, 3H, J ) 6.5
Hz, H6), 1.16 (d, 3H, J ) 6.2 Hz, H6′); 13C NMR (CDCl3) δ
167.9, 130.8, 128.3, 127.3, 127.1, 98.8, 97.8, 76.9, 74.3, 73.8,
70.0, 67.8, 66.0, 57.2, 54.6, 38.4, 30.1, 23.6, 20.6, 17.7, 17.1.
21: [a]22D -69° (c, 0.88, chloroform); 1H NMR (CDCl3) δ 8.10
-81.7°(c, 0.71, chloroform); 1H NMR (300 MHz, CDCl3) δ 7.40-
7.15 (m, 10H), 5.51(br s, 1H, NH), 5.39 (dd, 1H, J ) 9.4, 2.0
Hz, H1′), 5.18 (ddd, 1H, J ) 13.3, 4.9, 3.0 Hz H3′′), 5.17 (dd,
1H, J ) 3.0, 0.4 Hz, H4′′), 5.05 (br d, 1H, J ) 3.2 Hz, H1′′),
4.83 (br d, 1H J ) 3.0 Hz, H1), 4.54 and 4.50 (2d, 2H, J )
11.0 Hz, OBn), 4.50 and 4.34 (2d, 2H, J ) 11.0 Hz, OBn), 4.14
(dq, 1H, J ) 5.6, 0.4 Hz, H5′′), 3.95 (br s, 1H, H4), 3.88 (dq,
1H, J ) 9.3, 6.2 Hz, H5′), 3.84 (m, 1H, H3), 3.81 (bq, 1H, J )
6.5 Hz, H5), 3.30 (s, 3H, OCH3), 3.22 (d, 1H, J ) 9.3 Hz, H4′),
2.34 (dd, 1H, J ) 13.8, 2.0 Hz, H2eq), 2.14 (s, 3H, OAc), 1.99