Convenient synthesis of 3-(S)-amino-γ-butyrolactone

Article abstract of DOI:10.1055/s-2002-32597

An efficient two step conversion of N-t-Boc-L-aspartic acid β-benzyl ester to enantiopure 3-(S)-amino-γ-butyrolactone is described. In this route, chemoselective reduction of the α-carboxylic group in the starting material via a mixed anhydride with NaBH₄ afforded the corresponding alcohol in 95% yield without any loss of the optical purity. Subsequent acidic hydrolysis of the N-protected β-amino alcohol not only deprotected the amino group, but also produced the desired γ-lactone in 98% yield with complete retention of the optical activity.

Full text of DOI:10.1055/s-2002-32597

LETTER
1105
Convenient Synthesis of 3-(S)-Amino- -butyrolactone
S
ynthesis of 3-(
S
)-A
m
a
ino- -butyr
r
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
Fax +1(225)5783458; E-mail: David_Spivak@chem.lsu.edu
Received 15 April 2002
acetic anhydride is reduced regioselectively with NaBH4
in a 91% yield. The amino group is deprotected via cata-
lytic hydrogenation or acidic hydrolysis in 80–88%
yield.2a,5a,7 A third method involves treatment of tosyl de-
Abstract: An efficient two step conversion of N-t-Boc-L-aspartic
acid -benzyl ester to enantiopure 3-(S)-amino- -butyrolactone is
described. In this route, chemoselective reduction of the -carbox-
ylic group in the starting material via a mixed anhydride with
NaBH4 afforded the corresponding alcohol in 95% yield without rivatives of 4-hydroxymethyl oxazolines with CN– in
any loss of the optical purity. Subsequent acidic hydrolysis of the N-
protected -amino alcohol not only deprotected the amino group,
DMF to form a nitrile, which is hydrolyzed under acidic
conditions to give 1 in a 41% yield.9 Other syntheses re-
but also produced the desired -lactone in 98% yield with complete
ported involve the ozonolysis of aromatic -aminoacids10
retention of the optical activity.
and the conversion of chiral carnitine and derivatives by
Key words: amino acids, amino alcohols, lactones, reductions, ring
closure
intramolecular nucleophilic displacement in one step into
1 (R)-form, with a 77% yield.11
As part of a program directed toward the synthesis of
cross-linking monomers derived from amino acid precur-
sors, we have developed a facile synthesis of 3-(S)-amino-
Enantiopure 3-(S)-amino- -butyrolactone (1) (Figure) is
an important synthon used in the synthesis of biological
-butyrolactone without any loss of optical purity. Our ap-
molecules and natural products. A wide variety of synthe-
proach for the formation of this synthon is shown in
ses that have employed the use of this synthon include the
Scheme, which involved the use of N-t-Boc-L-aspartic ac-
preparation of platelet aggregation inhibitors,1 fibrinogen
id, -benzyl ester (2) as the starting material. Selective re-
duction of the -carboxylic acid in 2 afforded the
corresponding known alcohol 3 in a 95% yield with reten-
receptors antagonists,2 integrin antagonists,3 the inter-
lukin-1 converting enzyme (ICE),4 the synthesis of anti-
bacterials,5 antihistaminic and anti-inflammatory drugs,6
tion of optical activity as determined by HPLC, ee
and as a synthetic intermediate in the synthesis of the
>98%.12 This was obtained in a one pot reaction by
polyketide amphotericin B.7
chemoselective reduction with NaBH4 of the mixed anhy-
dride of the acid, according to the literature.13 Due to vig-
O
orous bubbling in water, methanol was used as co-
solvent.13d
O
HCl H2N
1
Figure
O
O
O
b)
a)
O
O
O
O
Several methodologies have been reported for the synthe-
sis of 3-amino- -butyrolactones; two of these make use of
the N-protected L-aspartic acid as the starting material.
The first approach involves the selective reduction of the
-carboxylic acid with BH3-THF or NaBH4 followed by
lactonization with either camphor sulphonic acid, p-
TsOH, or TFA; and subsequent deprotection of the amine
group with TFA, HCl, HBr, or catalytic hydrogenation to
give yields in the range of 60%.1,2b,3,4,8 In this method, the
use of TFA for lactone formation results in a mixture of
the deprotected amino- -butyrolactone and the deprotect-
ed -aminoalcohol. In the second method, the anhydride
of the N- protected L-aspartic acid initially formed with
O
HCl H2N
HN
O
OH
HN
O
OH
O
2
3
1
Scheme Synthesis of 3-(S)-amino- -butyrolactone.
a) NMM, i-BuCO2Cl, NaBH4, MeOH, in THF/N2, 95%; b) HCl–
Et2O, N2, 98%.
Deprotection of the amino group was carried out using
acidic hydrolysis with HCl–Et2O.14 Optimal conditions
for this hydrolysis are shown in entry 3, Table. Increasing
the ratio of 3/HCl from 1:20 to 1:40 did not improve the
Synlett 2002, No. 7, 01 07 2002. Article Identifier:
1437-2096,E;2002,0,07,1105,1106,ftx,en;S00502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1106
M. Sibrian-Vazquez, D. A. Spivak
LETTER
(5) (a) Chu, D. T.; Li, Q. U.S. Patent 5 252 747, 1993; Chem.
Abstr. 1993, 120, 298642. (b) Ashina, Y.; Fukuda, Y.;
Fukuda, H. E. P. Patent 443 498, 1991; Chem. Abstr. 1991,
115, 256018.
(6) Nagai, K.; Tanaka, R.; Murakami, H.; Sano, A. Arzneim-
Forsch. 1967, 17, 1575; Chem. Abstr. 1967, 68, 67444.
(7) McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara,
Y.; Oh, T. J. Am. Chem. Soc. 1986, 108, 4943.
yield (entry 2), nor did using a solvent mixture of 1:2
CH2Cl2–ether. Under optimal conditions, not only was the
amino group deprotected, the -hydroxy ester also easily
underwent lactonization forming a stable five member
ring without racemization. Based on the 1H NMR and 13C
NMR spectra, the product obtained corresponded to the
known 3-(S)-amino- -butyrolactone hydrochloride 1.
(8) Rinehart, K. L.; Harada, K.; Namikoshi, M.; Chen, C.;
Harvis, C. A.; Munro, M. H. G.; Blunt, J. W.; Mulligan, P.
E.; Beasley, V. R.; Dahlem, A. M.; Carmichel, W. W. J. Am.
Chem. Soc. 1988, 110, 8557.
(9) Atmani, A.; El Hallaoui, A.; El Hajji, S.; Roumestant, M. L.;
Viallefont, P. Synth. Commun. 1971, 21, 2383.
(10) Hvidt, T.; Szarek, W. A.; Maclean, D. B. Can. J. Chem.
1988, 66, 779.
(11) Calvisi, G.; Catini, R.; Chiariotti, W.; Giannessi, F.; Muck,
S.; Tinti, M. O.; De Angelis, F. Synlett 1997, 71.
(12) Benzyl (3S)-[(tert-butoxycarbonyl)amino]-4-hydroxy-
butanoate(3). Prepared from N-t-boc-L-aspartic acid
-benzyl ester following a literature procedure13d as a white
solid. Yield 95%, ee > 98%. Enantiomeric excess was
determined by HPLC using a normal phase Chiralpak AD
column, hexanes–isopropanol 90:10, 1 mL/min, at 250 nm,
mp 62–63.8 °C [ ]D25 –6.0 (c = 1, MeOH); lit.13e [ ]D –6.0 (c
= 1, MeOH). 1H NMR (250 MHz; CDCl3), : 7.33 (s, 5 H),
5.28 (s, 1 H), 5.11 (s, 2 H), 4.00 (s, 1 H), 3.64 (d, J = 4.7 Hz,
2 H), 2.88 (s, 1 H), 2.64 (d, J = 6.2 Hz, 2 H), 1.42 (s, 9 H).
13C NMR (67.5 MHz; CDCl3) : 172.06, 156.23, 135.99,
129.02, 128.76, 128.66, 107.82, 80.29, 67.05, 49.87, 36.47,
28.76. MS (FAB) (M + H+) calcd 310.16, found 310.10.
Anal. Calcd. for C16H23NO5: C, 62.12; H, 7.49; N, 4.53.
Found C, 61.72; H, 7.39; N, 4.41.
(13) (a) Seki, H.; Koga, K.; Matsu, H.; Ohki, S.; Matsuo, I.;
Yamada, S. Chem. Pharm. Bull. 1965, 13, 995. (b) Soai, K.
Bull. Chem. Soc. Jpn. 1984, 57, 2327. (c) Soai, K.;
Yokoyama, S.; Mochida, K. Synthesis 1987, 647.
(d) Kokotos, G. Synthesis 1990, 299. (e) Rodriguez, M.;
Linares, M.; Doulut, S.; Heitz, A.; Martinez, J. Tetrahedron
Lett. 1991, 32, 923.
Table Lactonization of Amino Alcohol 3
Entry
Ratio
3/HCl
Reaction
Temperature
Reaction
Solvent
Yield (%)
1
2
3
1/20
1/40
1/20
0 ºC/6 h
r.t./20 h
CH2Cl2–
Et2O, 1:2
89
75
98
0 ºC/6 h
r.t./12 h
Et2O
0 ºC/6 h
r.t./18 h
Et2O
In summary, a convenient method for the synthesis of 3-
(S)-amino- -butyrolactone with an overall yield of 93%
has been developed. This method represents an advantage
over other methodologies that were previously reported
with lower overall yields (41–81%).
References
(1) (a) Bovy, P. R.; Rico, J. G.; Rogers, T. E. U.S. Patent 6 037
365, 2000; Chem. Abstr. 2000, 132, 207753. (b) Bovy, P.
R.; Rico, J. G.; Rogers, T. E. U.S. Patent 9 506 038, 1995;
Chem. Abstr. 1995, 123, 33068. (c) Bovy, P. R.; Rico, J. G.;
Rogers, T. E. U.S. Patent 9 312 103, 1993; Chem. Abstr.
1993, 120, 106764.
(2) (a) Askew, B. C.; Hartman, G. D.; Duggan, M. E.; Young, S.
D.; Hutchinson, J. H.; Wai, J. S.; Egbertson, M. S.; Vassallo,
L. M.; Libby, L. A.; Ihle, N. C.; Krause, A. E.; Halczenko,
W. U.S. Patent 9 714 417, 1997; Chem. Abstr. 1997, 126,
5353. (b) Askew, B. C.; Hartman, G. D.; Duggan, M. E.;
Young, S. D.; Hutchinson, J. H.; Wai, J. S.; Egbertson, M.
S.; Vassallo, L. M.; Libby, L. A.; Ihle, N. C.; Krause, A. E.;
Halczenko, W. U.S. Patent 5 852 045, 1998; Chem. Abstr.
1998, 130, 66809. (c) Sato, M.; Mannaka, A.; Takahashi,
K.; Kawashima, Y.; Hatayama, K. J. P. Patent 7 206 860,
1995; Chem. Abstr. 1995, 124, 8804. (d) Hartman, G. D.;
Prugh, J. D.; Halczenko, W.; Egbertson, M.; Ihle, N. U.S.
Patent 9 504 531, 1995; Chem. Abstr. 1995, 123, 228162.
(3) Ruminski, P. G.; Clare, M.; Collins, P. W.; Desai, B. N.;
Lindmark, R. J.; Rico, J. G.; Rogers, T. E.; Russell, M. A.
U.S. Patent 9 708 145, 1997; Chem. Abstr. 1997, 126,
264011.
(14) 3-(S)-amino- -butyrolactone hydrochloride(1) The
amino alcohol 4 (1.26g, 4 mmol) was treated with 40 mL of
2 M HCl in diethyl ether. The temperature was kept at 0 °C
for 6 h, then allowed to rise to room temperature, and stirred
for 18 hours. The excess of HCl and ether were evaporated
first under a stream of N2 and then under vacuum. The
residue, a white solid was filtered out, washed with ethyl
ether (3 20 mL), and dried at room temperature. Yield
20
98%. mp 182–184 °C. [ ]D25 –59.3 (c = 1, H2O); lit.11 [ ]D
+ 56.7 (c = 1, H2O) (R) form. 1H NMR [250 MHz; (DMSO-
d6)] : 8.76 (s, 3 H), 4.5 (dd, J = 10.4 Hz, J = 6.6 Hz, 1 H),
4.36 (dd, J = 10.4 Hz, J = 2.7 Hz, 1 H), 4.10 (m, 1 H), 3.0
(dd, J = 18.3, J = 8.5 Hz, 1 H), 2.57 (dd, J = 18.3 Hz, J = 2.9
Hz, 1 H). 13C NMR: [67.5 MHz; (DMSO-d6)] : 175.39,
71.05, 41.19, 33.42. MS (FAB) (M + H+) calcd. 102.1, found
102.1. Anal. Calcd. for C4H8ClNO2: C, 34.92; H, 5.86; N,
10.18; Cl, 25.77. Found C, 34.99; H, 5.62; N, 10.08; Cl,
25.12.
(4) Mullican, M. D.; Lauffer, D. J.; Gillispie, R. J.; Matharu, S.
S.; Kay, D.; Porrit, G. M.; Evans, P. L.; Golec, J. M. C.;
Murcko, M. A. Bioorg. Med. Chem. Lett. 1994, 4(19), 2359.
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