Stereoselective synthesis of α-substituted serines from protected erythrulose oximes

Article abstract of DOI:10.1016/S0957-4166(98)00146-3

The additions of organolithium reagents to the C=N bond of several chiral oxime ethers derived from erythrulose afforded protected amino polyols with high diastereoselectivity. Four of the latter compounds have been convened into the α,α-disubstituted α-amino acids (R)-2-(-)-methylserine, (S)-2-(+)-methylserine, (R)-(+)-2-phenylserine and (R)-(-)-2-n-butylserine.

Full text of DOI:10.1016/S0957-4166(98)00146-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1703–1712
Stereoselective synthesis of α-substituted serines from protected
erythrulose oximes
M. Carda,a,∗ J. Murga,a S. Rodríguez,a F. González,a E. Castillo a and J. A. Marco b,∗
aDepart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón, E-12080 Castellón, Spain
bDepart. de Q. Orgánica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
Received 3 March 1998; accepted 7 April 1998
Abstract
The additions of organolithiumreagents to the C_N bond of several chiral oxime ethers derived from erythrulose
afforded protected amino polyols with high diastereoselectivity. Four of the latter compounds have been converted
into the α,α-disubstituted α-amino acids (R)-2-(−)-methylserine, (S)-2-(+)-methylserine, (R)-(+)-2-phenylserine
and (R)-(−)-2-n-butylserine. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Amino polyols1 and non-proteinaceous amino acids2 are two types of nitrogen-containing com-
pounds of particular biological relevance. The latter are secondary metabolites occurring in many living
organisms3 and also constitute part of the structure of many peptidic antibiotics.4 Furthermore, they are
used for the synthesis of modified peptides, which display useful properties as enzyme inhibitors and
peptidomimetics.5 Among the non-proteinaceous amino acids, α,α-disubstituted α-amino carboxylic
acids, which contain a nitrogen bound to a quaternary carbon atom, have attracted particular interest.6
Peptides which incorporate this type of amino acid are characterized by a higher conformational rigidity
and by an enhanced stability towards hydrolysis.6–8 There are not many methods of preparing such
compounds in enantiopure form. Most of them rely on the alkylation of chiral amino acid enolate
equivalents.9 This fact places some limits on their applicability, as certain α-amino acids, such as
those with α-tert-alkyl or α-aryl substituents, cannot be easily prepared in this way. Other methods
include aldol reactions with amino ester enolates,10 stereoselective rearrangements,11 ring-opening of
suitably substituted β-lactams,7g,12 enzymatic resolutions,13 etc. Very few procedures, aside from the
Strecker reaction and its variants,14 rely on stereoselective additions of carbon nucleophiles to C_N
bonds.15 We have shown that the additions of organolithium reagents to chiral ketoxime ethers (E)/(Z)-2
∗
Corresponding authors. E-mail: alberto.marco@uv.es
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00146-3

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(R1–R3=protecting groups) prepared from L-erythrulose derivatives of general formula 1 (Eq. 1), often
take place with high stereocontrol to yield the diastereoisomeric, differentially protected amino polyols
3 and/or 4 (Eq. 2).16 These amino alcohols can then be converted through standard synthetic manipu-
lations into enantiopure amino polyols and α,α-disubstituted α-amino acids, including those not easily
available by previous methodologies. In the present paper, we describe in full the preparation of the α,α-
disubstituted α-amino acids (R)-2-(−)-methylserine, (S)-2-(+)-methylserine, (R)-(+)-2-phenylserine and
(R)-(−)-2-n-butylserine by means of this methodology.
2. Results and discussion
The starting materials were protected amino polyols 3 (R=Me, nBu, Ph) obtained with a high
diastereoisomeric ratio (d.r. >95:5) by addition of the corresponding organolithium reagents to oximes
(E)-2.16
(1)
(2)
Various protecting groups R1–R3 have been used for this purpose. Amino polyol acetonides 3 (R1,
R2=acetonide and R3=tert-butyldiphenylsilyl, TPS, or trityl, Tr) with R=Me, nBu and Ph, obtained with
a high d.r. from the appropriate oximes (E)-2,16 were selected for transformation into α-substituted
serines.17 In the case of (R)-2-(−)-methylserine, for instance, compounds (−)-5a/(−)-5b were the starting
materials.
Desilylation of (−)-5a, as well as detritylation of (−)-5b, provided the protected amino polyol (−)-
6,16b which still contained a small amount of the minor stereoisomer. Treatment of the latter with
carbonyldiimidazole (CDI) afforded oxazolidinone (−)-7 and its minor stereoisomer, which could
now be separated by chromatography on silica gel. Acetonide cleavage catalyzed by pyridinium p-

M. Carda et al. / Tetrahedron: Asymmetry 9 (1998) 1703–1712
1705
toluenesulphonate (PPTS) gave diol (+)-8, which was then oxidized via a two-step procedure18 to acid
9a, isolated and purified as the methyl ester (−)-9b. Basic hydrolysis removed both the oxazolidinone
and methyl ester groups and furnished N-benzyloxy amino acid (−)-10. Reductive cleavage of the N–O
bond was best achieved via hydrogenolysis with a Pd/C catalyst to yield (R)-2-methylserine (−)-11.
Physical and spectral data of the obtained product (see Experimental) were essentially coincident with
those reported in the literature.9a,b,12a,14a
The amino acids (R)-2-n-butylserine (−)-18 and (R)-2-phenylserine (+)-25 were prepared along the
same lines as for the synthesis of (−)-11. The only difference was the means of cleavage of the acetonide
moiety, which was performed by transacetalization with ethanedithiol and p-toluenesulphonic acid.19
The preparation of (R)-2-n-butylserine has not been previously described in the literature. The amino
acid 2-phenylserine has previously been described only in racemic form,20 although a derivative with
unknown configuration was obtained with 67% enantiomeric excess via a metal-catalyzed process.21
The methodology described in this paper does not only allow the synthesis of serine derivatives with
the (R)-configuration. Their antipodes with the opposite (S)-configuration may also be obtained by using
D-erythrulose precursors as the starting materials.22 Therefore, we also synthesized (S)-2-methylserine

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(+)-11 from compound (+)-5a by the same series of reactions described above for (−)-11. Compound
(+)-5a was in turn prepared in two steps16b from the D-erythrulose derivative (+)-26.22
The methodology we have described above is therefore very useful for the preparation of many
types of α,α-disubstituted α-amino acids in enantiopure form, including those not easily available by
alternative procedures. Furthermore, the protected amino polyols obtained with this procedure possess
several hydroxyl groups, a fact which opens the way to the synthesis of other biologically relevant,
polyfunctionalized compounds, such as polyhydroxylated amino acids,23 diamino acids,24 N-hydroxy
amino acids,25 and branched aminosugars.26 Finally, since D-erythrulose derivatives are also easily
available,22 all these compounds can be prepared in either antipodal form. Further research in these
directions is in progress.
3. Experimental
For general experimental details, see the preceeding article.16b All obtained products gave satisfactory
microanalytical data (C, H, ꢀ0.5%).
3.1. (4R)-3-Benzyloxy-4-methyl-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,3-oxazolidin-2-one, (−)-7
Amino alcohol (−)-616b (1.406 g, 5 mmol) was dissolved in dry benzene (40 ml) and treated with
CDI (973 mg, 6 mmol). The reaction mixture was heated at reflux under Ar for 4 h. Work-up (Et2O)
and column chromatography (hexane:EtOAc=4:1) afforded (−)-7 (1.25 g, 81%) together with its minor
diastereomer (100 mg, ca. 6%). Oxazolidinone (−)-7 was isolated as a white solid, mp 99–100°C, [α]D
−7.2 (CHCl3, c 1); IR νmax cm−1: 1782 (C_O); EIMS, m/z 307.1411 (M+). Calcd for C16H21NO5,
1
M=307.1420; H NMR: δ 7.45–7.30 (5H, m, arom.), 5.01, 4.95 (2H, AB system, J=11 Hz, NOCH2Ph),
4.31 (1H, d, J=8.5 Hz, H-5a), 4.21 (1H, dd, J=7.2, 5.5 Hz, H-40), 3.96 (1H, dd, J=9, 7.2 Hz, H-50 ),
a
3.86 (1H, d, J=8.5 Hz, H-5b), 3.67 (1H, dd, J=9, 5.5 Hz, H-50 ), 1.41, 1.29 (2×3H, 2×s, acetonide Me),
b
0.98 (3H, s, MeC4); 13C NMR: δ 158.5 (C-2), 135.3 (arom. C), 129.9, 128.9, 128.5 (arom. CH), 109.8
(acetonide C), 78.6 (NOCH2Ph), 76.0 (C-40), 68.8 (C-5), 68.4 (C-50), 63.4 (C-4), 25.9, 24.3 (2×acetonide
Me), 17.1 (MeC4). Primed numbers in NMR data correspond to atoms of the dioxolane ring. Anal. calcd
for C16H21NO5: C, 62.53; H, 6.89; N, 4.56. Found: C, 62.63; H, 7.00; N, 4.31.

M. Carda et al. / Tetrahedron: Asymmetry 9 (1998) 1703–1712
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3.2. (4S)-3-Benzyloxy-4-methyl-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,3-oxazolidin-2-one, (+)-7
Obtained from amino alcohol (+)-616b under the same conditions as for (−)-7: [α]D +7 (CHCl3, c 1.8).
The other physical properties are identical to those of (−)-7. Anal. calcd for C16H21NO5: C, 62.53; H,
6.89; N, 4.56. Found: C, 62.75; H, 6.96; N, 4.44.
3.3. (4R)-3-Benzyloxy-4-methyl-4-[(1R)-1,2-dihydroxyethyl]-1,3-oxazolidin-2-one, (+)-8
Oxazolidinone (−)-7 (1.23 g, 4 mmol) and PPTS (50 mg, 0.2 mmol) were dissolved in a 9:1
MeOH:H2O mixture (20 ml) and heated at reflux for 12 h. Work-up16b and column chromatography
(hexane:EtOAc=1:1) afforded (+)-8 (987 mg, 92%) as a white solid, mp 118–120°C, [α]D +17.4
(MeOH, c 2.7); IR νmax cm−1: 3400 (br, OH), 1764 (C_O); FABMS, m/z 268.1183 (M+H+). Calcd
1
for C13H18NO5, M=268.1185; H NMR: δ 7.45–7.30 (5H, m, arom.), 5.04, 4.95 (2H, AB system,
J=11 Hz, NOCH2Ph), 4.43 (1H, d, J=8.8 Hz, H-5), 3.86 (1H, d, J=8.8 Hz, H-50), 3.65–3.40 (3H, m,
CH2OHCHOH), 2.50 (2H, br s, 2 OH), 1.15 (3H, s, MeC4); 13C NMR: δ 159.4 (C-2), 135.3 (arom. C),
130.0, 129.3, 128.8 (arom. CH), 77.9 (NOCH2Ph), 71.6 (CHOH), 68.5 (C-5), 65.7 (C-4), 62.1 (CH2OH),
18.2 (MeC4). Anal. calcd for C13H17NO5: C, 58.42; H, 6.41; N, 5.24. Found: C, 58.63; H, 6.60; N, 5.31.
3.4. (4S)-3-Benzyloxy-4-methyl-4-[(1S)-1,2-dihydroxyethyl]-1,3-oxazolidin-2-one, (−)-8
Obtained from oxazolidonone (+)-7 under the same conditions as for (+)-8: [α]D −16.8 (MeOH, c
2.2). The other physical properties are identical to those of (+)-8. Anal. calcd for C13H17NO5: C, 58.42;
H, 6.41; N, 5.24. Found: C, 58.55; H, 6.30; N, 5.11.
3.5. (4R)-3-Benzyloxy-4-methyl-4-methoxycarbonyl-1,3-oxazolidin-2-one, (−)-9b
Diol (+)-8 (962 mg, 3.6 mmol) was dissolved in THF (10 ml) and treated with a solution of NaIO4
(1.54 g, 7.2 mmol) in water (2 ml). The reaction mixture was stirred at room temperature for 2 h. Work-up
(EtOAc) afforded an oily material which was dissolved in tBuOH (70 ml) and treated successively with 2-
methyl-2-butene (20 ml), 25% aqueous NaClO2 (13 ml, ca. 36 mmol) and NaH2PO4 (3.8 g). The reaction
mixture was stirred at room temperature for 12 h. Work-up (EtOAc) afforded an oily material which was
directly esterified with ethereal diazomethane. Solvent removal in vacuo and column chromatography
(hexane:EtOAc=4:1) provided (−)-9b (716 mg, 75% overall) as an oil, [α]D −9.4 (CHCl3, c 1.7); IR
νmax cm−1: 1793, 1747 (C_O); EIMS, m/z 266.1027 (M+H+, 1), 206 (M+−COOMe, 30), 100 (45), 91
1
(100). Calcd for C13H16NO5, M=266.1028; H NMR: δ 7.45–7.30 (5H, m, arom.), 5.06, 4.99 (2H, AB
system, J=10.7 Hz, NOCH2Ph), 4.31 (1H, d, J=9 Hz, H-5), 4.00 (1H, d, J=9 Hz, H-50), 3.77 (3H, s,
OMe), 1.36 (3H, s, MeC4); 13C NMR: δ 170.4 (ester C_O), 157.9 (C-2), 135.1 (arom. C), 129.8, 128.9,
128.4 (arom. CH), 78.8 (NOCH2Ph), 69.5 (C-5), 65.4 (C-4), 53.2 (OMe), 18.3 (MeC4). Anal. calcd for
C13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C, 58.59; H, 5.55; N, 5.15.
3.6. (4S)-3-Benzyloxy-4-methyl-4-methoxycarbonyl-1,3-oxazolidin-2-one, (+)-9b
Obtained from diol (−)-8 under the same conditions as for (−)-9b: [α]D +9.0 (CHCl3, c 1.8). The
other physical properties are identical to those of (−)-9b. Anal. calcd for C13H15NO5: C, 58.86; H, 5.70;
N, 5.28. Found: C, 58.67; H, 5.81; N, 5.35.

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3.7. (2R)-3-Hydroxy-2-(N-benzyloxyamino)-2-methylpropionic acid, (−)-10
Methyl ester (−)-9b (663 mg, 2.5 mmol) was dissolved in EtOH (10 ml) and treated with a 2 M
aqueous solution of sodium hydroxide (10 ml). The reaction mixture was stirred at room temperature for
12 h. After this time, most of the EtOH was removed in vacuo and the pH of the solution was adjusted
to 1 with 5 M aq HCl. Work-up (EtOAc) and column chromatography (EtOAc:MeOH=1:1) provided
(−)-10 (366 mg, 65%) as an oil, [α]D −5.4 (MeOH, c 0.2); IR νmax cm−1: 3300 (br, OH), 1591, 1414
(COO−); CIMS, m/z 194.0815 (M+−CH2OH). Calcd for C10H12NO3, M=194.0817; 1H NMR (CD3OD):
δ 7.40–7.20 (5H, m, arom.), 4.70 (2H, s, NOCH2Ph), 3.75 (1H, d, J=10.7 Hz, H-3), 3.63 (1H, d, J=10.7
Hz, H-30), 1.20 (3H, s, MeC2); 13C NMR (CD3OD): δ 181.0 (C-1), 139.3 (arom. C), 129.3, 129.2, 128.6
(arom. CH), 77.5 (NOCH2Ph), 67.4 (C-2), 65.9 (C-3), 19.0 (MeC2). Anal. calcd for C11H15NO4: C,
58.66; H, 6.71; N, 6.22. Found: C, 58.38; H, 6.56; N, 6.05.
3.8. (2S)-3-Hydroxy-2-(N-benzyloxyamino)-2-methylpropionic acid, (+)-10
Obtained from methyl ester (+)-9b under the same conditions as for (−)-10: [α]D +5.0 (MeOH, c 0.3).
The other physical properties are identical to those of (−)-10. Anal. calcd for C11H15NO4: C, 58.66; H,
6.71; N, 6.22. Found: C, 58.87; H, 6.76; N, 6.30.
3.9. (R)-(−)-2-Methyl serine, (−)-11
Pd/C catalyst (50 mg) was suspended in MeOH (3 ml) and stirred under an H2 atmosphere for 10
min. Acid (−)-10 (225 mg, 1 mmol) dissolved in MeOH (15 ml) was then injected via syringe. The
mixture was stirred under the H2 atmosphere at room temperature for 48 h. After this time, the catalyst
was removed by filtration and the solvent was removed in vacuo. Aqueous 1 M HCl was added to the
residue until pH 1. The solution was then evaporated to dryness and the residue was purified through
a Dowex 50WX8-400 column according to the described procedure.9b This yielded (R)-(−)-2-methyl
serine, (−)-11 (65 mg, 55%) as a white solid, mp 225–230°C (dec.), lit.9a mp 240–245°C (dec.), lit.12a
mp 235–245°C (dec.); [α]D −6.3 (H2O, c 1.1), lit.9a [α]D −5.8 (H2O, c 0.289), lit.12a [α]D −6.1 (H2O, c
0.9); IR νmax cm−1: 3400 (br, OH), 1650, 1450, 1410, 1380, 1275, 1088, 1050, 880; CIMS, m/z 120.0692
1
(M+H+). Calcd for C4H10NO3, M=120.0660; H NMR (D2O): δ 3.95 (1H, d, J=12 Hz, H-3), 3.70 (1H,
d, J=12 Hz, H-30), 1.45 (3H, s, Me-C2); 13C NMR (D2O): δ 177.2 (C-1), 66.3 (C-3), 63.1 (C-2), 19.9
(Me-C2).
3.10. (S)-(+)-2-Methyl serine, (+)-11
Obtained from acid (+)-10 under the same conditions as for (−)-11: [α]D +6.1 (H2O, c 0.9). The other
physical properties are identical to those of (−)-11.
3.11. (4R)-3-Benzyloxy-4-n-butyl-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,3-oxazolidin-2-one,
(−)-14
Obtained in 75% yield from amino alcohol (−)-1316b under the same conditions as for (−)-7: white
solid, mp 85–87°C, [α]D −8.5 (CHCl3, c 1.2); IR νmax cm−1: 1782 (C_O); CIMS, m/z 350.1971
1
(M+H+). Calcd for C19H28NO5, M=350.1967; H NMR: δ 7.40–7.30 (5H, m, arom.), 5.00 (2H, s,
NOCH2Ph), 4.27 (1H, d, J=8.8 Hz, H-5a), 4.24 (1H, dd, J=7, 6 Hz, H-40), 4.03 (1H, d, J=8.8 Hz,

M. Carda et al. / Tetrahedron: Asymmetry 9 (1998) 1703–1712
1709
H-5b), 3.95 (1H, dd, J=9, 7 Hz, H-50 ), 3.62 (1H, dd, J=9, 6 Hz, H-50 ), 1.60 and 1.30–1.15 (6H, m,
a
b
CH2CH2CH2), 1.43, 1.30 (2×3H, 2×s, acetonide Me), 0.85 (3H, t, J=7 Hz, MeCH2); 13C NMR: δ 158.4
(C-2), 135.3 (arom. C), 129.3, 128.7, 128.4 (arom. CH), 109.7 (acetonide C), 78.4 (NOCH2Ph), 76.4
(C-40), 65.9, 64.7 (C-5, C-50), 65.7 (C-4), 30.8 (CH2C3H7), 25.9, 24.4 (2×acetonide Me), 24.9, 22.9
(CH2CH2), 13.8 (MeCH2). Primed numbers in NMR data correspond to atoms of the dioxolane ring.
Anal. calcd for C19H27NO5: C, 65.31; H, 7.79; N, 4.01. Found: C, 65.40; H, 7.66; N, 4.14.
3.12. (4R)-3-Benzyloxy-4-n-butyl-4-[(1R)-1,2-dihydroxyethyl]-1,3-oxazolidin-2-one, (+)-15
Oxazolidinone (−)-14 (1.048 g, 3 mmol), 1,2-ethane dithiol (2.5 ml, ca. 30 mmol) and p-
toluenesulphonic acid monohydrate (19 mg, 0.1 mmol) were dissolved in dry CHCl3 (25 ml) and heated
at reflux for 2 h. Work-up (CH2Cl2) and column chromatography (hexane:EtOAc=1:1) furnished (+)-15
(753 mg, 81%) as a white solid, mp 74–76°C, [α]D +54.4 (CHCl3, c 1.7); IR νmax cm−1: 3400 (br,
1
OH), 1765 (C_O); FABMS, m/z 310.1642 (M+H+). Calcd for C16H24NO5, M=310.1655; H NMR:
δ 7.45–7.35 (5H, m, arom.), 5.10, 5.00 (2H, AB system, J=11.3 Hz, NOCH2Ph), 4.41 (1H, d, J=9
Hz, H-5), 3.96 (1H, d, J=9 Hz, H-50), 3.60 (1H, m, CH2OH), 3.40 (2H, m, CH2OH, CH2OH), 2.30,
2.10 (2H, 2×br s, 2×OH), 1.60–1.20 (6H, m, CH2CH2CH2), 0.89 (3H, t, J=7.2 Hz, Me); 13C NMR: δ
159.6 (C-2), 135.4 (arom. C), 129.8, 129.4, 128.9 (arom. CH), 77.3 (NOCH2Ph), 71.8 (CHOH), 67.9
(C-4), 66.7 (C-5), 62.0 (CH2OH), 32.5 (CH2C3H7), 24.9, 23.0 (CH2CH2), 13.9 (Me). Anal. calcd for
C16H23NO5: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.33; H, 7.46; N, 4.34.
3.13. (4R)-3-Benzyloxy-4-n-butyl-4-methoxycarbonyl-1,3-oxazolidin-2-one, (−)-16b
Obtained in 90% yield from diol (+)-15 under the same conditions as for (−)-9b: oil, [α]D −6.5
(CHCl3, c 1.3); IR νmax cm−1: 1790, 1746 (C_O); EIMS, m/z 308.1494 (M+H+, 1), 248 (M+–COOMe,
8), 142 (15), 91 (100). Calcd for C16H22NO5, M=308.1498; 1H NMR: δ 7.45–7.35 (5H, m, arom.), 5.10,
5.06 (2H, AB system, J=10.3 Hz, NOCH2Ph), 4.38 (1H, d, J=9 Hz, H-5), 4.16 (1H, d, J=9 Hz, H-50),
3.78 (3H, s, OMe), 1.85 (2H, m, CH2C3H7), 1.30–1.20 (4H, m, CH2CH2), 0.86 (3H, t, J=7 Hz, MeCH2);
13C NMR: δ 170.4 (ester C_O), 158.0 (C-2), 135.1 (arom. C), 129.5, 128.7, 128.4 (arom. CH), 78.7
(NOCH2Ph), 67.9 (C-4), 67.3 (C-5), 53.0 (OMe), 32.1 (CH2C3H7), 24.9, 22.7 (CH2CH2), 13.7 (Me).
Anal. calcd for C16H21NO5: C, 62.53; H, 6.89; N, 4.56. Found: C, 62.43; H, 7.01; N, 4.54.
3.14. (2R)-2-(N-Benzyloxyamino)-2-(hydroxymethyl)hexanoic acid, (+)-17
Obtained in 73% yield from methyl ester (−)-16b under the same conditions as for (−)-10: white
solid, mp 120–125°C (dec.), [α]D +1.7 (CHCl3, c 0.3); IR νmax cm−1: 3300 (br, OH), 1586, 1426, 1264,
1091, 874; FABMS, m/z 268.1538 (M+H+). Calcd for C14H22NO4, M=268.1549; 1H NMR (CD3OD): δ
7.40–7.20 (5H, m, arom.), 4.75, 4.71 (2H, AB system, J=11.5 Hz, NOCH2Ph), 3.79 (1H, d, J=10.7 Hz,
CH2OH), 3.67 (1H, d, J=10.7 Hz, CH2OH), 1.55 (2H, m, H-3), 1.40–1.20 (4H, m, H-4, H-5), 0.87 (3H,
t, J=7 Hz, H-6); 13C NMR (CD3OD): δ 180.5 (C-1), 139.0 (arom. C), 129.4, 129.3, 128.8 (arom. CH),
77.5 (NOCH2Ph), 70.9 (C-2), 64.2 (CH2OH), 31.6 (C-3), 26.9, 24.3 (C-4, C-5), 14.5 (C-6). Anal. calcd
for C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found: C, 62.83; H, 7.61; N, 5.46.

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M. Carda et al. / Tetrahedron: Asymmetry 9 (1998) 1703–1712
3.15. (R)-(−)-2-n-Butyl serine, (−)-18
Obtained in 50% yield from acid (+)-17 under the same conditions as for (−)-11: white solid, mp
225–232°C (dec.); [α]D −11.8 (H2O, c 0.3); IR νmax cm−1: 3300 (br, OH), 1625, 1449, 1092; FABMS,
1
m/z 162.1133 (M+H+). Calcd for C7H16NO3, M=162.1130; H NMR (D2O:CD3OD=4:1): δ 3.90 (1H,
d, J=11.5 Hz, CH2OH), 3.66 (1H, d, J=11.5 Hz, CH2OH), 1.80–1.60 (2H, m, CH2C3H7), 1.50–1.15 (4H,
m, CH2CH2), 0.87 (3H, t, J=7 Hz, Me); 13C NMR (D2O:CD3OD=4:1): δ 175.6 (C-1), 67.3 (C-2), 65.4
(CH2OH), 32.9 (C-3), 25.9, 23.0 (C-4, C-5), 13.9 (C-6). Anal. calcd for C7H15NO3: C, 52.16; H, 9.38;
N, 8.69. Found: C, 52.33; H, 9.60; N, 8.56.
3.16. (4R)-3-Benzyloxy-4-phenyl-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,3-oxazolidin-2-one,
(−)-21
Obtained in 93% yield from amino alcohol (−)-2016b under the same conditions as for (−)-7: white
solid, mp 90–92°C, [α]D −36.2 (CHCl3, c 1.4); IR νmax cm−1: 1788 (C_O); FABMS, m/z 370.1651
1
(M+H+). Calcd for C21H24NO5, M=370.1655; H NMR: δ 7.40–7.20 (10H, m, arom.), 5.07, 4.72 (2H,
AB system, J=10.2 Hz, NOCH2Ph), 4.94 (1H, dd, J=7.5, 4.8 Hz, H-40), 4.67 (1H, d, J=9 Hz, H-5a),
4.44 (1H, d, J=9 Hz, H-5b), 4.12 (1H, dd, J=9.3, 7.4 Hz, H-50 ), 3.65 (1H, dd, J=9.3, 4.8 Hz, H-50 ),
a
b
1.49, 1.35 (2×3H, 2×s, acetonide Me); 13C NMR: δ 158.3 (C-2), 136.8, 134.8 (arom. C), 129.3, 128.9,
128.6, 128.3, 126.9 (arom. CH), 110.4 (acetonide C), 78.6 (NOCH2Ph), 74.8 (C-40), 68.5 (C-5), 68.3
(C-4), 65.4 (C-50), 25.7, 24.0 (2×acetonide Me). Primed numbers in NMR data correspond to atoms of
the dioxolane ring. Anal. calcd for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.39; H, 6.44; N,
3.56.
3.17. (4R)-3-Benzyloxy-4-phenyl-4-[(1R)-1,2-dihydroxyethyl]-1,3-oxazolidin-2-one, (+)-22
Obtained in 66% yield from oxazolidinone (−)-21 under the same conditions as for (+)-15: white
solid, mp 68–70°C, [α]D +24.0 (CHCl3, c 0.7); IR νmax cm−1: 3400 (br, OH), 1778 (C_O); CIMS, m/z
1
330.1345 (M+H+). Calcd for C18H20NO5, M=330.1341; H NMR: δ 7.50–7.20 (10H, m, arom.), 5.15,
4.87 (2H, AB system, J=10.2 Hz, NOCH2Ph), 4.44 (1H, t, J=4 Hz, CHOH), 4.38 (1H, br d, J=12 Hz, H-
5a), 4.26 (1H, br d, J=12 Hz, H-5b), 4.00 (2H, br d, J=4 Hz, CH2OH), 3.30 (2H, br s, 2 OH); 13C NMR: δ
159.6 (C-2), 137.2, 134.8 (arom. C), 129.2, 129.0, 128.7, 128.6, 128.3, 126.1 (arom. CH), 82.7 (CHOH),
78.4 (NOCH2Ph), 71.3 (C-4), 60.6 (C-5), 58.6 (CH2OH). Anal. calcd for C18H19NO5: C, 65.64; H, 5.81;
N, 4.25. Found: C, 65.42; H, 5.70; N, 4.44.
3.18. (4R)-3-Benzyloxy-4-phenyl-4-methoxycarbonyl-1,3-oxazolidin-2-one, (−)-23b
Obtained in 61% overall yield from diol (+)-22 under the same conditions as for (−)-9b: oil, [α]D
−17.7 (CHCl3, c 1.3); IR νmax cm−1: 1794, 1753 (C_O); EIMS, m/z 328.1175 (M+H+, 1), 312 (M+−Me,
1
1), 268 (M+−COOMe, 38), 162 (20), 91 (100). Calcd for C18H18NO5, M=328.1185; H NMR: δ
7.40–7.30 (10H, m, arom.), 5.19, 5.05 (2H, AB system, J=10 Hz, NOCH2Ph), 4.71 (1H, d, J=9 Hz,
H-5), 4.54 (1H, d, J=9 Hz, H-50), 3.86 (3H, s, OMe); 13C NMR: δ 169.5 (ester C_O), 157.1 (C-2),
134.8, 134.3 (arom. C), 129.3, 129.0, 128.6, 128.3, 126.5 (arom. CH), 78.9 (NOCH2Ph), 71.1 (C-4),
69.9 (C-5), 53.3 (OMe). Anal. calcd for C18H17NO5: C, 66.05; H, 5.23; N, 4.28. Found: C, 66.22; H,
5.40; N, 4.49.

M. Carda et al. / Tetrahedron: Asymmetry 9 (1998) 1703–1712
1711
3.19. (2R)-3-Hydroxy-2-(N-benzyloxyamino)-2-phenylpropionic acid, (+)-24
Obtained in 70% yield from methyl ester (−)-23b under the same conditions as for (−)-10: white solid,
mp 144–146°C, [α]D −12.5 (MeOH, c 1.7); IR νmax cm−1: 3300 (br, OH), 1589, 1412, 1091, 913, 874;
1
FABMS, m/z 288.1227 (M+H+). Calcd for C16H18NO4, M=288.1236; H NMR (CD3OD): δ 7.45 (2H,
m, arom.), 7.30–7.15 (8H, m, arom.), 4.61, 4.53 (2H, AB system, J=10.5 Hz, NOCH2Ph), 4.25 (1H, d,
J=10.5 Hz, H-3), 4.07 (1H, d, J=10.5 Hz, H-3); 13C NMR (CD3OD): δ 180.5 (C-1), 140.6, 138.8 (arom.
C), 129.6, 129.5, 129.3, 129.0, 128.8, 128.7, 128.4 (arom. CH), 77.7 (NOCH2Ph), 73.8 (C-2), 65.1 (C-3).
Anal. calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 66.72; H, 5.70; N, 4.69.
3.20. (R)-(+)-2-Phenyl serine, (+)-25
Obtained in 60% yield from acid (+)-24 under the same conditions as for (−)-11: white solid, mp
248–250°C (dec.); [α]D +19.5 (H2O, c 0.3); IR νmax cm−1: 3400 (br, OH), 1624, 1407, 1087, 875;
1
FABMS, m/z 182.0822 (M+H+). Calcd for C9H12NO3, M=182.0817; H NMR (D2O:CD3OD=4:1):
δ 7.55–7.40 (5H, m, arom.), 4.35 (1H, d, J=12 Hz, H-3), 4.24 (1H, d, J=12 Hz, H-3); 13C NMR
(D2O:CD3OD=4:1): δ 174.3 (C-1), 135.6 (arom. C), 130.3, 130.2, 126.8 (arom. CH), 68.5 (C-2), 64.5
(C-3). Anal. calcd for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.45; H, 6.38; N, 7.58.
Acknowledgements
This research has been financially supported by the Spanish Ministry of Education and Science
(DGICYT projects PB95-1089 and PB96-0760) and by BANCAJA (project P1B95-21). E.C. thanks the
Conselleria de Educaciò de la Generalitat Valenciana for a pre-doctoral fellowship.
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