A. Cipollone et al. /Bioorg. Med. Chem. 10 (2002) 1459–1470
1467
4-O-(3-N-allyloxycarbonyl-4-O-p-nitrobenzoyl-2,3,6-tri-
deoxy-ꢀ-L-lyxo-hexopyranosyl)-2,3,6-trideoxy-1-O-p-ni-
trobenzoyl - ꢀ - L - lyxo - hexopyranoside (36). The
disaccharide 33 was treated according to the general
procedure B to give 36 (80%). 1H NMR (CDCl3) d 8.4–
8.2 (8H, m, Ph), 6.5 (1H, br s, H-1), 6.0–5.8 (1H, m,
CH2¼CH), 5.5 (1H, s, H-40), 5.4–5.2 (2H, m,
CH2¼CH), 5.1 (1H, br s, H-10), 4.7–4.4 (4H, m, OCH2–
CH, H-30, NH), 4.3 (1H, q, H-50), 4.2 (1H, q, H-5), 3.7
(1H, s, H-4), 2.4–1.8 (6H, m, H-2, H-20, H-3), 1.3 (3H,
d, H-6), 1.2 (3H, d, H-60). ESMS m/z calcd for
C30H33N3O13 (M+H)+ 644.2, found 644.5.
m, 3ÂCH2¼CH), 5.6 (1H, s, H-10), 5.0–5.4 (11H, m,
3ÂCH2¼CH, H-100, H-30, H-7, H-14), 4.9 (1H, d, H-400),
4.7–4.5 (6H, m, 3ÂOCH2–CH), 4.4 (1H, q, H-500), 4.3
(1H, m, H-300), 4.1 (1H, q, H-50), 3.9 (1H, s, H-40), 3.2
(2H, q, H-10), 2.5–1.7 (6H, m, H-20, H-200, H-8), 2.2
(3H, s, COCH3), 1.4–1.2 (6H, m, H-60, H-600). ESMS m/
z calcd for C46H51NO20 (M+H)+ 938.9, found 938.7.
7-{3-O-allyloxycarbonyl-4-O-[3-O-allyloxycarbonyl-2,6-
dideoxy-4-O-(3-N-allyloxycarbonyl-2,3,6-trideoxy-4-O-p
-nitrobenzoyl-ꢀ-L-lyxo-hexopyranosyl)-ꢀ-L-lyxo-hexo-
pyranosyl]-2,6-dideoxy-ꢀ-L-lyxo-hexopyranosyl-14-acet-
oxy-4-demethoxyadriamycinone (43). The aglycone 41
and the trisaccharide 26 were coupled according to the
general procedure C to afford the glycoside 43 (60%).
1H NMR (CDCl3) d 13.6 (1H, s, OH-6), 13.2 (1H, s,
OH-11), 8.4 (2H, m H-1, H-4), 8.3–8.2 (4H, m, Ph), 7.8
(2H, m, H-2, H-3), 6.0–5.7 (3H, m, 3ÂCH2¼CH), 5.55
(1H, br s, H-10), 5.45 (1H, br s, H-4000), 5.4–5.2 (9H, m,
3ÂCH2¼CH, H-7, H-14), 5.1 (1H, m, H-300), 5.0 (1H, br
s, H-1000), 4.9 (1H, br s, H-100), 4.8 (1H, m, H-30), 4.7–4.5
(7H, m, 3ÂOCH2–CH, NH), 4.35 (1H, q, H-5000), 4.2
(1H, q, H-500), 4.1 (1H, m, H-3000), 4.05 (1H, q, H-50),
3.95 (1H, br s, H-400), 3.9 (1H, br s, H-40), 3.15 (2H, q,
H-10), 2.4–2.2 (2H, m, H-8), 2.2 (3H, s, COCH3), 2.1–
1.6 (6H, m, H-20, H-200, H-2000), 1.3 (3H, d, H-60) 1.2 (3H,
d, H-600), 1.1 (3H, d, H-6000). ESMS m/z calcd for
C59H64N2O26 (M+H)+ 1218.2, found 1218.4.
p-Methoxybenzyl 4- O-(3-N, 4 -O-di-allyloxycarbonyl-
2,3,6 - trideoxy - ꢀ - L - arabino - hexopyranosyl) - 2,3,6-tri-
deoxy-ꢀ-L-lyxo-hexopyranoside (37). The p-methoxy-
benzyl 2,3,6-trideoxy fucoside 32 was reacted with the
thiophenyl acosaminide 7, following the general proce-
1
dure A to give 37 (75%). H NMR (CDCl3) d 7.3–6.8
(4H, m, Ph), 6.0–5.8 (2H, m, 2ÂCH2¼CH), 5.4–5.2 (4H,
m, 2ÂCH2¼CH), 5.0 (1H, d, NH), 4.9 (1H, s, H-10), 4.8
(1H, dt, H-3), 4.7–4.5 (5H, m, 2ÂOCH2–CH, H-1), 4.5–
4.3 (2H, m, OCH2–Ph), 4.0 (1H, q, H-5), 3.9 (1H, m, H-
30), 3.8 (3H, s, OCH3), 3.7. (1H, br s, H-4), 3.5 (1H, m,
H-50), 2.2–1.5 (6H, m, H-2, H-20, H-3), 1.3 (3H, d, H-6),
1.2 (3H, d, H-60). ESMS m/z calcd for C26H35NO10
(M+H)+ 522.2, found 522.3.
4-O-(3-N,4-O-di-allyloxycarbonyl-2,3,6-trideoxy-ꢀ-L -
arabino - hexopyranosyl) - 2,3,6 - trideoxy-1-O-p-nitroben-
zoyl-ꢀ-L-lyxo-hexopyranoside (40). Application of the
general procedure B to the disaccharide 37 gave 40 in
80% yield. 1H NMR (CDCl3) d 8.4–8.2 (4H, m, Ph), 6.5
(1H, bs, H-1), 6.0–5.8 (2H, m, CH2¼CH), 5.4–5.2 (4H,
m, CH2¼CH), 5.0 (1H, d, NH), 4.9–4.8 (2H, m, H-30,
H-10), 4.7–4.5 (5H, m, OCH2–CH, H-40), 4.3 (1H, m, H-
50), 4.1 (1H, q, H-5), 4.0 (1H, s, H-4), 2.2–1.5 (6H, m, H-2,
H-20, H-3), 1.3 (3H, d, H-6), 1.2 (3H, d, H-60). ESMS m/z
calcd for C26H32N2O12 (M+H)+ 565.2, found 565.4.
7-[4-O-(2, 3, 6-Trideoxy-3-N-allyloxycarbonyl-4-O-p-ni-
trobenzoyl-ꢀ-L-lyxo-hexopyranosyl)-2,3,6-trideoxy-ꢀ-L-
lyxo-hexopyranosyl]-14-acetoxy-4-demethoxyadriamyci-
none (44). The aglycone 41 and the disaccharide 36
were reacted following the general procedure C obtain-
1
ing the glycoside 44 in 45% yield. H NMR (CDCl3) d
13.6 (1H, s, OH-6), 13.3 (1H, s, OH-11), 8.4 (2H, m, H-
1, H-4), 7.8 (2H, m, H-2, H-3), 6.0–5.8 (1H, m,
CH2¼CH), 5.5 (1H, s, H-10), 5.4–5.2 (3H, m, CH2¼CH,
H-7), 4.5 (3H, m, H-14, NH), 4.9 (1H, s, H-10), 4.8 (2H,
d, OCH2–CH), 4.6 (1H, d, OH-9), 4.2–3.9 (3H, m, H-30,
H-50, H-500), 3.7 (1H, d, H-400), 3.6 (1H, s, H-40), 3.4–3.0
(2H, q, H-10), 3.0 (1H, t, OH-14), 2.4–1.8 (11H, m,
COCH3, H-20, H-200, H-30, H-8), 1.3–1.2 (6H, m, H-60,
H-600). ESMS m/z calcd for C45H46N2O18 (M+H)+
903.9, found 903.7.
General procedure C for the synthesis of fully protected
glycosides 42–45
To a mixture of 14-acetoxy-4-demethoxyadriamycinone
(1 mmol) 41, disaccharide (1 mmol) and activated
molecular sieves (5 g) in anhydrous dichloromethane/die-
thyl ether (3:1, 110 mL), trimethylsylil triflate (1.5 mmol)
was added dropwise at ꢀ30 ꢁC. After 1.5 h, 2% aq
NaHCO3 (60 mL), at 0 ꢁC, and then dichloromethane
(125 mL) were added to the reaction mixture. The organic
layer was washed with water (100 mL), dried over Na2SO4
and evaporated in vacuo. The crude residue was flash
chromatographed on silica gel using dichloromethane/
acetone (19:1) to afford the protected glycosides.
7-[4-O-(3-N,4-O-di-allyloxycarbonyl-2,3,6-trideoxy-ꢀ-L-
arabino-hexopyranosyl)-2,3,6-trideoxy-ꢀ-L-lyxo-hexo-
pyranosyl]-14-acetoxy-4-demethoxyadriamycinone (45).
The aglycone 41 and the disaccharide 40 were coupled
according to the general procedure C. The obtained
residue was purified by preparative HPLC (Merck col-
umn, LiChrosphere RP-18,
7
mm, 250Â25 mm,
CH3CN+0.1% TFA/H2O + 0.1% TFA, 80:20, flow 8
mL/min) giving the glycoside 45 (55%). 1H NMR
(CDCl3) d 13.6 (1H, s, OH-6), 13.3 (1H, s, OH-11), 8.4
(2H, m, H-1, H-4), 7.8 (2H, m, H-2, H-3), 6.0–5.8 (2H,
m, 2ÂCH2¼CH), 5.5 (1H, s, H-10), 5.4–5.2 (5H, m,
2ÂCH2¼CH, H-100), 4.9 (1H, s, H-400), 4.8 (1H, d, NH),
4.7–4.5 (4H, m, 2ÂOCH2–CH), 4.4 (2H, m, H-14), 4.2
(1H, m, H-300), 4.1–3.9 (2H, m, H-50, H-500), 3.6 (1H, s,
H-40), 3.4–3.0 (2H, q, H-10), 2.4–2.0 (8H, m, H-20, H-200,
H-30, H-8), 2.1 (3H, s, COCH3), 1.4–1.2 (6H, m, H-60,
7-[4-O-(2,3,6-trideoxy-3-N,4-O-di-allyloxycarbonyl-ꢀ-L-
arabino-hexopyranosyl)-2,6-dideoxy-3-O-allyloxycarbo-
nyl-ꢀ-L-lyxo-hexopyranosyl]-14-acetoxy-4-demethoxy-
adriamycinone (42). The aglycone 41 and the
disaccharide 15 were reacted following the general pro-
1
cedure C to obtain the glycoside 42 (73%). H NMR
(CDCl3) d 13.6 (1H, s, OH-6), 13.3 (1H, s, OH-11), 8.4
(2H, m, H-1, H-4), 7.8 (2H, m, H-2, H-3), 6.0–5.8 (3H,