Journal of Medicinal Chemistry
Article
quenched with water and extracted with CH2Cl2, and the solvent was
dried (Na2SO4) and evaporated. The crude material was purified by
flash chromatography (2−3% MeOH in EtOAc) to afford the (S)-
dried (MgSO4), and the solvent was evaporated. The crude product
was purified by column chromatography (hexane/EtOAc 1:1) to
afford (S)-6 as a yellowish oil (1.64 g, 52%). IR: 3445, 3349, 3193,
3086, 3064, 3030, 2964, 2875, 1726, 1668, 1621, 1493, 1455, 1403,
1
isomer of the intermediate alkyne as a yellow oil (79 mg, 80%). H
1
NMR (600 MHz, CDCl3): δ (ppm) 0.91 (t, J = 7.3 Hz, 3H), 1.59−
1.80 (m, 7H), 1.98 (t, J = 2.7 Hz, 1H), 2.00 (s, 1H), 2.06 (quint, J =
6.7 Hz, 2H), 2.13−2.18 (m, 1H), 2.42 (td, J = 2.6, 6.9 Hz, 2H), 2.44−
2.48 (m, 1H), 2.65−2.76 (m, 2H), 2.78−2.95 (m, 5H), 3.20−3.26 (m,
1H), 3.46−3.51 (m, 2H), 3.89 (s, 3H), 4.14 (t, J = 6.3 Hz, 2H), 6.54
(d, J = 8.0 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H),
6.92, (t, J = 7.6 Hz, 1H), 7.09−7.13 (m, 1H), 7.38 (dd, J = 1.9, 8.3 Hz,
1H), 7.48 (d, J = 2.0 Hz, 1H). 13C NMR (CDCl3, 150 MHz): δ (ppm)
11.7, 15.2, 19.9, 23.3, 23.8, 24.0, 24.6, 27.0, 28.0, 30.7, 39.2, 50.0, 52.0,
56.0, 57.7, 67.3, 69.0, 83.3, 111.3, 111.9, 112.4, 119.7, 120.7, 122.7,
1310, 1239, 1205, 1165, 1136, 1101, 1060, 1028, 967, 906 cm−1. H
NMR (600 MHz, CDCl3) δ (ppm) 0.87 (t, J = 7.4 Hz, 3 H), 0.99 (t, J
= 7.5 Hz, 3 H), 1.41−1.59 (m, 2 H), 1.68−1.74 (m, 2 H), 1.91−1.97
(m, 1 H), 2.00−2.05 (m, 1 H), 2.17 (ddd, J = 7.6, 7.6, 15.0 Hz, 1 H),
2.29 (ddd, J = 6.3, 8.0, 14.9 Hz, 1 H), 2.49 (ddd, J = 4.5, 8.5, 13.0 Hz,
1 H), 2.59 (ddd, J = 8.0, 8.0, 12.9 Hz, 1 H), 3.32 (dd, J = 5.5, 9.6 Hz, 1
H), 3.60 (d, J = 13.9 Hz, 1 H), 3.90 (d, J = 13.9 Hz, 1 H), 4.08 (dt, J =
6.7, 10.7 Hz, 1 H), 4.12 (dt, J = 6.7, 10.7 Hz, 1H), 7.20−7.36 (m, 5
H). 13C NMR (90 MHz, CDCl3) δ (ppm) 10.63, 11.70, 21.71, 22.17,
25.24, 32.22, 52.52, 55.27, 61.16, 65.90, 126.96, 128.27, 128.97,
140.11, 172.74, 174.75. APCI-MS m/z 321.2 [M+ + 1]. [α]29D −104.7°
(c 1.16, CHCl3). (R)-6 (1.73 g, 55%, [α]21D +106.3° (c 1.66, CHCl3))
was prepared from (R)-5 (2.33 g, 9.84 mmol) as described above for
(S)-6.
126.5, 127.4, 149.3, 151.0, 154.5, 167.4. [α]23 = −22.0 (c 2.20,
D
MeOH). ESI-MS m/z 494.0 [M+ + 1]. HPLC: tR = 16.0 min, purity
99%. The (R)-isomer of the intermediate alkyne (147.5 mg, 92%,
[α]26 = +25.8 °C (c 1.13, MeOH)) was prepared from (R)-19 (73.7
D
(S)-4-(Benzylpropylamino)-5-hydroxypentanamide (7). A solution
of (S)-6 (1.01 g, 3.15 mmol) in THF (30.00 mL) was cooled to −37
°C, and a 2.4 M solution of LiAlH4 in THF (1.97 mL, 4.74 mmol) was
added slowly. After stirring at −37 °C for 1 h, the reaction was
quenched by careful addition of aqueous NaHCO3. The resulting
suspension was filtered through a pad of Celite, the filtrate was
concentrated, and the residue was purified by flash chromatography
(CH2Cl2/MeOH saturated with NH3 40:1) to isolate (S)-7 as
yellowish oil (639.5 mg, 77%). IR: 3350, 3196, 3086, 3062, 3027,
2958, 2871, 2823, 1666, 1617, 1493, 1455, 1408, 1322, 1259, 1134,
1028 cm−1. 1H NMR (600 MHz, CDCl3) δ (ppm) 0.84 (t, J = 7.4 Hz,
3 H), 1.43 (dddd, J = 6.9, 8.3, 13.3, 14.9 Hz, 1 H), 1.47−1.56 (m, 2
H), 2.04 (dddd, J = 4.3, 6.7, 9.4, 13.7 Hz, 1 H), 2.15 (ddd, J = 6.7, 8.7,
15.3 Hz, 1 H), 2.21 (ddd, J = 6.2, 9.2, 15.3 Hz, 1 H), 2.43−2.52 (m, 2
H), 2.76 (dddd, J = 4.4, 5.1, 9.5, 9.5 Hz, 1 H), 3.24 (s, 1 H), 3.40 (dd, J
= 10.2, 10.2 Hz, 1 H), 3.48 (d, J = 13.6 Hz, 1 H), 3.49 (dd, J = 5.2,
10.4 Hz, 1 H), 3.80 (d, J = 13.6 Hz, 1 H), 5.45 (s, 2 H), 7.23−7.33 (m,
5 H). 13C NMR (90 MHz, CDCl3) δ (ppm) 11.67, 21.22, 21.83, 32.91,
51.04, 54.04, 59.95, 60.80, 127.08, 128.40, 128.90, 139.73, 174.47.
mg, 0.36 mmol) as described above. A solution of the alkyne (38 mg,
0.08 mmol), 1-azidobutane (6 mg, 0.06 mmol), copper(II) sulfate
pentahydrate (15 mg, 0.06 mmol), and sodium ascorbate (35 mg, 0.18
mmol) in 5 mL of CH2Cl2 and 1 mL of methanol was stirred overnight
at room temperature. The reaction was quenched with water and
extracted with CH2Cl2. The solvent was dried using sodium sulfate and
evaporated in vacuo. The crude material was purified by HPLC (40−
80% methanol/0.1% aq formic acid) to afford (S)-4 a white solid (16
1
mg, 46%). H NMR (600 MHz, (CD3)2SO) δ (ppm) 0.81−0.91 (m,
6H), 1.22 (sextet, J = 7.6 Hz, 2H), 1.38−1.59 (m, 7H), 1.76 (quint, J =
7.3 Hz, 2H), 1.94−2.00 (m, 1H), 2.05 (quint, J = 7.2 Hz, 2H), 2.36−
2.45 (m, 1H), 2.48−2.54 (3H, overlaid by DMSO signal), 2.59 (t, J =
6.8 Hz, 2H), 2.64−2.86 (m, 5H), 2.88−2.95 (m, 1H), 3.25 (q, J = 6.0
Hz, 2H), 3.80 (s, 3H), 4.04 (t, J = 6.2 Hz, 2H), 4.28 (t, J = 7.1 Hz,
2H), 6.50 (d, J = 7.6 Hz, 1H), 6.57 (d, J = 7.8 Hz, 1H), 6.86 (t, J = 7.7
Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 7.41−7.45 (m, 2H), 7.89 (s, 1H),
8.32 (t, J = 5.5 Hz, 1H). 13C NMR (150 MHz, (CD3)2SO) δ (ppm)
11.65, 13.26, 19.06, 21.11, 21.58, 23.41, 24.79, 25.36, 27.03, 28.45,
31.42, 31.68, 48.84, 49.56, 51.67, 55.58, 56.25, 67.44, 110.86, 111.52,
111.88, 119.72, 120.25, 121.81, 122.76, 125.89, 127.04, 137.20, 146.02,
148.34, 150.35, 154.75, 165.55 (one carbon peak overlaid by DMSO
APCI-MS m/z 265.1 [M+ + 1]. [α]30 +75.9° (c 1.19, CHCl3). (R)-7
D
(1.00 g, 71%, [α]25D −74.3° (c 0.96, CHCl3)) was prepared from (R)-
6 (1.71 g, 5.34 mmol) as described above for (S)-7.
signal). [α]23 = −21.6 (c 0.91, MeOH). HR-EIMS calcd 591.3785;
D
found 591.3785. ESI-MS m/z 593.0 [M+ + 1]. HPLC: system 1, tR =
16.2 min, purity 100%; system 2 tR = 12.4 min, purity 97%. (R)-4 (9
mg, 40%, [α]25D = −21.6 (c 0.91, MeOH). HPLC: system 1, tR = 16.0
min, purity 98%; system 2, tR = 12.3 min, purity 98%) was prepared
from the (R)-isomer of the intermediate alkyne (18 mg, 0.04 mml)
and 1-azidobutane (5 mg, 0.05 mmol) as described for (S)-4.
(S)-N-Benzylglutamine (5). Benzaldehyde (8.2 mL, 80.8 mmol) was
added dropwise to a solution of (S)-glutamine (5.90 g, 40.4 mmol)
and NaOH (1.62 g, 40.4 mmol) in a 7:3 mixture of H2O and MeOH
(100.0 mL), and the reaction was stirred at room temperature for 4
h.51 After cooling the reaction mixture to 0 °C and addition of NaBH4
(1.83 g, 48.5 mmol), the reaction was stirred at room temperature for
1 h. Then the solution was acidified by adding glacial acid until the
product precipitated. The product was filtered off, washed, and dried
(MgSO4) to give (S)-5 as a white solid (6.97 g, 73%); mp 200 °C. 1H
NMR (600 MHz, pyridin-d5/D2O) δ (ppm) 1.72−1.85 (m, 2 H),
2.05−2.14 (m, 2 H), 3.29 (dd, J = 5.8, 6.7 Hz, 1 H), 3.66 (d, J = 12.8
Hz, 1 H), 3.76 (d, J = 12.8 Hz, 1 H), 6.72−6.76 (m, 1 H), 6.79−6.83
(m, 2 H), 6.97−6.02 (m, 2 H). 13C NMR (150 MHz, pyridin-d5/D2O)
δ (ppm) 27.73, 33.18, 52.17, 63.51, 125.09, 130.81, 130.88, 131.62,
133.58, 138.18, 174.94, 179.07. APCI-MS m/z 237.0 [M+ + 1]. (R)-5
(6.41 g, 79%) was prepared from (R)-glutamine (5.04 g, 34.5 mmol)
as described above for (S)-5.
(S)-5-Hydroxy-4-(propylamino)pentanamide (8). A mixture of
(S)-7 (1.0 g, 3.79 mmol) and 10% Pd/C in MeOH (40 mL) was
stirred at room temperature under H2 atmosphere (balloon) for 5 h.
Then, the catalyst was removed by filtration through a pad of Celite,
and the solvent was evaporated to afford (S)-8 as a white solid (665.1
mg, quant); mp 99 °C. IR: 3305, 3186, 2958, 2930, 2870, 1668, 1537,
1
1456, 1410, 1358, 1291, 1123, 1043, 991 cm−1. H NMR (600 MHz,
CD3OD) δ (ppm) 0.95 (t, J = 7.4 Hz, 3 H), 1.48−1.57 (m, 2 H), 1.68
(dddd, J = 6.8, 7.0, 8.7, 14.0 Hz, 1 H), 1.79 (dddd, J = 5.2, 7.0, 8.8,
14.0 Hz, 1 H), 2.25 (ddd, J = 7.0, 8.6, 14.7 Hz, 1 H), 2.28 (ddd, J =
6.6, 8.7, 14.8 Hz, 1 H), 2.53−2.64 (m, 3 H), 3.43 (dd, J = 6.4, 11.1 Hz,
1 H), 3.60 (dd, J = 4.7, 11.1 Hz, 1 H). 13C NMR (90 MHz, CD3OD) δ
(ppm) 12.00, 23.83, 27.77, 32.98, 49.88, 60.07, 63.82, 178.75. APCI-
MS m/z 175.0 [M+ + 1]. [α]30D +18.8° (c 0.76, MeOH). (R)-8 (586.1
mg, 90%, [α]25 −19.4° (c 1.03, MeOH)) was prepared from (R)-7
D
(990.3 mg, 3.75 mmol) as described above for (S)-8.
4-Azidobutanol (9). To an ice-cold suspension of NaBH4 (839.8
mg, 22.2 mmol) in dry THF (60 mL) a solution of I2 (9.39 g, 97.0
mmol) in THF (24 mL) was added slowly under N2 atmosphere. After
stirring at room temperature for 3 h, a solution of NaN3 (9.62 g, 148.0
mmol) in H2O (20 mL) was added dropwise and the reaction mixture
was stirred for 24 h. Then the mixture was diluted with H2O (50 mL)
and extracted with diethyl ether. The combined organic layers were
washed successively with aqueous Na2S2O3, H2O, and brine and
subsequently dried using MgSO4. The solvents were evaporated at 32
°C to furnish 9 as yellowish oil (4.03 g, 95%). Analytical data as
described in literature.52
(S)-Propyl 5-Amino-2-(N-benzyl-N-propylamino)-5-oxopena-
noate (6). To a solution of (S)-5 (2.33 g, 9.84 mmol) in DMF/
H2O (70.0 mL/25.0 mL), DIPEA (16.7 mL, 98.40 mmol) and propyl
iodide (14.3 mL, 147.60 mmol) were added successively. The reaction
mixture was stirred at 70 °C for 24 h. After addition of saturated
aqueous NaHCO3 and basification with 6 N NaOH, the aqueous layer
was extracted with diethyl ether. The combined organic layers were
(S)-4-((4-Azidobutyl)propylamino)-5-hydroxypentanamide (10).
To an ice-cold solution of 9 (959.3 mg, 8.33 mmol) in CH2Cl2/
DMSO (8.0 mL/4.0 mL), Et3N (4.6 mL, 33.30 mmol), and SO3·
I
J. Med. Chem. XXXX, XXX, XXX−XXX