A practical method for the conversion of β-hydroxy carboxylic acids into the corresponding β-amino acids

Article abstract of DOI:10.1055/s-1998-1928

Optically active α- or β-substituted βamino acids were synthesized from the corresponding β-hydroxy acids in 4 steps in excellent yield. Stereochemistry was retained at the α-position and reversed at the β-position during the conversion.

Full text of DOI:10.1055/s-1998-1928

November 1998
SYNLETT
1189
A Practical Method for the Conversion of β-Hydroxy Carboxylic Acids into the
Corresponding β-Amino Acids
Yonghao Jin and Dong H. Kim,*
Center for Biofunctional Molecules and Department of Chemistry
Pohang University of Science and Technology San 31 Hyojadong, Pohang 790-784, Korea
Fax: +82-562-279-5877; E-mail: dhkim@vision.postech.ac.kr
Received 27 July 1998
Abstract: Optically active α- or β-substituted β-amino acids were
R1
R1
R1
synthesized from the corresponding β-hydroxy acids in 4 steps in
excellent yield. Stereochemistry was retained at the α-position and
reversed at the β-position during the conversion.
HO
i
ii
HO
CO2H
R2
O
CONHOBn
N
R2
R2
OBn
3
1
2
Lately, β-amino acids have received increasing attention as
pharmacological agents and as constituents of peptides having
interesting biological actvities.1 More recently, β-amino acids have
been extensively utilized for the study of peptide folding: peptides
consisting of β-amino acids are known to form well-defined,
remarkably stable helixes which serve as models for folding of
peptides.2 Accordingly, β-peptides are thought to be of interest as new
functional polymers with interesting biological properties. Numerous
synthetic methods for the preparation of optically active substituted β-
amino acids have been reported.3 They are, however, mostly for the
synthesis of β-substituted β-amino acids. The known methods for the
preparation of α-substituted β-amino acids may be classified into three
approaches: stereoselective alkylation of chiral enolates that are
synthetically equivalent to the enolate from β-alanine,4 stereoselective
amidomethylation,5 and conjugate addition of a carbon nucleophile to
α-methlyene β-alanine derivatives.6 The literature methods are,
however, limited to the preparation of α- or β-substituted β-amino
acids, laborious to conduct, or suffer from low product yield. We wish
to report herein a practical method for the preparation of optically active
substituted β-amino acids from the readily obtainable corresponding β-
hydroxy acids.7
R1
R1
iii or iv
v
BnOHN
H2N
CO2H
CO2H
R2
R2
R2
4
5
R1
a
Me
CHMe2
H
H
H
b
c
CH2CHMe2
CH2C6H5
H
d
e
H
Me
Scheme 1. Reagents and conditions (yields): (I) EDCI (1.5 eq),
BnONH2 (2.0 eq), THF-H2O (>95%); (ii) DEAD (1.0 eq), Ph3P (1.1
eq), THF (>85%); (iii) 4N HCl in dioxane (100%); (iv) LiOH, THF-
MeOH-H2O, 0 °C (100%); (v) Pd/C, H2, MeOH (>98%)
Table 1. β-amino acids 5
overall
5
mp (oC) (lit.)
[α]D (lit.)
yield (%)a
192-194 (194-196)b
228-230
-14.2 (-15.4)b
-11.4
a
b
c
81
80
β-Hydroxy carboxylic acids
benzylhydroxylamine using
1
were coupled with O-
1-(dimethylaminopropyl)-3-ethyl
219-220
84
81
+6.1
carbodiimide (EDCI) in THF-H2O solution at pH 4.5 to give O-
benzylhydroxamates 2, which upon treatment with Ph3P and DEAD in
dry THF under the Mitsunobu conditions provided β-lactams 3 in high
yield. During the cyclization reaction there occurs an inversion of the
stereochemistry at the β-position. The β-lactams were then converted to
the corresponding β-amino acid derivatives 4 under acidic or basic
hydrolysis conditions in excellent yield. Hydrogenolysis of 4 over Pd-C
in methanol at atmospheric pressure afforded β-amino acids 5 in over
80% overall yield (Scheme 1).8
+17.8 (+11.3)c
224-226 (225-226)c
d
e
+36.6 (+32.2)d
209-211 (208-210)d
89
a Overall yield from 1. b Ref. 9. c Ref. 4b. d Juaristi, E.; Escalante, J.;
Lamatsch, B.; Seebach, D. J. Org. Chem. 1959, 31, 57.
g, 28.8 mmol) was added in one portion. The resulting solution was
stirred for 2 h at room temperature while controlling pH at 4.5 with 1N
HCl using a pH stat. After removel of THF, the residue was extracted
with ethyl acetate (50 mL × 3) and the organic layer was washed with
10% citric acid (20 mL × 3), 5% NaHCO3 (20 mL × 2), and dried over
MgSO4. Evaporation of the organic solvent afforded the product 2a as a
white solid (3.90 g, 97%). An analytical sample was recrystallized from
EtOAc-hexane: mp 67 °C; [α]D26 11.6 (c 1.00, MeOH); IR (KBr) 3382,
3238, 1666, 1515, 1462, 1422, 1373, 1092, 1073, 1034 cm-1; 1H
NMR(CDCl3) δ 8.55 (b, 1H), 7.33 (m, 5Η), 4.91 (s, 2H), 3.65 (m, 2H),
2.33 (m, 1H), 2.10 (b, 1H), 1.11 (d, 3H); Anal. Calcd for C11H15NO3:
C, 63.14; H, 7.23; N, 6.70. Found: C, 63.26; H, 7.15; N, 6.59.
In summary, optically active α- or β-substituted β-hydroxy carboxylic
acids were converted into the corresponding β-amino acids in four steps
and in excellent overall yield. The present method is versatile that can
be used for the synthesis of both α- and/or β-substituted β-amino acids
and easy to conduct. Since the optically active substituted β-amino acids
are readily prepared according to the Evans chiral auxiliary protocol, the
present method may be a method of choice for the preparation of
optically active variously substituted β-amino acids.
Typical Experimental Procedure:
(2R)-3-Hydroxy-2-methyl-N-benzyloxypropanamide 2a. To a stirred
mixture of β-hydroxy acid 1a (2.00 g, 19.2 mmol) in THF-H2O (4:1,
100 mL), was added BnONH2 HCl (6.13 g, 38.4 mmol). The pH of the
solution was adjusted to 4.5 with 1N NaOH, and then 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 5.52
(3R)-N-Benzyloxy-3-methyl-2-azetidinone 3a. To a stirred, cooled (0
°C) solution of O-benzylhydroxamate 2a (2.09 g, 10 mmol) and PPh3
(2.88 g, 11 mmol) in dry THF (100 mL) was added DEAD (1.57 mL, 10
mmol) dropwise. The resulting solution was stirred for 4 h at room

1190
LETTERS
SYNLETT
temperature. After evaporation of THF, the residue was purified by
(6) Barnish, I. T.; Corless, M.; Dunn, P. J.; Ellis, D.; Finn, P. W.;
column chromatography (hexane/EtOAc, 5:1) to give the product 3a as
Hardstone, J. D.; James, K. Tetrahedron Lett. 1993, 34, 1323.
14
a colorless oil (1.62 g, 84%): [α]D +34.4 (c 1.11, EtOAc); IR (film)
(7) Optically active β-hydroxy carboxylic acids 1 (except 1e which
was obtained from Aldrich) are readily prepared using Evans
chiral auxiliary by a standard method.10 The procedure for the
preparation of 1a is representative: To a stirred, cooled (0 °C)
solution of (4R)-4-benzyl-3-(1-oxopropyl)oxazolidin-2-one (6.53
g, 28 mmol) in CH2Cl2 (150 mL) was added TiCl4 (3.22 mL, 29.4
mmol) dropwise. The resulting yellowish slurry was stirred for 10
min at 0 °C, and then (i-Pr)2NEt (5.37 mL, 30.8 mmol) was added
by a syringe. The resulting dark red solution was stirred for 1 h at
0 °C, and then BnOCH2Cl (8.77 mL, 56 mmol) was added
dropwise to the solution. The reaction mixture was stirred at 0 °C
for additional 6 h until the starting material was completely
consumed. Saturated aqueous NH4Cl (100 mL) was added to the
solution and the aqueous layer was extracted with additional
CH2Cl2 (50 mL × 3). The combined organic layer was washed
with water (30 mL × 2), dried (MgSO4), and concentrated. The
residue was purified by column chromatography (hexane/EtOAc,
3:1) to give (4R)-4-benzyl-3-[(2R)-3-benzyloxy-2-methyl-1-
oxopropyl]oxazolidin-2-one (9.80 g, 99%).
1
1766, 1456, 1380, 1213, 1061, 961 cm-1; H NMR(CDCl3) δ 7.40 (m,
5H), 4.95 (s, 2H), 3.40 (m, 1H), 2.87 (m, 2H), 1.22 (d, 3H); 13C
NMR(CDCl3) δ 13.8, 31.4, 40.1, 53.5, 129.0, 129.4, 129.6, 135.6,
167.8; MS (CI) m/z 192 (M+H+).
(2R)-3-Benzyloxyamino-2-methylpropionic acid 4a. To a stirred,
cooled (0 °C) solution of β-lactam 3a (382 mg, 2.0 mmol) in THF-
MeOH (3:1, 8 mL), was added LiOH H2O (100 mg, 2.4 mmol) in water
(2 mL). The resulting solution was stirred at 0 °C until no starting
material remained by TLC check. The solution was acidified to pH 2
with 4N HCl, and then the organic solvents were evaporated. The
residue was extracted with ethyl acetate (30 mL × 3) and the combined
organic layer was washed with brine (10 mL × 2), dried (MgSO4), and
evaporated to give 4a (418 mg, 100%): [α]D20 25.3 (c 1.20, MeOH); IR
(film) 3000, 1707, 1456, 1365, 1209; 1H NMR(CDCl3) δ 7.33(m, 5H),
5.91 (b, 2H), 4.74 (q, 2H), 3.09 (m, 2H), 2.83 (m, 1H), 1.20 (d, 3H); 13C
NMR(CDCl3) δ 13.8, 36.9, 54.6, 76.8, 128.6, 129.0, 137.3, 180.0;
HRMS (CI) calcd for (C11H15NO3+ H+): 210.1131, found: 210.2125.
3-Amino-2-methylpropanoic acid 5a. A solution of 4a (418 mg, 2
mmol) in MeOH (30 mL) was hydrogenated in the presence of 10% Pd/
C (100 mg) at atmospheric pressure. After the reaction was completed
(TLC check), Pd/C was filtered off and the solvent was evaporated to
give 5a as a white solid (206 mg, 100%): mp 192-194 °C, lit.9 194-196
To a stirred, cooled (0 °C) solution of (4R)-4-benzyl-3-[(2R)-3
benzyloxy-2-methyl-1-oxopropyl]oxazolidin-2-one (8.84 g, 25.0
mmol) in THF-H2O (4:1, 125 mL) under N2 was added 30%
aqueous H2O2 (10 mL, 100 mmol), followed by LiOH H2O (2.03
g, 50 mmol) in water (25 mL). After the solution was stirred for
1h, sodium sulfite (12.6 g, 100 mmol) in water (50 mL) was
added. THF was evaporated under reduced pressure at 25 °C, and
the resulting mixture was extracted with CH2Cl2 (50 mL × 3) to
remove the oxazolidinone auxiliary. The aqueous layer was
acidified to pH 2 with 4N HCl, saturated with NaCl, and then
extracted with Et2O (50 mL × 3). The combined ether layer was
dried over MgSO4 and concentrated. The residue was dissolved in
methanol and hydrogenated over 10% Pd/C at atmospheric
pressure. The mixture was filtered and evaporated to give 1a as a
°C; [α]D 14.2 (c 1.00, H2O), lit.9 [α]D 15.4 (c 1, H2O); 1H
NMR(D2O) δ 2.97 (m, 2H), 2.51 (m, 1H), 1.10 (d, 3H); 13C NMR(D2O)
δ 24.9, 49.0, 52.2, 191.4.
17
27
Acknowledgement: We thank the Korea Science and Engineering
Foundation for financial support of this work.
References and Notes
25
(1) See, for example: a) Spatola, A. F. In Chemistry and Biochemistry
of Amino Acids, Peptides and Proteins; Weinstein, B. (Ed.)
Marcell Dekker: New York, 1983; Vol. 7, p 331. b) Drey, C. N. C.
In Chemistry and Biochemistry of Amino Acids; Barret, G. C.
(Ed.) Chapman and Hall: London, 1992.
colorless oil (2.42 g, 93%). Data for 1a: [α]D 13.0 (c 10.0,
EtOH), lit.11 [α]D +12.72 (c 12.5, EtOH) for (S) enantiomer.
20
18
Data for 1b: mp 75-76 °C; [α]D 6.8 (c 1.00, CHCl3); IR (KBr)
3230, 2970, 1702, 1470, 1375, 1292, 1250, 1069, cm-1; 1H
NMR(CDCl3) δ 6.50 (b, 2H), 3.83 (m, 2H), 2.06 (m, 1H), 1.00
(dd, 6H); 13C NMR(CDCl3) 20.5, 21.0, 28.1, 54.5. 61.8, 180.4;
Anal. Cacld for C6H12O3: C, 54.53; H, 9.15. Found: C, 54.54; H,
(2) a) Seebach, D.; Matthews, J. L. Chem. Commum. 1997, 2015. b)
Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
16
9.20. Data for 1c: [α]D +5.0 (c 1.01, CHCl3); IR (film) 3400,
(3) a) Juaristi, E.; Quintana, D.; Escalante, J. Alderichimica Acta
1994, 27, 3. b) Cole, D. C. Tetrahedron 1994, 50, 9517. c)
Juaristi, E. (Ed.) Enantioselective Synthesis of β-Amino Acids,
VCH Publishers: New York, 1997.
1712, 1470, 1254, 1202, 1028 cm-1; 1H NMR(CDCl3) δ 5.40 (bs,
2H), 3.75 (d, 2H), 2.68 (m, 1H), 1.63 (m, 2H), 1.28 (m, 1H), 0.92
(dd, 6H); 13C NMR(CDCl3) 22.7, 23.0, 26.3, 37.6, 46.2, 63.8,
180.8. MS (EI) m/z 146 (M+). Data for 1d: mp 69 °C, lit.12 69 °C;
[α]D16 +15.9 (c 1.14, CHCl3), lit.12 [α]D20 +14.9 (c 1.11, CHCl3).
(4) a) Juaristi, E.; Quintana, D; Lamastsch, B.; Seebach, D. J. Org.
Chem. 1991, 56, 2553. b) Juaristi, E.; Quintana, D.; Balderas, M.;
Garcia-Perez, E. Tetrahedron: Asymmetry 1996, 7, 2233.
c) Arvanitis, E.; Motevalli, M.; Wyatt, P. B. Tetrahedron Lett.
1996, 37, 4277. d) Rottmann, A.; Bartoczek, M.; Libsher, J.
Synthesis 1997, 313.
(8) All new compounds are fully characterized with satisfactory
spectral and microanalytical data.
(9) Kakimoto, Y.; Armstrong, M. D. J. Biol. Chem. 1961, 236, 3283.
(10) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141.
(5) a) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M.
T. J. Am. Chem. Soc. 1990, 112, 8215. b) DSouza, A. A.;
Motevalli, M.; Robinson, A. J.; Wyatt, P. B. J. Chem. Soc. Perkin
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Org. Chem. 1976, 41, 3505.
(12) Nakano, M.; Atsuumi, S.; Koike, Y.; Tanaka, S.; Funabashi, H.;
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