A convenient route to optically pure α-alkyl-β-(sec-amino) alanines

Article abstract of DOI:10.1007/s00726-011-1055-3

The cyclization of N-Boc-α-alkylserines to corresponding β-lactones under Mitsunobu reaction conditions and the ring opening with heterocyclic amines (pyrrolidine, piperidine, morpholine and thiomorpholine) produced N-Boc-α-alkyl-β-(sec-amino)alanines. The removal of the Boc group gives di-hydrochlorides of non-protein amino acids.

Full text of DOI:10.1007/s00726-011-1055-3

Amino Acids (2012) 42:2525–2528
DOI 10.1007/s00726-011-1055-3
SHORT COMMUNICATION
A convenient route to optically pure a-alkyl-b-(sec-amino)alanines
•
A. Olma A. Lasota A. Kudaj
•
Received: 20 June 2011 / Accepted: 30 July 2011 / Published online: 17 August 2011
Ó The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract The cyclization of N-Boc-a-alkylserines to
corresponding b-lactones under Mitsunobu reaction con-
ditions and the ring opening with heterocyclic amines
(pyrrolidine, piperidine, morpholine and thiomorpholine)
produced N-Boc-a-alkyl-b-(sec-amino)alanines. The removal
of the Boc group gives di-hydrochlorides of non-protein
amino acids.
glycines continue to stimulate the development of new
routes to these compounds (Soloshonok and Sorochinsky
2010; Soloshonok et al. 2001; Soloshonok 2002; Ohfune
and Shinada 2005; Fustero et al. 2011). In our laboratory,
we have focused on the synthesis of a-alkylserines and
their incorporation into bioactive peptide analogues (for
example, see: Metzger et al. 1987; Olma et al. 1998,
2001, 2003; Łempicka et al. 1999; Olma and Tourwe
2000; Zabłotna et al. 2006). N-Boc-a-alkylserines can be
easily cyclized under Mitsunobu reaction conditions to
M-protected b-lactones (Olma and Kudaj 2005; Fukujama
and Xu 1993; Smith and Goodman 2003; Olma 2004),
which are excellent starting materials for further deriva-
tization in medicinal chemistry. We recently reported the
synthesis of a-alkyl-b-azido-and a-alkyl-b-aminoalanines
as well as a-halogenomethyl-a-alkylglycines (Kudaj and
Olma 2007, 2008) via ring opening of 3-amino-3-alkyl-2-
oxetanones. Enantiomerically pure N-Boc-a-alkylserines
are easily available using a procedure developed in our
laboratory, involving the synthesis of racemic a-hydroxy-
Keywords a-Alkyl-b-(sec-amino)alanines ꢀ N-Boc-a-
alkylserines b-lactones ꢀ a,a-Disubstituted glycines ꢀ
Mitsunobu reaction
Introduction
a,a-Disubstituted glycines are excellent tools for the
designing of peptidomimetics with potential therapeutic
properties. Their incorporation into biologically active
peptide chains restricts flexibility and enhances biological
activity and resistance to enzymatic hydrolyses (Cativiela
et al. 2007). Moreover, a,a-disubstituted glycines are
often found in nature, either in the free form or as con-
stituents of biologically active natural products (for
example, see: Burges and Leach 1973; Seebech et al.
1987). The biological significance and synthetic utility of
symmetrically and asymmetrically a,a-disubstituted
´
methyl analogues of various amino acids (Kaminski et al.
1973) and their resolution by fractional crystallization of
appropriate diastereoisomeric salts. The absolute configu-
ration of some a-alkylserines was determined by chemical
correlation with relevant a-methyl amino-acids or by X-ray
analysis (Olma 1996; Wieczorek et al. 1991). a-Alkylse-
rines could also be obtained via the diastereoselective
alkylation of pyramidalized bicyclic serine enolates
[(bicyclic N,O-acetals derived from serine, (Jimenez-Oses
et al. 2007)] or in an asymmetric version of the Strecker
synthesis (Ohfune and Shinada 2005).
Electronic supplementary material The online version of this
article (doi:10.1007/s00726-011-1055-3) contains supplementary
material, which is available to authorized users.
Herein, we present the use of N-Boc-a-alkylserine
b-lactones for the preparation of a-alkyl-b-(sec-amino)
alanines. Naturally occurring heterocyclic b-alkylamino-
L-alanines (non-proteinogenic amino acids) were found in
A. Olma (&) ꢀ A. Lasota ꢀ A. Kudaj
´ ´
Institute of Organic Chemistry, Technical University of Łodz,
_
Zeromskiego 116, 90-924 Lodz, Poland
e-mail: aleksandra.olma@p.lodz.pl
123

2526
A. Olma et al.
nature as free acids and as constituents of biologically
active peptides (Ikegami and Murakoshi 1994).
We also applied selected heteroaromatic amines (pyra-
zole and imidazole) as nucleophiles. The ring opening of
M-Boc- a-alkylserine b-lactones with pyrazole as nucleo-
phile failed, however, the use of imidazole followed by
treatment with diazomethane provided N-Boc-a-alkyl-b-
imidazol-1-yl-alanine methyl ester with low yields
(30–40%).
Scheme 1 outlines our method of synthesis of (R)-a-
alkyl-b-(sec-amino) alanines. Heterocyclic amines, such as
pyrrolidine, piperidine, morpholine and thiomorpholine
were used as nitrogen nucleophiles.
The cyclization of N-Boc-(R)-a-alkylserines 1 was car-
ried out in anhydrous ethyl acetate under conventional
Mitsunobu conditions. Corresponding a-alkylserine b-lac-
tones 2 were obtained in 86–91% yield—slightly lower
than that in modified Mitsunobu conditions (Olma and
Kudaj 2005), however, the procedure described here is
significantly simplified. Modified Mitsunobu conditions are
a method of choice for the synthesis of serine and threonine
b-lactones (for example, see: Lee et al. 1985; Adam et al.
1984; Ramer et al. 1986; Pansare et al. 2002; Lall et al.
2002; Schneider et al. 2006). The ring opening of N-pro-
tected serine b-lactones with nitrogen nucleophiles can
give a mixture of amide (acyl-oxygen cleavage) and N-
protected b-aminoalanines (alkyl-oxygen cleavage). The
reaction is very sensitive not only to nitrogen nucleophiles,
but also to the solvent and reaction conditions. The use of
trialkylsilyl derivatives of ammonia as well as primary,
secondary and heterocyclic amines allows the synthesis of
b-aminoalanine derivatives (Ratemi and Vederas 1994).
The treatment of M-Boc-a-alkylserine b-lactones with free
amines (pyrrolidine, piperidine, morpholine or thiomorph-
oline) gives suitable, enantiomerically pure M-protected a-
alkyl-b-(sec-amino) alanines. The results are presented in
Table 1. We did not observe the formation of amides
arising from acyl-oxygen cleavage in different solvents
(acetonitrile, dimethylformamide or methylene chloride).
The removal of the Boc group gives dihydrochlorides of
non-protein amino acids 7–10 (Table 1).
General procedure for the preparation
N-Boc-(R)-a-alkyL-serine b-lactones (2)
To a solution of N-Boc-(R)-a-hydroxymethylamino acids 1
(3 mmol) and triphenylphosphine (943 mg, 3.6 mmol) in
3 ml of dry ethyl acetate, a solution of DEAD (563 ll,
3.6 mmol) in 3 ml of dry ethyl acetate was dropped at
-10°C for 20 min. The mixture was stirred at 0°C for 1.5 h
and at room temperature for 2 h; then, 6 ml of n-hexane
was added and the mixture was left in a refrigerator
overnight. The solid (most of the triphenylphosphine oxide
and N,N-diethoxycarbonyl hydrazine) was filtered off and
washed with a small amount of ethyl acetate–n-hexane
(1:1). The solvent was removed in vacuo and the crude
product was purified by flash chromatography on silica gel
60 (230–400 mesh) using ethyl acetate–n-hexane (1:2) as
eluent. Pure N-Boc-(R)-a-alkyl-serine b-lactones 2 were
obtained in 86–91% yield.
General procedure for the preparation
of N-Boc-(R)-a-alkyl-b-(sec-amino)alanines (3–6)
To a solution of N-Boc-(R)-a-alkylserine b-lactone 2
(1 mmol) in 2 ml of CH2Cl2, 3 mmol of amine (pyrrolidine,
R
BocNH
CO2H
OH
1
H
N
R
R
R
R
HN
BocNH
CO2H
N
H2N
CO2H
N
BocNH
BocNH
CO2H
N
H2N
CO2H
N
R
O
BocNH
3
7
4
8
O
S
HN
HN
O
2
R
R
9
R
R
BocNH
CO2H
N
H2N
CO2H
N
CO2H
N
H2N
CO2H
N
O
O
S
S
5
6
10
Scheme 1 R = CH3 (a), CH(CH3)3 (b), CH2CH(CH3)2 (c), CH2C6H5 (d)
123

A convenient route to optically pure a-alkyl-b-(sec-amino)alanines
2527
Table 1 Preparation of N-Boc-
No.
Yield Mp (oC) [a]D
No. Yield Mp (oC) [a]D
(R)-a-alkyl-b-(sec-
(%)
(c = 1,
MeOH)
(%)
(c = 1,
H2O)
amino)alanines (3–6) and (R)-a-
alkyl-b-(sec-amino)alanines x
2HCl (7–10)
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
CH3
Pyrrolidine
Pyrrolidine
82
95
55
71
90
95
69
90
92
95
75
89
95–97 -11.9
7a
7b
7c
7d
8a
8b
8c
8d
9a
9b
9c
9d
87
89
98
92
93
97
99
84
98
92
91
94
218–220
-6.0
CH(CH3)2
133–135 -12.6
223–224 -14.3
218–220 2.8
208–210 -12.9
223–225 -8.1
218–220 -16.6
230–232 -4.0
240–241 -11.2
193–195 -9.8
224–225 -19.6
217–219 -1.8
228–230 -12.3
265–267 -5.3
213–215 -12.6
CHCH2(CH3)2 Pyrrolidine
123–125
112–114
10.1
45.3
CH2C6H5
CH3
Pyrrolidine
Piperidine
Piperidine
97–99 -11.3
CH(CH3)2
161–162 -11.4
CHCH2(CH3)2 Piperidine
147–149
93–95
14.1
38.2
CH2C6H5
CH3
Piperidine
Morpholine
Morpholine
94–96 -13.1
CH(CH3)2
138–140 -12.8
CHCH2(CH3)2 Morpholine
108–110
120–122
90–92
17.9
41.3
-8.3
4.7
CH2C6H5
CH3
Morpholine
Thiomorpholine 94
Thiomorpholine 89
10a 98
10b 89
10c 90
10d 94
CH(CH3)2
173–175
91–93
CHCH2(CH3)2 Thiomorpholine 88
CH2C6H5 Thiomorpholine 99
11.8
39.2
296–299
208–210
-6.0
-9.4
100–102
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