3698 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 22
Kinder et al.
(CDCl3): δ 8.00 (d, J ) 6.3, 1H), 5.93 (t, J ) 5.5, 1H), 5.83 (d,
J ) 15.8, 1H), 5.42 (dd, J ) 15.7 and 7.3, 1H), 4.93 (m, 1H),
4.55 (dd, J ) 9.5 and 6.3, 1H), 4.23 (m, 2H), 3.82 (m, 2H), 3.61
(t, J ) 6.1, 1H), 3.57 (m, 1H), 3.55 (s, 3H), 3.49 (dd, J ) 15.6
and 5.2, 1H), 3.29 (d, J ) 7.3, 1H), 3.10 (s, 1H), 2.50 (m, 1H),
2.17 (m, 1H), 1.95 (m, 4H), 1.70 (m, 1H), 1.65 (m, 2H), 1.55
(m, 4H), 1.47 (m, 4H), 1.02 (s, 9H). 13C NMR (CDCl3): δ 176.17,
174.07, 172.14, 145.75, 123.20, 81.08, 74.51, 72.76, 72.44,
66.79, 59.95, 51.67, 45.07, 43.36, 33.03, 31.95, 30.91, 30.84,
29.43, 28.24, 28.21, 26.26, 25.73. Anal. (C26H44N2O8‚0.6H2O)
C, H, N.
r id yl]eth oxy)-2H-a zep in -3-yl]n on -6-en a m id e (8i). Follow-
ing essentially the procedure described for 8a and using in
place of myristic acid an approximately equivalent amount of
a mixture consisting of 3-pyridylacetic acid, EDCI, and DMAP,
8i was obtained. HPLC reverse-phase retention time ) 7.9
1
min; normal-phase retention time ) 12.1 min (method 2). H
NMR (CDCl3): δ 8.51 (s, 2H), 7.98 (d, J ) 6.0, 1H), 7.61 (d, J
) 7.8, 1H), 7.27 (m, 2H), 6.29 (m, 1H), 5.80 (d, J ) 15.6, 1H),
5.4 (dd, J ) 15.6 and 7.3, 1H), 4.96 (m, 1H), 4.55 (m, 1H), 4.21
(m, 1H), 3.82 (m, 2H), 3.67-3.45 (m, 9H), 2.2-1.7 (m, 5H),
1.0 (s, 9H). 13C NMR (CDCl3): δ 174.1, 172.0, 169.9, 150.2,
148.7, 145.7, 136.9, 129.4, 123.6, 123.4, 81.5, 74.4, 72.6, 72.6,
68.3, 59.8, 51.6, 43.2, 38.6, 33.0, 31.8, 29.5, 25.6.
(2R,3R,4S,5R,6E)-3,4,5-Tr ih yd r oxy-2-m et h oxy-8,8-d i-
m eth yl-N-[(3S,6R)-h exa h yd r o-2-oxo-6-(cycloh exylm eth -
ylca r bon yl)oxy-2H-a zep in -3-yl]n on -6-en a m id e (8e). Fol-
lowing essentially the procedure for 8a and using in place of
myristic acid an approximately equivalent amount of cyclo-
hexylacetic acid, 8e was obtained. HPLC reverse-phase reten-
tion time ) 13.8 min, normal-phase retention time ) 7.7 min
(2R,3R,4S,5R,6E)-3,4,5-Tr ih yd r oxy-2-m et h oxy-8,8-d i-
m e t h yl-N -[(3S ,6R )-h e xa h yd r o-2-oxo-6-(1-oxo-3-[3-p y-
r id yl]p r op oxy)-2H-a zep in -3-yl]n on -6-en a m id e (8j). Fol-
lowing essentially the procedure described for 8a and using
in place of myristic acid an approximately equivalent amount
of 3-pyridinepropionic acid, 8j was obtained. HPLC reverse-
phase retention time ) 8.1 min; normal-phase retention time
1
(method 1). H NMR (CDCl3): δ 7.98 (d, J ) 6.2, 1H), 5.83-
5.7 (m, 1H), 5.80 (d, J ) 15.6, 1H), 4.94 (m, 1H), 4.52 (m, 1H),
4.2 (m, 2H), 3.78 (m, 2H), 3.6-3.48 (m, 3H), 3.52 (s, 3H), 3.23
(d, J ) 7.3, 1H), 3.06 (m, 1H), 2.80 (d, J ) 7, 2H), 2.13-1.63
(m, 12H), 1.30-0.85 (m, 5H), 1.0 (s, 9H). 13C NMR (CDCl3): δ
174.0, 172.3, 172.2, 145.7, 123.3, 81.1, 74.5, 72.8, 72.5, 67.0,
60.0, 51.7, 43.5, 42.1, 35.0, 33.0, 32.0, 29.5, 26.1, 26.0, 25.7.
1
) 12.9 min (method 2). H NMR (CDCl3): δ 8.46 (s, 2H), 7.97
(d, J ) 6.2, 1H), 7.53 (m, 1H), 7.23 (m, 1H), 5.88 (t, J ) 6.0,
1H), 5.81 (d, J ) 15.6, 1H), 5.4 (dd, J ) 15.6 and 7.3, 1H),
4.93 (m, 1H), 4.27 (s, 1H), 4.23-4.19 (m, 1H), 3.8 (m, 2H), 3.59
(d, J ) 5.2, 1H), 3.52 (s, 3H), 3.48 (m, 2H), 3.28 (s, 1H), 3.19
(s, 1H), 2.95 (t, J ) 7.3, 2H), 2.67 (t, J ) 7.3, 2H), 2.1-1.67
(m, 6H), 1.0 (s, 9H). 13C NMR (CDCl3): δ 174.0, 172.0, 171.5,
149.7, 148.0, 145.7, 136.0, 135.5, 123.6, 123.2, 81.2, 74.5, 72.7,
72.5, 67.6, 59.8, 51.6, 43.3, 35.2, 33.0, 31.8, 29.4, 28.0, 25.5.
(2R,3R,4S,5R,6E)-3,4,5-Tr ih yd r oxy-2-m et h oxy-8,8-d i-
m e t h y l -N -[ ( 3 S ,6 R ) -h e x a h y d r o -2 -o x o -6 -( 1 -o x o -2 -
p h en yleth oxy)-2H-a zep in -3-yl]n on -6-en a m id e (8f). Fol-
lowing essentially the procedure described for 8a and using
in place of myristic acid an approximately equivalent amount
of phenylacetic acid, 8f was obtained. HPLC reverse-phase
retention time ) 11.9 min, normal-phase retention time ) 7.8
min (method 1). 1H NMR (CDCl3): δ 7.96 (d, J ) 6.2, 1H),
7.28 (m, 5H), 5.80 (d, J ) 15.8, 1H), 5.68 (t, J ) 6.4, 1H), 5.39
(dd, J ) 15.8 and 7.3, 1H), 4.93 (m, 1H), 4.53-4.47 (m, 1H),
4.22-4.18 (m, 2H), 3.60-3.56 (m, 2H), 3.52 (s, 3H), 3.48-3.38
(m, 2H), 3.27 (d, J ) 6.6, 1H), 3.08 (s, 1H), 2.15-1.67 (m, 5H),
1.0 (s, 9H). 13C NMR (CDCl3): δ 173.9, 172.1, 170.8, 145.8,
133.6, 129.2, 128.8, 127.4, 123.2, 81.1, 74.5, 72.7, 72.4, 67.6,
59.9, 51.6, 43.2, 41.5, 33.0, 31.8, 29.4, 25.5.
(2R,3R,4S,5R,6E)-3,4,5-Tr ih yd r oxy-2-m et h oxy-8,8-d i-
m et h yl-N-[(3S,6R)-h exa h yd r o-2-oxo-6-(1-oxo-3-p h en yl-
p r op oxy)-2H -a zep in -3-yl]n on -6-en a m id e (8g). Following
essentially the procedure for 8b and using in place of cyclo-
pentanecarbonyl chloride an approximately equivalent amount
of 3-phenylpropionyl chloride, 8g was obtained; mp 75-77 °C;.
1H NMR (CDCl3): δ 7.96 (d, J ) 6.2, 1H), 7.31 (t, J ) 7.3,
2H), 7.23 (t, J ) 7.6, 1H), 7.20 (d, J ) 7.4, 2H), 5.82 (d, J )
15.8, 1H), 5.62 (s, 1H), 5.41 (dd, J ) 15.8 and 7.1, 1H), 4.92 (s,
1H), 4.49 (dd, J ) 9.5 and 6.3, 1H), 4.22 (m, 2H), 3.80 (m, 2H),
3.60 (s, 1H), 3.52 (s, 3H), 3.37 (m, 3H), 3.17 (s, 1H), 2.95 (t, J
) 7.6, 2H), 2.67 (t, J ) 7.7, 2H), 2.06 (d, J ) 12.0, 1H), 1.96 (t,
J ) 12.8, 1H), 1.88 (s, 1H), 1.70 (m, 1H), 1.02 (s, 9H). 13C NMR
(CDCl3): δ 173.96, 172.05, 172.00, 145.68, 140.08, 128.61,
128.42, 126.52, 123.21, 81.18, 74.46, 72.69, 72.50, 67.14, 59.83,
51.49, 43.22, 35.78, 33.02, 31.79, 31.07, 29.43, 25.58. Anal.
(C27H40N2O8‚0.52H2O) C, H, N.
(2R,3R,4S,5R,6E)-3,4,5-t r ih yd r oxy-2-m et h oxy-8,8-d i-
m et h yl-N-[(3S,6R)-h exa h yd r o-2-oxo-6-(1-oxo-3-p h en yl-
2-p r op en oxy)-2H-a zep in -3-yl]n on -6-en a m id e (8h ). Fol-
lowing essentially the procedure for 8b and using in place of
cyclopentanecarbonyl chloride an approximately equivalent
amount of cinnamoyl chloride, 8h was obtained; mp 83-85
°C. 1H NMR (DMSO): δ 8.03 (m, 1H), 7.71 (d, J ) 16, 1H),
7.54 (m, 2H), 7.41 (m, 2H), 6.45 (d, J ) 16, 1H), 5.97 (m, 1H),
5.81 (d, J ) 16, 1H), 5.45 (dd, J ) 16 and 8, 1H), 5.09 (m, 1H),
4.58 (m, 1H), 4.22 (m, 2H), 3.81 (m, 2H), 3.62 (m, 4H), 3.54 (s,
3H), 3.30 (d, J ) 8, 1H), 3.10 (s, 1H), 2.25 (m, 1H), 2.00 (m,
3H), 1.02 (s, 9H). 13C NMR (DMSO): δ 174.10, 172.15, 166.01,
145.91, 145.75, 134.03, 130.70, 129.00, 128.22, 123.20, 117.34,
81.10, 74.50, 72.76, 72.46, 67.29, 59.93, 51.67, 43.51, 33.03,
32.00, 29.43, 25.75. Anal. (C27H38N2O8‚H2O) C, H, N.
(2R,3R,4S,5R,6E)-3,4,5-Tr ih yd r oxy-2-m et h oxy-8,8-d i-
m et h yl-N-[(3S,6R)-h exa h yd r o-2-oxo-6-(p h en ylca r b on -
yl)oxy-2H-a zep in -3-yl]n on -6-en a m id e (8k ). Following es-
sentially the procedure for 8b and using in place of cyclopen-
tanecarbonyl chloride an approximately equivalent amount of
benzoyl chloride, 8k was obtained. 1H NMR: δ 8.06 (d, J )
8.4, 2H), 7.63 (t, J ) 7.4, 1H), 7.50 (t, J ) 7.8, 2H), 5.82 (d, J
) 15.8, 1H), 5.44 (dd, J ) 15.8 and 7.6, 1H), 4.75 (dd, J ) 9.5
and 3.2, 1H), 4.16 (t, J ) 7.7, 1H), 3.88 (d, J ) 7.3, 1H), 3.80
(dd, J ) 7.1 and 2.0, 1H), 3.72 (d, J ) 15.6, 1H), 3.60 (dd, J )
6.9 and 2.0, 1H), 3.45 (s, 3H), 2.30 (d, J ) 15.3, 1H), 2.20 (m,
1H), 1.99 (m, 1H), 1.06 (s, 9H). 13C NMR: δ 175.05, 171.57,
165.44, 144.53, 132.97, 130.06, 129.19, 128.17, 123.98, 82.11,
73.77, 72.95, 71.20, 68.23, 57.34, 51.50, 47.52, 42.39, 32.34,
.
31.41, 28.46, 25.40. Anal. (C25H36N2O8 0.83H2O) C, H, N.
(2R,3R,4S,5R,6E)-3,4,5-Tr ih yd r oxy-2-m et h oxy-8,8-d i-
m et h yl-N-[(3S,6R)-h exa h yd r o-2-oxo-6-([4-p en t ylp h en -
yl]ca r bon yl)oxy-2H-a zep in -3-yl]n on -6-en a m id e (8l). Fol-
lowing essentially the procedure for 8b and using in place of
cyclopentanecarbonyl chloride an approximately equivalent
amount of 4-pentylbenzoyl chloride, 8l was obtained. 1H
NMR: δ 7.94 (d, J ) 8.5, 2H), 7.29 (d, J ) 8.1, 2H), 5.79 (d, J
) 15.4, 1H), 5.41 (dd, J ) 15.8 and 7.7, 1H), 5.17 (m, 1H),
4.72 (m, 1H), 4.12 (t, J ) 7.0, 1H), 3.85 (d, J ) 7.4, 1H), 3.76
(dd, J ) 7.0 and 1.8 1H), 3.61 (d, J ) 5.2, 1H), 3.57 (dd, J )
7.0 and 2.2, 1H), 3.42 (s, 3H), 2.67 (t, J ) 7.7, 2H), 2.20 (m,
2H), 1.95 (m, 2H), 1.63 (m, 2H), 1.32 (m, 4H), 1.02 (s, 9H),
0.89 (t, J ) 7.0, 3H). 13C NMR: δ 176.96, 173.72, 167.31,
150.82, 146.39, 131.14, 130.11, 129.08, 125.79, 83.93, 75.71,
74.78, 73.46, 73.07, 59.19, 53.29, 46.01, 37.30, 34.37, 34.20,
.
32.99, 32.48, 30.29, 30.14, 23.97, 14.79. Anal. (C30H46N2O8
0.5H2O) C, H, N.
(2R,3R,4S,5R,6E)-3,4,5-Tr ih yd r oxy-2-m et h oxy-8,8-d i-
m eth yl-N-[(3S,6R)-h exa h yd r o-2-oxo-6-([4-d ecylp h en yl]-
ca r bon yl)oxy-2H-a zep in -3-yl]n on -6-en a m id e (8m ). Fol-
lowing essentially the procedure described for 8a and using
in place of myristic acid an approximately equivalent amount
of decylbenzoic acid, 8m was obtained; mp 60-64 °C. 1H NMR
(CDCl3): δ 8.06 (d, J ) 6, 1H), 7.94 (d, J ) 8, 2H), 7.26 (d, J
) 8, 2H), 6.10 (t, J ) 7, 1H), 5.85 (d, J ) 16, 1H), 5.45 (dd, J
) 8 and 16, 1H), 5.22 (d, J ) 3, 1H), 4.64 (dd, J ) 6 and 8,
1H), 4.25 (t, J ) 6, 2H), 3.84 (dd, J ) 6 and 11, 2H), 3.69 (t, J
) 7, 1H), 3.63 (dd, J ) 5 and 8, 2H), 3.56 (s, 3H), 2.68 (t, J )
8, 2H), 2.34 (d, J ) 13, 1H), 2.14 (t, J ) 12, 1H), 2.04 (t, J )
11, 1H), 1.96 (t, J ) 3, 1H), 1.63 (m, 2H), 1.32 (m, 18H), 1.82
(2R,3R,4S,5R,6E)-3,4,5-Tr ih yd r oxy-2-m et h oxy-8,8-d i-
m e t h yl-N -[(3S ,6R )-h e xa h yd r o-2-oxo-6-(1-oxo-3-[3-p y-