A practical method for the synthesis of β-amino α-hydroxy acids. Synthesis of enantiomerically pure hydroxyaspartic acid and isoserine

Article abstract of DOI:10.1055/s-1999-2927

The iodocyclization of 3-benzoylamino carboxylic acid derivatives gives oxazoline-5-carboxylates which are precursors of β-amino-α-hydroxy acids.

Full text of DOI:10.1055/s-1999-2927

LETTER
1727
A Practical Method for the Synthesis of b-Amino a-Hydroxy Acids. Synthesis
of Enantiomerically Pure Hydroxyaspartic Acid and Isoserine
Giuliana Cardillo, Luca Gentilucci, Alessandra Tolomelli, Claudia Tomasini
Dipartimento di Chimica “G. Ciamician”, Università di Bologna and C.S.F.M, via Selmi 2, 40126 Bologna, Italy
Tel.: ++39 51 2099570. Fax.: ++39 51 2099456. e-mail: cardillo@ ciam.unibo.it
Received 15 July 1999
Abstract: The iodocyclization of 3-benzoylamino carboxylic acid
derivatives gives oxazoline-5-carboxylates which are precursors of
b-amino-a-hydroxy acids.
Key words: amino acids, cyclization, iodine, chiral auxiliaries, nat-
ural products
Optically active a- and b-hydroxy amino acids are an im-
portant class of compounds present in natural peptide an-
tibiotics and components of pharmaceuticals. Recently,
hydroxy-amino derivatives emerged as protease inhibi-
tors, since the hydroxyl group serves as mimic for the tet-
rahedral intermediate of proteolysis and is bound tightly
to the active site.1 Furthermore these compounds repre-
Scheme 1
sent useful chiral building blocks in the synthesis of bio-
logically active compounds. For this reason, the
asymmetric synthesis of hydroxy amino acids is a subject
Oxazolines are important intermediates in organic chem-
of current interest. In particular, some biologically active
istry due to their synthetic utility. These heterocycles may
structures contain a-hydroxy b-amino acids: for instance
be considered indeed as protected forms of amino alcohol
(2R,3S)-phenylisoserine is the well known component of
derivatives.10 In fact, the partial hydrolysis of the oxazo-
the anticancer taxol,2 the hydroxyaspartate is present in
line 2 in THF/0.1N HCl afforded the N-benzoyl derivative
4 in 70% yield, while by refluxing 2 in 6N HCl for 6h hy-
droxy amino acid 5 was obtained in 95% yield (Scheme
the macrocyclic antibiotic lysobactine3 and isoserine is a
component of the polypeptide antibiotics tatumine and
edeine.4 Furthermore, the biological activity of some anti-
2).11
biotics was enhanced by replacing naturally occurring
amino acids with isoserine.5
In conjunction with our current effort in the synthesis of
polypeptide sequences of lysobactine antibiotics, we have
been interested in the synthesis of optically pure (2S,3S)-
3-hydroxyaspartic acid and (S)-isoserine.
Although effective methods for the preparation of 3-hy-
droxyaspartic acid have been described in the literature,6
we wish to disclose here a simple and highly stereoselec-
tive synthesis of (2S,3S)-hydroxyaspartic acid (Scheme 1
and Scheme 2): it is based on the regioselective deproto-
nation of N-benzoyl dimethyl aspartate at C3, followed by
quenching the resulting dienolate with I2.7
The anti relationship of b-amidoester metallation fol-
lowed by quenching with an electrophile has been previ-
ously reported by Seebach.8 In our case the halogenation
Scheme 2
reaction proceeds towards the removal of iodide to afford
in one step exclusively the corresponding trans oxazoline
2, accompanied by the elimination product 3 in 20% yield.
No traces of the cis oxazoline could be detected. Any at-
On the basis of these results we turned our attention to the
synthesis of isoserine, that represents an object of interest
tempt to avoid elimination by changing the reaction con-
in our laboratory in this last period.
ditions (metallating agent, solvent, temperature) failed.9
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1728
G. Cardillo et al.
LETTER
First of all we treated the N-benzoylamido-methyl ester 6
of commercially available b-alanine with 2 equivalents of
LiHMDS, followed by treatment with I2. The oxazoline 7,
obtained in 95% yield, was hydrolysed to isoserine with
5N HCl. The resolution of the racemic mixture was per-
formed by protecting isoserine as N,O-diacetate methyl
ester and by treating this compound with Candida Cilin-
dracea lipase in the presence of n-BuOH (Scheme 3).12
The enzymatic resolution allowed to obtain optically ac-
tive (R)-N-acetyl-isoserine 9 ([a]D -17.7, c 0.2, CHCl3;
lit.12 [a]D -14.5, c 1, CHCl3) in 42% yield and (S)-N,O-di-
acetyl-isoserine 10 ([a]D +7.0, c 0.2, CHCl3; lit.12 [a]D
+8.6, c 1, CHCl3) in 43% yield.
Scheme 4
Scheme 3
In order to transform this synthetic pathway in a EPC syn-
thesis (enantiomerically pure compound synthesis) of
isoserine, we utilised (4R,5S)-1,5-dimethyl-4-phenyl-imi-
dazolidin-2-one13 as chiral auxiliary. Thus, the imidazoli-
dinone magnesium salt, in THF at 0 °C, was added
dropwise to a solution of N-benzoyl-b-alanine chloride in
THF. The imidate 11 was obtained in 85% yield. This
compound was treated under a variety of conditions af-
fording an easily separable mixture of oxazoline diastere-
oisomers in high yield (Scheme 4).14 The results are
reported in Table 1.
In summary, we have elaborated a useful method for the
synthesis of non-proteinogenic (2S,3S)-3-hydroxyaspartic
acid starting from aspartic acid, through a completely ste-
reoselective cyclization to trans oxazoline. The synthesis
of (S)-isoserine from non chiral b-alanine requires an en-
zymatic resolution with CCL or the use of a chiral auxil-
iary which gives rise to a separable mixture of oxazolines
in good diastereomeric ratio.
The major isomer 12, obtained pure by flash chromatog-
raphy, was treated with TEA and MeOH under the condi-
tions recently reported by Davies15 and afforded the
optically pure methoxyoxazoline (5S)-7 in 95% yield. The
specific rotation of the isolated oxazoline 716 was in agree-
ment with the data reported in literature, thus confirming
the (S) absolute configuration of the starting oxazoline 12.
Furthermore, hydrolysis of oxazoline 12 with 5N HCl and
MeOH, gave the hydroxy amino acid (S)-14 as hydrochlo-
ride in 85% yield (Scheme 5).12,16
Synlett 1999, No. 11, 1727–1730 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Practical Method for the Synthesis of b-Amino a-Hydroxy Acids
1729
and a solution of iodine (3.77 mmol, 0.96 g) in dry THF (10
mL) was added dropwise. The reaction was quenched after 1h
with an aqueous saturated solution of NH4Cl (10 mL), and the
solvent was removed under reduced pressure. The residue was
dissolved in ethyl acetate and washed twice with a solution of
Na2S2O3. The organic layer was dried over Na2SO4 and
concentrated. Oxazoline 2 was obtained as an oil in 80% yield
(1.51 mmol, 0.4 g) after flash chromatography on silica gel
(cyclohexane/ethyl acetate 9:1 as eluent).
2: IR (film) 1744, 1650, 1438, 1229 cm-1; 1H-NMR (CDCl3) d
3.83 (s, 3H), 3.85 (s, 3H), 5.03 (d, 1H, J = 6.6 Hz), 5.45 (d, 1H,
J = 6.6 Hz), 7.30-7.50 (m, 3H), 8.00 (m, 2H); 13C-NMR
(CDCl3) d 52.9, 53.1, 72.8, 78.0, 126.1, 128.4, 128.7, 132.2,
165.4, 169.5, 170.0; [a]D +42,2 (c 1.2, CHCl3).
(2S,3S)-N-Benzoyl-3-hydroxy-dimethylaspartate 4: A
solution of oxazoline 2 (1.33 mmol, 0.35 g) in THF/0.1N HCl
(10:1, 11 mL) was stirred at r.t. for 2h. After removing the
solvent under reduced pressure, the residue was dissolved in
EtOAc (10 mL) and washed twice with water. The organic
layer was dried over Na2SO4 and concentrated. Compound 4
was obtained as an oil in 70% yield (0.93 mmol, 0.26 g).
4: 1H-NMR (CDCl3) d 3.84 (s, 6H), 4.82 (d, 1H, J = 2.1 Hz),
5.33 (dd, 1H, J = 2.1, 9.6 Hz), 6.90 (d, 1H, J = 9.6 Hz), 7.30-
7.50 (m, 3H), 7.90 (m, 2H); 13C-NMR (CDCl3) d 53.1, 53.4,
54.9, 71.0, 127.1, 128.6, 128.7, 131.9, 167.3, 170.0, 172.3; [a]D
+8.8 (c 5, CHCl3).
Scheme 5
Acknowledgement
We thank M.U.R.S.T. Cofin ‘98 (Roma) and Bologna University
(funds for selected topics: “Sintesi e caratterizzazione di biomole-
cole”) for the financial support to this research.
References and Notes
(2S,3S)-3- Hydroxyaspartic acid 5: A solution of oxazoline
2 (1.33 mmol, 0.35 g) in 6N HCl (10 mL) was refluxed for 6h.
The acid aqueous solution was then washed twice with
EtOAc, concentrated under reduced pressure and replaced
with water (2 mL). The mixture was adsorbed on cation
exchange resin and the resin was washed with distilled H2O
until the washing came out neutral, then with 1.5 N aqueous
NH4OH to recover compound 5 in 95% yield (1.26 mmol,
0.19 g).
(1) Kempf, D. J.; Norbeck, D. W.; Codacovi, L. M.; Wang, X. C.;
Kohlbrenner, W. E.; Wideburg, N. E.; Paul, D. A.; Knigge, M.
F.; Vasavanonda, S.; Craig-Kennard, A.; Saldivar, A.;
Rosenbrook, W. J.; Clement, J. J.; Plattner, J. J.; Erickson, J.
J. Med. Chem. 1990, 33, 2687. Mimoto, T.; Imai, J.; Kisanuki,
S.; Enomoto, H.; Hattori, N.; Akaji, K.; Kiso, Y. Chem.
Pharm. Bull. 1992, 40, 2251.
(2) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int.
Ed. Engl. 1994, 33, 15. Enantioselective Synthesis of b-Amino
Acids; Juaristi E., Ed.; VCH Publishers: New York, 1996 and
references cited therein.
(3) O’ Sullivan, J.; McCullough, J. E.; Tymiak, A. A.; Kirsch, D.
R.; Trejo, W. H.; Principe, P. A. J. Antibiot. 1988, 41, 1740.
Kato, T.; Hinoo, H.; Terui, Y.; Kikuchi, J.; Shoji, J. J.
Antibiot. 1988, 41, 719. Kato, T. J. Antibiot. 1989, 42, C-2.
Tymiak, A. A.; McCormick, T. J.; Unger, S. E. J. Org. Chem.
1989, 54, 1149.
(4) Hettinger, T. P.; Craig, L. C. Biochemistry 1970, 9, 1224.
Heaney-Kieras, J.; Kurylo-Borowska, Z. J. Antibiot. 1980, 33,
359.
(5) Woo, P. W. K.; Dion, H. W.; Bartz, Q. R. Tetrahedron Lett.
1971, 2617. Wright, J. J.; Cooper, A.; Daniels, P. J. L.;
Nagabhushan, T. L.; Rane, D.; Turner, W. N.; Weinstein, J. J
Antibiot. 1976, 29, 714.
(6) Hanessian, S.; Vanasse, B. Can. J. Chem. 1993, 71, 1401.
Fernández-Megía, E.; Paz, M. M.; Sardina, F. J. J. Org. Chem.
1994, 59, 7643.
(7) Seebach, D.; Wasmuth, D. Angew. Chem., Int. Ed. Engl. 1981,
20, 971. Baldwin, J. E.; Moloney, M. G.; North, M.
Tetrahedron, 1989, 45, 6309. Cardillo, G.; Gentilucci, L.;
Tolomelli, A.; Tomasini, C. J. Org. Chem. 1998, 63, 2351.
(8) Seebach, D.; Estermann, H. Tetrahedron Lett. 1987, 28, 3103.
(9) Humphrey, J. M.; Bridges, R. J.; Hart, J. A.; Chamberlin, A.
R. J. Org. Chem. 1994, 59, 2467.
5: 1H-NMR (D2O) d 4.24 (bs, 1H), 4.71 (bs, 1H); [a]D -13.3 (c
0.2, H2O), lit.17 [a]D -11.9, c 1, H2O); [a]D +7.5 (c 1, HCl 5N);
lit.18 [a]D +6.4 (c 1, HCl 5N).
(12) Lu, Y.; Miet, C.; Kunesch, N.; Poisson, J. E. Tetrahedron:
Asymmetry 1991, 2, 871.
(13) Roder, H.; Helmchen, G.; Peters, E. M.; Peters, K.; von
Schnering, H. G. Angew. Chem. Int. Ed. Engl. 1984, 23, 898.
Cardillo, G.; D’Amico, A.; Orena, M.; Sandri, S. J. Org.
Chem. 1988, 53, 2354.
(14) (4R,5S)-1,5-Dimethyl-3-[(3’-N-benzoyl-amino)-
propanoyl]-4-phenylimidazolidin-2-one 11: To a stirred
solution of (4R,5S)-1,5-Dimethyl-4-phenylimidazolidin-2-
one (5.2 mmol, 1 g) in dry THF (30 mL), MeMgCl (6.3 mmol,
2.1 mL 3M solution in THF) was added in one portion, under
inert atmosphere at 0 °C. After 30 min, the mixture was added
dropwise at 0 °C by means of a teflon cannula to a solution of
N-benzoyl-b-alanine chloride (5.2 mmol, 1.1 g) in dry THF
(15 mL). The reaction was allowed to stir at room temperature
for 4h and then quenched with an aqueous saturated solution
of NH4Cl (10 mL). After removing the solvent under reduced
pressure, the residue was dissolved in ethyl acetate and
washed twice with water. The organic layer was dried over
Na2SO4 and concentrated. Compound 11 was obtained in 85%
yield (4.4 mmol, 1.6 g) after flash chromatography on silica
gel (cyclohexane/ethyl acetate 8:2 as eluent).
11: m.p. 72-75 °C; IR (film) 1722, 1675, 1652 cm-1; 1H-NMR
(CDCl3) d 0.78 (d, 3H, J = 6.6 Hz), 2.80 (s, 3H), 3.30 (m, 2H),
3.70 (m, 2H), 3.88 (dq, 1H, J = 6.6 Hz, 9 Hz), 5.28 (d, 1H, J =
9 Hz), 6.92 (bs, 1H), 7.30-7.70 (m, 5H); 13C-NMR (CDCl3) d
14.4, 28.3, 35.3, 36.0, 54.1, 58.3, 126.9, 127.3, 128.2, 128.3,
128.5, 128.7, 131.3, 134.7, 155.7, 167.2, 172.0; [a]D -67.7 (c
1.9, CHCl3).
(10) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837 and
references cited therein.
(11) (4S,5S)-2-Phenyl-4,5-dimethoxycarbonyloxazoline 2: To a
stirred solution of (2S)-N-benzoyl-dimethylaspartate 1 (1.89
mmol, 0.5 g) in dry THF (20 mL) was added LiHMDS (3.77
mmol, 3.77 mL 1M solution in THF) in one portion, under
argon at 0 °C. After 30 min, the mixture was cooled to -78 °C,
Synlett 1999, No. 11, 1727–1730 ISSN 0936-5214 © Thieme Stuttgart · New York

1730
G. Cardillo et al.
LETTER
(4R,5S,5’S)- and (4R,5S,5’R)-1,5-Dimethyl-3-(2’-phenyl-
4’-oxazolylcarbonyl)-4-phenylimidazolidin-2-one 12 and
13: To a stirred solution of 11 (1.36 mmol, 0.5 g) in dry THF
(20 mL) was added MHMDS ( M = Li, N, K; 2.74 mmol, 2.74
mL 1M solution in THF) in one portion, under argon at 0°C.
After 30 min, the mixture was cooled to the required
temperature (see Table 1), and a solution of iodine (2.74
mmol, 0.69 g) in dry THF (10 mL) was added dropwise. After
1h, the reaction was quenched with an aqueous saturated
solution of NH4Cl (10 mL), and the solvent was removed
under reduced pressure. The residue was dissolved in ethyl
acetate and washed twice with a solution of Na2S2O3. The
organic layer was dried over Na2SO4 and concentrated.
Oxazolines 12 and 13 were obtained as oils after flash
chromatography on silica gel (cyclohexane/ethyl acetate 9:1
as eluant).
(16) (5S)-2-Phenyl-5-methoxycarbonyl-oxazoline 7 : A solution
of 12 (0.83 mmol, 0.3 g) and TEA (4.96 mmol, 0.7 mL) in
MeOH (5 mL) was refluxed for 2h. After removing the solvent
under reduced pressure, the residue was dissolved in EtOAc
and washed twice with water. The organic layer was dried
over Na2SO4 and solvent removed to give oxazoline 7 as a
yellow oil in 95% yield ( 0.79 mmol, 0.16 g).
7: IR (film) 1741, 1656 cm-1; 1H-NMR (CDCl3) d 3.81 (s, 3H),
4.15 (dd, 1H, J = 7.0 Hz, 15.1 Hz), 4.35 (dd, 1H, J = 10.9 Hz,
15.1 Hz), 5.08 (dd, 1H, J = 7.0 Hz, 10.9 Hz), 7.30-7.80 (m,
10H); 13C-NMR (CDCl3) d 52.5, 59.2, 75.6, 126.7, 128.2,
128.3, 131.5, 163.8, 170.8; [a]D -141.3 (c 0.2, CHCl3);
lit.19(opposite enantiomer) [a]D +166.8 (c 0.2, CHCl3).
(2S)-Isoserine 14: A solution of oxazoline 12 (0.83 mmol, 0.3
g) in 5N HCl (5 mL) and MeOH (5 mL) was refluxed for 6h.
After removing methanol, the acid aqueous solution was
washed twice with EtOAc, concentrated under reduced
pressure and replaced with water (2 mL). The mixture was
adsorbed on cation exchange resin and the resin was washed
with distilled H2O until the washing came out neutral, then
with 1.5N aqueous NH4OH to recover compound 8 in 85%
yield (0.7 mmol, 0.075 g).
12: m.p. 135-137 °C; IR (film) 1730, 1700, 1654 cm-1; 1H-
NMR (CDCl3) d 0.85 (d, 3H, J = 6.6 Hz), 2.87 (s, 3H), 4.02
(dd, 1H, J = 6.5 Hz, 15.3 Hz), 4.04 (dq, 1H, J = 6.4 Hz, 8.4
Hz), 4.57 (dd, 1H, J = 10.9 Hz, 15.3 Hz), 5.31 (d, 1H, J = 8.4
Hz), 6.14 (dd, 1H, J = 6.4 Hz, 10.9 Hz), 7.10-7.50 (m, 10H);
13C-NMR (CDCl3) d 15.4, 28.5, 29.8, 55.2, 59.6, 60.5, 127.5,
127.7, 128.5, 128.7, 128.9, 129.3, 131.9, 136.3, 155.9, 165.0,
169.5; [a]D -237 (c 1.3, CHCl3).
14: 1H-NMR (D2O) d 3.05 (bs, 1H), 3.25 (bs, 1H), 4.35 (bs,
1H).
(17) Dakin, H. D. J. Biol. Chem. 1921, 48, 273.
(18) Okai, H.; Imamura, N.; Izumiya, N. Bull. Chem. Soc. Jpn.
1967, 40, 2154.
(19) Beresford, K. J.; Young, D. W. Tetrahedron 1996, 52, 9891.
13: IR (film) 1729, 1709, 1659 cm-1;1H-NMR (CDCl3) d 0.83
(d, 3H, J = 6.5 Hz), 2.87 (s, 3H), 3.99 (dq, 1H, J = 6.5 Hz, 8.4
Hz), 4.08 (dd, 1H, J = 6.5 Hz, 15.1 Hz),), 4.53 (dd, 1H, J =
10.8 Hz, 15.1 Hz), 5.27 (d, 1H, J = 8.4 Hz), 6.16 (dd, 1H, J =
6.5 Hz, 10.8 Hz), 7.10-7.50 (m, 10H); 13C-NMR (CDCl3) d
14.9, 28.2, 29.7, 54.7, 59.3, 60.4, 126.9, 128.1, 128.3, 128.6,
131.3, 135.8, 155.4, 163.5, 169.2; [a]D +27.4 (c 1.1, CHCl3).
Article Identifier:
1437-2096,E;1999,0,11,1727,1730,ftx,en;G18799ST.pdf
(15) Davies, S. G.; Dixon, D. J. Synlett 1998, 963.
Synlett 1999, No. 11, 1727–1730 ISSN 0936-5214 © Thieme Stuttgart · New York