H. Lu, C. E. Berkman / Bioorg. Med. Chem. 9(2001) 395±402
399
3.78 (s, 3H), 4.30±4.45 (m, 2H), 4.93 (dt, J=7.5 Hz,
J=4.7 Hz, 1H). 13C NMR (300 MHz, CDCl3) d 14.19,
20.06 (d, J=6.3 Hz), 22.29 (d, J=5.4 Hz), 22.57, 26.36
(d, J=141.6 Hz), 28.30 (d, J=7.0 Hz), 29.32, 30.35 (d,
J=17.6 Hz), 31.37, 52.08, 52.85, 60.18 (d, J=7.0 Hz),
73.06 (d, J=7.0 Hz), 117.02, 171.02, 172.78.
13C NMR (300 MHz, CDCl3) d 6.90 (d, J=7.1 Hz),
19.68 (d, J=7.5 Hz), 28.24 (d, J=110.5 Hz), 27.98 (d,
J=6.4 Hz), 29.39, 52.00 (d, J=6.6 Hz), 52.71 (d, J=
6.0 Hz), 60.64 (d, J=6.0Hz), 74.07 (d, J=6.9 Hz), 116.90,
170.88, 172.66. Anal. calcd for C12H20NO6PS: C, 42.72;
H, 5.93; N, 4.15. Found: C, 43.29; H, 5.58; N, 3.68.
(+)P-2-(S)-[2-Cyanoethoxy(n-hexyl)phosphinoyloxy]-pent-
1
(+)P -2-(S)-[2-Cyanoethoxy(ethyl)phosphinothioyloxy]-
1
anedioic acid dimethyl ester (5b). H NMR (300 MHz,
pentanedioic acid dimethyl ester (7b). 66.74% yield. H
CDCl3) d 0.89 (t, J=7.0 Hz, 3H), 1.27±1.42 (dm, 6H),
1.63±1.67 (m, 2H), 1.87±1.93 (m, 2H), 2.10±2.34 (m,
2H), 2.38±2.57 (m, 2H), 2.75 (t, J=6.2 Hz, 2H), 3.70
and 3.78 (s, 3H), 4.15±4.32 (m, 2H), 4.98 (ddd, J=
8.3 Hz, J=3.5 Hz, J=1.1 Hz, 1H). 13C NMR (300 MHz,
CDCl3) d 14.14, 20.07 (d, J=6.7 Hz), 22.26 (d, J=
5.6 Hz), 22.53, 26.28 (d, J=139.4 Hz), 28.29 (d, J=
5.8 Hz), 29.21, 30.31 (d, J=17.8 Hz), 31.35, 52.01, 52.75,
59.54 (d, J=6.4 Hz), 73.07 (d, J=6.6 Hz), 116.74,
170.49 (d, J=2.4 Hz), 172.85.
NMR (300 MHz, CDCl3) d 1.22 (dt, J=23.3 Hz,
J=7.6 Hz, 3H), 2.07±2.28 (m, 4H), 2.35±2.54 (m, 2H),
2.73 (t, J=6.3 Hz, 2H), 3.68 and 3.75 (s, 3H), 4.07±4.37
(dm, 2H), 5.09 (ddd, J=11.8 Hz, J=7.0 Hz, J=4.8 Hz,
1H). 13C NMR (300 MHz, CDCl3) d 7.37 (d, J=5.0 Hz),
20.25 (d, J=9.0 Hz), 28.23, 28.62 (d, J=3.6 Hz), 29.75,
52.43 (d, J=5.2 Hz), 53.07 (d, J=5.2 Hz), 60.59 (d,
J=6.0 Hz), 74.45 (d, J=5.7 Hz), 117.24, 170.96, 173.26.
Anal. calcd for C12H20NO6PS: C, 42.72; H, 5.93; N, 4.15.
Found: C, 43.22; H, 5.87; N, 3.94.
General procedure for phosphonothionates 6±9. Re¯ux-
ing a solution of 2±5 (0.11 g, 0.34 mmol) and Lawesson's
reagent (0.076 g, 0.19 mmol) in toluene (2 mL) for 6 h
followed by concentration in vacuo gave a yellow oil
that was puri®ed by reversed phase (C-18) preparative
TLC [methanol:water, 70:30, v:v (6a: Rf=0.43. 6b:
Rf=0.40. 7a: Rf=0.54. 7b: Rf=0.51. 8a: Rf=0.37. 8b:
Rf=0.33) and methanol:water, 80:20, v:v (9a: Rf=0.42.
9b: Rf=0.40)].
(À)P-2-(S)-[2-Cyanoethoxy(n-butyl)phosphinothioyloxy]-
1
pentanedioic acid dimethyl ester (8a). 68.46% yield. H
NMR (300 MHz, CDCl3) d 0.94 (t, J=7.2 Hz, 3H),
1.42±1.47 (m, 2H), 1.61±1.68 (m, 2H), 2.00±2.17 (dm,
4H), 2.40±2.47 (m, 2H), 2.75±2.79 (m, 2H), 3.70 and
3.78 (s, 3H), 4.28±4.35 (m, 2H), 5.07±5.11 (m, 1H). 13C
NMR (300 MHz, CDCl3) d 14.23, 20.25 (d, J=7.6 Hz),
24.00 (d, J=19.8 Hz), 25.34 (d, J=4.1 Hz), 28.53 (d,
J=7.7 Hz), 29.93, 35.16 (d, J=113.8 Hz), 52.55, 53.31,
61.15 (d, J=6.9 Hz), 74.52 (d, J=7.5Hz), 117.56, 171.48
(d, J=3.7 Hz), 173.29. Anal. calcd for C14H24NO6PS: C,
46.00; H, 6.57; N, 3.83. Found: C,46.22; H, 6.66; N, 3.69.
(À)P-2-(S)-[2-Cyanoethoxy(phenyl)phosphinothioyloxy]-
1
pentanedioic acid dimethyl ester (6a). 71.28% yield. H
NMR (300 MHz, CDCl3) d 2.11±2.17 (m, 2H), 2.27±
2.33 (m, 2H), 2.77±2.86 (m, 2H), 3.59 and 3.82 (s, 3H),
4.34±4.44 (dm, 2H), 5.12±5.15 (m, 1H), 7.49±7.53 (dm,
3H), 7.90±7.98 (m, 2H). 13C NMR (300 MHz, CDCl3) d
20.24 (d, J=8.3 Hz), 28.46 (d, J=6.8 Hz), 29.73, 52.42,
53.35, 61.54 (d, J=5.6 Hz), 74.64 (d, J=6.2 Hz), 117.43,
129.09, 129.29, 131.43, 131.59, 132.82 (d, J=158.3 Hz),
133.55 (d, J=3.3 Hz), 171.33 (d, J=1.8 Hz), 173.20.
Anal. calcd for C16H20NO6PS: C, 49.86; H, 5.19; N,
3.63. Found: C, 49.49; H, 4.89; N, 3.67.
(+)P-2-(S)-[2-Cyanoethoxy(n-butyl)phosphinothioyloxy]-
1
pentanedioic acid dimethyl ester (8b). 67.24% yield. H
NMR (300 MHz, CDCl3) d 0.94 (t, J=7.3 Hz, 3H), 1.39±
1.49 (m, 2H), 1.60±1.73 (m, 2H), 2.09±2.29 (m, 4H),
2.47±2.57 (m, 2H), 2.74 (t, J=6.2 Hz, 2H), 3.70 and 3.77
(s, 3H), 4.09±4.38 (dm, 2H), 5.11 (ddd, J=11.7 Hz,
J=6.9 Hz, J=4.9 Hz, 1H). 13C NMR (300 MHz, CDCl3)
d 13.60, 19.68 (d, J=7.9 Hz), 23.36 (d, J=19.8 Hz),
24.60 (d, J=4.8 Hz), 28.05 (d, J=6.0 Hz), 29.19, 34.73
(d, J=110.3 Hz), 51.90, 52.54, 59.93 (d, J=6.3 Hz),
73.85 (d, J=6.5 Hz), 116.63, 170.41 (d, J=3.3 Hz),
172.73. Anal. calcd for C14H24NO6PS: C, 46.00; H,
6.57; N, 3.83. Found: C,46.11; H, 6.15; N, 3.92.
(+)P-2-(S)-[2-Cyanoethoxy(phenyl)phosphinothioyloxy]-
1
pentanedioic acid dimethyl ester (6b). 76.92% yield. H
NMR (300 MHz, CDCl3) d 2.18±2.35 (m, 2H), 2.42±
2.59 (m, 2H), 2.76 (dt, J=6.2 Hz, J=2.3 Hz, 2H), 3.61
and 3.70 (s, 3H), 4.29 (dt, J=9.5Hz, J=6.2 Hz, 2H), 5.12
(ddd, J=12 Hz, J=7.0 Hz, J=4.9 Hz, 1H), 7.45±7.61
(dm, 3H), 7.91±7.98 (m, 2H). 13C NMR (300MHz,
CDCl3) d 20.30 (d, J=8.2 Hz), 28.80 (d, J=5.9Hz), 29.79,
52.56, 53.03, 61.33 (d, J=4.7Hz), 74.64 (d, J=5.7Hz),
117.21, 128.96, 129.17, 131.67, 131.84, 132.60 (d,
J=153.9 Hz), 133.51 (d, J=3.3 Hz), 170.49 (d, J=
3.5 Hz), 173.39. Anal. calcd for C16H20NO6PS: C, 49.86;
H, 5.19; N, 3.63. Found: C, 49.55; H, 5.02; N, 3.48.
(À)P-2-(S)-[2-Cyanoethoxy(n-hexyl)phosphinothioyloxy]-
1
pentanedioic acid dimethyl ester (9a). 74.63% yield. H
NMR (300MHz, CDCl3) d 0.89 (t, J=7.0 Hz, 3H), 1.25±
1.39 (m, 6H), 1.62±1.74 (m, 2H), 2.02±2.31 (m, 4H), 2.40±
2.52 (m, 2H), 2.73±2.79 (m, 2H), 3.69 and 3.78 (s, 3H),
4.27±4.35 (m, 2H), 5.04±5.10 (m, 1H). 13C NMR
(300 MHz, CDCl3) d 14.21, 19.78 (d, J=7.7 Hz), 22.60,
22.80 (d, J=4.1 Hz), 28.08 (d, J=7.7 Hz), 29.48, 30.07
(d, J=19.3 Hz), 31.42, 34.96 (d, J=113.5 Hz), 52.08,
52.84, 60.69 (d, J=6.8 Hz), 74.05 (d, J=7.4 Hz), 117.09,
171.04, 172.81. Anal. calcd for C16H28NO6PS: C, 48.85;
H, 7.12; N, 3.56. Found: C, 48.64; H, 7.18; N, 3.41.
(À)P -2-(S)-[2-Cyanoethoxy(ethyl)phosphinothioyloxy]-
1
pentanedioic acid dimethyl ester (7a). 73.26% yield. H
NMR (300 MHz, CDCl3) d 1.32 (dt, J=23.3 Hz,
J=7.6 Hz, 3H), 2.11±2.41 (m, 4H), 2.47±2.63 (m, 2H),
2.78±2.95 (m, 2H), 3.69 and 3.77 (s, 3H), 4.36±4.50 (m,
2H), 5.17 (ddd, J=11.8 Hz, J=7.3 Hz, J=4.4 Hz, 1H).
(+)P-2-(S)-[2-Cyanoethoxy(n-hexyl)phosphinothioyloxy]-
1
pentanedioic acid dimethyl ester (9b). 70.26% yield. H
NMR (300 MHz, CDCl3) d 0.89 (t, J=6.9 Hz, 3H),