Stereoselective synthesis of trans-4,5-disubstituted oxazolidin-2-ones by intramolecular conjugate addition of N-p-toluenesulfonyl carbamates

Article abstract of DOI:10.3987/com-03-9724

p-Toluenesulfonyl carbamates (2a-d) were prepared starting from allylic alcohols (3), in which the double bond is conjugated with an electron withdrawing group. In the presence of a catalytic amount of DBU, an intramolecular cyclisation occurred, leading

Full text of DOI:10.3987/com-03-9724

HETEROCYCLES, Vol. 60, No. 5, 2003
1173
HETEROCYCLES, Vol. 60, No. 5, 2003, pp. 1173 - 1183
Received, 22nd January, 2003, Accepted, 28th February, 2003, Published online, 3rd March, 2003
STEREOSELECTIVE SYNTHESIS OF TRANS-4,5-DISUBSTITUTED
OXAZOLIDIN-2-ONES
BY
INTRAMOLECULAR
CONJUGATE
ADDITION OF N- p-TOLUENESULFONYL CARBAMATES
Marco Ciclosi,a Cristiana Fava,a Roberta Galeazzi,a Mario Orena,a,* José
Sepúlveda-Arques, b and Maria Eugenia González-Rosende c,*
a Dipartimento di Scienze dei Materiali e della Terra - Università Politecnica delle
Marche, Via Brecce Bianche, I-60131 Ancona, Italy orena@mta01.unian.it
b Department of Organic Chemistry, Faculty of Pharmacy - University of Valencia,
Avda. Vicent Andrés Estelles s/n, 46100 Burjassot, Valencia, Spain
c
Department of Chemistry - University Cardenal Herrera - CEU, Edificio
Seminario s/n, 46133 Moncada, Valencia, Spain eugenia@uch.ceu.es
Abstract – p-Toluenesulfonyl carbamates (2a-d) were prepared starting from
allylic alcohols (3), in which the double bond is conjugated with an electron
withdrawing group. In the presence of a catalytic amount of DBU, an
intramolecular cyclisation occurred, leading to trans-4,5-disubstituted
oxazolidin-2-ones (1a-d) with total stereoselection, which can be precursors of
syn-4-hydroxy-3-amino acids.
Intramolecular conjugated addition of nitrogen nucleophiles to activated double bonds has been scarcely
reported and in some cases the reaction must be carried out under an inert atmosphere.1-9 In this field one
10
of us
has already obtained enantiomerically pure diamino acids by cyclisation of a chiral
4-p-toluenesulfonylamino-2- butenoate, leading to an equimolar, easily separable diastereomeric mixture
of imidazolidin-2-ones. Within a project directed towards the synthesis of non-proteinogenic amino
acids,11-17 we report here a convenient approach to trans-4,5-disubstituted oxazolidin-2-ones (1) by
intramolecular conjugate addition of N-p-toluenesulfonyl carbamates (2) (Scheme 1).

1174
HETEROCYCLES, Vol. 60, No. 5, 2003
Ts
O
Ts
O
N
N
EWG
HO
EWG
O
R
H
O
R
EWG
R
3
1
2
EWG = COOR, SO2Ph
R = Alkyl, Ph, H
OH
R
EWG
NH2
4
Scheme 1
In fact, trans-4,5-disubstituted oxazolidin-2-ones (1) can be precursors of the syn-1-hydroxy-2-amino
moiety (4) (EWG = COOR), a functional pattern which occurs in γ-substituted β-amino-γ-hydroxy acids
with biological activity as subunits of antibiotic peptides, like tuberactinomycins A and N,18,19 or
gastroprotective natural products such as aminocoumacin C and AI-77-B.20-23 Moreover, the 2-amino
alcohol unit occurs as a sub-structure in β-amino-γ-hydroxy acids biologically active such as 5 24-26 and in
inhibitors of proteases, such as 6 (Scheme 2).27,28
NH2
NH2
HO
HO
COOH
6
5
Scheme 2
First, hydroxy derivatives (3a-f) were prepared according literature methods.8,29,30 These compounds were
subsequently treated with p-toluenesulfonyl isocyanate in DCM to give the corresponding
N-p-toluenesulfonyl carbamates (2a-f) which were directly used in the following step without further
purification (Scheme 3). In the presence of a catalytic amount of DBU in dichloromethane at room
temperature, carbamates (2) underwent intramolecular conjugated addition to the activated double bond
affording oxazolidin-2-ones (1a-f) in good yield, the ring size being determined by IR absorption of the
carbonyl (1750 cm-1).31-35 When R was an alkyl or an aryl group, total stereoselection was observed, and
trans-4,5-disubstituted oxazolidin-2-ones (1a-d) were isolated as the sole products, whose configuration
1
was assigned on the basis of the J4,5 value (about 4.0 Hz) in the H NMR spectrum and n.O.e.
experiments.31-35 The exclusive formation of the trans-isomer can be explained by the reaction conditions,

HETEROCYCLES, Vol. 60, No. 5, 2003
1175
an equilibrium occurring in the presence of DBU, leading to the most stable product. These compounds
could be precursors of syn-3-amino-4-hydroxy acids after removal of the p-toluenesulfonyl group and
cleavage of the heterocyclic ring carried out following literature methods.10
Ts
Ts
H
Ts
O
O
O C N
N
N
EWG
i
ii
O
O
+
HO
EWG
R
R
EWG
1
2
R
3
a. R = n-Bu, EWG = COOMe, 76%
b. R = Ph, EWG = COOEt, 88%
d. R = Et, EWG = COOBn, 78%
e. R = H, EWG = SO2Ph, 75%
f. R = H, EWG = COOBn, 78%
c. R = Me, EWG = SO2Ph, 75%
Reagents and conditions: i: DCM, rt, quantitative yield; ii: DBU (10 mol%), DCM, rt.
Scheme 3
However, when R = H (1e,f), only a regioselective functionalisation of the double bond was observed, no
matter of stereoselection. Nevertheless, the usefulness of compound (1f) was proven by conversion into
racemic 5 through simple steps. In fact, simply by treating 1f with Li in liquid NH3, followed by cleavage
of the heterocyclic ring under basic conditions,10 racemic 5 was obtained in good yield.
H
O
N
i
ii
1f
(R,S)-5
COOH
O
7
Reagents and conditions: i: Li, NH3, -78 °C; ii: NaOH, refluxing H2O; Dowex AG 50W-X2, 1M NH4OH as eluant, 52%.
Scheme 4
In conclusion, N-p-toluenesulfonyl carbamates (2) were disclosed to be useful starting material in order to
prepare trans-4,5-disubstituted oxazolidin-2-ones with total stereoselection by intramolecular conjugated
addition. Given the mild conditions required for the cyclisation, together with the access to an interesting
class of compounds, the reported strategy would provide valuable intermediates for synthetic applications.
EXPERIMENTAL
Melting points were measured on a Electrothermal IA 9000 apparatus and are uncorrected. IR spectra were
recorded in CHCl3 on a Nicolet Fourier Transform Infrared 20-SX spectrophotometer. GC analyses were

1176
HETEROCYCLES, Vol. 60, No. 5, 2003
performed using a Chrompack 9001 instrument equipped with a Chrompack 7720 capillary column (50 m
x 0.25 mm i.d.; stationary phase CP-Sil-5 CB). 1H and 13C NMR spectra were recorded at 200 MHz and 50
MHz, respectively, on a Varian Gemini 200 spectrometer, using CDCl3 as a solvent. Chemical shifts (δ)
are reported in ppm relative to TMS and coupling constants (J) in Hz. Assignments were aided by
decoupling and homonuclear two-dimensional experiments. GC-MS spectral analyses were performed
with a Hewlett-Packard spectrometer 5890, series II, using a HP-5 capillary column (30 m x 0.25 mm i.d.;
stationary phase 5% phenyl methyl silicone). MS spectral analysis was performed with a Fisons VG
Autospec TRIO 1000 instrument.
Methyl (E)-4-hydroxy-2-octenoate (3a).
To a solution of methyl (E)-4-bromo-2-octenoate (4.7 g; 20 mmol) in DMF (10 mL) anhydrous sodium
acetate was added (2.5 g; 30 mmol) and the mixture was heated for 4 h at 70 °C. After cooling, H2O (40
mL) was added and the mixture was extracted with ethyl acetate (2 x 150 mL). After drying (Na2SO4) and
removal of the solvent under reduced pressure, the residue was purified by silica gel chromatography
(cyclohexane:ethyl acetate 60:40) to give the corresponding 4-acetoxy derivative (3.6 g; 85% yield) as a
colorless oil. IR (CHCl3): 1744, 1715 cm-1; 1H NMR: 0.86 (t, 3H, J = 6.2), 1.21 - 1.39 (m, 4H), 1.56 - 1.73
(m, 2H), 2.08 (s, 3H), 3.73 (s, 3H), 5.37 (dt, 1H, J = 5.3, J = 5.3), 5.91 (d, 1H, J = 15.8), 6.83 (dd, 1H, J =
13
5.3, J = 15.8); C NMR: 14.3, 21.4, 22.8, 27.5, 33.9, 52.1, 72.9, 121.5, 146.3, 166.9, 170.5. A solution
containing this compound (4.2 g; 20 mmol) in methanol (30 mL) was slowly added to the resin IRA 900
(5.0 g) in the methoxide form 35 suspended in methanol (30 mL). The mixture was stirred at rt for 1 h, then
the resin was filtered off and washed with methanol (10 mL). After removal of the solvent under reduced
pressure, the title product was obtained in a quantitative yield (3.4 g) as a colorless oil. IR (CHCl3): 3351,
1718 cm-1; 1H NMR: 0.89 (t, 3H, J = 6.2), 1.21 - 1.48 (m, 4H), 1.51 - 1.68 (m, 2H), 1.89 (br s, 1H, OH),
3.73 (s, 3H), 4.23 - 4.37 (m, 1H), 6.04 (d, 1H, J = 15.8), 6.95 (dd, 1H, J = 5.0, J = 15.8); 13C NMR: 14.4,
23.0, 27.8, 36.8, 52.1, 71.6, 120.1, 151.1, 167.5; GC-MS (EI, 70 eV): 172 (M+), 157, 139, 113. Anal. Calcd
for C9H16O3: C, 62.77; H, 9.36. Found: C, 62.74; H, 9.40.
Ethyl (E)-4-phenyl-4-hydroxy-2-butenoate (3b).
To a solution containing ethyl (E)-4-phenyl-4-oxo-2-butenoate (2.0 g; 10 mmol) in dry methanol (50 mL)
at -15 °C KBH4 (0.7 g; 10 mmol) was added and the mixture was stirred for 1 h. Solid NH4Cl (2.0 g) was
added, then the mixture was poured in H2O (40 mL) and extracted with ethyl acetate (3 x 100 mL). After
drying (Na2SO4) and removal of the solvent under reduced pressure, the residue was purified by silica gel
chromatography (cyclohexane:ethyl acetate 80:20) to give the title compound (1.9 g; 91% yield) as a
colorless oil. IR (CHCl3): 3352, 1711 cm-1; 1H NMR: 1.26 (t, 3H, J = 7.2), 3.02 (br s, 1H, OH), 4.16 (q, 2H,

HETEROCYCLES, Vol. 60, No. 5, 2003
1177
J = 7.2), 5.29 (m, 1H), 6.12 (dd, 1H, J = 1.7, J = 15.7), 7.02 (dd, 1H, J = 3.0, J = 15.7), 7.33 (m, 5 ArH);
13C NMR: 14.6, 61.1, 73.7, 120.3, 127.1, 128.0, 128.6, 128.9, 129.2, 141.6, 149.8, 167.3; GC-MS (EI, 70
eV): 206 (M+), 177, 128, 77. Anal. Calcd for C12H14O3: C, 69.89; H, 6.84. Found: C, 69.85; H, 6.81.
Preparation of compounds (3c-f). General Procedure.
To a solution of the appropriate 2-alkenyl phenyl sulphone or benzyl 3-alkenoate (20 mmol) in chloroform
(100 mL), m-chloroperbenzoic acid (50%; 8.6 g; 25 mmol) was added and the suspension was refluxed for
5 h. After cooling and removal of the solvent under reduced pressure, the residue was dissolved in ethyl
acetate (100 mL) and the organic layer was washed with aqueous saturated Na2CO3 (2 x 50 mL). After
drying (Na2SO4), the solvent was removed in vacuo and the residue was purified by silica gel
chromatography (cyclohexane:ethyl acetate 50:50) to give the corresponding epoxide. To a solution of the
epoxide (18 mmol) in dichloromethane (100 mL) DBU (0.3 mL) was added and the mixture was stirred for
2 h at rt. The organic phase was then washed with 1 M HCl (40 mL) and water (2 x 100 mL) and after
drying (Na2SO4) the solvent was removed under reduced pressure. The residue was purified by silica gel
chromatography (cyclohexane:ethyl acetate 60:40) to give compounds (3c-f).
(E)-1-Benzenesulfonyl-1-buten-3-ol (3c).
Starting from (E)-(2-butenyl)phenylsulfone the title compound was prepared in 79% overall yield as a low
1
melting solid. IR (CHCl3): 3345 cm-1; H NMR: 1.26 (d, 3H, J = 6.9), 2.94 (br s, 1H. OH), 4.29 - 4.57 (m,
1H), 6.55 (dd, 1H, J = 1.8, J = 14.9), 6.94 (dd, 1H, J = 3.6, J = 14.9), 7.46 - 7.65 (m, 3 ArH), 7.78 - 7.92 (m,
2 ArH); 13C NMR: 22.8, 66.7, 128.1, 129.3, 129.8, 134.0, 140.1, 149.9; GC-MS (EI, 70 eV): 212 (M+), 194,
141, 77, 70. Anal. Calcd for C10H12O3S: C, 56.59; H, 5.70. Found: C, 56.54; H, 5.66.
Benzyl (E)-4-hydroxy-2-hexenoate (3d).
Starting from benzyl (E)-3-hexenoate, the title compound was prepared in 81% overall yield as a colorless
oil. IR (CHCl3): 3348, 1721 cm-1; 1H NMR: 0.97 (t, 3H, J = 7.4), 1.55 - 1.75 (m, 2H), 4.21 - 4.32 (m, 1H),
4.45 (br s, 1H, OH), 5.20 (s, 2H), 6.10 (dd, 1H, J = 1.8, J = 15.8), 7.02 (dd, 1H, J = 4.8, J = 15.8), 7.31 -
7.43 (m, 5 ArH); 13C NMR: 10.0, 29.9, 66.9, 72.8, 120.5, 128.7, 129.1, 130.3, 131.7, 134.1, 151.0, 167.0;
GC-MS (EI, 70 eV): 220 (M+), 202, 129, 91, 77. Anal. Calcd for C13H16O3: C, 70.89; H, 7.32. Found: C,
70.84; H, 7.35.
(E)-3-Benzenesulfonyl-2-propenol (3e).
Starting from allyl phenylsulfone, the title compound was prepared in 77% overall yield as a colorless oil.
IR (CHCl3): 3351 cm-1; 1H NMR: 1.88 (br s, 1H, OH), 4.41 (m, 2H), 6.67 (dt, 1H, J = 2.2, J = 14.9), 7.07

1178
HETEROCYCLES, Vol. 60, No. 5, 2003
(dt, 1H, J = 3.3, J = 14.9), 7.48 - 7.71 (m, 3 ArH), 7.85 - 7.97 (m, 2 ArH); 13C NMR: 60.5, 127.8, 129.1,
129.7, 133.9, 140.4, 147.1; GC-MS (EI, 70 eV): 198 (M+), 141, 77, 57. Anal. Calcd for C9H10O3S: C,
54.53; H, 5.08. Found: C, 54.48; H, 5.04.
Benzyl (E)-4-hydroxy-2-butenoate (3f).
Starting from benzyl 3-butenoate, the title compound was prepared in 78% overall yield as a colorless oil.
IR (CHCl3): 3347, 1698 cm-1; 1H NMR: 1.78 (br s, 1H, OH), 4.36 (dd, 2H, J = 2.2, J = 3.9), 5.20 (s, 2H),
6.16 (dt, 1H, J = 2.2, J = 15.8), 7.09 (dt, 1H, J = 3.9, J = 15.8), 7.29 - 7.42 (m, 5 ArH); 13C NMR: 62.3, 66.7,
120.3, 128.6, 128.7, 128.9, 129.0, 136.4, 148.0, 166.7; GC-MS (EI, 70 eV): 192 (M+), 190, 101, 91, 77.
Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.79; H, 6.25.
Preparation of N-p-toluenesulfonyl carbamates (2a-f). General Procedure.
To a solution containing the compounds (3a-f) (15 mmol) in dichloromethane (50 mL) p-toluenesulfonyl
isocyanate (3.2 g; 16 mmol) dissolved in dichloromethane (10 mL) was added at rt. The solution was
stirred for 4 h and then the solvent was removed under reduced pressure. The residue was purified by silica
gel chromatography (cyclohexane:ethyl acetate 80:20) to give the pure compounds (2a-f).
Methyl (E)-4-p-toluenesulfonylaminocarbonyloxy-2-octenoate (2a).
Starting from compound (3a), the title compound was prepared in 86% yield as a colorless oil. IR (CHCl3):
3332, 1742, 1714 cm-1; 1H NMR: 0.84 (t, 3H, J = 6.6), 1.12 - 1.34 (m, 4H), 1.53 - 1.67 (m, 2H), 2.45 (s, 3H),
3.73 (s, 3H), 5.28 (dt, 1H, J = 5.2, J = 5.3), 5.81 (d, 1H, J = 15.7), 6.73 (dd, 1H, J = 5.3, J = 15.7), 7.35 (d,
2 ArH, J = 8.1), 7.61 (s, 1H, NH), 7.91 (d, 2 ArH, J = 8.1); 13C NMR: 14.1, 21.9, 22.6, 27.0, 33.8, 52.2, 75.7,
121.6, 128.6, 130.0, 136.3, 145.3, 145.4, 150.6, 167.0; GC-MS (EI, 70 eV): 369 (M+), 214, 155, 91. Anal.
Calcd for C17H23NO6S: C, 55.27; H, 6.28; N, 3.79. Found: C, 55.24; H, 6.31; N, 3.81.
Ethyl (E)-4-phenyl-4-p-toluenesulfonylaminocarbonyloxy-2-butenoate (2b).
Starting from compound (3b), the title compound was prepared in 85% yield as a colorless oil. IR (CHCl3):
3349, 1746, 1712 cm-1; 1H NMR: 1.25 (t, 3H, J = 7.0), 2.38 (s, 3H), 4.18 (q, 2H, J = 7.0), 5.99 (dd, 1H, J =
1.6, J = 15.6), 6.25 (dd, 1H, J = 1.6, J = 5.0), 6.91 (dd, 1H, J = 5.0, J = 15.6), 7.12 - 7.32 (m, 7 ArH), 7.87
(d, 2 ArH, J = 8.3); 13C NMR: 14.6, 22.0, 61.4, 77.1, 122.3, 127.7, 128.6, 129.3, 129.4, 130.1, 136.2, 136.6,
144.3, 145.4, 150.4, 166.6; GC-MS (EI, 70 eV): 403 (M+), 246, 155, 91. Anal. Calcd for C20H21NO6S: C,
59.54; H, 5.25; N, 3.47. Found: C, 59.50; H, 5.27; N, 3.44.
(E)-1-Benzenesulfonyl-3-p-toluenesulfonylaminocarbonyloxy-1-butene (2c).

HETEROCYCLES, Vol. 60, No. 5, 2003
1179
Starting from compound (3c), the title compound was prepared in 82% yield as a colorless oil. IR (CHCl3):
3347, 1746 cm-1; 1H NMR: 1.32 (d, 3H, J = 6.8), 2.45 (s, 3H), 5.41 (ddq, 1H, J = 6.8, J = 4.1, J = 1.6), 6.45
(dd, 1H, J = 15.1, J = 1.6), 6.82 (dd, 1H, J = 15.1, J = 4.1), 7.30 (d, 2 ArH, J = 8.2), 7.49 - 7.68 (m, 4H, 3
ArH + NH), 7.74 - 7.93 (m, 4 ArH); 13C NMR: 22.2. 71.3, 126.8, 128.3, 128.5, 128.7, 128.8, 129.7, 129.9,
130.2, 131.1, 134.2, 140.0, 143.7, 145.7, 150.0, 169.3; GC-MS (EI, 70 eV): 409 (M+), 254, 208, 155, 125,
91, 77. Anal. Calcd for C18H19NO6S2: C, 52.80; H, 4.68; N, 3.42. Found: C, 52.77; H, 4.65; N, 3.45.
Benzyl (E)-4-p-toluensulfonylaminocarbonyloxy-2-hexenoate (2d).
Starting from compound (3d), the title compound was prepared in 86% yield as a colorless oil. IR (CHCl3):
1
3347 cm-1; H NMR: 0.83 (t, 3H, J = 7.4), 1.53 - 1.76 (m, 2H), 2.40 (s, 3H), 5.17 (s, 2H), 5.18 - 5.29 (m,
1H), 5.83 (dd, 1H, J = 1.5, J = 15.8), 6.77 (dd, 1H, J = 5.2, J = 15.8), 7.31 (d, 2 ArH, J = 8.1), 7.36 (m, 5
13
ArH), 7.89 (d, 2 ArH, J = 8.1), 7.98 (s, 1H, NH); C NMR: 9.5, 22.1, 67.1, 77.0, 122.2, 128.8, 129.0,
129.1, 130.2, 135.9, 136.1, 145.0, 145.7, 150.5, 166.2; GC-MS (EI, 70 eV): 417 (M+), 262, 202, 170, 155,
91, 77. Anal. Calcd for C21H23NO6S: C, 60.42; H, 5.55; N, 3.36. Found: C, 60.38; H, 5.57; N, 3.33.
(E)-1-Benzenesulfonyl-3-p-toluenesulfonylaminocarbonyloxy-1-propene (2e).
Starting from compound (3e), the title compound was prepared in 88% yield as a white solid. mp 69-71 °C
(ethyl acetate); IR (CHCl3): 3335, 1744 cm-1; 1H NMR: 2.37 (s, 3H), 4.69 (dd, 2H, J = 2.0, J = 3.7), 6.46
(dt, 1H, J = 2.0, J = 15.1), 6.82 (dt, 1H, J = 3.7, J = 15.1), 7.24 (d, 2 ArH, J = 8.9), 7.46 - 7.65 (m, 3 ArH),
7.74 - 7.84 (m, 4 ArH); 13C NMR: 22.0, 63.4, 128.1, 128.4, 129.9, 130.0, 131.7, 134.2, 136.3, 139.3, 139.9,
145.3, 151.1; GC-MS (EI, 70 eV): 395 (M+), 240, 155, 91. Anal. Calcd for C17H17NO6S2: C, 51.63; H,
4.33; N, 3.54. Found: C, 51.58; H, 4.28; N, 3.50.
Benzyl (E)-4-p-toluenesulfonylaminocarbonyloxy-2-butenoate (2f).
Starting from compound (3e), the title compound was prepared in 92% yield as a colorless oil. IR (CHCl3):
3343, 1745, 1704 cm-1; 1H NMR: 2.42 (s, 3H), 4.74 (dd, 2H, J = 1.9, J = 4.6), 5.18 (s, 2H), 5.95 (dt, 1H, J
= 1.9, J = 15.8), 6.86 (dt, 1H, J = 4.6, J = 15.8), 7.35 (d, 2 ArH, J = 8.4), 7.37 (m, 5 ArH), 7.63 (br s, 1H,
NH), 7.92 (d, 2 ArH, J = 8.4); 13C NMR: 22.2, 65.0, 67.1, 122.9, 128.8, 129.1, 130.2, 135.7, 136.1, 140.9,
145.8, 150.5, 165.9; GC-MS (EI, 70 eV): 389 (M+), 234, 155, 91. Anal. Calcd for C19H19NO6S: C, 58.60;
H, 4.92; N, 3.60. Found: C, 58.55; H, 4,87; N, 3.65.
Preparation of oxazolidin-2-ones (1a-f). General procedure.
To a solution containing compounds (2a-f) (5 mmol) in dichloromethane (50 mL) DBU (0.3 mL) was
added and the mixture was stirred for 12 h. Most of the solvent was removed under reduced pressure, ethyl

1180
HETEROCYCLES, Vol. 60, No. 5, 2003
acetate (150 mL) was added and the organic phase was washed with 1 M HCl (50 mL) and subsequently
with water (100 mL). After drying (Na2SO4), the solvent was removed under reduced pressure and the
residue was purified by silica gel chromatography (cyclohexane:ethyl acetate 70:30), to give the pure
oxazolidin-2-ones (1a-f).
Methyl trans-(5-butyl-3-p-toluenesulfonyl-1,3-oxazolidin-2-on-4-yl)acetate (1a).
Starting from 2a, the title compound was prepared in 76% yield as a colorless oil. IR (CHCl3): 1748, 1740
cm-1; 1H NMR: 0.83 (t, 3H, J = 6.3), 1.14 - 1.41 (m, 4H), 1.42 - 1.73 (m, 2H), 2.44 (s, 3H), 2.78 (dd, 1H, J
= 9.5, J = 16.9), 3.16 (dd, 1H, J = 3.2, J = 16.9), 3.68 (s, 3H), 4.26 (dt, 1H, J = 4.9, J = 2.9), 4.33 (ddd, 1H,
J = 2.9, J = 3.2, J = 9.5), 7.37 (d, 2 ArH, J = 8.2), 7.94 (d, 2 ArH, J = 8.2); 13C NMR: 14.2, 22.2, 22.6, 26.3,
34.8, 38.9, 52.6, 58.4, 80.8, 128.8, 128.9, 129.0, 130.3, 135.2, 146.3, 151.9, 170.5; GC-MS (EI, 70 eV):
369 (M+), 214, 155, 91. Anal. Calcd for C17H23NO6S: C, 55.27; H, 6.28; N, 3.79. Found: C, 55.31; H, 6.24;
N, 3.75.
Ethyl trans-(5-phenyl-3-p-toluenesulfonyl-1,3-oxazolidin-2-on-4-yl)acetate (1b).
Starting from 2d, the title compound was prepared in 88% yield as a white solid. mp 78-80 °C (ethyl
acetate); IR (CHCl3): 1748, 1741 cm-1; 1H NMR: 1.28 (t, 3H, J = 7.1), 2.45 (s, 3H), 2.98 (dd, 1H, J = 9.8,
J = 17.1), 3.22 (dd, 1H, J = 3.5, J = 17.1), 4.57 (ddd, 1H, J = 2.6, J = 3.5, J = 9.8), 5.34 (d, 1H, J = 2.6), 7.12
- 7.38 (m, 7 ArH), 7.81 (d, 2 ArH, J = 8.4); 13C NMR: 14.6, 22.2, 39.1, 61.8, 61.9, 80.6, 125.5, 127.8, 128.6,
128.8, 129.5, 130.1, 130.3, 134.8, 137.9, 143.7, 146.3, 152.1, 170.2; GC-MS (EI, 70 eV): 403 (M+), 248,
155, 91. Anal. Calcd for C20H21NO6S: C, 59.54; H, 5.25; N, 3.47. Found: C, 59.49; H, 5.29; N, 3.44.
Trans-3-p-toluenesulfonyl-4-benzenesulfonylmethyl-5-methyl-1,3-oxazolidin-2-one (1c).
Starting from 2c, the title compound was prepared in 75% yield as a colorless oil. IR (CHCl3): 1748 cm-1;
1H NMR: 1.33 (d, 3H, J = 6.5), 2.46 (s, 3H), 3.50 (dd, 1H, J = 10.9, J = 13.6), 3.93 (dd, 1H, J = 2.1, J =
13.6), 4.28 (ddd, 1H, J = 2.1, J = 2.4, J = 10.9), 4.93 (dq, 1H, J = 6.5, J = 2.4), 7.32 (d, 2 ArH, J = 8.2), 7.62
- 7.75 (m, 3 ArH), 7.67 - 7.75 (m, 2 ArH), 7.96 (d, 2 ArH, J = 8.2); 13C NMR: 22.0, 22.2, 58.4, 58.9, 76.9,
126.9, 128.4, 129.6, 129.9, 130.2, 130.3, 130.6, 134.3, 135.2, 139.1, 146.8, 151.2; GC-MS (EI, 70 eV): 409
(M+), 254, 155, 91. Anal. Calcd for C18H19NO6S2: C, 52.80: H, 4.68; N, 3.42. Found: C, 52.74; H, 4.64; N,
3.45.
Benzyl trans-(5-ethyl-3-p-toluenesulfonyl-1,3-oxazolidin-2-on-4-yl)acetate (1d).
Starting from 2d, the title compound was prepared in 78% yield as a colorless oil. IR (CHCl3): 1746, 1741
cm-1; 1H NMR: 0.85 (t, 3H, J = 7.3), 1.49 - 1.73 (m, 2H), 2.42 (s, 3H), 2.83 (dd, 1H, J = 9.6, J = 17.0), 3.20

HETEROCYCLES, Vol. 60, No. 5, 2003
1181
(dd, 1H, J = 3.3, J = 17.0), 4.22 (ddd, 1H, J = 3.0, J = 4.8, J = 7.4), 4.37 (ddd, 1H, J = 3.0, J = 3.3, J = 9.6),
5.12 (ABq, 2H, J = 12.1), 7.35 (d, 2 ArH, J = 8.4), 7.36 (m, 5 ArH), 7.92 (d, 2 ArH, J = 8.4); 13C NMR: 8.8,
22.2, 28.2, 39.0, 58.1, 67.5, 81.8, 128.8, 129.0, 129.1, 129.2, 130.0, 130.4, 130.6, 135.2, 135.6, 146.3,
152.0, 169.9; GC-MS (EI, 70 eV): 417 (M+), 162, 155, 91. Anal. Calcd for C21H23NO6S: C, 60.42: H, 5.55;
N, 3.36. Found: C, 60.37; H, 5.51; N, 3.40.
3-p-Toluenesulfonyl-4-benzenesulfonylmethyl-1,3-oxazolidin-2-one (1e).
Starting from 2e, the title compound was prepared in 75% yield as a white solid. mp 75-77 °C (ethyl
acetate); IR (CHCl3): 1744 cm-1; 1H NMR: 2.45 (s, 3H), 3.49 (dd, 1H, J = 10.5, J = 13.7), 4.12 (dd, 1H, J =
2.0, J = 13.7), 4.48 - 4.76 (m, 3H), 7.28 - 7.39 (m, 3 ArH), 7.62 - 7.85 (m, 4 ArH), 7.96 (d, 2 ArH, J = 6.8);
13C NMR: 22.2, 52.4, 59.2, 67.9, 126.9, 128.4, 128.9, 130.2, 130.3, 130.5, 135.2, 139.0, 143.5, 146.9;
GC-MS (EI, 70 eV): 395 (M+), 240, 155, 91. Anal. Calcd for C17H17NO6S2: C, 51.63; H, 4.33; N, 3.54.
Found: C, 51.58; H, 4.39; N, 3.51.
Benzyl (3-p-toluenesulfonyl-1,3-oxazolidin-2-on-4-yl)acetate (1f).
Starting from 2f, the title product was obtained in 78% yield as a colorless oil. IR (CHCl3): 1751 cm-1; 1H
NMR: 2.44 (s, 3H), 2.83 (dd, 1H, J = 9.7, J = 17.1), 3.35 (dd, 1H, J = 3.3, J = 17.1), 4.13 (dd, 1H, J = 4.4,
J = 9.2), 4.51 (dd, 1H, J = 8.9, J = 9.2), 4.75 (dddd, 1H, J = 3.3, J = 4.4, J = 8.9, J = 9.7), 5.13 (ABq, 2H, J
= 12.2), 7.35 (d, 2 ArH, J = 8.4), 7.37 (m, 5 ArH), 7.93 (d, 2 ArH, J = 8.4); 13C NMR: 22.2, 39.0, 53.7, 67.5,
68.6, 128.9, 129.1, 129.2, 130.4, 135.0, 135.6, 146.4, 152.6, 170.0; GC-MS (EI, 70 eV): 389 (M+), 234,
155, 91. Anal. Calcd for C19H19NO6S: C, 58.60; H, 4.92; N, 3.60. Found: C, 58.55; H, 4.86; N, 3.65.
(R,S)-3-Amino-4-hydroxybutanoic acid (5).
In a flask under inert atmosphere NH3 (about 50 mL) was condensed at -78 °C and then Li (210 mg; 30
mmol) was added. When the metal dissolved in NH3, a solution containing 1f (1.9 g; 5 mmol) in
THF-t-BuOH 9:1 (20 mL) was quickly added. After 15 min NH3 was removed , H2O (15 mL) was slowly
dropped and then the mixture was extracted with ethyl acetate (2 x 50 mL). To the solution NaOH (1.5 g)
was added and the mixture was heated under reflux for 12 h. After removal of the H2O under reduced
pressure, the residue was redissolved in H2O (5 mL) and the solution was adsorbed on ion-exchange resin
Dowex AG 50W-X2. The resin was washed with distilled water and then eluted with 1 M NH4OH to give
1
the compound (5) (0.3 g; 52%) as a white solid. mp 223-225 °C (methanol) (lit.,24 228 °C); H NMR
(CD3OD + NaOH): 2.17 (dd, 1H, J = 8.1, J = 16.6), 2.34 (dd, 1H, J = 5.1, J = 16.6), 3.09 - 3.22 (m, 1H),
13
3.39 (dd, 1H, J = 6.7, J = 10.7), 3.54 (dd, 1H, J = 4.8, J = 10.7), 4.96 (br s, 3H, OH + NH2); C NMR
(CD3OD + NaOH): 43.3, 52.2, 67.7, 180.6; MS (EI): 120 (M+ +1), 84. Anal. Calcd for C4H9NO3: C, 40.33;

1182
HETEROCYCLES, Vol. 60, No. 5, 2003
H, 7.62; N, 11.76. Found: C, 40.29; H, 7.59; N, 11.79.
ACKNOWLEDGEMENTS
M.I.U.R., Italy, is acknowledged for financial support within PRIN 2000 project.
REFERENCES AND NOTES
1. M. P. Georgiadis and E. A. Couladouros, J. Heterocycl. Chem., 1990, 27, 1757.
2. M. Hirama and S. Ito, Heterocycles, 1989, 28, 1229.
3. H.A. Bates, L. Smilowitz, and S. B. Rosenblum, J. Chem. Soc., Chem. Commun., 1985, 353.
4. M. Hirama, T. Shigemoto, and S. Ito, J. Org. Chem., 1987, 52, 3342.
5. K. Shishido, Y. Sukegawa, K. Fukumoto, and T. Kametani, J. Chem. Soc., Perkin Trans. I, 1987, 993.
6. B. W. Bycroft and S. R. Chabra, J. Chem. Soc., Chem. Commun., 1989, 423.
7. M. Hirama, H. Hioki, S. Ito, and C. Kabuto, Tetrahedron Lett., 1988, 29, 3121. M. Hirama, H. Hioki,
and S. Ito, Tetrahedron Lett., 1988, 29, 3125.
8. E. Dominguez and J. C. Carretero, Tetrahedron, 1990, 46, 7197. J. C. Carretero and E. Dominguez, J.
Org. Chem., 1992, 57, 3867.
9. M. Hirama, T. Shigemoto, Y. Yamazaki, and S. Ito, J. Am. Chem. Soc., 1985, 107, 1797.
10. G. Cardillo, M. Orena, M. Penna, S. Sandri, and C. Tomasini, Synlett, 1990, 543.
11. R. Galeazzi, G. Mobbili, and M. Orena, Tetrahedron, 1996, 52, 1069.
12. R. Galeazzi, S. Geremia, G. Mobbili, and M. Orena, Tetrahedron: Asymmetry, 1996, 7, 79.
13. R. Galeazzi, S. Geremia, G. Mobbili, and M. Orena, Tetrahedron: Asymmetry, 1996, 7, 3573.
14. R. Galeazzi, G. Mobbili, and M. Orena, Tetrahedron: Asymmetry, 1997, 8, 133.
15. R. Galeazzi, G. Mobbili, and M. Orena, Tetrahedron, 1999, 55, 261. R. Galeazzi, G. Mobbili, and M.
Orena, Tetrahedron, 1999, 55, 4029. J. M. Jordá-Gregori, M. E. González-Rosende, J.
Sepúlveda-Arques, R. Galeazzi, and M. Orena, Tetrahedron: Asymmetry, 1999, 10, 1135.
16. C. Fava, R. Galeazzi, M. E. González-Rosende, and M. Orena, Tetrahedron Lett., 2000, 41, 8577.
17. J. M. Jordá-Gregori, M. E. González-Rosende, P. Cava-Montesinos, J. Sepúlveda-Arques, R.
Galeazzi, and M. Orena, Tetrahedron: Asymmetry, 2000, 11, 3769.
18. T. Shiba, T. Wakamiya, T. Teshima, and S. Nomoto, Pept. Chem., 1977, 127.
19. T. Shiba, T. Wakamiya, T. Teshima, and T. Kaneko, Bull. Chem. Soc. Jpn, 1972, 45, 3668.
20. Y. Shimoijma, H. Hayashi, T. Ooka, and M. Shibukawa, Tetrahedron, 1984, 40, 2519.
21. J. Itoh, S. Omoto, T. Shomura, N. Nishizawa, S. Miyado, Y. Yuda, U. Shibata, and S. Inouye, J.
Antibiotics, 1981, 34, 611.

HETEROCYCLES, Vol. 60, No. 5, 2003
1183
22. Y. Shimojima, T. Shirai, T. Baba, and H. Hayashi, J. Med. Chem., 1985, 28, 3.
23. G. Delle Monache, D. Misiti, P. Salvatore, and G. Zappia, Tetrahedron: Asymmetry, 2000, 11, 1137.
24. K. Nagai, R. Tanaka, H. Murakami, and A. Sano, Arzneim. Forsch., 1967, 17, 1575.
25. K. Nagai, Arzneim. Forsch., 1970, 20, 1608.
26. Y. B. Kim, Arch. Pharmacol. Res., 1985, 8, 1.
27. S. H. Rosenberg, K. W. Woods, H. D. Kleinert, H. Stein, H. N. Nellans, D. J. Hoffman, S. G. Spanton,
R. A. Pyter, J. Cohen, D. A. Egan, J. J. Plattner, and T. J. Perun, J. Med. Chem., 1989, 32, 1371.
28. R. Hirose, N. Hamamichi, Y. Kitao, T. Matsuzaki, K. Chiba, and T. Fujita, Bioorg. Med. Chem. Lett.,
1996, 6, 2647.
29. M. Orena, G. Porzi, and S. Sandri, J. Chem. Res. (S), 1990, 376; (M), 1990, 2701.
30. During the preparation of alkenols (3), a base-induced rearrangement was observed (see: D. M.
Hodgson, L. A. Robinson, and M. L. Jones, Tetrahedron Lett., 1999, 40, 8637, and references cited
therein). In fact, when the epoxides (Ia,b) were treated with a catalytic amount of DBU, the
corresponding hydroxy compounds were not observed at all, the 4-oxo derivatives (IIa,b) being the
sole products, probably owing to the acidity of the benzylic hydrogen. IIa: IR (CHCl3): 1745, 1697
cm-1; 1H NMR (200 MHz; CDCl3): 2.74 (t, 2H, J = 6.5), 3.32 (t, 2H, J = 6.5), 3.71 (s, 3H), 7.41 - 7.62
(m, 3 ArH), 7.94 - 8.04 (m, 2 ArH); 13C NMR (50 MHz; CDCl3): 28.5, 33.9, 52.3, 128.5, 129.1, 133.7,
137.0, 173.8, 198.5. IIb: IR (CHCl3): 1698 cm-1. 1H NMR (200 MHz; CDCl3): 3.43 - 3.61 (m ,4H),
7.38 - 7.71 (m, 6 ArH), 7.74 - 7.99 (m, 4 ArH); 13C NMR (50 MHz; CDCl3): 31.9, 51.5, 128.4, 128.5,
129.0, 129.3, 129.6, 129.9, 134.3, 134.4, 136.3, 139.5, 195.9.
O
O
O
DBU
X
X
X
I
II
a. X = COOMe, b. X = SO2Ph
31. S. J. Kemp, J. Bao, and S. F. Pedersen, J. Org. Chem., 1996, 61, 7162.
32. D. D. Dhavale, L. Gentilucci, M. G. Piazza, and C. Trombini, Liebigs Ann. Chem., 1992, 1289.
33. S. Futagawa, T. Inui, and T. Shiba, Bull. Chem. Soc. Jpn., 1973, 46, 3308.
34. T. A. Foglia and D. Swern, J. Org. Chem., 1969, 34, 1680.
35. I. A. Reed III, P. A. Risbood, and L. Goodman, J. Chem. Soc., Perkin Trans. I, 1980, 2516.