A novel synthesis of allophenylnorstatine from (R)-aspartic acid

Article abstract of DOI:10.1055/s-1999-3495

Highly stereoselective hydroxylation of all oxazoline-4-acetate 4 derived from (R)-aspartic acid followed by deprotection leads to allophenylnorstatine 1 in good yield.

Full text of DOI:10.1055/s-1999-3495

924
SHORT PAPER
A Novel Synthesis of Allophenylnorstatine from (R)-Aspartic Acid1
Masahiko Seki,* Kazuo Matsumoto
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku, Osaka 532–8505, Japan
Fax +81(6)3002576; E-mail: m-seki@tanabe.co.jp
Received 16 November 1998; revised 28 December 1998
Abstract: Highly stereoselective hydroxylation of an oxazoline-4-
acetate 4 derived from (R)-aspartic acid followed by deprotection
leads to allophenylnorstatine 1 in good yield.
Key words: allophenylnorstatine, a-hydroxy-b-amino acid, (R)-as-
partic acid, oxazoline-4-acetate, hydroxylation
a-Hydroxy b-amino acids are one of the most important
classes of amino acids because of their crucial role to ex-
hibit potent pharmacological activities in drugs and natu-
ral products.2, 3 Although many synthetic methods for
these amino acids have been developed,2 stereoselective
syntheses of their erythro isomers are scanty2a–c and await
further investigation. Allophenylnorstatine 1, a compo-
nent of potent HIV protease inhibitors KNI 227 and KNI
272,3 represents a typical example of theerythro isomer of
the a-hydroxy b-amino acids. As one of the steadiest ac-
cesses to 1, we envisioned a possible use of (R)-aspartic
acid which carries the required b-amino acid fragment and
chiral center in its molecule. We now describe a novel
synthesis of 1 by regio- and stereoselective introduction of
a phenyl group and a hydroxyl group at C-1 and C-3
carbon atoms of the aspartic acid skeleton with oxazoline-
4-acetate 4 used as a key intermediate (Scheme).
Scheme
83% yield. Lithium enolate of 4 generated by the treat-
ment with lithium bis(trimethylsilyl)amide smoothly re-
acted with 3-phenyl-2-(phenylsulfonyl)oxaziridine5 to
give the hydroxylated compound 5 in 62% yield as a sole
product. The structure of 5 was unequivocally confirmed
by X-ray analysis of the antipode [(2R, 4’R, 5’R)-isomer]
of 5 derived from (S)-aspartic acid (Figure).6 The target
compound 1 was simply obtained by hydrogenation of 5
followed by acid hydrolysis, which showed an optical ro-
20
tation ([a]D –5.5 (c, 0.5, 1M HCl)) in good accordance
20
with the reported value (Lit.2b [a] D –5.4 (c, 0.51, 1N
HCl)).
In conclusion, a facile synthesis of allophenylnorstatine
was accomplished. The present synthetic method is con-
venient in terms of good availability of the starting mate-
rial, high stereoselectivity and simple procedure (e.g. ease
of crystallization of the intermediates). In addition, a vari-
ety of allophenylnorstatine derivatives would be accessi-
ble by employing various electrophiles other than the
5-Phenyl-2-oxazolidinone-4-acetate 3 was prepared from
N-methoxycarbonyl-(R)-aspartic acid b-ethyl ester 2 ac-
cording to our previously reported procedure through the
introduction of a phenyl group at C-1 carbon atom of the
aspartic acid skeleton with the chiral center retained as
such.4 O-Benzylation of 3 was conducted using silver
carbonate as the base to give the oxazoline-4-acetate 4 in
Synthesis 1999, No. 6, 924–926 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Novel Synthesis of Allophenylnorstatine from (R)-Aspartic Acid
[a]D25 +55.3 (c, 1.1, MeOH).
925
C19H19 NO4 calc.
(325.369) found
C
70.14
69.91
H
5.89
5.74
N
4.31
4.09
Methyl (2S, 4’S, 5’S)-2-(2’-Benzyloxy-5’-phenyl-1’,3’-oxazolin-
4’-yl)-2- hydroxyacetate (5)
Into a solution of 4 (2 g, 6.1 mmol) in THF (7 mL) was added por-
tionwise LiHMDS (1.0 M in THF, 7.4 mL, 7.4 mmol) at –78 °C for
10 min and the mixture was stirred at –78 °C for 1 h. 3-Phenyl-2-
(phenylsulfonyl)oxaziridine5 (1.93 g, 7.4 mmol) in THF (10 mL)
was added at –78°C and the mixture was stirred at –78°C for 1 h. To
the mixture was added sat. aq ammonium chloride (50 mL) and
THF was evaporated in vacuo. The residue was extracted with
CH2Cl2 (3 x 30 mL) and combined extracts were washed with brine,
dried (MgSO4) and evaporated in vacuo. The residue was purified
by silica gel column chromatography (hexane/EtOAc = 4:1 to 2:1 to
1:1) to give 5 (1.3 g, 62%) in colorless crystals. Mp 84–86 °C.
IR (Nujol): nmax= 3380, 1734 cm–1.
1H NMR (CDCl3): d = 2.28 (d, J = 5.2 Hz, 1H), 3.52 (s, 3H), 4.11–
4.16 (m, 1H), 4.70 (dd, J = 4, 10 Hz, 1H), 5.33 (d, J = 12 Hz, 1H),
5.40 (d, J = 12 Hz, 1H), 5.82 (d, J = 10 Hz, 1H), 7.26–7.48 (m, 10H).
13C NMR (CDCl3): d = 52.21 (q), 69.84, 71.28 (2d), 72.52 (t), 84.25,
126.86, 128.09, 128.22, 128.47, 128.59, 129.01 (7d), 134.59,
135.14, 163.57, 172.00 (4s).
SIMS m/z = 342 (M++1).
[a]D25 +107.8 (c, 1.05, MeOH).
Figure ORTEP II Diagram of Compound 56
C19H19 NO5 calc.
(341.369) found
C
66.85
66.65
H
5.61
5.61
N
4.10
4.10
Methyl (2S, 3S)-3-Amino-2-hydroxy-4-phenylbutanoate
Hydrochloride (6)
Davis reagent in the reaction with the oxazoline-4-acetate
4.
A mixture of 5 (694 mg, 2.03 mmol), 4M HCl in 1, 4-dioxane (0.75
mL, 3 mmol) and 10% Pd/C (50% wet, 200 mg) in MeOH (54 mL)
was hydrogenated at 25 °C for 4 h in Parr apparatus (H2: 3.5 kg/
cm2). The mixture was filtered and the filtrate was evaporated in
vacuo. The crystals formed were collected by adding diethyl ether
to afford 6 (429 mg, 86%) as colorless crystals. Mp 144–145 °C.
IR (KBr): nmax= 3417, 1744, 1615 cm–1.
1H NMR (D2O): d = 3.00 (dd, J = 7.7, 15 Hz, 1H), 3.10 (dd, J = 7.7,
15 Hz, 1H), 3.50 (s, 3H), 4.15 (dt, J = 2.9, 7.7 Hz, 1H), 4.64 (d, J =
2.9 Hz, 1H), 7.30–7.47 (m, 5H).
Infrared spectra were recorded on a Perkin-Elmer 1640 IR spectro-
photometer and are reported as lmax (cm–1). 1H NMR spectra were
measured on a Bruker AC-200 (200 MHz) spectrometer in CDCl3
or D2O with TMS or sodium 3-(trimethylsilyl)propionate used re-
spectively as an internal standard. Mass spectra were taken on a Hi-
tachi M-2000A spectrometer at an ionizing potential of 70 eV.
Microanalysis were performed by a Perkin-Elmer 2400 Series II
CHNS/O Analyzer. Flash chromatography was accomplished by
using Kieselgel 60 (230–400 mesh, E. Merck). Compound 3 was
prepared from N-methoxycarbonyl-(R)-aspartic acid b-ethyl ester 2
as described.4
13C NMR (D2O): d = 35.70 (t), 55.70 (q), 57.20, 72.06, 130.53,
131.76, 132.47 (5d), 137.49, 175.17 (2s).
SIMS m/z = 210 (M+–HCl+1).
[a]D25 +13.8 (c, 1.1, MeOH).
Methyl (4’R, 5’S)-2-(2’-Benzyloxy-5’-phenyl-1’,3’-oxazolin-4’-
yl)acetate (4)
A mixture of 34 (5 g, 21.3 mmol), benzyl bromide (8.8 g, 25.7
mmol) and silver carbonate (4.7 g, 17 mmol) in toluene (64 mL) was
stirred at 60 °C for 6 h. The mixture was filtered through Celite and
the filtrate was evaporated in vacuo. The residue was purified by sil-
ica gel column chromatography (hexane:EtOAc = 4:1) to give 4
(5.72 g, 83%) in colorless oil.
C11H15 NO3 HCl 1/2H2O calc.
(254.73) found
C
51.86 H 6.72 N 5.50
51.77 6.44 5.38
(2S, 3S)-3-Amino-2-hydroxy-4-phenylbutanoic Acid: Allophe-
nylnorstatine (1)
A mixture of 6 (250 mg, 1.02 mmol), concentrated hydrochloric
acid (37%, 2 mL) and H2O (2 mL) was refluxed for 3 h and the mix-
ture was evaporated. Into the residue was added acetone (5 mL) and
evaporated. The residue was dissolved in EtOH (2.4 mL), H2O (0.7
mL) and propylene oxide (1.2 mL) and the mixture was refluxed for
1 h. The mixture was evaporated and the crystals formed were col-
lected by adding Et2O to give 1 (169 mg, 85%) in colorless crystals.
Mp 197–200 °C (dec.) [lit.2b 195 °C (dec.)].
IR (KBr): nmax= 3030, 1609 cm–1.
IR (Nujol): nmax = 1736, 1669 cm–1.
1H NMR (CDCl3): d = 2.03 (dd, J = 8.3, 16 Hz, 1H), 2.34 (dd, J =
6.8, 16 Hz, 1H), 3.48 (s, 3H), 4.77–4.89 (m, 1H), 5.31 (s, 2H), 5.83
(d, J = 9.1 Hz, 1H), 7.17–7.46 (m, 10H).
13C NMR (CDCl3): d = 41.99 (t), 52.49 (q), 69.36 (d), 72.73 (t),
80.05, 126.78, 128.12, 128.44, 128.54, 128.70, 129.73 (6d), 135.13,
136.58, 161.70, 170.32 (4s).
SIMS m/z = 326 (M++1).
Synthesis 1999, No. 6, 924–926 ISSN 0039-7881 © Thieme Stuttgart · New York

926
M. Seki, K. Matsumoto
SHORT PAPER
T. J. Chem. Soc. Chem. Commun. 1989, 938.
(e) Herranz, R.; Castro-Pichel, J.; Garcia-Lopez, T. Synthesis
1989, 703.
1H NMR (D2O): d = 2.95 (dd, J = 8.7, 14 Hz, 1H), 3.05 (dd, J = 6.4,
14 Hz, 1H), 4.03–4.12 (m, 1H), 4.62 (d, J = 3.1 Hz, 1H), 7.31–7.46
(m, 5H).
(f) Kobayashi, Y.; Takemoto, Y.; Kamijo, T.; Harada, H.; Ito,
Y.; Terashima, S. Tetrahedron 1992, 48, 1853.
(g) Pearson, W. H.; Hines, J. V. J. Org. Chem. 1989, 54, 4235.
(h) Norman, B. H.; Morris, M. L. Tetrahedron Lett.1992, 33,
6803.
13C NMR (D2O): d = 35.79 (t), 57.58, 72.25, 130.72, 131.98, 132.53
(5d), 137.72 (s), 176.53 (s).
SIMS m/z = 196 (M++1).
[a]D20 –5.5 (c, 0.1, 1M HCl) [lit.2b [a]D20 –5.4 (c, 0.51, 1M HCl)].
(i) Kawabata, T.; Kiryu, Y.; Sugiura, Y.; Fuji, K. Tetrahedron
Lett. 1993, 34, 5127.
C10H13NO3 calc.
(195.222) found
C
61.52
61.73
H
6.71
6.59
N 7.18
6.95
(3) Mimoto, T.; Imai, J.; Kisanuki, S.; Enomoto, H.; Hattori, N.;
Akaji, K.; Kiso, Y. Chem. Pharm. Bull. 1992, 40, 2251.
Kageyama, S.; Mimoto, T.; Murakawa, Y.; Nomizu, M.; Ford,
H. Jr.; Shirasaka, T.; Gulnik, S.; Erickson, J.; Takada, K.;
Hayashi, H.; Broder, S.; Kiso, Y.; Mitsuya, H. Antimicrob.
Agents Chemother. 1993, 37, 810.
Acknowledgment
The authors are indebted to Mr. Hajime Hiramatsu in this company
for the X-ray analysis.
(4) Seki, M.; Matsumoto, K. Biosci. Biotech. Biochem. 1996, 60,
916.
(5) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919.
(6) Displacement ellipsoids are drawn at 50% probability level.
Johnson, C. K. ORTEP II, Report ORNL-5138, Oak Ridge
National Laboratory, Oak Ridge, TN, USA, 1976. The X-ray
data have been deposited to Cambridge Crystallographic Data
Centre.
References
(1) Synthesis of Amino Acids and Related Compounds. 47. Part
46: Seki, M.;Matsumoto, K. Tetrahedron Lett. 1996, 37, 3165.
(2) (a) Sasai, H.; Kim, W.-S.; Suzuki, T.; Shibasaki, M.
Tetrahedron Lett. 1994, 35, 6123.
(b) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J.; Ichihara,
O. Tetrahedron 1994, 50, 3975.
(c) Reetz, M. T.; Drewes, M. W.; Harms, K.; Reif, W.
Tetrahedron Lett. 1988, 29, 3295.
(d) Herranz, R.; Castro-Pichel, J.; Vinuesa, S.; Garcia-Lopez,
Article Identifier:
1437-210X,E;1999,0,06,0924,0926,ftx,en;F08799SS.pdf
Synthesis 1999, No. 6, 924–926 ISSN 0039-7881 © Thieme Stuttgart · New York