A simple organocatalytic enantioselective synthesis of pregabalin

Article abstract of DOI:10.1002/ejoc.200801220

This paper describes a new procedure for the enantioselective synthesis of the important anticonvulsant drug Pregabalin, which shows biological properties as the (S) enantiomer only. The key step of the synthetic sequence is the Michael addition reaction of Meldrum's acid to a nitroalkene mediated by a quinidine derived thiourea. A variety of novel catalysts bearing different groups at the thiourea moiety were synthesized and tested. The most successful catalyst that incorporates a trityl substituent provided up to 75 % ee of (S)- 4. The conjugate addition reaction was carried out on a multigram scale with low loadings of catalyst (10 mol-%). Moreover, the catalyst can be recycled showing the same capability in chemical yield and asymmetric induction. Then, hydrogenation of nitroalkane 4 followed by decarboxylation of diacid 5 provides Pregabalin hydrochloride in 59% overall yield. Enantioenrichment by crystallization of the free amino acid 1 improves the (S)/(R) enantiomeric ratio to 9:1. ? Wiley-VCII Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200801220

FULL PAPER
DOI: 10.1002/ejoc.200801220
A Simple Organocatalytic Enantioselective Synthesis of Pregabalin
Oriol Bassas,[a] Juhani Huuskonen,[b][‡] Kari Rissanen,[b][‡] and Ari M. P. Koskinen*[a]
Keywords: Pregabalin / Conjugate additions / Alkaloids / Thiourea / Organocatalysis / Enantioenrichment / Enantio-
selectivity / Michael addition / Asymmetric synthesis
This paper describes a new procedure for the enantioselec- multigram scale with low loadings of catalyst (10 mol-%).
tive synthesis of the important anticonvulsant drug Pregaba-
lin, which shows biological properties as the (S) enantiomer
only. The key step of the synthetic sequence is the Michael
addition reaction of Meldrum’s acid to a nitroalkene medi-
ated by a quinidine derived thiourea. A variety of novel cata-
lysts bearing different groups at the thiourea moiety were
synthesized and tested. The most successful catalyst that in-
corporates a trityl substituent provided up to 75% ee of (S)-
4. The conjugate addition reaction was carried out on a
Moreover, the catalyst can be recycled showing the same
capability in chemical yield and asymmetric induction. Then,
hydrogenation of nitroalkane 4 followed by decarboxylation
of diacid 5 provides Pregabalin hydrochloride in 59% overall
yield. Enantioenrichment by crystallization of the free amino
acid 1 improves the (S)/(R) enantiomeric ratio to 9:1.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Because only the (S) enantiomer exhibits the desired
pharmacological activity[2] enantioselective syntheses are in
demand. The initial industrial preparation of Pregabalin in-
volved a resolution of rac-1 with (+)-(S)-mandelic acid.[3]
The process provided 1 in low yields accompanied by
high manufacturing costs. Due to the need of preparing
compounds in enantiopure form, several asymmetric syn-
theses have been reported.[4] To mention some selected ex-
amples, Yuen et al.[4a] prepared both enantiomers of Prega-
balin using Evans’ chiral oxazolidinone alkylation chemis-
try. Brenner and Seebach[4b] prepared (R)-N-Boc Pregabalin
methyl ester by 1,4-addition of a titanium enolate generated
from an N-acetyloxazolidinone to the corresponding (iso-
butyl)(nitro)alkene. Catalytic methods for the enantiomer-
ical preparation of Pregabalin have also been developed.
The Pfizer manufacturing process[4c] is based on asymmet-
ric hydrogenation of a prochiral substituted 3-cyanohex-
enoic acid by using Chirotech’s commercially available rho-
dium catalyst. Sammins and Jacobsen[4e] have described a
highly enantioselective route to 1 through conjugate ad-
dition of cyanide to α,β-unsaturated imide by salen Al ca-
talysis. Shibasaki’s group[4g] developed a catalytic enantio-
selective conjugate addition reaction of cyanide to α,β-un-
saturated N-acylpyrrole mediated by a chiral gadolinium
catalyst. On the other hand, recently Armstrong et al.[4h]
described the synthesis of enantiopure Pregabalin through
conjugate addition of cyanide to a chiral α,β-unsaturated
isobutyloxazolidinone. Poe et al.[4j] have also synthesized 1
by a one-pot reaction between isovaleraldehyde, nitrometh-
ane and dimethyl malonate promoted by two microencap-
sulated catalysts. Pregabalin has also been obtained by cata-
lytic enantioselective conjugate addition of nitroalkanes to
Introduction
Pregabalin is the international non-proprietary name for
(3S)-3-(aminomethyl)-5-methylhexanoic acid (1) (Figure 1).
It belongs to the group of 3-substituted analogues of the
inhibitory neurotransmitter γ-aminobutyric acid (GABA),
such as gabapentin and baclofen. Discovered by Silverman
et al.[1] in 1991, Pregabalin is an anticonvulsant drug used
to treat epilepsy and neurophatic pain marketed by Pfizer
under the brand name Lyrica®. It is considered as one of
the drugs of the future due to its high and broad thera-
peutic activity and reaches blockbuster status (1 billion $
annual sales or more); thus, the development of simple ef-
ficient synthetic processes has become an important re-
search goal for medicinal and organic chemists.
Figure 1. Pregabalin and GABA analogues.
[a] Department of Chemistry, Helsinki University of Technology,
P. O. Box 6100, 02015 TKK, Espoo, Finland
Fax: +358-94512538
E-mail: ari.koskinen@hut.fi
[b] NanoScience Center, Department of Chemistry, University of
Jyväskylä,
P. O. Box 35, 40014 Jyväskylä, Finland
E-mail: kari.rissanen@jyu.fi
[‡] X-ray crystallography.
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Eur. J. Org. Chem. 2009, 1340–1351

A Simple Organocatalytic Enantioselective Synthesis of Pregabalin
α,β-unsaturated aldehydes using diphenylprolinol silyl ether obtained cleanly by Knoevenagel condensation in water
as organocatalyst.[4m] Moreover, very recently 1 has been from both commercially available Meldrum’s acid and iso-
industrially produced by chemoenzymatic methods.[4o]
valeraldehyde[8] by carrying out the reaction in a closed ves-
Our synthetic strategy towards enantiopure Pregabalin is sel at 75 °C for 2 h. On the other hand, nitro olefin 3 was
depicted in Scheme 1. We envisaged that the target com- synthesized in good yields as the (E) isomer, by a Henry
pound could be obtained from chiral nitroalkane 4 through reaction between nitromethane and isovaleraldehyde, fol-
reduction of the nitro group and simultaneous removal of lowed by dehydration of the intermediate nitro alcohol with
the acetonide followed by decarboxylation. In turn, the ni- trifluoroacetic anhydride and triethylamine.[9]
tro compound 4 could be accessible by two possible routes,
A and B, that rely on enantioselective conjugate addition
reactions. Route A implies unsaturated Meldrum’s acid de-
rived acceptor 3 as the electrophile and nitromethane as the
nucleophile, whereas route B is based on the use of nitro
olefin 3 as the Michael acceptor and Meldrum’s acid as the
nucleophile. Our choice of Meldrum’s acid as the malonate
surrogate was based on the expected ease of the operation
for the release of the eventual acid under mild, slightly
acidic conditions. For the catalytic asymmetric conjugate
addition[5] step we decided to employ thioureas derived
from cinchona alkaloids[6] as organocatalysts for both
routes. These systems, bearing a tertiary amine and a thio-
urea moiety, offer a dual activation of the substrate and
reagent. In previous work, the enantioselective conjugate
addition of nitroalkanes to enones by using cinchona alka-
loid based thioureas has been described by Soós’ and Ye’s
Scheme 2. Synthesis of Michael acceptors 2 and 3.
groups.[6b,6p,6q,7] Additionally, asymmetric Michael addition
reactions of malonate esters to nitro olefins catalyzed by
Preparation of the thiourea organocatalysts started by
epicinchona alkaloid derivatives have recently been report-
obtaining a range of isothiocyanates, which serve as thio-
ed.[6c,6d,6o] We decided to synthesize the previously reported
urea functionality. 3,5-Bis(trifluoromethyl)phenyl isothiocy-
9-amino-(9-deoxy-)epiquinidine-derived thiourea catalyst 8
anate (18) and trityl isothiocyanate (19) were purchased
and novel catalysts 9–17, which incorporate different substi-
from commercial sources. Compounds 20–23 were obtained
tution pattern at the thiourea moiety. This family of organ-
in moderate to excellent yields (Scheme 3) from the corre-
ocatalysts were tested under Michael addition reactions for
sponding chiral or achiral primary amines by reaction with
both routes to nitroalkane 4.
carbon disulfide and DCC.[10] The synthesis of compound
24 was accomplished by nucleophilic substitution in ace-
tone between potassium thiocyanate[11] and 9-bromo-9-
phenylfluorene. In this case, a separable mixture of the cor-
responding isothiocyanate and thiocyanate was obtained.
Isothiocyanate 27 was prepared from commercially avail-
able 1-bromonaphthalene by a Grignard reaction with ethyl
formate[12] to alcohol 26 which was converted to isothiocya-
Scheme 1. Synthetic strategy towards Pregabalin.
In this paper, we report the preparation of the Michael
acceptors, catalysts and our results concerning the enantio-
selective conjugate addition reactions for routes A and B.
The resulting optically active nitro compound 4 may then
be transformed to Pregabalin (1).
Synthesis of the Substrates and Organocatalysts
The starting electron-poor alkenes 2 and 3 were accessed
from isovaleraldehyde (Scheme 2). Michael acceptor 2 was Scheme 3. Sources of isothiocyanates 18–23.
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O. Bassas, J. Huuskonen, K. Rissanen, A. M. P. Koskinen
FULL PAPER
Scheme 4. Synthesis of isothiocyanates 24, 27, 29.
nate 27 by an oxalic acid catalyzed reaction with sodium
The synthesis of thiourea organocatalysts can be con-
thiocyanate.[13] Isothiocyanate 29 was prepared on a ducted according to two complementary procedures. First,
multigram scale by conversion of 1-bromo-3,5-dimethylben- condensation of the free amine derived from quinidine with
zene to the aryllithium species and its reaction with com- isothiocyanates provided thioureas 8–15 in good yields
mercially available methyl 3,5-dimethylbenzoate to give the (Scheme 5). The second method is based on the treatment
corresponding alcohol 28 in excellent yield.[14] Similarly, of the chiral isothiocyanate 23 obtained from amine 7 with
alcohol 28 was converted to isothiocyanate 29 following ox- primary amines. This procedure gave thioureas 16 and 17
alic acid catalyzed nucleophilic substitution with potassium (Scheme 6).
thiocyanate (Scheme 4).
Scheme 5. Organocatalysts 8–15 obtained by condensation of amine 7 with isothiocyanates.
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A Simple Organocatalytic Enantioselective Synthesis of Pregabalin
Scheme 6. Organocatalysts 16 and 17 obtained by condensation of free chiral amines with isothiocyanate 23.
As a representative example, the structure of catalyst 12
Better results were obtained according to route B. The
was confirmed by X-ray crystallography (Figure 2).[15]
initial reaction was performed in DCM in the presence of
5 mol-% of catalyst 8 at 5 °C. The nitro compound 4 was
obtained in 65% conversion and moderate enantio-
selectivity (33% ee) after 16 h (Table 2, Entry 1). Next, thio-
urea 9 afforded complete conversion and 56.5% ee (Table 2,
Entry 2). Organocatalysts 10 and 11 incorporate a benzhy-
dryl and a bis(1-naphthyl)methyl substituent, respectively.
They provided full conversion of the substrate and a good
level of enantiocontrol (65 and 63.4% ee, respectively,
Table 2, Entries 3 and 4). Catalyst 12, bearing a phenylfluo-
renyl group, gave high conversions and slightly lower
enantioselectivities when compared to catalysts 10 and 11
(Table 2, Entry 5). The best results with regard to the
enantioselectivity were obtained with tritylthiourea 13
(74.6% ee, Table 2, Entry 6). Catalyst 14 was tested to ana-
lyze the influence of substitution in the aromatic rings of
the trityl group. Unfortunately, the enantioselectivity de-
creased to 55.5% (Table 2, Entry 7). We then turned our
attention to organocatalysts 15 and 16, which incorporate
a chiral naphthylethyl moiety. They showed small matched/
mismatched effects providing Michael adduct 4 in high
yields and in 52.6 and 57.2% ee, respectively (Entries 8 and
9). Finally, thiourea 17 gave full conversion but lower
enantioselectivity (Entry 10).
Figure 2. X-ray structure for catalyst 12.
Screening of the Catalysts
We started our investigations by testing these organocat-
alysts to evaluate their ability to promote the conjugate ad-
dition of nitromethane to compound 2. Initially, we selected
catalyst 8[6b] that incorporates a 3,5-bis(trifluoromethyl)-
Enantioselective Synthesis of Pregabalin
The high level of asymmetric induction and efficiency ex-
phenylthiourea. After 4 d at room temperature, the reaction hibited by thiourea 13 to provide nitro compound 4 accord-
was complete but gave a very modest enantioselectivity ing to route B prompted us to choose it as the organo-
(21.4% ee, Table 1, Entry 1) affording the nitro compound catalyst for the enantioselective synthesis of Pregabalin. The
4 with the desired stereochemistry.
Performing the reaction with tert-butylthiourea 9 the en- (3S)-3-(aminomethyl)-5-methylhexanoic acid (1) is outlined
antiocontrol was much lower (4.5% ee, Table 1, Entry 2). in Scheme 7. Reaction of nitroalkene (100 mol-%,
sequence of the present enantioselective synthesis of
3
Unfortunately, similar results were obtained with catalysts 33.6 mmol), Meldrum’s acid (100 mol-%, 33.6 mmol), and
10 and 12 (Table 1, Entries 3 and 4). Moderate enantio- organocatalyst 13 (10 mol-%, 3.36 mmol) in DCM (1 ) at
meric excess of the wrong enantiomer (37% ee, Table 1, En- room temp. for 23 h provided 4 in 84% yield and in 74.6%
try 5) was obtained with thiourea 13 bearing a trityl group ee after purification by column chromatography. Moreover,
at the end of the thiourea arm. Unluckily, organocatalyst catalyst 13 was recovered in good yield (55%) after column
14, with substitution in the aromatic rings, provided very chromatography and was reused. The recovered catalyst
poor levels of asymmetric induction (3.7% ee, Table 1, En- was also effective in the second reaction, showing the same
try 6). Finally, we examined the influence of introducing activity and selectivity. The chemical yield of the second
new elements of chirality and functionality in the organoca- run was 82% and the ee again 74.6%. Then, hydrogenation
talyst. Thiourea 17 that bears a chiral amino alcohol moiety of 3-(nitromethyl)alkane 4 in the presence of Raney-Ni as
provided full conversion, but marginal enantioselectivity.
catalyst in acetic acid at room temp. and atmospheric pres-
Eur. J. Org. Chem. 2009, 1340–1351
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O. Bassas, J. Huuskonen, K. Rissanen, A. M. P. Koskinen
FULL PAPER
Table 1. Enantioselective Michael addition of nitromethane to unsaturated Meldrum’s acid derivative 2 by using quinidine alkaloid derived
organocatalysts.
Entry
Catalyst
Mol-%
Solvent
T [°C]
t [d]
Conversion [%][a]
ee [%][b]
Configuration[c]
1
2
3
4
5
6
7
8
5
toluene
DCM
DCM
DCM
DCM
DCM
DCM
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
4
3.6
4
Ͼ 95
Ͼ 95
Ͼ 95
Ͼ 95
Ͼ 95
Ͼ 95
Ͼ 95
21.4
4.5
4.5
7.4
37
3.7
3.5
(S)
(S)
(R)
(S)
(R)
(S)
(S)
9
10
10
10
10
10
10
10
12
13
14
17
3
3.5
3.7
4
1
[a] Determined by H NMR spectroscopy of the crude product. [b] Determined by chiral HPLC analysis of the anilide derived from 4.
[c] The absolute stereochemistry was established by conversion to Pregabalin.
Table 2. Enantioselective Michael addition of Meldrum’s acid to nitro olefin 3 by using quinidine alkaloid derived chiral thiourea organo-
catalysts.
Entry
Catalyst
Mol-%
Solvent
T [°C]
t [h]
Conversion [%][a]
ee [%][b]
Configuration[c]
1
2
3
4
5
6
7
8
9
8
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
5
16
15
20
17
20
22
22
19
21
22
65
33
56.5
65
63.4
60.5
74.6
55.5
52.6
57.2
51.6
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
9
10
10
10
10
10
10
10
10
10
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
10
11
12
13
14
15
16
17
10
1
[a] Determined by H NMR spectroscopy of the crude product. [b] Determined by chiral HPLC analysis of the anilide derived from 4.
[c] The absolute stereochemistry was established by conversion to Pregabalin.
sure afforded amino diacid 5, which after treatment with bearing the nitro group. As seen from the X-ray structure
6  HCl yielded hydrochloride 1. Enantioenrichment by of 12 (Figure 3), in the solid state this catalyst exists as a
crystallization[16] of the free amino acid from 2-propanol/ trans/cis rotamer (based on the HNCS angle) which appar-
water furnished 1 as a white crystalline solid with 80% ee.
ently is less accessible for hydrogen bonding than the
trans/trans rotamer. Tsogoeva et al.[17] have also reported
the trans/cis conformer in the solid state of a chiral (methyl-
pyridyl)thiourea displaying intramolecular hydrogen bond-
ing between one of the thiourea NH groups and the basic
nitrogen atom of the pyridyl group as well as an intermo-
lecular hydrogen bond from the H atom of the thiourea NH
group to the sulfur atom of a second molecule leading to a
dimer. They claim that these interactions do not allow its
imine substrate to be placed in a bridging mode between
the two thiourea hydrogen atoms. According to them, this
Scheme 7. Asymmetric synthesis of Pregabalin.
Origin of the Enantioselectivity
The nitro group is well known to interact with thiourea
through hydrogen bonding. Thioureas have two hydrogen
bonds to bind the H bond acceptor. These interactions in-
crease the electrophilicity of the electron-deficient alkene Figure 3. trans/cis-Conformer in the solid state for 12.
1344 Eur. J. Org. Chem. 2009, 1340–1351
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A Simple Organocatalytic Enantioselective Synthesis of Pregabalin
may be the reason of the very poor levels of enantio-
selectivity (6% ee) observed in the Strecker synthesis by em-
ploying this catalyst.
Conclusions
We have developed a simple short procedure for prepar-
ing multigram quantities of the antiepileptic drug Pregaba-
lin by organocatalytic conjugate addition reaction of Meld-
rum’s acid to nitroalkene 3. We have synthesized and tested
a family of novel catalysts to promote the above reaction.
The best enantioselectivity was obtained with catalyst 13,
which incorporates a trityl substituent in the thiourea moi-
ety and can be recycled. The key intermediate nitro com-
pound 4 was obtained in high chemical yield after purifica-
tion by column chromatography and up to 75% ee of the
(S) enantiomer. Moreover, the overall yield for the process
starting from 3 is 59%, and enantioenrichment by crystalli-
zation of the free amino acid provides almost enantiopure
Pregabalin.
In our case, our catalysts provide very good enantio-
selectivities (up to 75% ee), even though we observed the
same disposition. In solution, thioureas typically are pres-
ent as a mixture of trans/trans and trans/cis conformers
(Figure 4).[18] In the first conformation the two oxygen
atoms of the nitroalkene would form two hydrogen bonds
with both H atoms of the thiourea at the same time,
whereas the trans/cis conformer can only provide one point
of attachment, thus giving a less restricted substrate binding
and weakened enantiocontrol.
Experimental Section
General Considerations: All moisture-sensitive reactions were per-
formed under argon in flame-dried, round-bottomed flasks fitted
with rubber septa and/or glass stoppers. For reactions run at low
temperatures, flasks were flushed with argon, and double septa to
Figure 4. Hydrogen bonding for disubstituted thioureas.
In the Michael addition of 1,3-dicarbonyl compounds to minimize the introduction of adventitious water. Stainless steel sy-
ringes were used to transfer air- or moisture-sensitive liquids.
nitro olefins catalyzed by bifunctional thioureas Takemoto
et al.[19] suggested that the active monomeric organocatalyst
binds the nitroalkene through double hydrogen bonding. In
our case of Meldrum’s acid addition to nitro olefin 3 we
propose a transition-state model similar to that by Takem-
oto, which would imply activation of the Michael acceptor
3 through double NH hydrogen bonding. The quinuclidine
ring is orientated towards the same direction where the two
NH groups are and placed on the same face with the trityl
group, but both away from each other to avoid steric inter-
action. On the basis of the product configuration, delivery
of the enolate from the top face to the s-cis nitroalkene
would provide (S)-4 (Figure 5). In agreement with this in-
terpretation, the decrease in ee of product 4 with catalyst 14
could be attributed to steric hindrance between the methyl
substituents at the meta position of the trityl group and the
isopropyl moiety of the nitroalkene 3. This repulsion would
shift the nitroalkene to the s-trans conformation, in which
delivery of the enolate from the top face would lead to
(R)-4.
Materials: Unless otherwise indicated, reagents were used as pur-
chased from suppliers. Solvents were dried prior to use according
to standard procedures. Toluene was distilled from sodium, tetra-
hydrofuran from sodium/benzophenone ketyl, dichloromethane,
triethylamine and diethylamine from calcium hydride (CaH2). All
reactions were performed under a positive pressure of argon when
necessary. Thin layer chromatography was done on SiO2 (silica gel
60 F254, Merck, coated aluminium plates), and the spots were lo-
cated with UV light (254 nm), with aqueous potassium permanga-
nate and ninhydrin solutions. Flash column chromatography or
Combi Flash chromatography was carried out on SiO2 (silica gel
60, 230–400 mesh ASTM, Merck). Drying of the organic extracts
during the workup of the reactions was performed with MgSO4.
A racemic Michael adduct sample for chiral HPLC analysis was
prepared in the absence of the catalyst by combining (route A):
Michael acceptor 2 (9.4 mmol), nitromethane (47.2 mmol) and di-
ethylamine (14.1 mmol) in DCM (20 mL) at room temp.; (route B):
nitroalkene 3 (7.7 mmol), Meldrum’s acid (11.6 mmol) and dieth-
ylamine (1.2 mL) in DCM (20 mL) at room temp.
Representative Procedure for Screening of the Catalyst. Route A:
Meldrum’s acid derivative 2 (125 mg, 0.58 mmol) and the chosen
thiourea catalyst (0.05 mmol) in the appropriate solvent (0.5 mL)
were loaded in a capped vial. After 5 min, nitromethane (1.6 mmol)
was added, and stirring was maintained at room temp. The conver-
1
sion was determined by H NMR spectroscopy of the crude prod-
uct. Route B: Nitroalkene 3 (100 mg, 0.77 mmol) and the chosen
thiourea catalyst (0.07 mmol) in the appropriate solvent (0.5 mL)
were loaded in a capped vial. After 5 min, Meldrum’s acid
(1.44 mmol) was added and stirring was maintained at the specified
temperature. The conversion was determined by 1H NMR spec-
troscopy of the crude product.
Instrumentation: Evaporation of the solvents was accomplished
1
with a rotary evaporator. H and 13C NMR spectra were recorded
in CDCl3, [D4]methanol or D2O with a Bruker Avance 400 (1H:
399.98 MHz; 13C: 100.59 MHz) spectrometer. The chemical shifts
Figure 5. Proposed transition state leading to the major enantiomer
(S)-4.
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O. Bassas, J. Huuskonen, K. Rissanen, A. M. P. Koskinen
FULL PAPER
are reported in ppm relative to residual CHCl3 (δ = 7.26 ppm),
residual MeOH (δ = 3.31 ppm) or residual H2O (δ = 4.79 ppm) for
1H NMR spectroscopy. Coupling constants (J) are given in Hz.
The multiplicities are abbreviated as s (singlet), d (doublet), t (trip-
let), q (quadruplet), m (multiplet); the prefix br. is applied when
the signal in question is broadened. For the 13C NMR spectra, the
solvent peaks of CDCl3 (δ = 77.0 ppm) and [D4]methanol (δ =
49.0 ppm) were used as the internal standard. High-resolution mass
1.15 mmol) were successively added to a solution of the Boc-pro-
tected amino acid 1 (300 mg, 1.15 mmol) in THF (3 mL) at –20 °C.
After an activation period of 5 min, 40% aqueous methylamine
(4.60 mmol) in THF (2 mL) was added, and the resulting solution
was stirred at –20 °C for 1 h prior the addition of 5% NaHCO3
(5 mL). After 30 min of stirring at room temp., the mixture was
extracted with DCM. The organic layers were washed with 5%
NaHCO3, dried and concentrated to provide a pale yellow oil,
spectrometric data were obtained at the Helsinki University of which after purification by column chromatography (50% EtOAc
Technology Mass Spectrometry Facility with Waters LCT Premier-
spectrometer. IR spectra were recorded with a Perkin–Elmer instru-
ment, the data are represented as wavenumbers in cm–1. Optical
rotations were obtained with a Perkin–Elmer 343 polarimeter (λ =
589 nm) with a 1 dm path length. Chiral HPLC analysis was per-
formed by using a Waters 501 pump, a Waters UV 2487 dual
in hexane) yielded the desired compound (259 mg, 83%) as a white
solid. The enantiomeric ratio was determined by HPLC: Chiralcel
OD column (0.46 cmϫ25 cm), hexane/2-propanol (98:2), flow
0.2 mL/min, detector λ = 215 nm, retention time 1: 77.33 min, %
area: 10.2, retention time 2: 81.84 min, % area: 89.8.
2,2-Dimethyl-5-(3Ј-methylbutylidene)-1,3-dioxane-4,6-dione (2): A
mixture of Meldrum’s acid (4.40 g, 30.5 mmol) and freshly distilled
isovaleraldehyde (3 mL, 27.9 mmol) in water (60 mL) was stirred in
a closed vessel at 75 °C for 2 h. After cooling to room temp., the
crude mixture was made alkaline with a saturated aqueous solution
of sodium carbonate and extracted with diethyl ether. The extracts
lambda-absorbance detector and
a Chiralcel OD column
(0.46ϫ25 cm). Elemental analyses were performed with a Perkin–
Elmer (PE) 2400 Series II CHNS/O Analyzer. Melting points were
determined in open capillary tubes and are uncorrected.
(+)-(3S)-3-(Aminomethyl)-5-methylhexanoic Acid Hydrochloride
(1·HCl):[4e] Diacid 5 (4.77 g, 23.5 mmol) was dissolved in 6  HCl were dried, filtered and concentrated under reduced pressure to
(35 mL) and refluxed for 28 h. Then, the brown aqueous solution
was extracted with DCM. Heating of the aqueous layer with acti-
vated charcoal followed by filtration through Celite and concentra-
tion of the aqueous layer to dryness under reduced pressure fur-
nished a residue, which was dried at 50 °C for 48 h. After this
period, 1·HCl (Pregabalin hydrochloride) was obtained (4.34 g,
94% yield). [α]2D0 = +6.72 (c = 1.1, H2O) {ref.[4e] [α]2D0 = +7.0 (c =
give pure 2 (3.10 g, 53%) as a pale yellow oil, which was used with-
out further purification. Rf = 0.31 (40% Et2O in hexane); visualiza-
tion: KMnO . IR (film): ν = 3054, 2987, 2685, 1736, 1627, 1421,
˜
4
1263 cm–1. H NMR (CDCl3, 400 MHz): δ = 7.96 (t, J = 7.6 Hz,
1
1 H), 2.86 (dd, J = 7.6, 7.2 Hz, 2 H), 1.99–1.91 (m, 1 H), 1.74 (s,
6 H), 1.01 (d, J = 6.6 Hz, 6 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 167.5, 161.6, 159.6, 118.6, 104.6, 39.7, 28.6, 28.4, 27.6,
22.3 ppm. HRMS: calcd. for C11H16O4Na [M + Na] 235.0938;
found 235.0946.
1.1, H O) for 96% ee}. IR (film): ν = 3223, 3120, 2998, 1721, 1412,
˜
2
1390, 1227 cm–1. 1H NMR (D2O, 400 MHz): δ = 3.04 (d, J =
8.0 Hz, 2 H), 2.53 (dd, J = 16.0, 6.0 Hz, 1 H), 2.45 (dd, J = 16.0,
4.0 Hz, 1 H), 2.26 (m, 1 H), 1.67–1.62 (m, 1 H), 1.26 (dd, J = 7.2,
7.2 Hz, 2 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 3 H)
ppm. 13C NMR (CD3OD, 100 MHz): δ = 175.7, 44.4, 41.9, 37.2,
32.4, 26.0, 23.1, 22.6 ppm. A crop of Pregabalin hydrochloride was
converted into the free amino acid by addition of 1  NaOH solu-
tion until the pH = 7.5. After evaporation of water, a white solid
compound was obtained. Crystallization of this material from 30%
2-propanolinwaterafforded1(Pregabalin)asawhitecrystallinesolid.[3]
[α]2D0 = +8.2 (c = 1.07, H2O) {ref.[3] [α]2D0 = +10.1 (c = 1.1, H2O)}.
M.p. 174–175 °C (ref.[3] 175–176 °C). 1H NMR (D2O, 400 MHz): δ
= 3.02 (dd, J = 13.0, 5.4 Hz, 1 H), 2.95 (dd, J = 13.0, 6.6 Hz, 1
H), 2.33 (dd, J = 14.6, 5.9 Hz, 1 H), 2.24 (dd, J = 14.6, 7.2 Hz, 1
H), 2.15 (m, 1 H), 1.66 (m, 1 H), 1.21 (dd, J = 7.0, 6.9 Hz, 2 H),
0.89 (dd, J = 6.6, 4.8 Hz, 6 H) ppm. 13C NMR (D2O + drops of
CD3OD, 100 MHz): δ = 182.1, 44.7, 41.8, 41.6, 32.7, 25.4, 23.0,
22.5 ppm. For the purposes of the ee determination after crystalli-
zation, the amine was Boc-protected and the acid converted into
the N-methyl amide.[20]
(E)-4-Methyl-1-nitro-1-pentene (3): An aqueous 10  sodium hy-
droxide solution (45.4 mL, 0.45 mol) was added dropwise under
mechanical stirring (to prevent the formation of a solid mass) to a
solution of isovaleraldehyde (49.4 mL, 0.45 mol) and nitromethane
(25 mL, 0.46 mol) in EtOH (200 mL) cooled to 0 °C. A yellow foam
was obtained. After 10 min at 0 °C, the crude mixture was warmed
to room temp. and stirred overnight. Then, acetic acid (25.7 mL,
0.45 mol) was added. The aqueous layer was extracted with diethyl
ether. The extracts were washed with water until the pH of the
washings was 6. After drying, filtration and concentration in vacuo,
the corresponding nitro alcohol (58 g, 88% yield) was obtained and
used without further purification. Rf = 0.25 (30% Et2O in hexane);
visualization: KMnO . IR (film): ν = 3944, 3757, 3691, 3601, 3054,
˜
4
2987, 2963, 2872, 2685, 2521, 2410, 2126, 1556, 1468, 1421, 1382,
1
1270 cm–1. H NMR (CDCl3, 400 MHz): δ = 4.43–4.35 (m, 3 H),
2.50 (br. s, 1 H), 1.89–1.79 (m, 1 H), 1.55–1.47 (m, 1 H), 1.27–1.20
(m, 1 H), 0.97 (d, J = 8.0 Hz, 3 H), 0.96 (d, J = 8.0 Hz, 3 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 80.9, 66.9, 42.3, 24.2, 23.0,
21.6 ppm. HRMS (ESI): calcd. for C6H13NO3Na [M + Na]
170.0801; found 170.0793.
N-Boc Protection of Free Amino Acid 1: NaHCO3 (791 mg,
9.42 mmol) and Boc2O (822 mg, 3.77 mmol) were added consecu-
tively at 0 °C to a solution of the free amino acid 1 (crystallized
from 30% 2-propanol in water, 500 mg, 3.14 mmol) in a 1:1 mixture
of THF/H2O (20 mL). After 30 min, the white suspension was
stirred at room temp. overnight. Then, the mixture was extracted
with Et2O. The aqueous layer was acidified to pH = 4 by addition
of 5% citric acid solution at 0 °C and extracted with DCM. The
extracts were dried and concentrated to give the corresponding
Boc-amino acid (512 mg, 63%) as a white solid, which was used
without further purification.
Dehydration of 3-Methyl-1-(nitromethyl)butanol: Trifluoroacetic an-
hydride (59.5 mL, 0.42 mol) and then dropwise TEA (117 mL,
0.84 mol) were added successively to a solution of 3-methyl-1-(ni-
tromethyl)butanol (58 g, 0.40 mol) in DCM (500 mL) cooled to
0 °C. The reaction mixture was warmed to room temp. After stir-
ring overnight, DCM (200 mL) was added. The organic phase was
washed several times with water, saturated aqueous ammonium
chloride solution and brine, then dried. After filtration and evapo-
ration in vacuo, distillation under aspirator vacuum at 115 °C af-
forded compound 3 (36 g, 70%), only detected as the (E) isomer.
Rf = 0.61 (30% Et2O in hexane); visualization: KMnO4. IR (film):
N-Methyl Amidation of Protected Amino Acid 1: N-Methylmorph-
oline (146 µL, 1.15 mmol) and isobutyl chloroformate (150 µL,
ν = 3944, 3757, 3691, 3625, 3054, 2987, 2965, 2872, 2685, 2521,
˜
1346
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1340–1351

A Simple Organocatalytic Enantioselective Synthesis of Pregabalin
2410, 2126, 1712, 1649, 1525, 1421, 1351, 1270 cm–1. 1H NMR tered through a pad of Celite, and the green filtrate was diluted
(CDCl3, 400 MHz): δ = 7.29–7.22 (m, 1 H), 6.98 (dt, J = 16.0, with water and adjusted to pH values between 2 and 3. The aque-
4.0 Hz, 1 H), 2.18–2.13 (m, 2 H), 1.89–1.1.79 (m, 1 H), 0.97 (d, J ous layer was extracted with DCM four times, and the extracts
= 6.60 Hz, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 141.5,
were dried, filtered and the solvents evaporated under vacuum to
140.0, 37.1, 27.6, 22.1 ppm. HRMS: calcd. for C6H11NO2Na [M + give diacid 5 (4.99 g, 75%) as a yellowish oil used in the next step
Na] 152.0698; found 152.0687.
without further purification. [α]2D0 = –53.6 (c = 1.25, CHCl3). IR
(film): ν = 3434, 3247, 3155, 2961, 2903, 1766, 1723, 1468, 1384,
˜
2,2-Dimethyl-5-[(1ЈS)-3Ј-methyl-1Ј-(nitromethyl)butyl]-1,3-dioxane-
4,6-dione (4). 1st Batch: To a solution of nitroalkene 3 (4.33 g,
33.6 mmol) in DCM (35 mL) was added organocatalyst 13 (2.1 g,
3.36 mmol). After 5 min, Meldrum’s acid (4.84 g, 33.6 mmol) was
added, and the solution was stirred at room temp. for 23 h. Then,
the crude mixture was poured into 5% aqueous citric acid solution,
and the aqueous layer was extracted with DCM. After washing
with brine, the extracts were dried, filtered and the solvents evapo-
rated in vacuo to give a yellow oil. This was purified by column
chromatography (50% to 80% EtOAc in hexane) providing com-
pound 4 [7.7 g, 84%, (S)/(R) = 87.3:12.7] as a white solid and cata-
lyst 13 (1.15 g, 55% recovery). 2nd Batch: The recovered catalyst
was reused in the conjugate addition reaction showing the same
activity and selectivity. To a solution of nitroalkene 3 (2.46 g,
19.1 mmol) in DCM (20 mL) was added organocatalyst 14 (1.09 g,
1.74 mmol). After 5 min, Meldrum’s acid (2.51 g, 17.4 mmol) was
added, and the solution was stirred at room temp. for 24 h. Usual
workup followed by purification by column chromatography (50%
to 80% EtOAc in hexane) provided compound 4 [3.89 g, 82%, (S)/
(R) = 87.3:12.7] as a white solid. Rf (10% EtOH in AcOEt) = 0.28.
1284 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 10.34 (br. s, 1 H),
7.18 (br. s, 1 H), 3.59 (dd, J = 16.0, 8.0 Hz, 1 H), 3.07 (d, J =
8.0 Hz, 1 H), 3.04 (dd, J = 12.0, 8.0 Hz, 1 H), 2.95–2.85 (m, 1 H),
1.68–1.55 (m, 2 H), 1.42–1.36 (m, 1 H), 0.93 (d, J = 6.4 Hz, 6 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 175.2, 175.4, 54.0, 47.2,
43.2, 36.9, 25.8, 22.7, 22.1 ppm.
9-Amino-9-deoxyepiquinidine (7):[21] Diisopropyl azodicarboxylate
(DIAD, 7.33 mL, 37.0 mmol) was added to a solution of the quini-
dine alkaloid (10 g, 30.8 mmol) and triphenylphosphane (9.7 g,
37.0 mmol) in absolute THF (100 mL) at 0 °C all at once. After
5 min, a solution of diphenylphosphoryl azide (DPPA, 8.02 mL,
37 mmol) in dry THF (50 mL) was added dropwise at 0 °C. The
mixture was warmed to room temp. After being stirred overnight,
the solution was heated at 50 °C for 2 h. Then, triphenylphosphane
was added, and the heating was maintained until the gas evolution
had ceased. The solution was cooled to room temp., and water
(10 mL) was added. After stirring for 4 h, the solvents were re-
moved, and the residue was dissolved in DCM and 2  HCl (1:1,
200 mL). The aqueous phase was extracted with DCM
(3ϫ100 mL). Then, the aqueous phase was made alkaline with a
saturated aqueous solution of Na2CO3 and extracted with DCM.
Concentration of the dried extracts afforded a residue, which was
purified by column chromatography to yield the desired product 7
M.p. 74–76 °C. [α]2D0 = –14 (c = 1.0, CHCl ). IR (film): ν = 3020,
˜
3
2964, 1747, 1554, 1469, 1383 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 5.00 (dd, J = 16.0, 12.0 Hz, 1 H), 4.54 (dd, J = 12.0, 8.0 Hz, 1
H), 3.89 (d, J = 4.0 Hz, 1 H), 3.34 (m, 1 H), 1.81 (s, 3 H), 1.79 (s,
3 H), 1.66–1.52 (m, 2 H), 1.25–1.17 (m, 1 H), 0.98 (d, J = 8.0 Hz, (5.15 g, 52%). Rf = 0.25 (DCM/MeOH/TEA, 85:15:5); visualiza-
3 H), 0.94 (d, J = 8.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): tion: ninhydrin. [α]2D0 = +79.6 (c = 1.05, CHCl3) {ref.[21] [α]2D0 = +69
δ = 164.1, 163.9, 104.6, 75.7, 47.1, 38.1, 34.1, 28.1, 27.6, 25.5, 23.0,
(c = 2.51, CHCl )}. IR (film): ν = 3374, 3291, 3154, 3079, 2940,
˜
3
21.3 ppm. C12H19NO6 (273.1): calcd. C 52.74, H 7.01, N 5.13; 2874, 1793, 1622, 1508 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
found C 52.90, H 7.05, N 5.05.
8.75 (d, J = 4.0 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.62 (br. s, 1
H), 7.53 (d, J = 4.0 Hz, 1 H), 7.38 (dd, J = 12.0, 4.0 Hz, 1 H),
5.92–5.85 (ddd, J = 17.1, 10.6, 6.5 Hz, 1 H), 5.10–5.05 (m, 2 H),
4.68 (d, J = 8.0 Hz, 1 H), 3.97 (s, 3 H, OMe), 3.12–2.90 (m, 5 H),
2.35–2.28 (m, 1 H), 2.15 (br. s, 2 H), 1.63–1.55 (m, 3 H), 1.21–1.12
(m, 1 H), 1.00–0.88 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 157.1, 147.2, 146.9, 144.1, 140.2, 131.2, 128.2, 121.1, 119.4,
113.9, 101.0, 61.8, 54.9, 51.8, 49.0, 46.8, 38.9, 27.0, 26.1, 24.4 ppm.
Method for the Determination of the Enantiomeric Excess: Enantio-
meric excesses of the Michael adducts 4 were assayed by chiral
HPLC analysis of the derived anilides of the corresponding mono-
carboxylic acids. After heating racemic compound 4 in a mixture
DMF/aniline (10:1) at 100 °C for 3 h, rac-5-methyl-3-(nitromethyl)-
N-phenylhexanamide was obtained in moderate yield. IR (film): ν
˜
= 3430, 3155, 2961, 2930, 1793, 1686, 1549, 1440 cm–1. H NMR
1
(CDCl3, 400 MHz): δ = 7.53 (d, J = 8.0 Hz, 2 H), 7.40 (br. s, 1 H),
7.35 (dd, J = 8.0, 8.0 Hz), 7.15 (dd, J = 8.0, 8.0 Hz, 1 H), 4.61–
4.52 (m, 2 H), 2.81–2.75 (m, 1 H), 2.53–2.49 (m, 2 H), 1.79–1.69
Preparation of Thiourea Catalysts 8–15: A solution of the corre-
sponding isothiocyanate in THF (0.8 ) was added to a stirred
solution of the free amine 7 in THF (0.8 ) at room temp. After
(m, 1 H), 1.35 (t, J = 8 Hz, 2 H), 0.97–0.94 (m, 6 H) ppm. 13C reaction overnight, the solvent was removed under reduced pres-
NMR (CDCl3, 100 MHz): δ = 169.1, 137.5, 129.0, 124.6, 120.0,
78.6, 40.4, 39.1, 32.6, 25.0, 22.5, 22.3 ppm. HRMS: calcd. for
C14H20N2NaO3 [M + Na]+ 287.1372; found [M + Na]+ 287.1372.
HPLC: Chiralcel OD column (0.46 cmϫ25 cm), hexane/2-propa-
nol (75:25), flow 1 mL/ min, detector λ = 254 nm, retention time 1:
7.12 min, % area: 50.37, retention time 2: 8.42 min, % area: 49.63.
The absolute configuration was determined by conversion of en-
antioenriched samples of 4 to Pregabalin. Enantiomer at 7.12 min
shows (S) configuration, whereas enantiomer at 8.42 min shows (R)
configuration.
sure and the residue submitted to flash column chromatography.
N-[3,5-Bis(trifluoromethyl)phenyl]-NЈ-[(9R)-6Ј-methoxycinchonan-9-
yl]thiourea (8):[6b] Thiourea 8 (570 mg, 55%) was obtained as an
amorphous solid after purification by column chromatography
from amine 7 (568 mg, 1.75 mmol) and commercially available
3,5-bis(trifluoromethyl)phenyl isothiocyanate (18) (477 mg,
1.75 mmol). Rf = 0.19; visualization: KMnO4 (5% MeOH in
EtOAc, five drops of TEA). [α]2D0 = +174 (c = 0.52, CHCl3) [ref.[6b]
[α]2D0 = +225.3 (c = 0.50, CHCl )}. IR (film): ν = 3944, 3757, 3690,
˜
3
3054, 3020, 2987, 2685, 2521, 2409, 2156, 1622, 1550, 1422 1263,
1217, 1181, 1139 cm–1. 1H NMR ([D4]methanol, 400 MHz): δ =
8.68 (d, J = 4.0 Hz, 1 H), 8.11 (br. s, 2 H), 8.04 (br. s, 1 H), 7.94
(d, J = 8.0 Hz, 1 H), 7.60 (br. s, 1 H), 7.58 (d, J = 4.0 Hz, 1 H),
7.44 (d, J = 8.0 Hz, 1 H), 6.40 (d, J = 8.0 Hz, 1 H), 5.96 (ddd, J =
16.0, 12.0, 4.0 Hz, 1 H), 5.24 (d, J = 16.0 Hz, 1 H), 5.16 (d, J =
12.0 Hz, 1 H), 4.03 (s, 3 H), 3.45–3.35 (m, 2 H), 3.09–3.01 (m, 3
2-[(1ЈS)-1Ј-(Aminomethyl)-3Ј-methylbutyl]propandioic Acid (5): Ni-
tro compound 4 (9.04 g, 32.9 mmol) in AcOH (200 mL) was added
to a solution of Raney-Ni in water (4.5 g of the commercially avail-
able wet suspension). The resulting black suspension was stirred at
room temp. under H2 at atmospheric pressure for 22 h (reaction
1
monitored by H NMR spectroscopy). The crude mixture was fil-
Eur. J. Org. Chem. 2009, 1340–1351
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1347

O. Bassas, J. Huuskonen, K. Rissanen, A. M. P. Koskinen
FULL PAPER
H), 2.42–2.37 (m, 1 H), 1.66–1.64 (m, 3 H), 1.28–1.19 (m, 1 H), δ = 8.45 (d, J = 4.6 Hz, 1 H), 7.91 (d, J = 9.2 Hz, 1 H), 7.82 (dd,
1.12–1.03 (m, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 181.6, J = 12.2, 7.4 Hz, 2 H), 7.61 (m, 3 H), 7.49 (m, 3 H), 7.41–7.24 (m,
2
158.6, 147.3, 146.8, 144.1, 142.1, 140.6, 131.7 (q, JC-F = 33.0 Hz),
130.2, 129.2, 123.5 (q, 1JC-F = 271.0 Hz), 123.0, 122.7, 119.7, 116.9,
114.4, 103.0, 60.5, 55.6, 54.4, 49.2, 47.6, 39.0, 27.6, 25.4 ppm.
7 H), 7.20 (br. s, 1 H), 6.05 (br. s, 1 H), 5.81 (ddd, J = 17.0, 9.0,
6.0 Hz, 1 H), 5.25 (d, J = 10.0 Hz, 1 H), 5.05 (m, 2 H), 3.95 (s, 3
H), 2.45 (m, 1 H), 2.36–2.20 (m, 3 H), 2.12–1.98 (m, 2 H), 1.48 (m,
1 H), 1.37 (m, 1 H), 1.30–1.15 (m, 2 H), 0.60 (m, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 181.1, 157.2, 147.2, 146.6, 146.2,
144.0, 142.5, 140.3, 139.7, 139.4, 131.1, 129.3, 129.1, 128.8, 128.5,
128.2, 125.1, 125.1, 121.7, 120.8, 120.3, 118.1, 114.3, 101.4, 71.8,
61.7, 55.2, 48.9, 45.9, 38.6, 26.8, 26.4, 24.6 ppm. C42H40N4OS
(622.3): calcd. C 77.74, H 6.21, N 8.63, S 4.94; found C 77.79, H
6.16, N 9.12, S 5.46.
N-tert-Butyl-NЈ-[(9R)-6Ј-methoxycinchonan-9-yl]thiourea (9): Thio-
urea 9 (578 mg, 70%) was obtained after flash column chromatog-
raphy as an amorphous solid from amine 7 (626 mg, 1.94 mmol)
and tert-butyl isothiocyanate (20) (245 mg, 2.13 mmol). Rf = 0.40
(15% MeOH in EtOAc); visualization: KMnO4. [α]2D0 = +314 (c =
0.62, CHCl ). IR (film): ν = 3683, 3620, 3426, 3019, 2976, 2896,
˜
3
1622, 1590, 1510, 1475, 1431, 1392, 1215, 1046 cm–1. 1H NMR
(CDCl3, 400 MHz): δ = 8.68 (d, J = 4.8 Hz, 1 H), 8.02 (br. s, 1 H),
7.95 (d, J = 9.2 Hz, 1 H), 7.51 (d, J = 4.8 Hz), 7.45 (dd, J = 9.2,
2.6 Hz, 1 H), 6.15 (d, J = 10 Hz, 1 H), 6.00 (ddd, J = 17.0, 10.5,
6.0 Hz, 1 H), 5.26 (dd, J = 17.0, 1.4 Hz, 1 H), 5.18 (dd, J = 10.5,
1.4 Hz, 1 H), 4.90 (br. s, 2 H), 4.07 (s, 3 H), 3.32–3.25 (m, 1 H),
3.25–3.18 (m, 1 H), 3.06–3.00 (m, 1 H), 2.42–2.39 (m, 1 H), 1.65–
1.57 (m, 3 H), 1.45 (s, 9 H), 1.32–1.25 (m, 1 H), 0.98–0.94 (m, 1
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 181.3, 157.6, 147.5,
144.5, 140.0, 131.9, 131.6, 128.1, 121.9, 119.2, 114.9, 101.6, 61.8,
55.4, 52.9, 48.8, 46.7, 46.0, 38.8, 29.2, 27.1, 26.4, 25.1 ppm.
N-[(9R)-6Ј-Methoxycinchonan-9-yl]-NЈ-tritylthiourea (13): Thiourea
13 (2.17 g, 79%) was obtained as a white solid after flash column
chromatography (5 % MeOH in DCM) from amine 7 (1.43 g,
4.41 mmol) and commercially available trityl isothiocyanate (19)
(1.33 g, 4.41 mmol); crystallization from MeOH/CHCl3 (5:1) gave
needle-like crystals. M.p. 189–190 °C (dec.). Rf = 0.5 (10% MeOH
in DCM). [α]2D0 = +177.4 (c = 1.5, CHCl ). IR (film): ν = 3415,
˜
3
3258, 3155, 2981, 2941, 2874, 1816, 1793, 1622, 1511, 1475,
1
1382 cm–1. H NMR (CDCl3, 400 MHz): δ = 8.45 (d, J = 4.6 Hz,
1 H), 7.92 (d, J = 9.2 Hz, 1 H), 7.58 (d, J = 2.4 Hz, 1 H), 7.38–
7.28 (m, 16 H), 6.73 (d, J = 2.4 Hz, 1 H), 6.02 (d, J = 4.6 Hz, 1
H), 5.87 (ddd, J = 17.0, 10.6, 6.3 Hz, 1 H), 5.47 (d, J = 10.6 Hz, 1
H), 5.13–5.09 (m, 2 H), 3.98 (s, 3 H), 2.77–2.72 (m, 1 H), 2.64–2.58
(m, 1 H), 2.50–2.46 (m, 2 H), 2.24–2.16 (m, 2 H), 1.52–1.51 (m, 1
H), 1.39–1.37 (m, 1 H), 1.32–1.17 (m, 2 H), 0.74–0.68 (m, 1 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 179.9, 157.3, 147.0, 145.8,
144.0, 142.8, 140.2, 131.1, 128.6, 128.4, 128.2, 127.4, 121.7, 118.0,
114.4, 101.4, 72.2, 61.3, 55.4, 55.1, 48.5, 46.7, 38.9, 26.9, 26.3,
24.5 ppm. C40H40N4OS (624.3): calcd. C 76.89, H 6.45, N 8.97, S
5.13; found C 76.08, H 6.37, N 9.37, S 5.30.
N-Benzhydryl-NЈ-[(9R)-6Ј-methoxycinchonan-9-yl]thiourea (10):
Thiourea 10 (700 mg, 55 %) was obtained after flash column
chromatography as an amorphous solid from amine 7 (750 mg,
2.32 mmol) and benzhydryl isothiocyanate 22 (522 mg, 2.32 mmol).
Rf = 0.5 (5% MeOH in DCM); visualization: KMnO4. [α]2D0 = +271
(c = 0.5, CHCl ). IR (film): ν = 3684, 3418, 3019, 2976, 2895, 1710,
˜
3
1622, 1521, 1476, 1421, 1364, 1215 cm–1 1H NMR (CDCl3,
.
400 MHz): δ = 8.61 (d, J = 4.0 Hz, 1 H), 7.95 (br. s, 1 H), 7.91 (d,
J = 8.0 Hz, 1 H), 7.41 (m, 2 H), 7.28–7.11 (m, 11 H), 6.5 (br. s, 1
H), 6.16 (d, J = 8.0 Hz), 5.94 (ddd, J = 16.0, 8.0, 4.0 Hz, 1 H), 5.20
(d, J = 16.0 Hz, 1 H), 5.11 (d, J = 8.0 Hz, 1 H), 3.95 (s, 3 H), 3.31–
3.18 (m, 2 H), 2.97–2.95 (m, 3 H), 2.34–2.32 (m, 1 H), 1.61–1.59
(m, 3 H), 1.24–1.19 (m, 1 H), 0.99–0.94 (m, 1 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 181.6, 157.8, 147.4, 144.5, 140.0, 131.8,
131.6, 128.7, 128.5, 127.6, 127.3, 127.1, 122.1, 119.3, 114.6, 101.1,
62.4, 61.0, 57.8, 55.4, 48.5, 46.3, 38.6, 27.1, 26.2, 24.7 ppm.
N-[(9R)-6Ј-Methoxycinchonan-9-yl]-NЈ-[tris(3,5-dimethylphenyl)-
methyl]thiourea (14): Thiourea 14 (868 mg, 72%) was obtained as
a white foam after flash column chromatography (2% MeOH in
Et2O) from amine 7 (550 mg, 1.54 mmol) and isothiocyanate 29
(596 mg, 1.54 mmol); crystallization from MeOH/CHCl3 (5:1) gave
needle-like crystals. M.p. 131–133 °C (dec.). Rf = 0.28 (2% MeOH
in Et2O). [α]2D0 = +114 (c = 0.63, CHCl ). IR (film): ν = 3415, 3155,
˜
N-[Bis(1-naphthyl)methyl]-NЈ-[(9R)-6Ј-methoxycinchonan-9-yl]-
thiourea (11): Thiourea 11 (732 mg, 89%) was obtained after flash
column chromatography as a white foam from amine 18 (411 mg,
1.27 mmol) and isothiocyanate 27 (413 mg, 1.27 mmol). Rf = 0.27
(5% MeOH in DCM); visualization: KMnO4. [α]2D0 = +188 (c =
3
2941, 1793, 1622, 1595, 1510, 1474, 1381, 1226, 1216, 1169, 1095,
1
910 cm–1. H NMR (CDCl3, 400 MHz): δ = 8.45 (d, J = 4.6 Hz, 1
H), 7.92 (d, J = 9.0 Hz, 1 H), 7.66 (d, J = 2.4 Hz, 1 H), 7.31 (dd,
J = 9.0, 2.4 Hz, 1 H), 7.20 (br. s, 1 H), 6.90 (s, 3 H), 6.89 (s, 6 H),
6.54 (d, J = 3.6 Hz, 1 H), 6.10 (d, J = 4.6 Hz, 1 H), 5.86 (ddd, J =
17.0, 10.4, 6.2 Hz, 1 H), 5.56 (dd, J = 10.6, 3.7 Hz, 1 H), 5.10 (m,
2 H), 3.99 (s, 3 H), 2.81 (m, 1 H), 2.64–2.49 (m, 3 H), 2.26 (s, 18
H), 2.25 (m, 1 H), 1.51 (m, 1 H), 1.39 (m, 1 H), 1.26 (m, 1 H), 1.16
(m, 1 H), 0.86 (m, 1 H), 0.70 (m, 1 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 180.0, 157.5, 147.3, 146.4, 144.3, 143.3, 140.5, 137.6,
131.2, 129.1, 128.7, 126.5, 122.0, 118.0, 114.6, 101.9, 72.3, 61.5,
55.7, 55.4, 49.0, 47.3, 39.2, 27.2, 26.6, 25.0, 21.6 ppm.
1.04, CHCl ). IR (film): ν = 3944, 3757, 3691, 3396, 3054, 2987,
˜
3
2685, 2521, 2410, 2126, 1622, 1598, 1550, 1508, 1421, 1267,
1158 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.60 (br. s, 1 H), 8.01–
7.75 (m, 10 H), 7.46–7.17 (m, 8 H), 7.01 (br. s, 1 H), 6.12 (br. s, 1
H), 5.95 (m, 1 H), 5.17 (m, 2 H), 3.93 (s, 3 H), 3.25 (br. s, 2 H),
2.95 (br. s, 3 H), 2.34 (br. s, 1 H), 1.60 (br. s, 3 H), 1.25 (m, 1 H),
0.98 (br. s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 182.5,
158.0, 147.3, 144.4, 139.6, 136.7, 133.8, 131.9, 131.1, 131.0, 128.6,
127.4, 126.7, 125.8, 125.1, 125.0, 124.4, 123.7, 122.1, 114.7, 99.9,
61.7, 56.5, 55.3, 47.9, 45.9, 38.3, 29.5, 27.0, 25.7, 24.5 ppm.
N-[(9R)-6Ј-Methoxycinchonan-9-yl]-NЈ-[(1R)-1-naphthylethyl]-
thiourea (15): Thiourea 15 (484 mg, 81%) was obtained after flash
N-[(9R)-6Ј-Methoxycinchonan-9-yl]-NЈ-(9-phenylfluoren-9-yl)- column chromatography as an amorphous solid from amine 7
thiourea (12): Thiourea 12 (805 mg, 72%) was obtained after flash
column chromatography (10% MeOH in EtOAc) as a crystalline
solid from amine 7 (586 mg, 1.81 mmol) and isothiocyanate 24
(362 mg, 1.12 mmol) and (1R)-1-(1-naphthyl)ethyl isothiocyanate
(21) (238 mg, 1.12 mmol). Rf = 0.29 (15% MeOH in EtOAc); visu-
alization: KMnO4. [α]2D0 = +195 (c = 2.16, CHCl ). IR (film): ν =
˜
3
(543 mg, 1.81 mmol); recrystallization from EtOAc gave cube-like 3684, 3620, 3411, 3019, 2975, 1710, 1622, 1512, 1475, 1419,
1
crystals. M.p. 201–202 °C (dec.). Rf = 0.38 (10% MeOH in EtOAc);
1363 cm–1. H NMR (CDCl3, 400 MHz): δ = 8.72 (d, J = 4.0 Hz,
1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.92–
7.90 (d, J = 8.0 Hz, 1 H), 7.81 (dd, J = 8.0 Hz, 1 H), 7.58–7.29 (m,
9 H), 5.77–5.69 (m, 1 H), 5.23 (br. s, 1 H), 5.06–5.00 (m, 2 H), 3.88
visualization: KMnO4. [α]2D0 = +362 (c = 1.0, CHCl ). IR (film): ν
˜
3
= 3944, 3757, 3691, 3402, 3054, 2987, 2685, 2521, 2410, 2126, 2054,
1622, 1507, 1475, 1421, 1264 cm–1. 1H NMR (CDCl3, 400 MHz):
1348
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1340–1351

A Simple Organocatalytic Enantioselective Synthesis of Pregabalin
(s, 3 H), 2.95–2.20 (br. s, 3 H), 2.04 (br. s, 2 H), 1.65–1.50 (m, 5
KMnO . IR (film): ν = 3944, 3757, 3691, 3054, 2986, 2113, 1712,
˜
4
1
H), 1.26–1.14 (m, 3 H), 0.83 (br. s, 1 H) ppm. 13C NMR (CDCl3, 1421, 1369, 1264 cm–1. H NMR (CDCl3, 400 MHz): δ = 1.44 (s,
100 MHz, more significant signals): δ = 181.5, 157.5, 147.3, 144.4,
139.7, 137.9, 133.8, 131.4, 130.5, 128.8, 128.2, 128.1, 126.4, 125.7,
122.4, 121.8, 119.0, 114.6, 101.3, 60.9, 55.3, 50.1, 47.6, 45.8, 38.3,
26.8, 25.8, 24.5, 22.0 ppm. HRMS: calcd. for C33H36N4OS [M +
H]+ 536.2690; found 537.2688.
9 H, tert-butyl) ppm. 13C NMR (CDCl3, 100 MHz): δ = 129.6,
58.1, 30.7 ppm.
(1R)-1-(1-Naphthyl)ethyl Isothiocyanate (21): According to the pre-
vious general procedure, from commercially available (+)-(1R)-1-
(1-naphthyl)ethylamine (1 g, 5.85 mmol) compound 21 was ob-
tained as a colorless oil (0.979 g, 79%) after purification by combi
flash chromatography (5 % EtOAc in hexane). Rf = 0.35 (5 %
EtOAc in hexane); visualization: KMnO4. [α]2D0 = –116 (c = 1.05,
Preparation of Thiourea Catalysts 16 and 17: A solution of the cor-
responding amine in THF (0.6 ) was added to a stirred solution of
the isothiocyanate 23 in THF (0.6 ) at room temp. After reaction
overnight, the solvent was removed under reduced pressure and the
residue submitted to flash column chromatography.
CHCl3) {ref.[25] [α]2D0 = –109 (c = 1.0, CHCl )}. IR (film): ν = 3944,
˜
3
3757, 3691, 3054, 2987, 2685, 2096, 1712, 1599, 1512, 1421, 1361,
1263 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.92 (dd, J = 11.0,
9.0 Hz, 2 H), 7.83 (d, J = 8.2 Hz, 1 H), 7.55 (m, 3 H), 5.71 (q, J =
6.8 Hz, 1 H), 1.84 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 135.2, 133.7, 132.4, 129.3, 129.0, 128.8, 126.6, 125.8,
125.3, 122.8, 122.0, 53.9, 23.8 ppm.
N-[(9R)-6Ј-Methoxycinchonan-9-yl]-NЈ-[(1S)-1-naphthylethyl]-
thiourea (16): Thiourea 16 (349 mg, 65%) was obtained after flash
column chromatography as a white foam from isothiocyanate 23
(366 mg, 1 mmol) and commercially available (1S)-1-(1-naphthyl)-
ethylamine (174 mg, 1 mmol). Rf = 0.21 (5% MeOH in DCM);
visualization: KMnO4. [α]2D0 = +203 (c = 1.95, CHCl3). IR (film):
Benzhydryl Isothiocyanate (22):[23] According to the previous gene-
ν = 3393, 3155, 2941, 2874, 1793, 1623, 1509, 1474, 1381, 1225,
ral procedure, from commercially available benzhydrylamine (2 g,
˜
1
1095 cm–1. H NMR (CDCl3, 400 MHz): δ = 8.41 (d, J = 4.0 Hz, 10.9 mmol) compound 22 was obtained as a white solid (1.01 g,
1 H), 7.98 (br. s, 1 H), 7.87 (d, J = 8.0 Hz, 2 H), 7.76 (d, J = 4.0 Hz, 41 %) after purification by combi flash chromatography (5 %
1 H), 7.50 (br. s, 2 H), 7.34 (br. s, 3 H), 7.29 (dd, J = 9.2, 2.4 Hz,
2 H), 6.95 (br. s, 1 H), 5.74 (br. s, 2 H), 5.06–4.96 (m, 2 H), 3.88
EtOAc in hexane). M.p. 61–62 °C. Rf = 0.76 (5% EtOAc in hex-
ane); visualization: KMnO . IR (film): ν = 3691, 3053, 2986, 2685,
˜
4
(s, 3 H), 2.68 (br. s, 2 H), 2.61 (br. s, 3 H), 2.17 (d, J = 7.12 Hz, 1 2062, 1712, 1598, 1550, 1494, 1453, 1343 cm–1. H NMR (CDCl3,
1
H), 1.82 (br. s, 1 H), 1.66 (d, J = 6.6 Hz, 3 H), 1.50 (br. s, 1 H), 400 MHz): δ = 7.39–7.27 (m, 10 H), 5.98 (s, 1 H) ppm. 13C NMR
1.46 (br. s, 2 H), 1.34 (br. s, 1 H), 1.06 (br. s, 1 H), 0.76 (br. s, 1 H)
ppm. 13C NMR (CDCl3, 100 MHz, significant signals): δ = 180.8,
157.8, 147.2, 144.3, 139.8, 137.6, 133.6, 131.7, 130.5, 128.8, 128.2,
126.5, 126.3, 125.7, 125.1, 122.3, 121.9, 119.3, 114.7, 100.9, 61.3,
55.4, 50.2, 48.4, 46.3, 38.5, 27.1, 26.0, 24.6, 21.0 ppm. HRMS:
calcd. for C33H36N4OS [M + H]+ 536.2690; found 537.2688.
(CDCl3, 100 MHz): δ = 139.1, 134.4, 128.8, 128.2, 126.5, 64.5 ppm.
(9-Deoxy)epiquinidine Isothiocyanate (23): According to the pre-
vious general procedure, from 7 (1.02 g, 3.17 mmol) title compound
23 was obtained as a white solid (0.845 g, 73%) after purification
by flash chromatography (10 % MeOH in Et2O). Crystallization
from MeOH/CHCl3 (5:1) gave star-like crystals. M.p. 109–110 °C
(dec.). Rf = 0.16 (10% MeOH in Et2O); visualization: KMnO4.
1-[(1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl]-NЈ-[(9R)-6Ј-meth-
oxycinchonan-9-yl]thiourea (17): Thiourea 17 (203 mg, 61%) was
obtained after flash column chromatography as a white foam from
isothiocyanate 23 (236 mg, 0.65 mmol) and commercially available
(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (96 mg, 0.65 mmol);
Rf = 0.52 (15% MeOH, 5% Et3N in DCM); visualization: ninhyd-
[α]2D0 = +15.1 (c = 1.3, CHCl ). IR (film): ν = 3155, 2955, 2049,
˜
3
1816, 1793, 1622, 1547, 1512, 1473, 1382 cm–1. H NMR (CDCl3,
1
400 MHz): δ = 8.75 (d, J = 4.5 Hz, 1 H), 8.03 (d, J = 9.2 Hz, 1 H),
7.45 (d, J = 4.5 Hz, 1 H), 7.38 (dd, J = 9.2, 2.6 Hz, 1 H), 7.31 (d,
J = 2.6 Hz, 1 H), 5.86 (ddd, J = 16.8, 10.6, 5.9 Hz, 1 H), 5.40 (d,
J = 10 Hz, 1 H), 5.23 (m, 2 H), 3.95 (s, 3 H), 3.75 (m, 1 H), 3.51
rin; [α]2D0 = +314 (c = 0.62, CHCl ). IR (film): ν = 3620, 3399, 2976,
˜
3
2896, 1623, 1511, 1475, 1392, 1215, 1047 cm–1. 1H NMR (CD3OD, (m, 1 H), 3.29 (m, 2 H), 3.17 (m, 1 H), 2.65 (m, 1 H), 2.05 (br. s,
400 MHz): δ = 8.67 (m, 1 H), 8.13 (br. s, 1 H), 7.95 (dq, J = 9, 1.4 1 H), 1.96–1.73 (m, 3 H), 1.60 (m, 1 H) ppm. 13C NMR (CDCl3,
Hz, 1 H), 7.57 (br. s, 1 H), 7.45 (m, 1 H), 7.21 (m, 3 H), 6.48 (br.
s, 1 H), 5.99 (m, 2 H), 5.82 (br. s 1 H), 5.29 (d, J = 17 Hz, 1 H),
5.17 (dd, J = 10, 1.4 Hz, 1 H), 4.88 (br. s, 4 H), 4.53 (br. s, 1 H),
4.07 (s, 3 H), 3.6–3.3 (m, 5 H), 3.15–3.02 (m, 4 H), 2.85 (d, J = 17
Hz, 1 H), 2.4 (m, 1 H), 1.20 (m, 1 H), 1.01 (br. s, 1 H). HRMS:
calcd. for C30H35N4O2S [M + H]+ 515.2481; found 515.2487.
100 MHz): δ = 157.8, 147.8, 144.4, 141.9, 136.1, 131.7, 127.1, 121.7,
119.6, 117.2, 101.1, 67.3, 65.7, 55.5, 52.0, 50.9, 37.4, 27.9, 24.7,
24.2 ppm.
9-Phenylfluoren-9-yl Isothiocyanate (24): Potassium thiocyanate
(0.3 g, 3.1 mmol) was added to a solution of 9-bromo-9-phenylfluo-
rene (1 g, 3.1 mmol) in acetone (5 mL). The white suspension was
stirred at room temp. for 20 min. Then the solvent was removed,
and the residue was partitioned between water and EtOAc. The
organic phases were dried, filtered and concentrated to afford an
oil, which was purified by flash chromatography (5% EtOAc in
hexane). Isothiocyanate 24 was isolated as a white solid {Rf = 0.37
(5% EtOAc in hexane) (446 mg, 48% yield); along with the corre-
sponding thiocyanate [Rf = 0.24 (315 mg, 34%); visualization:
General Procedure for the Preparation of Isothiocyanates from Pri-
mary Amines: To a solution of the corresponding primary amine
(100 mol-%) in dry diethyl ether or THF (1 ) at –10 °C were added
CS2 (600 mol-%) and DCC (100 mol-%). The reaction mixture was
warmed slowly to room temp. over a period of 3 h and then stirred
at room temp. overnight. The thiourea, which precipitated, was re-
moved by filtration, and the solvent was subsequently removed un-
der vacuum. The residue was taken up in diethyl ether and more
of the thiourea was removed by filtration. The solvent was removed
under reduced pressure, and the residue was purified by flash
chromatography.
tert-Butyl Isothiocyanate (20):[22] According to the previous general
procedure, from commercially available tert-butylamine (4 g,
54.8 mmol) compound 20 was obtained as a colorless oil (4.09 g,
65 %) after purification by combi flash chromatography (5 %
EtOAc in hexane). Rf = 0.39 (5% EtOAc in hexane); visualization:
KMnO ]}. M.p. 86–88 °C. IR (film): ν = 3944, 3691, 3054, 2831,
˜
4
2685, 2054, 1599, 1711, 1421, 1263 cm–1 1H NMR (CDCl3,
.
400 MHz): δ = 7.73–7.68 (m, 2 H), 7.48–7.15 (m, 11 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 147.7, 140.8, 139.8, 135.8, 130.2,
129.3, 129.2, 128.6, 125.7, 125.0, 121.0, 74.6 ppm.
Bis(1-naphthyl)methanol (26): Commercially available 1-bromo-
naphthalene (3.52 g, 17 mmol) dissolved in THF (3 mL) was added
dropwise to a stirred suspension of magnesium turnings (0.41 g,
17 mmol) in anhydrous THF (3 mL) over a period of 10 min. Heat
Eur. J. Org. Chem. 2009, 1340–1351
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1349

O. Bassas, J. Huuskonen, K. Rissanen, A. M. P. Koskinen
FULL PAPER
evolved, and the mixture turned into a green suspension. After 2 h,
ethyl formate (0.67 mL, 8.1 mmol) was added as a solution in THF
(2 mL) over a period of 10 min. After stirring for 2 h at room temp.,
the mixture was poured into ice/2  HCl (1:1, 50 mL), and the
aqueous layer was extracted with Et2O. The extracts were dried,
filtered and concentrated to provide 26 as a white foam (1.72 g,
75%) that was used without further purification. Rf = 0.29 (30%
Acknowledgments
We gratefully acknowledge financial support from the Academy of
Finland (AMPK no. 105834 and KR no. 212588) and Dr. Jari
Koivisto and Ms. Tiia Juhala for the HRMS and elemental analy-
ses.
CHCl3 in hexane); visualization: KMnO . IR (film): ν = 3597,
˜
4
3155, 3063, 2984, 1816, 1793, 1643, 1598, 1510, 1470, 1382 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 8.04 (d, J = 8.0 Hz, 2 H), 7.90
(d, J = 8.0 Hz, 2 H), 7.82 (d, J = 8.0 Hz, 2 H), 7.50–7.28 (m, 8 H),
7.24 (d, J = 4.0 Hz, 1 H), 2.40 (d, J = 4.0 Hz, 1 H, OH) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 138.3, 133.7, 130.9, 128.6, 128.3,
126.2, 125.5, 125.3, 124.9, 123.7, 69.2 ppm.
[1] a) R. B. Silverman, R. Andruszkiewicz, S. M. Nanavati, C. P.
Taylor, M. G. Vartanian, J. Med. Chem. 1991, 34, 2298–2300;
b) R. B. Silverman, Angew. Chem. Int. Ed. 2008, 47, 3500–3504.
[2] C. P. Taylor, M. G. Vartanian, P. W. Yuen, C. Bigge, N. Su-
man Chauhan, D. R. Hill, Epilepsy Res. 1993, 14, 11–15.
[3] M. S. Hoekstra, D. M. Sobieray, M. A. Schwindt, T. A.
Mulhern, T. M. Grote, B. K. Huckabee, V. S. Hendrickson,
L. C. Franklin, E. J. Granger, G. L. Karrick, Org. Process Res.
Dev. 1997, 1, 26–38.
Bis(1-naphthyl)methyl Isothiocyanate (27): Powdered oxalic acid
(0.32 g, 3.52 mmol) and NaSCN (0.34 g, 4.22 mmol) were added to
a solution of 26 (1 g, 3.52 mmol) in nitromethane (8 mL). The mix-
ture was stirred at 60 °C for 3 h. Then, the crude mixture was
poured into a saturated solution of sodium carbonate and extracted
with Et2O. The extracts were dried, filtered and concentrated to
give a pale yellow oil. This was purified by flash column
chromatography (5 % EtOAc in hexane) to give compound 27
(0.96 g, 84%) as a white foam and minor amounts of the corre-
sponding thiocyanate (0.068 g, 6%). Rf = 0.39 (10% EtOAc in hex-
[4] a) P. Yuen, G. D. Kanter, C. P. Taylor, M. G. Vartanian, Bioorg.
Med. Chem. Lett. 1994, 4, 823–826; b) M. Brenner, D. Seebach,
Helv. Chim. Acta 1999, 82, 2365–2379; c) M. J. Burk, P. D.
de Koning, T. M. Grote, M. S. Hoekstra, G. Hoge, R. A. Jen-
nings, W. S. Kissel, T. V. Le, I. C. Lennon, T. A. Mulhern, J. A.
Ramsden, R. A. Wade, J. Org. Chem. 2003, 68, 5731–5734; d)
G. Hoge, H.-P. Wu, W. S. Kissel, D. A. Pflum, D. J. Green, J.
Bao, J. Am. Chem. Soc. 2004, 126, 5966–5967; e) G. L. Sam-
mins, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125, 4442–4443;
f) Z. Chen, Y. Jiang, W. Hu, Synlett 2004, 10, 1763–1765; g) T.
Mita, K. Sasaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2005, 127, 514; h) A. Armstrong, N. J. Convine, M. E. Popkin,
Synlett 2006, 1589–1591; i) V. Rodriguez, L. Quintero, F. Sart-
illo-Piscil, Tetrahedron Lett. 2007, 48, 4305–4307; j) S. Poe, M.
Kobaslija, T. McQuade, J. Am. Chem. Soc. 2007, 129, 9216–
9221; k) T. Ok, A. Jeon, J. Lee, J. H. Lim, C. S. Hong, H.-S.
Lee, J. Org. Chem. 2007, 72, 7390–7393; l) Z. Hamersak, I.
Stipetic, A. Avdagic, Tetrahedron: Asymmetry 2007, 18, 1481–
1485; m) H. Gotoh, H. Ishikawa, Y. Hayashi, Org. Lett. 2007,
9, 5307; for a review of stereoselective syntheses of Pregabalin
and its analogues, see: n) M. Ordóñez, C. Cativiela, Tetrahe-
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ane); visualization: KMnO . IR (film): ν = 3943, 3692, 3054, 2986,
˜
4
2685, 2056, 1599, 1511, 1421, 1269 cm–1 1H NMR (CDCl3,
.
400 MHz): δ = 7.95–7.84 (m, 6 H), 7.54–7.40 (m, 9 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 135.2, 133.8, 133.5, 130.1, 129.4,
129.0, 127.0, 126.0, 125.6, 125.3, 122.6, 58.3 ppm.
Tris(3,5-dimethylphenyl)methanol (28):[24] Commercially available 1-
bromo-3,5-dimethylbenzene (7 g, 37.8 mmol) in dry Et2O (5 mL)
was added dropwise to a stirred suspension of granular lithium
(0.66 g, 95.1 mmol) in dry Et2O (15 mL) at –10 °C. The mixture
reacted exothermically and refluxed spontaneously. After the ad-
dition was complete, the mixture was stirred at room temp. for
10 min. Then, commercially available methyl 3,5-dimethylbenzoate
(2.48 g, 15.1 mmol) in dry Et2O (10 mL) was added dropwise, and
the mixture was stirred at room temp. overnight. Then the excess
of lithium and the lithium salts were removed by filtration, and the
filtrate was poured into a saturated aqueous solution of ammonium
chloride. After Et2O extraction of the aqueous layer, the organic
phases were dried, filtered and concentrated to yield alcohol 28 as
a white solid (4.746 g, 91%). Crystallization from hexane gave nee-
dle-like crystals. M.p. 155–156 °C (ref.[24] 158 °C). Rf = 0.21 (5%
[5] For recent reviews on asymmetric organocatalytic conjugate
addition reactions, see: a) D. Almasi, D. Alonso, C. Nájera,
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Et O in hexane); visualization: anisaldehyde. IR (film): ν = 3944,
˜
2
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3691, 3054, 2987, 2685, 1598, 1551, 1421, 1263 cm–1 1H NMR
.
(CDCl3, 400 MHz): δ = 6.94 (s, 3 H), 6.92 (s, 6 H), 2.70 (s, 1 H,
OH); 2.30 (s, 18 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 147.1,
137.1, 128.7, 125.7, 81.8, 21.5 ppm.
Tris(3,5-dimethylphenyl)methyl Isothiocyanate (29): Powdered ox-
alic acid (0.34 g, 3.78 mmol) and KSCN (0.44 g, 4.53 mmol) were
added to a solution of 28 (1.3 g, 3.78 mmol) in nitromethane
(10 mL). The mixture was stirred at 60 °C for 3 h. Then, the crude
mixture was poured into a saturated solution of Na2CO3 and ex-
tracted with Et2O. The extracts were dried, filtered and concen-
trated to give a pale yellow oil. This was purified by flash column
chromatography (2% Et2O in hexane) to give pure compound 29
(1.29 g, 89%) as a white solid. Crystallization from hexane gave
colorless crystals. M.p. 161–162 °C. Rf = 0.58 (2% Et2O in hexane);
visualization: KMnO . IR (film): ν = 3597, 3153, 3010, 2920, 2085,
˜
4
1796, 1597, 1464, 1378, 1288 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 6.94 (s, 3 H), 6.75 (s, 6 H), 2.27 (s, 18 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 143.2, 137.6, 132.9, 129.6, 125.9, 21.4 ppm.
1350
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1340–1351

A Simple Organocatalytic Enantioselective Synthesis of Pregabalin
Chem. 2008, 73, 3475–3480; q) P. Li, Y. Wang, X. Liang, J. Ye,
Chem. Commun. 2008, 3302–3304.
= 153.0(1) K, 2θmax = 52.0°, 6495 reflections used, 5801 with
Io Ͼ 2σ(Io), 426 parameters, 0 restraints, GoF = 1.080, R1
=
0.040, wR2 = 0.090 (all reflections), 0.19 Ͻ ∆ρ Ͻ –0.20 eÅ–3.
CCDC-685194 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Received: December 5, 2008
Published Online: February 5, 2009
Eur. J. Org. Chem. 2009, 1340–1351
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1351