4
502 J . Org. Chem., Vol. 66, No. 13, 2001
Svedhem et al.
3
2
0H), 3.47-3.43 (m, 2H), 2.9 (br s, 1H), 2.57-2.48 (dt, 2H),
.17 (t, J ) 7 Hz, 2H), 1.61-1.5 (m, 4H), 1.45-1.1 (m, 22H);
C NMR δ 173.2, 72.5, 70.3, 70.2, 69.9, 61.7, 39.1, 36.7, 34.0,
9.6, 29.5, 29.4, 29.3, 29.0, 28.4, 25.7, 24.6. Analytical data:
Analytical data: Calcd for C24
N 2.83%. Found: C 58.01%, H 10.09%, N 2.79%.
N-(11-H yd r oxy-3,6,9-t r ioxa u n d ecyl) 6-Mer ca p t oh ex-
H
49NO
7
S: C 58.15%, H 9.96%,
1
3
2
a n a m id e (3a ) [HS(CH
2 5 2 2 4
) CONH(CH CH O) H]. The general
4
5
9
Calcd for C32H65NO S: C 60.06%, H 10.24%, N 2.19%. Found:
C 59.8%, H 10.1%, N 2.3%.
procedure for amine coupling of 18 and 11a yielded 93%. TLC
1
f
(EtOAc/MeOH 10:1) R 0.2; H NMR δ 3.8-3.6 (12H), 3.44 (m,
N-(29-Hyd r oxy-3,6,9,12,15,18,21,24,27-n on a oxa n on a co-
2H), 2.53 (m, 2H), 2.86 (t, 2H), 2.32 (s, 3H), 2.18 (t, 2H), 1.7-
syl) 16-Mer ca p toh exa d eca n a m id e (1f) [HS(CH
CH CH O)10H]. The general procedure for amine coupling
of 16 and 11d yielded 90% as a white solid. TLC (EtOAc/MeOH
2
)
15CONH-
1.5 (4H), 1.35 (m, 2H).
(
2
2
Acidic deprotection yielded 73%. TLC (EtOAc/MeOH 4:1) R
f
1
0.5 H NMR δ 7.10 (br, 1H), 3.8-3.6 (12H), 3.47 (m, 2H), 3.45
(m, 2H), 2.53 (dt, 2H), 2.19 (t, 2H), 1.75-1.55 (4H), 1.43 (m,
2H), 1.31 (t, 1H); 13C NMR δ 173.09, 72.57, 70.66, 70.43, 70.37,
70.0-69.9, 61.55, 39.08, 36.29, 33.73, 28.00, 25.14, 24.44.
1
2
3
3
2
3
f
:1) R 0.2; H NMR δ 6.14 (br s, 1H), 3.74-3.47 (m, 38H),
.43 (m, 2H), 2.86 (t, J ) 7 Hz, 2H), 2.6 (br s, 1H), 2.32 (s,
H), 2.17 (t, J ) 7 Hz, 2H), 1.64-1.50 (m, 4H), 1.45-1.15 (m,
1
3
2H); C NMR δ 196.0, 173.3, 72.5, 70.4, 70.2, 70.0, 61.7, 39.1,
5
Analytical data: Calcd for C14H29NO S: C 51.99%, H 9.04%,
N 4.33%. Found: C 51.75%, H 8.9%, N 4.3%.
N-(17-Hyd r oxy-3,6,9,12,15-p en ta oxa h ep ta d ecyl) 6-Mer -
ca p toh exa n a m id e (3b) [HS(CH
The general procedure for amine coupling of 18 and 11b
yielded 85%. TLC (EtOAc/MeOH 10:1) R
6.7, 30.6, 29.6, 29.5, 29.4, 29.1, 28.8, 25.8.
Basic deprotection yielded 91% of a white solid. TLC (EtOAc/
1
2 5 2 2 6
) CONH(CH CH O) H].
MeOH 3:1) R
f
0.2. H NMR δ 6.19 (br s, 1H), 3.74-3.54 (m, 38
4
5
H), 3.46 (m, 2H), 2.67 (br s, 1 H), 2.50(dt, 2H), 2.17 (t, J ) 7
1
1
3
f
0.2; H NMR δ 3.8-
Hz, 2H), 1.7-1.5 (m, 4H), 1.4-1.15 (m, 22H); C NMR δ 173.3,
3
1
.5 (22H), 3.44 (m, 2H), 2.86 (t, 2H), 2.32 (s, 3H), 2.19 (t, 2H),
7
2
2.5, 70.4, 70.2, 70.0, 61.7, 39.2, 36.7, 34.1, 29.64, 29.58, 29.5,
73
9.4, 29.1, 28.4, 25.8, 24.6. Analytical data: Calcd for C36H -
.7-1.5 (4H), 1.35 (m, 2H).
Acidic deprotection yielded 82%. TLC (EtOAc/MeOH 4:1) R
f
NO11S: C 59.39%, H 10.11%, N 1.92%. Found: C 59.5%, H
1
1
<
0.1. H NMR δ 6.48 (br, 1H), 3.5-3.7 (22H), 3.45 (m, 2H),
0.1%, N 2.0%.
2
(
7
.53 (dt, 2H), 2.20 (t, 2H), 1.75-1.55 (4H), 1.43 (m, 2H), 1.35
t, 1H); 13C NMR δ 172.97, 72.60, 70.63, 70.6-70.5, 70.28,
0.16, 69.96, 61.69, 39.20, 36.38, 33.70, 27.97, 25.08, 24.44.
Analytical data: Calcd for C18 S: C 52.53%, H 9.06%,
N-(35-Hyd r oxy-3,6,9,12,15,18,21,24,27,30,33-d od eca oxa -
p en ta tr ia con tyl) 16-m er ca p toh exa d eca n a m id e (1g) [HS-
CH 15CONH(CH CH O)12H]. To a solution of 16 (23 mg,
.067 mmol), 11e (44 mg, 0.081 mmol), HOBt (9.0 mg, 0.10
mmol), and TEA (28 µL, 0.20 mmol) in CH Cl (20 mL) was
(
0
2
)
2
2
H
37NO
7
N 3.40%. Found: C 52.5%, H 9.3%, N 3.5%.
N-(11-Hyd r oxy-3,6,9-tr ioxa u n d ecyl) 3-Mer ca p top r op i-
2
2
added EDC (19 mg, 0.010 mol) at 0 °C. After 19 h, the solution
was acidified with hydrochloric acid (2 mL, 1 M HCl) and
on a m id e (4a ) [HS(CH
2 2 2 2 4
) CONH(CH CH O) H]. Compound
4
a was prepared following the general procedure for amine
concentrated. Chromatography of the residue (CH
0:1 f 15:1) yielded 64 mg of a crude product (contaminated
with TEA according to NMR). The product fraction was
dissolved in CH Cl
(20 mL) and washed with water (2 × 10
mL). The water phase was separated, and the CH Cl phase
was concentrated followed by preparative HPLC (MeOH/H
0:10) to provide the pure acetylated amide (16 mg, 28%). TLC
2 2
Cl /MeOH
4
4
coupling of 19 and 11a with the exception that chloroform/
3
EtOH 2:1 was used for extraction during workup. Yield 66%.
1
TLC (EtOAc/MeOH 10:1) R
f
0.1; H NMR δ 3.8-3.6 (12H), 3.52
2
2
(m, 2H), 3.45 (m, 2H), 3.15 (t, 2H), 2.50 (t, 2H), 2.32 (s, 3H).
2
2
Deacetylation was performed under acidic conditions as
described above with the exception that extraction during
workup was exchanged for coevaporation with toluene prior
2
O
9
1
f
(EtOAc/MeOH 3:1) R 0.1; H NMR δ 6.23 (br s, 1H), 3.74-
to purification by flash chromatography. Yield: 79%. TLC
3
1
2
3
.37 (m, 48H), 2.86 (t, J ) 7 Hz, 2H), 2.32 (s, 3H), 2.3 (br s,
H), 2.17 (t, J ) 7 Hz, 2H), 1.62-1.50 (m, 4H), 1.4-1.2 (m,
1
(
EtOAc/MeOH 4:1) R
f
0.4; H NMR δ 7.28 (br, 1H), 3.8-3.6
1
3
(12H), 3.48 (m, 2H), 3.45 (m, 2H), 2.82 (dt, 2H), 2.51 (t, 2H),
2H); C NMR δ 196.0, 173.3, 72.6, 70.6, 70.3, 70.2, 70.0, 61.7,
1
7
.62 (t, 1H); 13C NMR δ 170.91, 72.58, 70.69, 70.40, 70.22,
0.0-69.9, 61.55, 40.20, 39.17, 20.58. Analytical data: Calcd
9.2, 36.7, 30.6, 29.64, 29.58, 29.5, 29.4, 29.2, 29.1, 28.8, 25.8.
Basic deprotection and subsequent purification by HPLC
for C11
6.8%, H 8.3%, N 4.9%.
N-(17-Hyd r oxy-3,6,9,12,15-p en ta oxa h ep ta d ecyl) 3-Mer -
ca p top r op ion a m id e (4b) [HS(CH CONH(CH CH O) H].
5
H23NO S: C 46.96%, H 8.24%, N 4.98%. Found: C
1
yielded 7.5 mg (56%). TLC (EtOAc/MeOH 3:1) R
δ 6.13 (br s, 1H), 3.74-3.41 (m, 48H), 2.50 (dt, 2H), 2.17 (t, J
)
1
2
f
0.1; H NMR
4
7 Hz, 2H), 1.7-1.55 (m, 4H), 1.4-1.2 (m, 22H); 13C NMR δ
73.3, 72.5, 70.6, 70.4, 70.3, 70.0, 61.7, 39.1, 36.7, 34.1, 29.6,
9.5, 29.4, 29.1, 28.4, 25.8, 24.7. Analytical data: Calcd for
2
)
2
2
2
6
4
4
Compound 4b was prepared from compounds 19 and 11b
using the same procedure as for compound 4a . Amine coupling
yielded 59%. TLC (EtOAc/MeOH 10:1) R
40
C H81NO13S: C 58.87%, H 10.00%, N 1.72%. Found: C 58.9%,
H 10.1%, N 1.7%.
1
f
0.1; H NMR δ 3.5-
3
.8 (22H), 3.44 (m, 2H), 3.15 (t, 2H), 2.52 (t, 2H), 2.32 (s, 3H).
Acidic deprotection yielded 80%. TLC (EtOAc/MeOH 4:1) R
N-(11-Hyd r oxy-3,6,9-tr ioxa u n d ecyl) 12-m er ca p tod od e-
f
ca n a m id e (2a ) [HS(CH
eral procedure for amine coupling of 17 and 11a yielded 70%.
TLC (EtOAc/MeOH 10:1) R
2
)
11CONH(CH
2
CH
2
O)
4
H]. The gen-
1
<
0.1; H NMR δ 6.71 (br, 1H), 3.75-3.55 (22H), 3.45 (m, 2H),
13
2
7
2
8
.82 (dt, 2H), 2.52 (t, 2H), 1.65 (t, 1H); C NMR δ 170.85,
2.60, 70.63, 70.6-70.5, 70.28, 70.19, 69.81, 61.69, 40.29, 39.32,
1
f
0.2; H NMR δ 3.8-3.6 (12H), 3.54
(m, 2H), 3.44 (m, 2H), 2.86 (t, 2H), 2.32 (s, 3H), 2.17 (t, 2H),
7
0.53. Analytical data: Calcd for C15H31NO S: C 48.76%, H
1
.7-1.5 (4H), 1.4-1.2 (14H).
Acidic deprotection yielded 78%. TLC (EtOAc/MeOH 4:1) Rf
.46%, N 3.79%. Found: C 48.7%, H 8.6%, N 3.9%.
N-[18-(N-H exa d ecylca r b a m oyl)m et h yl-3,6,9,12,15,18-
0
.6; H NMR δ 6.98 (br, 1H), 3.8-3.6 (12H), 3.47 (m, 2H), 3.44
h exa oxa octa d ecyl] 16-(Acetylth io)h exa d eca n a m id e (20)
AcS(CH 15CONH(CH CH O) CH COOH]. Compounds 15
(
m, 2H), 2.52 (dt, 2H), 2.17 (t, 2H), 1.7-1.5 (4H), 1.4-1.2 (15H);
[
2
)
2
2
6
2
1
3
C NMR δ 173.44, 72.60, 70.66, 70.5-70.4, 70.1-69.9, 61.55,
9.05, 36.64, 34.05, 29.6-29.4, 29.05, 28.38, 25.82, 24.64.
and 16 were coupled following the general procedure for amine
coupling described above. The eluant for column chromatog-
3
5
Analytical data: Calcd for C20H41NO S: C 58.93%, H 10.14%,
N 3.44%. Found: C 58.94%, H 10.25%, N 3.35%.
raphy was toluene/EtOAc (3:1 to 0:1). Yield: 80%. TLC (EtOAc/
1
MeOH 10:1) R
f
0.5; H NMR δ 6.23 (br, 1H), 4.02 (s, 2H), 3.7-
N-(17-H yd r oxy-3,6,9,12,15-p en t a oxa h ep t a d ecyl) 12-
3.6 (20H), 3.55 (t, 2H), 3.45 (m, 2H), 2.86 (t, 2H), 2.32 (s, 3H),
1
3
Me r ca p t od od e ca n a m id e
CH CH O) H]. The general procedure for amine coupling of
7 and 11b yielded 76%. TLC (EtOAc/MeOH 10:1) R
(2b )
[H S(CH
2
)
11CONH -
2.17 (t, 2H), 1.7-1.5 (4H), 1.48 (s, 9H), 1.4-1.2 (22H); C NMR
δ 196.05, 173.28, 169.66, 81.52, 70.73, 70.7-70.5, 70.02, 70.00,
69.02, 39.14, 36.73, 30.64, 29.7-29.3, 29.2-29.1, 28.82, 28.11,
25.76.
(
1
2
2
6
1
f
0.2; H
NMR δ 3.8-3.5 (22 H) 3.44 (m, 2H), 2.86 (t, 2H), 2.32 (s, 3H),
2
.18 (t, 2H), 1.7-1.5 (m, 4H), 1.4-1.2 (14H).
TFA (5 mL) was added to a solution of the t-Bu-protected
Acidic deprotection yielded 70%. TLC (EtOAc/MeOH 4:1) R
f
compound (120 mg, 0.16 mmol) in CH
mixture was stirred for 6 h. The solvent was coevaporated
twice with toluene. The residue was diluted with CH Cl (5
mL) and washed twice with water (10 mL) (until pH ) 7). The
organic solution was dried and evaporated to yield 109 mg
2 2
Cl (5 mL), and the
1
0
(
1
3
.1; H NMR δ 6.40 (br, 1H), 3.7-3.5 (22H), 3.45 (m, 2H), 2.52
1
3
dt, 2H), 2.18 (t, 2H), 1.7-1.5 (4H), 1.4-1.2 (15H); C NMR δ
2
2
73.32, 72.60, 70.63, 70.6-70.5, 70.28, 70.16, 70.02, 61.69,
9.17, 36.70, 34.05, 29.3-29.6, 29.05, 28.38, 25.76, 24.64.