Expedient synthesis of cis- and trans-3-aminocyclobutanecarboxylic acids

Article abstract of DOI:10.1080/00397911.2010.491595

An expedient approach to cis- and trans-3-aminocyclobutanecarboxylic acids was developed starting from 1,1-cyclobutanedicarboxylic acid. Stereochemistry of the title compounds was established by nuclear Overhauser effect spectroscopy experiments.

Full text of DOI:10.1080/00397911.2010.491595

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Expedient Synthesis of cis- and trans-3-
Aminocyclobutanecarboxylic Acids
Dmytro S. Radchenko a b , Anton Tkachenko a b , Oleksandr O.
Grygorenko a b & Igor V. Komarov a b
a Enamine Ltd., Kyiv, Ukraine
b Kyiv National Taras Shevchenko University, Kyiv, Ukraine
Version of record first published: 20 Apr 2011.
To cite this article: Dmytro S. Radchenko , Anton Tkachenko , Oleksandr O. Grygorenko & Igor V.
Komarov (2011): Expedient Synthesis of cis- and trans-3-Aminocyclobutanecarboxylic Acids, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:11, 1644-1649
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Synthetic Communications1, 41: 1644–1649, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.491595
EXPEDIENT SYNTHESIS OF CIS- AND TRANS-
3-AMINOCYCLOBUTANECARBOXYLIC ACIDS
Dmytro S. Radchenko, Anton Tkachenko,
Oleksandr O. Grygorenko, and Igor V. Komarov
Enamine Ltd., Kyiv, Ukraine and Kyiv National Taras Shevchenko
University, Kyiv, Ukraine
GRAPHICAL ABSTRACT
Abstract An expedient approach to cis- and trans-3-aminocyclobutanecarboxylic acids was
developed starting from 1,1-cyclobutanedicarboxylic acid. Stereochemistry of the title
compounds was established by nuclear Overhauser effect spectroscopy experiments.
Keywords Amino acids; conformational restriction; cyclobutanes; drug design; GABA
analogs
INTRODUCTION
Conformationally restricted amino acids have been shown to be efficient
scaffolds in modern drug design.[1] The restriction is often achieved by the use of
small rings; small-ring-derived amino acids have attracted much attention in recent
decades, partially because of their occurrence in nature. In particular, a number of
cyclobutane-derived analogs of natural amino acids, either isolated from living
organisms or synthesized in the laboratory, were described in the literature.[1,2]
In this work, we report our results on the synthesis of 3-aminocyclobutane-
carboxylic acid 1, which is the simplest achiral cyclic conformationally restricted
c-aminobutyric acid analog (Figure 1). c-Aminobutyric acid (GABA) 2 is the chief
inhibitory neurotransmitter in the mammalian central nervous system.[3] A number
of drugs are aimed at GABA receptors as their biological targets, and hence it is not
surprising that many c-aminobutyric acid analogs were reported in the literature.[4]
Despite the fact that both isomers of 1 showed only moderate or poor activity on
Received October 29, 2009.
Address correspondence to Oleksandr O. Grygorenko, Department of Chemistry, Kyiv National
Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01033, Ukraine. E-mail: gregor@univ.kiev.ua
1644

3-AMINOCYCLOBUTANECARBOXYLIC ACIDS
1645
Figure 1. c-Amino acids 1 and 2.
Figure 2. Key intermediates in the syntheses of 1 reported previously.
GABA receptors,[5–7] they are promising building blocks for drug discovery. For
example, recently both isomers of amino acid 1 were used in the design of cholesteryl
ester transfer protein (CETP) inhibitors,[8] sphingosine 1-phosphate receptor S1P1=
Edg1 agonists,[9] and phosphodiesterase PDE4 inhibitors.[10]
Several syntheses of amino acid 1 were reported in the literature. In particular,
compound 1 was prepared as a mixture of stereoisomers in nine steps starting from
epibromohydrine, azide 3 being the key intermediate (Figure 2). Pure cis-isomer 1a
was obtained by tedious crystallization of the mixture; isolation of the trans-isomer
1b required transformation of 1 to the corresponding methyl ester of its N-carbox-
ybenzyl derivative.[5] In another approach, a mixture of isomers 1a and 1b was pre-
pared from epichlorohydrine in nine steps via tosylate 4; ion-exchange
chromatography was used to separate the diastereomers of the title amino acid.[6]
Recently, a method for the synthesis of both cis- and trans-isomers of Boc-aminoe-
ster 5 was reported;[10] it commenced from the keto ester 6. Column chromatography
was used to separate diastereomers. The main disadvantage of the latter approach is
that the starting compound 6 is not easily available. Finally, multistep methods for
the stereoselective synthesis of cis-isomer 1a were described in the literature.[5,6]
RESULTS AND DISCUSSION
All the previous methods for the preparation of amino acid 1 relied on the
construction of 1,3-disubstituted cyclobutane core as one of the key steps in the
synthesis. In our approach to the synthesis of 1, the functional group at C-3 atom
of cyclobutane ring was introduced after the construction of cyclobutane ring
(Scheme 1). 1,1-Cyclobutanedicarboxylic acid (which is readily available from
commercial sources) was chlorinated to give 1,1,3-trisubstituted cyclobutane 7.[11]
Compound 7 was decarboxylated to afford 3-chlorocyclobutanecarboxylic acid 8
as a mixture of diastereomers. Esterification of 8 followed by reaction with sodium

1646
D. S. RADCHENKO ET AL.
Scheme 1. Synthesis of amino acids 1a and 1b.
Figure 3. NOESY correlations in the spectra of cis- and trans-3-aminocyclobutanecarboxylic acids 1a and
1b.
azide led to the azido esters 10a and 10b, which were easily separated by column
chromatography (Rf ¼ 0.39 and 0.50, respectively). Both compounds 10a and 10b
were transformed to the corresponding amino acids 1a and 1b by a hydrogenation–
hydrolysis sequence. The assignment of the stereochemistry of 2a and 2b was done
using nuclear Overhauser effect spectroscopy (NOESY) experiments (Fig. 3).
In conclusion, an expedient synthesis of both isomers of 3-aminocyclobutane-
carboxylic acid 1 was developed. The high efficiency (six steps, 16% total yield) of the
synthesis permits multigram preparation of the title amino acids.
EXPERIMENTAL
Solvents were purified according to the standard procedures. All starting
materials were purchased from Acros, Merck, and Fluka. Analytical thin-layer

3-AMINOCYCLOBUTANECARBOXYLIC ACIDS
1647
chromatography (TLC) was done using Polychrom SI F254 plates. Column chroma-
tography was performed using Kieselgel Merck 60 (230–400 mesh) as the stationary
1
phase. H, 13C NMR, and all two-dimentional NMR spectra were recorded on a
1
Bruker 170 Avance 500 spectrometer (at 499.9 MHz for H, 124.9 MHz for 13C).
Chemical shifts are reported in parts per million (ppm) downfield from tetramethyl-
1
silane (TMS; H, 13C) as an internal standard. Mass spectra were recorded on an
Agilent 1100 LCMSD SL instrument [chemical ionization (CI)] and Agilent 5890
series II 5972 gas chromatography–mass spectrometry (GCMS) instrument [electron
impact ionization (EI)]. Elemental analyses were performed on Elementar Vario
MICRO Cube CHNS=O analyzer.
3-Chlorocyclobutanecarboxylic Acid (8)
3-Chlorocyclobutane-1,1-dicarboxylic acid (22.6 g, 0.127 mol)[11] was dissolved
in pyridine (250 mL), and the solution was refluxed for 18 h. After cooling, most of
the solvent was removed in vacuo, and water (200 mL) was added to the residue, fol-
lowed by 6 N HCl, to adjust the pH to 2. The resulting mixture was extracted with
dichloromethane (DCM, 2 ꢀ 150 mL). The combined organic phases were washed
with brine, dried over sodium sulfate, and evaporated at reduced pressure to afford
a mixture of cis- and trans-3-chlorocyclobutanecarboxylic acids 8 (10.9 g, 0.081 mol,
64%), which was pure enough for the next step. For spectral and physical data, see
Ref.[12]
Methyl 3-Chlorocyclobutanecarboxylate (9)
3-Chlorocyclobutanecarboxylic acid 8 (10.9 g, 0.081 mol) was dissolved in
DCM (100 mL), and thionyl chloride (7.1, 0.097 mol) was added carefully. The
resulting mixture was refluxed for 1 h. The volatiles were removed in vacuum, and
methanol (100 mL) was added to the residue. The solution was refluxed for 1 h,
then cooled and evaporated. The residue was distilled under reduced pressure (bp
52–53 ꢁC=2 mmHg) to give an equimolar mixture of cis- and trans-methyl
3-chlorocyclobutanecarboxylates as colorless liquids (9.8 g, 0.066 mol, 81%). For
spectral and physical data, see Ref.[12]
cis- and trans-Methyl 3-azidocyclobutanecarboxylates (10a and 10b)
Methyl 3-chlorocyclobutanecarboxylate 9 (5.6 g, 0.038 mol) was dissolved in
dimethylformamide (60 mL), and sodium azide (5.9 g, 0.091 mol) was added. The
resulting mixture was stirred at 100 ꢁC for 75 h. After cooling, water (80 mL) was
added, and the resulting mixture was extracted with DCM (2 ꢀ 50 mL). The com-
bined organic phases were washed with brine, dried over sodium sulfate, and evapo-
rated in vacuum. The residue was subjected to flash column chromatography to
afford methyl trans-3-azidocyclobutanecarboxylate 10b (1.87 g, 0.012 mol, 32%,
eluted first) and cis-3-azidocyclobutanecarboxylate 10a (1.70 g, 0.011 mol, 29%,
eluted next) as pure colorless liquids. 10a: MS (m=z, EI): 124 (Mþ–OCH3), 113
(Mþ–N3), 99, 87, 68, 59, 41 (COOCH3þ). Anal. calcd. for C6H9N3O2: C 46.45, H
1
5.85, N 27.08, found C 46.71, H 6.08, N 26.99; H NMR (CDCl3), d: 3.75 (quint,

1648
D. S. RADCHENKO ET AL.
J ¼ 8.0 Hz, 1H, 3-CH), 3.66 (s, 3H, COOCH3), 2.78 (quint, J ¼ 8.8 Hz, 1H, 1-CH),
2.49–2.55 (m, 2H, 2- and 4-CHH), 2.30–2.36 (m, 2H, 2- and 4-CHH); 13C NMR
(CDCl3), d: 174.0 (COOCH3), 52.0, 50.8, 32.6, 30.6. 10b: MS (m=z, EI): 124 (Mþ–
OCH3), 113 (Mþ–N3), 99, 87, 68, 59, 41 (COOCH3þ). Anal. calcd. for C6H9N3O2:
1
C 46.45, H 5.85, N 27.08, found C 46.28, H 5.87, N 27.24; H NMR (CDCl3), d:
4.14 (quint, J ¼ 7.8 Hz, 1H, 3-CH), 3.68 (s, 3H, COOCH3); 3.07–3.13 (m, 1H,
1-CH), 2.53–2.58 (m, 2H, 2- and 4-CHH), 2.29–2.34 (m, 2H, 2- and 4-CHH); 13C
NMR (CDCl3), d: 175.4 (COOCH3), 51.9, 49.4, 32.7, 32.1.
cis-3-Aminocyclobutanecarboxylic acid (1a)
Azide 10a (0.30 g, 1.9 mmol) was dissolved in methanol (5 mL); then 6 N HCl
(2 mL) and 10% palladium on charcoal were added to the solution. The resulting
mixture was stirred under 1 bar of hydrogen for 3 h, then the catalyst was filtered
off, and the solvent was removed under reduced pressure. The residue was dissolved
in 6 N HCl (5 mL) and refluxed upon stirring for 1 h, then evaporated in vacuum.
The residue was purified by ion-exchange chromatography (Amberlite1 IR-
120(plus) ion-exchange resin, 3.5% aqueous ammonia as an eluent) to give cis-3-
aminocyclobutanecarboxylic acid 1a (0.16 g, 1.4 mmol, 71%) as white powder:
mp > 250 ꢁC (dec.); Anal. calcd. for C5H9NO2: C 52.16, H 7.88, N 12.17, found C
1
51.93, H 7.96, N 12.01; H NMR (D2O), d: 3.66 (quint, J ¼ 8.0 Hz, 1H, 3-CH),
2.80 (quint, J ¼ 9.0 Hz, 1H, 1-CH), 2.49–2.54 (m, 2H, 2- and 4-CHH), 2.12–2.18
(m, 2H, 2- and 4-CHH); 13C NMR (D2O), d: 182.7 (COO–), 41.2 (3-CH), 33.9, 31.1.
trans-3-Aminocyclobutanecarboxylic acid (1b)
Compound 1b was obtained from azide 10b analogously to the cis-isomer in
67% (0.17 g) yield as white solid: mp > 250 ꢁC (dec.). Anal. calcd. for C5H9NO2:
1
C, 52.16; H, 7.88; N, 12.17; found C, 52.42; H, 8.10; N, 11.92. H NMR (D2O), d:
3.84 (quint, J ¼ 8.0 Hz, 1H, 3-CH), 3.06 (tt, J ¼ 10.3 Hz and 5.1 Hz, 1H, 1-CH),
2.47–2.53 (m, 2H, 2- and 4-CHH), 2.30–2.36 (m, 2H, 2- and 4-CHH); 13C NMR
(D2O), d: 183.3 (COOꢂ), 44.0 (3-CH), 35.2, 30.2.
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