Journal of Medicinal Chemistry
Article
CDCl3) δ 0.85−0.97 (m, 2 H), 1.12−1.22 (m, 2 H), 1.24−1.28 (m, 2
H), 1.36−1.46 (m, 4 H), 1.42 (s, 9 H), 1.49−1.58 (m, 2 H), 1.63−1.72
(m, 4 H), 1.74−1.76 (m, 2 H), 1.96−2.08 (m, 2 H), 2.16−2.29 (m, 2
H), 2.37−2.49 (m, 2 H), 2.76−2.83 (m, 2 H), 2.86−2.98 (m, 2 H),
3.11−3.24 (m, 2 H), 3.66−3.76 (s, 3 H), 4.0−4.15 (br s, 1H), 4.54−
4.64 (m, 2 H), 7.02−7.15 (m, 1 H), 7.92−8.04 (d, 1 H), 8.45 (d, J =
7.9 Hz, 1 H). HRMS (ESI) calcd for C31H53N6O9, [M + H]+:
653.3874. Found: 653.3871.
Synthesis of Macrocyclic Oxadiazole Esters 9a−h. General
Procedure. To a solution of compound 8 (2.0 g, 3.5 mmol) in dry
DMF (750 mL) were added EDCI (0.87 g, 4.55 mmol, 1.3 equiv),
HOBt (0.7 g, 4.55 mmol, 1.3 equiv), DIEA (1.35 g, 10.5 mmol, 3.0
equiv), and the mixture was stirred for 18 h at room temperature while
monitoring the reaction by TLC. The solvent was removed, and the
residue was partitioned between ethyl acetate (200 mL) and 10% citric
acid (2 × 50 mL). The ethyl acetate layer was further washed with
saturated aqueous NaHCO3 (2 × 50 mL), followed by saturated NaCl
(50 mL). The organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated. The crude product was purified by flash
chromatography to yield compounds 9a−h.
Methyl (7S,10S,13S)-13-((tert-Butoxycarbonyl)amino)-10-
isobutyl-4,9,12-trioxo-3,8,11-triaza-1(2,5)-oxadiazolacyclote-
tradecaphane-7-carboxylate (9a). Yield (60%), mp 160−163 °C.
1H NMR (400 MHz, DMSO-d6) δ 0.88 (dd, J = 12.52, 6.57 Hz, 6 H),
1.43 (s, 9 H), 1.59−1.70 (m, 2 H), 2.09−2.18 (m, 1 H), 2.20−2.28
(m, 1 H), 2.35−2.45 (m, 1 H), 3.12−3.21 (m, 1 H), 3.27 (dd, J =
15.01, 7.01 Hz, 1 H), 3.31−3.40 (m, 1 H), 3.56−3.69 (m, 1 H), 3.56−
3.69 (s, 3 H), 4.07−4.18 (m, 1 H), 4.27−4.39 (m, 1 H), 4.39−4.50
(m, 1 H), 4.50−4.61 (m, 1 H), 4.78 (dd, J = 16.01, 7.91 Hz, 1 H), 6.17
(dd, J = 7.88, 0.12 Hz, 1 H), 7.31−7.43 (m, 1 H), 8.16−8.24 (m, 1 H),
8.27 (d, J = 8.45 Hz, 1 H). HRMS (ESI) calcd for C23H36N6O8Na, [M
+ Na]+: 547.2492. Found: 547.2504.
8.39−8.46 (m, 1 H), 9.95 (s, 1 H). HRMS (ESI) calcd for
C26H42N6O8, [M + Na]+: 589.2962. Found: 589.2962.
Methyl (9S,12S,15S)-15-((tert-Butoxycarbonyl)amino)-12-
(cyclohexylmethyl)-6,11,14-trioxo-5,10,13-triaza-1(2,5)-
oxadiazolacycloheptadecaphane-9-carboxylate (9f). Yield
1
(65%), mp 177−180 °C. H NMR (400 MHz, DMSO-d6) δ 0.79−
0.91 (m, 2 H), 1.08−1.20 (m, 6 H), 1.40−1.43 (s, 9 H), 1.56−1.69
(m, 3 H), 1.75−1.88 (m, 4 H), 1.97−2.02 (m, 2 H), 2.09−2.21 (m, 1
H), 2.47−2.53 (m, 2 H), 2.68−2.78 (m, 3 H), 2.85−2.96 (m, 2 H),
3.17 (d, J = 4.83 Hz, 1 H), 3.33 (t, 2 H), 3.63−3.68 (s, 3 H), 3.97−
4.06 (m, 2 H), 4.33−4.42 (m, 1 H), 6.88−7.00 (m, 1 H), 7.88−8.00
(m, 1 H), 8.37−8.45 (m, 1 H). HRMS (ESI) calcd for C29H46N6O8Na,
[M + Na]+: 629.3275. Found: 629.3267.
Methyl (4S,7S,10S)-4-((tert-Butoxycarbonyl)amino)-7-(cyclo-
hexylmethyl)-5, 8, 13-trioxo-6, 9, 14-triaza-1(2,5)-
oxadiazolacyclooctadecaphane-10-carboxylate (9g). Yield
1
(51%), mp 98−101 °C. H NMR (400 MHz, DMSO-d6) δ 0.83−
0.95 (m, 2 H), 1.09−1.21 (m, 3 H), 1.32−1.43 (m, 5 H), 1.36 (s, 9 H)
1.56−1.69 (m, 4 H), 1.75−1.88 (m, 4 H), 1.96−2.07 (m, 2 H), 2.09−
2.23 (m, 2 H), 2.40−2.47 (m, 1 H), 2.49−2.53 (m, 1 H), 2.66−2.79
(m, 3 H), 2.84−2.93 (m, 1 H), 3.56−3.68 (s, 3 H), 3.95−4.06 (m, 2
H), 4.36−4.44 (m, 2 H), 6.66−6.75 (dd, J = 8.4 Hz, 1 H), 8.14−8.24
(dd, J = 8.2 Hz, 1 H), 8.38−8.45 (dd, J = 8.2 Hz, 1 H), 9.93−9.98 (m,
1 H). HRMS (ESI) calcd for C30H48N6O8Na, [M + Na]+: 643.3431.
Found: 643.3412.
Methyl (4S,7S,10S)-4-((tert-Butoxycarbonyl)amino)-7-(cyclo-
hexylmethyl)-5, 8, 13-trioxo-6, 9, 14-triaza-1(2,5)-
oxadiazolacyclooctadecaphane-10-carboxylate (9h). Yield
1
(51%), mp 181−183 °C. H NMR (400 MHz, CDCl3) δ 0.77−0.90
(m, 2 H), 0.90−1.01 (m, 2 H), 1.12−1.20 (m, 4 H), 1.24−1.35 (m, 4
H), 1.37−1.46 (m, 6 H), 1.43 (s, 9 H), 1.50−1.58 (m, 2 H), 1.60−1.71
(m, 4 H), 1.72−1.80 (m, 3 H), 2.23−2.32 (m, 2 H), 2.88 (ddd, J =
10.79, 7.62, 4.64 Hz, 2 H), 2.98−3.10 (m, 2 H), 3.64−3.76 (s, 3 H),
4.51−4.61 (m, 1 H), 6.83−6.95 (m, 1 H), 7.39−7.50 (d, 1 H), 7.6−7.7
(d, 1 H), 7.8−7.9(d, 1 H). HRMS (ESI) calcd for C31H50N6O8Na, [M
+ Na]+: 657.3588. Found: 657.3590.
Methyl (7S,10S,13S)-13-((tert-Butoxycarbonyl)amino)-10-
isobutyl-4,9,12-trioxo-3,8,11-triaza-1(2,5)-oxadiazola-
cyclopentadecaphane-7-carboxylate (9b). Yield (67%), mp 177−
1
180 °C. H NMR (400 MHz, DMSO-d6) δ 0.80−0.93 (m, 6 H),
Synthesis of Alcohols 10a−h. General Procedure. To a
solution of ester 9 (3.25 mmol) in anhydrous THF (25 mL) was
added dropwise lithium borohydride (2 M in THF, 4.9 mL, 9.75
mmol) followed by absolute ethyl alcohol (15 mL), and the reaction
mixture was stirred at room temperature overnight. The reaction
mixture was then acidified by adding 1.5 M potassium bisulfate until
the pH of the solution was ∼3. Removal of the solvent left a residue
which was taken up in ethyl acetate (150 mL). The organic layer was
washed with brine (25 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated to yield compounds 10a−h.
tert-Butyl ((7S,10S,13S)-7-(Hydroxymethyl)-10-isobutyl-
4,9,12-trioxo-3,8,11-triaza-1(2,5)-oxadiazolacyclotetra-
decaphane-13-yl)carbamate (10a). 170d °C, yield (82%). 1H
NMR (400 MHz, DMSO-d6) δ 0.79−0.91 (m, 6 H), 1.15−1.20 (m, 1
H), 1.33−1.45 (s, 9 H), 1.53−1.65 (m, 2 H), 1.73−1.85 (m, 1 H),
1.86−1.96 (m, 1 H), 1.96−2.03 (m, 1 H), 2.15−2.27 (m, 1 H), 2.38
(br s, 1 H), 2.51 (dquin, J = 3.48, 1.74, 1.74, 1.74, 1.74 Hz, 1 H),
2.85−2.97 (m, 1 H), 3.19−3.26 (m, 1 H), 3.28−3.40 (m, 1 H), 3.62−
3.73 (m, 1 H), 3.99−4.08 (m, 1 H), 4.27 (br s, 2 H), 7.31−7.38 (m, 1
H), 7.39−7.45 (m, 1 H), 7.51−7.62 (m, 1 H), 7.66−7.76 (m, 1 H),
7.90−8.02 (m, 1 H). HRMS (ESI) calcd for C22H37N6O7, [M + H]+:
497.2724. Found: 497.2710
tert-Butyl ((7S,10S,13S)-7-(Hydroxymethyl)-10-isobutyl-
4,9,12-trioxo-3,8,11-triaza-1(2,5)-oxadiazolacyclopenta-
decaphane-13-yl)carbamate (10b). Yield (80%), mp 183−186 °C.
1H NMR (400 MHz, DMSO-d6) δ 0.78−0.90 (m, 6 H), 1.15−1.23
(m, 1 H), 1.38 (s, 9 H), 1.57−1.63 (m, 1 H), 1.70−1.81 (m, 1 H),
1.87−1.95 (m, 1 H), 2.48−2.56 (m, 3 H), 2.77−2.86 (m, 1 H), 2.88−
2.98 (m, 1 H), 3.20−3.26 (m, 1 H), 3.29−3.42 (m, 2 H), 3.59−3.66
(m, 1 H), 3.66−3.75 (m, 1 H), 4.27 (br s, 2 H), 4.40−4.50 (m, 3 H),
6.99−7.03 (d, 1 H), 7.22−7.29 (d, 1 H), 7.62−7.70 (d, 1 H), 7.90−
8.00 (d, 1 H). HRMS (ESI) calcd for C23H38N6O7Na, [M + Na]+:
533.2700. Found: 533.2721.
1.33−1.41 (s, 9 H), 1.42−1.47 (m, 2 H), 1.57−1.69 (m, 1 H), 1.81−
1.93 (m, 2 H), 1.94−2.04 (m, 2 H), 2.18−2.27 (m, 1 H), 2.30−2.40
(m, 1 H), 2.44−2.56 (m, 2 H), 2.78−2.90 (t, 2 H), 3.29−3.40 (m, 1
H), 3.55−3.67 (s, 3 H), 3.98−4.08 (m, 1 H), 4.38−4.46 (s, 2 H),
7.03−7.15 (m, 1 H), 7.82−7.93 (m, 1 H). HRMS (ESI) calcd for
C24H38N6O8Na, [M + Na]+: 561.2649. Found: 561.2643.
Methyl 14-((tert-Butoxycarbonyl)amino)-11-isobutyl-
5,10,13-trioxo-4,9,12-triaza-1(2,5)-oxadiazolacyclohexa-
1
decaphane-8-carboxylate (9c). Yield (57%), mp 155−157 °C. H
NMR (400 MHz, DMSO-d6) δ 0.80−0.93 (m, 6 H), 1.33−1.45 (s, 9
H), 1.84−1.97 (m, 2 H), 1.99−2.04 (m, 1 H), 2.78 (br s, 1 H), 2.79
(d, J = 5.08 Hz, 1 H), 2.85−2.97 (m, 2 H), 3.29−3.41 (m, 8 H), 3.56−
3.68 (m, 3 H), 3.56−3.68 (m, 3 H), 4.37−4.45 (m, 1 H), 6.98−7.02
(dd, 1H), 7.30−7.35 (dd, 1H), 7.89−8.00 (dd, 1 H), 8.21 (dd, J =
11.55, 8.42 Hz, 1 H). HRMS (ESI) calcd for C25H40N6O8Na, [M +
Na]+: 575.2805. Found: 575.2824.
Methyl (8S,11S,14S)-14-((tert-Butoxycarbonyl)amino)-11-
(cyclohexylmethyl)-5,10,13-trioxo-4,9,12-triaza-1(2,5)-
oxadiazolacyclohexadecaphane-8-carboxylate (9d). Yield
1
(70%), mp 197−200 °C. H NMR (400 MHz, DMSO-d6) δ 0.80−
0.91 (m, 2 H), 1.07−1.20 (m, 3 H), 1.33−1.41 (m, 6 H), 1.38 (s, 9 H),
1.42−1.46 (m, 2 H), 1.58−1.67 (m, 4 H), 1.89−2.01 (m, 1 H), 2.47−
2.56 (m, 2 H), 2.78−2.84 (m, 1 H), 2.86−2.93 (t, 2 H), 3.30−3.43 (t,
2 H), 3.55−3.67 (s, 3 H), 4.03 (d, J = 7.13 Hz, 1 H), 4.43−4.50 (t, 2
H), 7.89−8.00 (m, 1 H), 7.15 (dd, 1H), 7.3 (dd, 1H), 8.21 (dd, J =
11.55, 8.42 Hz, 1 H). HRMS (ESI) calcd for C28H44N6O8Na, [M +
Na]+: 615.3118. Found: 615.3112.
Methyl (9S,12S,15S)-15-((tert-Butoxycarbonyl)amino)-12-
i s o b u t y l - 6 , 1 1 , 1 4 - t r i o x o - 5 , 1 0 , 1 3 - t r i a z a - 1 ( 2 , 5 ) -
oxadiazolacycloheptadecaphane-9-carboxylate(9e). Yield
1
(72%), mp 218−220 °C. H NMR (400 MHz, DMSO-d6) δ 0.81−
0.93 (m, 6 H), 1.35 (s, 9 H), 1.62 (d, J = 6.79 Hz, 1 H), 1.80−1.89 (m,
4 H), 2.49 (br s, 1 H), 2.50 (dt, J = 3.75, 1.86 Hz, 4 H), 2.66−2.72 (m,
1 H), 2.73−2.79 (m, 2 H), 3.32 (s, 2 H), 3.32−3.35 (m, 4 H), 3.62 (s,
3 H), 4.37 (br s, 1 H), 4.37−4.44 (m, 1 H), 8.16−8.22 (m, 1 H),
tert-Butyl ((8S,11S,14S)-8-(Hydroxymethyl)-11-isobutyl-
5,10,13-trioxo-4,9,12-triaza-1(2,5)-oxadiazolacyclohexa-
J
J. Med. Chem. XXXX, XXX, XXX−XXX