Ceric ammonium nitrate (CAN) mediated esterification of N-Boc amino acids allows either retention or removal of the N-Boc group

Article abstract of DOI:10.1016/j.tetlet.2004.01.136

Reaction of N-Boc amino acids with ceric ammonium nitrate in an alcohol as the solvent at room temperature resulted in the esterification of N-Boc amino acids with Boc group retention. When the reaction was conducted at reflux temperature, esterification was accompanied with simultaneous removal of the Boc group. Both reactions gave the desired products in good yields.

Full text of DOI:10.1016/j.tetlet.2004.01.136

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2663–2665
Ceric ammonium nitrate (CAN) mediated esterification of N-Boc
amino acids allows either retention or removal of the N-Boc group
Ashani Kuttan, Shiek Nowshudin and M. N. A. Rao*
Divis Laboratories Limited, C-26, Sanathnagar, Hyderabad 500018, India
Received 12 November 2003; revised 16 January 2004; accepted 23 January 2004
Abstract—Reaction of N-Boc amino acids with ceric ammonium nitrate in an alcohol as the solvent at room temperature resulted in
the esterification of N-Boc amino acids with Boc group retention. When the reaction was conducted at reflux temperature, ester-
ification was accompanied with simultaneous removal of the Boc group. Both reactions gave the desired products in good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Esters of N-tert-butoxycarbonyl (Boc) amino acids are
widely used in peptide chemistry and in preparing sev-
eral chiral auxiliaries such as b-amino alcohols, oxazo-
esterification of N-Boc amino acids. This paper
describes one such simple and inexpensive method.
1
2
lidinones, and a-amino aldehydes. N-Boc amino esters
can be prepared either from amino esters by reacting
with di-tert-butyl dicarbonate (diBoc), or from N-Boc
amino acids by esterification. Both methods are unsatis-
factory. In the first method, the reaction with diBoc
requires alkaline conditions in which the ester group is
not stable, although in some cases weaker bases can be
used but these require longer reaction times, and the
yields are moderate. In the second method, commonly
used esterification protocols involving reaction with an
alcohol in the presence of acid catalysts such as, HCl,
Recently, Pan et al. reported that phenylacetic acids and
oleic acid react with alcohols in the presence of ceric
11
ammonium nitrate (CAN) to give esters. Earlier, Hwu
et al. had shown that CAN removes the Boc group from
12
amines, alcohols, and thiols. These reports prompted
us to study the effect of CAN on alcoholic solutions of
N-Boc amino acids expecting to obtain esters with
simultaneous removal of the Boc group. However,
contrary to the expectation, we obtained N-Boc amino
esters in good yield and no removal of the Boc group
was observed. Although the reaction solution was acidic
(pH ¼ 2) throughout, the Boc group was retained. Fur-
ther, and interestingly, when the reaction was conducted
at higher temperature, esterification was accompanied
by the removal of the Boc group (Scheme 1). Thus,
CAN mediated reaction of N-Boc amino acids with
alcohols offers a simple and inexpensive alternative
method for preparing the corresponding esters with
either retention or removal of the Boc group.
2 4
H SO , thionyl chloride, PTSA, etc. cannot be used
3
since the Boc group is unstable in acidic conditions.
Presently, N-Boc amino esters are often prepared from
N-Boc amino acids using expensive dehydrating agents
4;5
such as carbodiimides or unsafe reagents such as alkyl
6
;7
8;9
10
halides, diazomethane, or chloroformates. Thus
there is a need for simple alternative methods for the
2
5+5 °C
1
-
Boc-NH-C(R)H-COOR
1
Boc-NH-C(R)H-COOH + R OH + CAN
Reflux
1
NH -C(R)H-COOR
2
Scheme 1.
Keywords: Ceric ammonium nitrate; Esterification; Boc-deprotection.
*
Corresponding author. Tel.: +91-40-23704657; fax: +91-40-23733242; e-mail: mnaprag@sancharnet.in
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.136

2664
A. Kuttan et al. / Tetrahedron Letters 45 (2004) 2663–2665
The procedure is illustrated by a typical example. CAN
10.6 mmol) was added to a solution of N-Boc alanine
a, (10.6 mmol) in dry methanol (20 mL) and the mix-
Table 2. Esterification and Boc deprotection of N-Boc amino acids by
CAN in methanol at reflux temperature
(
1
a
b
Entry Starting material (1) Product (3)
Yield (%)
ture stirred at 25 ± 5 °C until the starting material dis-
appeared (TLC) (24 h). EtOAc (50 mL) and water
1
2
3
4
5
6
7
8
9
1
1
Boc-Ala-OH 1a
Boc-Gly-OH 1b
Boc-Leu-OH 1c
Boc-Phe-OH 1d
Boc-Tyr-OH 1e
Boc-Asp-OH 1f
Boc-Asn-OH 1g
Boc-Trp-OH 1h
Boc-Pro-OH 1i
Boc-Orn-OH 1j
Boc-isonipecotic
acid 1k
H-Ala-OMe 3a
H-Gly-OMe 3b
H-Leu-OMe 3c
H-Phe-OMe 3d
H-Tyr-OMe 3e
82
80
47
52
57
(
20 mL) were added and the mixture stirred. The organic
layer was separated, washed with water (20 mL), and
dried over anhydrous Na SO . The solvent was removed
2
4
H-Asp(OMe)-OMe 3f 82
in vacuo and the residue was purified by column chro-
mato- graphy to give N-Boc alanine methyl ester 2a, in
H-Asn-OMe 3g
H-Trp-OMe 3h
H-Pro-OMe 3i
78
47
73
42
74
8
3% yield as a colorless oil (Table 1). To remove the
N-Boc group, the methanolic solution containing CAN
10.6 mmol) and 1a (10.6 mmol) was refluxed for 24 h.
0
1
H-Orn-OMe 3j
Isonipecotic-OMe 3k
(
The solvent was removed in vacuo and the residue was
purified by column chromatography to give alanine
methyl ester 3a (Table 2) (82%) as a colorless oil.
a
1
The HPLC and H NMR data of the isolated products were identical
to those of the authentic samples.
Isolated yield.
b
When the initial solution was made neutral, neither
esterification nor Boc removal took place. At tempera-
tures below 25 ± 5 °C, esterification was incomplete even
after 48 h. At 40 °C and above, esterification was
accompanied with partial removal of the Boc group.
When the CAN concentration was varied, it was found
that with 0.5 equivalents, esterification was incomplete
and with 1.5 equivalents, there was no significant in-
crease in the rate or yield of esterification but removal of
the Boc group was observed even at room temperature.
Table 3. Esterification of Boc-Ala-OH with alcohols using CAN at
room temperature
a
b
Entry
Alcohol
Product 4
Yield (%)
1
2
3
4
n-PrOH
i-PrOH
t-BuOH
BzOH
Boc-Ala-O-n-Pr 4a
Boc-AlaO-i-Pr 4b
Boc-Ala-O-t-Bu 4c
Boc-Ala-OBz 4d
83
73
No reaction
65
a
1
The HPLC and H NMR data of the isolated products were identical
to those of authentic samples.
Isolated yield.
The generality of the method was examined by studying
various N-Boc amino acids (Tables 1 and 2). In most
cases, except ornithine (Tables 1 and 2, entry 10),
treatment of methanolic solutions of N-Boc amino acids
with CAN at 25 ± 5 °C and at reflux temperature, gave
the corresponding N-Boc amino esters and N-depro-
tected amino esters, respectively, in high yields. Aspartic
acid (Tables 1 and 2, entry 6), being a dicarboxylic acid,
gave a diester. The products 2 and 3 were analyzed for
their stereochemical integrity and no racemization was
found to have occurred during the reaction. A similar
conclusion was drawn by Hwu et al. in their studies on
the removal of the N-Boc group from amino acids using
b
Esterification was also studied using other alcohols
Table 3). n-Propanol (entry 1) reacted with 1a in the
(
presence of CAN to afford an n-propyl ester 4a in 83%
yield. Isopropanol (entry 2), afforded a lower yield of
ester 4b (72%), while with tert-butanol (entry 3) there
was no esterification even after 48 h. Benzyl alcohol
(entry 4) afforded only a 65% yield of benzyl ester 4d.
These results show that the CAN mediated esterification
is influenced by steric factors.
12
In conclusion, the use of CAN affords a simple and
useful method for the conversion of N-Boc amino acids
to N-Boc amino esters, which are difficult to prepare.
Further, the method is also useful for converting N-Boc
amino acids to their esters with simultaneous removal of
the Boc group.
CAN.
Table 1. Esterification of N-Boc amino acids by CAN in methanol at
room temperature
a
b
Entry Starting material 1 Product 2
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
Boc-Ala-OH 1a
Boc-Gly-OH 1b
Boc-Leu-OH 1c
Boc-Phe-OH 1d
Boc-Tyr-OH 1e
Boc-Asp-OH 1f
Boc-Asn-OH 1g
Boc-Trp-OH 1h
Boc-Pro-OH 1i
Boc-Orn-OH 1j
Boc-isonipecotic
acid 1k
Boc-Ala-OMe 2a
Boc-Gly-OMe 2b
Boc-Leu-OMe 2c
Boc-Phe-OMe 2d
Boc-Tyr-OMe 2e
83
78
38
76
62
Acknowledgements
We thank Mr. Murali K. Divi, Chairman and Managing
Director, Divis Laboratories Limited, for permission to
publish this work. We also thank Dr. P. Gundu Rao,
Director, for his encouragement.
Boc-Asp(OMe)-OMe 2f 80
Boc-Asn-OMe 2g
Boc-Trp-OMe 2h
Boc-Pro-OMe 2i
Boc-Orn-OMe 2j
Boc-isonipecotic-OMe
2k
77
51
77
38
80
0
1
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1
The HPLC and H NMR data of the isolated products were identical
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Isolated yield.
b
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