F. Manzenrieder et al. / Bioorg. Med. Chem. 15 (2007) 4136–4143
4141
dissolved in 10 mL dry THF and added dropwise to the
acid solution. The solution was stirred overnight and
was allowed to slowly warm to room temperature. The
solvent was removed and enantiomerically pure 1-S-
(475 mg, 13%) and 1-R-((S)-1-(naphthalen-2-yl)ethyla-
mino)-3-methylbutylphosphinic acid (954 mg, 27%)
was obtained by HPLC purification.
4.1.11. (1S)-1-(N-((S)-1-(Naphthalen-7-yl)ethyl)acetam-
ido)-3-methylbutylphosphinic acid (11). 50 mg of 9 was
taken and treated like 10 to yield 53 mg of 11 (94 %).
1H NMR (900 MHz, DMSO-d6) d 7.95 (d, J = 8.1 Hz,
1H), 7.93 (s(br), 1H), 7.92–7.89 (m, 2H), 7.55–7.50 (m,
3H), d 6.95 (d, J = 571 Hz, 1H), 5.34 (q, J = 6.5 Hz,
1H), 2.89–2.80 (m, 1H), 2.28 (s, 3H), 1.88–1.81 (m,
1H), 1.65 (d, J = 6.5 Hz, 3H), 1.04–0.96 (m, 1H), 0.73–
0.65 (m, 1H), 0.29 (d, J = 5.8 Hz, 3H), ꢁ0.09 (d,
J = 5.8 Hz, 3H). 13C NMR (225 MHz, DMSO-d6) d
169.9, 137.1, 132.8, 132.4, 127.9, 127.7, 127.3, 127.1,
1H NMR (900 MHz, DMSO-d6) d 8.04–7.99 (m, 2H),
7.96–7.90 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.58–7.55
(m, 2H), 6.99 (d, J = 526 Hz, 1H), 4.98 (q, J = 6.5 Hz,
1H), 2.57–2.52 (m, 1H), 1.70–1.66 (m, 1H), 1.65 (d,
J = 6.5 Hz, 3H), 1.50–1.43 (m, 1H), 1.40–1.34 (m,
1H), 0.66 (d, J = 6.5 Hz, 3H), 0.39 (d, J = 6.5 Hz,
1
126.3, 126.2, 126.0, 56.0, 52.5 (d, JPC = 99.6 Hz), 37.1,
24.1, 22.8, 21.9, 20.4, 17.2. 31P NMR (146 MHz,
DMSO-d6) d 34.4 MS (ESI) m/z 348.2 (M+H)+, 717.4
(2M+Na)+, 1080.4 (3M+K)+. RP–HPLC tR = 19.9
(10–90%).
3H). 13C NMR (225 MHz, DMSO-d6)
d 134.5,
132.7, 132.5, 128.7, 127.8, 127.7, 127.5, 126.6, 124.3,
57.2, 52.5 (d,1JPC = 88.7 Hz), 35.6, 23.7, 21.9, 21.1,
20.0. d. 31P NMR (243 MHz, DMSO-d6) d 19.6 MS
(ESI) m/z 306.1 (M+H)+, 611.3 (2M+H)+, 938.4
(3M+Na)+, 954.4 (3M+K)+. RP–HPLC tR = 14.3
(10–90%).
4.1.12. 2-Methyl-3-[(1S)-1-(N-((S)-1-(naphthalen-7-yl)
ethyl)acetamido)-3-methyl-butyl-hydroxy-phosphinoyl]-
propionic acid methyl ester (12). A suspension of 10 mg
of 11 (28.8 lmol, 347.4 g/mol) in 1 mL freshly distilled
hexamethyldisilazane was heated at 110 °C for 1 h under
argon atmosphere. 2-Methyl-acrylic acid methyl ester
(1.1 equiv.) was added at this temperature and the reac-
tion mixture was stirred for 3 h. Then, absolute ethanol
(1 mL) was added dropwise. After cooling to room tem-
perature, the mixture was evaporated in vacuo. The res-
idue was dissolved in ACN/H2O and purified by semi-
preparative HPLC to yield 10.9 mg of 12 (85%). 1H
NMR (500 MHz, CDCl3-d1) d 7.91–7.78 (m, 4H),
7.55–7.48 (m, 2H), 7.43–7.36 (m, 1H), 5.35–5.27 (m,
1H), 3.74/3,68 (two singlets due to 2 diastereomers,
3H), 3.54–3.42/3.30–3.19 (two multiplets due to 2 diaste-
reomers, 1H), 3.15–3.05/3.03–2.93 (two multiplets due
to 2 diastereomers, 1H), 2.41 (s(br), 3H), 2.01–1.85 (m,
2H), 1.79/1.75 (two doublets due to 2 diastereomers,
J = 6.8 Hz, 3H), 1.49–1.44 (m, 1H), 1.34/1.30 (two dou-
blets due to 2 diastereomers, J = 7 Hz, 3H), 1.00–0.78
(m, 2H), 0.33 (m, 3H), 0.05 (m, 3H). 31P NMR
(101 MHz, DMSO-d6) d 46.8, 46.6 (2 diastereomers)
MS (ESI) m/z 448.3 (M+H)+, 917.6 (2M+Na)+, 933.6
(2M+K)+, 1380.5 (3M+K)+. RP–HPLC tR = 23.3 and
23.4 (two diastereomers) (10–90%).
4.1.9. (1S)-1-((S)-1-(Naphthalen-6-yl)ethylamino)-3-
methylbutylphosphinic acid (9). See Ref.8.
1H NMR (600 MHz, MeOH-d4) d 8.05–8.01 (m, 1H),
7.99 (d, J = 9.2 Hz, 1H), 7.93–7.88 (m, 2H), 7.64 (d,
J = 8.7 Hz, 1H), 7.58–7.52 (m, 2H), 7.00 (d,
J = 530 Hz, 1H), 4.96–4.89 (m, 1H), 2.89–2.81 (m,
1H), 1.91–1.81 (m, 2H), 1.79 (d, J = 6.6 Hz, 3H), 1.65–
1.51 (m, 1H), 0.94 (d, J = 5.7 Hz, 3H), 0.76 (d,
J = 5.7 Hz, 3H). 13C NMR (225 MHz, MeOH-d4) d.
135.1, 134.7, 130.6, 129.2, 129.0, 128.9, 128.2, 128.0,
1
125.2, 58.6, 55.2 (d, JPC = 88.8 Hz), 36.3, 26.1, 23.5,
21.9, 19.5. 31P NMR (243 MHz, MeOH-d4) d 18.7. MS
(ESI) m/z 306.1 (M+H)+, 611.3 (2M+H)+, 916.3
(3M+H)+, 938.3 (3M+Na)+, 954.3 (3M+K)+. RP–
HPLC tR = 14.9 (10–90%).
4.1.10. (1R)-1-(N-((S)-1-(Naphthalen-7-yl)ethyl)acetam-
ido)-3-methylbutylphosphinic acid (10). 110 mg of 8
(360.2 lmol, 305.4 g/mol) was dissolved in 10 mL abso-
lute THF under argon. The solution was cooled to 0 °C
and 3 equiv. of 151 lL NEt3 was added. After 2 h 1.5
equiv. of 44 lL AcBr (540 lmol, 122.9 g/mol) was added
dropwise and the reaction mixture was stirred at room
temperature overnight. The next morning the solution
was evaporated to dryness. The crude product was taken
up in 1 N HCl and extracted three times with 20 mL
DCM. The organic layers were dried over Na2SO4 and
the DCM was removed under vacuum to yield 91 mg
4.1.13.
2-Methyl-3-[(1S)-1-acetamido-3-methyl-butyl-
hydroxy-phosphinoyl]- propionic acid (13). 10.9 mg of
12 (24.4 lmol, 447.5 g/mol) was dissolved in 2 mL of
57% HI and heated to 100 °C for 2 h. After cooling
the mixture was evaporated in vacuo. The residue was
dissolved in ACN/H2O and purified by semi-preparative
HPLC to yield 4.2 mg of 13 (62%). 1H NMR (250 MHz,
DMSO-d6) d 12.01 (s(br), 1H), 8.06–7.90 (m, 1H), 4.10–
3.91 (m, 1H), 2.73–2.53 (m, 1H), 2.00–1.85 (m, 1H), 1.83
(s, 3H), 1.64–1.33 (m, 4H), 1.17–1.09 (m, 3H), 0.87 (d,
J = 6.3 Hz, 3H), 0.78 (d, J = 6.3 Hz, 3H). 31P NMR
(101 MHz, DMSO-d6) d 46.5. MS (ESI) m/z 597.2
(2M+K)+, 619.2 (2M+K+Na-H)+, 914.2 (3M+2K-H)+.
RP–HPLC tR = 8.6 (10–90%).
1
of 10 (73%) H NMR (900 MHz, DMSO-d6) d 8.05 (s,
1H), 7.94–7.91 (m, 1H), 7.91-7.58 (m, 1H), 7.87 (d,
J = 7.9 Hz, 1H), 7.62–7.57 (m, 1H), 7.53–7.48 (m, 2H),
6.91 (d, J = 573 Hz, 1H), 5.34–5.30 (m, 1H), 3.05–2.90
(m, 1H), 2.15 (s, 3H), 1.78–1.65 (m, 5H), 1.33–1.24 (m,
1H), 0.89–0.82 (m, 6H). 13C NMR (225 MHz, DMSO-
d6) d 170.1, 137.7, 132.7, 132.2, 128.0, 127.7, 127.3,
1
126.4, 125.9, 125.5, 56.4, 53.1 (d, JPC = 99.6 Hz), 37.7,
24.9, 23.2, 21.8, 21.5, 18.4. 31P NMR (146 MHz,
DMSO-d6) d 34.0 MS (ESI) m/z 348.2 (M+H)+, 717.4
(2M+Na)+, 1064.5 (3M+Na)+, 1080.4 (3M+K)+. RP–
HPLC tR = 20.2 (10–90%).
4.1.14. 2-Methyl-3-[(1S)-1-(N-(9-fluorenylmethoxycar-
bonyl))amino-3-methyl-butyl- hydroxy-phosphinoyl]-pro-
pionic acid (14). 4.2 mg of 13 (15 lmol, 279.3 g/mol)
were dissolved in 1 mL of 8N HCl and heated to