3434 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 13
Dardonville et al.
5.18-5.02 (m, 4H), 4.55-4.3 (m, 1H), 4.15-3.95 (m, 2H), 3.95-
3.7 (m, 2H), 3.1-2.85 (m, 2H), 2.15 (br s, 1H); 13C NMR (CDCl3)
δ 165.6 (s), 165.3 (s), 136.0 (s), 135.9 (s), 135.2 (s), 129.2 (CH),
129.1 (CH), 129.0 (2 × CH), 128.6 (CH), 128.5 (CH), 71.1 (d,
CH2, J ) 6 Hz), 70.95 (d, CH2, J ) 6 Hz), 70.2 (m, CH2), 68.26
(CH2), 68.24 (CH2), 65.54 (d, CH, J ) 6 Hz), 65.2 (d, CH, J )
6 Hz), 56.6 (CH2), 56.1 (CH2), 55.8 (CH2), 53.5 (CH2); 31P NMR
(CDCl3) δ +0.8; MS (ES+), m/z 555 [M + Na]; Anal. (C26H29O8-
PS/1H2O) C; Calcd H, 5.13.; S, 5.82; P, 5.62. Found: H, 4.63;
S, 5.08; P, 6.36.
G. [(2R)-2-Acetoxy-3-(bis(benzyloxy)phosphoryloxy)-
propane-1-sulfinyl]acetic Acid Benzyl Ester (8). A solu-
tion of 7 (45 mg, 0.084 mmol), acetic anhydride (20 µl, 0.2
mmol), and DMAP (3 mg, 0.24 mmol) in pyridine (1 mL) was
stirred for 19 h at room temperature. The solvent was removed
in vacuo, and the crude oil was partitioned between CH2Cl2
and saturated NH4Cl aqueous solution. The aqueous phase
was extracted with CH2Cl2 (two times). The combined organic
extracts were dried (MgSO4) and concentrated under reduced
pressure. Chromatography (Isolute 1 g SI) with hexane/EtOAc,
0 f 50%, afforded 8 as a yellowish oil (37 mg, 77%): Rf 0.55
(100% EtOAc); 1H NMR (CDCl3) δ 7.4 (br s, 15H), 5.38 (m,
1H), 5.24 (m, 2H), 5.18-5.0 (m, 4.5H), 4.4-4.0 (m, 2.5H), 3.79
(ABX, J ) 14.1 and 31.6 Hz, 1H), 3.73 (ABX, J ) 14 and 17.7
Hz, 1H), 3.1 (m, 2H), 2.04 (d, 3H); 13C NMR (CDCl3) δ 170.4
(s), 170.2 (s), 165.1 (s), 165.05 (s), 136.0 (s), 135.9 (s), 135.1
(s), 129.19 (d), 129.16 (d), 129.13 (d), 129.0 (d), 128.5 (d), 70.05
(d, JC-P ) 5.6 Hz), 68.38 (t), 68.35 (t), 67.7 (d, JC-P ) 5.4 Hz),
67.45 (d, JC-P ) 5.6 Hz), 67.4 (d, JC-P ) 7.4 Hz), 66.95 (d, JC-P
) 7.3 Hz), 56.8 (t), 55.8 (t), 54.3 (t), 52.7 (t), 21.23 (q), 21.15
(q); 31P NMR (CDCl3) δ +0.33, +0.23; MS (ES+), m/z 597 [M +
Na]; Anal. (C28H31O9PS/0.5 H2O) C, H; Calcd: S, 5.49; P, 5.31.
Found: S, 4.87; P, 4.03.
168.9 (s), 71.1 (m, t), 70.8 (m, t), 67.2 (m, d), 66.6 (m, d), 58.0
(t), 56.3 (t); 31P NMR (D2O) δ +1.16 (br); MS (ES-), m/z 261
[M - H]; ESHRMS, m/z 260.9836 (C5H10O8PS requires
260.9839).
Synthesis of Hydroxamic Acid Analogues. A. (2R,3R)-
2,3,4,N-Tetrahydroxybutyramide (13). Fifty percent aque-
ous hydroxylamine (0.3 mL, 5 mmol) was added to a solution
of D-erythronic acid-γ-lactone (126 mg, 1.07 mmol) in water
(1.7 mL). After 20 min at room temperature, the solvent was
evaporated under reduced pressure to dryness (bath temper-
ature of 25 °C). To remove the excess of hydroxylamine, water
was added to the residue and evaporated again under high
vacuum. The oily residue was triturated with cold EtOH to
give a white gum. The product was crystallized with EtOH
and rinsed with Et2O: white solid (126 mg, 83%); [R]20
)
D
+3.75 (c 0.8, H2O); 1H NMR (D2O) δ 4.03 (br s, 1H), 3.75 (br s,
1H), 3.5 (br s, 2H); 13C NMR (D2O) δ 170.6 (s), 72.6 (d), 71.5
(d), 61.8 (t); Anal. (C4H9NO5) C, H, N.
B. (3R,4R)-3,4-Di(tetrahydro-2H-2-pyranyloxy)tetrahy-
dro-2-furanone (14). A solution of D-erythronic acid-γ-lactone
(565 mg, 4.8 mmol), 3,4-dihydropyran (4.3 mL, 48 mmol), and
PPTS (360 mg, 1.4 mmol) in CH2Cl2 (5 mL) was stirred at room
temperature for 18 h. Et3N was added to the reaction mixture
(0.2 mL, 1.4 mmol), and the solvent was removed under
reduced pressure. Chromatography (Isolute 25 g SI column
prewashed with CH2Cl2/Et3N and sequentially rinsed with
CH2Cl2 and hexane) with hexane/EtOAc, 0 f 40%, afforded
the product as a colorless oil that solidified on standing (1.18
g, 86%): 1H NMR (CDCl3) δ 5.05 (t, 1H), 4.92 (t, 1H), 4.5 (m,
2H), 4.32 (m, 2H), 3.9-3.7 (m, 2H), 3.55-3.4 (m, 2H), 1.9-
1.35 (m, 12H); 13C NMR (CDCl3) δ 174.5 (s), 99.7 (d), 98.8 (d),
73.1 (d), 72.4 (d), 71.6 (t), 62.95 (t), 62.86 (t), 30.46 (t), 30.43
(t), 25.7 (t), 25.65 (t), 19.43 (t), 19.37 (t); MS (ES+), m/z 309
[M + Na].
C. 4,N-Dihydroxy-(2R,3R)-2,3-bis(tetrahydropyran-2-
yloxy)butyramide (15). Fifty percent aqueous hydroxyl-
amine (0.6 mL, 10 mmol) was added to a solution of 14 (290
mg, 1 mmol) in THF (7 mL). After 18 h at room temperature,
the solvent was evaporated under reduced pressure. To remove
the excess of hydroxylamine, water was added and evaporated
again. The product was dried under high vacuum: 1H NMR
(CDCl3) δ 4.9-4.65 (m, 2H), 4.55-4.4 (m, 1H), 4.2-3.5 (m, 7H),
2.0-1.5 (br m, 12H); 13C NMR (CDCl3) δ 167.8 (s), 167.4 (s),
167.0 (s), 166.8 (s), 99.4 (d), 99.1 (d), 96.5 (d), 96.0 (d), 79.3
(d), 78.7 (d), 75.3 (d), 75.2 (d), 74.4 (d), 73.3 (d), 63.0 (d), 62.4
(d), 61.3 (d), 61.1 (d), 61.0 (d), 60.5 (d), 58.9 (d), 30.0 (t), 29.8
(t), 29.7 (t), 29.5 (t), 29.3 (t), 29.1 (t), 29.0 (t), 24.3 (t), 24.2 (t),
20.0 (d), 19.3 (t), 18.8 (t), 18.5 (t), 18.2 (t), 18.0 (t), 17.7 (t),
17.5 (t); MS(ES-), m/z 318 [M - H]; ESHRMS, m/z 320.1703
(C14H26O7N requires 320.1709).
D. (3aR,6aR)-2,2-Dimethyldihydrofuro[3,4-d][1,3]dioxol-
4-one (16). A solution of D-erythronic acid-γ-lactone (3.015 g,
25.5 mmol), 2,2-dimethoxypropane (10 mL, 81 mmol), and
PPTS (1 g, 4 mmol) was stirred for 20 h at room temperature.
The reaction was quenched with Et3N (0.6 mL), and the
volatiles were removed under reduced pressure. Chromatog-
raphy (Isolute 50 g SI) with hexane/EtOAc, 0 f 50%, afforded
the product as a white solid (2.85 g, 71%): 1H NMR (CDCl3) δ
4.94 (dd, 1H, J ) 3.6 and 5.6 Hz), 4.8 (d, 1H, J ) 5.6 Hz), 4.53
(d, 1H, J ) 10.8 Hz), 4.46 (dd, 1H, J ) 11 and 3.6 Hz), 1.55 (s,
3H), 1.46 (s, 3H); [R]24D ) -113.3 (c 0.3, H2O) [Lit.22 -103.4 (c
1, H2O)].
E. (4R,5R)-5-Hydroxymethyl-2,2-dimethyl-[1,3]dioxo-
lane-4-carboxylic Acid Benzyloxyamide (17). Regenera-
tion of BnONH2 Base. A solution of O-benzylhydroxylamine
hydrochloride (2.18 g, 13.6 mmol) in MeOH (10 mL) was
treated at 0 °C with a MeONa methanolic solution (700 mg,
13 mmol, 10 mL MeOH). After 1 h at 0 °C, the reaction mixture
was diluted with CH2Cl2 and filtered. The mother liquor was
concentrated under reduced pressure, and the residue was
treated with hot EtOAc. The solution was filtered, and the
mother liquor was concentrated to give O-benzylhydroxy-
lamine as a free base (1.6 g, 13 mmol). A mixture of lactone
16 (1.43 g, 9 mmol) and BnONH2 (1.6 g, 13 mmol) in CH2Cl2
H. [(2R)-2-Acetoxy-3-phosphonooxypropane-1-sulfin-
yl]acetic acid (9). Hydrogenolysis of a solution of 8 (25 mg/
0.043 mmol) in MeOH with 5% Pd-C (15 mg) for 20 min
afforded 9 as a colorless oil (13 mg, 99%): 1H NMR (D2O) δ
5.4-5.2 (m, 1H), 4.1-3.85 (m, 3H), 3.8 (d, 1H), 3.35-3.1 (m,
2H), 1.98 (d, 3H); 13C NMR (D2O) δ 173.4, 173.34, 169.1, 168.9,
68.8, 68.7, 67.5, 67.4, 65.91 (JC-P ) 5.2 Hz), 65.8 (JC-P ) 5.2
Hz), 52.5, 51.8, 20.7, 20.5; 31P NMR (D2O) δ +1.13; MS (ES-),
m/z 303 [M - H]; ESHRMS, m/z 302.9941 (C7H12O9PS requires
302.9940).
I. (2R)-[3-(Bis(benzyloxy)phosphoryloxy)-2-(tetrahy-
dropyran-2-yloxy)propane-1-sulfinyl]acetic Acid (10). A
solution of 7 (110 mg, 0.21 mmol), 3,4-dihydropyran (1 mL, 9
mmol), and PPTS (10 mg, 0.04 mmol) in CH2Cl2 (1.5 mL) was
stirred at room temperature for 30 h. The reaction was
quenched with a few drops of Et3N, and the solvent was
removed under reduced pressure. Chromatography (Isolute 2
g SI column) with hexane/EtOAc, 0 f 100%, afforded the
product as a colorless oil (103 mg, 79%): Rf 0.12 (hexane/
1
EtOAc, 1/2); H NMR (CDCl3) δ 7.4 (br s, 15H), 5.22 (m, 2H),
5.2-5.0 (m, 4H), 4.82-4.65 (m, 1H), 4.42-4.18 (m, 2H), 4.1-
3.7 (m, 4H), 3.5 (m, 1H), 3.25-2.9 (m, 2H), 1.85-1.4 (m, 6H);
13C NMR (D2O) δ 165.6 (s), 165.5 (2 × s), 165.4 (s), 136.2 (s),
136.1 (2 × s), 136.0 (s), 135.3 (s), 135.2 (s), 129.1 (2 × d), 129.0
(d), 128.9 (d), 128.5 (d), 101.8 (d), 99.9 (d), 99.2 (d), 96.5 (d),
72.1 (d, J ) 7 Hz), 70.9 (d, J ) 7 Hz), 69.9 (m, CH2), 69.6 (d,
J ) 6 Hz), 69.4 (t, J ) 6 Hz), 69.0 (t, J ) 6 Hz), 68.2 (t, J ) 6
Hz), 68.15 (t, J ) 6 Hz), 67.6 (t, J ) 6.7 Hz), 67.05 (t, J ) 6
Hz), 64.2 (t), 63.5 (t), 63.3 (t), 63.1 (t), 57.2 (t), 56.8 (t), 56.3
(t), 56.2 (t), 55.6 (t), 54.5 (t), 52.9 (t), 31.1 (t), 31.0 (2 × t), 29.5
(t), 25.5 (t), 20.4 (t), 20.1 (t), 19.9 (t), 19.6 (t); 31P NMR (D2O)
δ +0.47, +0.34, +0.18; MS (ES+), m/z 640 [M + Na].
J. (2R)-(2-Hydroxy-3-phosphonooxypropane-1-sulfin-
yl)acetic Acid (11). Hydrogenolysis of a solution of 10 (80
mg, 0.13 mmol) in MeOH (5 mL) with 5% Pd-C (50 mg) for
20 min afforded a colorless oil. The oil was dissolved in H2O
and stirred at room temperature overnight. The solvent was
removed in vacuo. Ether-mediated precipitation of the crude
product dissolved in a little MeOH afforded 11 as a white
powder (15 mg, 44%): 1H NMR (CD3OD) δ 4.25 (m, 1H), 4.15-
3.70 (br m, 4H), 3.1 (m, 2H); 13C NMR (CD3OD) δ 169.9 (s),