60%) as a colourless oil; Rf: 0.47 (EtOAc–hexane, 3 : 1); [α]2D3
=
47.4 (d); 32.6 (t); 28.65 (d, J 7.5, CH2); 12.9 (q); δP (CD3OD)
ϩ1.37; m/z (ESϪ) 241 (M Ϫ H); m/z (ESϪ) 241.0478 (M Ϫ H.
C7H14O7P requires 241.0477).
Ϫ4.3 (c 0.23, MeOH); δH (CDCl3) 7.4 (15H, m); 5.2 (2H, s,
OCH2Ph); 5.1 (2H, d, J 3.3, POCH2Ph); 5.08 (2H, d, J 3.3,
POCH2Ph); 4.06 (2H, m, CH2CH2OP); 3.9 (1H, m, CHOH);
2.86 (1H, d, J 4.9, OH ); 2.58 (1H, qd, J 7.2 and 3.8, CHMe);
1.85 (1H, m); 1.7 (1H, m); 1.45 (2H, m); 1.23 (3H, d, J 7.2,
CH3); δC (CDCl3) 176.2 (s); 136.3 (2 × s); 136.1 (s); 129.1 (d);
129.0 (2 × d); 128.8 (d); 128.6 (d); 128.4 (d); 71.7 (d); 69.6 (d,
J 7.5, CH2); 68.2 (d); 66.9 (t); 45.0 (d); 30.2 (t); 27.4 (d, J 7.5,
CH2); 11.3 (q); δP (CD3OD) ϩ 0.5; m/z (ESϩ) 535 (M ϩ Na);
m/z (ES) 513.2047 (M ϩ H. C28H34O7P requires: 513.2042).
(2R,3S)-3-Acetoxy-2-methyl-6-phosphonoxyhexanoic acid (10)
A suspension of 7 (25 mg, 0.045 mmol) and 5% Pd–C in MeOH
(5 cm3) was hydrogenated for 1 h to yield 10 as a colourless oil
(16 mg, 100%); [α]2D4 = Ϫ6.2 (c 0.16, MeOH); δH (CD3OD) 5.2
(1H, br m); 4.0 (2H, br); 2.7 (1H, m); 2.05 (3H, s, CH3CO);
1.8–1.5 (4H, br m); 1.15 (3H, d, J 6.9, CHCH3); δC (CD3OD)
177.82 (s); 172.84 (s); 75.59 (d); 67.33 (t); 44.75 (d); 30.0 (t);
28.22 (t); 21.28 (q); 12.87 (q); δP (CD3OD) ϩ1.42; m/z (ESϪ) 283
(M Ϫ H); m/z (ESϩ) 307.0554 (M ϩ Na. C9H17NaO8P requires
307.0559).
(2R,3S)-3-Acetoxy-6-bis(benzyloxy)phosphoryloxy-2-methyl-
hexanoic acid benzyl ester (7)
A solution of 6 (80 mg, 0.156 mmol), acetic anhydride (16 µl,
0.17 mmol) and DMAP (4 mg, 0.03 mmol) in pyridine (2 cm3)
was stirred for 18 h at rt. Pyridine was removed in vacuo and the
crude oil was chromatographed with 50% EtOAc–hexane to
afford 7 as a colourless oil (48 mg, 56%); Rf: 0.34 (50% EtOAc–
hexane); [α]2D2 = Ϫ4 (c 0.25, MeOH); δH (CDCl3) 7.4 (15H, m);
5.2 (1H, m, CHOAc); 5.13 (2H, s, OCH2Ph); 5.1 (2H, m,
POCH2Ph); 5.05 (2H, m, POCH2Ph); 4.0 (2H, m, CH2CH2OP);
2.75 (1H, m, CHMe); 2.0 (3H, s, CH3CO); 1.65 (4H, m); 1.2
(3H, d, J 7.1, CHCH3); δC (CDCl3) 173.8 (s); 170.89 (s); 136.3
(s); 136.21 (s); 136.16 (s); 129.03 (d); 129.0 (d); 128.84 (d);
128.76 (d); 128.39 (d); 73.86 (d); 69.73 (t); 69.66 (t); 67.7 (J 5.9,
CH2); 67.03 (t); 43.48 (d); 28.35 (t); 26.8 (d, J 7.3, CH2);
21.2 (q); 12.1 (q); δP (CDCl3) ϩ 0.32; m/z (FAB/3-nitrobenzyl
alcohol (NOBA) matrix) 555 (M ϩ H); m/z (FAB) 555.2143
(M ϩ H. C30H36O8P requires: 555.2148).
(2R,3S)-3-Methoxy-2-methyl-6-phosphonoxyhexanoic acid (11)
A suspension of 8a (45 mg) and 5% Pd–C in MeOH (4 cm3) was
hydrogenated for 22 h at rt to yield 11 as a yellowish oil.
δH (CD3OD) 4.0 (2H, br); 3.7 (1H, br d); 3.55 (1H, br m); 3.4
(3H, s, OCH3); 2.62 (1H, m); 1.9–1.6 (4H, m); 1.15 (3H, d, J 7.2,
CHCH3); δC (CD3OD) 179 (s); 83.6 (d); 67.6 (t); 58.6 (q); 44.4
(d); 29.4 (t); 28.0 (t); 12.4 (q); δP (CD3OD) ϩ1.33; m/z (ESϪ) 255
(M Ϫ H); m/z (ESϪ) 255.0632 (M Ϫ H. C8H16O7P requires
255.0638).
(4R)-4-Benzyl-3-{(2R,3S)-4-[(1S)-2,2-dimethyl-[1,3]-dioxolan-
4-yl]-3-hydroxy-2-methylbutyryl}oxazolidin-2-one (16)
Dibutylboron triflate (3.55 cm3, 14 mmol) was added dropwise
to a solution of (3R)-3-propionyl-4-benzyloxazolidin-2-one
(2.995 g, 12.8 mmol) in dry CH2Cl2 (20 cm3) at 0 ЊC, followed by
Et3N (2.1 cm3, 15.4 mmol), keeping the internal temperature
below ϩ3 ЊC. The clear light yellow solution was then cooled to
Ϫ65 ЊC and a solution of aldehyde 15 (2.4 g, 16.7 mmol) in
CH2Cl2 (20 cm3) was added dropwise. The solution was stirred
for 40 min at Ϫ65 ЊC and 1 h at Ϫ5 ЊC. The reaction was
quenched with pH 7.2 phosphate buffer (20 cm3) and MeOH
(40 cm3). Then, 42 cm3 of a 2 : 1 solution of MeOH–H2O2 (30%
in water) was added dropwise, keeping the internal temperature
below ϩ10 ЊC. This mixture was stirred for 1 h at 0 ЊC. Solvent
was removed in vacuo and the resulting oil was partitioned
between water and EtOAc. The aqueous phase was extracted
with EtOAc (2 × 70 cm3). Organic extracts were washed with
5% NaHCO3, brine, and dried (MgSO4). Removal of the sol-
vent afforded an oil that was chromatographed. The aldol
product 16 (2.313 g, 60%) was eluted first (hexane–EtOAc,
50 100%) and then, the deprotected aldol product 17 (790 mg)
was eluted with EtOAc–MeOH 10%. 16 is a colourless oil that
(2R,3S)-6-Bis(benzyloxy)phosphoryloxy-3-methoxy-2-methyl-
hexanoic acid benzyl ester (8a)
A solution of 6 (100 mg, 0.195 mmol), Ag2O (68 mg, 0.29 mmol)
and MeI (0.5 cm3, 8 mmol) in CH3CN (2.5 cm3) was stirred
for 1 day at rt and 3 days at 60–70 ЊC. The reaction mixture
was diluted with CH2Cl2 and filtered on a path of Celite. Evap-
oration of the solvent gave an orange oil that was chromato-
graphed with 50% EtOAc–hexane. The expected product 8a (20
mg, 39% conversion) was eluted first, then the starting material
6 (50 mg, 50%) and finally the methyl ester by-product 8b (40
mg, 47%). [α]2D1 = Ϫ2.5 (c 2, MeOH); δH (CDCl3) 7.4 (15H, br s);
5.2 (2H, d, J 4.4, OCH2Ph); 5.12 (2H, m, POCH2Ph); 5.09 (2H,
m, POCH2Ph); 4.0 (2H, m, CH2CH2OP); 3.5 (1H, m, CHOH);
3.3 (3H, s, OCH3); 2.65 (1H, m, CHMe); 1.9–1.5 (4H, m); 1.2
(3H, d, J 7.2, CHCH3); δP (CDCl3) ϩ 0.45; m/z (ESϩ) 549 (M ϩ
Na); m/z (ES) 527.2195 (M ϩ H. C29H36O7P requires 527.2198).
solidified on standing. Rf: 0.4 (50% EtOAc in hexane); [α]2D3.7
=
Ϫ10.7 (c 0.28, CH2Cl2); δH (CDCl3) 7.45–7.2 (5H, m); 4.74 (1H,
m, CHN); 4.39 (1H, m); 4.33–4.12 (4H, m, OCH2CHN,
CH2CH(OH)CH2(O) and CH(OH)CH2OC); 3.86 (1H, qd, J 3
and 7, CHMe); 3.65 (1H, dd, J 7.4 and 8.0, CH(OH)CH2OC);
3.3 (1H, dd, J 3.3 and 13.4,CH2Ph); 3.24 (1H, br, OH ); 2.85
(1H, dd, J 9.4 and 13.4, CH2Ph); 1.9–1.65 (2H, m, CHCH2CH);
1.47 (3H, s, CCH3); 1.42 (3H, s, CCH3); 1.33 (3H, d, J 7,
CHCH3); δC (CDCl3) 177.6 (s); 153.5 (s); 135.4 (s); 129.9 (d);
129.4 (d); 127.9 (d); 109.2 (s); 73.9 (d); 70.4 (t); 69.1 (d); 66.6 (t);
55.5 (d); 42.9 (d); 38.2 (t); 38.0 (t); 27.4 (q); 26.1 (q); 11.3 (q);
m/z (ESϩ) 400 (M ϩ Na); m/z (ESϩ) 378.1910 (M ϩ H. C20H28-
NO6 requires 378.1916).
(2R,3S)-6-Bis(benzyloxy)phosphoryloxy-3-hydroxy-2-methyl-
hexanoic acid methyl ester (8b)
δH (CDCl3) 7.4 (10H, br s); 5.1 (2H, m, POCH2Ph); 5.05 (2H,
m, POCH2Ph); 4.1 (2H, m, CH2CH2OP); 3.9 (1H, m, CHOH);
3.75 (3H, s, COOCH3); 2.72 (1H, br d, J 4.7, OH); 2.54 (1H, qd,
J 3.5 and 7.2, CHMe); 1.9 (1H, m); 1.7 (1H, m); 1.5 (2H, m);
1.2 (3H, d, J 7.1, CHCH3); δP (CDCl3) ϩ 0.5; m/z (ESϩ) 459
(M ϩ Na); m/z (ESϩ) 437.1729 (M ϩ H. C22H30O7P requires:
437.1729).
(2R,3S)-3-Hydroxy-2-methyl-6-phosphonoxyhexanoic acid (9)
A solution of 6 (54 mg, 0.1 mmol) in MeOH (2 cm3) was hydro-
genated for 5 h with 5% Pd–C (12 mg). The catalyst was filtered
off and the solvent evaporated to yield a colourless oil (24 mg).
Et2O-mediated precipitation of the product dissolved in a little
MeOH yielded 9 as a very hygroscopic colourless solid (24 mg,
94%). [α]2D2 = Ϫ8.3 (c 0.24, MeOH); δH (CD3OD) 4.0 (2H, br m);
3.8 (1H, br m); 2.45 (1H, m); 1.9 (1H, br m); 1.8–1.4 (4H, br m);
1.2 (3H, d, J 7, CH3); δC (CD3OD) 179.3 (s); 73.5 (d); 68.0 (t);
(4R)-4-Benzyl-3-[(2R,3S)-3,5,6-trihydroxy-2-methylhexanoyl]-
oxazolidin-2-one (17)
White foam; Yield: 18%; Rf: 0.18 (EtOAc); [α]2D6 = Ϫ141.7
(c 0.24, MeOH); δH (CDCl3) 7.45–7.2 (5H, m); 4.8 (1H, m,
CHN); 4.4–4.2 (3H, m); 4.05 (1H, br m); 3.95–3.5 (4H, m); 3.3
(1H, dd, J 13.3 and 3.3, CH2Ph); 2.85 (1H, dd, J 9.3 and 13.3,
CH2Ph); 2.48 (1H, br s); 1.8–1.4 (3H, m); 1.3 (3H, d, J 7,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 5 5 2 – 5 5 9
556