First asymmetric synthesis of an acyclic β,β-dialkylated-γ-aminobutyric acid

Article abstract of DOI:10.1016/j.tet.2006.06.021

Enantiomerically pure (R)-γ-amino-β-benzyl-β-methylbutyric acid, an acyclic β,β-dialkyl GABA derivative, is efficiently synthesised from (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate by a sequence based on benzylation, Arndt-Eistert homol

Full text of DOI:10.1016/j.tet.2006.06.021

Tetrahedron 62 (2006) 8142–8146
First asymmetric synthesis of an acyclic b,b-dialkylated-
g-aminobutyric acid
*
Daniel Aguirre, Carlos Cativiela, Marıa D. Dıaz-de-Villegas and Jose A. Galvez
*
´
´
ꢀ
ꢀ
´
ꢀ
ꢀ
ꢀ
´
Departamento de Quımica Organica, Instituto de Ciencia de Materiales de Aragon, Instituto Universitario de Catalisis Homogenea,
Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain
Received 23 March 2006; revised 18 May 2006; accepted 1 June 2006
Available online 27 June 2006
Abstract—Enantiomerically pure (R)-g-amino-b-benzyl-b-methylbutyric acid, an acyclic b,b-dialkyl GABA derivative, is efficiently syn-
thesised from (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate by a sequence based on benzylation, Arndt–Eistert homo-
logation and nitrile reduction. Benzylation of (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate using potassium carbonate
under not strictly anhydrous conditions occurs diastereoselectively to afford (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl (S)-2-cyano-2-
methyl-3-phenylpropanoate, the key chiral intermediate from which the desired g-amino acid is obtained in five steps in 65% overall yield.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
For instance, g-amino-b-(4-chlorophenyl)butyric acid, or
Baclofen (1), was introduced in 1973 for the therapy of
muscle spasticity and is still the prototype of a selective
GABABR agonist.5 Although the desired biological activity
is known to reside in the (R)-enantiomer,6 Baclofen is thera-
peutically commercialised (LioresalÒ and BaclonÒ) as a
racemate for the treatment of multiple sclerosis and cerebral
palsy.
In recent years the need for enantiomerically pure g-amino
acids has grown markedly, not only due to their biological
activity1 and presence in the structures of natural products
with antitumoral activity,2 but also because peptides consist-
ing of optically active g-amino acids can form stable helical
structures in solution and in the solid state, even for peptides
consisting of as few as four residues.3
Gabapentin (2), a b,b-disubstituted GABA analogue, has
been commercialised by Pfizer under the name NeurontinÒ.
Gabapentin is used for the treatment of cerebral diseases
such us epilepsy, faintness, hypokinesis and cranial
traumas.7 Furthermore, to date it is the only drug specifically
licenced for the treatment of neuropathic pain. This
compound shows few, if any, toxic side effects at clinically
relevant doses. Moreover, a Gabapentin-lactam is neuropro-
tective in retinal ischaemia.8
g-Aminobutyric acid (GABA), the simplest g-amino acid, is
the major inhibitory neurotransmitter in the central nervous
system (CNS) of mammalians.4 Its derivatives, in particular
those analogues bearing substituents at the b-position, have
been the subject of extensive investigations because of their
potential biological activity.1b A number of these compounds
are important therapeutic agents for a range of CNS dis-
orders (Fig. 1).
(S)-g-Amino-b-isobutylbutyric acid, or Pregabalin (3), is
another b-substituted GABA analogue. Like Gabapentin this
compound has anticonvulsant, anxiolytic-like and analgesic
properties but it displays more potent and robust activity
than Gabapentin in preclinical models for epilepsy, neuro-
pathic pain and anxiety.9
CO2H
NH2
CO2H
NH2
CO2H
NH2
Cl
(R)-Baclofen, 1
Gabapentin, 2
(S)-Pregabalin, 3
A careful search in ScifinderÒ database showed that among
the several hundred scientific studies on b-substituted
GABA analogues that have been published in the last 10
years, not one deals with the stereoselective preparation of
acyclic b,b-dialkylated g-aminobutyric acids. Thus, we
wish to report here the development of a new, efficient and
concise methodology for the asymmetric synthesis of this
Figure 1. Structures of (R)-Baclofen, Gabapentin and (S)-Pregabalin.
Keywords: g-Amino acids; Asymmetric synthesis; Diastereoselective alkyl-
ation.
* Corresponding authors. Tel.: +34 976762274; fax: +34 976761202
(M.D.D.); tel.: +34 976762273; fax: +34 976761202 (J.A.G.); e-mail
addresses: loladiaz@unizar.es; jagl@unizar.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.021

D. Aguirre et al. / Tetrahedron 62 (2006) 8142–8146
8143
CO2H
CO2R*
CO2R*
CN
kind of g-amino acid from chiral a-cyanoesters. As a model
i
ii
Ph
Ph
to establish the synthetic methodology, the preparation of
enantiomerically pure (R)-g-amino-b-benzyl-b-methylbuty-
ric acid was selected. This route started from the 2-cyano-
propanoate derived from the commercially available chiral
alcohol (1S,2R,4R)-10-dicyclohexylsulfamoylisoborneol,
known as (ꢀ)-Oppolzer’s alcohol.10
CH3
CN
CN
100%
d.r. = 82/18
93%
CH3
CH3
8
(S)-9
10
CO2CH3
CN
O
CHN2
iii
98%
iv
95%
Ph
Ph
Ph
CN
CH3
12
CH3
11
O
CO2H
NH2
2. Results and discussion
v
vi
NH
Ph
90%
83%
According to the retrosynthetic analysis shown in Scheme 1,
we envisaged that the aminomethyl moiety in the target
compound could be obtained by nitrile reduction (NR) of
3-cyano-3-methyl-4-phenylbutyrate and the carboxymethyl
moiety could be obtained by Arndt–Eistert homologation11
(AEH) of 2-cyano-2-methyl-3-phenylpropanoate. Enantio-
merically pure 2-cyano-2-methyl-3-phenylpropanoate can
be obtained by diastereoselective a-benzylation (DB) of
a chiral 2-cyanopropanoate.
CH3
CH3
13
14
Scheme 2. Reagents and conditions: (i) K2CO3, BnBr, acetone; (ii) KOH,
i
MeOH, D; (iii) ClCO2 Bu, NMM, THF, ꢀ20 ꢁC, then dry CH2N2 in ether;
(iv) AgBzO, Et3N, MeOH, THF; (v) H2, Ni (Ra), NH3/MeOH, 35 ꢁC; (vi)
HCl, D.
Arndt–Eistert reaction is the most important and most com-
monly used procedure for converting a carboxylic acid into
its acid or ester homologue with one extra carbon in only two
steps.16 The synthesis of sterically hindered diazoketones is
often inefficient or even impossible to achieve using stan-
dard procedures.17 However, we tested the acylation of di-
azomethane using acyl chlorides or mixed anhydrides as
activated carboxylic acid derivatives. Firstly, the a-cya-
noacyl chloride obtained from 10 and thionyl chloride was
treated with an excess of a dry ethereal solution of diazome-
thane.18 This reaction yielded a mixture of the desired diazo-
ketone 11, with a quaternary a-carbon atom, and the methyl
ester derived from 10 in a 3/1 ratio. Diazoketone 11 was a sta-
ble solid that could be isolated by column chromatography
without noticeable degradation. The partial success of the
aforementioned procedure is clearly due to the hydrolysis
of the highly activated acid chloride under the reaction con-
ditions and subsequent esterification with diazomethane.
Alternatively, cyanoacid 10 was converted to a mixed
anhydride using isobutyl chloroformate in the presence of
N-methylmorpholine at low temperature. Subsequent addi-
tion of a dry ethereal solution of diazomethane gave rise to
diazoketone 11 in 98% yield, which was sufficiently pure
to be used in the next step without purification.
CO2H
CN
CO2H
NH2
NR
AEH
Ph
Ph
CH3
CH3
4
5
CO2H
CN
CO2R*
CN
DB
Ph
CH3
CH3
6
7
Scheme 1. Retrosynthetic steps to (R)-g-amino-b-benzyl-b-methylbutyric
acid from chiral cyanopropanoates.
In a previous paper,12 we described how the diastereoselec-
tive a-benzylation of 2-cyanopropanoate 8, yielded
(1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyano-2-
methyl-3-phenylpropanoate 9 in 96% yield as a mixture of
diastereoisomers (S/R¼91/9). This reaction was performed
using LDA as the base in an anhydrous medium and in the
presence of HMPA.13 As the reported pKa value of methyl
a-cyanoacetate is about 13,14 we reasoned that the a-benzyl-
ation reaction could be promoted by weaker bases than LDA.
Such bases would not require the use of strictly anhydrous
reaction conditions and harmful reagents. In this context
the use of potassium carbonate as a base was tested. To
our delight, treatment of a solution of 2-cyanopropanoate 8
and benzyl bromide in acetone with potassium carbonate
at room temperature cleanly afforded compound 9 in
quantitative yield as a mixture of diastereoisomers. A dia-
Wolff rearrangement19 of diazoketone 11 to methyl ester 12
was achieved using the procedure described by Savithri
et al.20 This approach involved the addition of a catalytic
amount of silver benzoate in triethylamine to a homogeneous
solution of compound 11 and methanol in THF. Although it
has recently been suggested17 that the silver-catalysed Wolff
rearrangement tends to fail with sterically hindered diazo-
ketones, we cleanly obtained b-cyanoester 12 in 95% yield.
Alternatively, we found that the triethylamine and silver
benzoate-catalysed Wolff rearrangement of 11 also pro-
ceeded at 70 ꢁC in a mixture of dioxane and water to give
the corresponding b-cyanoacid in 90% yield. The configu-
rational stability in the silver-catalysed Wolff rearrange-
ment was assessed by 1H NMR using Eu(hfc)3. The
addition of 0.2 equiv of the lanthanide shift reagent, suffi-
cient to cause splitting in a racemic mixture, to methyl
ester 12 gave rise to only one set of signals. Accordingly,
this compound was obtained with an enantiomeric excess
greater than 96%.
1
stereomeric ratio of 82/18 was determined by H NMR
spectroscopy of the crude reaction mixture. The major dia-
stereoisomer (S)-9 could be easily isolated in satisfactory
yield by recrystallisation from methanol. Although the dia-
stereoselectivity decreased slightly, these new reaction con-
ditions are safer and more convenient for large-scale work.15
(R)-g-Amino-b-benzyl-b-methylbutyric acid (14) was effi-
ciently prepared from chiral 2-cyanopropanoate 8 by the
six-step procedure outlined in Scheme 2. After benzylation
the isolated cyanoacetate (S)-9 was hydrolysed with 2 N
potassium hydroxide in methanol to afford cyanoacid 10
in 93% yield. This compound was then subjected to the
corresponding homologation process.

8144
D. Aguirre et al. / Tetrahedron 62 (2006) 8142–8146
Hydrogenation of the cyano group in compound 12 was
cleanly achieved at atmospheric pressure and 35 ꢁC using
Raney nickel as catalyst and a solution of 0.5% ammonia
in methanol as the solvent. This procedure afforded g-lactam
13 in 90% yield. This compound was hydrolysed by heating
under reflux with 5 N aqueous HCl. Elution of the g-amino
acid hydrochloride through an ion-exchange column yielded
(R)-g-amino-b-benzyl-b-methylbutyric acid (14) in 83%
yield. It is worth mentioning that although compounds 12
and 13 were isolated for characterisation purposes by filtra-
tion through a short silica gel pad, the crude products were
sufficiently pure to carry out the next step without any puri-
fication.
million and the coupling constants (J) in hertz. The follow-
ing abbreviations are used: s, singlet; d, doublet; q, quartet;
dd, doublet of doublets; m, multiplet; br s, broad singlet.
Elemental analyses were performed using a C, H, N, S ele-
mental analyser. High-resolution mass spectra were obtained
using the FAB+ ionisation mode with a 3-NBA matrix.
4.2. (1S,2R,4R)-10-Dicyclohexylsulfamoylisobornyl
(S)-2-cyano-2-methyl-3-phenylpropanoate (S)-9
Potassium carbonate (3.45 g, 25 mmol) was added to a
solution of (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl
(R/S)-2-cyanopropanoate (8) (2.4 g, 5 mmol) and benzyl
bromide (1.7 g, 10 mmol) in acetone (60 mL) and the result-
ing mixture was stirred at room temperature for 24 h. The re-
action mixture was filtered and the solid residue was washed
with diethyl ether. The combined filtrates were concentrated
in vacuo and the residue was dissolved in diethyl ether,
washed with water, dried over anhydrous MgSO4, filtered
and concentrated in vacuo to afford 2.84 g (100% yield) of
9 as an 82/18 mixture of diastereoisomers. Silica gel column
chromatography (first eluent: diethyl ether/hexanes 1/6, sec-
ond eluent: diethyl ether/hexanes 1/2) and recrystallisation
from methanol yielded 2.17 g (76% yield) of major dia-
stereoisomer (S)-9 as a white solid. The physical and spec-
troscopic data of the product are consistent with those
reported previously.12
(R)-2-Cyano-2-methyl-3-phenylpropanoic acid ent-9 can
clearly be obtained by a-benzylation of the 2-cyano-
propanoate derived from the commercially available (+)-
Oppolzer’s alcohol or, alternatively as described previously
by us,21 by diastereoselective a-methylation of the 3-phenyl-
2-cyanopropanoate derived from (ꢀ)-Oppolzer’s alcohol.
Therefore, the methodology described here also constitutes
a formal synthesis of (S)-g-amino-b-benzyl-b-methylbutyric
acid ent-14.
3. Conclusion
We have developed a concise, practical and efficient proce-
dure for the asymmetric synthesis of (R)-g-amino-b-benzyl-
b-methylbutyric acid in overall high yield from a chiral ester
derived from 2-cyanopropanoic acid and (1S,2R,4R)-(ꢀ)-
10-dicyclohexylsulfamoylisoborneol as the chiral auxiliary.
Highly diastereoselective a-alkylations of chiral 2-cyano es-
ters derived from this alcohol have been achieved previously
in our laboratory with good yields to afford a wide variety of
enantiopure dialkylated cyanoacetates.21 For this reason, we
believe that the present synthetic methodology should find
broad application in the stereoselective synthesis of other
enantiopure b,b-dialkylated g-amino acids of interest.
4.3. (S)-2-Cyano-2-methyl-3-phenylpropanoic acid 10
(S)-9 (2.3 g, 4 mmol) was added to a solution of 2 N KOH in
methanol (20 mL) and the reaction mixture was refluxed for
4 h. The resulting solution was cooled and the solvent was
evaporated in vacuo. The residue was diluted in water
(20 mL) and washed with diethyl ether (2ꢂ40 mL). The
aqueous layer was then acidified and extracted with diethyl
ether (2ꢂ40 mL). The organic layer was dried over anhy-
drous MgSO4 and concentrated in vacuo to yield 703 mg
(93% yield) of 10 as a white solid. The physical and spectro-
scopic data of the product are consistent with those reported
previously.12
4. Experimental
4.1. General
4.4. (S)-2-Benzyl-4-diazo-2-methyl-3-oxobutyronitrile
11
All reagents for reactions were of analytical grade and were
used as obtained from commercial sources. Compound 8
was obtained according to Ref. 12. Whenever possible the
reactions were monitored by TLC. TLC was performed on
precoated silica gel polyester plates and products were
visualised using UV light (254 nm) and phosphomolybdic
acid. Column chromatography was performed using silica
gel (Kieselgel 60, 230–400 mesh). Melting points were
determined in open capillary tubes and are uncorrected.
FTIR spectra of liquids were recorded as thin films on
NaCl plates and FT-IR spectra of solids were recorded as
Nujol dispersions on NaCl plates; nmax values expressed in
cmꢀ1 are given for the main absorption bands. Optical rota-
tions were measured in a cell with a 10 cm path length and
N-Methylmorpholine (0.45 mL, 4.08 mmol) and isobutyl
chloroformate (0.54 mL, 4.08 mmol) were consecutively
added dropwise to a stirred solution of 10 (700 mg,
3.70 mmol) in dry THF (65 mL) at ꢀ20 ꢁC under argon
and stirred at this temperature for 30 min. An excess of
dry ethereal solution of diazomethane in diethyl ether (ca.
10 mmol) was added and the solution was allowed to
warm to room temperature. [Caution: diazomethane is
a very harmful reagent and must be handled with extreme
care in an efficient fume cupboard.]22 After 2 h, several
drops of acetic acid were added to destroy the excess diazo-
methane and the solvent was removed by distillation in
vacuo. The residue was dissolved in diethyl ether (40 mL)
and the resulting organic solution was washed successively
with 10% aqueous citric acid (20 mL), saturated aqueous
sodium hydrogen carbonate (20 mL), dried over anhydrous
MgSO4 and concentrated in vacuo to yield 772 mg (98%
yield) of 11 as a white solid. Mp¼72 ꢁC; [a]D26 245.0 (c 2,
1
concentrations are given in g/100 mL. H and 13C NMR
spectra were acquired at room temperature in the corre-
sponding deuterated solvent at 300 and 75 MHz, respec-
tively. The chemical shifts (d) are reported in parts per

D. Aguirre et al. / Tetrahedron 62 (2006) 8142–8146
8145
CHCl3); IR (Nujol) 2236, 2118, 1639 cmꢀ1
;
1H NMR
hydrochloride. This material was submitted to ion-exchange
column chromatography on Dowex 50Wx8 to afford 430 mg
(83% yield) of 14 as a white solid. Mp¼159 ꢁC; [a]D25 13.6 (c
1, H2O); IR (Nujol) 1624 cmꢀ1; 1H NMR (D2O, 300 MHz)
d 0.96 (s, 3H), 2.29 (s, 2H), 2.61 (d, 1H, J¼13.3 Hz), 2.75 (d,
1H, J¼13.3 Hz), 2.90 (d, 1H, J¼13.1 Hz), 3.00 (d, 1H,
J¼13.1 Hz), 7.15–7.40 (m 5H); 13C NMR (D2O, 75 MHz)
d 22.0, 35.4, 44.8, 47.2, 48.4, 126.9, 128.4, 131.0, 136.9,
180.5. Elemental analysis calcd (%) for C12H17NO2:
C, 69.54; H, 8.27; N, 6.76. Found: C, 69.87; H, 8.33; N,
6.64.
(CDCl3, 300 MHz) d 1.54 (s, 3H), 2.91 (d, 1H, J¼
13.5 Hz), 3.21 (d, 1H, J¼13.5 Hz), 5.72 (s, 1H), 7.21–7.33
(m 5H); 13C NMR (CDCl3, 75 MHz) d 23.3, 43.3, 48.1,
55.3, 121.3, 127.7, 128.5, 130.1, 134.4, 188.7. Elemental
analysis calcd (%) for C12H11N3O: C, 67.59; H, 5.20; N,
19.71. Found: C, 67.78; H, 5.11; N, 19.58.
4.5. (R)-Methyl 3-cyano-3-methyl-3-phenylbutyrate 12
A solution of silver benzoate (220 mg, 0.96 mmol) in tri-
ethylamine (3.09 mL, 22.1 mmol) was added dropwise to
a stirred solution of 11 (717 mg, 3.36 mmol) and methanol
(0.34 mL, 8.4 mmol) in dry THF (20 mL) at room tempera-
ture under argon. After 3 h, an additional solution of silver
benzoate (110 mg, 0.48 mmol) in triethylamine (1.55 mL,
11.1 mmol) and methanol (0.17 mL, 4.2 mmol) was added.
After 4 h, the solvent was evaporated under reduced pressure
and the residue was dissolved in diethyl ether (40 mL). The
organic layer was filtered, then washed successively with
1 N aqueous HCl, saturated aqueous sodium hydrogen car-
bonate and brine, dried over anhydrous MgSO4 and concen-
trated in vacuo. The crude methyl ester was purified by
filtration through a short silica gel pad using a mixture of di-
ethyl ether/hexane 1/1 as eluent to give 692 mg (95% yield)
of 12 as an oil. [a]2D4 ꢀ5.2 (c 2, CHCl3); IR (film) 2236,
Acknowledgements
This work was supported by the Spanish MCYTand FEDER
ꢀ
(Project CTQ2004-05358) and the Diputacion General de
ꢀ
Aragon.
References and notes
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1
1740 cmꢀ1; H NMR (CDCl3, 300 MHz) d 1.43 (s, 3H),
2.49 (d, 1H, J¼15.8 Hz), 2.60 (d, 1H, J¼15.8 Hz), 2.92 (d,
1H, J¼13.6 Hz), 3.03 (d, 1H, J¼13.6 Hz), 3.72 (s, 3H),
7.23–7.36 (m 5H); 13C NMR (CDCl3, 75 MHz) d 24.0,
35.1, 41.7, 44.3, 51.8, 122.7, 127.4, 128.3, 130.2, 134.5,
169.4. HRMS (FAB+) calcd for C13H16NO2 (MH+):
218.1181. Found: 218.1175.
4.6. (R)-4-Benzyl-4-methyl-2-pyrrolidinone 13
A solution of 12 (698 mg, 3.22 mmol) in 0.5% ammonia/
methanol (40 mL) was hydrogenated at 35 ꢁC and atmo-
spheric pressure using 50% slurry of RaneyÒ nickel 2800
in water (1.36 mL) as the catalyst. The reaction was moni-
tored by TLC and, on completion (20 h), the catalyst was
filtered off and washed with several portions of ethanol
and dichloromethane. The filtrate was evaporated to dryness
in vacuo and the residue was purified by filtration through
a short silica gel pad using ethyl acetate as eluent to give
547 mg (90% yield) of 13 as a white solid. Mp¼110 ꢁC;
[a]D26 ꢀ12.7 (c 2, CHCl3); IR (Nujol) 1681, 1660 cmꢀ1; 1H
NMR (CDCl3, 300 MHz) d 1.12 (s, 3H), 2.01 (d, 1H,
J¼16.6 Hz), 2.36 (d, 1H, J¼16.6 Hz), 2.73 (s, 2H), 2.98
(d, 1H, J¼9.6 Hz), 3.32 (d, 1H, J¼9.6 Hz), 6.31 (br s, 1H),
7.10–7.31 (m 5H); 13C NMR (CDCl3, 75 MHz) d 25.4,
40.1, 43.5, 45.9, 53.3, 126.6, 128.2, 130.1, 137.6, 177.7.
Elemental analysis calcd (%) for C12H15NO: C, 76.16; H,
7.99; N, 7.40. Found: C, 75.97; H, 8.15; N, 7.53.
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ꢀ
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4.7. (R)-g-Amino-b-benzyl-b-methylbutyric acid 14
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A mixture of compound 13 (473 mg, 2.5 mmol) and 5 N
aqueous HCl (10 mL) was heated under reflux for 20 h.
The solvent was removed under reduced pressure to give
a residue, which was dissolved in water. The resulting
aqueous solution was washed with dichloromethane and
evaporated in vacuo to give the crude g-amino acid

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D. Aguirre et al. / Tetrahedron 62 (2006) 8142–8146
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