Mild regeneration of the carboxylic group of amino acid alkyl esters by aqueous methanolic sodium hydrogen carbonate via 5-oxazolidinones

Article abstract of DOI:10.1016/j.tetlet.2003.08.028

A simple racemization-free procedure allows the regeneration of the carboxylic acid group of amino acid alkyl esters by way of an intermediate 5-oxazolidinone which is hydrolyzed by treatment with sodium hydrogen carbonate in aqueous methanol.

Full text of DOI:10.1016/j.tetlet.2003.08.028

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7663–7665
Mild regeneration of the carboxylic group of amino acid alkyl
esters by aqueous methanolic sodium hydrogen carbonate via
5-oxazolidinones
Pietro Allevia,* and Mario Anastasiab
aDipartimento di Medicina, Chirurgia e Odontoiatria, Universita` di Milano, via A. Di Rudin`ı 8, I-20142 Milano, Italy
bDipartimento di Chimica, Biochimica e Biotecnologie per la Medicina, Universita` di Milano, via Saldini 50, I-20133 Milano,
Italy
Received 3 July 2003; revised 28 July 2003; accepted 7 August 2003
Abstract—A simple racemization-free procedure allows the regeneration of the carboxylic acid group of amino acid alkyl esters
by way of an intermediate 5-oxazolidinone which is hydrolyzed by treatment with sodium hydrogen carbonate in aqueous
methanol.
© 2003 Published by Elsevier Ltd.
One of the key issues in peptide synthesis, both in solid
phase and solution, is to have optically pure amino
acids protected with acid–base stable protecting groups
that are readily cleavable under non racemizing condi-
tions.1 This field has been extensively developed over
the past few decades and some amino protecting groups
have emerged as very satisfactory,1–4 such as the benzyl-
oxycarbonyl (Cbz),5 the tert-butyloxycarbonyl (Boc),6
the 9-fluorenylmethyloxycarbonyl (Fmoc),7 and the
recently introduced 1,1-dioxobenzo[b]thiophene-2-
ylmethyloxycarbonyl (Bsmoc)8a and 2-(tert-butylsul-
fonyl)-2-propenoxycarbonyl (Bspoc)8b,c groups. On the
other hand, protection of the carboxylic group, typi-
cally carried out with the easily formed methyl or ethyl
esters, still suffers from problems associated with
hydrolytic cleavage, which requires strongly basic con-
ditions and may compromise the configuration of the
regenerated amino acid or may damage other base
labile groups present in the molecule. Thus, milder
methods have been reported for the hydrolysis of
methyl esters,9 and other esters have been used,1a
including tert-butyl esters10 which are usually more
difficult to obtain but can be cleaved under acidic
conditions,11 allyl esters12 which can be removed with
palladium complexes,13,14 and benzyl esters which gen-
erally can be removed by catalytic hydrogenation.14
We report herein a successful protocol for a two-step
cleavage of easily accessible methyl esters of Cbz-,
Fmoc- and Boc-protected amino acids. This protocol
consists of two simple reactions: the preparation of
5-oxazolidinones by acid-catalyzed condensation of
protected amino esters, and their hydrolysis by treat-
ment with sodium hydrogen carbonate in aqueous
methanol (Scheme 1). Under these very mild conditions
the regeneration of the amino acid carboxylic group
occurs without racemization, and they are potentially
compatible with many base-labile groups.
5-Oxazolidinones can be prepared by reaction of N-
acylated amino acids with paraformaldehyde and cata-
lytic amounts of a sulfonic acid, according to a
procedure first described by Ben-Ishai.15 The possibility
of preparing them from the corresponding alkyl esters
Scheme 1. Reagents and conditions: (i) paraformaldehyde (5
equiv. of CH2O when R2=Cbz; 50 equiv. of CH2O when
R2=Fmoc or Boc), p-TsOH (0.1 equiv.), toluene (0.01 M
solution of 1), 100°C, 0.5–2 h; (ii) NaHCO3 (a saturated
solution in MeOH–H2O 1:1 v/v), 0.01 M for 3, reflux, 5–10
min.
* Corresponding author. Fax: +39 0250316040; e-mail: pietro.allevi@
unimi.it
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.08.028

7664
P. Alle6i, M. Anastasia / Tetrahedron Letters 44 (2003) 7663–7665
Table 1.
Entry
Amino ester 1
Yielda (%) of 2
Final amino acid 3
Yielda (%) of 3
R1
R2
R1
R2
1
2
3
4
5
6
7
8
9
(CH2)2SCH3
CH2C6H5
CH2(CH3)2
(CH2)3CO2Me
(CH2)2SCH3
CH2C6H5
CH2(CH3)2
(CH2)2SCH3
CH2(CH3)2
(CH2)3CO2Me
Cbz
Cbz
Cbz
Cbz
Fmoc
Fmoc
Fmoc
Boc
Boc
Boc
85–90
85–90
60–65
80–85
85–90
70–75
80–85
35–40
25–35
50–55
(CH2)2SCH3
CH2C6H5
CH2(CH3)2
(CH2)3CO2Me
(CH2)2SCH3
CH2C6H5
CH2(CH3)2
(CH2)2SCH3
CH2(CH3)2
(CH2)3CO2Me
Cbz
Cbz
Cbz
Cbz
H
H
H
Boc
Boc
Boc
>95
>95
>95
>95
>95
>95
>95
75
80
5
10
a All starting esters were from commercial sources or obtained by esterification of commercial protected amino acids.
Acknowledgements
via a similar reaction was not reported. Our work has
shown that a-substituted glycines can be similarly
transformed into the corresponding 5-oxazolidinones,
and that the 5-oxazolidinone ring can be hydrolyzed by
treatment with aqueous sodium hydrogen carbonate.
5-Oxazolidinones have previously been cleaved by cata-
lytic hydrogenolysis or by saponification with strong
bases (i.e. 1 M NaOH).16
This work is dedicated to the memory of Professor
Giovanni Galli and was supported financially by Italian
MIUR (Ministero dell’Istruzione, dell’Universita` e della
Ricerca).
References
Our method was applied to various N-protected amino
1. (a) Green, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3nd ed.; New York: John Wiley, 1999;
(b) Jarowicki, K.; Kocienski, P. J. Chem. Soc., Perkin
Trans. 1 1998, 4005–4037; ibid. 2000, 2495–2572.
2. Allevi, P.; Anastasia, M. Tetrahedron: Asymmetry 2003,
14, 2005–2012 and references reported therein.
3. Allevi, P.; Anastasia, M. Tetrahedron: Asymmetry 2000,
11, 3151–3160.
4. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870–
876.
5. Paquet, A. Can. J. Chem. 1982, 60, 976–980.
6. Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368–6380
and references reported therein.
acid methyl esters (Scheme 1, Table 1).17
The protocol worked well with Cbz- and Fmoc-pro-
tected amino acids (entries 1–7) while unsatisfactory
yields were obtained with Boc-protected amino acids
(entries 8–10), due mainly to the low yields observed in
the transformation of the Boc aminoesters to 5-oxazo-
lidinones. Of particular interest is the possibility of
selectively hydrolyzing the amino acid methyl ester of
the dimethyl glutamate (entry 4).
In the case of Boc-protected amino acids the conversion
was low and some by-products were formed before all
the starting compound had reacted. However the yields
were comparable to those observed in the preparation
of the same 5-oxazolidinones from the free amino
acids.15 Hydrolysis of the 5-oxazolidinone rings was
very satisfactory, in all but one case (entry 10).
7. (a) Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 37,
3404–3409; (b) Ciommer, M.; Kunz, H. Synlett 1991,
593–595.
8. (a) Carpino, L. A.; Philbin, M.; Ismail, M.; Truran, G.
A.; Mansour, E. M. E.; Iguchi, S.; Ionescu, D.; El-
Faham, A.; Riemer, C.; Warras, R.; Weiss, M. S. J. Am.
Chem. Soc. 1997, 119, 9915–9916; (b) Carpino, L. A.;
Ismail, M.; Truran, G. A.; Mansour, E. M. E.; Iguchi, S.;
Ionescu, D.; El-Faham, A.; Riemer, C.; Warras, R. J.
Org. Chem. 1999, 64, 4315–4323; (c) Carpino, L. A.;
Ismail, M.; Truran, G. A.; Mansour, E. M. E.; Iguchi, S.;
Ionescu, D.; El-Faham, A.; Riemer, C.; Warras, R. J.
Org. Chem. 1999, 64, 4324–4338.
9. (a) Furlan, R. L. E.; Mata, E. G.; Mascaretti, O. A.
Tetrahedron Lett. 1996, 37, 5229–5232. For a review on
the deprotection of esters, see: (b) Salomon, J. C.; Mata,
E. G.; Mascaretti, O. A. Tetrahedron 1993, 49, 3691–
3734.
Interestingly the opening of Fmoc-protected 5-oxazo-
lidinones results in hydrolysis of the Fmoc group
thereby regenerating the amine. The reaction involves a
simple and unreported hydrolysis of the Fmoc group by
means of aqueous hydrogen carbonate, instead of mild
organic bases such as morpholine, which in some cases
require repetitive treatment which can result in
epimerization.1b,19
In conclusion, a two-step procedure for the regenera-
tion of the carboxylic group of amino acid alkyl esters
is reported. This work utilizes 5-oxazolidinones as inter-
mediates in the deprotection of amino acid esters under
mild conditions.
10. (a) Wright, S. W.; Hageman, D. L.; Wright, A. S.;
McClure, L. D. Tetrahedron Lett. 1997, 38, 7345; (b)
Loffet, A.; Galeotti, N.; Jouin, P.; Castro, B. Tetrahedron
Lett. 1989, 30, 6859–6860.

P. Alle6i, M. Anastasia / Tetrahedron Letters 44 (2003) 7663–7665
7665
11. Allevi, P.; Galligani, M.; Anastasia, M. Tetrahedron:
Asymmetry 2002, 13, 1901–1910.
12. Kunz, H.; Waldmann, H. Angew. Chem., Int. Ed. Engl.
cated by the presence of rotamers for Cbz protected
derivatives. The optical purity of the final compounds
was checked by chiral HPLC. After regeneration of the
amino group (H2, Pd/C, MeOH, room temp., 12 h for
R2=Cbz or CF3CO2H: H2O 95:5, v/v, room temp., 1 h
for R2=Boc) the amino acids obtained were esterified
with methanolic HCl (1 M; 0.2 mL; room temp.; 12 h)
and then trifluoroacetylated [(CF3CO)2O:CF3CO2H; 1:1,
v/v, room temp., 2 h)] and their behaviour on chiral
1980, 23, 71–72.
13. (a) Noyori, R.; Uchiyama, M.; Kato, H.; Wakabayashi,
S.; Hayakawa, Y. Pure Appl. Chem. 1990, 62, 613–622;
(b) Hayakawa, Y.; Hirose, M.; Noyori, R. J. Org. Chem.
1993, 58, 5551–5555.
14. Holm, B.; Broddefalk, J.; Floddell, S.; Wellner, E.;
Kihlberg, J. Tetrahedron 2000, 56, 1579–1586.
15. Ben-Ishai, D. J. Am. Chem. Soc. 1957, 79, 5736–5738.
16. (a) Itho, M. Chem. Pharm. Bull. 1969, 1679–1686; (b)
Williams, R. M.; Yuan, C. J. Org. Chem. 1994, 59,
6169–6193.
GLC3,18
[octakis(3-O-butyryl-2,6-di-O-pentyl)-g-cyclo-
dextrin (Lipodex E) capillary column] was examined and
compared with that of the corresponding derivatives like-
wise prepared from natural commercial and racemic
amino acids.
18. Konig, W. A. J. High Resolut. Chromatogr. 1993, 16,
569–586.
19. Wildemann, D.; Drewello, M.; Fisher, G.; Schutkowski,
M. Chem. Commun. 1999, 1809–1810.
17. All isolated and purified compounds gave satisfactory
NMR (1H and 13C), mass spectrometry and infrared
data, identical to those of commercial or authentic sam-
ples. The NMR spectra of 5-oxazolidinones were compli-