M. H. R. I. El-Hamamsy et al. / Bioorg. Med. Chem. 15 (2007) 4552–4576
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oil: NMR dH 1.25 (2.7H, s, Me), 1.34 (2.7H, s, Me),
1.40 (0.3 H, s, Me), 1.51 (0.3H, s, Me), 1.67-1.88 (2H,
m, CH2CH2CO), 1.98–2.08 (0.2H, m, CH2CO), 2.60–
2.80 (1.8 H, m, CH2CO), 3.45 (1H, dd, J = 12.1,
6.0 Hz, CHOBn), 3.47 (1H, dd, J = 12.1, 6.0 Hz,
CHOBn), 4.00 (0.9H, ddd, J = 8.6, 6.0, 2.3 Hz, 4-H),
4.22 (0.9H, q, J = 6.0 Hz, 5-H), 4.29 (0.1H, ddd,
J = 10.14, 6.0, 3.9 Hz, 4-H), 4.39 (0.1H, q, J = 6.0 Hz,
5-H), 4.45 (0.1H, d, J = 11.5 Hz, CHPh), 4.49 (0.1H,
d, J = 11.5 Hz, CHPh), 4.51 (0.9H, d, J = 11.9 Hz,
CHPh), 4.56 (0.9H, d, J = 11.9 Hz, CHPh), 5.52
(0.1H, s, CHCN), 7.16 (0.2H, d, J = 8.6 Hz, Ar 2,6-
H2), 7.25–7.32 (5H, m, Ph-H5), 7.35 (1.8H, d,
J = 8.6 Hz, Ar 3,5-H2), 7.84 (1.8H, d, J = 8.6 Hz, Ar
2,6-H2), 9.33 (0.9H, br, OH); MS m/z 430.1604
(M+H) (C24H2637ClNO4 requires 430.1599), 428.1618
(M+H) (C24H2735ClNO4 requires 428.1628), 370
(MꢀC2H4NO), 91 (Bn).
6.28. (4R,5S)-5-Benzyloxymethyl-4-(4-cyano-3-methoxy-
4-phenylbut-3-enyl)-2,2-dimethyl-1,3-dioxolane (24a) and
6-(2-((4R,5S)-5-benzyloxymethyl-2,2-dimethyl-1,3-dioxo-
lan-4-yl)ethyl)-5-phenylpyrimidine-2,4-diamine (25a)
Compound 22a/23a (1.5 g, 3.7 mmol) in THF (5 mL)
was treated with CH2N2 (8.0 mmol) in Et2O (20 mL)
at 10 ꢁC for 16 h. Excess CH2N2 was destroyed by care-
ful addition of AcOH (30% in THF). Evaporation gave
24a (1.2 g, 81%) as a yellow oil: NMR dH 1.37 (3H, s, 2-
Me), 1.46 (3H, s, 2-Me), 1.77–1.88 (2H, m, CH2CHO),
2.78–2.86 (1H, m, CHC@C), 2.90–2.98 (1H, m,
CHC@C), 3.53 (2H, d, J = 5.9 Hz, CH2OBn), 3.78
(3H, s, OMe), 4.22 (1H, m, 4-H), 4.33 (1H, m, 5-H),
4.51 (1H, d, J = 12.1 Hz, CHPh), 4.59 (1H, d,
J = 12.1 Hz, CHPh), 7.21–7.59 (10 H, m, 2· Ph-H5);
MS m/z 408.2166 (M+H) (C25H30NO4 requires
408.2174), 350 (MꢀC2H3NO), 91 (Bn). NaOMe (140
g, 2.6 mmol) was stirred with guanidine.HCl (300 mg,
2.6 mmol) in MeO(CH2)2OH (10 mL) for 5 min at
30 ꢁC. The filtered solution was boiled under reflux with
24a (700 mg, 1.8 mmol) for 16 h. Evaporation and chro-
matography (CHCl3/MeOH, 19:1) gave 25a (400 mg,
46%) as a highly hygroscopic pale yellow solid: IR mmax
3415, 1685 cmꢀ1; NMR dH 1.23 (3H, s, Me), 1.24 (3H, s,
Me), 1.61–1.67 (2H, m, CH2CHO), 2.24 (1H, m, Pyr-
CH), 2.51 (1H, m, Pyr-CH), 3.4 (2H, d, J = 6.0 Hz,
CH2OBn), 3.95-4.00 (1H, m, dioxolane 4-H), 4.15 (1H,
q, J = 6.0 Hz, dioxolane 5-H), 4.44 (1H, d,
J = 12.3 Hz, CHPh), 4.53 (1H, d, J = 12.3 Hz, CHPh),
4.68 (2H, br, NH2), 5.01 (2H, br, NH2), 7.09–7.39
(10H, m, 2· Ph-H5); MS m/z 435.2423 (M+H)
(C25H31N4O3 requires 435.2396), 200 (MꢀC14H18O3),
91 (Bn).
6.26. (4R,5S)-5-Benzyloxymethyl-4-(4-(4-bromophenyl)-
4-cyano-3-oxobutyl)-2,2-dimethyl-1,3-dioxolane (22c)/
(4R,5S)-5-benzyloxymethyl-4-(4-cyano-3-hydroxy-4-(4-
bromophenyl)but-3-enyl)-2,2-dimethyl-1,3-dioxolane
(23c)
4-Bromophenylacetonitrile and 21 were condensed, as
for the synthesis of 22a/23a, to give 22c/23c (18%) as a
pale yellow oil: NMR dH 1.27 (3H, s, 2-Me), 1.35 (3H,
s, 2-Me), 1.70–1.82 (2H, m, CH2CHO), 2.62–2.78 (2H,
m, CH2C@O), 3.45–3.47 (2H, m, CH2OBn), 4.00 (1H,
ddd, J = 10.1, 6.2, 3.9 Hz, 4-H), 4.22 (1H, q,
J = 6.2 Hz, 5-H), 4.45 (1H, d, J = 11.9 Hz, CHPh),
4.49 (1H, d, J = 11.9 Hz, CHPh), 5.48 (0.35H, s,
CHCN), 7.21–7.35 (5H, m, Ph-H5), 7.45 (1.3H, d,
J = 8.8 Hz, Ar 2,6-H2), 7.55 (1.3H, d, J = 8.8 Hz, Ar
3,5-H2), 7.59 (0.7H, d, J = 8.6 Hz, Ar 3,5-H2), 7.76
(0.7H, d, J = 8.6 Hz, Ar 2,6-H2), 9.35 (0.65H, s, OH);
MS m/z 474.1100 (M+H) (C24H2781BrNO4 requires
474.1102), 472.1094 (M+H) (C24H2779BrNO4 requires
472.1123), 415/413 (MꢀC2H4NO), 91 (Bn).
6.29. (4R,5S)-5-Benzyloxymethyl-4-(-4-(4-chlorophenyl)-
4-cyano-3-methoxybut-3-enyl)-2,2-dimethyl-1,3-dioxo-
lane (24b) and 6-(2-((4R,5S)-5-benzyloxymethyl-2,2-
dimethyl-1,3-dioxolan-4-yl)ethyl)-5-(4-chlorophenyl)-
pyrimidine-2,4-diamine (25b)
6.27. (4R,5S)-5-Benzyloxymethyl-4-(4-(3,4-dichlorophe-
nyl)-4-cyano-3-oxobutyl)-2,2-dimethyl-1,3-dioxolane (22d)/
(4R,5S)-5-benzyloxymethyl-4-(4-cyano-3-hydroxy-4-(3,4-
dichlorophenyl)but-3-enyl)-2,2-dimethyl-1,3-dioxolane
(23d)
Compound 22b/23b was treated with CH2N2, as for the
synthesis of 24a, to give 24b (97%) as a pale yellow oil:
NMR dH 1.36 (3H, s, 2-Me), 1.45 (3H, s, 2-Me), 1.74
(1H, m, CHCHO), 1.85 (1H, m, CHCHO), 2.80 (1H,
m, CHC@C), 2.94 (1H, m, CHC@C), 3.51 (1H, dd,
J = 11.7, 6.0 Hz, CHOBn), 3.53 (1H, dd, J = 11.7,
6.0 Hz, CHOBn), 3.80 (3H, s, OMe), 4.22 (1 H, ddd,
J = 9.4, 6.0, 3.1 Hz, 4-H), 4.33 (1H, q, J = 6.0 Hz, 5-
H), 4.50 (1H, d, J = 12.1 Hz, CHPh), 4.59 (1H, d,
J = 12.1 Hz, CHPh), 7.28 (2H, d, J = 8.6 Hz, Ar 2,6-
H2), 7.30–7.36 (5H, m, Ph-H5), 7.52 (2H, d,
J = 8.6 Hz, Ar 3,5-H2); MS m/z 444.1746 (M+H)
(C25H2937ClNO4 requires 444.1755), 442.1764 (M+H)
(C25H2935ClNO4 requires 442.1785), 428/426 (MꢀCH3),
386/384 (MꢀC2H3NO), 91 (Bn). Compound 24b was
treated with guanidine, as for the synthesis of 25a (chro-
matographic eluant CHCl3/MeOH, 9:1), to give 25b
(25%) as a pale buff solid: mp 55–56 ꢁC; NMR dH 1.28
(6H, s, Me2), 1.62–1.71 (2H, m, CH2CHO), 2.25 (1H,
ddd, J = 13.5, 10.1, 5.9 Hz, Pyr-CH), 2.51 (1H, ddd,
J = 13.5, 10.1, 5.9 Hz, Pyr-CH), 3.43 (2H, d,
J = 5.9 Hz, CH2OBn), 4.01 (1H, ddd, J = 10.1, 5.9,
3,4-Dichlorophenylacetonitrile and 21 were condensed,
as for the synthesis of 22a/23a, to give 22d/23d (16%)
as a highly hygroscopic white solid: NMR dH 1.41
(3H, s, 2-Me), 1.52 (3H, s, 2-Me), 1.73–1.87 (2H, m,
CH2CHO), 2.71–2.84 (2H, m, CH2C@O), 3.47 (1H,
dd, J = 11.7, 6.0 Hz, CHOBn), 3.49 (1H, dd, J = 11.7,
6.0 Hz, CHOBn), 3.98 (1H, m, 4-H), 4.22 (1H, q,
J = 6.0 Hz, 5-H), 4.47 (1H, d, J = 12.3 Hz, CHPh),
4.56 (1H, d, J = 12.3 Hz, CHPh), 7.26-7.37 (5H, m,
Ph-H5), 7.45 (1H, d, J = 8.6 Hz, Ar 5-H), 7.50 (1H,
dd, J = 8.6, 2.0 Hz, Ar 6-H), 7.83 (1H, d, J = 2.0 Hz,
Ar 2-H), 9.61 (1H, s, OH); MS m/z 466.1178 (M+H)
(C24H2637Cl2NO4 requires 466.1179), 464.1193 (M+H)
(C24H2637Cl35ClNO4 requires 464.1209), 462.1217
(M+H) (C24H2635Cl2NO4 requires 462.1238), 407/405/
403 (MꢀC2H4NO), 91 (Bn).