3578 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19
Florent et al.
6H, 2 OAc); MS (CI) m/z 476 [M + NH4]+. Anal. (C20H23FO11
C, H.
)
OAc), 2.06 (s, 6H, 2 OAc); MS (CI) m/z 503 (M + NH4)+. Anal.
(C20H23NO13) C, H, N.
N-[4-O-(Met h yl (2,3,4-t r i-O-a cet yl-â-D-glu cop yr a n o-
side)uronate)-3-nitrobenzyloxycarbonyl]doxorubicin (23c):
obtained from 22c (prepared from 21c by the same protocol
Meth yl (2-flu or o-4-p-n itr op h en yl ca r bon a te 2,3,4-tr i-
O-acetyl-â-D-glu copyr an oside)u r on ate (22b): obtained from
21b, following protocol as for preparation of 13, and isolated
as for 22b) and doxorubicin in 74% yield; mp 114 °C; [R]20
in 66% yield after chromatography; mp 138-140 °C; [R]20
D
D
-27° (c 0.37, CHCl3); IR (CHCl3) ν 1760 (F), 1223 (F) cm-1; 1H
NMR (CDCl3) δ 8.29 (d, 2H, J ) 9 Hz, Ar), 7.39 (d, 2H, J ) 9
Hz, Ar), 7.25-7.15 (m, 4H, Ar), 5.36-5.31 (m, 3H, H-2, H-3,
H-4), 5.23 (s, 2H, CH2), 5.08 (d, 1H, J ) 7 Hz, H-1), 4.15 (d,
1H, J ) 9 Hz, H-5), 3.76 (s, 3H, CH3), 2.10, 2.06, and 2.05 (3s,
+121° (c 0.048, CHCl3); IR (CHCl3) ν 3457 (OH), 1760, 1225,
1040 (OAc) cm-1. Anal. (C48H50N2O25 + 2 H2O) C, H, N.
N-[4-O-(Meth yl â-D-glu cop yr a n osid eu r on a te)-3-n itr o-
ben zyloxyca r bon yl]d oxor u bicin (24c): obtained from 23c
in 95% yield after purification by flash chromatography (CH2-
3 × 3H, OAc); MS (CI) m/z 641 [M + NH4]+. Anal. (C27H26
-
Cl2-MeOH, 98/2 then 95/5); mp 150 °C; [R]20 +85° (c 0.048,
D
THF); IR (KBr) ν 3416 (OH), 1735 (CdO), 1250 (Ar) cm-1; MS
(FAB) m/z 951 (M + Na+). Anal. (C42H44N2O22) C, H, N.
N-[4-O-(Met h yl â-D-glu cop yr a n osylu r on a t e)-3-n it r o-
ben zyloxyca r bon yl]d oxor u bicin (HMR 1826) (25c): ob-
tained from 24c and isolated (80% yield) as a crystalline
FNO15) C, H, N.
N-[4-O-(Meth yl (2,3,4-tr i-O-acetyl-â-D-glu copyr an oside)-
u r on a te)-3-flu or oben zyloxyca r bon yl]d oxor u bicin (23b):
obtained from 22b and doxorubicin and isolated in 95% yield
as a crystalline compound after purification by flash chroma-
tography (toluene-acetone, 4/1 then 3/1, v/v); mp 147-149 °C;
compound; mp 210 °C; [R]20 -78° (c 0.05, H2O); IR (KBr) ν
D
[R]20 +135° (c 0.02, CHCl3); 1H NMR (CDCl3) δ 13.85 (s, 1H,
3540 (OH, NH), 1720 (CdO), 1620 (Ar) cm-1; 1H NMR (DMSO-
d6) δ 14.00 (bs, 2H, PhOH), 8.00-6.90 (m, 6H, Ar), 5.48 (s,
1H, H-1′ or 7), 5.23 (s, 1H, H-7 or 1′), 5.07 (d, 1H, J ) 6.4 Hz,
H), 4.98 (m, 2H, CH2O), 4.59 (m, 2H, CH2-14), 4,15 (m, 1H,
H-5′′′), 3.99 (s, 3H, OCH3), 3,70 (m, 1H, H-3′), 3.30-3.10 (m,
5H, H-2′′′, H-3′′′, H-4′′′, H-4′, H-5′), 2.96 (d, 1H, J ) 19 Hz,
H-10a), 2.91 (d, 1H, J ) 19 Hz, H-10b), 2.20 (d, 1H, J ) 11.5
Hz, H-8a), 2.13 (d, 1H, J ) 11.5 Hz, H-8b), 1.87 (d, 1H, J ) 13
Hz, H-2′a), 1.48 (d, 1H, J ) 13 Hz, H-2′b), 1.13 (d, 3H, J ) 6.5
Hz, CH3-6′); 13C NMR (D2O) δ 206.5 (C-13), 186.8 (C-5, C-12),
177.4 (COOH), 162.2 (C-4), 159.0 (CONH), 157.6 (C-6), 156.1
(C-11), 151.8 (C-4′′), 141.4, 138.5, 137.2, 135.6, 133.5 (C-6a,
C-10a, C-12a, C-1′′, C-3′′, C-6′′), 121.3 (C-1, C-4a), 120.3 (C-3,
C-5′′), 112.1 (C-5a, C-11a), 103.0 (C-1′, C-1′′′), 78.8, 77.6, 74.9,
73.9 (C-9, C-2′′′, C-3′′′, C-4′′′, C-5′′′), 71.6 (C-7), 71.4 (C-5′), 70.0
(C-4′), 67.5 (CH2O), 66.8 (C-14), 58.4 (OCH3), 49.4 (C-3′), 34.6
(C-8), 32.2 (C-10, C-2′), 18.4 (CH3-6′); MS (FAB) m/z 937 (M +
Na+). Anal. (C41H41N2O22Na) C, H, N.
D
PhOH), 13.06 (s, 1H, PhOH), 7.91 (dd, 1H, J ) 8, J ′ ) 2 Hz,
H-1), 7.77 (dd, 1H, J ) J ′) 8 Hz, H-2), 7.40 (dd, 1H, J ) 8, J ′
) 2 Hz, H-3), 7.13-6.98 (m, 3H, Ar), 5.50 (d, 1H, J ) 1.5 Hz,
H-1′), 5.32 (m, 4H, H-2′′′, H-3′′′, H-4′′′, H-7), 5.19 (m, 1H, H-4′),
5.00 (d, 1H, J ) 7 Hz, H-1′′′), 4.95 (s, 2H, CH2O), 4.75 (s, 2H,
CH2-14), 4.55 (s, 1H, NH), 4.13 (m, 2H, H-5′, H-5′′′), 4.08 (s,
3H, OCH3), 3.85 (m, 1H, H-3′), 3.72 (s, 3H, COOCH3), 3.66 (s,
1H, OH), 3.26 (d, 1H, J ) 19 Hz, H-10a), 2.98 (d, 1H, J ) 19
Hz, H-10b), 2.33 (dd, 1H, J ) 16, J ′ ) 2 Hz, H-8a), 2.19 (ddd,
1H, J ) 16, J ′ ) 4, J ′′ ) 2 Hz, H-8b), 2.06, 2.04, and 2.03 (3s,
3 × 3H, OAc), 1.84 (ddd, 1H, J ) 12, J ′ ) 3, J ′′ ) 1.5 Hz,
H-2′a), 1.29 (m, 1H, H-2′b), 1.10 (d, 3H, J ) 6 Hz, CH3-6′);
LRMS (FAB) m/z 1028 (M + H+). Anal. (C48H50FNO23
C, H, N.
)
N-[4-O-(Meth yl â-D-glu cop yr a n osylu r on a te)-3-flu or o-
ben zyloxyca r bon yl]d oxor u bicin (24b): obtained from 23b
according to the general procedure, purified by flash chroma-
tography (CH2Cl2-MeOH, 97:3 then 93:7), and isolated in 57%
yield as crystals; mp 170-172 °C; [R]20D +209° (c 0.02, MeOH);
IR (KBr) ν 3320 (OH, NH), 1725 (CdO), 1210 (F) cm-1. Anal.
(C42H44FNO20) C, H, N.
N-[4-O-(â-D-Glu copyr an oside)u r on ic acid)-3-flu or oben -
zyloxyca r bon yl]d oxor u bicin (25b): obtained from 24b and
isolated in 80% yield as crystals; mp > 350 °C; [R]20D -112° (c
0.016, H2O); IR (Nujol) ν 3320 (OH, NH), 1720 (CdO) cm-1;13C
NMR (D2O) δ 214.0 (C-13), 188.1 and 187.6 (C-5 and C-12),
180.3 (C-6′′′), 162.2 (C-4), 158.3 (CONH), 156.4 (C-6), 155.9
(C-11), 150.8 (C-4′′), 145.7 and 136.8 (C-1′′ and C-2), 136.0 and
135.5 (C-6a and C-12a), 132.5 (2C) and 125.0 (C-10a, C-2′′, and
C-6′′), 123 (C-3′′), 120.7 and 120.2 (2C, (C-1, C-4a, and C-5′′),
118.3 (C-3), 116.4 (C-11a), 111.8 (C-5a), 101.3 (C-1′ and C-1′′′),
77.0, 75.3, 74.7, and 74.1 (C-2′′′, C-3′′′, C-4′′′, C-5′′′), 73.0 (C-
7), 71.0 (C-5′), 68.9 (C-4′), 67.7 (CH2OCO), 65.3 (C-14), 58.3
(OCH3), 49.5 (C-3′), 37.3 (C-8), 37.2 (C-10), 31.2 (C-2′), 18.5
(C-6′); MS (FAB) m/z 910 (M + Na+).
Meth yl (2-for m yl-4-ch lor op h en yl 2,3,4-tr i-O-a cetyl-â-
D-glu cop yr a n osid e)u r on a te (27a ): obtained from 14 and 17
in 55% yield; mp 156-157 °C; [R]20D -39° (c 1, CHCl3); IR (CH2-
Cl2) ν 1745 (OAc), 1680 (CHO) cm-1; 1H NMR (CDCl3) δ 10.27
(s, 1H, CHO), 7.80 (d, 1H, J ) 2.4 Hz, Ar), 7.54 (dd, 1H, J )
8.4, J ′ ) 2.4 Hz, Ar), 7.11 (d, 1H, J ) 8.4 Hz, Ar), 5.40-5.20
(m, 4H, H-1, H-2, H-3, H-4), 4.25 (d, 1H, J ) 8.6 Hz, H-5),
3.74 (s, 3H, CH3), 2.10, 2.09, and 2.08 (3s, 3 × 3H, OAc); DCI/
NH3 m/z 492 (M + NH4)+; HRMS (FAB) m/z calcd for C20H21
ClO11 + Li+ 479.7757, found 479.7765.
-
Meth yl (2-(h yd r oxym eth yl)-4-ch lor op h en yl 2,3,4-tr i-O-
a cetyl-â-D-glu cop yr a n osid e)u r on a te (28a ): obtained from
27a in 90% yield; mp 120 °C; [R]20 -20° (c 0.9, CHCl3); IR
D
(CH2Cl2) ν 3600 (OH), 1750 (OAc) cm-1
;
1H NMR (CDCl3) δ
7.36 (d, 1H, J ) 2.4 Hz, Ar), 7.21 (dd, 1H, J ) 8.4, J ′ ) 2.4
Hz, Ar), 6.94 (d, 1H, J ) 8.4 Hz, Ar), 5.34 (m, 3H, H-2, H-3,
H-4), 5.08 (d, 1H, J ) 6.5 Hz, H-1), 4.73 and 4.43 (2d, 2H, J )
13 Hz, CH2OH), 4.12 (d, 1H, J ) 9 Hz, H-5), 3.71 (s, 3H,
COOCH3), 2.11, 2.07, and 2.05 (3s, 3 × 3H, OAc). Anal.
(C20H23ClO11) C, H.
Meth yl (4-for m yl-2-n itr op h en yl 2,3,4-tr i-O-a cetyl-â-D-
glu cop yr a n osid e)u r on a te (20c): obtained in 90% from
4-hydroxy-3-nitrobenzaldehyde (19) and 14 in 89% yield after
purification by chromatography (CH2Cl2/MeOH, 95/5, v/v) and
Meth yl (2-(p-n itr oben zyloxyca r bon yl)-4-ch lor op h en yl
2,3,4-tr i-O-a cetyl-â-D-glu cop yr a n osid e)u r on a te (29a ): ob-
tained in 66% yield from 28a ; mp 136 °C; [R]20 -145° (c 1,
recrystallization from dichloromethane; mp 172-173 °C; [R]20
D
D
CHCl3); IR (CH2Cl2) ν 1750 (OAc) cm-1
;
1H NMR (CDCl3) δ
+10° (c 1, CHCl3); IR (syrup) ν 1760, 1230 (F) cm-1; H NMR
1
8.29 (d, 2H, J ) 9 Hz, Ar), 7.43-7.30 (m, 4H, Ar), 7.05 (d, 1H,
J ) 9 Hz, Ar), 5.36-5.14 (m, 6H, H-1, H-2, H-3, H-4, CH2O),
4.21 (d, 1H, J ) 8.8 Hz, H-5), 3.74 (s, 3H, COOCH3), 2.08 (s,
3H, OAc), 2.06 (s, 6H, OAc). Anal. (C27H26ClNO15) C, H, N.
N-[2-O-(Meth yl (2,3,4-tr i-O-acetyl-â-D-glu copyr an oside)-
u r on a te)-5-ch lor oben zyloxyca r bon yl]d oxor u bicin (30a ):
obtained in 75% yield by condensation of 29a with doxorubicin;
(CDCl3) δ 9.97 (s, 1H, CHO), 8.31 (dd, 1H, J ) 7.5, J ) 1.8
Hz, Ar), 8.08 (dd, 1H, J ) 7.5, J ′) 1.8 Hz, Ar), 7.49 (d, 1H, J
) 7.5 Hz, Ar), 5.45-5.25 (m, 4H, H-2, H-3, H-4, H-5), 4.33 (d,
1H, J ) 8.2 Hz, H-1), 3.71 (s, 3H, COOCH3), 2.16, 2.12, and
2.07 (3s, 3 × 3H, OAc); MS (CI) m/z 501 (M + NH4)+. Anal.
(C20H21NO13) C, H, N.
Meth yl (4-(h yd r oxym eth yl)-2-n itr op h en yl 2,3,4-tr i-O-
a cetyl-â-D-glu cop yr a n osid e)u r on a te (21c): obtained from
the reduction of 20c and isolated in 99% yield by crystallization
mp 155-157 °C; [R]20 +40° (c 0.75, CHCl3); IR (CHCl3) 3442
D
(NH, OH), 1755 (CdO), 1720 (NHCO) cm-1; MS (electrospray)
m/z 1066/1068 (M + Na+), 1082/1084 (M + K+). Anal. (C48H50
ClNO23) C, H, N.
-
from dichloromethane; mp 173-174 °C; [R]20 +10° (c 1,
D
1
CHCl3); H NMR (CDCl3) δ 7.65 (d, 1H, J ) 1.8 Hz, Ar), 7.39
(dd, 1H, J ) 7, J ′ ) 1.8 Hz, Ar), 7.21 (d, 1H, J ) 7 Hz, Ar),
5.35-5.02 (m, 4H, H-2, H-3, H-4, H-5), 4.62 (s, 2H, CH2), 4.12
(d, 1H, J ) 8 Hz, H-1), 3.63 (s, 3H, COOCH3), 2.01 (s, 3H,
N-[2-O-(Meth yl â-D-glu cop yr a n osylu r on a te)-5-ch lor o-
ben zyloxyca r bon yl]d oxor u bicin (31a ): obtained from 30a
in 55% yield as crystals; mp 158-160 °C; [R]20D +13.5° (c 0.037,