ꢀ
Lopez-Ortiz et al.
of 1N NaOH was added; the mixture was extracted with
CH2Cl2 (3 9 25 mL); the organic phase was dried over
anhydrous sodium sulfate and concentrated under reduced
pressure to obtain 4.8 g (99% yield) of (S,S)-4 as white crys-
obtained 555 mg of (S)-7, as a light yellow solid (90% yield).
20
Mp: 56–57 °C; ½aꢁD = ꢀ14.2 (c 1, MeOH), {Lit. (8) Mp: 59–
20
60 °C; ½aꢁD = ꢀ12.9 (c 0.53, EtOH)}; 1H RMN (300 MHz,
CDCl3, d, ppm): 2.72 (dd, 1H, J2 = 4.9 Hz, J1 = 2.6 Hz),
2.87 (dd, 1H, J2 = 4.9 Hz, J1 = 4.3 Hz), 3.35-3.40 (m, 1H),
3.86 (s, 3H), 4.03 (dd, 1H, J2 = 11.4 Hz, J1 = 5.5 Hz), 4.23
20
tals. Mp: 131–132 °C; ½aꢁD = +25.1 (c 1, MeOH); IR (KBr
1
per cm) mmax: 3208, 2962, 2856, 1658, 1492, 767, 518; H
RMN (300 MHz, CDCl3, d, ppm): 1.68 (d, 1H, J = 9.9 Hz),
1.83 (d, 1H, J = 9.9 Hz), 2.22 (s, 6H), 2.76 (d, 1H,
J = 10.2 Hz), 2.84 (br, 1H), 2.96 (dd, 1H, J2 = 10.5 Hz,
J1 = 2.1 Hz), 3.01 (dd, 1H, J2 = 9.9 Hz, J1 = 2.4 Hz),
3.13 (dd, 1H, J2 = 10.5 Hz, J1 = 0.6 Hz), 3.31 (d, 1H, J =
16.8 Hz), 3.42 (d, 1H, J = 16.8 Hz), 3.47 (s, 1H), 3.65 (s,
1H), 7.05–7.09 (m, 3H), 8.65 (br, 1H); 13C RMN (75 MHz,
CDCl3, d, ppm): 18.5, 36.0, 49.7, 57.1, 59.2, 62.7, 63.2,
127.1, 128.1, 133.6, 135.0, 169.2; HRMS (FAB+): m/z cal-
culated for C15H22N3O [M+H]+: 260.1763, found: 260.1773.
(dd, 1H, J2 = 11.4 Hz, J1 = 3.6 Hz), 6.85–6.98 (m, 4H); 13
C
RMN (75 MHz, CDCl3, d, ppm): 44.8, 50.2, 55.8, 70.2,
112.0, 114.4, 120.8, 121.9, 148.0, 149.7.
General procedure for the synthesis of
analogues 5
In a round-bottom flask were dissolved (S,S)-4 and the cor-
responding oxirane 7 in MeOH. The reaction mixture was
stirred under reflux for 12 h, it was concentrated under
reduced pressure on the rotary evaporator, one equivalent
of 1N HCl was added, and the aqueous solution was
washed with AcOEt. One equivalent of 1N NaOH was
added to the aqueous solution and it was extracted with
AcOEt; the organic phase was dried over anhydrous sodium
sulfate and concentrated on the rotary evaporator to obtain
the crude product, which was recrystallized from AcOEt or
purified by column chromatography (20 parts of flash silica,
CH2Cl2/MeOH 95:5) to afford the pure product.
General procedure for the synthesis of
compounds 7
In a round-bottom flask, equipped with a magnetic stirrer,
a 0.7 M solution of 6 in epichlorohydrin was stirred at room
temperature for 24 h. The excess epichlorohydrin was dis-
tilled off (30 °C/0.005 mmHg); the residue was suspended
in AcOEt and rinsed with water. The organic phase was
dried over anhydrous sodium sulfate and concentrated on
a rotary evaporator, affording the crude product which
was purified by column chromatography (20 parts of flash
silica, hexane/AcOEt 9:1).
2-{(1S,4S)-5-[3-(2-methoxyphenoxy)-2-hydroxypropyl]
-2,5-diazabicyclo[2.2.1] heptan-2-yl}-N-(2,6-dimethyl
phenyl)acetamide {[(S,S,S)(S,S,R)]-5}. According to the
general procedure, 6.1 g (13.9 mmol) of [(S,S,S)(S,S,R)]-
5 was obtained from 4.7 g (18 mmol) of (S,S)-4 and 3.2 g
(18 mmol) of rac-7, as a white powder (77% yield). The
reaction was purified by recrystallization with AcOEt. Mp:
135-136 °C; IR (KBr, cmꢀ1) mmax: 3253, 2864, 1633,
1504, 1253, 1230, 1025, 769, 734; 1H RMN (300 MHz,
CDCl3, d, ppm): 1.76-1.82 (m, 2H), 2.23 (s, 6H), 2.61-2.89
(m, 4H), 2.93 (dd, 1H, J2 = 9.9 Hz, J1 = 2.4 Hz), 3.01 (dd,
1H, J2 = 10.2 Hz, J1 = 4.5 Hz), 3.31 (d, 1H, J = 16.5 Hz),
3.41 (s, 2H), 3.42 (d, 1H, J = 16.5 Hz), 3.59 (br, 1H), 3.83
(s, 3H), 3.93–4.07 (m, 3H), 6.87–6.95 (m, 4H), 7.05-7.09
(m, 3H), 8.64 (br, 1H); 13C RMN (75 MHz, CDCl3, d, ppm):
18.5, 34.3, 34.9, 55.8, 57.3, 57.5, 58.0, 58.6, 58.7, 59.4,
63.0, 63.2, 63.6, 67.7, 72.0, 72.1, 111.9, 114.7, 120.9,
121.8, 127.1, 128.2, 133.7, 135.0, 148.2, 149.8, 169.1.
( )-2-[(2-Methoxyphenoxy)methyl]oxirane (rac-7). Acc-
ording to the general procedure, from 30 mL of 0.7 M solu-
tion of 6 (21 mmol) in (ꢂ)-epichlorohydrin was obtained
3.5 g of rac-7, as a light yellow solid (95% yield). Mp: 38 °C,
[Lit. (9) Mp: 38–40 °C]; 1H RMN (300 MHz, CDCl3, d, ppm):
2.73 (dd, 1H, J2 = 5.1 Hz, J1 = 2.4 Hz), 2.86–2.89 (m, 1H),
3.35–3.40 (m, 1H), 3.86 (s, 3H), 4.03 (dd, 1H, J2 = 11.4 Hz,
J1 = 5.4 Hz), 4.23 (dd, 1H, J2 = 11.4 Hz, J1 = 3.6 Hz),
6.88–6.95 (m, 4H); 13C RMN (75 MHz, CDCl3, d, ppm):
44.8, 50.1, 55.8, 70.1, 112.0, 114.3, 120.8, 121.8, 148.0,
149.6.
(S)-2-[(2-Methoxyphenoxy)methyl]oxirane [(S)-7]. Acc-
ording to the general procedure, 4.9 mL of 0.7 M solution of
6 (3.4 mmol) in (R)-epichlorohydrin afforded 530 mg of
(S)-7, as a slightly yellow solid (86% yield). Mp: 55–56 °C;
2-{(1S,4S)-5-[(2S)-3-(2-methoxyphenoxy)-2-hydroxypro-
pyl]-2,5-diazabicyclo [2.2.1]heptan-2-yl}-N-(2,6-dimeth-
ylphenyl)acetamide [(S,S,S)-5]. According to the
general procedure, 748 mg (1.7 mmol) of (S,S,S)-5 was
obtained from 548 mg (2.1 mmol) of (S,S)-4 and 378 mg
(2.1 mmol) of (S)-7, as a white powder (81% yield). The
20
½aꢁD = +15.9 (c 1, MeOH), {Lit. (8) Mp: 59–60 °C;
20
½aꢁD = +13.0 (c 0.61, EtOH)}; 1H RMN (300 MHz, CDCl3, d,
ppm): 2.72 (dd, 1H, J2 = 4.9 Hz, J1 = 2.6 Hz), 2.87 (dd,
1H, J2 = 4.9 Hz, J1 = 4.1 Hz), 3.35–3.40 (m, 1H), 3.86 (s,
3H), 4.03 (dd, 1H, J2 = 11.4 Hz, J1 = 5.5 Hz), 4.23 (dd,
1H, J2 = 11.4 Hz, J1 = 3.6 Hz), 6.85–6.98 (m, 4H); 13C
RMN (75 MHz, CDCl3, d, ppm): 44.8, 50.1, 55.8, 70.4,
112.0, 114.4, 120.8, 121.9, 148.0, 149.7.
reaction was purified by column chromatography. Mp: 142-
20
143 °C; ½aꢁD = +8.57 (c 1, MeOH); IR (KBr, cmꢀ1) mmax
:
3388, 3254, 2865, 2805, 1634, 1505, 1253, 1026, 769,
734, 608, 457; 1H RMN (300 MHz, CDCl3, d, ppm): 1.77 (d,
1H, J = 9 Hz), 1.82 (d, 1H, J = 9 Hz), 2.22 (s, 6H), 2.75-
2.89 (m, 4H), 2.92 (d, 1H, J = 9 Hz), 3.03 (d, 1H, J = 9 Hz),
3.29 (d, 1H, J = 15 Hz), 3.42 (d, 1H, J = 15 Hz), 3.44 (d,
(R)-2-[(2-Methoxyphenoxy)methyl]oxirane [(R)-7]. Acc-
ording to the general procedure, from 4.9 mL of 0.7 M solu-
tion of 6 (3.4 mmol) in (S)-epichlorohydrin there was
712
Chem Biol Drug Des 2014; 83: 710–720