4008
A. Conejo-Garcia, C. J. Schofield / Bioorg. Med. Chem. Lett. 15 (2005) 4004–4009
11. High, A.; Prior, T.; Bell, R. A.; Rangachari, P. K. J.
Pharmacol. Exp. Ther. 1999, 288, 490.
12. Rangachari, P. K.; Prior, T.; Bell, R. A.; Huynh, T. Am. J.
Physiol. 1992, 263, 632.
13. Thomas, G.; Ramwell, P. W. Biochem. Biophys. Res.
Commun. 1989, 164, 889.
14. Lazare, R.; Watson, P. A. J. Pharm. Pharmacol. 1972, 24,
361.
2H), 1.64–1.67 (m, 2H), 2.09 (t, J = 6.5 Hz, 2H), 2.78 (br s,
1H); 3.57 (t, J = 6 Hz, 2H), 4.88 (s, 2H), 7.40–7.41 (m,
5H), 9.23 (s, 1H); 13C NMR (100.4 MHz, CD2Cl2): d 22.0,
32.1, 32.9, 62.1, 78.4, 128.7 (2·), 128.9, 129.5 (2·), 135.3,
176.1; HRESMS (m/z): calcd for C12H16NO3 222.1130
[MꢁN]ꢁ; found 222.1135. N-(benzyloxy)-6-hydroxyhex-
anamide 7. Colourless oil (72%); 1H NMR (400 MHz,
CD2Cl2): d 1.35–1.42 (m, 2H), 1.52–1.57 (m, 2H), 1.62–
1.66 (m, 2H), 1.72 (br s, 1H), 2.07 (m, 2H), 3.61 (t,
J = 6.5 Hz, 2H), 4.89 (s, 2H), 7.39–7.42 (m, 5H), 8.39 (br s,
1H); 13C NMR (128.5 MHz, CD2Cl2): d 24.9, 25.2, 32.3,
33.0, 62.3, 78.0, 128.5 (2·), 128.6, 129.2 (2·), 135.6, 170.7;
HRESMS (m/z): calcd for C13H18NO3 236.1287 [MꢁH]ꢁ;
found 236.1286. N-benzyl-4-hydroxybutanamide 8. White
solid, (99%); mp: 58.5–60 ꢁC; 1H NMR (400 MHz,
CD2Cl2): d 1.86 (dt, J = 6, 7 Hz, 2H), 2.39 (t, J = 7 Hz,
2H), 2.86 (br s, 1H), 3.67 (t, J = 6 Hz, 2H), 4.43 (d,
J = 6 Hz, 2H), 6.10 (br s, 1H), 7.30–7.31 (m, 3H), 7.35–
7.38 (m, 2H); 13C NMR (100.6 MHz, CD2Cl2): d 28.5,
34.3, 43.9, 62.7, 127.7, 128.0 (2·), 129.0 (2·), 139.0, 173.6;
HRESMS (m/z): calcd for C11H14NO2 192.1025 [MꢁN]ꢁ;
found 192.1025.
15. Free, C. A.; Majchrowicz, E.; Hess, S. M. Biochem.
Pharmacol. 1971, 20, 1421.
16. General procedure for the synthesis of compounds 1–8
and 19: To a stirring suspension of O-benzyl-N-hydrox-
ylamine hydrochloride (3 equiv) in dry THF at 0 ꢁC, a
solution of trimethylaluminium (2 M, 3 equiv) in toluene
was added; stirred was continued at 0 ꢁC for 30 min under
nitrogen. The reaction was later stirred at room temper-
ature for 20 min and cooled to ꢁ15 ꢁC when a solution of
the lactone (1 equiv) in dry THF was added dropwise.
The suspension was warmed to 0 ꢁC and stirred for 1.5 h.
The reaction was quenched with HCl (0.5 M) and
extracted with ethyl acetate. The organic extracts were
dried over Na2SO4 and evaporated. The crude product
was purified by flash column chromatography on silica
gel (ethyl acetate–hexane/4:1) to afford the desired
compound.
19. Liu, F.; Zha, H. Y.; Yao, Z. J. J. Org. Chem. 2003, 68,
6679.
20. Synthesis and characterization of tert-butyl 4-(acetyl-
17. Pirrung, M. C.; Chau, J. H. L. J. Org. Chem 1995, 60,
8084.
oxyl)butanoate 11: To a solution of 10 (350 mg,
2.18 mmol) and N,N0-dimethylaminopyridine (26.7 mg,
0.218 mmol) in pyridine (2 mL), was added acetic anhy-
dride (0.617 mL, 6.54 mmol) at room temperature. The
reaction mixture was stirred for 3 h, then poured into ice-
water (5 mL) and extracted with ether (3 · 5 mL). The
organic phase was washed with HCl aq (1 M, 15 mL),
water (15 mL), satd NaHCO3 (15 mL), water (15 mL), and
brine (10 mL), dried over MgSO4 and evaporated to afford
11 as a slightly brown oil (340 mg, 77%). 1H NMR
(400 MHz, CDCl3): d 1.44 (s, 9H), 1.91 (dt, J = 6.5 Hz, 7,
2H), 1.95 (s, 3H), 2.29 (t, J = 7 Hz, 2H), 4.09 (t,
J = 6.5 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): d 20.9,
24.1, 28.1 (3·), 32.0, 63.5, 80.4, 171.0, 172.1; HRCIMS
(m/z): calcd for C10H22NO4 220.1549 [M+NH4]+; found
220.1544.
18. Spectroscopic data for compounds 1–8: N-(benzyloxy)-4-
hydroxybutanamide 1. Colourless oil (58%), 1H NMR
(400 MHz, CDCl3): d 1.78 (dt, J = 6, 6.5 Hz, 2H), 2.16–
2.17 (m, 2H), 3.13 (br s, 1H), 3.58 (t, J = 6 Hz, 2H), 4.86
(s, 2H), 7.36–7.37 (m, 5H), 9.30 (br s, 1H); 13C NMR
(100.6 MHz, CDCl3): d 27.8, 30.1, 61.6, 78.1, 128.5 (2·),
128.7, 129.2 (2·), 135.3, 171.3; High Resolution Electro-
spray Ionisation MS (HRESMS) (m/z): calcd for
C11H14NO3 208.0974 [MꢁN]ꢁ; found 208.0968. N-(ben-
zyloxy)-4-hydroxypentanamide 2. White solid (74%); mp:
53–55 ꢁC; 1H NMR (500 MHz, CD2Cl2): d 1.17 (d,
J = 6 Hz, 3H), 1.63–1.67 (m, 1H), 1.77–1.78 (m, 1H),
2.19–2.20 (m, 2H), 2.65 (br s, 1H), 3.76–3.80 (m, 1H); 4.89
(s, 2H), 7.40–7.43 (m, 5H), 8.66 (br s, 1H); 13C NMR
(128.5 MHz, CD2Cl2): d 23.4, 29.8, 34.0, 67.2, 78.0, 128.5
(2·), 128.6, 129.2 (2·), 135.6, 171.2; HRESMS (m/z): calcd
for C12H16NO3 222.1130 [MꢁN]ꢁ; found 222.1134. N-
(benzyloxy)-4-hydroxyhexanamide 3. White solid (80%);
21. Synthesis and characterization of 4-(acetyloxy)butanoic
acid 12: To a solution (10 mL) of tert-butyl 4-hydroxy-
butanoate 11 (250 mg, 1.23 mmol) in toluene were added
p-TsOH (23.5 mg, 0.123 mmol) and one drop of water.
The mixture was heated at reflux for 2 h. After cooling,
ethyl acetate (10 mL) was added and the organic layer
washed with water (2 mL), dried (MgSO4) and evaporated
to afford a colourless oil (179.8 mg, 83%). 1H NMR
(400 MHz, CDCl3): d 1.99 (dt, J = 6.5, 7 Hz, 2H), 2.06 (s,
3H), 2.47 (t, J = 7 Hz, 2H), 4.13 (t, J = 6.5 Hz, 2H); 13C
NMR (100.6 MHz, CDCl3): d 20.8, 23.7, 30.4, 63.2, 171.0,
178.2; HRCIMS (m/z): calcd for C6H14NO4 164.0923
[M+NH4]+; found 164.0919.
1
mp: 57.5–59 ꢁC; H NMR (500 MHz, CD2Cl2): d 0.94 (t,
J = 7.5 Hz, 3H), 1.44–1.48 (m, 2H), 1.60–1.63 (m, 1H),
1.81–1.84 (m, 1H), 2.20–2.21 (m, 2H), 2.74 (br s, 1H), 3.49
(br s, 1H); 4.89 (s, 2H), 7.38–7.42 (m, 5H), 9.00 (br s, 1H);
13C NMR (128.5 MHz, CD2Cl2): d 9.8, 29.8, 30.4, 31.8,
72.5, 78.0, 128.5 (2·), 128.6, 129.2 (2·), 135.6, 171.4;
HRESMS (m/z): calcd for C13H18NO3 236.1287 [MꢁN]ꢁ;
found 236.1282. N-(benzyloxy)-4-hydroxy-4-phenylbu-
1
tanamide 4. White solid (83%); mp: 43–45 ꢁC; H NMR
(400 MHz, CD2Cl2): d 1.97–2.03 (m, 2H), 2.18 (br s, 2H),
3.44 (br s, 1H); 4.68–4.71 (m, 1H), 4.87 (s, 2H), 7.28–7.40
(m, 10H), 8.91 (br s, 1H); 13C NMR (100.6 MHz,
CD2Cl2): d 30.0, 34.6, 75.6, 78.4, 126.1 (2·), 127.7 (2·),
128.8 (2·), 128.9 (2·), 129.0, 129.6, 135.9, 144.9, 171.6;
HRESMS (m/z): calcd for C17H18NO3 284.1283 [MꢁN]ꢁ;
found 284.1283. N-(benzyloxy)-3-hydroxypropanamide 5.
White solid (87%), mp: 69–71 ꢁC; 1H NMR (400 MHz,
CD2Cl2): d 2.30–2.31 (m, 2H), 2.62 (br s, 1H), 3.83 (t,
J = 5.5 Hz, 2H); 4.91 (s, 2H), 7.42–7.43 (m, 5H), 8.65 (br s,
1H); 13C NMR (100.6 MHz, CD2Cl2): d 36.0, 58.8, 78.5,
128.9 (2·), 129.0, 129.6 (2·), 135.9, 176.4; HRESMS (m/z):
calcd for C10H12NO3 194.0817 [MꢁN]ꢁ; found 194.0822.
N-(benzyloxy)-5-hydroxypentanamide 6. Colourless oil
(50%); 1H NMR (400 MHz, CD2Cl2): d 1.49–1.57 (m,
22. Synthesis and characterization of 5-[(benzyloxy)amino]-4-
oxopentyl acetate 13: To a solution of 4-(acetyloxy)buta-
noic acid 12 in CHCl3 (10 mL), HOBt (110.9 mg,
0.821 mmol), EDCI (157.4 mg, 0.821 mmol), TEA
(480 mL, 3.421 mmol), and NH2OBn were added and
stirred at room temperature for 7 h. The reaction mixture
was washed with HCl aq (1 M, 2 · 5 mL), satd NaHCO3,
(2 · 5 mL), water (2 · 5 mL), dried (MgSO4) and evapo-
1
rated to afford a colourless oil (114.5 mg, 67%). H NMR
(400 MHz, D2O): d 1.83 (dt, J = 6.5, 7 Hz, 2H), 2.02 (s,
3H), 2.14 (t, J = 7 Hz, 2H), 4.13 (t, J = 6.5 Hz, 2H); 4.86
(s, 2H), 7.42 (s, 5H); 13C NMR (100.6 MHz, D2O): d 20.6,
24.0, 29.3, 64.4, 78.4, 129.0 (2·), 129.5, 130.1 (2·), 135.0,
172.3, 174.8; HRESMS (m/z): calcd for C13H16NO4
250.1079 [MꢁN]ꢁ, found 250.1084.