An efficient synthesis of orthogonally protected trans- and cis-4-aminopipecolic acid

Article abstract of DOI:10.1002/jhet.5570430539

A straightforward synthesis of orthogonally N^α/N ^γ-protected trans- and cis-4-aminopipecolic acid is reported, starting from methyl cis-4-hydroxypiperidine-2-carboxylate. The two diastereomers were synthesized with the aid of C-4 inv

Full text of DOI:10.1002/jhet.5570430539

Sep-Oct 2006
An Efficient Synthesis of Orthogonally Protected
trans- and cis-4-Aminopipecolic Acid
1387
István Szatmári, Loránd Kiss and Ferenc Fülöp*
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, POB 427 Hungary
e-mail: fulop@pharm.u-szeged.hu
Received December 28, 2005
NHBoc
OH
NHBoc
N
COOH
N
H
COOMe
N
COOH
Z
Z
A straightforward synthesis of orthogonally Nꢀ/Nꢁ-protected trans- and cis-4-aminopipecolic acid is
reported, starting from methyl cis-4-hydroxypiperidine-2-carboxylate. The two diastereomers were
synthesized with the aid of C-4 inversion (the trans isomer) or double C-4 inversion (the cis isomer).
J. Heterocyclic Chem., 43, 1387 (2006).
Introduction
Scheme I
The incorporation of conformationally constrained
amino acids into peptides is a powerful approach for the
generation of structurally defined peptides as conforma-
tional probes and bioactive agents [1].
OH
OH
(a)
Ref.s 10-12
Br
N
COOMe
N
Z
COOMe
Pipecolic acid derivatives bearing amino functionalities
at position C-4 are examples of endocyclic-Nꢀ/exocyclic-
Nꢁ basic constrained amino acids. Pipecolic acid
substituted with an amino group at position C-4 is a
naturally occurring non-proteinogenic ꢀ-amino acid found
in some plants: 4-aminopipecolic acid is present in the
leaves of Strophantus scandens (Apocinaceae) [2-4] and
(2S,4S)-4-acetylaminopipecolic acid has been isolated
from the leaves of Calliandra hamatocephala
(Leguminosae) [5].
H
1
2
3
(b)
NH2
N3
OMs
(d)
(c)
N
Z
COOMe
N
Z
COOMe
N
Z
COOMe
6
5
4
None of the earlier syntheses of 4-aminopipecolic
acid derivatives seemed suitable for the preparation of
orthogonally protected compounds [6-8]. Machetti et.
al. published a simple method for the preparation of
protected trans-4-aminopipecolic acid starting from
methyl cis-4-hydroxypiperidine-2-carboxylate [9]. Our
present aim was to develop a method suitable for the
synthesis of both diastereomers of 4-aminopipecolic
acid in the frame of an ongoing industrial research
project.
(e)
NHBoc
NHBoc
(f)
N
COOMe
N
Z
COOH
Z
7
8
(a) Z-Cl, Et3N, THF, 20 h, rt., 93%; (b) MsCl, DMAP, Py, 14 h, rt., 95%;
(c) NaN3, DMF, 16 h, 70 oC, 85%; (d) PPh3, THF/H2O, 2 days, rt., 75%;
(e) (Boc)2O, Et3N, THF, 10 h, rt., 85%; (f) NaOH, dioxane/H2O, 3 days, rt., 70%
Results and Discussion.
For the synthesis of the diastereomers of protected 4-
aminopipecolic acid derivatives 8 and 13, methyl cis-4-
hydroxypiperidine-2-carboxylate (2) was used as starting
material. The known synthetic pathway was applied to
obtain 2 from 4-bromo-1-butene (1, Scheme I) [10-12].
Our synthetic route began from 2-methyl cis-1-
benzyloxycarbonyl-4-hydroxypiperidine-2-carboxylate (3).
We started by treating the cis alcohol with methane-
sulfonyl chloride in pyridine to afford compound 4, which
was reacted without further purification with sodium
azide to obtain the azido compound 5 with C-4 inversion.
Reduction of 5 with triphenylphosphine in THF/H2O gave
the 4-aminopipecolic acid methyl ester (6). The amino
function at position 4 was then protected with a tert-
butoxycarbonyl group (7). Hydrolysis of methyl ester 7

1388
I. Szatmári, L. Kiss and F. Fülöp
Vol 43
DMAP were added. The resulting mixture was stirred at room
temperature for 14 h. 18% HCl was then added dropwise at 0 °C
until pH 3, and the mixture was extracted with EtOAc (3 x 250
mL). The combined organic layers were washed with water,
dried (Na2SO4) and concentrated.
The oily product was used in the next step without further
purification; 1H-NMR (400 MHz, CDCl3): ꢀ: 1.64-2.10 (3H, m);
2.72 (1H, t, J = 14.1 Hz); 2.98 (3H, s); 3.49 (1H, t, J = 13.1 Hz);
3.66-3.80 (3H, m); 3.99-4,20 (2H, m); 5.06 (1H, s); 5.12-5.21
(2H, m); 7.32-7.42 (5H, m)
with sodium hydroxide gave the desired orthogonally
protected trans-4-aminopipecolic acid 8 (Scheme I).
The strategy for the preparation of the cis-4-amino-
pipecolic acid isomer was based on the double inversion
of the configuration at C-4. The first inversion was carried
out by substitution of the mesylate 4 with lithium bromide
to give bromo compound 9, and the second one involved
the treatment of 9 with sodium azide, which led to azido
compound 10 with a further inversion at C-4. The azido
group could then be reduced with triphenylphosphine in
THF/H2O to give the diamino ester 11. The desired
orthogonally protected cis-4-aminopipecolic acid (13,
Scheme II) was obtained by protection of the amino
function at position 4 with a tert-butoxycarbonyl group
(12), followed by hydrolysis of the ester group under
alkaline conditions.
Anal. Calcd. for C16H21NO7S: C, 51.74; H, 5.70; N, 3.77.
Found: C, 51.82; H, 5.72; N, 3.72.
2-Methyl trans-1-benzyloxycarbonyl-4-azidopiperidine-2-
carboxylate (5).
The mesyl compound 4 (6.31 g, 17 mmol) and sodium azide
(3.25 g, 50 mmol) were dissolved in DMF (100 mL). After
stirring for 16 h at 70 °C, water (500 mL) was added to the
mixture, which was then extracted with EtOAc (3 x 120 mL).
The combined organic layers were washed with water, dried
(Na2SO4) and concentrated; Yield: 85%; a colorless oil; 1H-NMR
(400 MHz, CDCl3): ꢀ 1.40-1.57 (1H, m); 1.59-1.75 (1H, m);
1.91-2.06 (1H, m); 2.48 (1H, t, J = 12.6 Hz); 3.12 (1H, t, J =
12.6 Hz); 3.30-3.41 (1H, m); 3.64-3.81 (3H, m); 4.10-4.30 (1H,
m); 5.04-5.24 (3H, m); 7.23-7.46 (5H, m).
Scheme II
OMs
Br
N3
(a)
(b)
N
Z
COOMe
N
Z
COOMe
N
Z
COOMe
Anal. Calcd. for C15H18N4O4: C, 56.60; H, 5.70; N, 17.60.
Found: C, 56.82; H, 5.72; N, 17.65.
4
9
10
(c)
2-Methyl trans-1-benzyloxycarbonyl-4-aminopiperidine-2-
carboxylate (6).
The azido compound 5 (4.14 g, 13 mmol) and triphenyl-
phosphine (5.24 g, 20 mmol) were dissolved in THF (150 mL)
and water (10 mL). After stirring for 48 h, the mixture was
concentrated and chromatographed over silica gel (CHCl3-MeOH
9:1); Yield: 75%; a colorless oil; 1H-NMR (400 MHz, CDCl3): ꢀ:
1.17-1.36 (2H, m); 1.73-1.89 (1H, m); 2.36 (1H, t, J = 16.1 Hz);
2.68-2.79 (1H, m); 2.97-3.18 (1H, m); 3.65-3.79 (3H, m); 4.05-
4.24 (1H, m); 4.89-5.20 (3H, m); 7.28-7.41 (5H, m).
NHBoc
NHBoc
NH2
(e)
(d)
N
COOH
N
COOMe
N
Z
COOMe
Z
Z
13
12
11
Anal. Calcd. for C15H20N2O4: C, 61.63; H, 6.90; N, 9.58.
Found: C, 61.71; H, 6.87; N, 9.61.
(a) LiBr, DMF, 2 days, 70 oC, 65%; (b) NaN3, DMF, 3 days, 70 oC, 70%;
(c) PPh3, THF/H2O, 2 days, 60 oC, 65%; (d) (Boc)2O, Et3N, THF,
10 h, rt., 90%; (e) NaOH, dioxane/H2O, 3 days, rt., 60%
2-Methyl trans-1-benzyloxycarbonyl-4-[(tert-butoxycarbonyl)-
amino]piperidine-2-carboxylate (7).
In conclusion, a simple and efficient method has been
developed for the synthesis of both diastereomers of 4-
aminopipecolic acid from methyl cis-4-hydroxypiper-
idine-2-carboxylate. The trans isomer was synthesized via
an inversion at C-4, and the cis isomer through double
inversion at C-4.
To a solution of amino compound 6 (2.63 g, 9 mmol) and
triethylamine (3 mL) in THF (80 mL), di-tert-butyl dicarbonate
(2.61 g, 12 mmol) was added at 0 °C. After stirring for 10 h, the
mixture was taken up in EtOAc (200 mL), washed with water,
dried (Na2SO4) and concentrated; Yield: 85%; a colorless oil;
1H-NMR (400 MHz, CDCl3): ꢀ 1.44-1.49 (11H, m); 1.94-2.04
(1H, m); 2.43-2.58 (1H, m); 3.03-3.24 (1H, m); 3.67-3.75 (3H,
m); 4.09-4.27 (2H, m); 4.88-5.22 (3H, m); 7.31-7.43 (5H, m).
Anal. Calcd. for C20H28N2O6: C, 61.21; H, 7.19; N, 7.14.
Found: C, 61.31; H, 7.15; N, 7.19.
EXPERIMENTAL
Melting points were determined on a Kofler micro melting
point apparatus and were not corrected. Compounds 2 and 3
were prepared according to the literature procedure [10-12].
trans-1-Benzyloxycarbonyl-4-[(tert-butoxycarbonyl)amino]-
piperidine-2-carboxylic acid (8).
To a solution of amino ester 7 (2.35 g, 6 mmol) in dioxane
(70 mL) NaOH (1.12 g, 48 mmol) in water (70 mL), was added.
After stirring for 3 days, 10% HCl was added at 0 °C until pH 5.
The mixture was then extracted with CHCl3 (3 x 120 mL). The
combined organic layers were dried (Na2SO4) and concentrated
2-Methyl cis-1-benzyloxycarbonyl-4-[(methylsulfonyl)oxy]-
piperidine-2-carboxylate (4).
To a solution of 3 (17.58 g, 60 mmol) in dry pyridine (400
mL), methanesulfonyl chloride (13.67 g, 120 mmol) and 200 mg

Sep-Oct 2006 An Efficient Synthesis of Orthogonally Protected trans- and cis-4-aminopipecolic acid
1389
To a solution of amino compound 11 (2.34 g, 8 mmol) and
triethylamine (3 mL) in THF (80 mL), di-tert-butyl dicarbonate
(2.62 g, 12 mmol) was added at 0 °C. After stirring for 10 h, the
mixture was taken up in EtOAc (200 mL), washed with water,
dried (Na2SO4) and concentrated; Yield: 90%; a colorless oil;
1H-NMR (400 MHz, CDCl3): ꢀ 1.39-1.45 (10H, m); 1.69-1.96
(3H, m); 2.44-2.54 (1H, m); 3.72 (3H, s); 3.81-4.18 (3H, m);
5.12-5.20 (2H, m); 7.31-7.42 (5H, m)
under reduced pressure. The crude product was crystallized from
n-hexane (50 mL); Yield: 70%; a white solid; mp 170-172° C;
1H-NMR (400 MHz, DMSO): ꢀ 1.20-1.44 (10H, m); 1.45-1.60
(1H, m); 1.78 (1H, d, J = 12.6 Hz); 2.23 (1H, d, J = 12.1 Hz);
2.94-3.12 (1H, om); 3.24-3.35 (1H, m); 3.97 (1H, d, J = 11.1
Hz); 4.77 (1H, d, J = 5.5 Hz); 5.11 (2H, s); 6.58 (1H, bs); 7.31-
7.37 (5H, m); 12.12-13.43 (1H, bs).
Anal. Calcd. for C19H26N2O6: C, 60.30; H, 6.93; N, 7.40.
Found: C, 60.39; H, 6.90; S, 7.37.
Anal. Calcd. for C20H28N2O6: C, 61.21; H, 7.19; N, 7.14.
Found: C, 61.28; H, 7.20; N, 7.11.
2-Methyl trans-1-benzyloxycarbonyl-4-bromopiperidine-2-
carboxylate (9).
cis-1-Benzyloxycarbonyl-4-[(tert-butoxycarbonyl)amino]piperi-
dine-2-carboxylic acid (13).
To a solution of mesyl compound 4 (12.63 g, 34 mmol) in
DMF, LiBr was added (4.43 g, 51 mmol). The mixture was
stirred for 2 days at 70 °C, then taken up in EtOAc (200 mL),
washed with water, dried (Na2SO4) and concentrated; Yield:
65%; a colorless oil; H-NMR (400 MHz, CDCl3): ꢀ 1.62-2.09
(5H, m); 2.32-2.40 (1H, m); 3.66-3.81 (4H, m); 4.20-4.26 (1H,
m); 5.11-5.23 (2H, m); 7.32-7.42 (5H, m).
To a solution of amino ester 12 (2.36 g, 6 mmol) in dioxane
(70 mL) NaOH (1.92 g, 48 mmol) in water (70 mL), was added.
After stirring for 4 days 10% HCl was added at 0 °C until pH 5.
The mixture was then extracted with CHCl3 (3 x 120 mL). The
combined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The crude product was crystallized from
n-hexane (50 mL); Yield: 60%; a white solid; mp 138-140° C;
1H-NMR (400 MHz, DMSO): ꢀ 0.83-0.91 (1H, m); 1.24-1.54
(11H, m); 1.64-1.82 (2H, m); 2.15 (1H, d, J = 12.6 Hz); 3.64
(1H, s); 3.73 (1H, d, J = 12.6 Hz); 4.33 (1H, d, J = 4.5 Hz);
5.03-5.09 (2H, m); 7.16 (1H, bs); 7.26-7.44 (5H, m).
1
Anal. Calcd. for C15H18BrNO4: C, 50.58; H, 5.09; N, 3.93.
Found: C, 50.62; H, 5.11; N, 3.88.
2-Methyl cis-1-benzyloxycarbonyl-4-azidopiperidine-2-car-
boxylate (10).
Anal. Calcd. for C19H26N2O6: C, 60.30; H, 6.93; N, 7.40.
Found: C, 60.22; H, 6.95; N, 7.44.
Bromide derivative 9 (7.12 g, 20 mmol) and sodium azide
(3.57 g, 55 mmol) were dissolved in DMF (100 mL). After
stirring for 3 days at 70 °C, water (500 mL) was added to the
mixture, which was then extracted with EtOAc (3 x 150 mL).
The combined organic layers were washed with water, dried
(Na2SO4) and concentrated; Yield: 70%; a colorless oil; 1H-
NMR (400 MHz, CDCl3): ꢀ : 1.58-2.30 (6H, m); 3.62-3.81 (4H,
m); 4.10-4.33 (1H, m); 5.07-5.26 (2H, m); 7.28-7.44 (5H, m).
Anal. Calcd. for C15H18N4O4: C, 56.60; H, 5.70; N, 17.60.
Found: C, 56.55; H, 5.68; N, 17.62.
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2-Methyl cis-1-benzyloxycarbonyl-4-aminopiperidine-1,2-car-
boxylate (11).
The azido compound 10 (4.14 g, 13 mmol) and triphenyl-
phosphine (5.24 g, 20 mmol) were dissolved in THF (150 mL)
and water (10 mL). After stirring for 2 days at 60 °C, the
mixture was concentrated and chromatographed over silica gel
1
(CHCl3-MeOH 9:1); Yield: 65%; a colorless oil; H-NMR (400
MHz, CDCl3): ꢀ 1.60-2.01 (5h, m); 2.11-2.29 (1H, m); 3.31-3.37
(1H, m); 3.60-3.94 (4H, m); 4.69 (1H, s); 5.05-5.26 (2H, m);
7.28-7.34 (5H, m).
Anal. Calcd. for C15H20N2O4: C, 61.63; H, 6.90; N, 9.58.
Found: C, 61.65; H, 6.91; N, 9.53.
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2-Methyl cis-1-benzyloxycarbonyl-4-[(tert-butoxycarbonyl)-
amino]piperidine-2-carboxylate (12).