Journal of Medicinal Chemistry
Article
tert-Butyl 3-(6-amino-1-((benzyloxy)amino)-1-oxohexan-2-
yl)benzoate (11b). Similar to 11a, azide 10b (199 mg, 0.453
mmol) and 75 mg of Lindlar’s catalyst were used to prepare 11b as a
viscous gum (181 mg, 0.439 mmol, 97%). 1H NMR (600 MHz,
CDCl3): δ 7.84 (br s, 2H), 7.53 (br s, 1H), 7.33−7.21 (m, 6H),
4.82−4.74 (m, 2H), 3.23 (br s, 1H), 2.51 (br s, 2H), 2.08 (br s, 1H),
1.67 (br s, 1H), 1.60−1.52 (m, 2H), 1.57 (s, 9H), 1.35 (br s, 2H),
1.23 (br s, 1H), 1.14 (br s, 1H). 13C NMR (150 MHz, CDCl3): δ
170.6, 165.8, 140.1, 135.6, 132.1, 131.8, 129.4, 129.0, 128.6, 128.5,
128.3, 128.2, 81.2, 77.6, 49.3, 41.5, 32.65, 32.56, 28.3, 24.7. HRMS:
2H), 6.86 (d, J = 8.44 Hz, 2H), 4.81 (d, J = 13.94 Hz, 2H), 3.76 (s,
3H), 3.47 (s, 2H), 3.18−3.12 (m, 3H), 2.11 (br, 1H), 1.72 (br, 1H),
1.41 (dt, J = 7.9, 7.3 Hz, 2H), 1.22−1.10 (m, 2H). 13C NMR (150
MHz, CDCl3): δ 171.9, 171.2, 158.9, 139.3, 135.2, 130.6, 129.5,
128.8, 128.5, 128.3, 127.9, 127.4, 127.0, 78.0, 55.4, 49.7, 42.9, 39.4,
+
32.4, 29.1, 24.6. HRMS: m/z calcd for C28H33N2O4 , 461.2435 [M +
H]+; found, 461.2429. The above amide intermediate was
debenzylated using the same method for the synthesis of 5 (see
below), and then purified by HPLC to give hydroxamic acid 4 (16
mg, 0.043 mmol, 50%). 1H NMR (600 MHz, DMSO-d6): δ 10.62 (s,
1H), 8.78 (s, 1H), 7.31−7.27 (m, 4H), 7.22−7.19 (m, 1H), 7.13 (d, J
= 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 3.72 (s, 3H), 3.28 (s, 2H),
3.21 (cm, 1H), 2.97 (d, J = 7.0 Hz, 2H), 1.94−1.87 (m, 1H), 1.64−
1.58 (m, 1H), 1.38 (dt, J = 7.5, 7.4 Hz, 2H), 1.24−1.10 (m, 2H). 13C
NMR (150 MHz, DMSO-d6): δ 170.2, 170.1, 157.8, 140.7, 129.9,
128.4, 128.1, 127.6, 126.6, 113.6, 55.0, 48.2, 41.5, 41.45, 38.4, 38.3,
+
m/z calcd for C24H33N2O4 , 413.2435 [M + H]+; found, 413.2439.
2-Hydroxy-N-(6-(hydroxyamino)-6-oxo-5-phenylhexyl)-
benzamide (3). Adapting a procedure by Xu et al.,72 N-
methylmorpholine (33 μL, 0.30 mmol), and ethyl chloroformate
(23 μL, 0.24 mmol) were successively added to a solution of 2-
acetoxybenzoic acid (36 mg, 0.20 mmol) in dry THF (0.3 mL) and
dry DMF (0.1 mL) in an ice-water bath. After stirring the mixture at
the same temperature for 30 min, a solution of amine 11a (50 mg,
0.16 mmol) in dry THF (0.2 mL) and triethylamine (42 μL, 0.3
mmol) were successively added. The mixture was stirred for 18 h at rt,
diluted with water, and then extracted with ethyl acetate (× 3). The
combined extracts were washed with brine, dried with magnesium
sulfate, and concentrated in vacuo. The residue was purified by flash
chromatography (silica gel, 70% ethyl acetate/petroleum spirit) to
give the corresponding amide intermediate (14 mg, 0.030 mmol,
19%). 1H NMR (600 MHz, CDCl3): δ 8.25 (s, 1H), 7.66 (dd, J = 7.7,
1.6 Hz, 1H), 7.45 (ddd, J = 8.1, 7.5, 1.7 Hz, 1H), 7.31−7.21 (m,
11H), 7.08 (dd, J = 8.1, 1.0 Hz, 1H), 6.25 (s, 1H), 4.79 (cm, 2H),
3.36 (dt, J = 6.7, 6.6 Hz, 2H), 3.19 (br, 1H), 2.28 (s, 3H), 2.19 (br,
1H), 1.78 (br, 1H), 1.57 (dt, J = 7.5, 7.3 Hz, 2H), 1.38−1.24 (m,
2H). 13C NMR (150 MHz, CDCl3): δ 171.2, 169.5, 166.0, 148.0,
139.1, 135.2, 131.8, 129.6, 129.5, 129.0, 128.8, 128.6, 127.9, 127.6,
126.5, 123.3, 78.1, 50.0, 39.6, 32.5, 29.3, 24.8, 21.2. one q Ar signal
+
32.3, 28.9, 24.6. HRMS: m/z calcd for C21H27N2O4 , 371.1965 [M +
H]+; found, 371.1963.
2-((6-((Benzyloxy)amino)-6-oxo-5-phenylhexyl)-
carbamoyl)benzoic Acid (12a). Amine 11a (2.58 g, 8.25 mmol)
was dissolved in ethyl acetate (75 mL), and then phthalic anhydride
(1.35 g, 9.12 mmol) was added. The solution was stirred for 30 min.
The mixture was washed with aq hydrochloric acid (2 M, 20 mL) and
brine (20 mL), dried over magnesium sulfate, and then concentrated
in vacuo to give 12a as a white foam (3.80 g, 8.25 mmol, 100%). The
crude product was used in the next step without further purification.
ESMS: m/z 461.2 [M + H]+.
2-((6-((Benzyloxy)amino)-5-(3-(tert-butoxycarbonyl)-phe-
nyl)-6-oxohexyl)carbamoyl)benzoic Acid (12b). Similar to 12a,
amine 11b (55 mg, 0.132 mmol) was used to prepare 12b (74 mg,
0.132 mmol, 100%). Hydrochloric acid solution was omitted during
1
the aq work up. H NMR (600 MHz, CDCl3): δ 10.12 (br s, 1H),
8.03−8.00 (m, 2H), 7.92−7.85 (m, 5H), 7.81−7.79 (m, 2H), 6.90 (br
s, 1H), 4.68 (br s, 2H), 3.38−3.33 (m, 1H), 3.33−3.26 (m, 2H), 2.11
(br s, 1H), 1.65 (br s, 1H), 1.59−1.50 (m, 2H), 1.56 (s, 9H), 1.36−
1.18 (m, 2H). 13C NMR (150 MHz, CDCl3): δ 171.0, 169.1, 166.1,
162.9, 140.1, 137.6, 136.1, 135.1, 132.1, 132.0, 130.9, 129.9, 129.7,
129.4, 129.1, 128.6, 128.4, 128.3, 128.0, 125.8, 81.5, 78.0, 49.0, 40.1,
+
overlapped. HRMS: m/z calcd for C28H31N2O5 , 475.2227 [M + H]+;
found, 475.2222. The above amide intermediate (14 mg, 0.030
mmol) was debenzylated using the same method for the synthesis of 5
1
(see below). H NMR (600 MHz, CD3OD): δ 7.71 (d, J = 7.8 Hz,
1H), 7.37−7.35 (m, 3H), 7.29−7.20 (m, 3H), 6.89−6.85 (m, 2H),
3.48 (cm, 1H), 3.38−3.35 (m, 2H), 2.15−2.08 (m, 1H), 2.13 (s, 3H),
1.86−1.79 (m, 1H), 1.66 (cm, 2H), 1.50−1.31 (m, 2H). 13C NMR
(150 MHz, CD3OD): δ 173.24, 173.17, 171.0, 161.4, 141.3, 140.7,
134.6, 129.5, 129.46, 128.9, 128.8, 128.7, 128.2, 128.1, 119.9, 118.4,
117.0, 50.5, 50.3, 40.2, 34.1, 33.8, 30.15, 30.06, 26.1, 25.9, 18.0.
Without further purification, the crude debenzylated product (6.5 mg,
0.017 mmol) was dissolved in methanol (0.75 mL) and aq sodium
hydroxide solution (0.05 M, 0.75 mL) to effect acetyl hydrolysis. The
mixture was stirred at rt for 15 min and then acidified with
hydrochloric acid (2 M). The mixture was extracted with ethyl acetate
(×3). The combined extracts were washed with brine, dried with
magnesium sulfate, and concentrated in vacuo to give hydroxamic acid
3 in 42% yield (2.5 mg, 7.2 μmol). 1H NMR (600 MHz, DMSO-d6):
δ 10.62 (s, 1H), 8.78 (s, 1H), 7.81 (m, 1H), 7.39 (m, 1H), 7.31−7.26
(m, 4H), 7.20 (cm, 1H), 6.89−6.86 (m, 1H), 3.27−3.22 (m, 3H),
1.98−1.92 (m, 1H), 1.70−1.64 (m, 1H), 1.57−1.52 (m, 2H), 1.27−
1.17 (m, 2H). 13C NMR (150 MHz, DMSO-d6): δ 169.5, 169.0,
160.3, 140.7, 133.6, 128.1, 127.6, 127.5, 126.6, 118.5, 117.4, 115.0,
+
32.4, 28.5, 28.2, 24.7. HRMS: m/z calcd for C32H37N2O7 , 561.2595
[M + H]+; found, 561.2594.
N-(Benzyloxy)-6-(1,3-dioxoisoindolin-2-yl)-2-phenylhexa-
namide (13a). Acid 12a (3.80 g, 8.25 mmol) was dissolved in dry
THF (50 mL), and then 1,1′-carbonyldiimidazole (2.00 g, 12.3
mmol) was added. The solution was stirred at rt for 45 min, and then
diluted with ethyl acetate (250 mL). The mixture was washed with aq
hydrochloric acid (2 M, 2 × 50 mL) and brine (50 mL), dried over
magnesium sulfate, and then concentrated in vacuo. The residue was
purified by flash chromatography to give 13a as oil (2.81 g, 6.35
mmol, 77%). Rf 0.29 (50% ethyl acetate/petroleum spirit), 0.48 (60%
ethyl acetate/petroleum spirit), 0.64 (75% ethyl acetate/petroleum
1
spirit). H NMR (600 MHz, CDCl3): δ 7.95 (broad s, 1H), 7.84−
7.78 (m, 2H), 7.73−7.68 (m, 2H), 7.40−7.15 (m, 10H), 4.81 (broad
s, 2H), 3.65−3.59 (m, 2H), 3.16 (broad s, 1H), 2.38−2.12 (broad,
1H), 1.94−1.74 (broad, 1H), 1.74−1.50 (m, 3H), 1.39−1.17 (m,
2H). 13C NMR (150 MHz, CDCl3): δ 168.4, 133.9, 132.1, 129.4,
128.8, 128.7, 128.6, 127.8, 127.5, 123.2, 78.1, 50.0, 37.6, 32.3, 28.2,
24.7. ESMS: m/z 443.2 [M + H]+.
+
48.2, 38.7, 32.3, 28.6, 24.6. HRMS: m/z calcd for C19H23N2O4 ,
343.1652 [M + H]+; found, 343.1649.
tert-Butyl 3-(1-((Benzyloxy)amino)-6-(1,3-dioxoisoindolin-
2-yl)-1-oxohexan-2-yl)benzoate (13b). Similar to 13a, acid 12b
(19 mg, 0.034 mmol) was used to prepare 13b (12 mg, 0.022 mmol,
65%). Hydrochloric acid solution was omitted during the aq work up.
1H NMR (600 MHz, CDCl3): δ 8.00 (br s, 1H), 7.87 (m, 1H), 7.83−
N-Hydroxy-6-(2-(4-methoxyphenyl)acetamido)-2-phenyl-
hexanamide (4). A solution of HBTU (133 mg, 0.352 mmol), N,N-
diisopropylethylamine (167 μL, 0.96 mmol), and 4-methoxyphenyl-
acetic acid (53 mg, 0.32 mmol) in dry DMF (1.6 mL) was stirred at rt
under argon for 90 min. Amine 11a (100 mg, 0.32 mmol) was added,
and then the mixture was stirred overnight at rt under argon. The
mixture was diluted with ethyl acetate, washed with hydrochloric acid
(2 M), saturated sodium bicarbonate solution and brine, dried over
magnesium sulfate, and then concentrated in vacuo. The residue was
purified by flash chromatography to give the corresponding amide
intermediate (40 mg, 0.087 mmol, 27%). 1H NMR (600 MHz,
CDCl3): δ 8.00 (s, 1H), 7.33−7.22 (m, 10H), 7.12 (d, J = 8.6 Hz,
7.80 (m, 3H), 7.71−7.69 (m, 2H), 7.49 (m, 2H), 7.39−7.25 (m, 6H),
4.82 (br s, 2H), 3.63 (m, 2H), 3.19 (br s, 1H), 2.19 (br s, 1H), 1.81
(br s, 1H), 1.72−1.63 (m, 2H), 1.60 (s, 9H), 1.36−1.17 (m, 2H). 13C
NMR (150 MHz, CDCl3): δ 170.8, 168.6, 165.7, 139.2, 135.2, 134.0,
132.6, 132.3, 131.7, 129.6−128.7 (5), 123.3, 81.5, 78.3, 50.1, 37.8,
+
32.6, 29.9, 28.5, 24.9. HRMS: m/z calcd for C32H35N2O6 , 543.2490
[M + H]+; found, 543.2494.
2194
J. Med. Chem. 2021, 64, 2186−2204