Ring-opening of oxazolines derived from l-serine: a short and efficient stereoselective synthesis of all four diastereomers of 3-mercaptoaspartic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.08.041

Facile methods are described for accessing four diastereomerically pure 3-mercaptoaspartic acid derivative from l-aspartic acid. In our synthesis, ring-opening reactions of oxazoline-4,5-dicarboxylate with thiolacetic acid as well as the stereochemical interconversion of both α- and β-configuration via oxazoline chemistry were utilized as key steps.

Full text of DOI:10.1016/j.tetlet.2007.08.041

Tetrahedron Letters 48 (2007) 7309–7312
Ring-opening of oxazolines derived from L-serine: a short
and efficient stereoselective synthesis of all four diastereomers
of 3-mercaptoaspartic acid derivatives
Sang-Hyeup Lee,a,b Juhan Bok,a Xin Qi,c Sook Kyung Kim,c Yoon-Sik Leed,* and
Juyoung Yoonc,*
aSystemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea
bDepartment of Life Chemistry, Catholic University of Daegu, Gyeongsan 712-702, Republic of Korea
cDivision of Nano Sciences (BK21) and Department of Chemistry, Ewha Womans University, Seoul 120-750, Republic of Korea
dSchool of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
Received 5 July 2007; revised 8 August 2007; accepted 10 August 2007
Available online 15 August 2007
Abstract—Facile methods are described for accessing four diastereomerically pure 3-mercaptoaspartic acid derivative from L-aspar-
tic acid. In our synthesis, ring-opening reactions of oxazoline-4,5-dicarboxylate with thiolacetic acid as well as the stereochemical
interconversion of both a- and b-configuration via oxazoline chemistry were utilized as key steps.
Ó 2007 Elsevier Ltd. All rights reserved.
There is an ever-growing interest in the synthesis and
biological evaluation of non-proteinogenic amino acids,
peptides, and peptidomimetics.1 One particular syn-
thetic interest lies on the b-substituted aspartates, since
their derivatives are found in many biologically active
compounds, both synthetic and natural.2 However,
compared with other b-substituted derivatives such as
b-hydroxy, amino, or alkyl, the synthesis of b-mercap-
toaspartic acid has received little attention.3,4 This is
surprising since a thiol moiety has been extensively
utilized as zinc chelating group in the development of
potent inhibitors for numerous zinc-metalloproteases,
such as angiotensin converting enzyme and matrix
metalloproteinases, which play a crucial role in the acti-
vation or inactivation of regulatory peptides.5,6
L-aspartic acid using electrophilic sulfenylation as a key
step. Even though this approach is an efficient way
of preparing b-amino-a-mercapto acids, only erythro
isomers are accessible. It was also demonstrated that
the nucleophilic ring-opening of N-activated trans-
aziridine-2,3-dicarboxylate with alkylthiol afforded the
erythro b-(alkylthio)aspartic acid derivatives.4
2-Oxazolines 1 are versatile building blocks in organic
synthesis, and can be opened in two ways (Fig. 1).
1
R
2
3
1
N
2
O
5
4
3
R
R
1
"Hydrolytic ring-opening"
"Nucleophilic ring-opening"
synthetic equivalent of C-5 cation
General methods for the synthesis of b-amino-a-mer-
capto acids include the electrophilic sulfenylation of
N-protected b-amino esters, which can be available via
the Arndt–Eistert homologation of the corresponding
a-amino acids derivatives.5 Both the Baldwin3 and Ro-
ques6b,c groups reported the stereoselective synthesis of
protected erythro (2R,3R)-3-mercaptoaspartic acid from
masked β-aminoalcohol
path a
aq. HCl
path b
NuH
2
2
O
R
O
R
3
3
R
R
1
1
R
N
R
N
H
H
OH
Nu
2
3
inversion of configuration at C-5
retention of configuration at C-5
*
Corresponding authors. Tel.: +82 2 880 7073; fax: +82 2 880 1604
(Y.-S.L.); tel.: +82 2 3277 2400; fax: +82 2 3277 2384 (J.Y.); e-mail
addresses: yslee@snu.ac.kr; jyoon@ewha.ac.kr
Figure 1. 2-Oxazoline: masked b-aminoalcohol or synthetic equivalent
of C-5 cation.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.041

7310
S.-H. Lee et al. / Tetrahedron Letters 48 (2007) 7309–7312
Firstly, the oxazoline ring can be considered as masked
b-aminoalcohols 2 in the hydrolytic ring-opening, which
does not involve the configurational change at the C-5
position (path a).7 Secondly, oxazolines 1 can be consid-
ered as the synthetic equivalent of a C-5 cation in the
synthesis of substituted amine 3 with inversion of C-5
configuration (path b).8 The stereoselective nucleophilic
ring-opening reactions of oxazoline-5-carboxylates
developed by us has been successfully applied in the syn-
thesis of both syn and anti a-substituted-b-amino acid
derivatives, such as a,b-diamino acids,8,9 phenylisocy-
steins,8,10 and 20-mercaptopaclitaxel derivatives.11 Here-
in, we report an efficient stereoselective synthesis of the
unnatural amino acids containing thiol moiety at the
b-position, all four isomers of 3-mercaptoaspartic acid
derivative, from L-aspartic acid (4) via ring-opening of
oxazoline strategy (Scheme 1).
3-mercaptoaspartic acid derivative 7 in 68% yield with
a clean inversion of configuration at the C-5 position
of the parent oxazoline 6.14 The Campiani group15 re-
cently reported the synthesis of D-threo-3-hydroxyaspar-
tic acid from its L-threo-isomer in which inversion of
both the a- and b-configuration was achieved by base-
induced epimerization16 and deoxo-fluor-catalyzed cyli-
zation,17 respectively. Following this route, trans-
(4S,5S)-6 was hydrolyzed under mild acidic condition
to afford L-threo-3-hydroxyaspartic acid derivative 8,
which in turn was transformed to cis-(4S,5R)-oxazo-
line-4,5-dicarboylate 9 by the treatment of deoxo-fluor
with inversion of the C-5 configuration.13 cis-(4S,5R)-
Oxazoline 6, which is less reactive compared to its
trans-isomer,8–10 was treated with neat thiolacetic acid
at 90 °C for 12 h to provide the desired L-threo-
(2R,3S)-10 in 88% yield with a clean inversion of config-
uration at the C-5 position of the parent oxazoline 9.14
The key intermediate, trans-(4S,5S)-oxazoline-4,5-dicar-
boxylate 6, was synthesized starting from L-aspartic acid
(4). Esterification of both a- and b-carboxyl groups of 4
with dry HCl in methanol, followed by benzoylation of
the resulting diester with benzoyl chloride resulted in the
corresponding N-benzoyl diester 5 in 82% yield for the
two steps. Following a known procedure reported by
the Cardillo group,12 N-benzoyl diester 5 was then trea-
ted with 2 equiv of LiHMDS, followed by quenching
with I2, to give trans-(4S,5S)-oxazoline 6 as the exclusive
diastereomer.13 The nucleophilic ring-opening reaction
of trans-(4S,5S)-6 with thiolacetic acid/THF (1:1) at
70 °C for 12 h afforded the desired L-erythro-(2R,3R)-
The remaining two diastereomers with D-configuration
could be synthesized following the exactly same proce-
dure utilized in the preparation of two L-diastereomers
starting from D-aspartic acid. However, as shown in
Scheme 1, the remaining two diastereomers could also
be synthesized via further manipulation of both the 4-
and 5-configuration of oxazoline-4,5-dicarboxylates.15–17
Base-induced epimerization at C-4 configuration led to
the formation of the thermodynamically more stable
trans-(4R,5R)-isomer 11 in trans cis ratio of 95:5 dr,
which was then purified by flash chromatography to give
pure 11 in 77% yield.13 The ring-opening of (4R,5R)-
O
Ph
O
CH COSH/THF
(1:1, v/v)
i) 0.5M HCl/MeOH
reflux 16 h
3
NH
2
Ph
NH
ref. 12
N
O
CO H
2
Ph
NH
CO Me
HO C
2
2
o
MeO C
ii) BzCl, TEA
CH Cl , r.t.
i) LiHMDS
2
70 C, 12 h
CO Me
2
MeO C
MeO C
CO Me
2
2
2
2
ii) I
2
Me
S
4
, L-aspartic acid
2
(2
S
)-5
trans-(4S,5S)-6
O
L-erythro-(2R,3R)-7
Dioxane/0.1N HCl
(1:1,v/v)
ref. 12
O
Ph
O
Ph
NH
ref. 15
N
O
CH COSH
Ph
NH
3
CO Me
2
MeO C
CO Me
2
2
o
Deoxo-fluor
90 C, 12 h
MeO C
MeO C
CO Me
2
2
2
Me
S
OH
,3
cis-(4S,5R)-9
O
L-threo-(2R,3S)-10
L
-threo-(2
R
S
)-8
DBU cat.
ref. 15
O
O
Ph
Ph
CH COSH/THF
(1:1, v/v)
3
Ph
MeO C
NH
Ph
MeO C
NH
CH COSH
ref. 15
3
N
O
N
O
CO Me
CO Me
2
2
o
o
2
i) Dioxane/0.1N HCl
2
70 C, 12 h
90 C, 12 h
MeO C
CO Me
MeO C
CO Me
Me
(1:1,v/v)
S
Me
2
2
S
2
2
ii) Deoxo-fluor
trans-(4
R,5
R)-11
O
cis-(4
R,5
S
)-13
O
D-threo-(2S,3R)-14
D
-erythro-(2
S,3S)-12
Scheme 1.

S.-H. Lee et al. / Tetrahedron Letters 48 (2007) 7309–7312
7311
5. Gordon, E. M.; Godfrey, J. D.; Delaney, N. G.; Asaad,
M. M.; Langen, D. V.; Cushman, D. W. J. Med. Chem.
1988, 31, 2199.
trans-isomer with diluted thiolacetic acid afforded D-
erythro-3-mercaptoaspartic acid derivative 12 in 84%
yield.14 Following the same two-step reaction sequence
from trans-6 to its cis-isomer 9, trans-(4R,5R)-11 was
transformed to cis-(4R,5S)-isomer 13,13 which was then
ring-opened with neat thiolacetic acid to provide the D-
threo-(2S,3R)-14 in 84% yield.
6. For some recent examples, see: (a) Bischoff, L.; David, C.;
´
Martin, L.; Meudal, H.; Roques, B. P.; Fournie-Zaluski,
M.-C. J. Org. Chem. 1997, 62, 4848; (b) David, C.;
´
Bischoff, L.; Meudal, H.; Mothe, A.; Mota, N. D.;
`
´
DaNascimento, S.; Llorens-Cortes, C.; Fournie-Zaluski,
M.-C.; Roques, B. P. J. Med. Chem. 1999, 42, 5197; (c)
In conclusion, we have provided a convenient synthetic
access to all four diastereomers of 3-mercaptoaspartic
acid derivative 7, 10, 12, and 14 from L-aspartic acid.
In our synthesis, ring-opening reactions of oxazoline-
4,5-dicarboxylates with thiolacetic acid as well as the
stereochemical interconversion of a- and b-configura-
tion via oxazoline chemistry were utilized as key steps.
´
David, C.; Bischoff, L.; Roques, B. P.; Fournie-Zaluski,
M.-C. Tetrahedron 2000, 56, 209; (d) Martin, L.; Cornille,
´
F.; Coric, P.; Roques, B. P.; Fournie-Zaluski, M.-C. J.
Med. Chem. 1998, 41, 3450; (e) Gaucher, J. F.; Selkti, M.;
´
Tiraboschi, G.; Prange, T.; Roques, B. P.; Tomas, A.;
´
Fournie-Zaluski, M.-C. Biochemistry 1999, 38, 12569; (f)
Robl, J. A.; Sulsky, R.; Sieber-McMaster, E.; Ryono, D.
E.; Cimarusti, M. P.; Simpkins, L. M.; Karanewsky, D. S.;
Chao, S.; Asaad, M. M.; Seymour, A. A.; Fox, M.; Smith,
P. L.; Trippodo, N. C. J. Med. Chem. 1999, 42, 305; (g)
Baxter, A. D.; Bhogal, R.; Bird, J. B.; Buckley, G. M.;
Gregory, D. S.; Hedger, P. C.; Manallack, D. T.; Massil,
T.; Minton, K. J.; Montana, J. G.; Neidle, S.; Owen, D.
A.; Watson, R. J. Bioorg. Med. Chem. Lett. 1997, 7, 2765;
(h) Akasaka, K.; Akamatsu, H.; Kimoto, Y.; Komatsu,
Y.; Shimizu, T.; Shimomura, N.; Tagami, K.; Negi, S.
Chem. Pharm. Bull. 1999, 47, 1525; (i) Akasaka, K.;
Komatsu, Y.; Tagami, K.; Shimizu, T.; Shimomura, N.;
Naka, H.; Hayashi, K.; Negi, S. Chem. Pharm. Bull. 1999,
47, 1532; (j) Blommaert, A.; Turcaud, S.; Anne, C.;
Roques, B. P. Bioorg. Med. Chem. Lett. 2004, 12, 3055; (k)
Sukonpan, C.; Oost, T.; Goodnough, M.; Tepp, W.;
Johnson, E. A.; Rich, D. H. J. Pept. Res. 2004, 63,
181.
Acknowledgments
This work was supported by the SRC program of
the Korea Science and Engineering Foundation
(KOSEF) (R11-2005-008-02001-0), the Korea Research
Foundation Grant (KRF-2004-005-C00093) and the
research grant from KRIBB Research Initiative
Program, Korea.
Supplementary data
7. For some recent examples, see: (a) Cardillo, G.; Glen-
tilucci, L.; Tolomelli, A. Aldrichim. Acta 2003, 36, 39, and
references cited therein; (b) Feske, B. D.; Kaluzna, I. A.;
Stewart, J. D. J. Org. Chem. 2005, 70, 9654; (c) Voronkov,
M. V.; Gontcharov, A. V.; Wang, Z.-M.; Richardson, P.
1H and 13C spectra for the compounds 5–14. Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2007.08.041.
´
F.; Kolb, H. C. Tetrahedron 2004, 60, 9043; (d) Garcıa
´
Ruano, J. L.; Garcıa Paredes, C. Tetrahedron Lett. 2000,
41, 5357.
References and notes
8. Lee, S.-H.; Yoon, J.; Nakamura, K.; Lee, Y.-S. Org. Lett.
2000, 2, 1243.
9. Lee, S.-H.; Yoon, J.; Chung, S.-H.; Lee, Y.-S. Tetrahedron
2001, 57, 2139.
10. Lee, S.-H.; Qi, X.; Yoon, J.; Nakamura, K.; Lee, Y.-S.
Tetrahedron 2002, 58, 2777.
11. (a) Qi, X.; Lee, S.-H.; Yoon, J.; Lee, Y.-S. Tetrahedron
2003, 59, 7409; (b) Qi, X.; Lee, S.-H.; Yoon, J.; Lee, Y.-S.
Tetrahedron 2004, 60, 3599; (c) Qi, X.; Lee, S.-H.; Yoon,
J.; Lee, Y.-S. Tetrahedron 2004, 60, 4133.
1. (a) For some recent reviews, see: Chan, W. C., Higton, A.,
Davies, J. S. In Amino Acids, Peptides and Proteins, 2006;
pp 1–73; (b) Ager, D. J.; Fotheringham, I. G. Curr. Opin.
Drug Discov. Dev. 2001, 4, 800; (c) Asymmetric Synthesis
of Novel Sterically Constrained Amino Acids; Symposium-
in-Print, Hruby, V. J., Soloshonok, V. A. Eds., Tetrahe-
dron 2001, Vol. 57, p 6329 and references cited therein; (d)
Lee, K.-H. Curr. Pharm. Des. 2002, 8, 795; (e) Bouifraden,
S.; Drouot, C.; El Hadrami, M.; Guenoun, F.; Lecointe,
L.; Mai, N.; Paris, M.; Pothion, C.; Sadoune, M.;
Sauvagnat, B.; Amblard, M.; Aubagnac, J. L.; Calmes,
M.; Chevallet, P.; Daunis, J.; Enjalbal, C.; Fehrentz, J. A.;
Lamaty, F.; Lavergne, J. P.; Lazaro, R.; Rolland, V.;
Roumestant, M. L.; Viallefont, P.; Vidal, Y.; Martinez, J.
Amino Acids 1999, 16, 345; (f) Ohfune, Y. Acc. Chem. Res.
1992, 25, 360.
2. (a) Fernandez-Megia, E.; Paz, M. M.; Sardina, F. J. J.
Org. Chem. 1994, 59, 7643, and references cited therein;
(b) Charvillon, F. B.; Amouroux, R. Synth. Commun.
1997, 27, 395.
3. (a) Shibata, N.; Baldwin, J. E.; Jacobs, A.; Wood, W. E.
Tetrahedron 1996, 52, 12839–12852; (b) Shibata, N.;
Baldwin, J. E.; Jacobs, A.; Wood, W. E. Synlett 1996,
1996, 519.
12. Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C.
Synlett 1999, 1727.
13. The 1H, 13C NMR, and HRMS spectra of trans-oxazo-
lines were consistent with the data reported previously.12
Optical purity was verified by an optical rotation analysis,
which was compared to the reported values {[a]D +45.1 (c
1, CHCl3) for (4S,5S)-6; ꢀ46.9 (c 1, CHCl3) for (4R,5R)-
11; lit.12,15 +42.2 (c 1.2, CHCl3) and 41.8 (c 0.8, CHCl3)
for (4S,5S)-isomer; ꢀ42.6 (c 1, CHCl3) for (4R,5R)-
isomer}. The spectral data of the cis-oxazolines show a
distinct difference compared to their trans-isomers.
(4S,5R)-9: [a]D +178.5 (c 1, CHCl3); mp 80–82 °C; 1H
NMR (CDCl3, 300 MHz) d 3.77 (s, 3H), 3.79 (s, 3H), 5.24
(d, J = 10.5 Hz, 1H), 5.30 (d, J = 11.1 Hz, 1H), 7.38–7.58
(m, 3H), 7.96–8.08 (m, 2H); 13C NMR (CDCl3, 75 MHz) d
52.66, 52.75, 72.15, 78.17, 126.16, 128.41, 128.83, 132.28,
166.19, 168.53, 169.36; HRMS (FAB) m/z = 264.0868
(M+H)+, Calcd for C13H14N1O5 = 264.0872. (4R,5S)-13
4. Antolini, L.; Bucciarelli, M.; Caselli, E.; Davoli, P.; Forni,
A.; Moretti, I.; Prati, F.; Torre, G. J. Org. Chem. 1997, 62,
8784.

7312
S.-H. Lee et al. / Tetrahedron Letters 48 (2007) 7309–7312
shows same spectral data and optical rotation with
opposite sign compared with (4S,5R)-9.
1998, 39, 869; (c) Evans, D. A.; Janey, J. M.; Magomedov,
N.; Tedrow, J. S. Angew. Chem., Int. Ed. 2001, 40,
1884.
1
14. L-erythro-(2R,3R)-7: [a]D +60.7; mp 73–75 °C; H NMR
(CDCl3, 300 MHz) d 2.39 (s, 3H), 3.79 (s, 3H), 3.80 (s,
3H), 5.07 (d, J = 3.7 Hz, 1H), 5.37 (dd, J = 3.7, 9.3 Hz,
1H), 7.27 (br d, J = 9.3 Hz, 1H), 7.40–7.60 (m, 3H), 7.75–
7.90 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 30.05, 46.85,
53.05, 53.23, 53.38, 127.19, 128.61, 131.97, 133.44, 167.38,
169.66, 170.85, 192.21; HRMS (FAB) m/z = 340.0849
(M+H)+, Calcd for C15H18N1O6S1 = 340.0855. D-erythro-
(2S,3S)-12 shows same spectral data and optical rotation
with opposite sign compared with L-erythro-7. L-Threo-
(2R,3S)-10: [a]D +11.3; mp 160–162 °C; 1H NMR (CDCl3,
300 MHz) d 2.38 (s, 3H), 3.78 (s, 3H), 3.79 (s, 3H), 4.86 (d,
J = 4.2 Hz, 1H), 5.38 (dd, J = 4.2, 8.7 Hz, 1H), 6.98 (br d,
J = 8.7 Hz, 1H), 7.40–7.58 (m, 3H), 7.74–7.84 (m, 2H);
13C NMR (CDCl3, 75 MHz) d 30.02, 47.73, 53.13, 53.39,
53.84, 127.19, 128.65, 132.06, 133.24, 166.80, 169.62,
169.97, 192.92; HRMS (FAB) m/z = 340.0860 (M+H)+,
Calcd for C15H18N1O6S1 = 340.0855. D-threo-(2S,3R)-14
shows same spectral data and optical rotation with
opposite sign compared with L-threo-10.
17. Stereochemical interconversion of vicinal aminoalochols
via the formation of intermediate oxazoline is well
documented. For examples, of b-amino-a-hydroxy esters
accompanying C-a inversion via oxazoline-5-carboxylates,
see: (a) Sakakura, A.; Kondo, R.; Ishihara, K. Org. Lett.
2005, 7, 1971, and references cited therein; (b) Singh, O.
V.; Han, H. Tetrahedron Lett. 2003, 44, 5289; (c) Phillips,
A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org.
Lett. 2000, 2, 1165, and references cited therein; For
examples of b-hydroxy-a-amino esters accompanying C-b
inversion via oxazoline-4-carboxylates, see: (d) Tosaki, S.-
y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 2147; (e) Castagnolo, D.; Armaroli, S.;
Corelli, F.; Botta, M. Tetrahedron: Asymmetry 2004, 15,
941; (f) Hamamoto, H.; Mamedov, V. A.; Kitamoto, M.;
Hayashi, N.; Tsuboi, S. Tetrahedron: Asymmetry 2000,
4485; (g) Lee, J.-M.; Lim, H.-S.; Seo, K.-C.; Chung, S.-K.
Tetrahedron: Asymmetry 2003, 14, 3639; (h) Gou, D.-M.;
Liu, Y.-C.; Chen, C.-S. J. Org. Chem. 1993, 58, 1287; An
analogous stereochemical interconversion of 1,3-amino-
alcohols via the formation of intermediate oxazines, see:
(i) Singh, O. V.; Kampf, D. J.; Han, H. Tetrahedron Lett.
2004, 45, 7239.
15. De Angelis, M.; Campiani, G. Tetrahedron Lett. 2004, 45,
2355.
16. (a) Suga, H.; Ikai, K.; Ibata, T. J. Org. Chem. 1999, 64,
7040; (b) Suga, H.; Ikai, K.; Ibata, T. Tetrahedron Lett.