K. Misawa et al. / Bioorg. Med. Chem. 19 (2011) 5935–5947
5945
2.89 (1H, dd, J = 7.8, 13.6 Hz), 3.18 (1H, dd, J = 5.4, 13.6 Hz), 3.36
(1H, ddd, J = 6.0, 7.5, 13.6 Hz), 3.40–3.47 (1H, m), 3.81–3.92 (1H,
m), 4.80 (3H, br s), 5.06 (1H, d, J = 12.3 Hz), 5.09 (1H, d,
J = 12.3 Hz), 7.24–7.36 (8H, m), 7.40–7.44 (2H, m), 7.47 (1H, dd,
J = 5.7, 6.0 Hz), 7.51–7.58 (4H, m), 8.15 (1H, br s). 13C NMR (CDCl3,
d ppm): 14.8, 39.3, 39.5, 41.6, 55.7, 66.5, 127.0, 127.4, 127.5, 128.2,
128.3, 128.6, 128.8, 129.8, 135.3, 135.7, 140.1, 140.5, 165.5, 172.4,
174.9.
7.4 Hz), 7.20–7.36 (15H, m), 7.39–7.45 (2H, m), 7.46 (1H, dd,
J = 5.8, 7.0 Hz), 7.50–7.54 (2H, m), 7.56–7.59 (2H, m). 13C NMR
(CDCl3, d ppm): 15.0, 31.8, 35.2, 39.3, 39.6, 41.1, 60.3, 62.4, 66.4,
66.7, 126.1, 127.0, 127.20, 127.22, 128.0, 128.25, 128.29, 128.4,
128.5, 128.57, 128.62, 128.8, 129.8, 135.4, 135.7, 139.7, 140.7,
140.8, 173.2, 174.0, 174.9.
5.1.15. N-[1-(S)-Benzyloxycarbonyl-3-phenylpropyl]-
methylphenylalanyl- -(S)-methyl-b-alanine benzyl ester (17c)
Yellow oil, yield 57%. IR (ATR, cmꢀ1
3377, 3029, 2936, 1731,
L-4-
a
5.1.12.
ester formate (16c)
Pale yellow oil, yield 96%. IR (ATR, cmꢀ1
L
-4-Methylphenylalanyl-
a
-(S)-methyl-b-alanine benzyl
) m
1673, 1514, 1172, 749, 698. 1H NMR (CDCl3, d ppm): 1.16 (3H, d,
J = 7.3 Hz), 1.72–1.81 (1H, m), 1.83–2.00 (1H, m), 1.92 (1H, br s),
2.30 (3H, s), 2.50 (1H, ddd, J = 5.9, 10.4, 13.9 Hz), 2.59 (1H, ddd,
J = 5.9, 10.5, 13.9 Hz), 2.64–2.72 (2H, m), 3.01 (1H, dd, J = 4.4,
13.9 Hz), 3.16 (1H, dd, J = 6.8, 6.9 Hz), 3.27 (1H, dd, J = 4.4,
8.7 Hz), 3.30 (1H, ddd, J = 5.9, 8.0, 13.7 Hz), 3.46 (1H, ddd, J = 4.7,
7.0, 13.7 Hz), 4.94 (1H, d, J = 12.1 Hz), 5.05 (1H, d, J = 12.1 Hz),
5.06 (1H, d, J = 12.4 Hz), 5.09 (1H, d, J = 12.4 Hz), 7.01–7.06 (4H,
m), 7.07–7.10 (2H, m), 7.16 (1H, ddd, J = 1.3, 1.3, 7.4 Hz), 7.20–
7.25 (2H, m), 7.25–7.38 (10H, m), 7.43 (1H, dd, J = 4.7, 5.9 Hz).
13C NMR (CDCl3, d ppm): 14.9, 21.1, 31.8, 35.2, 39.3, 39.6, 41.1,
60.2, 62.5, 66.4, 66.7, 126.1, 128.0, 128.3, 128.4, 128.5, 128.60,
128.61, 129.2, 129.3, 133.5, 135.4, 135.8, 136.4, 140.8, 173.4,
174.0, 174.9.
)
m 3280, 2977, 2938,
1731, 1644, 1561, 1516, 1176, 753, 698. 1H NMR (CDCl3, d ppm):
1.14 (3H, d, J = 7.3 Hz), 2.31 (3H, s), 2.70 (1H, qdd, J = 5.2, 7.3,
8.0 Hz), 2.74 (1H, dd, J = 8.3, 13.8 Hz), 3.11 (1H, dd, J = 5.6,
13.8 Hz), 3.34 (1H, ddd, J = 5.8, 8.0, 13.6 Hz), 3.46 (1H, ddd,
J = 5.2, 6.6, 13.6 Hz), 3.75 (1H, dd, J = 5.6, 8.3 Hz), 4.02 (3H, br s),
5.10 (1H, d, J = 12.3 Hz), 5.13 (1H, d, J = 12.3 Hz), 7.07 (2H, d,
J = 7.9 Hz), 7.11 (2H, d, J = 7.9 Hz), 7.30–7.41 (6H, m), 8.09 (1H, br
s). 13C NMR (CDCl3, d ppm): 14.8, 21.1, 39.5, 41.6, 55.8, 66.5,
128.2, 128.4, 128.6, 129.1, 129.5, 133.3, 135.7, 136.8, 164.6,
172.8, 174.9.
5.1.13. N-[1-(S)-Benzyloxycarbonyl-3-phenylpropyl]-
biphenylalanyl-b-alanine benzyl ester (17a)
L
-4,40-
To a solution of (R)-2-hydroxy-4-phenylbutyric acid benzyl es-
ter (1.11 g, 4.09 mmol) in CH2Cl2 (28 mL) were added Et3N
(1.30 mL, 9.33 mmol) and trifluoromethanesulfonic anhydride
(Tf2O) (0.77 mL, 4.69 mmol) under Ar atmosphere at ꢀ78 °C and
stirred for 1 h. To the solution was added a solution of 16a
(0.835 g, 1.86 mmol) and Et3N (0.28 mL, 2.01 mmol) in CH2Cl2
(10 mL) under Ar atmosphere at ꢀ78 °C. The reaction mixture
was stirred at ꢀ78 °C to room temperature for 3 days. The solvent
was removed under reduced pressure and extracted with EtOAc
(30 mL ꢂ 3). The organic layer was poured with brine (50 mL)
and dried over MgSO4. The solvent was removed under reduced
pressure and the residue was purified by silica gel flash chromatog-
raphy using a gradient of EtOAc and n-hexane (0:100–50:50) as
eluting solvent to give 17a (0.982 g, 81% yield) as yellow oil.
5.1.16. N-[1-(S)-Carboxy-3-phenylpropyl]-
b-alanine (3)
L
-4,40-biphenylalanyl-
To a solution of 17a (0.894 g, 1.36 mmol) in DMF (27 mL) was
added 10% Pd/C (90.6 mg) and vigorously stirred at room temper-
ature for 23 h under hydrogen pressure (balloon). After removing
the Pd/C by filtration, the filtrate was concentrated under reduced
pressure. The residue was again dissolved in DMF (26 mL). To a
solution was added 10% Pd/C (91.4 mg) and vigorously stirred at
room temperature for 14.5 h under hydrogen pressure (balloon).
After removing the Pd/C by filtration, the filtrate was concentrated
under reduced pressure. The residue was recrystallized from 80%
DMF aq to give 3 (0.164 g, 25% yield) as white crystals.
UFLC: >99% purity. mp: 225.5–227.0 °C (dec.). IR (ATR, cmꢀ1
) m
3369, 3030, 2880, 1725, 1677, 1612, 1533, 1391, 1192, 760, 751,
703, 694. 1H NMR (DMSO-d6, d ppm): 1.73–1.85 (2H, m), 2.30
(2H, dd, J = 6.9, 6.9 Hz), 2.62 (2H, dd, J = 8.0, 8.0 Hz), 2.85 (1H, dd,
J = 7.0, 13.6 Hz), 2.89 (1H, dd, J = 6.2, 13.6 Hz), 3.02 (1H, dd,
J = 5.8, 6.9 Hz), 3.18–3.30 (2H, m), 3.31 (1H, dd, J = 6.2, 7.0 Hz),
7.15–7.20 (3H, m), 7.24–7.29 (4H, m), 7.35 (1H, ddd, J = 1.2, 1.2,
7.3 Hz), 7.43–7.47 (2H, m), 7.55–7.59 (2H, m), 7.63–7.67 (2H, m),
7.89 (1H, dd, J = 5.9, 5.9 Hz). 13C NMR (DMSO-d6, d ppm): 31.2,
33.6, 34.3, 34.4, 38.6, 58.9, 61.9, 125.7, 126.3, 126.4, 127.1,
128.16, 128.17, 128.8, 129.7, 136.8, 138.0, 139.9, 141.5, 172.1,
172.9, 175.0. HRMS (ESI, positive): calcd for C28H30N2O5 [M+H]+
475.2228, found 475.2222.
IR (ATR, cmꢀ1
) m 3378, 3030, 2950, 1732, 1672, 1518, 1171, 752,
733, 698. 1H NMR (CDCl3, d ppm): 1.76–1.86 (1H, m), 1.86–2.00
(1H, m), 1.98 (1H, br s), 2.50 (1H, t, J = 6.1 Hz), 2.53 (1H, dd,
J = 6.0, 10.2, 13.8 Hz), 2.62 (1H, ddd, J = 6.0, 10.1, 14.2 Hz), 2.86
(1H, dd, J = 8.0, 13.7 Hz), 3.09 (1H, dd, J = 4.4, 13.7 Hz), 3.18 (1H,
dd, J = 5.7, 5.7 Hz), 3.43 (1H, dd, J = 4.4, 8.0 Hz), 3.48 (2H, td,
J = 6.1, 6.1 Hz), 4.97 (1H, d, J = 12.1 Hz), 5.01 (2H, s), 5.07 (1H, d,
J = 12.1 Hz), 7.05–7.09 (2H, m), 7.15 (1H, ddd, J = 1.3, 1.3, 8.6 Hz),
7.21–7.36 (15H, m), 7.40–7.45 (2H, m), 7.48–7.54 (3H, m), 7.56–
7.59 (2H, m). 13C NMR (CDCl3, d ppm): 31.8, 34.1, 34.3, 35.1,
39.3, 60.2, 62.4, 66.7, 126.1, 127.0, 127.20, 127.24, 128.2, 128.30,
128.33, 128.4, 128.47, 128.48, 128.57, 128.63, 128.8, 129.8, 135.4,
135.5, 135.7, 139.8, 140.7, 140.8, 172.1, 173.1, 174.0.
Prepared similarly was the following compound.
Prepared similarly were the following compounds.
5.1.17. N-[1-(S)-Carboxy-3-phenylpropyl]-
-(S)-methyl-b-alanine (4)
White crystals (recrystallization from 90% DMF aq), yield 37%.
UFLC: >99% purity. mp: 243.0–243.8 °C (dec.). IR (ATR, cmꢀ1
) m
L
-4,40-biphenylalanyl-
a
5.1.14. N-[1-(S)-Benzyloxycarbonyl-3-phenylpropyl]-
biphenylalanyl- -(S)-methyl-b-alanine benzyl ester (17b)
Yellow oil, yield 62%. IR (ATR, cmꢀ1
3361, 3029, 2936, 1730,
L
-4,40-
a
)
m
3384, 3031, 2925, 1725, 1678, 1615, 1530, 1359, 1203, 757, 732,
703, 692. 1H NMR (DMSO-d6, d ppm): 0.90 (3H, d, J = 7.1 Hz),
1.74–1.86 (2H, m), 2.42 (1H, qdd, J = 6.3, 6.3, 7.1 Hz), 2.62 (2H,
dd, J = 8.1, 8.1 Hz), 2.86 (1H, dd, J = 7.0, 13.6 Hz), 2.90 (1H, dd,
J = 6.6, 13.6 Hz), 3.02 (1H, ddd, J = 6.0, 6.3, 13.1 Hz), 3.05 (1H, dd,
J = 5.9, 6.7 Hz), 3.30 (1H, ddd, J = 6.0, 6.3, 13.1 Hz), 3.35 (1H, dd,
J = 6.6, 7.0 Hz), 7.14–7.20 (3H, m), 7.23–7.29 (4H, m), 7.33–7.37
(1H, m), 7.43–7.48 (2H, m), 7.54–7.59 (2H, m), 7.62–7.66 (2H,
m), 7.90 (1H, dd, J = 6.0, 6.0 Hz). 13C NMR (DMSO-d6, d ppm):
14.5, 31.2, 34.5, 38.68, 38.70, 40.8, 59.0, 61.9, 125.7, 126.3, 126.4,
1672, 1517, 1172, 751, 736, 697. 1H NMR (CDCl3, d ppm): 1.16
(1H, d, J = 7.3 Hz), 1.75–1.83 (1H, m), 1.85–1.97 (1H, m), 1.95
(1H, br s), 2.52 (1H, ddd, J = 6.0, 10.2, 14.0 Hz), 2.60 (1H, ddd,
J = 5.9, 10.1, 14.0 Hz), 2.68 (1H, qdd, J = 4.6, 7.3, 8.2 Hz), 2.81 (1H,
dd, J = 8.1, 13.9 Hz), 3.07 (1H, dd, J = 4.5, 13.9 Hz), 3.14–3.22 (1H,
m), 3.30 (1H, ddd, J = 5.8, 8.2, 13.7 Hz), 3.33 (1H, dd, J = 4.5,
8.1 Hz), 3.47 (1H, ddd, J = 4.6, 7.0, 13.7 Hz), 4.96 (1H, d,
J = 12.1 Hz), 4.99 (1H, d, J = 12.3 Hz), 5.06 (1H, d, J = 12.1 Hz), 5.07
(1H, d, J = 12.3 Hz), 7.04–7.07 (2H, m), 7.16 (1H, ddd, J = 1.1, 1.1,