Journal of Medicinal Chemistry
Article
1H NMR (600 MHz, CDCl3): 1.02 (s, 6H, C(CH3)2), 1.76 (t, J =
7.2, 4H, 2× CH2), 4.30 (t, J = 7.2, 4H, 2× O−CH2), 3.03 (s, 6H, 2× S-
CH3).
(2S,11RS)-5-Thia-2,11-diaminododecanedioic Acid (10). Fol-
lowing the general procedure, the intermediate 9a was prepared from
L-methionine (0.50 g, 3.35 mmol, 1 equiv), sodium (0.239 g, 10.4
mmol, 3.1 equiv), and 8a (1.35 g, 3.69 mmol, 1.1 equiv; added as a
solution in 3 mL of THF).
13C NMR (150.9 MHz, CDCl3): 27.40 (2× CH3 (C(CH3)2), 31.79
(>C<), 37.49 (2× S-CH3), 40.20 (2× CH2), 66.64 (2× O−CH2).
HRMS (EI) calculated for C9H20O6NaS2, m/z 311.05935, found
311.05924 (M + Na)+.
After the ammonia had evaporated, the residue (crude 9a) was
dissolved in aqueous HCl (5 M, 30 mL) and heated under reflux for 2
h. The chilled solution was then passed through a column of Dowex
50 (H+-cycle) and washed successively with water, methanol, and
again water. The crude product was eluted with 10% aqueous NH3,
and the solution was evaporated to dryness. The residue was purified
by HPLC and lyophilized, giving 10 as di(trifluoroacetate) (white
solid, 0.70 g, 37% overall yield from 8a).
2-Carboxyethyl-2-acetamido-7-bromoheptanoic Acid (8a).
Sodium ethanolate was generated in situ by dissolving sodium (0.318
g, 13.83 mmol, 1.0 equiv) in abs EtOH (20 mL) at rt in a flask
equipped with a reflux condenser fitted with a calcium chloride tube.
Diethyl acetamidomalonate (DEAM, 3.0 g, 13.81 mmol, 1.0 equiv)
was added, and after 30 min, 1,5-dibromopentane (5.64 mL, 41.43
mmol, 3 equiv) was introduced, and the reaction was heated to reflux
for 5 h. The mixture was evaporated and partitioned between Et2O
and H2O, and the organic layer was dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica (elution with a linear gradient of EtOAc in
toluene) to give compound 8a as pale- yellow crystals (2.96 g, 58%).
1H NMR (600 MHz, CDCl3): 1.14 (m, 2H, C(4)H2), 1.26 (t, J =
7.1, 6H, 2× CH3 (OEt)), 1.45 (m, 2H, C(5)H2), 1.84 (m, 2H,
C(6)H2), 2.04 (s, 3H, CH3 (NHAc)), 2.33 (m, 2H, C(3)H2); 3.37 (t,
J = 6.8, 2H, C(7)H2), 4.25 (q, J = 7.1, 4H, 2× CH2 (OEt)), 6.78 (b,
1H, NH).
1H NMR (600 MHz, D2O): 1.41 (m, 1H) and 1.46 (m, 1H,
C(9)H2), 1.46 (m, 2H, C(8)H2), 1.62 (m, 2H, C(7)H2), 1.90 (m, 1H)
and 1.96 (m, 1H, C(10)H2), 2.16 (m, 1H) and 2.24 (m, 1H, C(3)H2),
2.60 (t, 2H, C(6)H2), 2.70 (t, 2H, C(4)H2), 4.01 (dd, J = 6.8 and 5.7,
C(11)H), 4.12 (dd, 1H, J = 6.9 and 5.8, C(2)H).
13C NMR (150.9 MHz, D2O): 26.39 (C-9), 29.06 (C-4), 30.09 (C-
8), 30.80 (C-7), 32.39 (C-3), 32.40 (C-10), 33.25 (C-6), 55.04 (C-2),
56.90 (C-11), 175.11 (C-12), 175.52 (C-1).
HRMS (ESI) calculated for C11H21O4N2S, m/z 277.1228, found
277.1228 (M − H)−.
(2S,8RS,11RS)-5-Thia-2,11-diamino-8-methyldodecanedioic
Acid (11). Following the general procedure, the intermediate 9b was
prepared from L-methionine (0.185 g, 1.24 mmol, 1 equiv), sodium
(0.089 g, 3.86 mmol, 3.1 equiv), and 8b (0.52 g, 1.37 mmol, 1.1 equiv;
added as a solution in 3 mL of THF).
13C NMR (150.9 MHz, CDCl3): 13.98 (2× CH3 (OEt)), 22.78 (C-
4), 23.07 (CH3 (NHAc)), 27.72 (C-5), 31.87 (C-3), 32.33 (C-6),
33.50 (C-7), 62.54 (2× CH2 (OEt)), 66.42 (C-2), 168.12 (2× C-1),
168.97 (CO (NHAc)).
HRMS (ESI) calculated for C14H25O5NBr, m/z 366.0911, found
After the ammonia had evaporated, the residue (crude 9b) was
dissolved in aqueous HCl (5 M, 30 mL) and heated under reflux for 2
h. The chilled solution was then passed through a column of Dowex
50 (H+-cycle) and washed successively with water, methanol, and
again water. The crude product was eluted with 10% aqueous NH3,
and the solution was evaporated to dryness. The residue was purified
by HPLC and lyophilized, giving 11 as di(trifluoroacetate) (white
solid, 0.104 g, 15% overall yield from 8b).
366.0911 (M + H)+.
(RS)-2-Carboxyethyl-2-acetamido-5-methyl-7-bromohepta-
noic Acid (8b). Using the procedure outlined for 8a, compound 8b
was prepared from 5b (2.246 g, 9.21 mmol), sodium (0.106 g, 4.60
mmol), and DEAM (1.00 g, 4.60 mmol) as pale-yellow crystals (0.544
g, 31%).
1H NMR (600 MHz, CDCl3): 0.89 (d, J = 6.8, 3H, C(5)-CH3),
0.97, and 1.13 m (2H, C(4)H2), 1.26 (t, J = 7.1, 6H, 2× CH3 (OEt)),
1.65 (m, 1H, C(5)H), 1.66 m and 1.84 (2H, C(6)H2), 2.04 (s, 3H,
CH3 (NHAc)), 2.36 and 2.42 m (2H, C(3)H2), 3.36 and 3.42 m (2H,
C(7)H2), 4.25 (q, J = 7.1, 4H, 2× CH2 (OEt)), 6.77 (b, 1H, NH).
13C NMR (150.9 MHz, CDCl3): 14.00 (2× CH3 (OEt)), 18.70
(CH3), 23.06 (CH3 (NHAc)), 29.33 (C-3), 29.97 (C-4), 31.28 (C-5),
31.64 (C-7), 38.46 (C-6), 62.54 and 62.57 (2× CH2 (OEt)), 66.48 (C-
2), 168.10 and 168.15 (2× C-1), 168.94 (CO (NHAc)).
HRMS (ESI) calculated for C15H26O5NBrNa, m/z 402.0887, found
402.0878 (M + Na)+.
1H NMR (600 MHz, D2O), 4 diastereoisomers, only some signals
resolved: 0.91 (d, 3H, J = 6.6, CH3), 1.23 m, 1.31 m, 1.39 and 1.47 m
(2H, C(9)H2), 1.47 and 1.61 m (2H, C(7)H2), 1.61 (m, 1H, C(8)H),
1.90−2.00 (m, 2H, C(10)H2), 2.17 and 2.26 m (2H, C(3)H2), 2.60
and 2.65 m (2H, C(6)H2), 2.71 (m, 2H, C(4)H2), 4.02 (t, J = 6.1, 1H,
H-11), 4.14 (t, J = 6.1, 1H, H-2).
13C NMR (150.9 MHz, D2O): 26.39 (C-9), 29.06 (C-4), 30.09 (C-
8), 30.80 (C-7), 32.39 (C-3), 32.40 (C-10), 33.25 (C-6), 55.04 (C-2),
56.90 (C-11), 175.11 (C-12), 175.52 (C-1).
HRMS (ESI) calculated for C12H23O4N2S, m/z 291.1384, found
2-Carboxyethyl-2-acetamido-5,5-dimethyl-7-iodoheptanoic
Acid (8c). Sodium ethanolate was generated in situ by dissolving
sodium (0.640 g, 27.8 mmol, 1.3 equiv) in abs EtOH (40 mL) at rt in
a flask equipped with a reflux condenser fitted with a calcium chloride
tube. Diethyl acetamidomalonate (DEAM, 5.58 g, 25.7 mmol, 1.2
equiv) was added; after 30 min, mesylate 7 (6.17 g, 21.4 mmol, 1
equiv; as solution in 15 mL of THF) was introduced, followed by
addition of NaI (6.41 g, 42.8 mmol, 2 equiv), and the reaction was
heated to reflux under argon for 3 days. The reaction mixture was then
partitioned between Et2O and 10% aqueous citric acid, and the organic
layer was dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by flash chromatography on silica (elution with a
linear gradient of EtOAc in toluene) to give compound 8c as dark-
orange crystals (2.16 g, 23%).
291.1384 (M − H)−.
(2S,11RS)-5-Thia-2,11-diamino-8,8-dimethyldodecanedioic
Acid (12). Following the general procedure, the intermediate 9c was
prepared from L-methionine (0.717 g, 4.8 mmol, 1 equiv), sodium
(0.343 g, 14.9 mmol, 3.1 equiv), and 8c (2.12 g, 4.8 mmol, 1 equiv;
added as a solution in 3 mL of THF).
After the ammonia had evaporated, the residue (crude 9c) was
dissolved in aqueous HCl (5 M, 50 mL) and heated under reflux for 2
h. The chilled solution was then passed through a column of Dowex
50 (H+-cycle) and washed successively with water, methanol, and
again water. The crude product was eluted with 10% aqueous NH3,
and the solution was evaporated to dryness. The residue was purified
by HPLC and lyophilized, giving 12 as di(trifluoroacetate) (white
solid, 0.177 g, 7% overall yield from 8c).
1H NMR (600 MHz, CDCl3): 0.85 (s, 6H, C(CH3)2), 0.98 (m, 2H,
C(4)H2), 1.26 (t, J = 7.1, 6H, 2× CH3 (OEt)), 1.88 (m, 2H, C(6)H2),
2.04 (s, 3H, CH3 (NHAc)), 2.30 (m, 2H, C(3)H2), 3.07 (m, 2H,
C(7)H2), 4.25 (q, J = 7.1, 4H, 2× CH2 (OEt)), 6.73 (b, 1H, NH).
13C NMR (150.9 MHz, CDCl3): 0.24 (C-7), 14.02 (2× CH3
(OEt)), 23.02 (CH3 (NHAc)), 26.20 (2× CH3 (C(CH3)2), 26.85
(C-3), 34.83 (C-4), 35.32 (C-5), 47.09 (C-6), 62.57 (2× CH2 (OEt)),
66.54 (C-2), 168.13 (2× C-1), 168.83 (CO (NHAc)).
1H NMR (600 MHz, D2O), 2 diastereoisomers, only some carbon
signals resolved: 0.90 (s, 6H, C(CH3)2), 1.26 and 1.36 m (2H,
C(9)H2), 1.51 (m, 2H, C(7)H2), 1.92 (m, 2H, C(10)H2), 2.18 and
2.26 m (2H, C(3)H2), 2.55 (m, 2H, C(6)H2), 2.72 (t, J = 7.6, 2H,
C(4)H2), 4.02 (m, 1H, H-11), 4.14 (dd, J = 6.7 and 6.0, 1H, H-2).
13C NMR (150.9 MHz, D2O): 27.50 (C-10); 28.45, 28.46, and
28.48 (2× CH3 (C(CH3)2); 28.56 (C-6); 29.05 (C-4); 32.34 (C-3);
34.96 (C-8); 38.15 and 38.17 (C-9); 43.25 and 43.26 (C-7); 54.94 (C-
2); 56.32 (C-11); 175.04 (C-1); 175.37 (C-12).
HRMS (ESI) calculated for C16H28O5NINa, m/z 464.09044, found
464.09039 (M + Na)+.
6829
dx.doi.org/10.1021/jm300571h | J. Med. Chem. 2012, 55, 6822−6831