Efficient synthesis of a new pipecolic acid analogue with a bicyclic structure

Article abstract of DOI:10.1016/j.tet.2006.08.006

This report describes the synthesis of 2-azabicyclo[2.2.2]octane-1-carboxylic acid, a constrained pipecolic acid analogue. The route gives a very good total yield starting from cheap and readily available compounds and uses very easy reactions.

Full text of DOI:10.1016/j.tet.2006.08.006

Tetrahedron 62 (2006) 10000–10004
Efficient synthesis of a new pipecolic acid analogue
with a bicyclic structure
*
Diego Casabona and Carlos Cativiela
´
Departamento de Quımica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza–CSIC,
ꢀ
ꢀ
50009 Zaragoza, Spain
Received 18 June 2006; accepted 1 August 2006
Available online 22 August 2006
Abstract—This report describes the synthesis of 2-azabicyclo[2.2.2]octane-1-carboxylic acid, a constrained pipecolic acid analogue. The
route gives a very good total yield starting from cheap and readily available compounds and uses very easy reactions.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
dramatic effect on the structure of the whole molecule. In an
optimal rational design of a peptide, once its bioactive
conformation has been clearly defined, the choice of the
appropriate constraint should provide the desired three-
dimensional topography.
Pipecolic acid (pipecolinic acid, homoproline or 2-piperidi-
necarboxylic acid) is a non-proteinogenic amino acid usu-
ally found as a component of several metabolites in plants
and fungi. This compound, which is a metabolite of lysine,
has been found incorporated into complex biologically
active molecules with interesting pharmacological activities,
e.g., immunosupressors (rapamycin, FK506 and immuno-
mycin) and the antitumor antibiotic sandramycin.1 Never-
theless, pipecolic acid and related compounds most often
occur free in biological systems, display interesting biolog-
ical properties and have been used as precursors for synthetic
peptides. Due to the great interest in these derivatives, a
recent resolution has been reported1 and the asymmetric
synthesis of these systems has been reviewed2 and recently
updated.3
In particular, the incorporation of quaternary a-amino acids
into peptides is a strategy that is widely used to restrict and
control peptide conformations. The stereoselective synthesis
of these constrained amino acids has been reviewed.5 In
the case of quaternary pipecolic acid derivatives, several
procedures have been reported and these include the dia-
stereoselective alkylation and subsequent cyclization of
chiral amino acid derivatives,6 the ruthenium-catalyzed
ring-closing olefin metathesis using a-alkyl-a-allylglycines
as starting materials7 or the asymmetric cyclization via
memory of chirality.8
On the other hand, interest in peptide-based drugs has shown
significant growth in recent years. Unmodified native pep-
tides exhibit some properties that make them unfavourable
for pharmacological purposes. The main limitations for their
use as drugs are their low selectivity between different
receptors, their ease of proteolysis by enzymes and the poor
variety of delivery systems. Unnatural amino acids are
currently playing a significant role in peptide research and
in many cases have led to an improvement in the pharmaco-
logical profile of native peptides. When designing peptide
analogues, the use of conformationally constrained amino
acids is a major strategy.4 The introduction of structural
constraints on certain residues of a peptide chain can have a
In recent years we have been involved in the synthesis of new
constrained amino acids and, in particular, we have focused
our attention on the synthesis of restricted prolines and
phenylalanines. In the course of our research we have
described the synthesis of 2,5-ethanoproline (7-azabicy-
clo[2.2.1]heptane-1-carboxylic acid).9 This compound has
been incorporated into a peptide of biological interest.10
Furthermore, a structural study11 and theoretical calculations
on some derivatives have already been published.12 Due to
the interesting properties observed we decided to undertake
a study into the behaviour of the homologue 2,5-ethanopipe-
colic acid (2-azabicyclo[2.2.2]octane-1-carboxylic acid)
(Fig. 1). The only synthesis of this compound described to
date corresponds to a patent13 in which the experimental
details are, to say the least, not particularly detailed. We
would therefore like to report here a very easy and reproduc-
ible procedure to obtain this compound using cheap and
readily available starting materials.
Keywords: Constrained amino acid; Quaternary amino acid; Proline ana-
logue; 2,5-Ethanepipecolic acid; Chemoselective reduction.
* Corresponding author. Tel./fax: +34 976761210; e-mail: cativiela@
unizar.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.006

D. Casabona, C. Cativiela / Tetrahedron 62 (2006) 10000–10004
10001
O
HN
OH
O
NH2
HO2C
N
H
N
H
COOH
COOH
NH
O
ii
i
iii
Figure 1. Structure of pipecolic acid and 2,5-ethanopipecolic acid.
CO2Me
1
CO2Me
2
CO2H
3
CO2H
4
2. Results
O
O
Taking into account the retrosynthetic analysis shown in
Figure 2, the key steps of the procedure should be the chemo-
selective reduction of the lactam and the stereochemical
control of the positions of the substituents in the cyclohexane
ring in order to achieve the corresponding cyclization. Other
possibilities from the disconnection approach do not seem to
lead to appropriate starting materials.
HN
N
N
iv
Ph
MeO2C
v
Ph
vi
MeO2C
MeO2C
5
6
7
•
HCl
N
vii
Ph
HO2C
The synthesis we report begins with the complete hydroge-
nation of the commercially available methyl 4-hydroxybenz-
oate (1). It has been reported that the use of 5% rhodium on
alumina14 as a catalyst enables the complete reduction of
aromatic rings to give the corresponding aliphatic cyclo-
hexane. We found that hydrogen pressures between 20 and
25 bar were sufficient to produce complete reduction in
quantitative yield. The stereochemistry of this reaction is
not relevant because of the fact that in the next step the
alcohol has to be converted into a carbonyl moiety. This
transformation was successfully achieved using pyridinium
chlorochromate (PCC) to give 4-carbomethoxycyclohexa-
none (2) in high yield (Scheme 1).
8
Scheme 1. Reagents and conditions: (i) (a) H2, Rh, Al2O3/MeOH, 20 bar;
(b) PCC, NaOAc, CeliteÒ/CH2Cl2; (ii) (a) 2 N KOH/MeOH; (b)
(NH4)2CO3, KCN/H2O; (iii) 5 N NaOH, reflux; (iv) (a) SOCl2/MeOH,
reflux; (b) 210–220 ꢀC; (v) NaH, NaI, BnBr/DMF; (vi) RhH(CO)(PPh3)3,
Ph2SiH2/THF; (vii) 6 N HCl.
O
HN
O
CN
H2N
NH
O
Strecker
Bucherer-Bergs
CO2R
CO2R
CO2R
The most important strategies to obtain an amino acid
moiety from a carbonyl compound are the Strecker synthesis
and the Bucherer–Bergs reaction. The first approach uses
ammonium hydroxide and potassium cyanide to obtain the
corresponding aminonitrile compound, whereas the second
employs ammonium carbonate and potassium cyanide to
form the hydantoin ring. In both cases, final hydrolysis
would allow the synthesis of the amino acid. In our case,
two stereoisomeric products are possible, although it has
been reported that in the case of 4-substituted cyclohexa-
nones both reactions behave in a complementary manner
(Fig. 3). In fact, Munday15 found that the Bucherer–Bergs
reaction of 4-tert-butylcyclohexanone predominantly gave
one of the stereoisomeric hydantoins. Later, Edward and
Jitrangsri16 established the stereochemical course of both
Strecker and Bucherer–Bergs reactions. These authors
proved that the severe steric hindrance between the develop-
ing C]NH group and the 3,5-axial hydrogen atoms, in the
key step of the mechanistic route, led to the compound in
which the NH and the carboxylic acid groups are in a cis
Figure 3. Relative stereochemistry of the products obtained by Strecker
synthesis and Bucherer–Bergs reaction.
disposition. However, in the Strecker reaction this hindrance
is not a factor and, as a result, this pathway furnished the
thermodynamically most stable product, which has a trans
disposition.
Bearing in mind that our objective was to obtain the cis con-
figuration between the amino and carboxylic acid groups
prior to the subsequent cyclization, the Bucherer–Bergs
reaction was used. In order to improve the final results, the
synthesis of the hydantoin was performed after saponifica-
tion of the methyl ester in order to increase the solubility
of the corresponding salt in the aqueous reaction medium.
This is a very important feature and markedly increases
the final yield. In this way, the reaction was achieved in
the presence of potassium cyanide and ammonium carbonate
using water as the solvent. Thus, the spirohydantoinic com-
pound 3 was obtained directly in good yield and with high
purity by precipitation in an acidic medium (Scheme 1).
Moreover, the new carboxylic acid moiety was a key ele-
ment in the next step.
CO2H
NH
CO2H
NH
NH2
HO2C
O
CO2H
OH
O
The hydantoinic systems are normally very much insoluble
and the opening of these rings requires very harsh conditions
like high temperatures and concentrated acidic or basic solu-
tions. In the present case, the carboxylic acid group makes
basic hydrolysis easy and complete opening of the hetero-
cyclic system was achieved by heating a solution of the
hydantoin at 120 ꢀC in 5 N NaOH. Precise adjustment of
HN
O
NH
O
CO2Me
CO2Me
CO2H
Figure 2. Retrosynthetic analysis for 2,5-ethanopipecolic acid.

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D. Casabona, C. Cativiela / Tetrahedron 62 (2006) 10000–10004
the pH led to the aminodicarboxylic compound (4) in excel-
lent yield and with very high purity.
or phosphomolybdic acid reaction, as appropriate. Column
chromatography was performed using silica gel (Kieselgel
60). Solvents were dried, when necessary, by standard
methods. Melting points were determined on a Gallenkamp
apparatus and were not corrected. IR spectra were registered
on a Mattson Genesis FTIR spectrophotometer; nmax is given
Recently, Chung and Ho17 described direct lactam formation
from a cis/trans mixture of 4-aminocyclohexane carboxylic
acid by heating a slurry of the substrate in DowthermÒ A at
250–256 ꢀC. On the other hand, several years ago, Werner
and Ricca18 found that the cyclization could be achieved
by working at lower temperatures when the carboxylic
acid was previously transformed into an ester. We therefore
decided to esterify the carboxylic acids in 4 using thionyl
chloride and methanol. The resulting oily product was then
heated for 10 min at 210–220 ꢀC to furnish lactam 5 with
an overall yield of 71%.
1
for the main absorption bands. H and 13C NMR spectra
were recorded on a Bruker AV-400 instrument at room
temperature in CDCl3, D2O or DMSO-d6, using the residual
solvent signal as the internal standard; chemical shifts (d) are
expressed in parts per million and coupling constants (J) in
hertz. Elemental analyses were carried out on a Perkin–
Elmer 200 C,H,N,S analyzer.
4.2. 4-Carbomethoxycyclohexanone (2)
The next step in our synthesis involved the chemoselective
reduction of lactam 5. Most of the methods described for
the reduction of lactams, e.g., the use of LiAlH4, NaBH4–
AlCl3, DIBAL-H, AlClH2 and AlCl2H,19 are not compatible
with the presence of ester groups. Some authors have de-
scribed the selective transformation of secondary lactams
with 9-borabicyclo[3.3.1]nonane (9-BBN) or borane–methyl
sulfide complex.20 Unfortunately, in the present case these
methodologies were unsuccessful. Other strategies require
a tertiary lactam to produce the chemoselective reduction
in the presence of an ester. In particular, it has been reported
that LiEt3BH/Et3SiH–Et2O$BF3 can be used to achieve a
highly chemoselective lactam reduction with N-Boc protec-
tion in the presence of groups such as double bonds, esters,
nitriles or carbamates.21 However, all attempts to reduce
our bicyclic system using this method resulted in very com-
plex mixtures and the yield was 28% in the best case. Fortu-
nately, much better results were obtained by following the
method described by Ito and co-workers for the reduction
of tertiary amides with diphenylsilane and rhodium cata-
lysts.22 In order to use this methodology, prior N-benzyl pro-
tection of compound 5 using benzyl bromide in the presence
of NaH was necessary. The reduction of the corresponding
N-benzyl lactam (6) was easily achieved and enabled the
synthesis of compound 7 in excellent yield. Finally, this iso-
quinuclidine was easily hydrolyzed in 6 N hydrochloric acid
to give the desired N-benzyl amino acid 8, which is suitably
protected for incorporation into a peptide chain.
A mixture of methyl p-hydroxybenzoate (1) (15.0 g,
99 mmol) and 5% rhodium on alumina (1.5 g) in MeOH
(60 mL) was shaken under hydrogen (20 bar) for 3 days.
The catalyst was removed by filtration through CeliteÒ and
then rinsed with MeOH. The combined filtrates were evapo-
rated to dryness under reduced pressure to give a colourless
oil (15.0 g, 95 mmol), which was used without further puri-
fication in the next step. To a mixture of dry CH2Cl2
(100 mL), oven-dried CeliteÒ (6.0 g) and NaOAc (1.9 g,
23 mmol), under Ar, was added pyridinium chlorochromate
(25.0 g, 116 mmol). CH2Cl2 (60 mL) was added to the reac-
tion mixture and then a solution of the oily compound
obtained in the previous step (12.8 g, 77 mmol) in CH2Cl2
(60 mL) was added by syringe under Ar. The mixture was
stirred for 3.5 h and Et2O (200 mL) was added with vigorous
stirring. The reaction mixture was filtered under vacuum
through silica gel and the silica gel was washed with Et2O.
The combined filtrates were concentrated to yield 2
(10.30 g, 66 mmol) as a colourless oil. Yield 82%. IR
1
(neat, cmꢁ1): 1731, 1711. H NMR (400 MHz, CDCl3):
d¼1.95–2.08 (m, 2H), 2.15–2.23 (m, 2H), 2.29–2.39 (m,
2H), 2.42–2.50 (m, 2H), 2.75 (tt, J¼3.9, 9.7 Hz, 1H), 3.71
(s, 3H). 13C NMR (100 MHz, CDCl3): d¼28.48, 39.69,
40.56, 51.54, 174.57, 210.0.
4.3. 4-Spirohydantoincyclohexanecarboxylic acid (3)
A 2 N solution of KOH in MeOH (50 mL) was added to
4-carbomethoxycyclohexanone (2) (10.30 g, 66 mmol) and
the mixture was stirred at room temperature until the starting
material had been consumed. The solvent was evaporated to
give a pale yellow solid, which was used without further
purification. To a solution of this solid in water (60 mL)
was added (NH4)2CO3 (25.34 g, 264 mmol) followed by
KCN (6.5 g, 100 mmol). The reaction mixture was stirred
for 16 h at room temperature, followed by 24 h at 50–
60 ꢀC. The mixture was allowed to cool and concentrated
HCl was added dropwise. The precipitated spirohydantoin
was filtered off under vacuum, washed with water and ace-
tone and dried (8.30 g, 39.2 mmol). Yield 59%. Mp 309–
311 ꢀC. IR (Nujol, cmꢁ1): 3450–2300, 1772, 1731, 1685.
1H NMR (400 MHz, DMSO-d6): d¼1.52–1.72 (m, 6H),
1.82–1.92 (m, 2H), 2.20–2.30 (m, 1H), 8.43 (br s, 1H),
10.59 (br s, 1H), 12.15 (br s, 1H). 13C NMR (100 MHz,
DMSO-d6): d¼23.41, 32.40, 40.58, 61.55, 156.28, 175.84,
178.39. Anal. Calcd for C9H12N2O4: C, 50.94; H, 5.70; N,
13.20; found: C, 51.12; H, 5.86; N, 13.37.
3. Conclusion
In summary, we have developed a new, competitive and
reproducible method for the synthesis of 2-azabicyclo-
[2.2.2]octane-1-carboxylic acid, an analogue of pipecolic
acid. The procedure gives a good overall yield starting
from methyl 4-hydroxybenzoate. The conformational ten-
dencies of the new amino acid are currently being studied
and the results will be published in due course.
4. Experimental
4.1. General
Thin layer chromatography was performed on Merck 60 F240
precoated silica gel polyester plates and products were visu-
alized under UV light (254 nm), iodine vapor, anisaldehyde

D. Casabona, C. Cativiela / Tetrahedron 62 (2006) 10000–10004
10003
4.4. cis-1-Aminocyclohexane-1,4-dicarboxylic acid (4)
4.7. Methyl N-benzyl-2-azabicyclo[2.2.2]octane-1-
carboxylate (7)
A solution of spirohydantoin 3 (3.5 g, 16.50 mmol) in 5 N
NaOH (25 mL) was heated at 120 ꢀC for 48 h. The mixture
was allowed to cool and the pH of the solution was adjusted
to 8.5–9 with 4 N HCl. The resulting precipitate was filtered
off. The mother liquor was then adjusted to pH 2.5 with 4 N
HCl to giveawhite solid (2.46 g, 13.14 mmol), which was fil-
tered off, washed with water and dried. Yield 80%. Mp 253–
256 ꢀC. IR (Nujol, cmꢁ1): 3529, 3437, 3300–2400, 1687. 1H
NMR (400 MHz, CDCl3): d¼1.78–1.93 (m, 6H), 2.05–2.16
(m, 2H), 2.55–2.60 (m, 1H), 10.17 (br s, 1H), 14.47 (br s,
1H). 13C NMR (100 MHz, CDCl3): d¼23.73, 30.15, 36.89,
58.81, 176.29, 179.16. Anal. Calcd for C8H13NO4: C,
51.33; H, 7.00; N, 7.48; found: C, 51.50; H, 7.13; N, 7.61.
To a mixture of lactam 6 (507 mg, 1.86 mmol) and
RhH(CO)(PPh3)3 (17 mg, 0.019 mmol) in anhydrous THF
was added Ph2SiH2 (857 mg, 4.65 mmol) under Ar. The
mixture was stirred for 12 h at room temperature. The sol-
vent was removed under vacuum and the oily residue was
partitioned between Et2O and 1 N HCl. The organic phase
was extracted several times with 1 N HCl and the combined
aqueous phases were neutralized with solid NaOH until pH
9–10. The resulting suspension was extracted with AcOEt
and the organic layers were combined, dried over anhydrous
MgSO4, filtered and the solvent removed to give 7 (462 mg,
1.79 mmol) as a white solid. Yield 96%. Mp 61–62 ꢀC. IR
(KBr, cmꢁ1): 1724. 1H NMR (400 MHz, CDCl3): d¼1.57–
1.78 (m, 5H), 1.79–1.88 (m, 2H), 2.24–2.35 (m, 2H), 2.75
(m, 2H), 3.59 (s, 2H), 3.71 (s, 3H), 7.22–7.42 (m, 5H). 13C
NMR (100 MHz, CDCl3): d¼24.56, 26.17, 28.03, 51.96,
55.28, 59.05, 60.22, 126.77, 128.17, 128.85, 139.69,
176.11. Anal. Calcd for C16H21NO2: C, 74.10; H, 8.16; N,
5.40; found: C, 74.24; H, 8.01; N, 5.56.
4.5. Methyl 3-oxo-2-azabicyclo[2.2.2]octane-1-carboxy-
late (5)
SOCl2 (2.8 g, 23.53 mmol) was added dropwise at 0 ꢀC to
a stirred suspension of 4 (2 g, 10.69 mmol) in anhydrous
MeOH (40 mL) under Ar. The reaction mixture was heated
at 80 ꢀC for 4 h with vigorous stirring and SOCl2 (1.4 g,
11.77 mmol) was added carefully. The reaction was main-
tained at 80 ꢀC for a further 4 h. The mixture was allowed
to cool and the solvent was evaporated. The solid residue
was fractionated between AcOEt and 5% NaHCO3 solution.
The aqueous solution was extracted with AcOEt, and the
combined organic phases were dried, filtered and the solvent
removed to give a pale oil residue, which was used in the
next step without further purification. This oil was placed
in a Schlenk tube and heated in a sand bath to 215–220 ꢀC
for 10 min under vacuum. On cooling a crystalline solid ap-
peared and this was recrystallized from CH2Cl2 to yield 5
(1.38 g, 7.53 mmol) as a white solid. Yield 71%. Mp 129–
132 ꢀC. IR (Nujol, cmꢁ1): 3173, 1724, 1673. 1H NMR
(400 MHz, CDCl3): d¼1.73–1.90 (m, 6H), 2.00–2.10 (m,
2H), 2.60 (m, 1H), 3.81 (s, 3H), 6.65 (br s, 1H). 13C NMR
(100 MHz, CDCl3): d¼23.45, 31.15, 37.70, 52.91, 58.76,
172.37, 175.80, Anal. Calcd for C9H13NO3: C, 59.00; H,
7.15; N, 7.65; found: C, 58.86; H, 7.22; N, 7.76.
4.8. N-Benzyl-2-azabicyclo[2.2.2]octane-1-carboxylic
acid hydrochloride (8)
Isoquinuclidine 7 (462 mg, 1.79 mmol) was suspended in
6 N HCl (30 mL) and heated under reflux for 12 h. The mix-
ture was allowed to cool and then evaporated to dryness. The
residue was partitioned between Et2O and H2O. The organic
layer was discarded and final lyophilization furnished pure 8
(494 mg, 1.75 mmol) as a white solid. Yield 98%. Mp 265–
266 ꢀC. IR (KBr, cmꢁ1): 3600–2200, 3400, 1732. 1H NMR
(400 MHz, D2O): d¼1.72–1.84 (m, 2H), 1.91–2.00 (m, 2H),
2.09–2.26 (m, 4H), 2.34–2.44 (m, 2H), 3.17–3.24 (m, 1H),
3.37–3.44 (m, 1H), 4.12–4.22 (m, 1H), 4.48–4.58 (m, 1H),
7.47–7.62 (m, 5H). 13C NMR (100 MHz, D2O): d¼20.22,
21.61, 21.82, 23.41, 28.96, 54.42, 58.49, 65.07, 129.22,
129.29, 130.10, 130.93, 173.76. Anal. Calcd for
C15H20ClNO2: C, 63.94; H, 7.15; N, 4.97; found: C, 64.13;
H, 6.98; N, 5.10.
4.6. Methyl 3-oxo-N-benzyl-2-azabicyclo[2.2.2]octane-1-
carboxylate (6)
Acknowledgements
NaH (72 mg, 2.99 mmol) was added to a solution of the
bicyclic lactam (500 mg, 2.73 mmol) in anhydrous DMF at
0 ꢀC under Ar. After 10 min, benzyl bromide (510 mg,
2.99 mmol) was added and the reaction mixture was stirred
at room temperature. After 4 h, saturated NH4Cl (10 mL)
was added and the mixture was extracted several times
with AcOEt. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered and evap-
orated to give a residue, which was chromatographed (elu-
ent: hexane/AcOEt 7/3) to furnish 6 (599 mg, 2.16 mmol)
as a white solid. Yield 80%. Mp 88–89 ꢀC. IR (KBr,
ꢀ
Financial support from Ministerio de Educacion y Ciencia–
FEDER (project CTQ2004-5358) and Diputacion General
ꢀ
de Aragon (project PIP206/2005 and group E40) is grate-
fully acknowledged. D.C. thanks CSIC for an I3P grant.
ꢀ
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1
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