Enantioselective decarboxylation-reprotonation of an α-amino malonate derivative as a route to optically enriched cyclic α-amino acid

Article abstract of DOI:10.1016/S0040-4039(03)00557-4

Chiral tertiary amines have been examined as enantioselective decarboxylation-reprotonation reagents for the synthesis of α-amino acids via α-aminomalonates. N-Acetyl pipecolic acid ethyl ester, as a model compound, was obtained in good yield and 52% enantiomeric excess using a quinidine derived base.

Full text of DOI:10.1016/S0040-4039(03)00557-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3047–3050
Enantioselective decarboxylation–reprotonation of an a-amino
malonate derivative as a route to optically enriched cyclic
a-amino acid
Louis M.-A. Rogers, Jacques Rouden, Ludovic Lecomte and Marie-Claire Lasne*
Laboratoire de Chimie Mole´culaire et Thioorganique, UMR CNRS 6507, ENSICAEN and Universite´ de Caen-Basse Normandie,
6 Boulevard du Mare´chal Juin, 14050 Caen Cedex, France
Received 23 December 2002; revised 25 February 2003; accepted 27 February 2003
Abstract—Chiral tertiary amines have been examined as enantioselective decarboxylation–reprotonation reagents for the synthesis
of a-amino acids via a-aminomalonates. N-Acetyl pipecolic acid ethyl ester, as a model compound, was obtained in good yield
and 52% enantiomeric excess using a quinidine derived base. © 2003 Elsevier Science Ltd. All rights reserved.
Interest in compounds containing a rigid a-amino acid
moiety is still growing since they can be used as confor-
mationally restricted units in peptide mimetics. More-
over, they are often present in natural and biologically
active compounds. As an example, the 2-piperidine
carboxylate sub-unit is a common structural moiety of
peptides1 and macrolides endowed with immunosup-
pressant (FK506),2 antibiotic (rapamicin esters)3 or
anti-inflammatory (ascomycin and derivatives)4 proper-
ties. However, unlike optically active acyclic a-amino
acids, catalytic asymmetric synthesis of cyclic a-amino
acids has been limited. The best current route to the
pure enantiomers is the classical resolution of the race-
mate.5 Kinetic resolutions of piperidine 2-carboxylic
acid derivatives have been described. They required the
search for specific esterases,6 or bacterial cells.7 Most of
the asymmetric examples developed8 up to now were
carried out under stoichiometric conditions,9 except the
phase transfer catalyst alkylation of a suitable imine,10
and the hydrogenation of tetrahydropyridines.11
As a part of our program on the synthesis of (R)- and
(S)-AF-DX 384,12 potent and selective muscarinic
antagonists, we studied the deracemization of the
methyl ester of pipecolic acid. A low enantiomeric
excess (36%)13 was obtained. More successful was the
deracemization using asymmetric protonation of
pipecolamides.14 Although efficient both in terms of
yields and enantiomeric excesses (ee’s >95%), the reac-
tion suffers from the use of sec-butyllithium15 at −78°C.
With the aim of avoiding this strong base and the low
temperature, we examined the enantioselective decar-
boxylation–reprotonation of a malonate precursor as
an alternative route to a-amino acid derivatives.
Whereas this methodology was known in the presence
of enzymes or microorganisms,16 it has received little
attention,17 although being probably the first asymmet-
ric synthesis.18 Recently,19 the treatment at rt of 2-aryl-
2-cyanopropionic acids with a catalytic amount of
cinchona alkaloids led to naproxen derivatives with ee’s
up to 72%. To our knowledge, the sequence decarboxyl-
Scheme 1. Reagents and conditions: (i) Cs2CO3, Br(CH2)4Br, MeCN, reflux, 16 h, 73%; (ii) CsOH, EtOH, rt, 16 h, 82%; (iii) chiral
base, THF, 16–24 h, 68–77%.
* Corresponding author. Tel.: +33-2-3145-2892; fax: +33-2-3145-2877; e-mail: lasne@ismra.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00557-4

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L. M.-A. Rogers et al. / Tetrahedron Letters 44 (2003) 3047–3050
ation–reprotonation has been only studied on acyclic
malonic derivatives bearing an aryl substituent able to
stabilize a carbanionic intermediate. Recent reports on
the enantioselective decarboxylation of b-ketobenzyl
esters20 prompt us to describe here our preliminary
results on the decarboxylation–reprotonation, in the
presence of a chiral base, of the N-acyl malonate
monoester 1 as a route to nonracemic piperidine-2-car-
boxylic acid ethyl ester 2.
configurations of carbons 8 and 9 and finally the modifi-
cations of the alkaloids by cyclization were studied. (+)-
Cinchonine 5, (−)-cinchonidine 6, (−)-quinine 7, (+)-
quinidine 8were purchasedfrom commercial sources.(+)-
Cupredine 9, (+)-cupredine cyclic ether 10, (+)-cin-
chonine cyclic ether 11, (+)-9-mesyloxyquinidine 12,
(+)-9-amino-9-deoxyquinidine 13, and (+)-2-methoxy-
benzamide 14 were prepared by literature methods.19,25
The results presented in Table 1 revealed that the asym-
metric induction is dependent on the presence of an
hydroxyl or methoxy group on the quinoline ring.
Indeed, cinchonine and cinchonidine gave poor ee’s com-
pared to quinine and quinidine under stoichiometric
(Table 1, entries 1–4) or catalytic conditions (Table 1,
entry 5). These results contrast with those reported for
the decarboxylation of the monoethyl ester of phenyl-
malonic acid where cinchonine gave a higher ee than the
other cinchona alkaloids.17e,f The crucial role of an oxy-
gen group in the 6% position was confirmed by the ee’s
obtained with the cyclic ethers 10 (R1=OH, ee 36.8%)
and 11 (R1=H, ee <5%).
The racemic carboxylic acid–ester 1 was prepared in
multigram quantities via a two steps sequence starting
from commercially available diethyl acetamidomalonate
3 in 60% overall yield (Scheme 1).
In order to test the feasability of the reaction, the decar-
boxylation of the acid–ester 1 was first studied in the pres-
ence of an achiral base. Yields up to 80% in ester 2 were
obtained with triethylamine in THF after 21 h at rt.21 The
enantioselective decarboxylation–reprotonation was
then carried out under the following conditions: the chi-
ral base was added to the acid 1 in THF (0.1 M) and
allowed to react for 16–24 h at rt. After work-up, the
reaction mixture was directly injected onto a chiral
HPLC column.22 Isolated yields of 68–77% were
obtained using cinchona alkaloids as the bases. The chro-
matograms showed only signals corresponding to the chi-
ral base and to the enantiomeric products 2. No starting
material 1 was detected either by HPLC or by 1H NMR
of the crude mixture. Each enantiomer of the ester 2 were
independently synthesized23 for unambiguous assigne-
ment of the HPLC signals. Among a number of chiral
amines24 screened for this reaction, cinchona alkaloids
gave the best results. The influence of the substituents on
the quinoline ring or on the 9 position, the role of the
In our experiments with alkaloids 5–14, the configuration
of the carbon-8 has a small influence compared to that
observed in the decarboxylation–reprotonation of aryl-
cyanopropionic acids.19 However, a clear pseudo enan-
tiomeric effect was observed with quinine and quinidine
whereas with cinchonine and cinchonidine this effect is
not so marked due to the low ee’s obtained (Table 1,
entries 1–5). One question remains concerning the role
of the configuration of C-9. The C-9 has an R configu-
ration in base 14 and S in bases 8–11, but all these
compounds generate the same S enantiomer of pipeco-
late 2. This was also observed previously but not
Table 1. Decarboxylation of malonate hemiester 1 in the presence of cinchona alkaloids
Entry
Base
C-8
C-9
R1
R2
2 eea
2 C-2b
nc
1
2
3
4
5
6
8
9
10
11
12
13
(+)-Cinchonine 5
(−)-Cinchonidine 6
(−)-Quinine 7
(+)-Quinidine 8
(+)-Quinidine 8, 10 mol%
(+)-Cupredine 9
(+)-10
(+)-10, 10 mol%
(−)-11
(+)-12
R
S
S
S
R
R
S
S
S
S
S
S
S
R
R
H
H
OH
OH
OH
OH
OH
OH
–
–
5.890.7
2.290.5
18.090.3
15.993.4
18.591.1
8.891.8
36.891.3
17.692.6
4.193.5
1.090.7
7.491.2
52.191.8
S
R
R
S
S
S
S
S
S
S
S
S
3
3
2
3
3
2
3
2
2
3
2
2
OMe
OMe
OMe
OH
OH
OH
H
OMe
OMe
OMe
R
R
R
R
R
R
R
R
R
–
OMs
NH2
(+)-13
(+)-14
NHCO(C6H4-2-OMe)
a Determined by chiral HPLC.
b Absolute configuration of the major enantiomer.
c Number of experiments.

L. M.-A. Rogers et al. / Tetrahedron Letters 44 (2003) 3047–3050
3049
discussed.19 To address this question it will be necessary
to synthesize the diastereoisomer of 14 with a C-9 of S
configuration.
other hand, hydrogen bonding between the phenolic
hydroxy group and the carbonyl of the amide group of
the substrate.28 The lower enantioselectivity excess
observed in our case under the best conditions com-
pared to that obtained in enantioselective decarboxyla-
tion of naproxene derivatives (52 versus 72%) could
result from the lack of an aromatic ring in our sub-
strate. With salt bridging and hydrogen bonding, the
p-stacking with the quinoline ring seems essential to
achieve a good enantioselectivity.29
The sterically more hindered dihydroquinidine deriva-
tives 15 and 16 with the C-8R, C-9S configurations
gave higher ee’s than their stereoisomers dihydroquini-
nes (C-8S, C-9R) 18 and 19 (Table 2). A pseudo
enantiomeric effect was not observed with these com-
pounds. The PHAL derivatives of quinidine 17 and
quinine 18 induced the formation of the same enan-
tiomer S of pipecolate 2 (Table 2, entries 5 and 6). With
the AQN derivatives of quinidine 15 and quinine 19 the
major enantiomers of 2 were respectively R (ee 20.3%)
and S (ee 7.1%), however, with different enantiomeric
excesses (Table 2, entries 1 and 7). The discrepancy in
the results obtained with these bases leads to a question
concerning the role of the spacer between the two
quinine/quinidine units. If the spacer is not directly
involved in the decarboxylation process, it probably
induces a conformational change compared to the
monomeric alkaloid. The dimeric cinchona derivatives
do not appear to be good candidates for further devel-
opments as basic catalysts for the reaction.
In conclusion, synthesis of optically enriched N-pro-
tected ethyl pipecolate has been achieved using an
enantioselective
decarboxylation–reprotonation
sequence in the presence of stoichiometric or catalytic
amounts of cinchona alkaloids. Although the enan-
tiomeric excess of the N-acyl ethylpipecolate seems
modest, it is the highest obtained for this substrate.
Indeed, kinetic resolutions or reactions of pipecolate
esters mediated by lipases have yet been limited by the
substituent on the substrate,6a,b and the purity of
enzymes.6c
If the highest ee was obtained with one the most
successful chiral base used in the decarboxylation of
naproxen derivatives, our preliminary results suggest
that much efforts are needed to propose a more selec-
tive catalyst. Our current work focus on further
improvement of the structure of a base which could
stabilize any putative intermediate by hydrogen bond-
ing and p-stacking and thus would probably slow down
Intramolecular hydrogen bonding have been proposed
to account for the high enantiomeric excesses obtained
in the decarboxylation reaction mediated by amides of
9-amino-9-deoxyepicinchonine.26,27 Such interactions
could also explain the highest enantioselectivity (52%)
(Table 1, entry 13) observed in our case with amide 14
and the poor results with the bases 12 and 13 (entries
11 and 12). With the cyclic ether 10, a relatively high ee
(Table 1, entry 8) was obtained. It could result from the
stabilization of the intermediate involving ionic interac-
tion between the positive quinuclidinium protonated
nitrogen and the anionic side of the substrate (before or
after decarboxylation) on the one hand, and on the
the reprotonation for
a better enantioselectivity.
Finally, as both the enantioselectivity of reactions using
cinchona alkaloids30 and the rate constants for decar-
boxylation of acid19,31 depend strongly on the solvent, a
study of the different parameters of the reaction will be
undertaken.
Table 2. Decarboxylation of malonate hemiester 1 in the presence of quinidine derivatives
Entry
Base
C-8
C-9
2 eea
2 C-2b
nc
1
2
3
4
5
6
7
(+)-(DHQD)2AQN 15
(+)-(DHQD)2AQN 15, 10 mol%
(+)-(DHQD)2PYR, 16
(+)-(DHQD)2PYR, 16, 10 mol%
(+)-(DHQD)2PHAL, 17
(−)-(DHQ)2PHAL, 18
R
R
R
R
R
S
S
S
S
S
S
R
R
20.391.2
13.290.1
23.590.6
24.691.3
14.090.7
7.391.2
S
S
S
S
S
S
R
2
3
2
3
2
2
2
(−)-(DHQ)2AQN, 19
S
7.190.9
a Determined by chiral HPLC.
b Absolute configuration of the major enantiomer.
c Number of experiments.

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L. M.-A. Rogers et al. / Tetrahedron Letters 44 (2003) 3047–3050
Acknowledgements
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This work was supported by the Poˆle Universitaire
Normand de Chimie Organique. The authors thank
Drs. Jean-Christophe Plaquevent and Dominique
Cahard (University of Rouen) for helpful discussions.
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