4096 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Agouridas et al.
was then added dropwise. After 1 h of stirring at -10 °C, 180
mL of water was added while maintaining the internal
temperature at 0 °C. The white precipitate was filtered off,
washed with cold water, and finally dissolved in ether. The
solution was dried over MgSO4 and concentrated to afford after
drying in vacuo 9.47 g (67%) of 44 as a white foam. MS(EI):
706+ (M+). 1H NMR (CDCl3): δ 0.95 (t, 3H) CH3CH2, 1.30 (s,
3H) 6-CH3, 1.84 (d, 3H) 10-CH3, 1.87 (s, 3H) 12-CH3, 2.05 (s,
3H) 2′-OCOCH3, 2.24 (s, 6H) N(CH3)2, 2.65 (m, 1H) H3′, 2.78
(s, 3H) 6-O-CH3, 3.03 (m, 1H) H4, 3.06 (m, 1H) H8, 3.5 (m, 1H)
H5′, 3.75 (q, 1H) H2, 4.12 (d, 1H) H5, 4.35 (d, 1H) H1′, 4.73 (dd,
1H) H2′, 5.69 (dd, 1H) H13, 6.8 (sl, 1H) H11, 7.08-7.38-8.10
(dd, 3H) imidazole.
1H) H2′, 3.50 to 3.65 (m, 4H) H11-H5′ and CH2NCO, 3.86 (q,
1H) H2, 4.09 (sl, 1H) H11, 4.25 (d,1H) and 4.29 (d, 1H) H1′ and
H5, 4.96 (dd, 1H) H13. Anal. (C35H60N2O11) C, H, N.
11,12-Did eoxy-3-d escla d in osyl-6-O-m eth yl-3-oxo-12,11-
(oxycar bon yl((3-ph en ylpr opyl)im in o))er yth r om ycin (48).
Yield: 19%. Mp: 210-212 °C. MS(EI): 731 (M+). 1H NMR
(CDCl3): δ 0.85 (t, 3H) CH3CH2, 1.32 (s, 3H) 6-CH3, 1.47 (s,
3H) 12-CH3, 2.27 (s, 6H) N(CH3)2, 2.45 (td, 1H) H3′, 2.53 (s,
3H) 6-O-CH3, 2.65 (m, 3H) H8 and CH2φ, 3.10 (m, 2H) H4 and
H10, 3.18 (dd, 1H) H2′, 3.54 (m, 1H) H5′, 3.60 (s, 1H) H11, 3.65
(m, 2H) CH2N, 3.84 (q, 1H) H2, 4.22 (d, 1H) and 4.28 (d, 1H)
H1′ and H5, 4.98 (dd, 1H) H13, 7.1-7.3 (m, 5H) phenyl. Anal.
(C40H62N2O10) C, H, N.
(10R)- a n d (10S)-11,12-Did eoxy-3-O-d escla d in osyl-6-O-
m eth yl-3-oxo-11,12-(im in oca r bon yloxy) (45a ,b). To a so-
lution of 44 (1.2 g, 1.69 mmol) in 24 mL of acetonitrile at -40
°C was added 24 mL of liquid ammonia. The reaction was
stirred for 6 h at -40 °C, then 2.4 mL of water was added,
and the reaction mixture was allowed to stand at room
temperature for 12 h. The solution was concentrated in vacuo,
diluted with methylene chloride, washed with water and brine,
and dried over MgSO4. The crude product was dissolved in
10 mL of methanol and stirred for 4 h 30 min at room
temperature. The solvent was removed, and the products were
purified by column chromatography eluting with 95:5 meth-
ylene chloride/methanol to afford 0.44 g (43%) of 45a and 0.22
g (22%) of 45b as white foams. 45a : MS(FAB): 613+ (M+H)+.
1H NMR (CDCl3): δ 0.88 (t, 3H) CH3CH2, 1.32 (s, 3H) 12-CH3,
1.48 (s, 3H) 6-CH3, 2.26 (s, 6H) N(CH3)2, 2.44 (m, 1H) H3′, 2.58
(m, 3H) H8, 2.61 (s, 3H) 6-O-CH3, 2.89 (ql, 1H) H10, 3.04 (m,
11,12-Did eoxy-3-d escla d in osyl-6-O-m eth yl-3-oxo-12,11-
(oxyca r b on yl((4-(3-ch lor op h e n yl)b u t yl)im in o))e r yt h -
r om ycin (49). Yield: 24%. Mp: 191-193 °C. MS(SIMS):
779+ (MH+). NMR (CDCl3): δ 0.85 (t, 3H) CH3CH2, 1.35 (s,
3H), 1.47 (s, 3H) 6-CH3, 12-CH3, 2.26 (s, 6H) N(CH3)2, 2.44
(m, 1H) H3′, 2.60 (m, 3H) H8 and CH2φ, 2.61 (s, 3H) 6-O-CH3,
3.07 (m, 1H) H4, 3.11 (ql, 1H) H10, 3.18 (dd, 1H) H2′, 3.54 (m,
1H) H5′, 3.57 (s, 1H) H11, 3.65 (m, 2H) CH2N, 3.85 (q, 1H) H2,
4.24 (d,1H) H5, 4.29 (d, 1H) H1′, 4.96 (dd, 1H) H13, 7.04 (m,
1H) and 7.15 (m, 3H) phenyl. Anal. (C41H63ClN2O10) C, H,
Cl, N.
11,12-Did eoxy-3-d escla d in osyl-6-O-m eth yl-3-oxo-12,11-
(oxyca r b on yl((3-(p h e n yla m in o)p r op yl)im in o))e r yt h -
r om ycin (50). Yield: 26%. Mp: 206 °C. MS(SIMS): 746+
(MH+). 1H NMR (CDCl3): δ 0.83 (t, 3H) CH3CH2, 1.35 (s, 3H)
6-CH3, 1.47 (s, 3H) 12-CH3, 2.26 (s, 6H) N(CH3)2, 2.45 (m, 1H)
H3′, 2.63 (s, 3H) 6-O-CH3, 2.65 (m, 1H) H8, 3.00-3.27 (m, 4H)
H4-H10 and CH2NH, 3.53 (m, 1H) H5′, 3.59 (s, 1H) H11, 3.65-
3.80 (m, 2H) CH2NCO, 3.85 (q, 1H) H2, 4.23 (d,1H) and 4.28
1H) H4, 3.17 (dd, 1H) H2′, 3.54 (m, 1H) H5′, 3.74 (sl, 1H) H11
3.83 (q, 1H) H2, 4,21 (d,1H) H5, 4.31 (d, 1H) H1′, 5.09 (dd, 1H)
13, 5.72 (s, 1H) NHCO. Anal. (C31H52N2O10) C, H, N. 45b:
,
H
(d, 1H) H1′ and H5, 4.95 (dd, 1H) H13, 6.62 (m, 2H) Horthophenyl
,
MS(FAB): 613+ (M + H)+. 1H NMR (CDCl3): δ 0.88 (t, 3H)
CH3CH2, 1.29 and 1.69 (s, 3H) 6-CH3 and 12-CH3, 2.28 (s, 6H)
N(CH3)2, 2.48 (m, 1H) H3′, 2.68 (m, 3H) H8, 2.78 (s, 3H) 6-O-
CH3, 2.82 (dq, 1H) H10, 3.03 (m, 1H) H4, 3.19 (dd, 1H) H2′, 3.53
(m, 1H) H5′, 3.55 (d, J ) 2.5 Hz, 1H) H11, 3.88 (q, 1H) H2, 4,19
(d,1H) H5, 4.30 (d, 1H) H1′, 5.02 (dd, 1H) H13, 5.41 (s, 1H)
NHCO. Anal. (C31H52N2O10) C, H, N.
6.66(m,1H)Hparaphenyl,7.15(m,2H)Hmetaphenyl. Anal. (C40H63N3O10)
C, H, N.
11,12-Did eoxy-3-d escla d in osyl-6-O-m eth yl-3-oxo-12,11-
(oxyca r b on yl((2-(p h en ylm et h oxy)et h yl)im in o))er yt h -
r om ycin (51). Yield: 20%. Mp: 206 °C. MS(SIMS): 747+
(MH+). 1H NMR (CDCl3): δ 0.86 (t, 3H) CH3CH2, 1.35 (s, 3H)
6-CH3, 1.48 (s, 3H) 12-CH3, 2.27 (s, 6H) N(CH3)2, 2.45 (m, 1H)
H3′, 2.60 (m, 1H) H8, 2.68 (s, 3H) 6-O-CH3, 3.10 (m, 2H) H4
11,12-Did eoxy-3-O-d escla d in osyl-6-O-m eth yl-3-oxo-12,-
11-(oxycar bon yl((4-ph en ylbu tyl)im in o))er yth r om ycin (46).
Sta ge A: A mixture of 44 (0.9 g, 1.275 mmol) and 4-phenyl-
butylamine (0.745 g, 5 mmol) in 3 mL of CH3CN and 0.3 mL
of water was stirred at 55 °C for 5 h. The reaction mixture
was poured into a 0.5 M aqueous solution of sodium dihydro-
genophosphate and extracted with ethyl acetate. The extracts
were washed with water, dried over Na2SO4, filtered, and
concentrated to give 0.9 g of oil. The product was purified by
column chromatography eluting with 96:4 ethyl acetate/
triethylamine to afford 0.63 g (63%) of 46-2′OAc as a white
foam.
Sta ge B: 46-2′OAc (0.6 g, 0.76 mmol) was stirred for 15 h
in 10 mL of methanol at room temperature. The solvent was
removed in vacuo, and the crude product was purified by
column chromatography eluting with 96:4 ethyl acetate/
triethylamine to afford 0.538 g (96%) of 46 as a white foam.
MS(FAB): 745+ (M + H+). 1H NMR (CDCl3): δ 0.85 (t, 3H)
CH3CH2, 1.34 (s, 3H) 6-CH3, 1.47 (s, 3H) 12-CH3, 2.29 (s, 6H)
N(CH3)2, 2.48 (m, 1H) H3′, 2.61 (s, 3H) 6-O-CH3, 2.60 (m, 3H)
H8 and CH2Φ, 3.10 (m, 2H) H4 and H10, 3.20 (dd, J ) 7.5 Hz,
1H) H2′, 3.50 (m, 1H) H5′, 3.59 (s, 1H) H11, 3.70 (m, 2H) CH2-
NCO, 3.85 (q, 1H) H2, 4.23 (d, J ) 8 Hz, 1H) H5, 4.27 (d, J )
7.5 Hz, 1H) H1′, 4.97 (dd, 1H) H13, 7.1-7.3 (m, 5H) phenyl.
Anal. (C41H64N2O10) C, H, N.
and H10, 3.18 (dd, 1H) H2′, 3.55 (m, 1H) H5′, 3.65 (s, 1H) H11
,
3.60-3.95 (m, 4H) -OCH2CH2NCO, 3.84 (q, 1H) H2, 4.25 (d,-
1H) and 4.30 (d, 1H) H1′ and H5, 4.59 (AB, 2H) O-CH2Φ, 5.11
(dd, 1H) H13, 7.18-7.33 (m, 5H) phenyl. Anal. (C40H62N2O11
C, H, N.
)
11,12-Did eoxy-3-d escla d in osyl-6-O-m et h yl-3-oxo-12,-
11-(oxyca r b on yl((2-(N ,N -p h e n ylm e t h yla m in o)e t h yl)-
im in o))er yth r om ycin (52). Yield: 35%. MS(FAB): 760+ (M
+ H+). 1H NMR (CDCl3): δ 0.77 (t, 3H) CH3CH2, 1.24 (s, 3H)
12-CH3, 1.48 (s, 3H) 6-CH3, 2.18 (s, 3H) N(CH3)2, 2.88 (s, 6H)
N(CH3)2, 2.4-2.8 (m, 4H) CH2N-H3′-H8, 2.65 (s, 3H) 6-O-CH3,
3.00-3.25 (m, 2H) H4 and H2′, 3.48-3.70 (d, 2H) CH2Φ, 3.57
(s, 1H) H11, 3.75-4.00 (m, 2H) CH2NCO, 3.81 (q, 1H) H2, 4.23
(d, 1H) H5, 4.28 (d, 1H) H1′, 5.08 (dd, 1H) H13, 7.15-7.35 (m,
5H) phenyl. Anal. (C41H65N3O10) C, H, N.
11,12-Did eoxy-3-d escla d in osyl-6-O-m eth yl-3-oxo-12,11-
(oxyca r bon yl((4-(6-m eth oxy-4-qu in olin yl)bu tyl)im in o))-
er yth r om ycin (53). Yield: 68%. MS(SIMS): 826+ (MH+).
1H NMR (CDCl3): δ 0.83 (t, 3H) CH3CH2, 1.33 (s, 3H) 6-CH3,
1.48 (s, 3H) 12-CH3, 2.32 (s, 6H) N(CH3)2, 2.50 (m, 1H) H3′,
2.60 (m, 1H) H8, 2.61 (s, 3H) 6-O-CH3, 3.07 (m, 2H) CH2-Ar,
3.00-3.2 (m, 2H) H4 and H10, 3.22 (dd, 1H) H2′, 3.55 (m, 1H)
H5′, 3.59 (s, 1H) H11, 3.73 (m, 2H) CH2NCO, 3.86 (q, 1H) H2,
3.98 (s, 3H) CH3O-Ar, 4.23 (d,1H) H5, 4.30 (d, 1H) H1′, 4.96
(dd, 1H) H13, [7.22 (d, 1H) H3, 7.25 (d, 1H) H5, 7.35 (dd, 1H)
H7, 8.00 (d, 1H) H8, 8.65 (d, 1H) H2, quinoline]. Anal.
(C45H67N3O11) C, H, N.
Following the same procedures as described for 46 and
starting from the appropriate amines, the following compounds
were made.
11,12-Did eoxy-3-O-d escla d in osyl-6-O-m eth yl-3-oxo-12,-
11-(oxyca r bon yl(bu tylim in o))er yth r om ycin (47). Yield:
60%. Mp: 220 °C. MS(EI): 669+ (M+). 1H NMR (CDCl3): δ
0.86 and 0.92 (t, 6H) CH3CH2, 1.35 (s, 3H), 1.47 (s, 3H) 6-CH3,
12-CH3, 2.28 (s, 6H) N(CH3)2, 2.48 (m, 1H) H3′, 2.60 (m, 1H)
H8, 2.67 (s, 3H) 6-O-CH3, 3.10 (m, 2H) H4 and H10, 3.19 (dd,
11,12-Did eoxy-3-d escla d in osyl-6-O-m eth yl-3-oxo-12,11-
(oxyca r bon yl((4-(8-m eth oxy-4-qu in olin yl)bu tyl)im in o))-
er yth r om ycin (54). Yield: 59%. MS(SIMS): 826+ (MH+).
1H NMR (CDCl3): δ 0.82 (t, 3H) CH3CH2, 1.35 (s, 3H) 6-CH3,
1.48 (s, 3H) 12-CH3, 2.30 (s, 6H) N(CH3)2, 2.50 (m, 1H) H3′,