Simple and efficient multigram scale synthesis of 1-aminocyclopent-3-ene-1- carboxylic acid

Article abstract of DOI:10.1055/s-2006-942458

A very simple and inexpensive synthesis of the valuable intermediate 1-aminocyclopent-3-ene-1-carboxylic acid on a multigram scale and with a high overall yield (80%) is reported. The efficiency of the procedure relies on the ready accessibility and high reactivity of the glycine equivalent used as the starting material. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942458

2
440
PRACTICAL SYNTHETIC PROCEDURES
Simple and Efficient Multigram Scale Synthesis of
-Aminocyclopent-3-ene-1-carboxylic Acid
1
1
D
-Aminocyclopent
i
-3-ene-
e
1-carboxyl
g
ic
A
cid o Casabona, Carlos Cativiela*
Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón,
Universidad de Zaragoza – CSIC, 50009 Zaragoza, Spain
Fax +34(976)761210; E-mail: cativiela@unizar.es
PSP
Received 16 March 2006; revised 30 March 2006
No67
Abstract: A very simple and inexpensive synthesis of the valuable intermediate 1-aminocyclopent-3-ene-1-carboxylic acid on a multigram
scale and with a high overall yield (80%) is reported. The efficiency of the procedure relies on the ready accessibility and high reactivity of
the glycine equivalent used as the starting material.
Key words: allylations, amino acids, heterocycles, metathesis, ring closure
O
O
(i)
O
(ii)
Ph
N
COOH
H
N
Ph
2
O
COOMe
O
(iii)
(iv)
N
NHCOPh
Ph
3
5
4
COOMe
COOH
(v)
NHCOPh
NH2·HCl
1·HCl
Scheme 1 Reagents: (i) DCC; (ii) DIPEA, NaI, allyl bromide (90% two steps); (iii) MeONa, MeOH (99%); (iv) Grubbs’ catalyst (91%);
v) 6 N HCl (99%).
(
Introduction
ceptors, the double bond in 1-aminocyclopent-3-ene-1-
carboxylic acid (1) (suitably protected in the N- and C-ter-
1
6–9
The incorporation of quaternary a-amino acids into pep- mini) has been subjected to different transformations.
2
tides restricts and controls peptide conformations. In par- ACPD itself and other compounds with promising phar-
ticular, 1-aminocycloalkane-1-carboxylic acids (Ac c, macological profiles have been obtained in this way.
n
Figure 1) stabilize helical and turn conformations.2
b–d,3
A
derivative of Ac c that is symmetrically disubstituted at
5
HOOC
NH2
HOOC
HOOC
NH2
NH2
HOOC
NH2
g,d imparts a helical-screw sense in the absence of chiral-
4
ity at the a-carbon.
Some Ac c derivatives exhibit intrinsic biological activity
5
HOOC
Acnc
Ac5c
ACPD
and are potential drugs in the treatment of neurodegener-
ative pathologies. Glutamic acid is the main excitatory
neurotransmitter in the mammalian central nervous sys-
tem, and its constrained analogue 1-aminocyclopentane-
1
,3-dicarboxylic acid (ACPD, Figure 1) behaves as a po-
1
5
tent ligand for the different glutamate receptors. In the
search for highly potent and selective ligands for these re- Figure 1 Structure of Ac c and some Ac c derivatives.
n
5
SYNTHESIS 2006, No. 14, pp 2440–2443
x
x.
x
x
.
2
0
0
6
Advanced online publication: 07.07.2006
DOI: 10.1055/s-2006-942458; Art ID: P03506SS
Georg Thieme Verlag Stuttgart · New York
©

PRACTICAL SYNTHETIC PROCEDURES
Scope and Limitations
1-Aminocyclopent-3-ene-1-carboxylic Acid
2441
ether developed by Schöllkopf and ethyl isocyanoacetate
were bis-alkylated with allyl bromide and subjected to
16
The considerations discussed above make protected 1 a RCM in the presence of the ruthenium(II) Grubbs’ cata-
versatile and useful intermediate, as evidenced by the sig- lyst. Whereas the expensive Schöllkopf chiral substrate
nificant effort devoted to its synthesis in recent years.8
–15
afforded poor yields of the desired product, ethyl isocy-
Two general strategies have been described to prepare anoacetate led to 1 protected as the N-Boc/acetyl ethyl es-
14
1
5
precursors of the target compound. The most frequently ter in 62–73% global yield. The low stability of the
applied approach (Scheme 2, route a) involves cycloalky- isocyano derivatives reported by the authors1 together
5a
lation of a glycine equivalent with a dielectrophile.8
–13
with the difficulty in handling them (ethyl isocyanoace-
More recently, bis-allylation of a glycine equivalent fol- tate is a potent lachrymator) constitute the main limita-
lowed by a ring-closing metathesis (RCM) process tions to scaling-up this high-yielding route (to our
(
Scheme 2, route b) has emerged as an attractive alterna- knowledge, details were not provided about the scale on
1
4,15
tive to prepare derivatives of 1.
which these reactions were carried out).
The clear advantage of glycine derivatives bearing a pro-
tected unmasked amino group prompted us to explore the
synthesis of 1-aminocyclopent-3-ene-1-carboxylic acid
COOR
COOR'
COOR
COMe
COOEt
N
CHAr
(
1) starting from 2-phenyl-5(4H)-oxazolone (2,
R = R' = Me
R = R' = Et
R = Me, R' = t-Bu
ref. 8,10
ref. 9,10
ref. 12
R = Me
ref. 10
R = t-Bu ref. 11
ref. 13
Scheme 1). There were two reasons for this choice: the ac-
cessibility of this compound (it is readily obtained from
hippuric acid, i.e., N-benzoylglycine, an inexpensive
commercial glycine derivative) and the high reactivity of
the oxazolone moiety in comparison with other amino
Cl
Cl
a
OOC
NH
17,18
acid synthons.
Treatment of hippuric acid with N,N¢-dicyclohexylcarbo-
diimide (DCC) led to the formation of 2-phenyl-5(4H)-
oxazolone (2), which was alkylated in situ with allyl bro-
mide to provide 4,4-diallyl-2-phenyl-5(4H)-oxazolone (3)
in good yield (Scheme 1). The high reactivity of the ox-
azolone moiety is evidenced by the fact that only a slight
excess of allylating agent was required and the process
was complete in a few hours at room temperature. It is
worth noting that a tertiary amine, N,N-diisopropylethyl-
amine (DIPEA), was used as a base to obtain 3.
i) Br
ii) RCM
b
18
N
OMe
COOEt
NC
MeO
N
ref. 14
ref. 15
Scheme 2 Different strategies reported for the synthesis of protec-
ted 1 (the references describing the use of each substrate are indica- Opening of the heterocyclic ring in 3 was achieved by
ted).
methanolysis in the presence of a catalytic amount of so-
dium methoxide. The resulting N-benzoyl-a,a-diallyl gly-
16
8
,10
cinate (4) cyclized by the action of Grubbs’ catalyst. The
RCM step proceeded smoothly at room temperature and
furnished the desired compound 5 in excellent yield. It is
interesting to note that when the metathesis process was
attempted prior to methanolysis of the oxazolone moiety,
the cyclopentene ring was formed much less efficiently,
an effect probably associated with the highly strained
spirooxazolone formed.
Several authors have reported the reaction of dimethyl
or diethyl
9
,10
malonate with cis-1,4-dichlorobut-2-ene.
Hydrolysis of one ester group followed by Curtius rear-
rangement of the resulting carboxylic acid has led to dif-
ferent N-carbamate esters of 1 in about 30% global yield.
have been proposed as non-symmetric
,3-dicarbonyl compounds but did not give a significant
improvement in the overall yield (32%), while a huge ex-
cess of reagent was needed in the haloform reaction to
generate the carboxylic acid prior to Curtius degrada-
tion. Among the 1,3-dicarbonyl compounds investigat-
ed, only the more expensive tert-butyl methyl malonate
1
0,11
Acetylacetates
1
In this way, 10 grams of compound 5 were prepared in a
single run. This is, to the best of our knowledge, the larg-
est-scale synthesis reported for an immediate precursor of
1
1
1
(in several cases, the scale of work was not mentioned).
1
2
8–12
has provided superior yields (61%). In all cases,
LiH
Moreover, 5 was obtained in 81% overall yield from hip-
puric acid, which is a much higher yield than those pro-
vided by most of the routes described to date for the
preparation of similar precursors of 1, and compares fa-
vorably with the most efficient approaches. The final ami-
no acid was obtained as its hydrochloride 1·HCl from
derivative 5 in almost quantitative yield by acid hydroly-
sis. As far as we know, this is the first time that the free
unprotected amino acid has been isolated.
was used as a base and cis-1,4-dichlorobut-2-ene as the di-
electrophile.
The Schiff base derived from 4-bromobenzaldehyde and
glycine ethyl ester reacted with cis-1,4-dichlorobut-2-ene
in the presence of excess NaH to afford, after mild acidic
hydrolysis, the ethyl ester of 1 in 67% yield. Two other
primary glycine synthons were also used to prepare pro-
tected 1 according to route b (Scheme 2): the bis-lactim
1
3
Synthesis 2006, No. 14, 2440–2443 © Thieme Stuttgart · New York

2
442
D. Casabona, C. Cativiela
PRACTICAL SYNTHETIC PROCEDURES
In summary, a synthesis of 1-aminocyclopent-3-ene-1- 1H NMR (400 MHz, CDCl
): d = 2.82 (br d, J = 15.6 Hz, 2 H), 3.16
br d, J = 15.6 Hz, 2 H), 3.78 (s, 3 H), 5.73 (m, 2 H), 6.77 (br s, 1
H), 7.40–7.54 (m, 3 H), 7.79 (m, 2 H).
3
(
carboxylic acid based on the use of the readily accessible
-phenyl-5(4H)-oxazolone as a glycine equivalent has
2
1
3
C NMR (100 MHz, CDCl ): d = 44.61, 52.85, 64.33, 127.0,
been developed. The strategy involves simple, high-yield-
ing transformations that are appropriate for large scale
3
1
27.89, 128.52, 131.68, 133.92, 166.84, 174.36.
synthesis and avoid most of the difficulties associated Anal. Calcd for C14
H
15NO
: C, 68.56; H, 6.16; N, 5.71. Found: C,
3
6
8.73; H, 6.22; N, 5.59.
with previously described methodologies, such as the use
of strong air-sensitive bases (LiH, NaH, BuLi), toxic un-
stable starting materials or large excesses of reagents, as
well as the need for rearrangement processes.
1
-Aminocyclopent-3-ene-1-carboxylic Acid Hydrochloride
(
1·HCl)
Compound 5 (10.62 g, 43.2 mmol) was suspended in aq 6 N HCl
150 mL) and refluxed for 24 h. After cooling, the mixture was
evaporated to dryness and the residue was partitioned between Et O
(
2
(
50 mL) and H O (50 mL). The organic layer was discarded and the
2
4
,4-Diallyl-2-phenyl-5(4H)-oxazolone (3)
aqueous phase was washed with an additional portion of Et O (20
mL). Final lyophilization furnished pure 1·HCl as a white solid;
yield: 6.99 g (99%).
2
A solution of N,N¢-dicyclohexylcarbodiimide (12.61 g, 61.2 mmol)
in anhyd THF (30 mL) was added dropwise to a suspension of hip-
puric acid (10.74 g, 60 mmol) in anhyd THF (50 mL) at 0 °C under
argon. The mixture was stirred overnight at r.t., and then cooled to
–
1
IR (Nujol): 3300–2350, 1729 cm .
–
30 °C. The white solid was filtered off, and the organic solution
1
H NMR (400 MHz, D O): d = 2.59 (br d, J = 17.2 Hz, 2 H), 3.03
2
was evaporated under reduced pressure to give 2-phenyl-5(4H)-ox-
azolone (2) as a yellow solid, which was used without further puri-
fication. To a solution of this solid in anhyd DMF under argon, were
added successively a spatula tip of NaI, allyl bromide (11.42 mL,
(
1
br d, J = 17.2 Hz, 2 H), 5.65 (m, 2 H).
3
C NMR (100 MHz, D O): d = 43.32, 63.61, 127.24, 175.14.
2
Anal. Calcd for C H ClNO : C, 44.05; H, 6.16; N, 8.56. Found: C,
4
6
10
2
1
32 mmol) and, dropwise, DIPEA (22.95 mL, 132 mmol) in anhyd
4.27; H, 6.24; N, 8.39.
DMF (10 mL). The mixture was stirred at r.t. for 6 h. Et O (20 mL)
2
and H O (20 mL) were added and the resulting biphasic system was
2
vigorously stirred. The layers were separated and the aqueous phase Acknowledgment
was further extracted with Et O (3 × 20 mL). The combined organic
2
Financial support from Ministerio de Educación y Ciencia–FEDER
project CTQ2004-5358) and Diputación General de Aragón (pro-
ject PIP206/2005, group E40) is gratefully acknowledged. D.C.
thanks CSIC for an I3P grant.
phases were washed with 5% aq citric acid and sat. NaHCO . The
3
(
organic solution was dried and filtered, and the solvent removed to
give a residue, which was chromatographed (eluent: hexanes–
EtOAc, 9:1) to yield 3 as an oil; yield: 13.04 g (90% from hippuric
acid).
–
1
IR (neat): 1817, 1654 cm .
1
References
H NMR (400 MHz, CDCl ): d = 2.52 (m, 4 H), 4.99 (m, 2 H), 5.07
m, 2 H), 5.55 (m, 2 H), 7.32–7.47 (m, 3 H), 7.89 (m, 2 H).
3
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(
1
3
C NMR (100 MHz, CDCl ): d = 40.88, 73.54, 120.35, 125.59,
27.78, 128.59, 130.51, 132.52, 159.85, 178.89.
3
1
645.
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tion of 3 (11.57 g, 48 mmol) in MeOH (20 mL) and the mixture was
stirred for 2 h at r.t. The solvent was removed and the oily residue
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2
2
2
2
washed with H O (20 mL) and dried (MgSO ). The solution was fil-
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2
4
tered and the solvent evaporated to give 4 as an oil; yield: 12.92 g
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(
2
004, 10, 617.
–
1
IR (neat): 3276, 1737, 1633 cm .
(
4) Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune,
1
H NMR (400 MHz, CDCl ): d = 2.62 (dd, J = 7.6, 14.0 Hz, 2 H),
3
H. Angew. Chem. Int. Ed. 2004, 43, 5360.
3
.37 (dd, J = 7.2, 14.0 Hz, 2 H), 3.81 (s, 3 H), 5.04–5.13 (m, 4 H),
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5
.64 (m, 2 H), 7.07 (br s, 1 H), 7.40–7.53 (m, 3 H), 7.77 (m, 2 H).
(
1
3
2000, 35, 1. (c) Pellicciari, R.; Costantino, G. Curr. Opin.
C NMR (100 MHz, CDCl ): d = 39.11, 52.82, 64.79, 119.19,
3
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1
26.79, 128.55, 131.47, 132.17, 134.94, 166.35, 173.66.
(
(
Methyl 1-Benzamidocyclopent-3-ene-1-carboxylate (5)
(
b) Conti, P.; De Amici, M.; Joppolo-di-Ventimiglia, S.;
A solution of 4 (12.92 g, 47.5 mmol) in anhyd toluene (80 mL) un-
der argon was treated with benzylidenebis(tricyclohexylphos-
phine)dichlororuthenium (3.13 g, 3.8 mmol) dissolved in anhyd
toluene (20 mL) and the mixture was stirred for 6 h at r.t. The sol-
vent was evaporated and the residue was purified by column chro-
matography (eluent: hexanes–EtOAc, 7:3) to give 5 as a white solid;
yield: 10.62 g (91%); mp 126–127 °C (hexanes–EtOAc).
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E.; De Sarro, G.; Bruno, G.; De Micheli, C. J. Med. Chem.
2
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C.; Undheim, K. J. Chem. Soc., Perkin Trans. 1 2000, 1691.
–
1
IR (Nujol): 3314, 1733, 1643 cm .
Synthesis 2006, No. 14, 2440–2443 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
1-Aminocyclopent-3-ene-1-carboxylic Acid
2443
(
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Synthesis 2006, No. 14, 2440–2443 © Thieme Stuttgart · New York