Practical syntheses of both enantiomers of the conformationally restricted GABA analogue cis-(2-aminocyclobutyl)acetic acid

Article abstract of DOI:10.1002/ejoc.201402676

Two efficient routes have been established for the preparation of both enantiomers of cis-(2-aminocyclobutyl)acetic acid, a conformationally restricted analogue of GABA. Both procedures converged on the racemic N-tert-butoxycarbonyl derivative of the target compound, which was resolved through chiral derivatization with an oxazolidinone auxiliary, which also allowed determination of the absolute configuration of the new compounds. The first route involved the homologation of cis-2-aminocyclobutanecarboxylic acid, whereas the second route employed an intramolecular photocyclization protocol, which provided an expedient, cisselective access to the lactam form of the target structure.

Full text of DOI:10.1002/ejoc.201402676

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DOI: 10.1002/ejoc.201402676
Practical Syntheses of Both Enantiomers of the Conformationally Restricted
GABA Analogue cis-(2-Aminocyclobutyl)acetic Acid
Hawraà Awada,[a,b] Sylvie Robin,[a,c] Régis Guillot,[a] Ogaritte Yazbeck,[b] Daoud Naoufal,[b]
Nada Jaber,[b] Ali Hachem,[b] and David J. Aitken*[a]
Keywords: Synthetic methods / Cyclization / Chiral resolution / Amino acids / GABA analogue
Two efficient routes have been established for the prepara- which also allowed determination of the absolute configura-
tion of both enantiomers of cis-(2-aminocyclobutyl)acetic
acid, a conformationally restricted analogue of GABA. Both
procedures converged on the racemic N-tert-butoxycarbonyl
derivative of the target compound, which was resolved
through chiral derivatization with an oxazolidinone auxiliary,
tion of the new compounds. The first route involved the
homologation of cis-2-aminocyclobutanecarboxylic acid,
whereas the second route employed an intramolecular
photocyclization protocol, which provided an expedient, cis-
selective access to the lactam form of the target structure.
Introduction
γ-Amino acids are of considerable interest to organic and
medicinal chemists alike, and a considerable number of
strategies have been developed for their stereoselective syn-
thesis.[1] The parent compound in the family, γ-aminobut-
yric acid (GABA), plays an important role in the mamma-
lian central nervous system and behaves as a major inhibi-
tory neurotransmitter (Figure 1).[2] GABA deficiency may
be related to significant neurological disorders and deriva-
tives and structural analogues of GABA are of considerable
potential for the treatment of neurodegenerative patholo-
gies, such as Parkinson’s and Alzheimer’s diseases.[3] GABA
derivatives that have been commercialized as therapeutics
include vigabatrin,[4] baclofen,[5] pregabalin,[6] and gabapen-
tin[7] (Figure 1). γ-Amino acids are becoming increasingly
popular as building blocks for peptidomimetics that display
well-defined conformational preferences.[8,9] Other synthetic
applications of γ-amino acid derivatives have been iden-
tified, e.g. in the preparation of nucleoside analogues[10] or
in organocatalysis,[11] and they are of general interest as
functional building blocks for drug discovery.
Figure 1. GABA and some commercialized derivatives that have
therapeutic applications.
GABA is a highly flexible molecule and to discover and
develop selective ligands for GABA receptors, conforma-
tionally restricted cyclic analogues of GABA have been of
particular interest[12] (Figure 2). In studies of the 2,3-meth-
ano-GABA core, (+)-cis-2-aminomethylcyclopropanecarb-
oxylic acid [(+)-CAMP] is a potent agonist of ρ1 and ρ2
GABAC receptors, whereas (–)-CAMP exerts weak antago-
nist activity.[13] Racemic (Ϯ)-trans-2-aminomethylcyclo-
propanecarboxylic acid (TAMP) is a substrate for GABA
and pyruvate transaminases,[14] and differentiates ρ3 from
other GABAC receptors in vitro.[15] Both enantiomers of
TAMP show partial agonist activity at both GABAC and
GABAA receptors.[13b] Recently, (1S,2R)-trans-3,4-meth-
ano-GABA showed inhibitory effects on the Type-3 GABA
transporter and on the Type-1 betaine-GABA trans-
porter.[16] Commensurate synthetic efforts have been made
to meet the demands for access to these compounds in non-
racemic form.[17–19]
[a] Université Paris Sud, CP3A Organic Synthesis Group,
ICMMO,
15 rue Georges Clemenceau, 91405 Orsay cedex, France
E-mail: david.aitken@u-psud.fr
http://www.icmo.u-psud.fr/Labos/LSOM/index.php
[b] Inorganic and Organometallic Coordination Chemistry
Laboratory, Faculty of Sciences (I) & PRASE-EDST, Lebanese
University,
Hadath, Lebanon
[c] Université Paris Descartes, UFR Sciences Pharmaceutiques et
Biologiques,
In contrast, much less is known about cyclobutane re-
stricted GABA analogues (Figure 2). Both cis and trans iso-
mers of 3-aminocyclobutanecarboxylic acid (2,4-methano-
GABA) were prepared and were found to exhibit moderate
4 avenue de l’Observatoire, 75270 Paris cedex 06, France
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FULL PAPER
velop a practical synthesis of cis-3,4CB-GABA that did not
rely on the use of this reagent and would be more amenable
to scale-up.[31] On this premise, we set out to establish a cis-
ACBC homologation sequence loosely inspired by
Kennewell’s approach for the synthesis of (2-aminocyclo-
alkyl)acetic acids[25] and also by the protocol later employed
by Krogsgaard-Larsen for the preparation of homo-β-
proline.[29]
Our starting material was racemic tert-butoxycarbonyl
(Boc)-cis-ACBC, 2, conveniently prepared on gram scale by
following a simple three-step procedure (65% yield) that
starts from uracil and ethylene.[32] Smooth transformation
into methyl ester derivative 3 was accomplished by using
MeOH and N,NЈ-dicyclohexylcarbodiimide (DCC)/4-di-
methylaminopyridine (DMAP), as described previously[33]
(Scheme 1). Selective reduction of 3 was achieved with
NaBH4 in EtOH at reflux temperatures without any detect-
able epimerization, which led to alcohol 4 in 97% yield.
Direct reduction of 2 to 4 by using BH3/tetrahydrofuran
(THF) could also be achieved, although the two-step pro-
cedure was actually easier and gave a better yield.
Figure 2. Previously studied small-ring restricted analogues of
GABA and the targets in this work.
affinity for GABA receptors.[20] The corresponding 2,2-di-
methyl derivative has been prepared in enantiomerically
pure form, although no biological data have been re-
ported.[21]
cis-2-(Aminomethyl)cyclobutane-1-carboxylic
(cis-2,3CB-GABA) has been prepared in enantiomerically
pure form,[17c,22] and the first preparation of trans-2,3CB-
GABA in non-racemic form was described very recently.[23]
An interesting bicyclic GABA analogue incorporating a
trans-2,3CB-GABA feature was prepared recently in racemic
form.[24] The third cyclobutane-restricted GABA manifold,
(2-aminocyclobutyl)acetic acid (3,4CB-GABA), is even less
well explored: only one lengthy synthesis of racemic cis- and
trans-3,4CB-GABAs has been described in the literature,
which starts from cis and trans cyclobutane-1,2-dicarboxy-
lic acids, respectively.[25,26] To expand the availability of con-
formationally restricted cyclobutane analogues of GABA,
we describe here a practical synthetic route to both enantio-
mers of cis-3,4CB-GABA, 1a and 1b (Figure 2).
Results and Discussion
Homologation of (؎) cis-ACBC
A plausible entry to the cis-3,4CB-GABA target structure
was the homologation of the corresponding β-amino acid,
cis-2-amino-cyclobutanecarboxylic
acid
(cis-ACBC).
Homologation has been a cornerstone strategy for the prep-
aration of enantiomerically enriched β3-amino acids from
their readily available α-amino acid counterparts.[27] The
technique has also been applied to the synthesis of certain
γ-amino acids from their appropriate β-amino acid precur-
sors, if the latter are available.[28,29]The best-known homolo-
gation methodology is the two-step Arndt–Eistert protocol.
Scheme 1. Synthesis of (Ϯ)-8 from Boc-cis-ACBC, (Ϯ)-2.
Several approaches were examined for the transforma-
However, this transformation employs the hazardous rea- tion of the alcohol group of 4 into a nucleofugal leaving
gent diazomethane, which is toxic, carcinogenic and explos- group, with the intention to introduce the homologating
ive. Furthermore, when the protocol has been applied for one-carbon unit as a cyanide ion (Scheme 1). After some
the homologation of β-amino acid derivatives,[28] yields of inconclusive attempts to convert 4 into the corresponding
γ-amino acids have been variable, and in some cases large iodo derivative (PPh3/I2/imidazole, CH2Cl2) or bromo de-
amounts of diazomethane have been required. Although rivative [PPh3/CBr4, dimethylformamide (DMF)], we fo-
laudable efforts are being made to reduce the risks associ- cused our attention on mesylate derivative 5. This com-
ated with the use of diazomethane,[30] we preferred to de- pound was prepared easily (MsCl, Et3N, Et2O) and isolated
2
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Syntheses of Both Enantiomers of cis-(2-Aminocyclobutyl)acetic Acid
as a stable material in 84% yield after chromatography.
Treatment of mesylate 5 with NaCN (5 equiv.) in hot di-
methyl sulfoxide (DMSO; 90 °C, 3 h) gave a crude product
mixture that contained several components, as indicated by
TLC analysis. Desired nitrile 6 was indeed present, but was
isolated in a disappointing 10% yield after chromatography.
One of the reaction by-products, isolated in up to 27%
yield, was bicyclic oxazinone 7.[26] The cyclization of N-Boc
O-sulfonyl derivatives of 1,3-amino alcohol fragments to
give oxazinones has been observed previously, and appears
to be induced by base and/or heating.[34] To suppress the
formation of 7 (and other by-products) during the nucleo-
philic substitution reaction, a lower reaction temperature
seemed warranted. In the event, nitrile 6 was obtained in a
gratifying 79% yield after exposure of mesylate 5 to NaCN
(10 equiv.) in DMSO at 35–40 °C for 3 days. N-Boc-cis-
3,4CB-GABA derivative 8 was obtained uneventfully by ba-
sic hydrolysis of nitrile 6 by using NaOH in EtOH at reflux
temperatures and was isolated in 73% yield after
chromatography (Scheme 1).
Scheme 2. Synthesis of (Ϯ)-8 from caprolactam 9.
rial obtained through this route was identical with samples
of 8 obtained through the first route (Scheme 1). With fewer
steps, less purification of intermediates, and a higher overall
yield (ca. 51% for six steps), the second route presents some
advantages over the first.
This homologation sequence provided N-protected deriv-
ative 8 of the target cis-3,4CB-GABA core in racemic form
in a reasonable about 44% overall yield from β-amino acid
starting material 2. Because the latter compound is also
available in single enantiomer form,[32a,32b,33] the sequence
should, in principle, be amenable to the preparation of each
enantiomer of 8. However, the total number of steps from
commercial precursors (including racemic preparation of 2)
is eight, with an overall yield of about 28%. Even though
this is more efficient than Kennewell’s synthesis[25] we felt
that the establishment of a more expedient access to deriva-
tive 8 would be a worthwhile achievement.
Chiral Resolution of N-Boc-Protected Derivative 8
As indicated above, the first route to 8 should accommo-
date enantiomerically pure starting material 2. However, a
convenient resolution procedure for (Ϯ)-8 is still warranted.
We considered several chiral resolving agents, and took into
account the yield of the derivatization step, the ease of sepa-
ration of diastereoisomers thus obtained, and the efficiency
of the chiral auxiliary cleavage and its recycling potential
(Scheme 3, Table 1).
Intramolecular Photocycloaddition of an Azepin-2-one
The axiom for the second approach to the preparation
of 8 arose from a perusal of earlier literature reports that
described rapid photochemical access to 2-azabicyclo-
Scheme 3. Chiral derivatization of (Ϯ)-8 for resolution studies.
Three chiral enantiopure alcohols were tested for the for-
[3.2.0]hept-6-en-3-one (10).[35] Irradiation of a solution of mation of diastereoisomeric esters from (Ϯ)-8 under stan-
1,3-dihydro-2H-azepin-2-one (9; prepared in two steps and dard coupling conditions (DCC, DMAP, CH2Cl2). Despite
60% yield from caprolactam,[36,37]) in Et2O for 3 h with a the relative lack of steric hindrance in the vicinity of the
400 W Hg vapor lamp and a quartz filter provided cycload- carboxylic acid function of (Ϯ)-8 the yields of esters were
dition adduct 10 cleanly in near quantitative yield rather disappointing. The ester obtained with (–)-N-methyl-
(Scheme 2).[35a,36,38] Without purification, this material was ephedrine (13) was isolated in 51% yield as diastereoiso-
promptly suspended in EtOAc and reduced overnight under meric mixture, inseparable by chromatography or crystalli-
H2 (1 atm) in the presence of 10% Pd/C. Bicyclic lactam 11 zation. The diastereoisomeric ester mixture obtained in
was obtained easily, again in near quantitative yield. With- 73% yield with (+)-menthol (14) could only be partly sepa-
out purification this compound was treated with Boc2O/ rated by chromatography or by crystallization from hot cy-
DMAP in acetonitrile to install the N-Boc protecting clohexane. The attempted esterification with (–)-N,N-dicy-
group; this operation was equally efficient and provided de- clohexyl-(1S)-isoborneol-10-sulfonamide (15) failed to pro-
rivative 12 after chromatography in a highly satisfactory gress even after 4 days.
95% overall yield for three steps.
We turned our attention to the use of an oxazolidinone,
Compound 12 underwent smooth lactam ring opening a chiral auxiliary that has proven useful in the resolution
upon treatment with LiOH in a THF/H2O mixture in mild of four-membered ring β-amino acids.[32a,39] The coupling
conditions, to provide racemic N-Boc-cis-3,4CB-GABA 8 in reaction of (Ϯ)-8 with (4S,5R)-4-methyl-5-phenyloxazol-
90% yield after chromatography (Scheme 2). Spectroscopic idin-2-one (16; prepared in accordance with the litera-
and physicochemical characterization confirmed that mate- ture[40]) gave a diastereoisomeric mixture in 85% yield and
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Table 1. Studies on the resolution of (Ϯ)-8.
Figure 3. Single-crystal X-ray diffraction structure of compound
17b.
[a] EtOAc/petroleum ether (50:50) as eluent: single spot, Rf 0.28.
[b] Solvent was cyclohexane. [c] EtOAc/petroleum ether (50:50) as
eluent: single spot, Rf 0.67. [d] Solvent was cyclohexane. [e] See Ex-
perimental Section for details.
Each derivative 17a and 17b was treated with LiOH/
H2O2 in THF/H2O to remove chiral auxiliary 16, which was
easily recovered during reaction work up and recycled
(Scheme 4). The resolved N-Boc-cis-3,4CB-GABA enantio-
mers 8a and 8b were therefore obtained in quantitative or
near quantitative yields. The enantiomeric excesses of these
materials were checked at this stage by GC analysis with a
chiral column, and it was found that 8a had an ee of 98.5%,
whereas 8b had an ee of 97.2%. Finally, the N-Boc group
cleavage from each derivative 8a and 8b was achieved by
using trifluoroacetic acid (TFA)/CH2Cl2 to provide single
enantiomers of cis-2-aminocyclobutylacetic acid, 1a and 1b,
in 83 and 96% yield, respectively (Scheme 4).
allowed straightforward chromatographic separation of dia-
stereoisomers 17a and 17b, obtained as single isomers in 40
and 45% yields, respectively (Scheme 4).
Conclusions
Two practical routes have been established for the synthe-
sis of both enantiomers of the conformationally restricted
γ-amino acid, cis-3,4CB-GABA, for the first time. The com-
plementary routes converge on a common N-Boc derivative
of the racemate, which is resolved through conversion into
diastereoisomeric derivatives with a chiral non-racemic ox-
azolidinone. The first route, although slightly longer, could
be applied to the starting material of the sequence in single
enantiomer form.
Experimental Section
General Procedures: THF and Et2O were distilled on sodium/
benzophenone under a nitrogen atmosphere. DMSO, DMF and
Et3N were distilled under reduced pressure from CaH2. NaCN was
finely ground and dried in vacuo at 120 °C for 20 h. Chiral com-
pounds 13, 14 and 15 were obtained from commercial sources and
had ee Ͼ 96%. Oxazolidinone 16 was prepared from commercial
(1R,2S)-norephedrine in accordance with the literature pro-
Scheme 4. Preparation of enantiomerically pure cis-3,4CB-GABA,
1a and 1b.
To determine the absolute configuration of these non-
racemic derivatives, a single crystal of diastereoisomer 17b
was analyzed by X-ray diffraction; the molecular structure
is shown in Figure 3. Because the configuration of the ox-
azolidinone fragment is known to be 4S,5R, the configura-
tion of the cyclobutane γ-amino acid moiety of this com-
pound could be identified unambiguously as R,R.
cedure[40] and had [α]2D4 = –161 (c = 1.00; CHCl3) {ref.[40] [α]2D3
=
–163.8 (c = 1.02; CHCl3). [α]2D0 = –170 (c = 1.20; CHCl3)}. Litera-
ture procedures were used to prepare compounds 2,[32] 3[33] and
9.[36,37] All other solvents and reagents were used as received from
commercial sources without further purification. Preparative
4
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Syntheses of Both Enantiomers of cis-(2-Aminocyclobutyl)acetic Acid
chromatography was performed on columns of silica either
CDCl3): δ = 18.8, 27.7, 28.4, 41.5, 47.7, 62.4, 79.7, 156.4 ppm. IR:
˜
C10H19NO3Na 224.1257; found 224.1260. C10H19NO3 (201.26):
calcd. C 59.68, H 9.52, N 6.96; found C 59.84, H 9.45, N 6.69.
manually (flash) or automatically piloted by an ISCO Combiflash
system (combiflash). In all cases, the stationary phase was SDS
silica gel 60A, 35–70 μm mesh, with the exception of the chromato-
graphic separation of compounds 17a and 17b, which was carried
out with Macherey–Nagel silica gel 60, 15–40 μm mesh. Analytical
TLC plates (silica gel 60 F254, Merck) were viewed by using UV
fluorescence at 254 nm then stained with basic aqueous KMnO4
solution or ninhydrin solution. Optical rotations were measured in
solution in a 10 cm quartz cell with a Jasco P-1010 polarimeter.
UV spectra were recorded for solutions in 1 cm quartz cells with
an Analytik-Jena Specord 205 instrument. IR spectra were re-
corded with a Bruker Vertex 70 FTIR spectrophotometer equipped
with an ATR accessory. NMR spectroscopic data were acquired
at 20 °C with Bruker AC250, AM300 or AM360 spectrometers.
Standard Bruker software was used for all experiments. Chemical
shifts are reported with respect to the residual proton signal in
deuterated chloroform (δ = 7.27 ppm) or deuterated water (δ =
ν = 1168, 1286, 1533, 1683, 2980, 3310 cm–1. HRMS: calcd. for
cis-(2-tert-Butoxycarbonylaminocyclobutyl)methyl Methanesulfon-
ate (؎)-5: At 0 °C under an argon atmosphere, Et3N (467 μL,
3.36 mmol) and MsCl (222 μL, 2.86 mmol) were added to a solu-
tion of alcohol 4 (439 mg, 2.18 mmol) in dry Et2O (40 mL). The
reaction was stirred for 5 h at room temperature. Additional por-
tions of Et3N (304 μL, 2.18 mmol) and MsCl (169 μL, 2.18 mmol)
were added and stirring was continued for 19 h. The solution was
filtered and the filtrate was concentrated under reduced pressure.
The crude product was purified by chromatography (combiflash)
with EtOAc/petroleum ether (30:70) as eluent, to give compound 5
as a white solid (511 mg, 1.83 mmol, 84%), m.p. 97 °C. Rf 0.69
1
(EtOAc/petroleum ether, 60:40). H NMR (250 MHz, CDCl3): δ =
1.42 (s, 9 H), 1.61–1.73 (m, 1 H), 1.88–2.05 (m, 2 H); 2.29–2.40 (m,
1 H), 2.82–2.89 (m, 1 H), 3.03 (s, 3 H), 4.32–4.43 (m, 3 H), 4.90
(d, J = 7.7 Hz, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 17.9,
1
4.70 ppm) for H, and with respect to CDCl3 (δ = 77.00 ppm) for
13C. Splitting patterns for 1H signals are designated as: s (singlet), d
(doublet), br. s (broad singlet) q (quartet) and m (multiplet). High-
resolution mass spectra were recorded on a Bruker MicroTOFq
instrument in electrospray ionization mode. Melting points were
recorded on a Reichert heating deck microscope. Elemental analy-
ses were carried out by the CNRS Microanalysis Service, Gif-sur-
Yvette, France. Enantiomeric excesses (ee) were determined by gas
28.0, 28.3, 37.3, 39.0, 46.0, 69.4, 79.5, 155.1 ppm. IR: ν = 1163,
˜
1178, 1339, 1512, 1683, 2991, 3372 cm–1. HRMS: calcd. for
C11H21NO5SNa 302.1046; found 302.1033.
cis-(2-tert-Butoxycarbonylaminocyclobutyl)acetonitrile (؎)-6: To a
stirred solution of 5 (500 mg, 1.79 mmol) in dry DMSO (10 mL)
at 0 °C, under an argon atmosphere, was added powdered NaCN
(877 mg, 17.89 mmol) in small portions. The reaction mixture was
stirred at 35–40 °C for 3 d. The solvent was evaporated under re-
duced pressure with the help of a water bath kept below 40 °C.
Brine (25 mL) was added to the residue and the aqueous layer was
extracted with CH2Cl2 (4ϫ 15 mL). Combined CH2Cl2 extracts
were washed with brine, dried with MgSO4, filtered, and concen-
trated under reduced pressure. The crude product was purified by
chromatography (combiflash) with EtOAc/petroleum ether as elu-
ent (20:80) to afford compound 6 as a white solid (297 mg,
1.42 mmol, 79%), m.p. 151 °C. Rf 0.82 (EtOAc/petroleum ether,
chromatography with
equipped with
a
Shimadzu GC-2010 Plus instrument
a
Supelco B-Dex225 chiral column
(30 mϫ0.25 mm; 0.25 μm) under the following conditions: helium
vector gas; isotherm 170 °C; injection split/splitless (split
1/50) and detection (FID) at 200 °C; constant linear speed 50 cm/
sec; pressure equivalence 215 kPa. Under these conditions, tR
17.5 min for 8a and tR = 16.4 min for 8b.
=
cis-(2-tert-Butoxycarbonylaminocyclobutyl)methanol (؎)-4. Method
A: Small portions of NaBH4 (1.64 g, 43.3 mmol, 10 equiv.) were
added at 0 °C, to a stirred solution of ester 3 (992 mg, 4.33 mmol)
in absolute EtOH (20 mL). The reaction mixture was slowly heated
to reflux for 1 h. After cooling to room temperature, lumps that
formed were broken up to give a slurry that was poured into brine
(20 mL). The mixture was filtered. The filtrate was concentrated
under reduced pressure and extracted with Et2O (6ϫ 15 mL). The
residual solid was extracted by stirring in Et2O (4ϫ 20 mL) for 2 h.
The combined ether extracts were dried with MgSO4, filtered, and
concentrated to give a white solid that was purified by chromatog-
raphy (combiflash) with EtOAc/petroleum ether as eluent (gradient
30:70 to 100:0). Compound 4 was obtained as a white solid
(840 mg, 4.18 mmol, 97%).
1
50:50). H NMR (250 MHz, CDCl3): δ = 1.44 (s, 9 H), 1.69–1.75
(m, 1 H), 1.99–2.16 (m, 2 H), 2.37–2.41 (m, 1 H), 2.44–2.63 (m, 2
H), 2.78–2.90 (m, 1 H), 4.27–4.33 (m, 1 H), 4.77 (br. s, 1 H) ppm.
13C NMR (62.5 MHz, CDCl3): δ = 17.6, 20.7, 26.5, 28.3, 36.5, 46.6,
79.7, 119.2, 155.1 ppm. IR: ν = 1161, 1275, 1525, 1680, 2248, 2984,
˜
3342 cm–1. HRMS: calcd. for C11H18N2O2Na 233.1260; found
233.1260. C11H18N2O2 (210.27): calcd. C 62.83, H 8.63, N 13.32;
found C 62.91, H 8.74, N 13.19.
Compound (؎)-7: To
a solution of compound 5 (117 mg,
0.42 mmol) in dry DMSO (700 μL) was added powdered NaCN
(105 mg, 2.15 mmol) in small portions. The reaction was heated at
90 °C and stirred for 3 h. After cooling, water (5 mL) was added
and the aqueous layer was extracted with CH2Cl2 (4ϫ 5 mL). The
combined organic layers were dried with MgSO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by chromatography (flash) with EtOAc/petroleum ether as eluent
(gradient 20:80 to 100:0) to afford compound 6 as a white solid
(10 mg, 0.04 mmol, 10%) and compound 7, not analytically pure,
as a yellow solid (15 mg, 0.12 mmol, 27%), m.p. 75 °C (ref.[26] m.p.
Method B: To a solution of 2 (250 mg, 1.16 mmol) in dry THF
(20 mL), cooled to 0 °C under an atmosphere of argon, was added
BH3·THF (5.7 mL, 5.7 mmol, 4.9 equiv.). The reaction mixture was
stirred at 0 °C for 7 h. Excess borane was quenched by dropwise
addition of water. The resulting solution was warmed to room tem-
perature, diluted with brine (20 mL) and extracted with EtOAc (2ϫ
40 mL). Combined organic layers were dried with MgSO4, filtered,
and concentrated in vacuo. The crude product was purified by
chromatography as described above. Compound 4 was obtained as
a white solid (100 mg, 0.50 mmol, 43%).
1
89.5–90.5 °C). Rf 0.20 (EtOAc). H NMR (250 MHz, CDCl3): δ =
1.93–2.19 (m, 3 H), 2.30–2.47 (m, 1 H), 2.79–2.98 (m, 1 H), 4.01
(m, 1 H), 4.25 (dd, J = 5.6, J = 11.2 Hz, 1 H), 4.34 (dd, J = 4.8, J =
11.2 Hz, 1 H), 5.85 (br. s, 1 H) ppm. 13C NMR (90 MHz, CDCl3): δ
M.p. 75 °C. Rf 0.51 (EtOAc/petroleum ether, 50:50). 1H NMR
(250 MHz, CDCl3): δ = 1.44 (s, 9 H), 1.57–1.70 (m, 1 H), 1.72–
1.97 (m, 2 H) 2.31–2.61 (m, 2 H), 2.64–2.78 (m, 1 H), 3.60 (dd, J
= 11.3, J = 4.1 Hz, 1 H), 3.76 (dd, J = 11.3, J = 8.5 Hz, 1 H), 4.20
= 19.0, 29.8, 31.3, 48.3, 68.4, 155.6 ppm. IR: ν = 1053, 1288, 1707,
˜
2920, 3226 cm–1. HRMS: calcd. for C6H9NO2Na 150.0525; found
150.0521.
cis-2-Azabicyclo[3.2.0]hept-6-en-3-one (؎)-10: A solution of azepi-
(q, J = 7.5 Hz, 1 H), 5.11 (br. s, 1 H) ppm. 13C NMR (62.5 MHz, none 9 (450 mg, 4.13 mmol) in dry Et2O (300 mL), in a water-co-
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D. J. Aitken at al.
FULL PAPER
oled photochemical quartz reactor fitted with a reflux condenser,
was degassed with an argon stream for 15 min. The stirred solution
chromatography (combiflash) with EtOAc/petroleum ether as elu-
ent (gradient 50:50 to 100:0). Compound 8 was obtained as a white
was irradiation with a 400 W medium-pressure mercury vapor solid (195 mg, 0.72 mmol, 90%), m.p. 118 °C. Rf 0.28 (EtOAc/pe-
1
lamp for 3 h and the solvent evaporated under reduced pressure.
Compound 10 was obtained as a yellow solid (450 mg), which was
used without purification in the next experiment. Rf 0.11 (Et2O).
1H NMR (250 MHz, CDCl3): δ = 2.27 (dd, J = 17.9, J = 3.4 Hz,
1 H), 2.46 (dd, J = 17.9, J = 10.2 Hz, 1 H), 3.53 (dt, J = 10.2, J =
3.4 Hz, 1 H), 4.43–4.44 (m, 1 H), 6.30–6.33 (m, 2 H), 7.05 (br. s, 1
troleum ether, 50:50). H NMR (360 MHz, CDCl3): δ = 1.43 (s, 9
H), 1.53–1.61 (m, 1 H), 1.87–1.94 (m, 1 H), 1.96–2.05 (m, 1 H),
2.32 (m, 1 H), 2.43 (dd, J = 15.8, J = 9.0 Hz, 1 H), 2.55 (dd, J =
15.8, J = 6.8 Hz, 1 H), 2.91 (m, 1 H), 4.04–4.30 (m, 1 H), 4.85 (br.
s, 0.7 H), 6.07 (br. s, 0.3 H), 11.00 (br. s, 1 H) ppm. 13C NMR
(90 MHz, CDCl3): δ = 21.3, 27.2, 28.3, 34.2, 36.8, 47.0, 79.4, 155.2,
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 33.7, 41.4, 57.9, 142.3, 177.8 ppm. IR: ν = 1155, 1168, 1275, 1684, 2986, 3361 cm–1.
˜
142.5, 178.7 ppm. IR: ν = 1250, 1302, 1645, 1676, 2961, 3266 cm–1. HRMS: calcd. for C11H19NO4Na 252.1206; found 252.1212.
˜
HRMS: calcd. for C6H8NO 110.600; found 110.0599.
C11H19NO4 (229.27): calcd. C 57.62, H 8.35, N 6.11; found C
57.74, H 8.46, N 6.31.
cis-2-Azabicyclo[3.2.0]heptan-3-one (؎)-11: To a suspension of
crude compound 10 (450 mg) in EtOAc (30 mL), was added Pd/C
catalyst (10%, 130 mg). The mixture was purged with a hydrogen
stream and stirred for 16 h under a hydrogen atmosphere. The reac-
tion mixture was then filtered through Celite and the filtrate evapo-
rated. Crude lactam 11 was obtained as a colorless liquid (439 mg),
Compounds 17a and 17b: To a solution of compound 8 (1.00 g,
4.37 mmol) in dry THF (40 mL) under an argon atmosphere, was
added Et3N (1.22 mL, 8.74 mmol). The mixture was cooled to
–78 °C, and pivaloyl chloride (565 μL, 4.59 mmol) was added
slowly. The mixture was warmed to 0 °C and stirred for 1 h, then
cooled again to –78 °C. In a separate flask, nBuLi (2.7 mL,
which was used without purification in the next experiment. Rf 0.11
1
(Et2O). H NMR (300 MHz, CDCl3): δ = 1.87 (m, 2 H), 2.17 (d, 4.37 mmol) was added to a solution of oxazolidinone 16 (774 mg,
J = 18.0 Hz, 1 H), 2.23–2.33 (m, 2 H), 2.47 (dd, J = 9.1, J =
4.37 mmol) in dry THF (20 mL) at –40 °C under an argon atmo-
sphere. This mixture was stirred for 5 min then transferred by can-
18.0 Hz, 1 H), 3.05–3.09 (m, 1 H), 4.04–4.07 (m, 1 H), 7.20 (br. s,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.5, 26.3, 33.1, 37.1, nula to the cold solution that contained compound 8. The com-
54.2, 179.3 ppm. IR: ν = 1287, 1310, 1677, 2939, 3237 cm–1.
bined mixture was stirred for 1 h at –78 °C then warmed to 0 °C.
A saturated solution of NaHCO3 (20 mL) was added. THF was
evaporated under reduced pressure and the residual aqueous layer
was extracted with CH2Cl2 (4ϫ 20 mL). Combined organic ex-
tracts were dried with MgSO4, filtered and concentrated under re-
duced pressure. The crude product was purified by flash
chromatography (combiflash) with Et2O/petroleum ether as eluent
(gradient 15:55 to 60:40) to afford compound 17a (679 mg,
1.75 mmol, 40% yield) and compound 17b (757 mg, 1.95 mmol,
45% yield) as white solids.
˜
HRMS: calcd. for C6H9NONa 112.0757; found 112.0761.
cis-2-tert-Butoxycarbonyl-3-oxo-2-azabicyclo[3.2.0]heptane (؎)-12:
To a solution of crude lactam 11 (439 mg) in acetonitrile (40 mL)
under argon atmosphere, was added DMAP (48 mg, 0.39 mmol).
The mixture was cooled to 0 °C then Boc2O (1.73 g, 7.93 mmol)
was added. The mixture was stirred at 0 °C for 5 min and then at
room temperature for 16 h. The solvent was evaporated and the
crude product was purified by chromatography (combiflash) with
Et2O/petroleum ether as eluent (gradient 5:95 to 100:0) to afford
compound 12 as a white solid (834 mg, 3.95 mmol, 95% overall
tert-Butyl N-[(1S,2S)-2-{2-[(4S,5R)-4-Methyl-2-oxo-5-phenyl-1,3-
yield for 3 steps), m.p. 51 °C. Rf 0.75 (EtOAc). 1H NMR oxazolidin-3-yl]-2-oxoethyl}cyclobutyl]carbamate
(17a):
M.p.
(360 MHz, CDCl3): δ = 1.50 (s, 9 H), 1.80–1.92 (m, 1 H), 1.96– 121 °C. Rf 0.44 (Et2O/petroleum ether, 50:50). [α]2D5 = –69 (c = 1.02;
1
2.06 (m, 1 H), 2.23–2.35 (m, 1 H), 2.39–2.53 (m, 2 H), 2.42 (dd, J
= 13.2, J = 5.4 Hz, 1 H), 2.91–3.00 (m, 1 H), 4.40–4.43 (m, 1
CHCl3). H NMR (250 MHz, CDCl3): δ = 0.90 (d, J = 6.5 Hz, 3
H), 1.45 (s, 9 H), 1.51–1.59 (m, 1 H), 1.84–2.10 (m, 2 H), 2.29–2.34
H) ppm. 13C NMR (90 MHz, CDCl3): δ = 25.1, 27.8, 28.0, 28.4, (m, 1 H), 2.96–3.14 (m, 2 H), 3.18–3.26 (m, 1 H), 4.21–4.31 (m, 1
39.5, 58.0, 82.5, 149.7, 175.1 ppm. IR: ν = 1140, 1164, 1295, 1760, H), 4.76 (q, J = 6.6 Hz, 1 H), 4.83 (br. s, 1 H), 5.68 (d, J = 7.6 Hz,
˜
2982 cm–1. HRMS: calcd. for C11H17NO3Na 234.1101; found 1 H), 7.29–7.43 (m, 5 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
234.1096. C11H17NO3 (211.26): calcd. C 62.54, H 8.11, N 6.63; 14.6, 21.4, 27.4, 28.4, 35.1, 36.4, 47.2, 54.8, 79.0, 79.3, 125.6, 128.7,
found C 62.51, H 8.23, N 6.65.
129.1, 133.4, 153.3, 155.2, 171.9 ppm. IR: ν = 1352, 1511, 1688,
˜
1711, 1771, 2982, 3377 cm–1. HRMS: calcd. for C21H28N2O5Na
411.1890; found 411.1881.
cis-(2-tert-Butoxycarbonylaminocyclobutyl)acetic
Acid
(؎)-8.
Method A: To a stirred solution of nitrile 6 (277 mg, 1.32 mmol) in
EtOH (7 mL) was added NaOH (6 m, 7 mL). The reaction mixture
was heated to reflux for 3.5 h before the solvent was evaporated
under reduced pressure. The residual mixture was cooled in an ice
bath and acidified with HCl (2 m, 30 mL) and extracted with
tert-Butyl N-[(1R,2R)-2-{2-[(4S,5R)-4-Methyl-2-oxo-5-phenyl-1,3-
oxazolidin-3-yl]-2-oxoethyl}cyclobutyl]carbamate
(17b):
M.p.
100 °C. Rf 0.35 (Et2O/petroleum ether, 50:50). [α]2D5 = +22 (c = 1.02;
1
CHCl3). H NMR (250 MHz, CDCl3): δ = 0.88 (d, J = 6.0 Hz, 3
EtOAc (4ϫ 20 mL). The combined organic extracts were dried H), 1.41 (s, 9 H), 1.47–1.54 (m, 1 H), 1.85–2.08 (m, 2 H), 2.27–2.38
with MgSO4, filtered, concentrated and purified by chromatog-
raphy (combiflash) with EtOAc/petroleum ether as eluent (gradient
30:70 to 100:0). Compound 8 was obtained as a white solid
(220 mg, 0.96 mmol, 73%).
(m, 1 H), 2.91 (dd, J = 16.4, J = 8.2 Hz, 1 H), 3.00–3.12 (m, 1 H),
3.30 (dd, J = 16.1, J = 6.6 Hz, 1 H), 4.31–4.36 (m, 1 H), 4.75 (q,
J = 7.6 Hz, 1 H), 4.93 (d, J = 7.3 Hz, 1 H), 5.67 (d, J = 7.0 Hz, 1
H), 7.28–7.44 (m, 5 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
14.4, 21.2, 27.6, 28.3, 35.2, 36.5, 46.8, 54.8, 79.0, 79.2, 125.6, 128.6,
Method B: A solution of compound 12 (200 mg, 0.95 mmol) in
THF (15 mL) and water (15 mL) was treated with LiOH (228 mg,
9.52 mmol) then stirred at room temperature for 16 h. THF was
evaporated under reduced pressure and the residual aqueous phase
133.2, 153.2, 155.1, 171.8 ppm. IR: ν = 1350, 1525, 1688, 1707,
˜
1777, 2979, 3361 cm–1. HRMS: calcd. for C21H28N2O5Na
411.1890; found 411.1871.
was acidified with HCl (0.5 m, to pH 1). The mixture was saturated cis-[(1S,2S)-2-tert-Butoxycarbonylaminocyclobutyl]acetic Acid (8a):
with solid NaCl and extracted with EtOAc (5ϫ 30 mL). The com-
bined organic extracts were dried with MgSO4, filtered and concen-
trated under reduced pressure. The crude product was purified by
To a solution of 17a (266 mg, 0.69 mmol) in THF/H2O (17 mL,
1:1) were added H2O2 (35 wt.-% solution in water; 400 μL,
4.12 mmol) and LiOH (82 mg, 3.42 mmol). The mixture was stirred
6
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Syntheses of Both Enantiomers of cis-(2-Aminocyclobutyl)acetic Acid
at room temperature for 16 h. A solution of Na2SO3 (1 m, 5 mL)
and a saturated solution of NaHCO3 (5 mL) were added success-
ively. THF was removed under reduced pressure and the residual
aqueous layer was extracted with CH2Cl2 (4ϫ 4 mL). The organic
extracts were dried with MgSO4, filtered and concentrated to afford
oxazolidinone 16 (120 mg, 0.68 mmol) for recycling. The aqueous
phase was cooled to 0 °C, acidified with concentrated HCl (to
pH 1) and extracted with CH2Cl2 (4ϫ 4 mL). The organic extracts
were dried with MgSO4, filtered and concentrated to afford com-
pound 8a as white solid (151 mg, 0.66 mmol, 96%), m.p. 127 °C.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of all significant com-
pounds, copies of chiral GC chromatograms for compounds (؎)-
8, 8a and 8b.
Acknowledgments
One of the authors (H. A.) is grateful for postgraduate research
funding from the Azm & Saade Association and from Campus
France through an Eiffel grant. The authors thank Ms Florence
Charnay-Pouget and Ms Emilie Kolodziej for their help in the
analysis of chiral compounds. COST Action CM 0803 is acknowl-
edged for travel grants to support constructive networking in rela-
tion to this work.
1
[α]2D7 = –69 (c = 0.99; CHCl3). ee = 98.5%. H NMR, 13C NMR,
and IR spectroscopic data were identical to those observed for (؎)-
8.
cis-[(1R,2R)-2-tert-Butoxycarbonylaminocyclobutyl]acetic Acid (8b):
Compound 17b (253 mg, 0.65 mmol) was treated in the same man-
ner as above, for a reaction time of 72 h. In addition to oxazolidi-
none 16 (113 mg, 0.64 mmol) for recycling, compound 8b was ob-
tained as a white solid (149 mg, 0.65 mmol, 100%), m.p. 127 °C.
[α]2D7 = +68 (c = 0.96; CHCl3). ee 97.2%. 1H NMR, 13C NMR, and
IR spectroscopic data were identical to those observed for (؎)-8.
[1] a) M. Ordóñez, C. Cativiela, Tetrahedron: Asymmetry 2007, 18,
3–99; b) J. R. Hanrahan, G. A. R. Johnston, in: Amino Acids,
Peptides and Proteins in Organic Chemistry (Ed.: A. E.
Hughes), Wiley-VCH, Weinheim, Germany, 2009, vol. 1, p.
573–689.
[2] a) K. E. McCarson, S. J. Enna, Neurochem. Res. 2014, DOI:
10.1007/s11064–014–1254-x; b) GABA in the Nervous System
(Eds.: D. L. Martin, R. W. Olsen), Lippincott, Williams & Wil-
kins, Philadelphia, 2000; c) The GABA Receptors, 3rd ed. (Eds.:
S. J. Enna, H. Möhler), Humana Press, Totowa, 2007.
[3] a) K. Gajcy, S. Lochynski, T. Librowski, Curr. Med. Chem.
2010, 17, 2338–2347; b) B. Froelund, U. Madsen, in: Textbook
of Drug Design and Discovery, 4th ed. (Eds.: P. Krogsgaard-
Larsen, K. Stromgaard, U. Madsen), CRC Press, Boca Raton,
2010, p. 239–262.
cis-[(1S,2S)-2-Aminocyclobutyl]acetic Acid (1a): A solution of 8a
(100 mg, 0.44 mmol) in CH2Cl2 (12 mL) was cooled to 0 °C and
TFA (670 μL, 8.74 mmol) was added. The solution was stirred for
2 h at room temperature. The mixture was evaporated under re-
duced pressure and the residue was taken up in water (3 mL) and
this solution applied to a column of cation-exchange resin (Dowex
50Wx8, H+, 50–100 mesh). Elution with aqueous NH3 (3 m) pro-
vided free amino acid 1a as a white solid (47 mg, 0.36 mmol, 83%),
m.p. 195 °C. [α]2D5 = +8 (c = 0.98; H2O). 1H NMR (250 MHz, D2O):
δ = 1.59–1.70 (m, 1 H), 1.95–2.10 (m, 2 H), 2.20–2.29 (m, 1 H),
2.31 (dd, J = 8.1, J = 14.8 Hz, 1 H), 2.40 (dd, J = 8.1, J = 14.8 Hz,
1 H), 2.75–2.89 (m, 1 H), 3.83 (q, J = 7.7 Hz, 1 H) ppm. 13C NMR
(90 MHz, D2O): δ = 21.6, 23.8, 34.4, 37.2, 47.5, 180.8 ppm. IR:
[4] J. A. Tolman, M. A. Faulkner, Expert Opin. Pharmacother.
2009, 10, 3077–3089.
[5] a) A. J. Muzyk, S. K. Rivelli, J. P. Gagliardi, CNS Drugs 2012,
26, 69–78; b) U. Misgeld, M. Bijak, W. Jarolimek, Prog. Neuro-
biol. 1995, 46, 423–462.
ν = 1425, 1530, 1563, 1677, 2943, 3419 cm–1. HRMS: calcd. for
˜
C6H11NO2Na 130.0863; found 130.0863.
[6] K. A. Lyseng-Williamson, M. A. A. Siddiqui, Drugs 2008, 68,
2205–2223.
cis-[(1R,2R)-2-Aminocyclobutyl]acetic Acid (1b): Compound 8b
(150 mg, 0.65 mmol) was treated in the same manner as above. Free
amino acid 1b was obtained as a white solid (81 mg, 0.62 mmol,
96%), m.p. 195 °C. [α]2D7 = –8 (c = 0.98; H2O). HRMS: calcd. for
[7] G. J. Sills, Curr. Opin. Pharmacol. 2006, 6, 108–113.
[8] For reviews, see: a) P. G. Vasudev, S. Chatterjee, N. Shamala,
P. Balaram, Chem. Rev. 2011, 111, 657–687; b) F. Bouillère, S.
Thétiot-Laurent, C. Kouklovsky, V. Alezra, Amino Acids 2011,
41, 687–707.
1
C6H11NO2Na 130.0863; found 130.0864. H NMR and 13C NMR
spectroscopic data were identical to those observed for 1a.
[9] For representative recent examples, see: a) R. Sonti, B. Dinesh,
K. Basuroy, S. Raghothama, N. Shamala, P. Balaram, Org.
Lett. 2014, 16, 1656–1659; b) J. Y. Lee, C. H. Chae, Y. K. Kang,
New J. Chem. 2014, 38, 966–973; c) S. V. Jadhav, R. Misra,
S. K. Singh, H. N. Gopi, Chem. Eur. J. 2013, 19, 16256–16262;
d) A. Mizuno, S. Miura, M. Watanabe, Y. Ito, S. Yamada, T.
Odagami, Y. Kogami, M. Arisawa, S. Shuto, Org. Lett. 2013,
15, 1686–1689; e) N. Rodriguez-Vázquez, S. Salzinger, L. F.
Silva, M. Amorin, J. R. Granja, Eur. J. Org. Chem. 2013, 3477–
3493; f) J. Aguilera, J. A. Cobos, R. Gutiérrez-Abad, C. Aco-
sta, P. Nolis, O. Ila, R. M. Ortuño, Eur. J. Org. Chem. 2013,
3494–3503; g) M. W. Giuliano, S. J. Maynard, A. M. Almeida,
A. G. Reidenbach, L. Guo, E. C. Ulrich, I. A. Guzei, S. H.
Gellman, J. Org. Chem. 2013, 78, 12351–12361.
X-ray Diffraction Study of Compound 17b: Diffraction data were
collected with a Kappa X8 APPEX II Bruker diffractometer with
graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). The
crystal was mounted on a CryoLoop (Hampton Research) with
Paratone-N (Hampton Research) as cryoprotectant and then flash-
frozen in a nitrogen gas stream at 100 K. The temperature of the
crystal was maintained at the selected value (100 K) by means of a
700 series Cryostream cooling device to within an accuracy of
Ϯ1 K. Data were corrected for Lorentz polarization, and absorp-
tion effects. The structure was solved by direct methods by using
SHELXS-97[41] and refined against F2 by full-matrix least-squares
techniques by using SHELXL-97[42] with anisotropic displacement
parameters for all non-hydrogen atoms. Hydrogen atoms were lo-
cated on a difference Fourier map and introduced into the calcula-
tions as a riding model with isotropic thermal parameters. All cal-
culations were performed by using the Crystal Structure crystallo-
graphic software package WINGX.[43]
[10] L. Kiss, E. Forró, R. Sillanpää, F. Fülöp, Synthesis 2010, 153–
160.
[11] L. Karadeniz, S. T. Astley, Res. Chem. Intermed. 2013, 39,
3407–3415.
[12] I. A. Levandovskiy, D. I. Sharapa, T. V. Shamota, V. N. Ro-
dionov, T. E. Shubina, Future Med. Chem. 2011, 3, 223–241.
[13] a) D. L. Crittenden, A. Park, J. Qiu, R. B. Silverman, R. K.
Duke, G. A. R. Johnston, M. J. T. Jordan, M. Chebib, Bioorg.
Med. Chem. 2006, 14, 447–455; b) R. K. Duke, M. Chebib,
V. J. Balcar, R. D. Allan, K. N. Mewett, G. A. R. Johnston, J.
Neurochem. 2000, 75, 2602–2610.
CCDC-1000621 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.
Eur. J. Org. Chem. 0000, 0–0
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D. J. Aitken at al.
FULL PAPER
[14]
[15]
[16]
[28] For illustrative examples, see: a) G. V. M. Sharma, V. B. Jadhav,
K. V. S. Ramakrishna, P. Jayaprakash, K. Narsimulu, V. Sub-
ash, A. C. Kunwar, J. Am. Chem. Soc. 2006, 128, 14657–14668;
b) M. V. DЈAuria, V. Sepe, R. DЈOrsi, F. Bellotta, C. Debitus,
A. Zampella, Tetrahedron 2007, 63, 131–140; c) N. B. Konde-
kar, R. S. V. Kandula, P. Kumar, Tetrahedron Lett. 2004, 45,
5477–5479; d) S. Y. Ko, J. Org. Chem. 2002, 67, 2689–2691; e)
T. Hintermann, K. Gademann, B. Jaun, D. Seebach, Helv.
Chim. Acta 1998, 81, 983–1002; f) D. Misiti, G. Zappia, Synth.
Commun. 1995, 25, 2285–2294; g) C. C. Tseng, S. Terashima,
S.-i. Yamada, Chem. Pharm. Bull. 1977, 25, 29–40; h) P. Buchs-
chacher, J.-M. Cassal, A. Fürst, W. Meier, Helv. Chim. Acta
1977, 60, 2747–2755.
[29] L. Nielsen, L. Brehm, P. Krogsgaard-Larsen, J. Med. Chem.
1990, 33, 71–77.
[30] a) V. D. Pinho, B. Gutmann, L. S. M. Miranda, R. O. M. A.
de Souza, C. O. Kappe, J. Org. Chem. 2014, 79, 1555–1562; b)
V. Pace, G. Verniest, J.-V. Sinisterra, A. R. Alcántara, N.
De Kimpe, J. Org. Chem. 2010, 75, 5760–5763.
[31] An additional problem is the commercial availability of the
standard precursor for diazomethane, Diazald, which is itself
considered a hazardous material and is subject to transpor-
tation restrictions.
[32] a) V. Declerk, D. J. Aitken, Amino Acids 2011, 41, 587–595; b)
C. Fernandes, E. Pereira, S. Faure, D. J. Aitken, J. Org. Chem.
2009, 74, 3217–3220; c) D. J. Aitken, C. Gauzy, E. Pereira, Tet-
rahedron Lett. 2002, 43, 6177–6179.
D. K. Dikshit, S. B. Litsas, A. Krantz, G. Byrnett, C. Walsh,
Chimica Chronika 1980, 9, 229–238.
J. Vien, R. K. Duke, K. N. Mewett, G. A. R. Johnston, R.
Shingai, M. Chebib, Br. J. Pharmacol. 2002, 135, 883–890.
K. Nakada, M. Yoshikawa, S. Ide, A. Suemasa, S. Kawamura,
T. Kobayashi, E. Masuda, Y. Ito, W. Hayakawa, T. Katayama,
S. Yamada, M. Arisawa, M. Minami, S. Shuto, Bioorg. Med.
Chem. 2013, 21, 4938–4950.
For non-racemic CAMP, see: a) M. Oikawa, Y. Sugeno, Y. Ishi-
kawa, H. Tukada, Synlett 2013, 24, 886–888; b) V. Rodríguez-
Soria, L. Quintero, F. Sartillo-Piscil, Tetrahedron 2008, 64,
2750–2754; c) I. R. Baxendale, M. Ernst, W.-R. Krahnert, S. V.
Ley, Synlett 2002, 1641–1644; d) R. K. Duke, R. D. Allan, M.
Chebib, J. R. Greenwood, G. A. R. Johnston, Tetrahedron:
Asymmetry 1998, 9, 2533–2548; e) R. Galeazzi, G. Mobbili, M.
Orena, Tetrahedron: Asymmetry 1997, 8, 133–137; f) T. Mori-
kawa, H. Sasaki, R. Hanai, A. Shibuya, T. Taguchi, J. Org.
Chem. 1994, 59, 97–103.
[17]
[18]
For non-racemic TAMP, see: a) D. J. Aitken, S. Bull, I. Davies,
L. Drouin, J. Ollivier, J. Peed, Synlett 2010, 2729–2782; b)
M. K. N. Qureshi, M. D. Smith, Chem. Commun. 2006, 5006–
5008; c) D. K. Mohaparta, Synth. Commun. 1999, 29, 4261–
4268; see also ref.[17d,17f]
.
[19]
[20]
For non-racemic trans-3,4-methano-GABA, see: D. J. Aitken,
L. Drouin, S. Goretta, R. Guillot, J. Ollivier, M. Spiga, Org.
Biomol. Chem. 2011, 9, 7517–7524; see also ref.[16]
.
a) D. S. Radchenko, A. Tkachenko, O. O. Grygorenko, I. V. [33] a) C. Fernandes, C. Gauzy, Y. Yang, O. Roy, E. Pereira, S.
Komarov, Synth. Commun. 2011, 41, 1644–1649; b) J. Safanda,
P. Sobotka, Collect. Czech. Chem. Commun. 1982, 47, 2440–
2447; c) R. D. Allan, D. R. Curtis, P. M. Headley, G. A. R.
Johnston, S. M. E. Kennedy, D. Lodge, B. Twitchin, Neuro-
chem. Res. 1980, 5, 393–400.
Faure, D. J. Aitken, Synthesis 2007, 2222–2232; b) C. Gauzy,
E. Pereira, S. Faure, D. J. Aitken, Tetrahedron Lett. 2004, 45,
7095–7097.
[34] a) Y. M. Lee, D. J. Baek, S. Lee, D. Kim, S. Kim, J. Org. Chem.
2011, 76, 408–416; b) P. D. Croucher, R. H. Furneaux, G. P.
Lynch, Tetrahedron 1994, 50, 13299–13313; c) T. P. Curran,
M. P. Pollastri, S. M. Abelleira, R. J. Messier, A. A. McCollum,
C. G. Rowe, Tetrahedron Lett. 1994, 35, 5409–5412.
[35] a) E. Vogel, E. Erb, G. Lenz, A. A. Bothner-By, Justus Liebigs
Ann. Chem. 1965, 682, 1–20; b) L. A. Paquette, J. Am. Chem.
Soc. 1964, 86, 500–503; c) O. L. Chapman, E. D. Hoganson, J.
Am. Chem. Soc. 1964, 86, 498–500.
[21] a) C. Balo, O. Caamaño, F. Fernández, C. López, Tetrahedron:
Asymmetry 2005, 16, 2593–2597; b) P. D. Rouge, A. G. Mog-
lioni, G. Y. Moltrasio, R. M. Ortuño, Tetrahedron: Asymmetry
2003, 14, 193–195; c) M. J. Figueira, J. M. Blanco, O. Caa-
maño, F. Fernández, X. Garcia-Mera, C. López, Synthesis
2000, 10, 1459–1463; d) K. Burgess, L. Shiming, J. Rebenspies,
Tetrahedron Lett. 1997, 38, 1681–1684.
[22] a) V. André, A. Vidal, J. Ollivier, S. Robin, D. J. Aitken, Tetra-
hedron Lett. 2011, 52, 1253–1257; b) R. Galeazzi, G. Mobbili,
M. Orena, Tetrahedron 1999, 55, 261–270.
[23] V. André, M. Gras, H. Awada, R. Guillot, S. Robin, D. J.
Aitken, Tetrahedron 2013, 69, 3571–3576.
[24] S. Petz, K. T. Wanner, Eur. J. Org. Chem. 2013, 4017–4025.
[36] J. B. Grimm, J. P. Stables, M. L. Brown, Bioorg. Med. Chem.
2003, 11, 4133–4141.
[37] L. Franzisket, A. Heesing, Chem. Ber. 1991, 124, 635–643.
[38] R. A. Odum, B. Schmall, J. Chem. Res. Synop. 1997, 278–289;
R. A. Odum, B. Schmall, J. Chem. Res. Miniprint 1997, 1850–
1869.
[25] P. D. Kennewell, S. S. Matharu, J. B. Taylor, R. Westwood, [39] V. Declerck, D. J. Aitken, J. Org. Chem. 2011, 76, 708–711.
P. G. Sammes, J. Chem. Soc. Perkin Trans. 1 1982, 2553–2562.
[26] For closely related work, see: C. C. Shroff, W. S. Stewart, S. J.
Uhm, J. W. Wheeler, J. Org. Chem. 1971, 36, 3356–3361.
[40] G. Bégis, D. E. Cladingboel, L. Jerome, W. B. Motherwell,
T. D. Sheppard, Eur. J. Org. Chem. 2009, 10, 1532–1548.
[41] G. M. Sheldrick, SHELXS-97, Program for Crystal Structure
Solution, University of Göttingen, Germany, 1997.
[27] a) Y. Bandala, E. Juaristi, in: Amino Acids, Peptides and Pro-
teins in Organic Chemistry (Ed.: A. E. Hughes), Wiley-VCH, [42] G. M. Sheldrick, SHELXL-97, Program for the Refinement of
Weinheim, Germany, 2009, vol. 1, p. 291–347; b) B. E. Sleebs,
Crystal Structures from Diffraction Data, University of
Göttingen, Germany, 1997.
T. T. Van Nguyen, A. B. Hughes, Org. Prep. Proced. Org. Prep.
Proc. Int. 2009, 41, 429–478; c) Enantioselective Synthesis of β- [43] L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837–838.
Amino Acids, 2nd ed. (Eds.: E. Juaristi, V. A. Soloshonok),
Wiley-VCH, Weinheim, Germany, 2005.
Received: June 2, 2014
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42676
/KAP1
Date: 24-09-14 16:45:19
Pages: 9
Syntheses of Both Enantiomers of cis-(2-Aminocyclobutyl)acetic Acid
Amino Acid Synthesis
H. Awada, S. Robin, R. Guillot,
O. Yazbeck, D. Naoufal, N. Jaber,
A. Hachem, D. J. Aitken* ................. 1–9
Practical Syntheses of Both Enantiomers
of the Conformationally Restricted GABA
Two complementary construction ap-
proaches Ϫ homologation of a β-amino
acid and atom-efficient photocyclization of
an azepin-2-one Ϫ followed by chiral reso-
lution provide access to both enantiomers
of this cyclobutane-restricted GABA ana-
logue.
Analogue
Acid
cis-(2-Aminocyclobutyl)acetic
Keywords: Synthetic methods
/ Cycli-
zation / Chiral resolution / Amino acids /
GABA analogue
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9