Y. Sawai et al. / Tetrahedron 65 (2009) 7122–7128
7127
J¼7.8 Hz, 1H), 7.33 (d, J¼8.0 Hz, 1H), 7.14 (d, J¼2.3 Hz, 1H), 7.06–6.94
(m,1H), 6.70–6.62 (m,1H), 4.57 (q, J¼6.7 Hz,1H), 3.98–3.90 (m, 2H),
3.63 (d, J¼6.8 Hz, 1H), 3.39–3.30 (m, 1H), 1.42 (d, J¼6.8 Hz, 3H), 1.29
(d, J¼7.1 Hz, 3H),1.00 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
mixture was allowed to warm and stirred at room temperature for
2.5 h. After adding water (24 mL) and ethyl acetate (24 mL), the
layers were separated. The aqueous layer was extracted with ethyl
acetate (24 mL). The combined organic layers were successively
washed with 1 M hydrochloric acid (2ꢁ24 mL) and water
(2ꢁ24 mL) and then concentrated in vacuo. Ethanol (24 mL) was
added to the residue, and the resultant solution was concentrated
in vacuo. After the addition of ethanol (40 mL), 4 M aq NaOH (8 mL)
was added dropwise to the resultant solution. The mixture was
stirred at room temperature for 4 h. Then, 4 M hydrochloric acid
(12 mL) was added dropwise to the mixture. After stirring at 0 ꢀC
for 1.5 h, the resultant precipitate was collected by filtration,
washed with ice-cooled ethanol/water (12 mL, 2:1), and dried in
vacuo to give 8 (4.17 g, 10.3 mmol, 88% yield, >99.9% ee,) as a white
d
174.4, 174.3, 151.9, 151.0, 136.8, 126.8, 123.1, 121.4, 118.9, 118.7,
116.6, 116.4, 116.1, 111.9, 73.3, 60.5, 59.4, 35.0, 19.0, 16.4, 14.3. Anal.
Calcd for C23H28N2O6$H2O: C, 61.87; H, 6.77; N, 6.27. Found: C,
61.74; H, 6.77; N, 6.20.
4.6. Synthesis of ethyl (2R,3S)-2-amino-3-(1H-indol-3-
yl)butanoate methanesulfonate ((2R,3S)-2$MeSO3H)
To a mixture of toluene (5.0 mL) and 1 M aq NaOH (5.0 mL) was
added (2R,3S)-2$(R)-5$H2O (1.00 g, 2.24 mmol, 92% ee). After sep-
arating the layers, the organic layer was washed with water (5.0 mL)
and concentrated in vacuo. n-Butyl acetate (5.0 mL) and ethanol
(0.5 mL) were added to the residue, and then methanesulfonic acid
(215 mg, 2.68 mmol) was added dropwise to the resultant solution
at room temperature. After stirring at room temperature for 2 h, the
resultant precipitate was collected by filtration, washed with 10:1
n-butyl acetate/ethanol (1.0 mL), and dried in vacuo to give (2R,3S)-
2$MeSO3H (648 mg, 1.89 mmol, 84% yield based on (2R,3S)-2$(R)-
5$H2O, >99% ee) as a white crystalline powder. Mp 129–130 ꢀC; IR
crystalline powder. Mp 162–167 ꢀC (decomp.); IR (KBr)
n
1736,1581,
þ42.0 (c
20
1512, 1194, 754 cmꢂ1; MS (FAB) m/z 406 (MþH)þ; [
a
]
D
1.04, MeOH); 1H NMR (300 MHz, DMSO-d6)
d 12.23 (br s, 1H), 10.82
(s, 1H), 7.56 (d, J¼7.7 Hz, 1H), 7.35–7.27 (m, 3H), 7.20–7.16 (m, 4H),
7.08–7.03 (m, 2H), 6.29 (d, J¼8.5 Hz,1H), 4.50 (dd, J¼8.2, 7.3 Hz,1H),
4.11 (t, J¼14.3 Hz, 2H), 3.59 (t, J¼7.1 Hz, 1H), 2.79–2.62 (m, 3H), 1.69
(d, J¼12.1 Hz, 2H), 1.49–1.34 (m, 5H); 13C NMR (75 MHz, DMSO-d6)
d
174.9, 158.2, 146.8, 137.0, 129.3, 127.5, 127.4, 127.0, 123.2, 121.6,
119.4, 119.1, 117.2, 112.3, 59.6, 45.3, 45.2, 42.7, 33.7, 33.6, 33.1, 18.3.
Anal. Calcd for C24H27N3O3$0.1H2O: C, 70.77; H, 6.73; N, 10.32.
Found: C, 70.75; H, 6.85; N, 10.27.
(KBr)
n
3298, 1743, 1520, 1205, 1184 cmꢂ1; MS (FAB) m/z 247
(MþH)þ; [
a
]
D
þ6.1 (c 0.97, MeOH); 1H NMR (300 MHz, DMSO-d6)
20
d
11.08 (s, 1H), 8.32 (s, 1H), 7.51 (d, J¼7.8 Hz, 1H), 7.39 (d, J¼8.0 Hz,
1H), 7.22 (d, J¼2.3 Hz,1H), 7.10 (t, J¼7.5 Hz,1H), 7.01 (t, J¼7.4 Hz,1H),
4.16 (d, J¼6.5 Hz, 1H), 4.04–3.92 (m, 2H), 3.67–3.58 (m, 1H), 2.34 (s,
3H), 1.45 (d, J¼7.2 Hz, 3H), 0.96 (d, J¼7.1 Hz, 3H); 13C NMR (75 MHz,
4.9. Synthesis of N-[(1R,2S)-1-({5-[(dimethylamino)methyl]-
2-ethoxyphenyl}aminocarbonyl)-2-(1H-indol-3-yl)propyl]-4-
phenyl-1-piperidinecarboxamide (1)
DMSO-d6) d 169.8, 137.2, 126.8, 124.5, 122.1, 119.4, 119.1, 113.5, 112.5,
62.4, 58.1, 40.6, 33.1,17.3,14.4. Anal. Calcd for C15H22N2O5S: C, 52.62;
H, 6.48; N, 8.18; S, 9.36. Found: C, 52.44; H, 6.44; N, 8.04; S, 9.33.
To a solution of 8 (700 g,1.73 mol) and 9 (462 g,1.73 mol) in DMF
(3.45 L), triethylamine (175 g, 1.73 mol) and EDCl (397 g, 2.07 mol)
were successively added at room temperature. The mixture was
stirred at room temperature for 1 h. Then, 2 M aq NaOH (1.73 L) and
5% aq Na2CO3 (1.73 L) were successively added. After stirring at
room temperature for 1.5 h, the resultant precipitate was collected
by filtration, washed with water (6.9 L), and dried in vacuo to give
crude-1 (1004 g,1.73 mol,100% yield) as a white crystalline powder.
To a solution of water (1.0 L) in acetone (9.0 L) was added crude-1
(1004 g,1.73 mol). The solution was filtered to remove any insoluble
dust, which was rinsed with 10:1 acetone/water (3.3 L). Water
(6.7 L) was added dropwise to the combined filtrates at room tem-
perature. After stirring at room temperature for 4 h, the resultant
precipitate was collected by filtration, washed with 1:1 acetone/
water (4 L), and then dried in vacuo to give 1 (880 g, 1.51 mol, 87%
4.7. Synthesis of ethyl (2S,3R)-2-amino-3-(1H-indol-3-
yl)butanoate methanesulfonate ((2S,3R)-2$MeSO3H)
To a solution of (R)-5 (1.85 g, 10.2 mmol) and water (0.5 mL) in
n-butyl acetate (50 mL) was added rac-threo-2 (5.00 g,
20.3 mmol). The mixture was stirred at room temperature for 4 h.
The resultant precipitate was filtered off and washed with n-butyl
acetate (10 mL). Ethanol (5.0 mL) and methanesulfonic acid
(980 mg, 12.2 mmol) were successively added dropwise to the
combined filtrates at room temperature. After stirring at room
temperature for 2 h, the resultant precipitate was collected by
filtration, washed with 10:1 n-butyl acetate/ethanol (11 mL), and
dried in vacuo to give (2S,3R)-2$MeSO3H (2.76 g, 8.06 mmol, 40%
yield based on rac-threo-2, >99% ee) as a white crystalline pow-
yield, >99.9% ee) as a white crystalline powder. Mp 164–165 ꢀC; IR
20
der. Mp 129–130 ꢀC; IR (ATR)
n
1742, 1517, 1163, 1044, 743 cmꢂ1
;
(KBr)
n
3361,1666,1219, 733 cmꢂ1; MS (FAB) m/z 582 (MþH)þ; [
a]
D
20
MS (ESI) m/z 247 (MþH)þ; [
a
]
ꢂ6.5 (c 1.03, MeOH); 1H NMR
þ4.0 (c 1.01, MeOH); 1H NMR (300 MHz, CDCl3)
d 8.50 (br s,1H), 8.25
D
(300 MHz, DMSO-d6)
d
11.08 (s, 1H), 8.27 (s, 1H), 7.50 (d, J¼7.8 Hz,
(d, J¼1.9 Hz, 1H), 8.05 (s, 1H), 7.79 (d, J¼7.6 Hz, 1H), 7.37–7.06 (m,
8H), 6.96 (dd, J¼8.3, 2.0 Hz, 1H), 6.73 (d, J¼8.3 Hz, 1H), 5.43 (d,
J¼7.6 Hz, 1H), 4.94 (t, J¼7.4 Hz, 1H), 4.17 (d, J¼13.2 Hz, 1H), 4.04 (d,
J¼13.3 Hz, 1H), 3.98–3.82 (m, 2H), 3.75–3.66 (m, 1H), 3.36 (s, 2H),
2.95–2.79 (m, 2H), 2.71–2.61 (m,1H), 2.46–2.31 (m,1H), 2.24 (s, 6H),
1.84 (d, J¼12.0 Hz, 2H), 1.73–1.51 (m, 5H), 1.26 (t, J¼7.0 Hz, 3H); 13C
1H), 7.38 (d, J¼8.0 Hz, 1H), 7.21 (d, J¼2.4 Hz, 1H), 7.09 (t, J¼7.1 Hz,
1H), 7.00 (t, J¼7.1 Hz, 1H), 4.15 (d, J¼6.5 Hz, 1H), 4.04–3.93 (m,
2H), 3.66–3.57 (m, 1H), 2.34 (s, 3H), 1.44 (d, J¼7.2 Hz, 3H), 0.95 (d,
J¼7.1 Hz, 3H); 13C NMR (DMSO-d6)
d 169.5, 136.9, 126.5, 124.2,
121.7, 119.1, 118.7, 113.2, 112.2, 62.0, 57.7, 40.3, 32.8, 17.0, 14.0. Anal.
Calcd for C15H22N2O5S: C, 52.62; H, 6.48; N, 8.18; S, 9.36. Found: C,
52.59; H, 6.44; N, 8.23; S, 9.43.
NMR(75 MHz, CDCl3) d 170.5, 157.6, 146.8, 145.9, 136.9, 131.6, 128.9,
127.4, 127.2, 127.0, 126.8, 124.7, 122.4, 121.1, 119.9, 119.7, 117.2, 111.7,
111.1, 64.6, 64.3, 60.7, 45.6, 45.2, 45.1, 43.0, 35.2, 33.4, 33.3, 18.2, 15.1.
Anal. Calcd for C35H43N5O3: C, 72.26; H, 7.45; N, 12.04. Found: C,
71.97; H, 7.39; N, 11.95.
4.8. Synthesis of (2R,3S)-3-(1H-indol-3-yl)-2-[(4-
phenylpiperidine-1-carbonyl)amino]butyric acid (8)
To a solution of CDI (2.09 g, 12.9 mmol) in DMF (12 mL) was
added a solution of (2R,3S)-2$MeSO3H (4.00 g, 11.7 mmol) in DMF
(12 mL) at 0 ꢀC. The mixture was stirred at 0 ꢀC for 1 h. Triethyl-
amine (5.21 g, 51.5 mmol) and 4-phenylpiperidine hydrochloride
(2.55 g, 12.9 mmol) were successively added at 0–10 ꢀC. The
Acknowledgements
We thank Dr. Masahiro Kajino, Dr. Shokyo Miki, Dr. Tomomi
Ikemoto, and Dr. Keisuke Majima for their helpful discussion.