Stereochemistry of terpene derivatives. Part 7: Novel rigidified amino acids from (+)-3-carene designed as chiral GABA analogues

Article abstract of DOI:10.1016/j.tetasy.2010.06.026

Several novel cyclopropyl-rigidified γ- and δ-amino acids 3-4 have been prepared starting from monoterpene (+)-3-carene 2. These compounds are proposed as chiral analogues of γ-aminobutyric acid (GABA) 1 and are expected to be of interest as potential inh

Full text of DOI:10.1016/j.tetasy.2010.06.026

Tetrahedron: Asymmetry 21 (2010) 2015–2020
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereochemistry of terpene derivatives. Part 7: Novel rigidified amino acids
from (+)-3-carene designed as chiral GABA analogues q
a
a
b
c
_
Kamila Gajcy , Jolanta Pe˛kala , Bozena Fra˛ckowiak-Wojtasek , Tadeusz Librowski ,
a,d,
*
´
Stanisław Lochynski
a
_
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspian´skiego 27, 50-370 Wrocław, Poland
b Faculty of Chemistry, Opole University, Oleska 48, 45-052 Opole, Poland
c Department of Pharmacodynamics, Collegium Medicum, Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland
d
´
Department of Cosmetology, Wrocław College of Physiotherapy, Kosciuszki 4, 50-038 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Several novel cyclopropyl-rigidified
terpene (+)-3-carene 2. These compounds are proposed as chiral analogues of
c
- and d-amino acids 3–4 have been prepared starting from mono-
-aminobutyric acid
(GABA) 1 and are expected to be of interest as potential inhibitors of GABA receptors.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 May 2010
Accepted 22 June 2010
Available online 24 July 2010
c
1. Introduction
tered orally or intravenously. To resolve this problem, GABA ana-
logues are being designed, as are compounds which have the
potential to cross the blood–brain barrier and have an effect on
the brain. Numerous compounds having a similar backbone to
the GABA structure show an anticonvulsant activity. The most pop-
ular GABA analogues are antiepileptic drugs, such as vigabatrin,
tiagabine, gabapentin, pregabalin, and felbamate. Recently there
has been an increasing interest in the synthesis and pharmacolog-
ical effects of new GABA derivatives, which can be considered as
potent drugs in the treatment of neurodegenerative disorders.
The present aim of our work was the synthesis of new rigid cyc-
Conformationally constrained amino acids containing small
rings have been the focus of both synthetic and medicinal chemis-
try particularly as they apply to the design of novel peptides.2 The
use of modified amino acids in peptide strands allows greater con-
trol over the chemical and conformational properties of oligopep-
tides and offers the promise of an increased metabolic stability
and an improved oral bioavailability.3 The peptide scaffold can be
used for probing the structural requirements of receptor-bound li-
gand conformations.2 They can also create unusual foldamers and
novel helical folds such as nanotubes,4 peptide segments with no-
vel structural and internal cavity properties.5
lic
c- and d-amino acids (+)-3, (ꢀ)-3, 4, considered as GABA ana-
logues. These amino acids are rigidified by a cyclopropyl moiety
with a gem-dimethyl group. (+)-3-Carene 2, a major component
of turpentine obtained from Pinus sylvestris (L.), is the source of a
chiral cyclopropyl group for the desired compounds (+)-3, (ꢀ)-3,
and 4, (Fig. 1). The ozonolysis of the unsaturated bond in this
monoterpene led to a ketocarboxylic acid 5, which was a key com-
pound for further transformations. Various organic reactions, such
as Schmidt and Curtius rearrangements, enabled the synthesis of
desired products in three to six steps with the chirality preserved
from (+)-3-carene 2.
Rigidified cyclic amino acids play an important role in drug de-
sign and development where they exert conformational con-
straints. They might also be considered as structural analogues of
neurotransmitters such as
c-aminobutyric acid (GABA) 1, which
is the main inhibitory neurotransmitter in the mammalian brain.6
It is well documented that GABA deficiency is associated with sev-
eral important neurological disorders such as Huntington’s chorea,
Parkinson’s, and Alzheimer’s disease in addition to psychiatric dis-
orders, such as anxiety, depression, pain, panic, and mania.7 When
the concentration of GABA diminishes below a threshold level in
the brain, convulsions occur; accordingly, raising the brain GABA
level terminates the seizures. Although it is known that increasing
the brain concentration of GABA prevents convulsions, the high
polarity and flexible structure of this compound are probably
responsible for its inefficiency as an anticonvulsant when adminis-
2. Results and discussion
(+)-[(1S,3R)-3-(Aminomethyl)-2,2-dimethylcyclopropyl]-acetic
acid (+)-3 was synthesized in a four-step procedure (Scheme 1).
The ozonolysis of (+)-3-carene 2 followed by the Brown–Garg oxi-
dation8 gave ketocarboxylic acid 5, which was the subject of a Cur-
tius rearrangement. Various modifications of the Curtius
rearrangement were checked to determine the most appropriate
conditions for obtaining the protected ketoamine 69 (Table 1). First,
q
Part 6. See Ref. 1.
* Corresponding author. Tel.: +48 71 320 24 00; fax: +48 71 328 40 64.
E-mail address: stanislaw.lochynski@pwr.wroc.pl (S. Lochyn´ ski).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.026

2016
K. Gajcy et al. / Tetrahedron: Asymmetry 21 (2010) 2015–2020
NH2
COOH
2
1
CO2
NH2
NH2
COOH
NH2
COOH
4
(-)-3
(+)-3
Figure 1. Novel GABA analogues obtained from (+)-3-carene 2.
COOH
NHCbz
COOH
NH2
a
b
c
d
O
O
COOH
NHCbz
7
6
5
(+)-3
2
Scheme 1. Reagents: (a) (1) O3; (2) Na2Cr2O7, H2SO4; (b) DPPA, TEA, PhCH3, PhCH2OH; (c) NaBrO, H2O; (d) H2, Pd/C, MeOH.
Table 1
The modification of the Curtius rearrangement reaction
Run
substrate [equiv]
PhCH3
DPPA [equiv]
TEA [equiv]
PhCH2OH [equiv]
Ag2CO3 [equiv]
Temp [°C]
Time [h]
Yield [%]
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
ꢀ
+
+
+
+
+
+
+
+
1.2
1.2
2.0
1.4
1.4
1.4
2.0
2.0
2.0
1.1
1.1
2.0
3.0
3.0
6.0
2.0
2.0
2.0
1.2
1.2
1.0
1.7
1.7
1.7
1.0
1.0
1.0
—
—
—
—
—
—
2.0
0.1
1.0
85
85
85
100
80
80
90
85
90
25
25
17
17
18
17
5
42
61
61
64
49
17
90
65
76
23
6
Substrate—ketocarboxylic acid 5, PhCH3—toluene, solvent of reaction, DPPA—diphenylphosphoryl azide, TEA—triethylamine, PhCH2OH—benzyl alcohol, Ag2CO3.
the reaction with DPPA in the presence of triethylamine and benzyl
alcohol was used. The yield of this reaction was sufficient when the
acyl azide was isolated, and the rearrangement was performed in a
separate step. However, the acyl azides are well known as unstable
and hazardous compounds, thus we attempted a one-pot method
that allowed the direct conversion of carboxylic acid 5 into amine
6. For a one-pot procedure it turned out that the addition of tolu-
ene as a solvent significantly improved the yield from 42% to 61%
(runs 1 and 2). An excess of DPPA (2.0 equiv) and TEA (2.0 equiv)
did not have any influence on the yield but the time was shortened
(run 3). When the Curtius reaction was conducted at a higher tem-
perature (100 °C) and in the presence of an excess of DPPA
(1.4 equiv), TEA (3.0 equiv), and PhCH2OH (1.7 equiv), product 6
was synthesized in a slightly better yield (run 4). For the reaction
with the same ingredients as in run 4 but carried out at a lower
temperature (80 °C), the conversion of substrate 5 was attempted
in the same time but the product 6 was isolated in only 49% yield
(run 5). In the presence of an excess of DPPA (1.4 equiv), TEA
(6.0 equiv), and PhCH2OH (1.7 equiv) the reaction was completed
in the same time but several by-products occurred and the product
was isolated in a very low yield (17%) (run 6). Next, we attempted
to investigate silver carbonate as an additional promoter to acti-
vate the isocyanate in the Curtius reaction.10 In fact, in the case
of Ag2CO3, the reactivity was greatly improved. The best result
was obtained in run 7, by using an excess of DPPA (2.0 equiv),
TEA (2.0 equiv), and Ag2CO3 (2.0 equiv). The time of the completed
reaction decreased by about threefold than in the experiment
without adding Ag2CO3 and product 6 was isolated in 90% yield
(run 3).
The N-Cbz-protected ketoamine 6 was then, in the haloform
reaction, converted into N-Cbz-protected amino acid 711 by treat-
ment with hypobromite. The hydrogenation of 7 (H2, Pd/C) gave
the first designed GABA analogues, amino acid (+)-312 (Scheme 1).
The (ꢀ)-enantiomer of
r-amino acid 3 was obtained in a three-
step procedure (Scheme 2). The key compound 5 was subjected to
the esterification using a 3% solution of hydrogen chloride in meth-
anol. In the Schmidt reaction with hydrazoic acid, prepared from
sodium azide and methanesulfonic acid in dimethoxyethane, car-
ried out at ꢀ30 °C to room temperature, methyl ester 8 was con-
verted into amido ester 9.13 The hydrolysis of the obtained
amino derivative 9 gave amino acid (ꢀ)-3.14 The values of specific
rotations for (+)-3 and (ꢀ)-3 were ½a D20
¼ þ34:1 (c 2.0, MeOH) and
ꢁ
½
a 2D4
ꢁ
¼ ꢀ34:1 (c 2.0, MeOH), respectively.
The last designed amino acid 4 was prepared starting from the
previously obtained methyl ester 8, in six steps. At first, the Bae-
yer–Villiger (B–V) reaction was investigated. The reaction was con-
ducted via two methods: with and without a solvent. Under
standard B–V reaction conditions, with chloroform as the solvent,
the reaction took a couple of days. In the second method, we
decided to use solvent-free conditions, which significantly short-
ened the reaction time; thus the reaction was nearly complete after
1 h. In this method, the B–V reaction was carried out with methyl
ester 8 using m-chloroperbenzoic acid without a solvent and after
1 h CH2Cl2 was added for easier stirring of the mixture, which al-
lowed the completion of the reaction leading to acetoxy ester
10.15 Next, the acetoxy ester was hydrolyzed in the presence of
K2CO3 and methanol gave hydroxy ester 11, which after oxidation
with the Brown–Garg reagent, giving carboxy ester 12.16 Using

K. Gajcy et al. / Tetrahedron: Asymmetry 21 (2010) 2015–2020
2017
O
NH
NH2
O
a
O
c
b
COOH
CO2Me
CO2Me
COOH
9
5
8
(-)-3
Scheme 2. Reagents: (a) 3% HCl in CH3OH; (b) NaN3, MeSO3H, DME; (c) NaOH, H2O, EtOH.
DPPA (2.0 equiv) in the presence of triethylamine (2.0 equiv) and
benzyl alcohol (1.0 equiv), with the additive of Ag2CO3 (2.0 equiv)
the N-Cbz-protected amino ester 1317 was obtained, which was
then hydrolyzed in the presence of KOH to the N-Cbz-protected
amino acid 14.18 Finally, deprotection of compound 14 by means
of H2 (Pd/C) led to the third designed GABA analogue 419 (Scheme 3).
and acetone (various ratios) as an eluent. IR spectra were taken
from liquid films or in KBr on Perkin Elmer 621 spectrometer. 1H
and 13C NMR spectra were recorded in CDCl3 with TMS as an inter-
nal standard on a Bruker Avance™ DRX 300 instrument. Chemical
shifts (d) are reported in ppm and coupling constants (J) are given
in Hertz. 13C–1H substitution was determined with HMQC correla-
tion and DEPT-135 experiments. The names of compounds are
compatible with IUPAC nomenclature. Numbering of carbon atoms
3. Conclusion
in all compounds was changed to simplify interpretation of 1H , 13
C
NMR spectra. Optical rotation measurements were obtained on a
PolAAr-31 automatic polarimeter (Optical Activity Ltd). Ozone
was generated by the IMPOZ-4 ozonator.
The preliminary results of pharmacological in vivo tests of ami-
do ester 9 showed that it had an influence on the central nervous
system. The compound investigated increased the spontaneous
locomotor activity in mice. It favorably prolonged the latency time.
Furthermore, the amido ester protected animals from death and
showed anticonvulsant activity. It was also indicated to be non-
toxic, which is a very important point for the design of potential
drugs. Further pharmacological tests of all the obtained amino
derivatives are currently in progress.
4.1. (ꢀ)-[(1R,3S)-2,2-Dimethyl-3-(2-oxopropyl)cyclopropyl]-
acetic acid 5
Ozone was bubbled through a cooled (0 °C) solution of (+)-3-
carene
2 (68.12 g, 0.50 mol) in a concentrated acetic acid
(200 ml) for 5 h. The cooled reaction mixture was then allowed
to warm up to room temperature and treated with water (50 ml).
The Brown–Garg reagent8 (312 ml) was added dropwise to a mag-
netically stirred solution of ozonolysis product kept at 25–30 °C
temperature. The solution was stirred at room temperature until
no starting material was detected by TLC (3.5 h). Water (500 ml)
was added to the mixture and the aqueous phase was extracted
with diethyl ether. The combined extracts were dried over MgSO4
and evaporated to give a crude product. Saturated aqueous NaH-
CO3 was added to a solution of crude ketocarboxylic acid 5 in
diethyl ether and biphasic mixture was stirred at room tempera-
ture until the evolution of CO2 ceased. The layers were separated
and the aqueous phase was acidified with 5% H2SO4 and extracted
with diethyl ether. The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The resulting
product (48.81 g, 53% yield) was purified by column chromatogra-
4. Experimental
(+)-3-Carene was purchased from Acros Organics (½a D20
¼ þ15:2
ꢁ
(neat); (n2D0 ¼ 1:4697, d = 0.864 g/cm3, bp = 171–172 °C, ee = 100%).
All materials were obtained from commercial suppliers: Sigma, Al-
drich, and POCh and were used without purification. The course of
all the reactions and the composition of products were checked by
thin-layer chromatography (TLC). TLC was carried out on precoated
TLC plates with silica gel 60 F254 0.2 mm (Merck) with visualization
by irradiation with a short-wavelength UV light. Plates were devel-
oped in a mixture of hexane and acetone and methanol applied in
various ratios and visualized with 20% ethanolic H2SO4, containing
0.1% of anisaldehyde or solution of ninhydrin (for amino acids).
Preparative column chromatography was carried out on silica gel
(230–400 mesh, Merck) with a mixture of hexane, ethyl acetate,
O
O
OH
a
c
b
CO2H
O
CO2Me
CO2Me
CO2Me
CO2Me
12
10
11
8
d
NH2
NHCbz
NHCbz
f
e
CO2H
CO2H
CO2Me
4
14
13
Scheme 3. Reagents: (a) mCPBA, then CH2Cl2; (b) K2CO3, MeOH; (c) Na2Cr2O7, H2SO4; (d) DPPA, Et3N, PhCH3, PhCH2OH; (e) NaOH, H2O, EtOH; (f) H2, Pd/C, MeOH.

2018
K. Gajcy et al. / Tetrahedron: Asymmetry 21 (2010) 2015–2020
phy eluting with hexane–acetone to give ketocarboxylic acid 5 as a
4.4. (+)-[(1S,3R)-3-(Aminomethyl)-2,2-dimethylcyclopropyl]-
acetic acid (+)-3
yellow oil. ½a 2D0
ꢁ
¼ ꢀ14:6 (c 5.0, CHCl3); n2D0 ¼ 1:4578; IR (film,
cmꢀ1): 2951 (s), 2735 (w), 1713 (vs), 1452 (m), 1376 (m), 1229
(m), 1168 (s); 1H NMR (CDCl3, 300 MHz): 0.94 and 1.14 (2s, 6H
at C-9 and C-10); 0.96–1.02 (m, 2H at C-3 and C-5); 2.19 (s, 3H
at C-8); 2.30 (dd, J = 8.6, 7.30 Hz, 2H at C-6); 2.38–2.43 (m, 2H at
C-2); 13C NMR (CDCl3, 75 MHz): 14.82 (C-9), 17.15 (C-4), 21.00
(C-5), 21.41 (C-3), 28.29 (C-10), 29.50 (C-8), 29.95 (C-6), 39.19
(C-2), 179.15 (C-7), 208.98 (C-1).
A mixture of 7 (0.10 g, 0.34 mmol) and 5% Pd/C (35.00 mg) in
MeOH (10 ml) was vigorously stirred under an H2 atmosphere for
3 h. The Pd-catalyst was filtered off, and the filtrate was evaporated
to gain (+)-3 ½a 2D0
¼ þ34:1 (c 2.0, MeOH); mp = 154–160 °C; IR
ꢁ
(KBr, cmꢀ1): 3424 (s), 2943 (m), 1563 (vs), 1396 (s), 741 (w); 1H
NMR (D2O, 300 MHz): 0.71–0.80 (m, 2H at C-3 and C-5); 0.82
and 0.91 (2s, 6H at C-7 and C-8); 1.96 (dd, J = 15.6, 10.0 Hz, 1H at
C-2); 2.22 (dd, J = 15.4, 5.3 Hz, 1H at C-2); 2.83 (dd, J = 13.4,
9.5 Hz, 1H at C-6); 3.02 (dd, J = 13.4, 6.2 Hz, 1H at C-6); 13C NMR
(D2O, 75 MHz): 14.00 and 27.70 (C-7 and C-8), 18.00 (C-4), 22.33
(C-3), 24.59 (C-5), 32.70 (C-2), 37.87 (C-6), 182.09 (C-1). Anal.
Calcd for C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 60.93;
H, 9.88; N, 9.06.
4.2. (ꢀ)-Benzyl {[(1R,3S)-2,2-dimethyl-3-(2-oxopropyl)cyclo-
propyl]methyl}carbamate 6
A solution of ketocarboxylic acid 5 (0.42 g, 2.23 mmol), DPPA
(0.97 ml, 4.48 mmol), and triethylamine (0.62 ml, 4.47 mmol) in
dry toluene (10 ml) was stirred at room temperature for 30 min,
and then warmed to 85 °C. After 30 min stirring the reaction mix-
ture was cooled to the room temperature. Next, benzoic alcohol
(0.24 ml, 2.27 mmol) and Ag2CO3 (1.24 g, 4.50 mmol) were added
and the reaction was carried out at 85 °C for 5 h. The reaction pro-
gress was monitored by TLC (3:1 hexane/acetone). The Ag2CO3 was
filtered and the toluene was removed at a reduced pressure to af-
ford carbamate 6. The residue was chromatographed on silica gel
4.5. (ꢀ)-Methyl [(1R,3S)-2,2-dimethyl-3-(2-oxopropyl)cyclo-
propyl]acetate 8
The ketocarboxylic acid 5 (10.00 g, 54.29 mmol) was taken up in
3% methanolic HCl (40.00 g) and after being left at room tempera-
ture and magnetic stirring for 4 h worked up to the required keto
ester 9, which was detected by TLC (5:1 hexane/acetone). The mix-
ture was then washed with saturated aqueous NaHCO3. The aque-
ous layer was extracted with diethyl ether and the combined
organic layers were dried over MgSO4. After solvent evaporation
under reduced pressure, the crude product (86% yield) was purified
by vacuum fractional distillation, which gave 8.50 g of appropriate
(30:1
hexane/acetone).
½
a 2D4
ꢁ
¼ ꢀ25:25
(c
2.0,
CHCl3);
n2D4 ¼ 1:5114; IR (film, cmꢀ1): 3341 (m), 2948 (ms), 2889 (m),
1717 (vs), 1528 (s), 1376 (m), 1167 (m), 698 (ms), 616 (w); 1H
NMR (CDCl3, 300 MHz): 0.72–0.85 (m, 2H at C-2 and C-4); 0.88
and 1.00 (2s, 6H at C-8 and C-9); 2.08 (s, 3H at C-7); 2.26 (dd,
J = 17.8, 7.7 Hz, 1H at C-1); 2.49 (dd, J = 17.6, 5.3 Hz, 1H at C-5);
2.88–2.97 (m, 1H at C-1); 3.23–3.28 (m, 1H at C-5); 4.9 (s, 1H at
N); 5.01 (s, 2H at C-11); 7.21–7.30 (m, 5H at C-13, C-14, C-15, C-
16, C-17); 13C NMR (CDCl3, 75 MHz): 14.96 (C-4), 17.39 (C-3),
21.47 (C-9), 25.65 (C-2), 28.55 (C-8), 29.85 (C-7), 37.72 (C-5),
38.86 (C-1), 66.47 (C-11), 127.98 (C-15), 128.25 (C-13, C-17),
128.43 (C-14, C-16), 136.66 (C-12), 156.26 (C-10), 209.12 (C-6).
Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C,
70.42; H, 8.23; N, 4.96.
keto ester 8 as a pale amber oil. ½a D24
¼ ꢀ23:0 (c 5.0 CHCl3);
ꢁ
n2D5 ¼ 1:4519; IR (film, cmꢀ1): 3621 (w), 2952 (s), 2868 (m), 1740
(vs), 1717 (vs), 1376 (m), 1167 (s); 1H NMR (CDCl3, 300 MHz):
0.79 and 1.00 (2s, 6H at C-9 and C-10); 0.82–0.91 (m, 2H at C-3
and C-5); 2.05 (s, 3H at C-8); 2.12 (dd, J = 11.5, 6.9 Hz, 2H at C-
2); 2.23–2.27 (m, 2H at C-6); 3.56 (s, 3H at C-11) ; 13C NMR (CDCl3,
75 MHz): 14.83 (C-9), 17.11 (C-4), 21.05 (C-5), 21.68 (C-3), 28.34
(C-10), 29.49 (C-8), 29.88 (C-6), 39.21 (C-2), 51.58 (C-11), 173.61
(C-7), 208.31 (C-1).
4.3. (+)-[(1S,3R)-3-({[(Benzyloxy)carbonyl]amino}methyl)-2,2-
dimethylcyclopropyl]acetic acid 7
4.6. (+)-Methyl {(1R,3S)-3-[(acetamino)methyl)-2,2-dimethyl-
cyclpropyl}acetate 9
To an ice-cooled solution of sodium hypobromite [prepared
from bromine (0.85 cm3, 16.50 mmol) and sodium hydroxide
(2.20 g, 55.00 mmol) in water (22.00 ml)], carbamate 6 was added
dropwise and the reaction mixture was stirred at room tempera-
ture for about 4 h. Then, the mixture was washed with diethyl
ether, treated with sodium sulfite and, finally, 10% H2SO4 was
added to reach pH 2–3. The acid solution was extracted with
diethyl ether and the combined organic extracts were dried over
magnesium sulfate. The solvent was removed to obtain protected
amino acid 7 (0.95 g, 84%) which was purified by column chroma-
Methanesulfonic acid (26 ml) was added dropwise to a stirred
mixture of keto ester 8 (5.00 g, 25.21 mmol) and dimethoxyethane
(17.20 ml) cooled to ꢀ30 °C. The sodium azide (4.92 g,
75.36 mmol) was then added portionwise under gentle stirring
keeping the temperature at ꢀ30 °C (2 h). The solution was allowed
to slowly reach room temperature until the evolution of nitrogen
ceased (4 h). More dimethoxyethane (52 ml) and 25% ammonium
hydroxide were added till pH 9 was reached. The resulting solution
was extracted with diethyl ether. The organic layer was dried over
MgSO4 and the solvent was evaporated giving amido ester 9
(3.67 g, 68%) as a yellow oil. The residue was purified by chroma-
tography on silica gel eluting with hexane/acetone mixture
tography (10:1 hexane/acetone). ½a D24
¼ þ15:9 (c 0.5, CHCl3);
ꢁ
n2D5 ¼ 1:4695; IR (film, cmꢀ1): 3334 (m), 3091 (s), 3034 (s), 2952
(s), 1714 (vs), 1531 (m), 1456 (s), 1349 (s), 1250 (vs), 1131 (s),
1047 (s), 754 (ms), 738 (ms), 698 (s), 600 (w); 1H NMR (CDCl3,
300 MHz): 0.70–0.86 (m, 2H at C-3 and C-5); 0.92 and 1.01; (2s,
6H at C-7 and C-8); 2.20 (dd, J = 16.6, 8.3 Hz, 1H at C-2); 2.39
(dd, J = 16.7, 6.2 Hz, 1H at C-6); 2.98 (dd, J = 16.3, 8.9 Hz, 1H at C-
2); 3.30 (dd, J = 16.8, 6.4 Hz, 1H at C-6), 5.03 (s, 1H at N); 5.07 (s,
2H at C-10); 7.23–7.27 (m, 5H at C-12, C-13, C-14, C-15, C-16);
13C NMR (CDCl3, 75 MHz): 14.85 (C-7 or C-8), 17.74 (C-4), 22.20
(C-3), 25.72 (C-5), 28.56 (C-7 or C-8), 29.64 (C-2), 37.79 (C-10),
66.71 (C-6), 128.09 and 128.54 (C-12, C-13, C-14, C-15, C-16),
136.62 (C-11), 156.45 (C-9), 179.08 (C-1). Anal. Calcd for
(4.5:1). ½a 2D4
ꢁ
¼ þ20:2 (c 1.0 CHCl3); n2D5 ¼ 1:4629; IR (film, cmꢀ1):
3293 (ms), 3083 (w), 2952 (ms), 1740 (vs), 1652 (vs), 1437 (s),
1375 (ms), 1173 (s), 712 (w); 1H NMR (CDCl3, 300 MHz): 0.81–
0.93 (m, 2H at C-3 and C-5); 0.98 and 1.08 (2s, 6H at C-9 and C-
10); 1.98 (s, 3H at C-11); 2.16 (dd, J = 16.5, 9.3 Hz, 1H at C-6);
2.55 (dd, J = 16.6, 9.2 Hz, 1H at C-6); 2.84 (ddd, J = 13.7, 9.6,
4.0 Hz, 1H at C-2); 3.70 (ddd, J = 13.7, 6.2, 4.2 Hz, 1H at C-2);
3.71 (s, 3H at C-8); 6.31 (s, 1H at N); 13C NMR (CDCl3, 75 MHz):
14.90 (C-10), 17.57 (C-4), 22.42 (C-3), 23.18 (C-9), 25.41 (C-5),
28.50 (C-11), 29.45 (C-2), 35.91 (C-6), 51.86 (C-8), 170.07 (C-1),
174.84 (C-7). Anal. Calcd for C11H19NO3: C, 61.95; H, 8.98; N,
6.57. Found: C, 61.76; H, 9.09; N, 6.74.
C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C, 65.63; H, 7.48;
N, 4.96.

K. Gajcy et al. / Tetrahedron: Asymmetry 21 (2010) 2015–2020
2019
4.7. (ꢀ)-[(1R,3S)-3-(Aminomethyl)-2,2-dimethylcyclopropyl]-
acetic acid (ꢀ)-3
(s), 2950 (s), 1720 (vs), 1438 (s), 1333 (ms), 1229 (s), 1201 (s),
1172 (s); 1H NMR (CDCl3, 300 MHz): 0.95–1.14 (m, 2H at C-3 and
C-5); 0.92 and 1.03 (2s, 6H at C-7 and C-8); 2.16 (dd, J = 16.2,
10.2 Hz, 1H at C-2); 2.51 (dd, J = 16.1, 5.0 Hz, 1H at C-2); 3.43
(dd, J = 12.0, 9.6 Hz, 1H at C-6); 3.65 (s, 3H at C-9); 3.73 (dd,
J = 12.0, 5.4 Hz, 1H at C-6); 13C NMR (CDCl3, 75 MHz): 15.23 (C-7
or C-8), 20.55 (C-4), 22.19 (C-3), 22.99 (C-7 or C-8), 23.90 (C-5),
31.14 (C-2), 51.22 (C-9), 66.45 (C-6), 170.33 (C-1). Anal. Calcd for
C9H16O3: C, 62.77; H, 9.36. Found: C, 62.50; H, 9.51.
A mixture of amido ester 9 (3.00 g, 14.07 mmol) and NaOH
(1.2 g, 30.00 mmol) in H2O (7.05 ml) and ethanol (17.60 ml) was
heated to reflux for 4.5 h until no starting material was detected
by TLC (1:1 hexane/acetone). The presence of amino acid (ꢀ)-3 in
the reaction mixture was detected by ninhydrin eluting with meth-
anol. The mixture was then evaporated to dryness under reduced
pressure. The residue was taken up in water (5 ml) and after neu-
tralizing with HCl was triturated with ethanol to afford (ꢀ)-3
4.10. (+)-(1S,3R)-3-(2-Methoxy-2-oxoethyl)-2,2-dimethylcyclo-
propanecarboxylic acid 12
(0.75 g, 34%) as a white solid. ½a D24
ꢁ
¼ ꢀ34:1 (c 2.00, MeOH);
mp = 154–160 °C; IR (KBr, cmꢀ1): 3424 (s), 2947 (m), 1643 (s),
1610 (s), 1253 (s), 741 (w); 1H NMR (D2O, 300 MHz): 0.62–0.75
(m, 2H at C-3 and C-5); 0.80 and 0.89 (2s, 6H at C-7 and C-8);
1.93 (dd, J = 15.5, 9.6 Hz, 1H at C-2); 2.15 (dd, J = 15.5, 5.8 Hz, 1H
at C-6); 2.66 (dd, J = 13.3, 9.0 Hz, 1H at C-2); 2.87 (dd, J = 17.3,
4.0 Hz, 1H at C-6); 13C NMR (D2O, 75 MHz): 13.80 and 22.90 (C-7
and C-8), 18.22 (C-4), 24.21 (C-3), 27.56 (C-5), 32.64 (C-2), 37.44
(C-6), 182.96 (C-1). Anal. Calcd for C8H15NO2: C, 61.12; H, 9.62;
N, 8.91. Found: C, 61.01; H, 9.78; N, 9.02.
The Brown–Garg reagent8 (34.00 ml) was added dropwise to a
magnetically stirred solution of hydroxy ester 11 (2.40 g,
13.93 mmol) in diethyl ether (120 ml) kept at 25–30 °C tempera-
ture. The solution was stirred at room temperature until no sub-
strate 12 was detected by TLC (2:1 hexane/acetone). After 19 h,
the reaction was diluted with water and the aqueous phase was
extracted with diethyl ether. The combined extracts were dried
over MgSO4 and evaporated to give 2.40 g of crude product which
was then purified by column chromatography eluting with hexane/
4.8. (+)-Methyl {(1R,3S)-3-[(acetyloxy)methyl]-2,2-dimethyl-
cyclopropyl}acetate 10
acetone (11.5:1) to give carboxy ester 12 as a yellow oil.
½
a 2D3
ꢁ
¼ þ49:7 (c 1.31, CHCl3); n2D4 ¼ 1:4566; IR (film, cmꢀ1): 3008
(m), 2956 (s), 2681 (w), 1740 (vs), 1693 (vs), 1438 (s), 1333 (ms),
1229 (s), 1171 (s), 1014 (s), 840 (w); 1H NMR (CDCl3, 300 MHz):
1.21 and 1.23 (2s, 6H at C-7 and C-8), 1.48–1.59 (m, 2H at C-3
and C-5), 2.76 (d, J = 6.9 Hz, 2H at C-2), 3.68 (s, 3H at C-9); 13C
NMR (CDCl3, 75 MHz): 14.14 (C-8), 26.53 (C-4), 27.95 (C-3),
28.54 (C-2), 28.67 (C-7), 29.03 (C-5), 51.70 (C-9), 173.51 (C-1),
177.39 (C-6). Anal. Calcd for C9H14O4: C, 58.05; H, 7.58. Found: C,
57.93; H, 7.70.
Method 1: To
a stirred solution of keto ester 8 (0.79 g,
3.98 mmol) in 100 ml CHCl3, cooled to 0 °C, 4.91 g (28.5 mmol) of
70–75% mCPBA and 4.91 g MgSO4 were added. After stirring for
90 h at room temperature, the reaction mixture was diluted with
25 ml of water and 25 ml of CH2Cl2. The two-phase system was
separated and the water layer was extracted with three portions
of CH2Cl2. The combined organic layers were washed three times
with saturated aqueous NaHCO3, three times with 10% aqueous
Na2S2O3 and twice with brine, dried over MgSO4 and evaporated
under reduced pressure to obtain acetoxyl ester in 80% yield, 10.
The residue was then chromatographed (acetone/hexane 13.6:1).
Method 2: Compound 8 (14.57 g, 73.53 mmol) was placed in a
500 ml round-bottomed flask and then 33.00 g of 70–75% mCPBA
was added portionwise. The reaction mixture was stirred at room
temperature by means of a stirring rod after every added portion.
After 1 h the reaction mixture was diluted with 100 ml of CH2Cl2
and warmed at 40 °C and stirring was continued for a few hours
until no substrate was detected by TLC (2:1 hexane/acetone). After
the work-up, as mentioned above, acetoxy ester 10 was isolated
(13.32 g, 84%) and then chromatographed on silica gel (80:1 hex-
4.11. (ꢀ)-Methyl [(1R,3S)-3-{[(benzyloxy)carbonyl]amino}-2,2-
dimethylcyclopropyl]acetate 13
A solution of carboxy ester 12 (2.18 g, 11.71 mmol), DPPA
(3.09 ml, 14.35 mmol), and triethylamine (1.83 ml, 13.20 mmol)
in dry toluene (10 ml) was stirred at room temperature for
30 min, and then was warmed to 85 °C. After 30 min of stirring,
the reaction mixture was cooled to room temperature to add the
benzoic alcohol (1.49 ml, 14.36 mmol) and the reaction was carried
out at 85 °C for the following 23.5 h. The reaction progress was
monitored by TLC (3:1 hexane/acetone). An excess of benzoic acid
and toluene was removed under reduced pressure to give 3.90 g of
13. The residue was chromatographed on silica gel (24:1 hexane/
ane/acetone). ½a D24
ꢁ
¼ þ28:7 (c 2.0, CHCl3); n2D8 ¼ 1:4426; IR (film,
cmꢀ1): 2953 (s), 1740 (vs), 1436 (s), 1369 (ms), 1243 (s), 1027
(s), 840 (w), 607 (w); 1H NMR (CDCl3, 300 MHz): 0.94–0.99 (m,
2H at C-3 and C-5); 0.92 and 1.03 (2s, 6H at C-9 and C-10); 1.95
(s, 3H at C-8); 2.26 (d, J = 7.2 Hz, 2H at C-2); 3.60 (s, 3H at C-11);
3.94 (dd, J = 12.0, 7.9 Hz, 1H at C-6); 4.05 (dd, J = 11.9, 7.3 Hz, 1H
at C-6); 13C NMR (CDCl3, 75 MHz): 14.83 (C-10), 18.54 (C-4),
20.99 (C-3), 22.74 (C-9), 24.20 (C-5), 28.52 (C-8), 29.77 (C-2),
51.64 (C-11), 62.25 (C-6), 171.19 (C-1), 173.54 (C-7). Anal. Calcd
for C11H18O4: C, 61.66; H, 8.47. Found: C, 61.43; H, 8.68.
ethyl acetate). ½a D24
ꢁ
¼ ꢀ42:0 (c 1.45, CHCl3); n2D7 ¼ 1:5109; IR (film,
cmꢀ1): 3352 (m), 2952 (s), 1725 (vs), 1498 (s), 1331 (ms), 1242
(vs), 1056 (s), 740 (s), 696 (s), 595 (w); 1H NMR (CDCl3,
300 MHz): 0.98 and 1.11 (2s, 6H at C-6 and C-7), 0.90–1.08 (m,
1H at C-3), 2.08–2.31 (m, 1H at C-5), 2.38 (dd, J = 7.0, 3.1 Hz, 2H
at C-2), 3.68 (s, 3H at C-8), 5.10 (s, 2H, at C-10), 5.16 (s, 1H at N),
7.26–7.39 (m, 5H, at C-12, C-13, C-14, C-15, C-16); 13C NMR (CDCl3,
75 MHz): 14.00 (C-7 or C-6), 19.64 (C-4), 23.33 (C-6 or C-7), 26.38
(C-3), 29.23 (C-2), 36.29 (C-5), 51.89 (C-8), 66.88 (C-10), 128.05 (C-
13 and C-15), 128.47 (C-12 and C-16), 128.61 (C-14), 136.50 (C-11),
157.66 (C-9), 173.62 (C-1). Anal. Calcd for C16H21NO4: C, 65.96; H,
7.27; N, 4.81. Found: C, 65.69; H, 7.33; N, 4.98.
4.9. (ꢀ)-Methyl [(1R,3S)-3-(hydroxymethyl)-2,2-dimethylcyclo-
propyl]acetate 11
A solution of 10 (0.50 g, 2.33 mmol) and K2CO3 (12.50 mg) in
methanol (12.95 ml) was stirred at room temperature. After 6 h,
an excess of K2CO3 was added (53.70 mg) and stirring was contin-
ued for a further 3 h. The reaction was quenched with saturated
aqueous NH4Cl, extracted with ethyl acetate, dried over MgSO4,
and concentrated under reduced pressure to yield 11 (80%)
4.12. (ꢀ)-[(1R,3S)-3-{[(Benzyloxy)carbonyl]amino}-2,2-
dimethylcyclopropyl]acetic acid 14
An aqueous NaOH solution (1.06 g, 26.50 mmol NaOH in
6.30 ml of water) was added to a stirred solution of N-Cbz-pro-
tected amino ester 13 (3.26 g, 11.19 mmol) in ethanol (15.50 ml),
after which the solution was warmed to 50 °C and stirring was con-
½
a 2D4
ꢁ
¼ ꢀ28:5 (c 1.52, CHCl3); n2D5 ¼ 1:4899, IR (film, cmꢀ1): 3337

2020
K. Gajcy et al. / Tetrahedron: Asymmetry 21 (2010) 2015–2020
tinued for next 4 h. The reaction mixture was extracted with
diethyl ether, and then the aqueous layer was treated with 10%
H2SO4 and washed with diethyl ether. The combined organic layers
were dried over MgSO4 and concentrated under reduced pressure
to give 14 (2.71 g, 88% yield), which was purified on silica gel (hex-
the Ministry of Science and Higher Education of Poland (Grant
N204 13332/3390).
References
ane/acetone 10:1). ½a D25
ꢁ
¼ ꢀ42:4 (c 0.8, CHCl3); n2D5 ¼ 1:5443; IR
1. For part 6, see: Kuriata, R.; Gajcy, K.; Turowska-Tyrk, I.; Lochyn´ ski, S.
Tetrahedron: Asymmetry 2010, 21, 805–809.
(film, cmꢀ1): 3350 (m), 3065 (s), 2940 (s), 1740 (s), 1700 (s),
1533 (ms), 1467 (s), 1351 (s), 1242 (vs), 1108 (s), 744 (s), 696
(s), 595 (w); 1H NMR (CDCl3, 300 MHz): 0.83 and 0.96 (2s, 6H at
C-6 and C-7), 0.90–1.05 (m, 1H at C-5), 2.04–2.34 (m, 1H at C-3),
2.49 (d, J = 14.6 Hz, 2H at C-2), 5.04 (s, 2H at C-9), 5.11 (s, 1H at
N), 7.20–7.30 (m, 5H at C-11, C-12, C-13, C-14, C-15); 13C NMR
(CDCl3, 75 MHz): 14.12 (C-6 or C-7), 19.70 (C-4), 23.20 (C-6 or C-
7), 26.29 (C-5), 29.29 (C-2), 36.32 (C-3), 67.32 (C-9), 128.06 (C-12
and C-14), 128.27 (C-11 and C-15), 128.57 (C-13), 136.14 (C-10),
158.90 (C-8), 178.10 (C-1). Anal. Calcd for C15H19NO4: C, 64.97;
H, 6.91; N, 5.05. Found: C, 64.75; H, 6.98; N, 5.15.
2. Park, K. H.; Kurth, M. J. Tetrahedron 2002, 58, 8629–8659.
3. Wipf, P.; Stephenson, C. R. J. Org. Lett. 2005, 7, 1137–1140.
4. (a) Amorìn, M.; Castedo, L.; Granja, J. R. J. Am. Chem. Soc. 2003, 125, 2844–2845;
(b) Baldauf, C.; Günther, R.; Hofmann, H. J. J. Org. Chem. 2005, 70, 5351–5361;
(c) Brea, R. J.; Amorìn, M.; Castedo, L.; Granja, J. R. Angew. Chem., Int. Ed. 2005,
44, 5710–5713.
5. (a) Woll, M. G.; Lai, J. R.; Guzei, I. A.; Taylor, S. J. C.; Smith, M. E. B.; Gellman, S.
H. J. Am. Chem. Soc. 2001, 123, 11077–11078; (b) Baldauf, C.; Günther, R.;
Hofmann, H. J. J. Org. Chem. 2006, 71, 1200–1208; (c) Farrera-Sinfreu, J.; Giralt,
E.; Castel, S.; Albericio, F.; Royo, M. J. Am. Chem. Soc. 2005, 127, 9459–9468; (d)
Vasudev, P. G.; Shamala, N.; Ananda, K.; Balaram, P. Angew. Chem., Int. Ed. 2005,
44, 4972–4975.
6. Owens, D. F.; Kriegstein, A. R. Rev. Neurosci. 2002, 3, 715–727.
7. (a) Ordóñez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3–99; (b) Gale,
K. Epilepsia 1989, 30, S1–S11; (c) Dalby, N. O. Eur. J. Pharmacol. 2003, 479, 127–
137; (d) Glass, M.; Dragunow, M.; Faull, R. L. M. Neuroscience 2000, 97, 505–
519; (e) Geffen, Y.; Nudelman, A.; Gil-Ad, I.; Rephaeli, A.; Huang, M.; Savitsky,
K.; Klapper, L.; Winkler, I.; Meltzer, H. Y.; Weizman, A. Eur.
Neuropsychopharmacol. 2009, 19, 1–13; (f) Kleppner, S. R.; Tobin, A. J. Emerg.
Ther. Targets 2001, 5, 219–239.
8. Brown, H. C.; Garg, C. P. J. Am. Chem. Soc. 1961, 83, 2952.
9. Lochynski, S.; Gajcy, K.; Pekala, J. Polish Patent Application P385632, 2008.
10. Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Tetrahedron Lett. 2006, 47,
7219–7233.
4.13. (ꢀ)-[(1R,3S)-3-Amino-2,2-dimethylcyclopropyl]acetic acid
4
A mixture of 14 (0.20 g, 0.72 mmol) and 5% Pd/C (0.10 g) in
MeOH (45 ml) was vigorously stirred under an H2 atmosphere
for 3 h. The Pd-catalyst was filtered off and the filtrate was evapo-
rated to give 4 (0.10 g). ½a D25
¼ ꢀ20:1 (c 0.69, MeOH); IR (KBr,
ꢁ
11. Lochynski, S.; Gajcy, K.; Frackowiak-Wojtasek, B. Polish Patent Application
P389321, 2009.
12. Lochynski, S.; Gajcy, K.; Frackowiak-Wojtasek, B. Polish Patent Application
P390968, 2010.
13. Lochynski, S.; Frackowiak, B; Gajcy, K.; Kusiak, A.; Librowski, T.; Kubacka, M.
Polish Patent Application P382189, 2007.
14. Lochynski, S.; Gajcy, K.; Frackowiak-Wojtasek, B. Polish Patent Application
P390970, 2010.
cmꢀ1): 3352 (m), 2952 (m), 1528 (s), 1242 (vs), 750 (w); 1H NMR
(D2O, 300 MHz): 0.90 (s, 3H at C-7) and 0.93 (s, 3H at C-6), 0.96–
1.08 (m, 1H at C-3), 2.20 (d, J = 8.0 Hz, 2H at C-2); 2.24 (d,
J = 8.0 Hz, 1H at C-5); 13C NMR (D2O, 75 MHz): 12.60 (C-7), 17.50
(C-4), 21.83 (C-3), 25.34 (C-6), 30.01 (C-2), 34.95 (C-5), 179.33
(C-1). Anal. Calcd for C7H13NO2: C, 58.72; H, 9.15; N, 9.78. Found:
C, 58.51; H, 9.23; N, 9.98.
15. Lochynski, S.; Gajcy, K.; Stawinoga, M. Polish Patent Application P388971,
2009.
16. Lochynski, S.; Gajcy, K. Polish Patent Application P389320, 2009.
17. Lochynski, S.; Gajcy, K. Polish Patent Application P389322, 2009.
18. Lochynski, S.; Gajcy, K. Polish Patent Application P390967, 2010.
19. Lochynski, S.; Gajcy, K. Polish Patent Application P390969, 2010.
Acknowledgements
This work was supported by a fellowship co-financed by the
European Union within the European Social Fund and Grant from