Synthesis of Daunorubicin Analogues
1
J4ax,4eq ) 16.6 Hz, H-4aeq), 2.39 (dd, 1H, J2ax,2eq ) 14.8 Hz, J1,2ax
) 3.6 Hz, H-2aax), 2.30 (dd, 1H, J2ax,2eq ) 14.8 Hz, J1,2eq ) 3.6
Hz, H-2aeq), 2.25 (s, 3H, C(O)CH3), 2.19 (s, 3H, OC(O)CH3), 2.05
(ddd, 1H, J2ax,2eq ) J2ax,3 ) 13.1 Hz, J1,2ax ) 4.0 Hz, H-2ax), 1.78
(dd, 1H, J2ax,2eq ) 13.1 Hz, J2eq,3 ) 4.0 Hz, H-2eq), 1.27 (d, 3H,
J5,6 ) 6.6 Hz, H-6). 13C NMR (125 MHz, CDCl3): δC 211.5 (Cd
O), 170.5 (OC(O)CH3), 133.8 (Ar), 131.8 (2 × Ar), 130.7 (Ar),
128.6 (Ar), 128.2 (Ar), 127.9 (Ar), 127.2 (Ar), 126.8 (Ar), 126.0
(Ar), 93.7 (C-1), 78.1 (C-3a), 72.2 (C-1a), 70.0 (C-4), 65.9 (C-5),
54.4 (C-3), 39.3 (C-4a), 37.8 (C-2a), 29.4 (C-2), 24.5 (C(O)CH3),
20.7 (OC(O)CH3), 16.9 (C-6). ESI HRMS calcd for C24H27N3O6-
Na: 476.1798 [M + Na]+. Found: 476.1792.
+72.4 (c 0.2, CHCl3). H NMR (300 MHz, CDCl3): δH 7.95 (s,
1H, Ar), 7.72-7.85 (m, 2H, Ar), 7.60 (s, 1H, Ar), 7.40-7.55 (m,
2H, Ar), 5.30 (dd, 1H, J1,2ax ) J1,2eq ) 2.9 Hz, H-1a), 4.85 (dd,
1H, J1,2ax ) 9.6 Hz, J1,2eq ) 1.9, H-1), 4.70 (dd, 1H, J4,5 ) J3,4
)
9.5 Hz, H-4), 4.00 (s, 1H, 3°-OH), 3.42-3.62 (m, 2H, H-3, H-5),
3.20 (s, 2H, H-4aax, H-4aeq), 2.20-2.40 (m, 6H, H-2ax, H-2aax,
H-2aeq, C(O)CH3), 2.15 (s, 3H, OC(O)CH3), 1.67-1.80 (m, 1H,
H-2eq), 1.30 (d, 3H, J5,6 ) 6.1 Hz, H-6). 13C NMR (125 MHz,
CDCl3): δC 212.0 (CdO), 169.9 (OC(O)CH3), 133.6 (Ar), 132.4
(Ar), 132.3 (Ar), 131.1 (Ar), 129.2 (Ar), 128.1 (Ar), 127.8 (Ar),
127.1 (Ar), 126.5 (Ar), 125.7 (Ar), 96.6 (C-1), 77.9 (C-3a), 74.8
(C-1a), 73.2 (C-4), 71.1 (C-5), 59.8 (C-3), 39.2 (C-4a), 36.3 (C-2a),
35.4 (C-2), 24.6 (C(O)CH3), 20.9 (OC(O)CH3), 17.5 (C-6). ESI
HRMS calcd for C24H27N3O6Na: 476.1798 [M + Na]+. Found:
476.1791.
(1S,3S)-1-O-(4-O-Acetyl-3-azido-2,3,6-deoxy-â-L-arabino-hexo-
pyranosyl)-3-acetyl-3-hydroxyl-1,2,3,4-tetrahydro-anthracene (54).
Yield 31%; Rf ) 0.30 (3:1, hexanes-EtOAc); [R]D -110.4 (c 0.5,
CHCl3). 1H NMR (400 MHz, CDCl3): δH 7.78-7.84 (m, 3H, Ar),
(1S,3S)-1-O-(3-Azido-4-O-benzyl-2,3,6-deoxy-â-L-arabino-hex-
opyranosyl)-3-acetyl-3-hydroxyl-1,2,3,4-tetrahydro-naphtha-
lene (62). Yield 46%; Rf ) 0.32 (3:1, hexanes-EtOAc); [R]D -82.2
7.65 (s, 1H, Ar), 7.40-7.55 (m, 2H, Ar), 5.10 (dd, 1H, J1,2ax
)
J1,2eq ) 3.6 Hz, H-1a), 5.02 (d, 1H, J1,2ax ) 3.9 Hz, H-1), 4.74 (dd,
1H, J4,5 ) J3,4 ) 9.8 Hz, H-4), 4.44 (s, 1H, 3°-OH), 3.88-4.00
(m, 2H, H-3, H-5), 3.30 (d, 1H, J4ax,4eq ) 16.9 Hz, H-4aax), 3.24
(d, 1H, J4ax,4eq ) 16.9 Hz, H-4aeq), 2.28-2.43 (m, 2H, H-2aax,
H-2aeq), 2.26 (s, 3H, C(O)CH3), 2.16 (s, 3H, OC(O)CH3), 2.00
(ddd, 1H, J2ax,2eq ) J2ax,3 ) 13.6 Hz, J1,2ax ) 3.9 Hz, H-2ax), 1.81
(dd, 1H, J2ax,2eq ) 13.6 Hz, J2eq,3 ) 4.0 Hz, H-2eq), 1.25 (d, 3H,
J5,6 ) 6.3 Hz, H-6). 13C NMR (125 MHz, CDCl3): δC 211.4 (Cd
O), 169.9 (OC(O)CH3), 133.7 (Ar), 131.7 (Ar), 131.6 (Ar), 130.6
(Ar), 128.4 (Ar), 128.1 (Ar), 127.8 (Ar), 127.1 (Ar), 126.7 (Ar),
125.9 (Ar), 92.9 (C-1), 78.0 (C-3a), 75.4 (C-1a), 71.9 (C-4), 66.6
(C-5), 57.4 (C-3), 39.2 (C-4a), 37.7 (C-2a), 34.9 (C-2), 24.4 (C(O)-
CH3), 20.8 (OC(O)CH3), 17.5 (C-6). ESI HRMS calcd for
C24H27N3O6Na: 476.1798 [M + Na]+. Found: 476.1793.
(1S,3S)-1-O-(4-Azido-2,3,4,6-tetradeoxy-â-L-threo-hexopyra-
nosyl)-3-acetyl-3-hydroxyl-1,2,3,4-tetrahydro-anthracene (55).
Yield 50%; Rf ) 0.24 (5:1, hexanes-EtOAc); [R]D -28.9 (c 0.4,
CHCl3). 1H NMR (400 MHz, CDCl3): δH 7.74-7.86 (m, 3H, Ar),
7.66 (s, 1H, Ar), 7.43-7.51 (m, 2H, Ar), 5.15 (d, 1H, J1,2ax ) 3.5
Hz, H-1a), 5.00-5.05 (m, 1H, H-1), 4.72 (s, 1H, 3°-OH), 4.15 (dq,
1H, J5,6 ) 6.5 Hz, J4,5 ) 1.7 Hz, H-5), 3.56 (br s, 1H, H-4), 3.32
(d, 1H, J4ax,4eq ) 16.0 Hz, H-4aax), 3.25 (d, 1H, J4ax,4eq ) 16.0 Hz,
H-4aeq), 2.28-2.41 (m, 5H, H-2aax, H-2aeq, C(O)CH3), 2.22-2.31
(m, 2H, H-3aax, H-3aeq), 2.12-2.22 (m, 1H, H-3eq), 1.90-2.00
(m, 2H, H-2ax, H-3ax), 1.40-1.47 (m, 1H, H-2eq), 1.35 (d, 3H,
J5,6 ) 6.5 Hz, H-6). 13C NMR (125 MHz, CDCl3): δC 211.9 (Cd
O), 133.7 (Ar), 131.8 (Ar), 131.6 (Ar), 130.8 (Ar), 128.8 (Ar), 128.2
(Ar), 127.9 (Ar), 127.1 (Ar), 126.6 (Ar), 125.9 (Ar), 93.3 (C-1),
78.3 (C-3a), 71.4 (C-1a), 66.1 (C-5), 59.9 (C-4), 39.4 (C-4a), 37.2
(C-2a), 24.6 (C(O)CH3), 23.9 (C-3), 22.9 (C-2), 18.1 (C-6). ESI
HRMS calcd for C22H25N3O4Na: 418.1743 [M + Na]+. Found:
418.1737.
1
(c 1.0, CHCl3). H NMR (500 MHz, CDCl3): δH 7.18-7.44 (m,
9H, Ar), 5.02 (d, 1H, J1,2ax ) 4.1 Hz, H-1), 4.88-4.94 (m, 2H,
H-1a, PhCH2), 4.67 (d, 1H, J ) 10.5 Hz, PhCH2), 4.55 (s, 1H,
3°-OH), 3.82-3.92 (m, 2H, H-3, H-5), 3.20 (d, 1H, J4ax,4eq ) 16.1
Hz, H-4aax), 3.00-3.10 (m, 2H, H-4, H-4aeq), 2.35 (s, 3H, C(O)-
CH3), 2.23-2.26 (m, 2H, H-2aax, H-2aeq), 2.00 (ddd, 1H, J2ax,2eq
) J2ax,3 ) 13.3 Hz, J1,2ax ) 4.1 Hz, H-2ax), 1.81 (dd, 1H, J2ax,2eq
) 13.3 Hz, J2eq,3 ) 4.1 Hz, H-2eq), 1.25 (d, 3H, J ) 6.2 Hz, H-6).
13C NMR (125 MHz, CDCl3): δC 212.3 (CdO), 137.4 (Ar), 134.1
(Ar), 131.7 (Ar), 130.1 (Ar), 130.0 (Ar), 129.3 (Ar), 128.6 (2 ×
Ar), 128.4 (2 × Ar), 128.1 (Ar), 126.1 (Ar), 93.3 (C-1), 83.8 (C-
4), 78.1 (C-3a), 75.4 (PhCH2), 71.2 (C-1a), 68.2 (C-5), 59.8 (C-3),
39.0 (C-4a), 36.2 (C-2a), 35.5 (C-2), 24.8 (C(O)CH3), 18.2 (C-6).
ESI HRMS calcd for C25H29N3O5Na: 474.2005 [M + Na]+.
Found: 474.2001.
(1S,3S)-1-O-(3-Azido-2,3,6-deoxy-â-L-lyxo-hexopyranosyl)-3-
acetyl-3-hydroxyl-1,2,3,4-tetrahydro-naphthalene (63). Yield
91%; Rf ) 0.31 (3:1, hexanes-EtOAc); [R]D -114.7 (c 0.8, CHCl3).
1H NMR (400 MHz, CDCl3): δH 7.18-7.37 (m, 4H, Ar), 5.13 (d,
1H, J1,2ax ) 4.0 Hz, H-1), 4.90 (dd, 1H, J1,2ax ) J1,2eq ) 3.4 Hz,
H-1a), 4.50 (s, 1H, 2°-OH), 4.01 (q, 1H, J5,6 ) 6.6 Hz, H-5), 3.70-
3.80 (m, 2H, H-3, H-4), 3.15 (d, 1H, J4ax,4eq ) 17.0 Hz, H-4aax),
3.02 (d, 1H, J4ax,4eq ) 17.0 Hz, H-4aeq), 2.32 (s, 3H, C(O)CH3),
2.22-2.26 (m, 2H, H-2aax, H-2aeq), 2.06 (ddd, 1H, J2ax,2eq ) J2ax,3
) 13.0 Hz, J1,2ax ) 4.0 Hz, H-2ax), 1.75 (dd, 1H, J2ax,2eq ) 13.0
Hz, J2eq,3 ) 4.0 Hz, H-2eq), 1.33 (d, 3H, J5,6 ) 6.6 Hz, H-6). 13C
NMR (100 MHz, CDCl3): δC 211.9 (CdO), 133.7 (Ar), 131.8 (Ar),
129.9 (Ar), 129.2 (Ar), 129.1 (Ar), 126.2 (Ar), 94.4 (C-1), 77.9
(C-3a), 71.9 (C-1a), 69.4 (C-4), 66.6 (C-5), 56.6 (C-3), 38.9 (C-4a),
36.1 (C-2a), 28.4 (C-2), 24.6 (C(O)CH3), 16.7 (C-6). ESI HRMS
calcd for C18H23N3O5Na: 384.1535 [M + Na]+. Found: 384.1530.
(1S,3S)-1-O-(3-Azido-2,3,6-deoxy-â-L-arabino-hexopyranosyl)-
3-acetyl-3-hydroxyl-1,2,3,4-tetrahydro-naphthalene (64). Yield
70%; Rf ) 0.38 (3:1, hexanes-EtOAc); [R]D -74.6 (c 0.7, CHCl3).
1H NMR (400 MHz, CDCl3): δH 7.19-7.38 (m, 4H, Ar), 5.03 (d,
1H, J1,2ax ) 3.5 Hz, H-1), 4.90 (dd, 1H, J1,2ax ) J1,2eq ) 3.5 Hz,
H-1a), 4.54 (br s, 1H, 2°-OH), 3.68-3.83 (m, 2H, H-3, H-5), 3.13-
3.21 (m, 2H, H-4, H-4aax), 3.01 (d, 1H, J4ax,4eq ) 17.2 Hz, H-4a-
eq), 2.33 (s, 3H, C(O)CH3), 2.23-2.27 (m, 2H, H-2aax, H-2aeq),
2.00 (m, 1H, H-2eq), 1.69 (ddd, 1H, J2ax,2eq ) J2ax,3 ) 12.9 Hz,
J1,2ax ) 3.5 Hz, H-2ax), 1.34 (d, 3H, J5,6 ) 6.2 Hz, H-6). 13C NMR
(100 MHz, CDCl3): δC 212.1 (CdO), 133.9 (Ar), 131.8 (Ar), 130.0
(Ar), 129.9 (Ar), 129.2 (Ar), 126.1 (Ar), 93.6 (C-1), 78.0 (C-3a),
75.9 (C-1a), 71.4 (C-4), 68.4 (C-5), 60.0 (C-3), 38.8 (C-4a), 36.1
(C-2a), 34.8 (C-2), 24.6 (C(O)CH3), 17.7 (C-6). ESI HRMS calcd
for C18H23N3O5Na: 384.1535 [M + Na]+. Found: 384.1531.
(1S,3S)-1-O-(3-Azido-2,3,6-deoxy-â-L-lyxo-hexopyranosyl)-3-
acetyl-3-hydroxyl-1,2,3,4-tetrahydro-anthracene (65). Yield 61%;
(1S,3S)-1-O-(4-O-Acetyl-3-azido-2,3,6-deoxy-â-L-arabino-hex-
opyranosyl)-3-acetyl-3-hydroxyl-1,2,3,4-tetrahydro-naphtha-
lene (56). Yield 31%; Rf ) 0.17 (3:1, hexanes-EtOAc); [R]D +65.4
1
(c 0.3, CHCl3). H NMR (400 MHz, CDCl3): δH 7.11-7.48 (m,
4H, Ar), 5.12 (dd, 1H, J1,2sx) J1,2eq ) 2.9 Hz, H-1a), 4.81 (dd, 1H,
J1,2ax ) 9.6 Hz, J1,2eq ) 1.9 Hz, H-1), 4.70 (dd, 1H, J4,5 ) J3,4
)
9.5 Hz, H-4), 4.14 (s, 1H, 3°-OH), 3.48-3.61 (m, 2H, H-3, H-5),
3.10 (d, 1H, J4ax,4eq ) 16.7 Hz, H-4aax), 2.99 (d, 1H, J4ax,4eq
)
16.7 Hz, H-4aeq), 2.36 (s, 3H, C(O)CH3), 2.16-2.28 (m, 3H, H-2ax,
H-2aax, H-2aeq), 2.14 (s, 3H, OC(O)CH3), 1.67-1.76 (m, 1H,
H-2eq), 1.29 (d, 3H, J5,6 ) 6.1 Hz, H-6). 13C NMR (125 MHz,
CDCl3): δC 212.3 (CdO), 169.9 (OC(O)CH3), 133.1 (Ar), 133.0
(Ar), 130.7 (Ar), 130.0 (Ar), 128.9 (Ar), 126.9 (Ar), 96.5 (C-1),
77.8 (C-3a), 74.8 (C-1a), 72.5 (C-4), 71.1 (C-5), 59.8 (C-3), 39.0
(C-4a), 36.3 (C-2a), 34.0 (C-2), 24.7 (C(O)CH3), 20.9 (OC(O)CH3),
17.6 (C-6). ESI HRMS calcd for C20H25N3O6Na: 426.1641 [M +
Na]+. Found: 426.1635.
1
(1S,3S)-1-O-(4-O-Acetyl-3-azido-2,3,6-deoxy-â-L-arabino-hexo-
pyranosyl)-3-acetyl-3-hydroxyl-1,2,3,4-tetrahydro-anthracene (57).
Rf ) 0.34 (1:1, hexanes-EtOAc); [R]D -55.4 (c 0.2, CHCl3). H
NMR (400 MHz, CDCl3): δH 7.77-7.86 (m, 3H, Ar), 7.67 (s, 1H,
Ar), 7.45-7.52 (m, 2H, Ar), 5.09-5.16 (m, 2H, H-1a, H-1), 4.50
Yield 19%; Rf
)
0.15 (3:1, hexanes-EtOAc); [R]D
J. Org. Chem, Vol. 72, No. 8, 2007 2927