2222 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7
Mores et al.
1
5.03–5.26 (m, 2H), 7.18–7.53 (m, 5H); 13C NMR (50 MHz, CDCl3)
B; t ) 45, 75% B; t ) 50, 100% B) tR ) 28.31, 29.79 min. H
δ 13.96, 19.19, 23.56, 24.54, 25.26, 25.83, 31.00 (d, 1JPC ) 89.98
NMR (200 MHz, DMSO-d6) δ 0.65–0.97 (m, 6H), 1.04–1.23 (m,
1H), 1.27–1.56 (m 3H), 1.67–2.25 (m, 6H), 2.56–2.80 (m, 1H),
3.12–3.37 (m, 1H), 3.42–3.62 (m, 1H), 3.88–4.09 (m, 1H),
4.97–5.18 (m, 2H), 7.23–7.46 (m, 5H); 13C NMR (50 MHz, DMSO-
1
1
Hz), 31.30 (d, JPC ) 89.98 Hz), 33.61, 47.13, 56.13 ((d, JPC
)
1
107.12 Hz), 56.61 (d, JPC ) 107.12 Hz), 60.64, 67.38, 127.80,
128.05, 128.44, 136.35, 155.74, 175.31; 31P NMR (81 MHz, CDCl3)
δ 56.13, 55.90; ESMS m/z calcd for C18H27NO6P (M + H)+, 384.1;
found, 384.1.
1
d6) δ 21.78, 23.03, 24.28, 24.96, 25.48, 30.97 (d, JPC ) 86.39
Hz) 36.98, 42.81, 46.88, 56.19 (d, 1JPC ) 107.34 Hz), 66.35, 127.61,
127.91, 128.50, 136.99, 154.77, 176.42; 31P NMR (81 MHz,
DMSO-d6) δ 46.29, 47.11; ESMS m/z calcd for C19H27NO6P (M
- H)–, 396.2; found, 396.5.
2-Benzyl-3-[(1-benzyloxycarbonylamino-ethyl)-hydroxy-phos-
phinoyl]-propionic Acid Ethyl Ester (9). Same experimental
procedure as for 3, method a, using 6, afforded product as white
solid. Yield 72%. TLC Rf (b) 0.64. HPLC (gradient t ) 0, 0% B;
t ) 10, 35% B; t ) 35, 100% B) tR ) 24.51, 24.67 min. 1H NMR
(200 MHz, CDCl3) δ 0.98–1.12 (m, 3H), 1.18–1.42 (m, 3H),
1.68–1.97 (m 1H), 2.02–2.29 (m, 1H), 2.74–3.17 (m, 3H), 3.88–4.11
(m, 3H), 4.97–5.18 (m, 2H), 6.99–7.43 (m, 10H); 13C NMR (50
2-[(2-Carboxy-propyl)-hydroxy-phosphinoyl]-pyrrolidine-1-
carboxylic Acid Benzyl Ester (14). Same experimental procedure
as for 12 using 5, afforded product as white solid. Yield 92%. TLC
Rf (b) 0.28. HPLC (gradient t ) 0, 0% B; t ) 10, 25% B; t ) 45,
1
75% B; t ) 50, 100% B) tR ) 20.11, 20.35 min. H NMR (200
1
MHz, CDCl3) δ 13.93, 14.07, 27.73 (d, JPC ) 91.9 Hz), 39.64,
MHz, DMSO-d6) δ 0.97–1.30 (m, 3H), 1.53–2.31 (m, 6H),
2.57–2.81 (m 1H), 3.15–3.61 (m, 2H), 3.91–4.12 (m, 1H), 4.93–5.20
(m, 2H), 7.18–7.49 (m, 5H); 13C NMR (50 MHz, DMSO-d6) δ
18.75, 23.31, 24.30, 24.96, 25.82, 31.56 (d, 1JPC ) 89.65 Hz), 33.22,
1
1
40.83, 45.06 (d, JPC ) 104.64 Hz), 45.80 (d, JPC ) 104.64 Hz),
60.84, 67.20, 126.72, 128.05, 128.08, 128.18, 128.41, 128.50,
129.04, 136.18, 137.72, 155.84, 174.05; 31P NMR (81 MHz, CDCl3)
δ 54.42, 54.68; ESMS m/z calcd for C22H29NO6P (M + H)+, 434.2;
found, 434.3.
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1
46.69, 56.15 (d, JPC ) 105.44 Hz), 56.55 (d, JPC ) 105.44 Hz),
66.36, 127.58, 127.89, 128.45, 136.88, 154.76, 176.72; 31P NMR
(81 MHz, d6-DMSO) δ 46.28, 47.17; ESMS m/z calcd for
C16H21NO6P (M - H)-, 354.1; found, 354.3.
2-Benzyl-3-[(1-benzyloxycarbonylamino-2-phenyl-ethyl)-hy-
droxy-phosphinoyl]-propionic Acid Ethyl Ester (10). Same
experimental procedure as for 3, method a, using 7, afforded product
as white solid. Yield 81%. TLC Rf (b) 0.58. HPLC (gradient t ) 0,
2-Benzyl-3-[(1-benzyloxycarbonylamino-ethyl)-hydroxy-phos-
phinoyl]-propionic Acid (15). Same experimental procedure as
for 12 using 9, afforded product as white solid. Yield 88%. TLC
Rf (b) 0.33. HPLC (gradient t ) 0, 0% B; t ) 10, 25% B; t ) 45,
0% B; t ) 10, 25% B; t ) 45, 75% B; t ) 50, 100% B) tR
)
1
41.96, 42.31 min. H NMR (200 MHz, CDCl3) δ 0.95–1.19 (m,
3H), 1.69–1.98 (m, 1H), 2.03–2.29 (m, 1H), 2.68–2.96 (m, 3H),
3.01–3.35 (m, 2H), 3.88–4.15 (m, 2H), 4.15–4.39 (m, 1H),
4.78–5.09 (m, 2H), 6.94–7.43 (m, 15H); 13C NMR (50 MHz,
1
75% B; t ) 50, 100% B) tR ) 26.73, 26.95 min. H NMR (200
MHz, DMSO-d6) δ 1.07–1.33 (m, 3H), 1.59–1.82 (m, 1H),
1.88–2.10 (m, 1H), 2.78–3.08 (m, 3H), 3.67–3.92 (m, 1H),
4.96–5.12 (m, 2H), 7.06–7.41 (m, 10H); 13C NMR (50 MHz,
1
CDCl3) δ 13.74, 28.21 (d, JPC ) 96.66 Hz), 33.87, 39.59, 40.86,
1
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50.77 (d, JPC ) 109.39 Hz), 51.70 (d, JPC)109.39 Hz), 60.84,
66.74, 126.53, 127.62, 127.87, 128.29, 128.95, 129.11, 136.27,
136.66, 137.65, 156.45, 174.10; 31P NMR (81 MHz, CDCl3) δ
53.79, 54.25; ESMS m/z calcd for C28H33NO6P (M + H)+, 510.2;
found, 510.1.
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1
DMSO-d6) δ 13.98, 27.36 (d, JPC ) 89.04 Hz), 27.74 (d, JPC
)
1
1
89.04 Hz), 46.70 (d, JPC ) 106.14 Hz), 46.18 (d, JPC ) 106.14
Hz), 65.66, 126.38, 127.68, 127.77, 127.88, 128.26, 128.45, 129.08,
129.12, 137.15, 138.93, 155.96, 175.33; 31P NMR (81 MHz,
DMSO-d6) δ 46.83; ESMS m/z calcd for C20H23NO6P (M - H)–,
404.1; found, 404.3.
2-Benzyl-3-[(1-benzyloxycarbonylamino-3-methyl-butyl)-hy-
droxy-phosphinoyl]-propionic Acid Ethyl Ester (11). Same
experimental procedure as for 3, method a, using 8, afforded product
as white solid. Yield 81%. TLC Rf (b) 0.58. HPLC (gradient t ) 0,
0% B; t ) 10, 25% B; t ) 45, 75% B; t ) 50 100% B) tR ) 39.42,
39.83 min. 1H NMR (200 MHz, d6-DMSO) δ 0.68–1.11 (m, 9H),
1.32–2.15 (m, 5H), 2.64–3.15 (m, 3H), 3.62–4.08 (m, 3H),
4.94–5.19 (m, 2H), 7.04–7.46 (m, 10H); 13C NMR (50 MHz,
2-Benzyl-3-[(1-benzyloxycarbonylamino-2-phenyl-ethyl)-hy-
droxy-phosphinoyl]-propionic Acid (16). Same experimental
procedure as for 12 using 10, afforded product as white solid. Yield
90%. TLC Rf (b) 0.38. HPLC (gradient t ) 0, 0% B; t ) 10, 25%
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B; t ) 45, 75% B; t ) 50, 100% B) tR ) 34.45, 34.67 min. H
NMR (200 MHz, DMSO-d6) δ 1.59–1.85 (m, 1H), 1.87–2.13 (m,
1H), 2.60–3.15 (m, 5H), 3.76–3.99 (m, 1H), 4.88–4.96 (m, 2H),
7.02–7.42 (m, 15H); 13C NMR (50 MHz, DMSO-d6) δ 28.06 (d,
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CDCl3) δ 13.86, 21.00, 23.46, 24.39, 27.88 (d, JPC ) 94.94 Hz),
36.18, 39.62, 40.76, 47.73 (d, 1JPC ) 106.75 Hz), 48.60 (d, 1JPC
)
1JPC ) 88.47 Hz), 27.68 (d, JPC ) 88.47 Hz), 32.78, 52.07 (d,
1
106.75 Hz), 60.69, 67.13, 126.57, 127.89, 128.07, 128.35, 128.46,
129.09, 136.29, 137.80, 156.11, 174.07; 31P NMR (81 MHz, d6-
DMSO) δ 46.37, 46.25; ESMS m/z calcd for C25H35NO6P (M +
H)+, 476.2; found, 476.3.
1JPC ) 104.56 Hz), 52.63 (d, JPC ) 104.56 Hz), 65.18, 126.27,
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126.36, 127.02, 127.08, 127.60, 128.20, 128.27, 129.10, 137.31,
138.49, 138.88, 156.16, 175.34; 31P NMR (81 MHz, DMSO-d6) δ
45.96; ESMS m/z calcd for C26H27NO6P (M - H)–, 480.2; found,
480.4.
2-[(2-Carboxy-3-phenyl-propyl)-hydroxy-phosphinoyl]-pyr-
rolidine-1-carboxylic Acid Benzyl Ester (12). NaOH (4 M, 6 mL)
was added to a solution of 3 (1.52 mmol, 0.7 g) in MeOH (16
mL), and the reaction mixture was stirred at rt for 12 h. Removal
of MeOH, dilution with H2O (10 mL), washings with Et2O (2 ×
10 mL), acidification with 2 M HCl to pH ) 1, extraction with
AcOEt (2 × 20 mL), and removal of solvent afforded the product
as white solid. Yield: 74%. TLC Rf (b) 0.27. HPLC (gradient t )
0, 0% B; t ) 10, 25% B; t ) 45, 75% B; t ) 50, 100% B) tR )
2-Benzyl-3-[(1-benzyloxycarbonylamino-3-methyl-butyl)-hy-
droxy-phosphinoyl]-propionic Acid (17). Same experimental
procedure as for 12 using 11, afforded product as white solid. Yield
95%. TLC Rf (b) 0.38. HPLC (gradient t ) 0, 0% B; t ) 10, 25%
B; t ) 45, 75% B; t ) 50, 100% B) tR ) 34.77 min. 1H NMR (200
MHz, DMSO-d6) δ 0.68–1.00 (m, 6H), 1.30–1.77 (m, 4H),
1.82–2.09 (m, 1H), 2.74–3.03 (m, 3H), 3.64–3.86 (m, 1H),
4.98–5.19 (m, 2H), 7.07–7.42 (m, 10H); 13C NMR (50 MHz,
DMSO-d6) δ 20.88, 23.37, 24.08, 27.41 (d, 1JPC ) 87.28 Hz), 27.8
(d, 1JPC ) 88.6 Hz), 35.75, 48.53 (d, 1JPC ) 107.12 Hz), 49.01 (d,
1JPC ) 107.12 Hz), 65.57, 126.33, 127.49, 127.59, 127.82, 128.23,
128.39, 129.08, 137.27, 156.40, 175.31; 31P NMR (81 MHz,
DMSO-d6) δ 46.96; ESMS m/z calcd for C23H31NO6P (M + H)+,
448.2; found, 448.1
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29.50, 30.01 min. H NMR (200 MHz, CDCl3) δ 1.62–2.41 (m,
6H), 2.68–3.19 (m, 3H), 3.24–3.66 (m 2H), 3.95–4.20 (m, 1H),
4.92–5.19 (m, 2H), 6.91–7.55 (m, 10H); 13C NMR (50 MHz,
DMSO) δ 23.38, 24.28, 24.99, 25.74, 29.86 (d, 1JPC ) 80.84 Hz),
46.79, 56.18 (d, 1JPC ) 106.1 Hz), 66.44, 126.34, 127.71, 127.91,
128.25, 128.48, 129.05, 136.97, 138.90, 154.78, 175.29; 31P NMR
(81 MHz, DMSO-d6) δ 46.23, 47.17; ESMS m/z calcd for
C22H25NO6P (M - H)–, 430.1; found, 430.0.
3-[(1-Amino-ethyl)-hydroxy-phosphinoyl]-2-benzyl-propion-
ic Acid (18). Pd/C (10%, 120 mg) was added to a solution of 15
(1 mmol, 405 mg) in MeOH/H2O (20/5 mL) and AcOH (2 drops)
at 0 °C. The reaction mixture was stirred for 2 h under H2, at rt
and 1 atm, and then filtered through a pad of celite. Removal of
2-[(2-Carboxy-4-methyl-pentyl)-hydroxy-phosphinoyl]-pyrro-
lidine-1-carboxylic Acid Benzyl Ester (13). Same experimental
procedure as for 12 using 4, afforded product as white solid. Yield
96%. TLC Rf (b) 0.36. HPLC (gradient t ) 0, 0% B; t ) 10, 25%