Bolognesi et al.
General procedure for the coupling of LA
6,8-Dimercapto-N-(2-mercaptoethyl)octanamide
3a)
(
1
Methyl 2-(5-(1,2-dithiolane-3-yl)pentanamido)
acetate (5)
To a solution of LA (1.5 eq, 3.6 mmol) in 10 mL of dry
DMF under N2 at 0 °C were added successively 0.5 mL
Yield 81%: colorless viscous oil. H-NMR d 5,81 (bs,
1H), 3.31–3.43 (m, 2H), 2.80–2.91 (m, 1H), 2.53–7.72
(m, 4H), 2.15 (t, J = 7.33 Hz, 2H), 1.75–1.80 (m, 1H),
13
1.33–1.60 (m, 7H), 1.22–1.33 (m, 3H);
C-NMR d
of Et
3
N, 1 eq of glycine methyl ester hydrochloride
172.8, 42.8, 42.2, 39.3, 38.7, 36.5, 26.6, 25.2, 24.7,
+
+
(2.40 mmol), and 1.5 eq (3.6 mmol) of 1-ethyl-3-[3-(dim-
22.3; MS (ESI ) m/z : 268.09 ([M + H] 100%); HRMS-
+
+
ethylamino)propyl]carbodiimide hydrochloride (EDCI•HCl).
The mixture was stirred at 0 °C for further 15 min and at
rt until completion (TLC monitoring). The mixture was
then diluted with water and extracted with ethyl acetate.
The organic layer was washed with brine, dried over
ESI m/z calcd for
C
10
H
22NOS
3
[M + H] 268.0864
Found 268.0862.
Ethyl 2-(6,8-dimercaptooctanamido)-3-
mercaptopropanoate (3b)
2 4
Na SO , and evaporated under vacuum. The crude
1
product was purified by flash column chromatography.
Yield 63%, colorless oil; H-NMR d 6.02 (bs, 1H), 4.05
Yield: 90%, colorless viscous oil; H-NMR d 6.28 (bs, 1H),
1
4.82-4.92 (m, 1H), 4.23-4.32 (m, 2H), 3.05 (dd,
J = 8.0 Hz, 2H), 2.85–2.96 (m, 1H), 2.63–2.74 (m, 3H),
2.28 (t, J = 7.7 Hz, 2H), 1.82–1.92 (m, 1H), 1.43–1.78 (m,
(
3
d, J = 6.0 Hz, 2H), 3.76 (s, 3H), 3.57 (m, 1H),
.07–3.19 (m, 2H), 2.41–2.49 (m, 1H), 2.26 (t,
J = 7.5 Hz, 2H), 1.74–1.97 (m, 1H), 1.64–1.72 (m, 4H),
13
6H), 1.26–1.47 (m, 6H); C-NMR d 172.5, 170.1, 62.1,
13
1
4
2
.44–1.53 (m, 2H); C-NMR d 172.8, 170.5, 56.4, 52.4,
1.2, 40.2, 38.5, 36.0, 34.6, 28.8, 25.2; MS (ESI ) m/z:
56.3, 53.4, 42.7, 39.3, 38.7, 36.2, 34.6, 26.9, 25.1, 14.2;
+
+
+
+
MS (ESI ) m/z: 340.11 ([M + H] 100%); HRMS-ESI m/z
+
+
+
78.09 ([M + H] 50%), 300.07 ([M + Na] 50%); HRMS-
calcd for
340.1079.
C
13
H
26NO
3
S
3
[M + H]
340.1075 Found
+
+
ESI m/z calcd for C H20NO3S2 [M + H] 278.0885
11
Found 278.0885.
6
,8-Dimercapto-N-(2-((2-mercaptoethyl)amino)-2-
2
-(5-(1,2-Dithiolane-3-yl)pentanamido)acetic acid (6)
oxoethyl)octanamide (8)
1
To a solution of 1.77 g. (6.4 mmol) of 5 in 24 mL of meth-
anol/THF (1/1) was added dropwise 12 mL of a 1.0 N
sodium hydroxide solution. The resulting mixture was stir-
red at rt overnight and then neutralized with a 1.0 N
hydrochloric acid solution. The mixture was then diluted
with water and extracted with ethyl acetate. The organic
Yield 81%, white solid, mp: 108 °C; H-NMR d 6.36 (s,
1H), 6.12 (s, 1H), 3.95 (d, J = 5.26 Hz, 2H), 3.42–3.51 (m,
2H), 3.88–3.95 (m, 1H), 2.62–2.78 (m, 4H), 2.28 (t,
J = 7.3 Hz, 2H), 1.83–1.98 (m, 1H), 1.62–1.81 (m, 4H),
13
1.42–1.53 (m, 3H), 1.25–1.42 (m, 3H); C-NMR d 173.5,
169.0, 43.4, 42.8, 42.4, 39.3, 38.7, 36.1, 26.6, 25.1,
+
+
layer was washed with brine, dried over Na
2
SO
4
, and
24.5, 22.3; MS (ESI ) m/z: 325.11 ([M + H] 100%);
+
+
evaporated under vacuum. The crude product was purified
HRMS-ESI
m/z calcd for
C
12
H
25
N
2
O
2
S
3
[M + H]
by flash column chromatography. Yield 65%, yellow solid,
325.1078 Found 325.1081.
1
mp: 206 °C; H-NMR
d
8.09 (bs, 1H), 3.73 (d,
J = 5.85 Hz, 2H), 3.63 (m, 1H), 3.12–3.26 (m, 2H), 3.39–
3
1
1
.49 (m, 1H), 2.16 (t, J = 7.15 Hz, 2H), 1.87–1.92 (m, 1H),
Methyl 2-(6,8-dimercaptooctanamido)acetate (9)
13
1
.52–1.72 (m, 4H), 1.41 (m, 2H);
C-NMR d 172.3,
Yield 74%, colorless oil; H-NMR d 5.88 (bs, 1H), 4.03 (d,
J = 5.1 Hz, 2H,), 3.77 (s, 3H), 2.83–2.96 (m, 1H), 2.62–
2.78 (m, 2H), 2.27 (t, J = 7.3 Hz, 2H), 1.86–1.96 (m, 1H),
1.63–1.82 (m, 4H), 1.42–1.53 (m, 3H), 1.28–1.38 (m, 2H);
71.3, 66.3, 56.1, 41.4, 38.0, 34.8, 34.0, 28.2, 24.9; MS
+
+
+
(ESI ) m/z: 286.05 ([M + Na] 100%); HRMS-ESI m/z
+
calcd for C10
86.0549.
3 2
H17NO S Na [M + Na] 286.0548 Found
1
3
2
C-NMR d 173.2, 170.2, 52.4, 42.8, 41.2, 39.3, 38.7,
+
+
3
1
6.1, 26.6, 25.1, 22.3; MS (ESI ) m/z: 280.10 ([M + H]
00%); HRMS-ESI m/z calcd for C11H NO S [M + H]
+
+
22
3 2
General procedure for the reduction in lipoic
derivatives
280.1041 Found 280.1045.
To a solution of the corresponding lipoic derivatives
(0.54 mmol) in 15 mL abs, EtOH was added at 0 °C
Antioxidant activity
NaBH4 (0.08 g, 2.2 mmol), and the mixture was stirred
at room temperature overnight. The reaction was
UV spectra were recorded on a Varian Cary 300 Bio UV/
Vis spectrometer.
quenched with H O, and EtOH was evaporated in
2
2 2 2
vacuo. The residue was extracted with CH Cl and H O.
The organic layer was washed with saturated aqueous
NaCl, dried over sodium sulfate, and the solvent was
evaporated in vacuo. The residue was purified by flash
column chromatography.
Scavenging effect on 1,1-diphenyl-2-picrylhydrazyl
(DPPH) radical
The scavenging effect of the synthesized compounds on
the DPPH radical was evaluated according to previously
6
90
Chem Biol Drug Des 2014; 83: 688–696