P. Allevi et al. / Tetrahedron: Asymmetry 15 (2004) 1355–1358
1357
were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm E. Merck silica gel plates (60
F254) using UV light, 50% sulfuric acid or 0.2% nin-
hydrin solution in ethanol and heat as developing agent.
E. Merck 230–400 mesh silica gel was used for flash
column chromatography.15
4.0, 3-Ha), 2.73 (1H, dd, J ¼ 14:1 and 8.5, 3-Hb). Anal.
Calcd for C10H13NO4: C, 56.86; H, 6.20; N, 6.63.
Found: C, 56.74; H, 6.10; N, 6.78.
4.3. Synthesis of benzyl (S)-4-(4H-1,3-benzodioxin-6-
ylmethyl)-5-oxo-1,3-oxazolane-3-carboxylate 4 from
benzyl (S)-4-(4-hydroxybenzyl)-5-oxo-1,3-oxazolane-3-
carboxylate 5
4.2. Synthesis of (S)-4-hydroxy-3-hydroxymethylphenyl-
alanine 1
A mixture of the oxazolidinone 57 (0.350 g; 1.1 mmol),
p-toluenesulfonic acid (0.020 g; 0.10 mmol) and toluene
(30 mL) were placed in a flask set for reflux and azeo-
tropic separation of water. Then paraformaldehyde
(0.264 g; 8.8 mmol) was added to the refluxing solution
in two portions, allowing the solution to clear before the
second addition. After 1 h, the reaction was stopped, the
solution was washed with aqueous NaHCO3 and dried
over anhydrous sodium sulfate. The solvent was then
evaporated under reduced pressure and the residue was
chromatographed (eluting with hexane/ethyl acetate
60:40, v/v) to afford the benzyl (S)-4-(4H-1,3-benzodi-
4.2.1. Synthesis of benzyl (S)-4-(4H-1,3-benzodioxin-6-
ylmethyl)-5-oxo-1,3-oxazolane-3-carboxylate 4. A mix-
ture of the (S)-N-benzyloxycarbonyltyrosine 3 (3.00 g;
9.5 mmol), p-toluenesulfonic acid (0.180 g; 0.95 mmol)
and toluene (160 mL) were placed in a flask set for reflux
and azeotropic separation of water. Then paraformal-
dehyde 2.28 g (76 mmol) was added to the refluxing
solution in five portions, allowing the solution to clear
before each subsequent addition. After 1 h the reaction
was stopped, the solution was washed with aqueous
NaHCO3 and dried over anhydrous Na2SO4. After
evaporation of the solvent under reduced pressure, the
residue was chromatographed (eluting with hexane/ethyl
acetate 60:40, v/v) to afford, the benzyl (S)-4-(4H-1,3-
benzodioxin-6-ylmethyl)-5-oxo-1,3-oxazolane-3-carbox-
oxin-6-ylmethyl)-5-oxo-1,3-oxazolane-3-carboxylate
4
(0.308 g; Y ¼ 78%): mp 97–98 ꢁC (from dichlorome-
thane, diisopropyl ether: sinterizes at 88 ꢁC);
½aꢀ ¼ þ194:5 (c 1, CHCl3). All physicochemical prop-
D
erties were identical to those reported above.
ylate
4
(2.81 g; Y ¼ 80%): mp 97–98 ꢁC, (from
dichloromethane, diisopropyl ether: sinterizes at 88 ꢁC);
½aꢀ ¼ þ193:4 (c 1, CHCl3); IR mmax (KBr) 1796,
D
1665 cmꢁ1; H NMR (DMSO-d6): 7.45–7.25 (5H, over-
4.4. Synthesis of benzyl (S)-4-(4H-1,3-benzodioxin-6-
ylmethyl)-5-oxo-1,3-oxazolane-3-carboxylate 4 from (S)-
N-benzyloxycarbonyl-4-hydroxy-3-hydroxymethylphenyl-
alanine 8
1
lapping, H-aromatics), 6.80 (1H, d, J ¼ 8:1, H-aro-
matic), 6.72 (1H, d, J ¼ 8:1, H-aromatic), 6.66 (1H, br s,
H-aromatic), 5.29 (1H, d, J ¼ 4:0), 5.25–5.16 (4H,
overlapping), 4.77–4.70 (2H, AB system), 4.63 (1H, d,
J ¼ 4:0), 4.57 (1H, m), 3.12 (1H, dd, J ¼ 14:1 and 3.4),
2.95 (1H, dd, J ¼ 14:1 and 4.5). 13C NMR (CDCl3): d
171.8, 152.5, 135.5, 129.4, 128.8, 128.4, 127.2, 125.1,
126.2, 121.5, 117.1, 91.2, 78.2, 78.8, 67.9, 67.7, 66.0,
56.4, 35.5, 34.3. Anal. Calcd for C20H19NO6: C, 65.03;
H, 5.18; N, 3.79. Found: C, 65.21; H, 5.06; N, 3.83.
A mixture of the benzyloxycarbonyl derivative 84;17
(0.200 g; 0.58 mmol), p-toluenesulfonic acid (0.11 g;
0.06 mmol) and toluene (20 mL) was placed in a flask set
for reflux and azeotropic separation of water. Then
paraformaldehyde (0.138 g; 4.6 mmol) was added to the
refluxing solution in two portions, allowing to the
solution to clear before the second addition. After 1 h
the reaction is stopped, the solution was washed with
NaHCO3 and dried over anhydrous sodium sulfate. The
solvent was then evaporated under reduced pressure and
the residue was chromatographed (eluting with hexane/
ethyl acetate 60:40, v/v) to afford, benzyl (S)-4-(4H-
1,3-benzodioxin-6-ylmethyl)-5-oxo-1,3-oxazolane-3-car-
boxylate 4 (0.192 g; Y ¼ 90%): mp 97–98 ꢁC (from
dichloromethane, diisopropyl ether: sinterizes at 88 ꢁC);
4.2.2. Regeneration of the protected functions of 4. The
(S)-4-(4H-1,3-benzodioxin-6-ylmethyl)-5-oxo-
benzyl
1,3-oxazolane-3-carboxylate 4 (0.300 g; 0.81 mmol) was
dissolved in dichloromethane (45 mL) and treated at
25 ꢁC with BCl3 (4.05 mL of a 1 M solution in dichlo-
romethane; 4.05 mmol). After 30 min, the solvent was
concentrated under reduced pressure and the reaction
mixture was poured into ice cold water. The aqueous
layer was applied on a Dowex 50X 8-200 cation-
exchange resin column, activated with 2 M HCl and
washed with water. After washing with water, the amino
acid 1 was recovered eluting with 0.5 M ammonia
solution.16 The eluates containing the amino acid were
collected and lyophilized to afford pure 1 (0.137 g,
Y ¼ 80%) as a white powder: mp >300 ꢁC; HPLC:
½aꢀ ¼ þ192:5 (c 1, CHCl3). All physicochemical prop-
D
erties were identical to those reported above.
4.5. Synthesis of (S)-N-benzyloxycarbonyl-4-hydroxy-3-
hydroxymethylphenylalanine 8 from benzyl (S)-4-(4H-
1,3-benzodioxin-6-ylmethyl)-5-oxo-1,3-oxazolane-3-car-
boxylate 4
Rt ¼ 1:31 min; ½aꢀ ¼ ꢁ10:3 (c 0.5, 0.1 M HCl),
D
[lit.4¼ꢁ9.5 (c 0.5, 0.1 M HCl), lit.2b ¼ ꢁ30.49]; 1H NMR
(DMSO-d6): d 7.16 (1H, d, J ¼ 1:3, 2-H aromatic), 6.92
(1H, dd, J ¼ 8:1 and 1.3, 5-H aromatic), 6.68 (1H, d,
J ¼ 8:1, 4-H aromatic), 4.45 (2H, s, CH2OH), 3.34 (1H,
dd, J ¼ 8:5 and 4.0, 2-H), 3.04 (1H, dd, J ¼ 14:1 and
The oxazolidinone 4 (0.300 g; 0.81 mmol) was dissolved
in dichloromethane (45 mL) and treated at 0 ꢁC with
BCl3 (2.43 mL, of a 1 M solution in dichloromethane;
2.43 mmol). After 3 h, the reaction mixture was poured
into a ice cold saturated solution of NaCl and the