966 J . Org. Chem., Vol. 66, No. 3, 2001
Kotsovolou et al.
2-[(t er t -Bu t oxyca r b on yl)a m in o]-1-[t er t -b u t oxyca r -
bon yl)a m in o]m eth yl]eth yl d eca n oa te (3a ): yield 0.32 g
(73%); mp 49-51 °C; 1H NMR δ 5.0 (m, 2H), 4.85 (m, 1H), 3.3
(m, 4H), 2.3 (t, 2H, J ) 11.1 Hz), 1.7-1.2 (m, 32H), 0.9 (t, 3H,
J ) 6.5 Hz); 13C NMR δ 173.1 (C), 156.1 (C), 79.5 (C), 71.5
(CH), 40.3 (CH2), 34.2 (CH2), 31.8 (CH2) 29.6 (CH2), 29.3 (CH2),
29.2 (CH2), 29.1 (CH2), 28.3 (CH3), 24.8 (CH2), 22.6 (CH2), 14.1
(CH3). Anal. Calcd for C23H44N2O6‚1.5H2O: C, 58.57; H, 10.04;
N, 5.94. Found: C, 58.74; H, 9.95; N, 6.36.
N-[2-Hexadecyloxy-3-[(2-h ydr oxyh exadecan oyl)am in o]-
pr opyl]-2-h ydr oxyh exadecan am ide (6b): yield 0.39 g (47%);
mp 90-92 °C. Anal. Calcd for C51H102N2O5‚1.5H2O: C, 72.03;
H, 12.44; N, 3.29. Found: C, 72.13; H, 12.45; N, 2.90.
Gen er al P r ocedu r es for th e Syn th esis of 2-Oxo Am ides
(7a ,b a n d 8a ,b). P r oced u r e A. Oxid a tion Usin g P DC. To
a solution of compound 5 or 6 (1.0 mmol) in glacial acetic acid
(4 mL) was added PDC (2.2 g, 6.0 mmol). After being stirred
for 2 h at room temperature, the mixture was neutralized with
5% aqueous NaHCO3 and extracted with EtOAc (20 mL × 3).
The combined organic layers were washed with brine and dried
(Na2SO4). The solvent was evaporated under reduced pressure,
and the crude product was purified by column chromatography
(petroleum ether 40-60 °C /EtOAc 7/3).
P r oced u r e B. Oxid a tion Usin g Na OCl/AcNH -TEMP O.
To a solution of compound 5 or 6 (1.0 mmol) in a mixture of
EtOAc/CH2Cl2/toluene 1:4:3 (14 mL), were added a solution
of NaBr (0.23 g, 2.2 mmol) in water (0.9 mL) and subsequently
AcNH-TEMPO (4 mg, 0.02 mmol) at 0 °C. To the resulting
biphasic system was added under vigorous stirring a solution
of NaOCl (0.16 g, 2.2 mmol) and NaHCO3 (0.17 g, 2.0 mmol)
in H2O (6 mL) dropwise at 0 °C over a period of 1 h. After the
mixture was stirred for 30 min at room temperature, EtOAc
(15 mL) and water (5 mL) were added. The organic layer was
washed with 10% aqueous citric acid (10 mL), which contained
KI (0.5 g), 10% aqueous Na2S2O3 (10 mL), and brine and dried
over Na2SO4. The solvent was evaporated under reduced
pressure, and the crude product was purified by column
chromatography (petroleum ether 40-60 °C/EtOAc 7/3).
2-[(t er t -Bu t oxyca r b on yl)a m in o]-1-[t er t -b u t oxyca r -
bon yl)a m in o]m eth yl]eth yl h exa d eca n oa te (3b): yield 0.37
1
g (70%); mp 54-56 °C; H NMR δ 5.0 (m, 2H), 4.85 (m, 1H),
3.3 (t, 4H), 2.3 (t, 2H, J ) 10 Hz), 1.95-1.2 (m, 44H), 0.9 (t,
3H, J ) 6.6 Hz). Anal. Calcd for C29H56N2O6: C, 65.87; H,
10.67; N, 5.30. Found: C, 65.52; H, 10.81; N, 5.52.
Gen er a l P r oced u r e for th e Syn th esis of ter t-Bu tyl
2-Alk oxy -3-[(t er t -b u t o x y c a r b o n yl)a m in o ]p r o p y lc a r -
ba m a tes (4a ,b). To a stirred solution of compound 2 (0.29 g,
1.0 mmol) and the appropriate alkyl bromide (3.0 mmol) in
benzene (5 mL), were added aqueous NaOH 50% (5 mL), and
Bu4NHSO4 (0.085 g, 0.25 mmol) at room temperature. After
vigorous stirring for 5 h at 50-60 °C, the reaction mixture
was allowed to obtain the ambient temperature and EtOAc
and water were added. The organic phase was washed with
brine and dried (Na2SO4). The residue was purified by column
chromatography (petroleum ether 40-60 °C/EtOAc 7/3).
ter t-Bu tyl 2-d ecyloxy-3-[(ter t-bu toxyca r bon yl)a m in o]-
p r op ylca r ba m a te (4a ): yield 0.22 g (53%); 1H NMR δ 5.0 (m,
2H), 3.5 (m, 4H), 3.35 (m, 1H), 3.1 (m, 2H), 1.6-1.25 (m, 34H),
0.9 (t, 3H, J ) 6.5 Hz); 13C NMR δ 156.3 (C), 79.3 (C), 76.3
(CH), 69.7 (CH2), 40.4 (CH2), 31.8 (CH2), 29.9 (CH2), 29.5 (CH2),
29.5 (CH2), 29.4 (CH2), 29.2 (CH2), 28.3 (CH3), 26.0 (CH2), 22.6
(CH2), 14.0 (CH3). Anal. Calcd for C23H46N2O5: C, 64.15; H,
10.77; N, 6.51. Found: C, 64.04; H, 10.86; N, 6.33.
2-[(2-Oxoh exadecan oyl)am in o]-1-[[(2-oxoh exadecan oyl)-
a m in o]m eth yl]eth yl d eca n oa te (7a ): procedure A yield 0.45
1
g (60%); mp 51 °C; TOF MS m/z 749 (M+, 100), 577 (38); H
NMR δ 7.4 (m, 2H, 2 × NH), 5.0 (m, 1H, CHOCO), 3.5 (m,
4H, 2 × CH2NH), 2.9 (t, 4H, 2 × COCOCH2, J ) 7.3 Hz), 2.3
(t, 2H, OCOCH2, J ) 6.0 Hz), 1.6-1.2 (m, 62H, 31 × CH2), 0.9
(t, 9H, 3 × CH3, J ) 6.7 Hz); 13C NMR δ 198.5 (C), 172.3 (C),
160.7 (C), 70.2 (CH), 39.4 (CH2), 36.7 (CH2), 34.1 (CH2), 31.9
(CH2), 31.8 (CH2), 29.6 (CH2), 29.4 (CH2), 29.3 (CH2), 29.2
(CH2), 29.0 (CH2), 24.8 (CH2), 23.1 (CH2), 22.6 (CH2), 14.1
(CH3). Anal. Calcd for C45H84N2O6‚1H2O: C, 70.45; H, 11.30;
N, 3.65. Found: C, 70.28; H, 11.42; N, 3.86.
2-[(2-Oxoh exadecan oyl)am in o]-1-[[(2-oxoh exadecan oyl)-
a m in o]m eth yl]eth yl h exa d eca n oa te (7b): procedure B
yield 0.43 g (51%); mp 58-59 °C; TOF MS m/z 833 (M+, 100),
577 (40); 1H NMR δ 7.4 (m, 2H, 2 × NH), 5.0 (m, 1H, CHOCO),
3.45 (m, 4H, 2 × CH2NH), 2.9 (t, 4H, 2 × COCOCH2, J ) 8.0
Hz), 2.3 (t, 2H, OCOCH2, J ) 6.6 Hz), 1.6-1.2 (m, 74H, 37 ×
CH2), 0.9 (t, 9H, 3 × CH3, J ) 6.5 Hz); 13C NMR δ 198.5 (C),
173.1 (C), 160.7 (C), 70.2 (CH), 39.4 (CH2), 36.7 (CH2), 34.1
(CH2), 31.9 (CH2), 29.6 (CH2), 29.4 (CH2), 29.3 (CH2), 29.0
(CH2), 24.8 (CH2), 23.1 (CH2), 22.6 (CH2), 14.1 (CH3). Anal.
Calcd. for C51H96N2O6‚1.5H2O: C, 71.19; H, 11.60; N, 3.05.
Found: C, 71.10; H, 11.65; N, 2.69.
ter t-Bu t yl 2-h exa d ecyloxy-3-[(ter t-b u t oxyca r b on yl)-
1
a m in o]p r op ylca r ba m a te (4b): yield 0.25 g (48%); H NMR
δ 5.0 (m, 2H), 3.5-3.1 (m, 7H), 1.6-1.25 (m, 46H), 0.9 (t, 3H,
J ) 6.5 Hz). Anal. Calcd for C29H58N2O5: C, 67.66; H, 11.36;
N, 5.44. Found: C, 67.48; H, 11.49; N, 5.36.
Gen er a l P r oced u r e for t h e Syn t h esis of 2-[(2-H y-
d r oxyh exa d eca n oyl)a m in o]-1-[[(2-h yd r oxyh exa d eca n -
oyl)a m in o]m et h yl]et h yl Alk a n oa t es (5a ,b ) a n d N-[2-
Alk yloxy-3-[(2-h yd r oxyh exa d eca n oyl)a m in o]p r op yl]-2-
h yd r oxyh exa d eca n a m id es (6a ,b). Compounds 3a ,b and
4a ,b (1.0 mmol) were treated with 4 N HCl in Et2O (16 mL)
for 1 h at room temperature. The solvent and the excess acid
were evaporated under reduced pressure and the residue was
reevaporated twice from Et2O. The hydrochloride salts were
used directly to the next step.
To a stirred solution of 2-hydroxyhexadecanoic acid (0.54
g, 2.0 mmol) and the appropriate hydrochloride derivative of
1,3-diaminopropan-2-ol (1.0 mmol) in CH2Cl2 (5 mL), Et3N (0.3
mL) and subsequently WSCI (0.57 g, 3.0 mmol) and HOBt
(0.32 g, 2.0 mmol) were added at 0 °C. The reaction mixture
was stirred for 1 h at 0 °C and at room temperature for 2 days.
The organic layer was washed with brine, dried over Na2SO4,
and evaporated under reduced pressure. The residue was
purified by column chromatography (CHCl3/MeOH 9:1).
2-[(2-Hydr oxyh exadecan oyl)am in o]-1-[[(2-h ydr oxyh exa-
d eca n oyl)a m in o]m eth yl]eth yl d eca n oa te (5a ): yield 0.45
g (61%); 1H NMR δ 5.55 (m, 2H), 4.9 (m, 1H), 3.1-3.6 (m, 4H),
2.3 (m, 2H), 1.8-1.1 (m, 66H), 0.9 (t, 9H, J ) 6.8 Hz). Anal.
Calcd for C45H88N2O6: C, 71.76; H, 11.78; N, 3.72. Found: C,
71.65; H, 11.83; N, 3.66.
2-[(2-Hydr oxyh exadecan oyl)am in o]-1-[[(2-h ydr oxyh exa-
d eca n oyl)a m in o]m eth yl]eth yl h exa d eca n oa te (5b): yield
0.45 g (54%); 1H NMR δ 5.2 (m, 2H), 4.8 (m, 1H), 3.1-3.6 (m,
4H), 2.3 (m, 2H), 1.8-1.1 (m, 78H), 0.9 (t, 9H, J ) 6.8 Hz).
Anal. Calcd for C51H100N2O6‚1H2O: C, 71.61; H, 12.02; N, 3.27.
Found: C, 71.43; H, 12.21; N, 3.22.
N -[2-De cyloxy-3-[(2-h yd r oxyh e xa d e ca n oyl)a m in o]-
pr opyl]-2-h ydr oxyh exadecan am ide (6a): yield 0.44 g (60%);
mp 65-67 °C. Anal. Calcd for C45H90N2O5‚1.5H2O: C, 70.53;
H, 12.23; N, 3.65. Found: C, 70.76; H, 12.25; N, 3.32.
N-[2-Decyloxy-3-[(2-oxoh exa d eca n oyl)a m in o]p r op yl]-
2-oxoh exa d eca n a m id e (8a ): procedure A yield 0.30 g (41%);
1
mp 61-63 °C; H NMR δ 7.4 (m, 2H, 2 × NH), 3.8-3.4 (m,
7H, CHO, CH2O, 2 × CH2NH), 2.9 (t, 4H, 2 × COCOCH2, J )
8.8 Hz), 2.0-1.2 (m, 64H, 32 × CH2), 0.9 (t, 9H, 3 × CH3, J )
6.8 Hz); 13C NMR δ 198.6 (C), 160.6 (C), 75.7 (CH), 70.1 (CH2),
39.6 (CH2), 36.7 (CH2), 31.8 (CH2), 29.8 (CH2), 29.6 (CH2), 29.4
(CH2), 29.3 (CH2), 29.0 (CH2), 26.0 (CH2), 23.1 (CH2), 22.6
(CH2), 14.1 (CH3). Anal. Calcd for C45H86N2O5‚0.5H2O: C,
72.63; H, 11.78; N, 3.42. Found: C, 72.39; H, 12.03; N, 3.07.
N -[2-H e xa d e cyloxy-3-[(2-oxoh e xa d e ca n oyl)a m in o]-
p r op yl]-2-oxoh exa d eca n a m id e (8b): procedure A yield 0.27
g (32%); procedure B yield 0.46 g (55%); 1H NMR δ 7.4 (m,
2H, 2 × NH), 3.6-3.2 (m, 7H, 2 × CH2NH, OCH2, CHO), 2.9
(t, 4H, 2 × COCOCH2, J ) 8.0 Hz), 1.9-1.2 (m, 76H, 38 ×
CH2), 0.9 (t, 9H, 3 × CH3, J ) 7.2 Hz); 13C NMR δ 198.6 (C),
160.6 (C), 70.1 (CH), 39.5 (CH2), 36.7 (CH2), 31.8 (CH2), 29.8
(CH2), 29.6 (CH2), 29.4 (CH2), 29.3 (CH2), 29.0 (CH2), 26.0
(CH2), 23.1 (CH2), 22.6 (CH2), 14.1 (CH3). Anal. Calcd for
C
51H98N2O5‚2H2O: C, 71.61; H, 12.02; N, 3.27. Found: C,
71.26; H, 12.11; N, 3.26.