.
Angewandte
Communications
process intensification and the highest Environmental (E)
factor in the chemical industry, with typical values ranging
from 25 to > 100.[15] This has encouraged pharmaceutical
companies to commence “green” chemistry programs.[16]
Despite the great effort made to optimize the synthesis of
a particular GABA analogue, a simple, general, and sustain-
able protocol to obtain all possible derivatives is still lacking.
Scheme 1 shows our proposal for a general chemical synthesis
of these relevant drugs by means of readily available solid
catalysts in two one-pot operations and with very low waste
generation. This protocol represents a conceptual and prac-
tical step forward with respect to the reported syntheses.
The synthetic route for the synthesis of GABA derivatives
is shown in Figure 2. First, the aldehyde is reacted with
Figure 3. Multicomponent reaction of aldehydes, nitromethane, and
malonates. [a] Chiral solid catalyst 9 was used. [b] Composite catalyst
10+11 was used.
(a complete set of results can be found in the Supporting
Information). Figure 3 shows the results attained for the
multicomponent reaction of aldehyde 1 with nitromethane
and dimethylmalonate. The chiral solid catalyst was prepared
in both pseudo-enantiomeric forms starting either from
quinine or quinidine and following a reported procedure
(see Supporting Information for details on the preparation
and characterization of the chiral solid catalyst).[17] Hybrid
solid catalyst 9 derived from quinidine proved efficient in
promoting the required asymmetric multicomponent trans-
formation affording the Michael adducts 4 in good yields and
reasonable enantiomeric ratios (Figure 3). The pseudo-enan-
tiomeric solid catalyst derived from quinine produced the
opposite Michael-adduct enantiomer with similar efficiency
and a similar level of enantiocontrol (data shown in the
Supporting Information, Scheme S1).
As many of the GABA pharmaceuticals are commercial-
ized in a racemic form, the multicomponent transformation
was assayed with a variety of commercial silica-based solid
catalysts. The optimum catalyst should include an amino-
propyl site that smoothly promotes the Henry condensation
and also a stronger base that would facilitate the subsequent
malonate Michael addition. Therefore, a composite solid
catalyst was used combining an aminopropyl-functionalized
silica material with a supported basic catalyst. Several organic
bases supported on siliceous materials were screened and an
enhanced performance was observed for commercially-avail-
able dimethylaminopropyl-functionalized silica. Extensive
optimization of the reaction conditions can be found in the
Supporting Information (Tables S1–S4). The best result in
terms of yield and selectivity was achieved when the trans-
formation was carried out in o-xylene at 708C for 18 h with
15 mol% of the aminopropyl-silica-based catalyst 10 com-
bined with 15 mol% of the dimethylaminopropyl-silica-based
solid 11. Figure 3 shows that under these conditions, product
4a derived from benzaldehyde (1a) is formed in 73% yield. A
substrate scope evaluation showed that the method is
applicable to different starting materials with varied func-
tionalities, which allows establishing the method as a general
procedure for the synthesis of new GABA analogues.
Figure 2. Catalytic sequence of seven chemical transformations in
a two-flask operation proposed for the preparation of GABA derivatives
using a single solvent. R=aromatic or aliphatic chain. * Represents
the generated chiral center.
nitromethane and dimethylmalonate in a multicomponent
transformation to form compound 4. The achiral transforma-
tion is catalyzed by commercially available solid catalysts,
while the asymmetric version is catalyzed by urea-modified
cinchona alkaloid derivatives on a mesoporous siliceous
material with additional pending aminopropyl groups.[17]
À
This multicomponent reaction forms two new C C bonds
(one of them in a stereoselective manner if desired) with high
atom economy. The raw compound 4 is then transferred to the
second reactor and subjected to the heterogeneous catalytic
hydrogenation of the nitro group to the primary amine 5.
Then, spontaneous amide cyclization followed by thermal
decarboxylation of the remaining ester group gives the
desired final product 8 after the four-step sequence. Purifi-
cation by a single column chromatography and recrystalliza-
tion of the final product would ensure the purity of the
compound as well as enhance the enantiopurity. Overall,
a linear sequence of seven chemical transformations is
performed with only two solid catalysts to directly give the
desired GABA derivatives either in racemic or enantiopure
form. The only by-products formed are H2O, MeOH, and
CO2. One solvent could be used for the whole procedure,
which is an additional benefit of our proposed reaction
sequence.
To optimize the sequence, each transformation was
examined independently and selected data is shown below
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!