Full Paper
+
+
3
found: 807.55; m/z calcd for C H N O +K : 823.53 [M+K ];
CH ), 3.05 and 2.92 (bs , bs , 9H, NÀCH ), 2.25 (t, J =7.5 Hz, 2H,
45
76
4
7
2
cis
trans
3
found: 823.53.
2S,4R)-4-((11-(3,5-Bis(decylcarbamoyl)benzamido)undecanoy-
l)oxy)pyrrolidine-2-carboxylic acid (1d): Starting from compound
d (35.1 mg, 0.037 mmol), the product 1d was obtained as
COÀCH ), 1.70–0.98 (m, 39H, aliphatic), 0.94 and 0.74–0.64 (d
,
trans
2
3
3
J
=5.3 Hz, m, 6H, CH ), 0.86 ppm (d, J =6.1 Hz, 12H, CH );
3 3
(
trans
1
3
C NMR (100 MHz, CDCl ): d=173.83, 170.03, 169.35, 137.28,
26.16, 60.10, 51.50, 49.79, 47.67, 45.96, 39.20, 37.44, 37.16, 35.52,
4.34, 33.84, 32.94, 30.86, 30.50, 29.66–29.08, 28.33, 27.89, 26.87,
26.48, 24.93, 24.62, 22.66, 22.57, 19.57, 19.25, 14.23 ppm; HRMS
MALDI-TOF): m/z calcd for C H N O : 742.61 [M+H ]; found:
3
1
3
6
a white solid (18 mg, 61%). No further purification was needed.
1
H NMR (400 MHz, MeOD): d=8.39 (s, 3H, ArÀH), 5.45–5.40 (m, 1H,
+
(
7
7
OÀCH), 4.58–4.51 (m, 1H, CHÀCO), 3.72–3.63 (m, 1H, NHÀCH ),
45 80 3 5
2
+
+
42.63; m/z calcd for C H N O +Na : 764.59 [M+Na ]; found:
45 79 3 5
64.61; m/z calcd for C H N O +K : 780.57 [M+K ]; found:
45 79 3 5
3
3
0
1
3
.51–3.28 (m, 7H), 2.61–2.52 (m, 1H, COÀCHÀCH ), 2.48–2.30 (m,
2
+
+
H), 1.72–1.52 (m, 8H, ÀCH À), 1.48–1.21 (m, 40H, aliphatic), 0.92–
2
3
1
780.59.
.85 ppm (m, 6H, CH ); C NMR (100 MHz, MeOD): d=172.85,
3
67.20, 135.38, 128.38, 72.37, 50.88, 39.80, 34.49, 33.35, 31.63,
0.39, 29.26–28.70, 26.68, 24.27, 22.30, 13.02 ppm; IR: n˜ =3349 (NÀ
À1
H stretch), 1645 (C=O stretch), 1539 cm (amide II); HRMS (MALDI-
N,N’,N’’-Trimethyl-N-(11-undecanoic acid)-N’,N’’-bis((S)-3,7-di-
+
TOF): m/z calcd for C H N O : 785.58 [M+H ]; found: 785.58; m/z
calcd for C H N O +Na : 807.56 [M+Na ]; found: 807.55.
4
5
77
4
7
methyloctyl)benzene-1,3,5-tricarboxamide (4b)
+
+
4
5
76
4
7
In a 50 mL round-bottomed flask, N,N’,N’’-trimethyl-N-(ethyl 11-un-
decanoate)-N’,N’’-bis((S)-3,7-dimethyloctyl)benzene-1,3,5-tricarboxa-
mide (3b, 62.5 mg, 0.084 mmol) was dissolved in dioxane (15 mL)
(
2S,4R)-4-((11-(3,5-Bis(octylcarbamoyl)benzamido)undecanoy-
l)oxy)pyrrolidine-2-carboxylic acid (1e): Starting from compound
e (61.4 mg, 0.069 mmol), the product 1e was obtained as a white
6
1
and a solution of LiOH·H O (35.3 mg, 0.842 mmol, 10 equiv) in
2
solid (40.2 mg, 80%). No further purification was needed. H NMR
water (5 mL) was added. The resulting milky white suspension was
stirred for 2 days at room temperature. The mixture was washed
with HCl (1m, 20 mL) and extracted with chloroform (3ꢀ15 mL).
The combined organic phases were washed with HCl (1m, 2ꢀ
(
4
400 MHz, MeOD): d=8.40 (s, 3H, ArÀH), 5.41–5.36 (m, 1H, OÀCH),
.30–4.21 (m, 1H, CHÀCO), 3.75–3.59 (m, 1H, NHÀCH ), 3.46–3.34
2
(
3
m, 7H), 2.54–2.31 (m, 4H), 1.72–1.53 (m, 8H, ÀCH À), 1.48–1.20 (m,
2
13
2H, aliphatic), 0.92–0.85 ppm (m, 6H, CH ); C NMR (100 MHz,
3
1
5 mL), water (15 mL), and brine (15 mL), and dried over MgSO4.
MeOD): d=172.96, 167.18, 135.36, 128.39, 72.92, 60.03, 50.64,
3
1
cm (amide II); HRMS (MALDI-TOF): m/z calcd for C H N O :
7
The solvent was evaporated in vacuo, to give the product 4b as
an off-white solid (43.4 mg, 72%). No further purification was
9.82, 35.08, 33.42, 31.58–28.73, 26.71, 26.66, 24.34, 22.29,
3.04 ppm; IR: n˜ =3302 (NÀH stretch), 1635 (C=O stretch), 1538
1
À1
needed. H NMR (400 MHz, CDCl
3
): d=7.44 (bs, 3H, ArÀH), 3.61–
4
1
69
4
7
+
3.41 and 3.29–3.14 (mtrans, mcis, 6H, NÀCH
2
), 3.04 and 2.91 (bscis
), 1.69–0.98 (m,
=5.7 Hz, m, 6H, CH ),
,
29.52 [M+H ]; found: 729.52; m/z calcd for C H N O : 727.50
41 67 4 7
3
+
À
bstrans, 9H, NÀCH
3
), 2.75 (t, J =7.3 Hz, 2H, COÀCH
2
[
MÀH ] ; found: 727.50.
3
3
0
1
3
2
9H, aliphatic), 0.93 and 0.68 (d , J
trans
13
trans
3
(
2R,4S)-4-((11-(3,5-Bis(((R)-3,7-dimethyloctyl)carbamoyl)benzami-
3
.85 ppm (d, J =6.5 Hz, 12H, CH ); C NMR (100 MHz, CDCl ): d=
3
3
do)undecanoyl)oxy)pyrrolidine-2-carboxylic acid (2): Starting
from compound 9 (61.4 mg, 0.069 mmol), the crude product 2 was
obtained as a white solid. The material was purified by reversed
phase column chromatography (MeOH/H O/THF, 80:10:10) to give
2
77.95, 170.15, 169.46, 137.19, 126.21, 51.52, 49.83, 47.69, 46.05,
9.20, 37.46, 37.16, 35.50, 33.95, 33.83, 32.99, 30.86, 30.49, 29.65–
8.29, 27.89, 26.73–26.43, 24.61, 22.66, 22.56, 19.55, 19.24 ppm;
HRMS (MALDI-TOF): m/z calcd for C H N O +Na : 736.56 [M+Na
; found: 736.56; m/z calcd for C H N O +K : 752.53 [M+K ];
43 75 3 5
2
+
+
1
43 75
3
5
as a white powder (46 mg, 38%). H NMR (400 MHz, MeOD): d=
+
+
]
3
8
.35 (s, 3H, ArÀH), 5.39 (t, J =8.0 Hz, 1H, OÀCH), 4.22–4.18 (m, 1H,
+
À
found: 752.53; m/z calcd for C H N O : 712.56 [MÀH ] ; found:
43
74
3
5
CHÀCO), 3.64–3.59 (m, 1H, NHÀCH ), 3.49–3.36 (m, 7H), 2.54–2.25
2
7
12.58.
3
(
m, 4H), 1.72–1.12 (m, 36H, aliphatic), 0.96 (d, J =8.0 Hz, 6H, CH ),
3
13
0
.87 ppm (d, J =8.0 Hz, 12H, CHÀCH ); C NMR (100 MHz, MeOH):
3
3
d=172.83, 167.22, 135.27, 128.28, 73.11, 59.9, 50.58, 39.77, 39.03,
3
2
O stretch), 1558 cm (amide II); HRMS (MALDI-TOF): m/z calcd for
C H N O : 785.58 [M+H ]; found: 785.60.
Synthesis of compounds 6b–e
7.91, 36.89, 36.08, 35.10, 33.39, 30.49, 29.16–28.72, 27.72, 26.64,
4.37, 21.67–21.58, 18.54 ppm; IR: n˜ =3238 (NÀH stretch), 1635 (C=
A 250 mL three-necked round-bottomed flask was charged with
a solution of the appropriate N-(11-undecanoic acid)-N’,N’’-di(alkyl)-
benzene-1,3,5-tricarboxamide 4a–e (1 equiv), tert-butyl (2S,4R)-N-
Boc-trans-4-hydroxyprolinate (19, 1.7 equiv) and 4-(dimethylami-
no)pyridinium 4-toluenesulfonate (DPTS) (1.7 equiv) in dry chloro-
form (20 mL). The mixture was cooled in an ice/salt bath to below
À1
+
4
5
77
4
7
N,N’,N’’-Trimethyl-N-(ethyl 11-undecanoate)-N’,N’’- bis((S)-3,7-
dimethyloctyl)benzene-1,3,5-tricarboxamide (3b)
0
8C and a cooled solution of N-(3-dimethylaminopropyl)-N’-ethyl-
carbodiimide hydrochloride (EDC·HCL) (3 equiv) in dry chloroform
5 mL) was added quickly and the clear solution was stirred for 2
days at room temperature. Chloroform (30 mL) was added and the
solution was washed with water (50 mL), sat. NaHCO (50 mL), and
A 5 mL microwave reaction vessel was charged with N-(ethyl 11-
undecanoate)-N’,N’’-bis((S)-3,7-dimethyloctyl)benzene-1,3,5-tricar-
boxamide (3a, 138 mg, 0.197 mmol), methyl iodide (0.308 mL,
(
4
.93 mmol, 25 equiv), sodium hydride (118 mg, 2.96 mmol, 15
3
brine (50 mL), and dried over MgSO . The solution was concentrat-
equiv), and dry THF (5 mL), and the solution was capped under an
argon atmosphere. The reaction was kept at a constant tempera-
ture of 1108C under microwave irradiation for 60 minutes. The mix-
ture was cooled to room temperature and quenched with 2 mL of
ethanol. The resulting clear solution was concentrated in vacuo
and the remaining solid was purified by column chromatography
4
ed in vacuo. The remaining crude material was purified by column
chromatography (heptane/EtOAc, 50:50).
(2S,4R)-Di-tert-butyl
4-((11-(3,5-bis(((S)-3,7-dimethyloctyl)(me-
thyl)carbamoyl)-N-methylbenzamido)undecanoyl)oxy)pyrroli-
dine-1,2-dicarboxylate (6b): Starting from compound 4b
(43.4 mg, 0.061 mmol), 6b was obtained as a thick, colorless oil
(
EtOAc/heptane gradient 60:40 to 100:0). Pure trimethylated BTA
b was obtained as a light yellow, viscous oil (100.8 mg, 69%).
3
(15 mg, 25%). Presence of the the product 6b was confirmed by
1
3
1
H NMR (400 MHz, CDCl ): d=7.49 (bs, 3H, ArÀH), 4.11 (q, J =
H NMR (400 MHz, CDCl ). The crude material was used directly for
3
3
7
.1 Hz, 2H, OÀCH ), 3.61–3.42 and 3.30–3.16 (m , m , 6H, NÀ
the next step without further purification.
2
trans
cis
Chem. Eur. J. 2015, 21, 1 – 10
7
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
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