Highly enantioselective decarboxylative protonation of α- aminomalonates mediated by thiourea Cinchona alkaloid derivatives: Access to both enantiomers of cyclic and acyclic α-aminoacids

Article abstract of DOI:10.1021/ol070712v

Equation Presented Thiourea derived cinchona alkaloids promote the asymmetric decarboxylase protonation of cyclic, acyclic, or bicyclic α-aminomalonate hemiesters under mild and metal-free conditions to afford enantioenriched aminoesters in high yields and enantioselectivities up to 93%. Both enantiomers of the aminoesters have been synthesized with the same selectivity when using organic base 3 and its pseudoenantiomer 6 derived from quinine.

Full text of DOI:10.1021/ol070712v

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2621-2624
Highly Enantioselective Decarboxylative
Protonation of -Aminomalonates
Mediated by Thiourea Cinchona Alkaloid
Derivatives: Access to Both
r
Enantiomers of Cyclic and Acyclic
r
-Aminoacids
Mukkanti Amere, Marie-Claire Lasne, and Jacques Rouden*
Laboratoire de Chimie Mole´culaire et Thio-organique, ENSICAEN, UniVersite´ de
Caen-Basse Normandie, CNRS, 6 BouleVard du Mare´chal Juin, 14050 Caen, France
jacques.rouden@ensicaen.fr
Received March 23, 2007
ABSTRACT
Thiourea derived cinchona alkaloids promote the asymmetric decarboxylative protonation of cyclic, acyclic, or bicyclic
r-aminomalonate
hemiesters under mild and metal-free conditions to afford enantioenriched aminoesters in high yields and enantioselectivities up to 93%. Both
enantiomers of the aminoesters have been synthesized with the same selectivity when using organic base 3 and its pseudoenantiomer 6
derived from quinine.
Asymmetric decarboxylative protonation of substituted ami-
nomalonates in the presence of a chiral base is a synthetically
convenient and straightforward route to synthesize a variety
of natural and unnatural optically pure R-aminoacids. This
synthetic methodology is based on the more general malonic
acid synthesis where the chirality of the product can be
generated during the enolate protonation step (Scheme 1).
In its enantioselective version, it is the first example of an
asymmetric reaction reported as early as 1904.1 Although
enantioselective decarboxylative protonation is a century old
reaction, it has not received much attention until recently.2
Whereas high selectivity was obtained performing this chemi-
cal transformation in the presence of enzymes3 or recently
with organometallic complexes,4 the highest enantiomeric
excess achieved for this reaction catalyzed by an organic
base was never more than 72%.5 The enantiomeric excesses
are strongly dependent both on the solvent and on the
substrate.
(2) (a) Verbit, L.; Halbert, T. R.; Patterson, R. B. J. Org. Chem. 1975,
40, 1649-1650. (b) Glusker, J. P.; Carrell, H. L.; Job, R.; Bruice, T. C. J.
Am. Chem. Soc. 1974, 96, 5741-5751. (c) Yashiro, M.; Ajioka, M.;
Yano, S.; Toriumi, K.; Ito, T.; Yoshikawa, S. Inorg. Chem. 1986, 25,
1709-1715. (d) Toussaint, O.; Capdevielle, P.; Maumy, M. Tetrahedron
Lett. 1987, 28, 539-542. (e) Roy, O.; Dieckmann, M.; Riahi, A.; He´nin,
F.; Muzart, J. Chem. Commun. 2001, 533-534. (f) Baur, M. A.; Riahi, A.;
He´nin, F.; Muzart, J. Tetrahedron: Asymmetry 2003, 14, 2755-2761. (g)
Roy, O.; Riahi, A.; He´nin, F.; Muzart, J. Eur. J. Org. Chem. 2002, 3986-
3994.
(1) (a) Marckwald, W. Ber. Dtsch. Chem. Ges. 1904, 37, 349. (b)
Marckwald, W. Ber. Dtsch. Chem. Ges. 1904, 37, 1368.
10.1021/ol070712v CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/19/2007

Scheme 1. Proposed Route to Optically Enriched
R-Aminoacids
Figure 1. Cinchona derivatives tested in decarboxylative proto-
nations.
As a part of our program on the synthesis of a selective
M2 muscarinic receptor antagonist6 and on the development
of new eco-friendly approaches to amino acid derivatives,
we became involved in enantioselective organocatalyzed
decarboxylative protonation.7 This methodology was used
for the preparation of enantioenriched pipecolic ester (72%
ee) on a multigram scale in good yield and mild conditions,
with 9-epi-cinchonine as the most efficient catalyst (10%
amount).5c
Recently, urea/thiourea-based bifunctional catalysts have
emerged as powerful catalysts in a wide range of asymmetric
transformations.8 Their high activity as well as their selectiv-
ity were assigned to their ability to activate both electrophilic
and nucleophilic centers of the reacting partners. Since
cinchona alkaloid derivatives were successfully used in
previous decarboxylative protonations5 we anticipated that
the urea/thiourea bases 1-6 (Figure 1) would afford the
conformational rigidity required for high selectivity.9 The
amine function could act as a chiral proton shuttle whereas
the urea/thiourea group, a strong hydrogen-bond donor,
would anchor the substrate to bring the chiral protonating
agent in a close proximity to the prochiral enolate. We report
here unprecedented enantioselectivities for metal-free de-
carboxylative protonations carried out in the presence of urea/
thiourea cinchona bases 1-6.
Compounds 1-6 derived from cinchona alkaloids were
prepared according to the described methods.9 They were
tested in a 1:1 ratio with substrate 7a in THF at room
temperature (Scheme 2). First, urea 1 afforded 7b with a
Scheme 2. (Thio)ureas Mediated
Decarboxylation-Protonation of Hemimalonic Esters
(3) (a) Miyamoto, K.; Ohta, H. J. Am. Chem. Soc. 1990, 112, 4077-
4078. (b) Sugai, T.; Ohta, H. Chem. Commun. 2000, 1519-1520. (c)
Matoishi, K.; Ueda, M.; Miyamoto, K.; Ohta, H. J. Mol. Catal. B: Enzym.
2004, 27, 161-168. (d) Ijima, Y.; Matoishi, K.; Terao, Y.; Doi, N.;
Yanagawa, H.; Ohta, H. Chem. Commun. 2005, 877-879. (e) Terao, Y.;
Ijima, Y.; Miyamoto, K.; Ohta, H. J. Mol. Catal. B: Enzym. 2007, 45, 15-
20.
(4) Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am.
Chem. Soc. 2006, 128, 11348-11349.
(5) (a) Brunner, H.; Schmidt, P. Eur. J. Org. Chem. 2000, 2119-2133.
(b) Brunner, H.; Baur, M. A. Eur. J. Org. Chem. 2003, 2854-2862. (c)
Seitz, T.; Baudoux, J.; Bekolo, H.; Cahard, D.; Plaquevent, J.-C.; Lasne,
M.-C.; Rouden, J. Tetrahedron 2006, 62, 6155-6165.
(6) (a) Martin, J.; Deagostino, A.-M.; Perrio, C.; Dauphin, F.; Ducandas,
C.; Morin, C.; Desbe`ne, P.-L.; Lasne, M.-C. Bioorg. Med. Chem. 2000, 8,
591-601. (b) Martin, J.; Lasne, M.-C.; Plaquevent, J.-C.; Duhamel, L.
Tetrahedron Lett. 1997, 38, 7181-7182.
(7) Rogers, L. M.-A.; Rouden, J.; Lecomte, L.; Lasne, M.-C. Tetrahedron
Lett. 2003, 44, 3047-3050.
(8) Selected bifunctional organocatalysis: (a) Okino, T.; Hoashi, Y.;
Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673. (b) Okino, T.;
Nakamura, Y.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625-627.
(c) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44,
4032-4035. (d) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X. N.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119-125. (e) Li, H. M.; Wang, Y.; Tang,
L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906-9907. (f) Li, H.; Wang,
Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew.
Chem., Int. Ed. 2005, 44, 105-108. (g) Li, H.; Song, J.; Liu, X.; Deng, L.
J. Am. Chem. Soc. 2005, 127, 8948-8849. (h) Matsui, K.; Takizawa, S.;
Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680-3681. (i) Shi, M.; Chen, L.
H.; Li, C. Q. J. Am. Chem. Soc. 2005, 127, 3790-3800. (j) Berkessel, A.;
Cleemann, F.; Mukherjee, S.; Muller, T. N.; Lex, J. Angew. Chem., Int.
Ed. 2005, 44, 807-811.(k) Berkessel, A.; Mukherjee, S.; Cleemann, F.;
Muller, T. N.; Lex, L Chem. Commun. 2005, 1898-1900. (l) Lattanzi, A.
Org. Lett. 2005, 7, 2579-2582.
low 24% ee (Table 1, entry 1) as expected from literature
precedent.9c By using the corresponding thiourea 2, pipeco-
late 7b was obtained in 80% yield and 64% ee (entry 2).
Encouraged by this result, we screened the thioureas 3-6
in the decarboxylation of 7a under similar reaction condi-
tions, varying only the temperature and time. Increasing the
temperature led to a decrease of the selectivity (entries 3
and 4). This result contrasts with those observed when the
reaction was catalyzed by cinchona alkaloids,5 the enantio-
selectivities being independent from the temperature, high-
lighting here the role of hydrogen bonding with thiourea-con-
2622
Org. Lett., Vol. 9, No. 14, 2007

Table 1. Preliminary Results on the Decarboxylative
Protonationa of the Model Substrate 7a with Urea-Thioureas
1-5
Table 2. Ee Values as a Function of Solvents and Substratesa
entry substrate solvent
product yieldb (%) eec (%)
THF
1
2
7a
7b
94
88
92
90
89
84
82
74
86
94
88
88
92
80
75
82
82
83
88
90
73
83
82
61
75
81
92
93
91
63
35
63
entry
base
temp (°C)
time (d)
yieldb (%)
eec (%)
8a
THF
8b
3
9a
THF
9b
1
2
3
4
5
6
7
8
9
1
2
2
2
3
3
3
4
5
25
25
40
60
25
0
2
2
2
1
2
7
7
7
7
80
80
95
98
85
94
25
85
20
24
64
58
24
70
82
83
10
15
4
5
6
7
8
9
10
11
12
13
14
15
16
10a
11a
12a
13a
14a
10a
10a
10a
10a
10a
10a
10a
10a
THF
THF
THF
THF
THF
THF/H2Od
Et2O
MeCN
acetone
toluene
CH2Cl2
DMF
10b
11b
12b
13b
14b
10b
10b
10b
10b
10b
10b
10b
10b
-15
0
0
a 7a (0.175 mmol), base (0.175 mmol) in THF (1 mL) under nitrogen.
b Isolated yields after column chromatography. c Determined by chiral HPLC
analysis. In all experiments, product 7b with the S configuration was
obtained as the major enantiomer.
EtOH
a 7a (0.175 mmol), base 3 (0.175 mmol), solvent (1 mL), 0 °C, 7 d.
b Isolated yields after column chromatography. c Determined by chiral HPLC
analysis. In all experiments, the S configuration of the product was obtained
as the major enantiomer. d 3/1 mixture.
taining cinchona bases.10 Thiourea 3, the quinidine analogue
of cinchonine derivative 2, afforded a slightly better enan-
tioselectivity at room temperature (entry 5). Decreasing the
temperature led to a notable improvement of selectivity with
an ee of 82-83%, while slowing the reaction rate (entries 6
and 7). At -15 °C, the isolated yield of 7b reached only
25% after 7 days (entry 7). Base 4, with no CF3 groups on
the N-phenylthiourea moiety, led to 7b with a poor selectivity
confirming the major role of the trifluoromethyl substituents.
By increasing the acidity of the NH protons of the thiourea
group, stronger H-bonds are formed with the substrate (entry
8). Surprisingly, 5 with the thiourea moiety on the quinoline
ring gave poor yield and enantiomeric excess (entry 9).
All compounds 1-5 generated the S configuration of 7b
as the major enantiomer.11 From this preliminary study 3
was found to be the best among all organic bases tested.
Therefore quinidine-based 3 and its pseudoenantiomer 6,
prepared from quinine, were employed in the following part
of this work. Further, we investigated the effect of N-acyl
substituents on both cyclic and acyclic substrates. For a given
substrate, the bulky benzoyl group gave lower ee values
while the acetyl provided higher selectivity (Table 2, compare
entries 1, 4, and 5, 7). Noteworthy are both the low yield
and the enantioselectivity obtained with the N-formyl deriva-
tive (entry 8). It appeared that both steric and electronic
properties of the acyl group influence the selectivity.
Therefore to increase H-bond acceptor properties of the
substrate, a 2-thiophenecarbonyl moiety was appended on
the nitrogen as compound 9a. Amino ester 9b was obtained
with a selectivity (88% ee) similar to that obtained with 10b
(compare entries 3 and 4). However, in this case we cannot
exclude a self-decarboxylation.12 Equally high levels of
stereoinduction (83% ee) were observed with the Cbz and
methoxycarbonyl derivatives 8a and 12a (entries 2 and 6).
The easy removal of these N-protecting groups shows the
practical utility of this chemistry.
In our previous work on decarboxylative protonation
catalyzed by cinchona alkaloids, where the selectivity was
mainly governed by ion-pair interactions, the highest enan-
tioselectivities were obtained in solvents of low polarity.5c
Here, a wide range of solvents either polar aprotic (CH3CN,
acetone) or apolar aprotic (toluene, ether, or THF) afforded
both good yields and high selectivities. Among the best
solvents, namely, THF, CH3CN, acetone, and toluene (Table
2, entries 4, 11-13), the observed enantioselectivities are
similar (within experimental error). Hence, further decar-
boxylations with thioureas 3 and 6 were carried out in THF,
acetone, or acetonitrile.
The decarboxylation of hemiester 7a by using 20 mol %
of thiourea 3 under optimized conditions (THF, 0 °C, 12
days) afforded 7b in 70% yield and 69% ee.13 This lower
selectivity could result from a competitive protonation of
the intermediate enolate by the carboxylic acid group of
unreacted starting compound due to the slow reaction rate.
Although low efficiency of base 3 was observed under
catalytic conditions, this compound could be considered as
a catalyst. Indeed, no reaction occurred without it and it was
recovered unchanged at the end of the reaction allowing its
recycling by acid-base workup.
(9) Thiourea catalysts of cinchona alkaloids: (a) Tillman, A. L.; Ye, J.;
Dixon, D. J. Chem. Commun. 2006, 1191-1193. (b) Ye, J.; Dixon, D. J.;
Hynes, P. S. Chem. Commun. 2005, 4481-4483. (c) McCooey, S. H.;
Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367-6370. (d) Vakulya,
B.; Varga, S.; Csampai, A.; Soo´s, T. Org. Lett. 2005, 7, 1967-1969. (e)
Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H.
Angew. Chem., Int. Ed. 2006, 45, 929-931. Song, J.; Wang, Y.; Deng, L.
J. Am. Chem. Soc. 2006, 128, 6048-6049.
(12) We observed the formation of 5% of product 9b in a CDCl3 sample
kept at rt for 7 days, whereas no decarboxylation was observed with 7a,
11a, or 15a under the same conditions. This suggests that the sulfur atom
of the thiophene ring is basic enough to promote self-decarboxylation.
(13) This result is similar to our previous attempt of a catalytic reaction
with substrate 7a. 7b was obtained with 72% ee with use of 10% of
epicinchonine at room temperature, see ref 5c.
(10) Connon, S. J. Chem. Eur. J. 2006, 12, 5418-5427.
(11) Absolute stereochemistry was determined by comparison with known
data (ref 5). New compounds were independently synthesized from the
corresponding optically pure aminoacids.
Org. Lett., Vol. 9, No. 14, 2007
2623

In summary, this work reports an asymmetric decarboxy-
lative protonation reaching 93% ee, the highest enantiose-
lectivity achieved for this reaction mediated by an organic
base. Unlike previous reports, the selectivity was shown to
be highly dependent on the temperature, due to supramo-
lecular association of the intermediates controlled by H-
bonding. Although 1 equiv of the base was used, its ready
access and reusability in combination with the broad range
of solvents that can be used and the Very mild conditions
make this transformation synthetically attractive. The general
applicability of the reaction for the synthesis of R-aminoacid
derivatives was demonstrated with structurally different types
of amino hemiester precursors. Both enantiomers of these
amino-esters could be synthesized with the same selectivity
when using organic bases 3 and 6. Easily removable
N-protecting groups such as CBz or methoxycarbonyl can
be used in place of acetyl with the same efficiency. In its
current achievment, this enantioselective decarboxylative
protonation mediated by an organic base is a valuable metal-
free alternative to asymmetric protonation of lithium enolates
and represents the first step toward highly selective orga-
nocatalyzed asymmetric protonation. We are currently search-
ing for bases that can be used in catalytic amounts to
overcome the slow reaction rate observed with the thioureas
used in this work.
Table 3. Enantioselective Decarboxylation Mediated by
Pseudoenantiomers 3 and 6 with N-Acetyl Substratesa
a Substrate (0.35 mmol), base (0.35 mmol), solvent (2 mL), 0 °C, 7 d.
b Isolated yields after column chromatography. c Determined by chiral HPLC
analysis.
Acknowledgment. We gratefully acknowledge the “Min-
iste`re de la Recherche et des Nouvelles Technologies” for
fellowships to M.A., and “PunchOrga” Network (Poˆle
Universitaire Normand de Chimie Organique), CNRS (Centre
National de la Recherche Scientifique), the “Re´gion Basse
Normandie”, and the European Union (FEDER funding) for
funding.
Finally, we chose the cheap and commercially available
N-acetyl aminomalonate to prepare hemimalonates 15a and
16a. We examined the scope of pseudoenantiomeric bases
3 and 6 by testing the decarboxylation with structurally
distinct substratessacyclic, cyclic, and bicyclic. Gratifyingly,
good consistency in the selectivity was observed with all
substrates. Furthermore, excellent enantioselectivities were
achieved with quinine derivative 6, which was found to be
equally efficient but opposite to 3 in terms of enantioselection
in the asymmetric decarboxylative protonation of all sub-
strates (Table 3, entries 1, 3, 7, and 10).
Supporting Information Available: Details of the pro-
cedure, spectral data for unknown compounds, and an HPLC
chromatogram. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL070712V
2624
Org. Lett., Vol. 9, No. 14, 2007