1204
P. Ventosa-Andrés et al. / Tetrahedron: Asymmetry 23 (2012) 1198–1205
516.26; Found 516.38 (100%). Anal. Calcd for C26H37N5O4S: C,
60.56; H, 7.23; N, 13.58. Found: C, 60.63; H, 7.37; N, 13.46.
and the mixture was hydrogenated at 1 atm of H2 and rt for 24 h.
Afterward, the mixture was filtered through Celite and this was
washed with methanol (3 ꢁ 50 mL). The filtrates were evaporated,
and the residue was dissolved in toluene (10 mL) and heated at
100 °C for 24 h. Next, the solvent was removed under reduced
pressure, and the residue was purified by flash chromatography,
using 20–60% EtOAc gradient in hexane as the eluent.
4.4. General procedure for the synthesis of
c and 11a,b
a-amino nitriles 9a–
At first, ZnCl2 (1.36 g, 10 mmol) or Boc-Pro-OH (5 mmol) was
added to a ꢀ20 °C cooled solution of the corresponding -amino acid
a
(R)-15a: (86 mg, 62%); HPLC–MS tR 3.03 min; 1H NMR
benzyl amides 3a–c (10 mmol) and aldehyde 4 or 5 (8 mmol) in
CH2Cl2 or MeOH (100 ml). After 1 h of stirring at ꢀ20 °C, TMSCN
(1.49 g, 2.09 ml, 15 mmol) was added and the mixture was stirred
at the temperature and for the time indicated in Table 1. Next, the
solvent was evaporated under vacuum. The residue was dissolved
in EtOAc (200 mL), washed with H2O (3 ꢁ 25 mL) and brine
(25 ml), and dried over Na2SO4. Evaporation, followed by flash chro-
matography, using 20–60% EtOAc gradient in hexane as eluent,
(400 MHz, CDCl3) d 1.44 (s, 9H, Boc), 1.29–1.96 (m, 4H, b- and c-
H), 2.74 (d, J = 7 Hz, 2H, 5-CH2) 3.01–3.26 (m, 5H, 5-, 6- and d-H),
3.43 (dd, J = 4 and 7 Hz, 1H, 3-H), 4.95 (s, 1H, NH-Boc), 6.28 (s,
1H, 1-H), 7.06–7.40 (m, 5H, aromatics); 13C NMR (100 MHz, CDCl3)
d 25.9(CH2, C ), 29.3 (CH3, Boc), 29.7 (CH2, Cb), 39.9 (CH2, 5-CH2),
c
40.2 (CH2, C ), 47.8 (CH2,C6), 53.8 (CH, C5), 58.5 (CH, C3), 79.1 (C,
c
Boc), 126.9, 128.4, 129.0 (CH, Ph), 141.6 (C, Ph), 155.9 (C, Boc),
172.7 (C, C2); ES-MS m/z [M+1]+ calcd for C19H30N3O3, 348.22;
found 348.42 (100%). Anal. Calcd for C19H29N3O3: C, 65.68; H,
8.41; N, 12.09. Found: C, 65.72; H, 8.63; N 11.97.
afforded the protected a-amino nitriles 9a–c and 11a,b whose more
significant analytical and spectroscopic data are shown in Tables 2
and 3.
(S)-15a: (98 mg, 71%); HPLC–MS tR 2.88 min; 1H NMR
(400 MHz, CDCl3) d 1.36 (s, 9H, Boc), 1.30–1.90 (m, 4H, b- and c-
4.5. Synthesis of (S)-methyl 5-[(tert-butoxycarbonyl)amino]-2-
[((R)- and (S)-1-cyano-2-phenylethyl)amino]-pentanoate (R)-
and (S)-14a
H), 2.70 (d, J = 7 Hz, 2H, 5-CH2), 2.93–3.08 (m, 3H, 6- and d-H),
3.17–3.28 (m, 2H, 5- and 6-H), 3.41 (dd, J = 4 and 9 Hz, 1H, 3-H),
4.76 (bs, 1H, NH-Boc), 6.82 (bs, 1H, 1-H), 7.11–7.27 (m, 5H, aromat-
ics); 13C NMR (100 MHz, CDCl3) d 25.5 (CH2, C ), 27.4 (CH3, Boc),
c
Triethylamine (250
lL, 1.8 mmol) was added to a solution of H-
28.2 (CH2, Cb), 38.05 (CH2, 5-CH2), 39.1 (CH2, C ), 46.4 (CH2,C6),
c
Orn(Boc)-OMeꢃHCl (509 mg, 1.8 mmol) in CH2Cl2 (20 mL). After
being stirred at rt for 15 min, the reaction mixture was cooled at
ꢀ20 °C. Next, ZnCl2 (244 mg, 1.8 mmol) and phenylacetaldehyde
47.4 (CH, C5), 55.3 (CH, C3), 78.0 (C, Boc), 125.8, 127.7, 128.0(CH,
Ph), 136.5(C, Ph), 154.9 (C, Boc), 171.9 (C, C2); ES-MS m/z [M+1]+
calcd for C19H30N3O3, 348.22; found 348.42(100%). Anal. Calcd for
(173 mg, 330
l
L, 1.44 mmol) were added, and the mixture was
C19H29N3O3: C, 65.68; H, 8.41; N, 12.09. Found: C, 65.68; H, 8.43;
stirred at this temperature for 1 h. Afterward, TMSCN (268 mg,
0.332 mL, 2.7 mmol) was added and the mixture was stirred over-
night at 0 °C. The reaction mixture was worked up as indicated
above for the synthesis of amino nitriles 9 and 11. Flash chroma-
tography, using 20–60% EtOAc gradient in hexane as eluent, al-
lowed the resolution of the two epimers.
N 11.99.
4.7. Synthesis of (S)-N-benzyl-5-[(tert-butoxycarbonyl)-amino]-
2-[((S)-1-cyano-2-phenylethyl)amino]-pentanamide (S)-9a from
(S)-14a
(R)-14a: (182 mg, 27%); HPLC tR 22.24 min; ½a D20
ꢂ
¼ þ7:5 (c 1,
At first, 1 M NaOH solution (0.4 ml, 0.4 mmol) was added to a
solution of (S)-14a (49 mg, 0.13 mmol) in (1:1) 1,4-dioxane/water
mixture (2 mL) and the mixture was stirred at room temperature
for 30 min. Next, the reaction mixture was acidified to pH 3 with
1 M HCl. The organic solvent was evaporated and the aqueous
phase was extracted with EtOAc (3 ꢁ 25 mL). The combined organ-
ic phases were dried over Na2SO4 and evaporated to dryness. The
residue (47 mg, 0.13 mmol) was dissolved in acetonitrile (5 mL).
To this solution, HOBt (18 mg, 0.13 mmol), DCC (55 mg,
MeOH); 1H NMR (400 MHz, CDCl3) d 1.44 (s, 9H, Boc), 1.54–1.90
(m, 4H, b- and
c-H), 2.99–3.10 (m, 4H, 3- and d-H), 3.37 (t,
J = 6 Hz, 1H
a-H), 3.71 (dd, J = 6 and 1 Hz, 1H, 2-H), 3.74 (s, 3H,
OMe), 4.52 (s, 1H, NH-Boc), 7.10–7.43 (m, 5H, aromatics); 13C
NMR (100 MHz, CDCl3) d 26.03 (CH2, C ), 28.64 (CH3, Boc), 30.12
c
(CH2, Cb), 40.1 (CH2,Cd), 40.22 (CH2,C3), 51.04 (CH, C2), 52.46
(CH3,OMe), 59.63 (CH, Ca), 77.9 (C, Boc), 119.48 (CN), 127.81,
128.98, 129.71 (CH, Ph), 135.19 (C, Ph), 156.13 (C, Boc), 174.25
(C, CO2); ES-MS m/z [M+1]+ calcd for C20H30N3O4, 376.22; found
376.50 (100%). Anal. Calcd for C20H29N3O4: C, 63.98; H, 7.79; N,
11.19. Found: C, 63.97; H, 7.84; N, 11.25.
0.27 mmol), and BnNH2 (14 mg, 15 lL, 0.13 mmol) were added
successively at rt. After 2 h, the precipitated dicyclohexyl urea
was filtered off and the filtrate was evaporated to dryness. The res-
idue was dissolved in EtOAc (25 mL). This solution was washed
with H2O (5 mL) and brine (5 mL), dried over Na2SO4 and evapo-
rated to dryness. Flash chromatography of the residue provided a
product (56 mg, 95%) identical to (S)-9a, whose synthesis by the
Strecker reaction is described above.
(S)-14a: (190 mg, 28%); HPLC tR 22.03 min; ½a D20
¼ ꢀ22:9 (c 1.2,
ꢂ
MeOH); 1H NMR (400 MHz, CDCl3) d 1.44 (s, 9H, Boc), 1.48–1.82
(m, 4H, b- and
c-H), 2.98–3.16 (m, 4H, 3- and d-H), 3.52 (dd, J = 7
and 5 Hz, 1H,
a-H), 3.70 (s, 3H, OMe), 3.85 (t, J = 7 Hz, 1H, 2-H),
4.58 (s, 1H, NH-Boc), 7.17–7.40 (m, 5H, aromatics); 13C NMR
(100 MHz, CDCl3) d 26.43 (CH2, Cc), 28.38 (CH3, Boc), 30.4 (CH2,Cb),
39.7 (CH2,Cd), 40.0 (CH2, C3), 50.5 (CH, C2), 52.1 (CH3, OMe), 58.7
Acknowledgments
(CH, C ), 77.9 (C, Boc), 119.3 (CN), 127.66, 128.8, 129.3 (CH, Ph),
a
134.7 (C, Ph), 155.9 (C, Boc), 174.0 (C, CO2): ES-MS m/z [M+1]+ calcd
This work was supported by the Spanish Ministerio de Ciencia e
Innovación Grant SAF2009-09323. P.V.-A. held a FPI fellowship
from the Ministerio de Ciencia e Innovación.
for C20H30N3O4, 376.22; found 376.50 (100%). Anal. Calcd for
C20H29N3O4: C, 63.98; H, 7.79; N, 11.19. Found: C, 64.03; H, 7.92;
N 10.98.
References
4.6. Synthesis of (3S,5R)- and (3S,5S)-3-[3-(tert-butoxy-carbonyl)-
aminopropyl]-5-phenylmethyl-2-oxopiperazine (R)- and (S)-
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At first, 10% Pd(C) (40 mg) was added to a solution of the corre-
sponding amino nitrile 14a (150 mg, 0.4 mmol) in MeOH (25 mL),