22
S. Ghirmai et al. / Carbohydrate Research 340 (2005) 15–24
0.035mmol) was used as the starting material. The crude
product was purified by flash chromatography using
CH3CN–CH2Cl2 (50:50) and then CH3CN–Et3N (99:1)
as mobile phase to give 8 (20.1mg, 72%) as a red solid,
4.10. 30-N-(4-Hydroxybenzyl)daunorubicin (12) and 30-N-
(4-hydroxybenzyl)-13-(R/S)-dihydrodaunorubicin (15)
A mixture of hydrochloride salt of daunorubicin 1a
(25mg, 0.044mmol), and 4-hydroxybenzaldehyde
(16mg, 0.13mmol) was dissolved in acetonitrile–water
(2:1, 6mL). To the stirred solution was added sodium
cyanoborohydride (2.4mg, 0.04mmol, 1M solution in
THF). The reaction mixture was stirred under a nitro-
gen atmosphere at rt in the dark for 24h, and the con-
sumption of the daunorubicin was followed by TLC.
Additional 4-hydroxyaldehyde (22mg) and sodium cya-
noborohydride (4mg) were added successively. The
reaction was stirred for another 2days. The solvent
was evaporated and the crude mixture was purified by
flash chromatography. Two fractions were isolated
and analyzed by NMR and LC/MS. The first fraction
(6mg, 22%) was found to be compound 12. The second
product (21mg, 75%) was analyzed and found to be
compound 15 (as a mixture of two diastereomers).
1
Rf = 0.3 CH2Cl2–CH3CN; 80:20; H NMR (CDCl3): d
14.00, 13.29 (s, 2H, 6,11-OH), 8.80 (m, 1H), 8.69 (m,
1H), 8.11 (m, 1H), 8.06 (dd, 1H, J = 7.7, 1.1Hz, 1-H),
7.78 (dd, 1H, J = 8.5, 7.7Hz, 2-H), 7.37 (dd, 1H,
J = 8.5, 1.1Hz, 3-H), 6.47 (d, 1H), 5.55 (m, 1H, 10-H),
5.30 (m, 1H, 7-H), 4.49 (s, 1H, 9-OH), 4.40 (m, 1H,
30-H), 4.33 (m, 1H, 50-H), 4.07 (s, 3H, 4-OCH3), 3.77
(m, 1H, 40-H), 3.28 (dd, 1H, J = 18.7, 2.0Hz, 10-Heq),
2.98 (d, 1H, J = 18.7Hz, 10-Hax), 2.43 (s, 3H, 14-
CH3), 2.36 (m, 1H, 40-OH), 2.18–2.03 (m, 2H, 8-Heq,
8Hax), 1.96 (m, 1H, 20-Heq), 1.88 (m, 1H, 20-Hax), 1.33
(d, 3H, J = 6.6Hz, 50-CH3), 0.34 (s with Sn satellites,
9H, Sn(CH3)3); 13C NMR (CDCl3): d 212.2, 187.4,
187.0, 165.7, 161.3, 158.1, 156.6, 156.1, 147.4, 142.7
137.7, 135.9, 135.8, 134.7, 134.2, 130.1, 121.3, 120.1,
118.7, 111.8, 111.6, 100.9, 70.4, 69.8, 67.3, 56.9, 46.2,
35.4, 33.8, 30.4, 25.1, 17.0, ꢀ9.2. HRMS: m/z calcd
for [C36H40N2O11Sn + Na+]: 819.1552. Found: m/z
819.1532.
4.10.1. Data for 30-N-(4-hydroxybenzyl)daunorubicin
(12). 1H NMR (CD3OD): d 7.93 (d, 1H, H-3), 7.82
(t, 1H, H-2), 7.56 (d, 1H, H-1), 7.20 (d, 2H, Ar), 6.71
(d, 2H, Ar), 5.46 (br s, 1H, H-10), 5.09 (br s, 1H, H-7),
4.27 (q, 1H, H-50), 3.90 (s, 3H, OCH3), 3.63 (br s, 1H,
H-40), 3.67–3.48 (m, 3H, H-30, H-10eq, H-10ax), 2.99
(m, 2H, CH2), 2.35 (s, 3H, COCH3), 2.33–2.10 (m,
2H, H-8), 2.05–1.90 (m, 2H, H-20), 1.29 (d, 3H, 50-
CH3); 13C NMR (CD3OD): d 213.4, 203.7, 164.3,
160.9, 137.2, 132.3, 121.9, 120.6, 120.5, 116.7, 113.1,
101.3, 97.3, 74.6, 71.8, 68.4, 66.2, 57.1, 54.6, 37.0, 33.2,
4.9. 30-N-5-Iodo-nicotinyldaunorubicin (9)
In a round-bottomed flask, compound 8 (14.0mg,
0.018mmol) was dissolved in 1mL of 1% AcOH/MeOH.
Then 105lL of NaI (5.27mg, 0.35mmol) in MeOH was
added, followed by 0.56mL chloramine-T (0.04g/mL
MeOH). The reaction mixture was stirred vigorously
and the color changed from red to slightly yellow after
13min. After this, the reaction was quenched by the
addition of 0.84mL of sodium metabisulfite (0.04mg/
mL in H2O), which gave the original color, red, again.
The solvent was evaporated under reduced pressure to
dryness at rt. The crude product was purified by flash
chromatography using 100% EtOAc as a mobile phase
29.1,
24.5,
17.1.
HRMS:
m/z
calcd
for
[C34H35NO11 + H+]: 634.2288. Found: m/z 634.2270.
4.10.2. Data for 30-N-(4-hydroxybenzyl)-13-(R/S)-
dihydrodaunorubicin (15). 1H NMR (CD3OD): d 7.77
(m, 2H, H-3, H-2), 7.48 (d, 1H, H-1), 7.01 (2H, Ph),
6.82 (2H, Ph), 6.54 (2H, Ph), 6.37 (2H, Ph), 5.45 (br s,
1H, H-10), 5.00 (br s, 1H, H-7), 4.25 (q, 1H, H-50), 3.98
(s, 3H, OCH3), 3.79 (m, 2H, H-14, H-40), 3.68–3.47 (m,
3H, CH2, H-30), 2.93 (m, 1H, H-10), 2.53 (m, 2H, H-10,
H-8), 2.17 (m, 1H, H-8), 1.96 (m, 2H, H-20), 1.92–1.33
(m, 6H, COCH3, CH3); 13C NMR (CD3OD): d 213.0,
188, 162.4, 159.3, 157.0, 137.0, 136.3, 136.2, 132.2,
132.1, 123.5, 120.9, 120.2, 116.6, 116.4, 112.4, 112.0,
101.1, 74.2, 73.9, 72.7, 71.8, 68.0, 65.9, 57.0, 54.6, 35.9,
33.3, 32.2, 29.2, 28.9, 17.2, 16.8. HRMS: m/z calcd for
[C34H37NO11 + H+]: 636.2445. Found: m/z 636.2418.
1
to give 9 (10.3mg, 77%) as slightly red solid; H NMR
(CDCl3): d 14.00, 13.30 (s, 2H, 6,11-OH), 8.91 (m,
1H), 8.89 (m, 1H), 8.34 (m, 1H), 8.06 (dd, 1H, J = 7.7,
1.1Hz, 1-H), 7.78 (dd, 1H, J = 8.5, 7.7Hz, 2-H), 7.37
(dd, 1H, J = 8.5, 1.1Hz, 3-H), 6.43 (d, 1H), 5.54 (m,
1H, 10-H), 5.32 (m, 1H, 7-H), 4.43 (s, 1H, 9-OH),
4.39–4.30 (m, 2H, 50-H, 30-H), 4.07 (s, 3H, 4-OCH3),
3.74 (m, 1H, 40-H), 3.29 (dd, 1H, J = 19.0, 2.0Hz, 10-
Heq), 2.98 (d, 1H, J = 19.0Hz, 10-Hax), 2.43 (s, 3H,
14-CH3), 2.35 (m, 1H, 40-OH), 2.14–2.04 (m, 2H, 8-
Heq, 8-Hax), 1.96 (m, 1H, 20-Heq), 1.86 (m, 1H, 20-
Hax), 1.33 (d, 3H, J = 6.6Hz, 50-CH3); 13C NMR
(CDCl3): d 212.1, 187.4, 187.0, 163.6, 161.3, 158.5,
156.6, 156.1, 146.5, 143.4, 135.9, 135.8, 134.7, 134.1,
121.3, 120.1, 118.7, 111.8, 111.6, 100.8, 70.4, 69.7,
67.2, 56.9, 46.3, 35.4, 33.7, 30.3, 25.0, 16.9. HRMS:
m/z calcd for [C33H31IN2O11 + Na+]: 781.0870. Found:
m/z 781.0869.
4.11. 30-N-(4-Hydroxy-3-iodobenzyl)daunorubicin (11)
and 30-N-(4-hydroxy-3-iodobenzyl)-13-(R/S)-dihydro-
daunorubicin (14)
To a solution of daunorubicin hydrochloride (30mg,
and
0.053mmol)
4-hydroxy-3-iodobenzaldehyde