1
494
A. D. Pehere, A. D. Abell / Tetrahedron Letters 52 (2011) 1493–1494
Table 1
Preparation of N-Cbz amino acids
Ph
S
OH i
Ph
S
Cl
NaHCO /Na CO
Cbz-Cl,
rt, pH=8-10, 3 h
3
2
3
O
O
(
S)-Amino Acid
N-Cbz-(S)-Amino acid
O
H
O
1
2
PhS
Producta
CO
2
ii,iii,iv
SPh
Entry
1
Substrate
H N CO H
Yield (%)
N
H
.
HCl
CbzHN
CO H
2
2
2
3
85
92
H
2
N
CO H
CbzHN
CO H
2
2
Ph
S
N
2
3
O
O
CO H
2
4
H N
CO H
CbzHN
CO H
2
2
2
95
Scheme 1. Reagents: (i) SOCl
2
, toluene; (ii) NaHCO3, Na
2
CO
3
; (iii) dicyclohexyl-
amine, EtOH, CH Cl ; (iv) KHSO .
2
2
4
CO H
CO H
2
2
gave a good yield (84%) of 4, however, very large volumes of water
(85 volumes) were required in this case due to the poor solubility
of boric acid. Our method reported here gives 4 in high yield using
manageable volumes of water (30 volumes) and as such is amena-
ble to both small and large scale reactions. This methodology has
recently been used in an industrial scale preparation of Zofenopril.7
In summary, we have reported a simple and convenient method
for the preparation of Cbz-protected amino acids in high yield and
optical purity. The methodology is amenable to both small and
large scale synthesis and can also be used for the introduction of
other amine protecting groups.
4
5
97
90
HO
HO
NH
CO H
NCbz
CO H
H N
CbzHN
2
2
2
Ph
Ph
H N
CO H
CbzHN
CO H
2
2
2
6
7
89
75
OH
OH
H N
CO H
CbzHN
CO H
2
2
2
CO H
Acknowledgements
2
CO H
2
H N
CO H
CbzHN
CbzHN
CO H
2
2
2
We thank Dr. Vinayak Gore (Mylan India Private Limited) for
carrying out the large scale reactions. The authors acknowledge
the financial support of an ARC DP grant (A.D.A.) and the University
of Adelaide for an AFSI scholarship to A.D.P.
8
9
75
95
CONH2
CONH2
H N
CO H
CO H
2
2
2
References and notes
a
1. (a) Isidro-Llobet, A.; Alvarez, M.; Fernando Albericio, F. Chem. Rev. 2009, 109,
All products were characterised by IR and NMR spectroscopy and optical
2
455; (b) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis;
Springer: Berlin, 1994. p 11; (c) Hernandez, J. N.; Martin, V. S. J. Org. Chem. 2004,
9, 3590–3592; (d) Pavan Kumar, V.; Narender, M.; Somi Reddy, M.; Surendra,
rotations.
6
K.; Nageswar, Y. V. D.; Rama Rao, K. Tetrahedron Lett. 2006, 47, 6393–6396; (e)
Berkowitz, D. B.; Pedersen, M. L. J. Org. Chem. 1994, 59, 5476–5478; (f) Maligres,
P. E.; Houpis, I.; Rossen, K.; Molina, A.; Sager, J.; Upadhyay, V.; Wells, K. M.;
Reamer, R. A.; Lynch, J. E.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron 1997,
Table 2
NaHCO /Na CO
3
3
2
(
S)-AminoAcid
N-R-(S)-Aminoacid
3
2, 10983–10992; (g) Abell, A. D.; Jones, M. A.; Coxon, J. M.; Morton, J. D.; Aitken,
RCl, rt, pH=8-10, 3h
S. G.; McNabb, S. B.; Lee, H. Y.-Y.; Mehrtens, J. M.; Alexander, N. A.; Stuart, B. G.;
Neffe, A. T.; Bickerstaffe, R. Angew. Chem., Int. Ed. 2009, 48, 1455–1458; (h) Abell,
A. D.; Oldham, M. D. J. Org. Chem. 1997, 62, 1509–1513; (i) Abell, A. D.; Taylor, J.
M. J. Org. Chem. 1993, 58, 14–15; (j) Edmonds, M. K.; Abell, A. D. J. Org. Chem.
2001, 66, 3747–3752; (k) Abell, A. D.; Gardiner, J. Org. Lett. 2002, 4, 3663–3666.
2. Krapcho, J.; Turk, C.; Cushman, D. W.; Powell, J. R.; DeForrest, J. M.; Spitzmiller, E.
R.; Karanewsky, D. S.; Duggan, M.; Rovnvak, G.; Schwartz, J.; Natarajan, S.;
Godfrey, J. D.; Ryono, D. E.; Neubeck, R.; Atwa, K. S.; Petrillo, E. W. J. J. Med. Chem.
Yielda
Entry
1
Substrate
Product
CO H
CO H
2
2
N
H
N
75
O
1
988, 31, 1148–1160.
3. The (S)-amino acid (10.0 g) was dissolved in
2.0 equiv) and NaHCO (1.0 equiv) were added at rt, with stirring, to give a
Ph
F
2 2 3
H O (300 ml) and Na CO
(
3
H N
CO H
H
N
2
2
O
CO H
clear solution. Acetone (4.0 vol, with respect to the amino acid) was added and
the slightly turbid solution was cooled in an ice water bath to 15–20 °C. Cbz-Cl
(1.25 equiv) was added slowly, with stirring, and the reaction mixture allowed
to warm to rt. After stirring for an additional 3 h at rt the mixture was extracted
2
S
2
80
O
with Et
pH of 2. The resulting oil was extracted into EtOAc (150 ml) and this was washed
with H O (100 ml) and then concentrated in vacuo to give the N-Cbz amino acid
2
O (50 ml). To the aqueous phase was slowly added aqueous HCl to give a
RCl = Ph(CH
2
2
) COCl or 4-FC
6
4
H SO
2
Cl.
a
2
Yield after column chromatography.
as a white solid, see Table 1.
4.
Kiviranta, P. H.; Salo, H. S.; Leppanen, J.; Rinne, V. M.; Kyrylenko, S.; Kuusisto, E.;
Suuronen, T.; Salminen, A.; Poso, A.; Lahtela-Kakkonen, M.; Wallen, E. A. Bioorg.
Med. Chem. 2008, 16, 8054.
by the simultaneous addition of 2 and 2% aqueous sodium hydrox-
ide to a solution of 3 in 2% aqueous sodium hydroxide, gave similar
problems. The addition of 2 to a solution of 3 in a mixture of boric
5. Shirasaki, Y.; Nakamura, M.; Yamaguchi, M.; Miyashita, H.; Sakai, O.; Inoue, J. J.
Med. Chem. 2006, 49, 3926–3932.
6
7
.
.
European Pharmacopoeia, 5th ed., 2005, p 434.
Work performed by our collaborator, Dr. Vinayak Gore of Mylan India (formally
known as the Merck Development Center).
6
acid, potassium chloride and sodium hydroxide (pH 9.5) buffer