Cyclobutane amino acids (CBAAs): Asymmetric Strecker synthesis of enantiopure cis- and trans-2,4-methanovalines

Article abstract of DOI:10.1016/S0957-4166(02)00868-6

Synthesis of enantiopure 2,4-methanovalines has been achieved by means of asymmetric Strecker synthesis starting from racemic 2-methylcyclobutanone. The trans-configured α-amino acids were obtained from cyanide additions carried out in methanol, whereas the cis-configured 2,4-methanovalines were accessible via reactions in hexane. Relative stereochemistry was elucidated from NOESY experiments, while absolute configurations were assigned from X-ray crystallographic analysis.

Full text of DOI:10.1016/S0957-4166(02)00868-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 497–502
Cyclobutane amino acids (CBAAs): asymmetric Strecker
synthesis of enantiopure cis- and trans-2,4-methanovalines
Franz-J. Volk, Marita Wagner and August W. Frahm*
Lehrstuhl fu¨r Pharmazeutische Chemie, Albert-Ludwigs-Universita¨t, Albertstraße 25, D-79104 Freiburg, Germany
Received 21 November 2002; accepted 17 December 2002
Abstract—Synthesis of enantiopure 2,4-methanovalines has been achieved by means of asymmetric Strecker synthesis starting
from racemic 2-methylcyclobutanone. The trans-configured a-amino acids were obtained from cyanide additions carried out in
methanol, whereas the cis-configured 2,4-methanovalines were accessible via reactions in hexane. Relative stereochemistry was
elucidated from NOESY experiments, while absolute configurations were assigned from X-ray crystallographic analysis. © 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
either achiral or racemic 1-aminocyclobutanecarboxylic
acids and corresponding 1,3-dicarboxylic acids, leading
us to investigate asymmetric Strecker synthesis as a tool
for the preparation of enantiomerically and
diastereomerically pure 1-amino-2-methylcyclobutane
carboxylic acids. Herein, we report on the first synthesis
of homochiral 2,4-methanovalines (2,4-MVals) starting
from racemic 2-methylcyclobutanone and 1-phenylethyl-
amine as a chiral auxiliary.
The structure of 1-aminocyclobutane carboxylic acids
has received increasing attention in the field of medici-
nal chemistry in recent years. Thus, in 1980 Bell et al.
reported on the first isolation of 2,4-methano amino
acids (2,4-MAAs) (Scheme 1), namely cis-2,4-
methanoglutamic acid (2,4-MGlu, I) and 2,4-
methanoproline (2,4-MPro, II) from the seeds of
Ateleia herbert smithii.1 Later, cis-1-amino-3-hydroxy-
methylcyclobutane carboxylic acid (III) was isolated
by Fellows et al. from the same source.2 In 1990
trans-2,4-methanoglutamic acid was described as a
highly potent NMDA agonist,3 whereas other 1,3-di-
substituted cyclobutane derived a-amino acids such as
IV operate as NMDA antagonists and anticonvulsive
drugs,4 respectively. Furthermore, incorporation of var-
ious 2,4-MAAs into bioactive peptides increased their
stability towards enzymatic degradation and altered
their biological properties remarkably.5 From a syn-
thetic point of view it is noteworthy that the Gaoni
approach6 provides access only to a wide range of
2. Results and discussion
The racemic starting material 2-methylcyclobutanone 1
was prepared in two steps from 1,3-dibromobutane and
tosylmethylioscyanide (TosMiC) according to a litera-
ture procedure.7 The racemic ketone 1 was allowed to
condense with an equimolar amount of (R)-1-
phenylethylamine under azeotropic removal of water,
yielding the ketoimine 2 in quantitative yields but as a
diastereomeric mixture of E-aR,2R-, E-aR,2S-, Z-
aR,2R- and Z-aR,2S-configured components. Accord-
Scheme 1. Structures of 2,4-methano a-amino acids I–IV.
* Corresponding author. Fax: 0761 203 6351; e-mail: august.wilhelm.frahm@pharmazie.uni-freiburg.de
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00868-6

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F.-J. Volk et al. / Tetrahedron: Asymmetry 14 (2003) 497–502
ing to 13C NMR analysis the E/Z ratio of the ketoimine
mixture was :8:1, whereas the 2R/2S quotient (1:1) of
the starting material was the same, indicating that no
epimerisation at C-2 took place during ketoimine for-
mation. The crude imine mixture 2 was then applied to
Lewis acid-catalyzed addition of trimethylsilylcyanide
(TMSCN) to yield the respective a-amino nitriles 3. In
this step, the prochiral sp2 hybridised imino carbon
atom of 2 is converted into the new third stereogenic
center. Since the configuration of the chiral auxiliary is
fixed, up to four diastereomeric a-amino nitriles 3a–d
can theoretically be formed in this reaction. In practice,
we observed the formation of four component mixtures
even under different reaction conditions (Scheme 2).
However, our earlier results8 on the solvent dependent
reversal of the trans/cis-diastereoselectivity could be
confirmed and accordingly, the use of methanol in the
a-amino nitrile synthesis led to the preferential forma-
tion of the trans products (reaction conditions iv in
Scheme 2), whereas completing the reaction with hex-
ane as the solvent drove the reaction towards cis
configured diastereomers as the major products (reac-
tion conditions v in Scheme 2). This difference in
behavior enabled us to subsequently isolate the two
trans-2,4-methanovalines and the two cis-2,4-
methanovalines starting from a-amino nitrile synthesis
carried out in different solvents (vide infra).
2.1. Preparation of trans-2,4-MVals (Scheme 2)
Treatment of the a-amino nitrile mixture 3a–d obtained
in MeOH (iv) with concentrated sulfuric acid for 3 h at
−10°C, 3 h at 0°C and finally 4 days at 25°C gave the
respective a-amino carboxamide in 55% yield again as
Scheme 2. Asymmetric Strecker synthesis of the 2,4-methanovalines 6a, 6b and 6c. Reagents and conditions: (i) NaH, DMSO/
Et2O, rt, 2 h, 62%; (ii) sulfolane, H2O/H2SO4, 110°C, 2 h, 70%; (iii) (R)-1-PEA, TsOH, toluene, reflux, 5 h, ca. 100%; (iv)
TMSCN, MeOH, ZnCl2, 0°C, 3 h, 98%; (v) TMSCN, hexane, ZnCl2, −10°C, 48 h, 75%; (vi) conc. H2SO4, −10°C 3 h, 0°C 3 h,
rt 96 h, 55%; CC: silica gel Si60 (230–400 mesh), EtOAc–cyclohexane (1:1), 78% recovery rate; (vii) conc. H2SO4–CH2Cl2, −10°C,
96 h, 80%; CC: silica gel Si60 (70–230 mesh), EtOAc–cyclohexane–Et2NH; (viii) MeOH, Pd/C (10%), HCOONH4, reflux, 2 h,
96%; (ix) HCl conc., reflux, 12 h.

F.-J. Volk et al. / Tetrahedron: Asymmetry 14 (2003) 497–502
499
Scheme 3. Asymmetric Strecker synthesis of the cis-2,4-methanovaline 6d. Reagents and conditions: (i) TMSCN, hexane, ZnCl2,
−10°C, 48 h, 75%; (ii) conc. H2SO4–CH2Cl2, −10°C, 96 h, 80%; (iii) silica gel Si60 (70–230 mesh), EtOAc–cyclohexane–Et2NH;
(iv) MeOH, Pd/C (10%), HCOONH4, reflux, 2 h, 96% (v) HCl conc., reflux, 12 h.
four component mixtures with practically unchanged
diastereomeric composition with respect to the 3a–d
mixture. The two trans-configured components 4a and
4b could be isolated from this crude a-amino carbox-
amide mixture by simple flash column chromatography,
whereas isolation of any cis-configured compounds
failed in this series. The diastereomerically pure a-
amino amides 4a and 4b, obtained in this way, were
separately hydrogenolysed using palladium on charcoal
(10%) and ammonium formate to yield the correspond-
ing primary a-amino amides 5a and 5b, respectively.
Finally, 5a and 5b were hydrolysed to the a-amino acid
hydrochlorides 6a and 6b by refluxing in 12 M HCl for
24 h.
obtained by column chromatography and transformed
into the respective a-amino acid 6d (Scheme 3).
In conclusion, all four stereomeric 1-amino-2-methylcy-
clobutanecarboxylic acids (2,4-methanovalines) could
be synthesised via asymmetric Strecker reactions carried
out in different solvents using (R)- and (S)-1-
phenylethylamine, respectively.
3. Remarks on the stereochemistry
The relative stereochemistry of the a-amino amides 4a
and 4b could be derived from 2D NMR experiments
carried out in CDCl3. As a result, we observed NOEs
between the carboxamide NH2-protons and the methyl
group at position 2 of the cyclobutane on the one site,
and between the amino NH-proton of the chiral auxil-
iary moiety and the methin proton at position 2 on the
other site, both indicating the trans configuration of the
methyl and the 1-phenylethylamino substituents (Fig.
1). The absolute stereochemistry of the trans com-
pounds was obtained from X-ray analysis, which
allowed us to unambiguously assign the aR,1S,2S
configuration to compound 4a. Consequently, the sec-
ond trans a-amino amide 4b must be aR,1R,2R
configured. In a series of earlier papers we have already
shown that the major product gained from a-amino
nitrile synthesis in hexane (kinetically controlled reac-
tions) always possesses the same absolute configuration
at C-1 as the chiral auxiliary (‘like-induction’). By
analogy, we can deduce the aR,1R,2S configuration for
the cis configured a-amino amide 4c and finally the
aS,1S,2R configuration for the second cis compound
2.2. Preparation of cis-2,4-MVals
Since the relative amount of cis configured compounds
in the a-amino nitrile mixtures 3a–d, obtained from
reactions in methanol (iv), was very small, it was unfea-
sible to isolate any of them after partial hydrolysis to
the corresponding a-amino amides. Therefore, we
needed to set up a second series, in which the hydrolysis
step with concentrated sulfuric acid started from the
a-amino nitrile mixture yielded from cyanide addition
in hexane (reaction conditions v). As shown in Scheme
2, this mixture contains 33% of the cis-configured
nitrile 3c. On hydrolysis, the stereochemical composi-
tion of this mixture remained almost unchanged. Subse-
quent column chromatography on silica gel using
cyclohexane/ethyl acetate/diethylamine as the mobile
phase yielded three fractions: the first contained the
diastereomerically pure trans-configured 4a, the second
consisted of a mixture of trans-4b and the minor cis
component 4d in a ratio of 85:15, and the third was
made up of the pure cis-configured a-amino amide 4c.
The conversion of cis-4c into the target cis-a-amino
acid 6c was done as described for 4a and 4b, respec-
tively (Scheme 2). Although the separation of the 4b/4d
mixture from above failed, the second cis-amino acid
6d was easily accessible from the same sequence starting
with Strecker synthesis using the enantiomerically pure
chiral auxiliary (S)-1-phenylethylamine. In this case
diastereomerically pure ent-4c, the precursor of 6d, was
Figure 1. NOE effects observed for compound 4b.

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F.-J. Volk et al. / Tetrahedron: Asymmetry 14 (2003) 497–502
ent-4c. Given that the hydrogenolysis of the chiral
auxiliary moiety as well as the final hydrolysis of the
carboxamides proceed under retention of the absolute
stereochemistry all assignments made above apply for
the primary amino amides 5a–d as well as for the
2,4-methanovalines 6a–d.
chloride (140 mg, 5 mol%) in hexane (100 ml)
trimethylsilylcyanide (3.4 ml, 0.025 mol) were added at
−10°C over a period of 30 min. The reaction mixture
was stirred for 48 h at −10°C, quenched with an
equimolar volume (1 ml) of methanol, stirred for fur-
ther 2 h at −10°C, filtered, concentrated under reduced
pressure and finally dried under high vacuum to yield
diastereomeric mixture of the a-amino nitriles 3a–d
(3.28 g, 77%), which was used directly in further reac-
tions without purification.
4. Experimental
Melting points are uncorrected. Solvents were purified
according to standard procedures. The given yields are
for isolated products. Elemental analyses were obtained
with a Perkin–Elmer elemental analyzer PE 240 at the
Department of Biochemistry and Organic Chemistry,
University of Freiburg. NMR spectra were run at 300
MHz (1H) and 75.4 MHz (13C), respectively, on a
Varian Unity 300 spectrometer. Chemical shifts are
reported as l values using either TMS (1H) or the
solvent peak (13C) as a reference. Optical rotation val-
ues were measured in a 1 dm cell with a Perkin–Elmer
241 polarimeter. Column chromatography was per-
formed on Merck silica gel (70–230 mesh ATSM).
Flash chromatography was carried out with silica gel
Si60 0.04–0.063 mm, Sigma-Aldrich Chemie GmbH.
4.5. Hydrolysis of the a-amino nitrile mixture 3a–d
obtained in MeOH
The diastereomeric mixture 3a–d (obtained under reac-
tion conditions iv, 1.85 g, 8.5 mmol) was added slowly
to conc. H2SO4 (15 ml) at −10°C. The mixture was
stirred for 3 h at −10°C, 3 h at 0°C and for 96 h at
20°C, decomposed on ice (80 g), and filtered. The
filtrate was adjusted to pH 8 with conc. NH3, and
extracted with diethyl ether (3×50 ml). The combined
organic phases were washed with water (1×50 ml), dried
over anhyd. Na2SO4, filtered, and the ether was evapo-
rated, yielding 1.1 g (55%) of a crude reaction product,
which was applied to flash chromatography (stationary
phase: Si60, 230–400 mesh; mobile phase: ethyl acetate/
cyclohexane=1/1; fraction size: 10 ml; compound: sta-
tionary phase=1:100; detection: TLC with ninhydrin
reagent), providing the diastereomerically pure a-amino
amides 4a (332 mg, 18%) and 4b (344 mg, 19%),
respectively.
4.1. (RS)-2-Methylcyclobutanone, 1
Compound 1 was prepared from 1,3-dibromobutane
and tosylmethylisocyanide (TosMic) following the pro-
cedure described in the literature.7 Overall yield: 43%
(lit.:7 57%).
4.5.1.
(aR,1S,2S)-2-Methyl-1-(1-phenylethylamino)-
4.2. (E/Z)-2-(R/S)-[N-(R)-1-Phenylethyl]methylcyclo-
cyclobutanecarboxamide, 4a. Mp 219°C (HCl-salt,
decomp.); [h]2D5=+61.9 (c 0.879, H3COH); 1H NMR
(CDCl3) l 0.98 (d, J=6.84 Hz, 3H), 1.41 (d, J=6.59
Hz, 3H), 1.5–1.7 (m, 2H), 1.82–2.0 (m, 2H), 2.2–2.34
(m, 1H), 2.73–2.83 (m, 1H), 3.75 (q, J=6.59 Hz, 1H),
4.9 (br.s, 1H), 6.4 (br.s, 1H), 7.15–7.4 (m, 5H); 13C
NMR (CDCl3) l 15.9 (q), 22.6 (t), 25.6 (q), 28.8 (t),
43.4 (d), 54.2 (d), 67.7 (s), 126.3 (d), 126.7 (d), 128.3 (d),
146.1 (s), 176.1 (s). Anal. calcd for C14H20N2O: C,
62.56; H, 7.87; N, 10.42. Found: C, 62.44; H, 7.80; N,
10.43%.
butylidenamines 2 (mixture of four diastereomers)
A mixture of (RS)-2-methylcyclobutanone 2 (1.68 g,
0.02 mol), (R)-(+)-1-phenylethylamine (2.42 g, 0.02
mol) and a catalytic amount of p-toluenesulfonic acid
was dissolved in toluene (50 ml) and heated under
reflux for 6 h using a Dean–Stark apparatus. The
solvent was evaporated in vacuum and the residue was
further dried under high vacuum to yield 2 (3.74 g,
99%) as a reddish oil, which was used directly in further
reactions without purification.
4.5.2.
(aR,1R,2R)-2-Methyl-1-(1-phenylethylamino)-
4.3. 2-Methyl-1-(1-phenylethylamino)cyclobutane-
cyclobutanecarboxamide, 4b. Mp 210°C (HCl-salt,
decomp.); [h]2D5=−19.3 (c 0.846, H3COH); 1H NMR
(CDCl3) l 0.98 (d, J=6.84 Hz, 3H), 1.28 (d, J=6.59
Hz, 3H), 1.46–1.62 (m, 2H), 1.67 (br.s, 1H); 1.74–1.84
(m, 1H), 2.1–2.23 (m, 1H), 2.32–2.45 (m, 1H), 3.86 (q,
J=6.59 Hz, 1H), 5.5 (br.s, 1H), 7.1 (br.s, 1H), 7.2–7.4
(m, 5H); 13C NMR (CDCl3) l 15.9 (q), 22.7 (t), 23.8
(q), 26.5 (t), 43.4 (d), 54.7 (d), 67.2 (s), 126.3 (d), 127.0
(d), 128.4 (d), 146.5 (s), 177.5 (s). Anal. calcd for
C14H20N2O: C, 62.56; H, 7.87; N, 10.42. Found: C,
62.32; H, 7.77; N, 10.35%.
carbonitrile mixture 3a–d (reaction conditions iv)
To a solution of 2 (1.87 g, 0.01 mol) and dry zinc
chloride (70 mg, 5 mol%) in methanol (20 ml)
trimethylsilylcyanide (1.66 ml, 0.0125 mol) were added
at 0°C over a period of 15 min. The reaction mixture
was stirred at 0°C for additional 3 h, filtered, concen-
trated under reduced pressure and dried under high
vacuum to give diastereomeric mixture of the a-amino
nitriles 3a–d (2.03 g, 95%) which was used directly in
further reactions without purification.
4.6. Hydrolysis of the a-amino nitrile mixture 3a–d
obtained in hexane
4.4. 2-Methyl-1-(1-phenylethylamino)cyclobutane-
carbonitrile mixture 3a–d (reaction conditions v)
The diastereomeric mixture 3a–d (obtained under reac-
tion conditions v, 3.2 g, 15 mmol) was dissolved in
To a solution of 2 (3.74 g, 0.02 mol) and dry zinc

F.-J. Volk et al. / Tetrahedron: Asymmetry 14 (2003) 497–502
501
dichloromethane (40 ml) and added slowly to conc.
H2SO4 (30 ml) at −10°C. The mixture was kept for 3 h
at −10°C, allowed to warm up to rt, and stirring was
continued for 96 h. The reaction mixture was worked-
up as described above, to yield crude product (2.78 g,
80%), which was purified by column chromatography
(stationary phase: Si 60, 70–230 mesh; mobile phase:
cyclohexane/ethyl acetate/diethylamine=6/4/0.3) to
give the diastereomerically pure a-amino amides 4a
(110 mg, 3.2%) and 4c (620 mg 18%), respectively.
4.7.3. (1R,2S)-1-Amino-2-methylcyclobutanecarboxam-
ide hydrochloride, 5c. Mp 198°C (decomp.); [h]2D5=+7.1
1
(c 1.03, H3COH); H NMR (CD3OD) l 1.13 (d, J=
7.33 Hz, 3H), 1.88–2.02 (m, 1H), 2.10–2.36 (m, 2H),
2.62–2.76 (m, 1H), 2.98–3.12 (m, 1H); 13C NMR
(CD3OD) l 14.7 (q), 23.9 (t), 28.3 (t), 38.3 (d), 63.2 (s),
174.3 (s); MS (CI, isobutane, 200 eV): m/z (%) 129
(100) [M+], 111.9 (23) [M+−17 (NH3)], 85 (6) [M+−44
(CONH2)]; HRMS (EI, 70 eV): m/z (%) 128 [M−1+],
C6H12N2O: calcd 128.0947, found 128.0950.
4.7.4. (1S,2R)-1-Amino-2-methylcyclobutanecarboxam-
ide hydrochloride, 5d. Mp 199°C (decomp.); [h]2D5=−7.4
4.6.1.
(aR,1R,2S)-2-Methyl-1-(1-phenylethylamino)-
1
(c 1.015, H3COH); H NMR (CD3OD) and 13C NMR
cyclobutanecarboxamide, 4c. Mp 208°C (HCl-salt,
decomp.); [h]D25=+2.6 (c 0.74, H3COH); 1H NMR
(CDCl3) l 1.06 (d, J=7.17 Hz, 3H), 1.26 (d, J=6.72
Hz, 3H), 1.28–1.40 (m, 1H), 1.66–1.78 (m, 1H), 1.96
(br.s, 1H), 2.0–2.1 (m, 1H), 2.36–2.46 (m, 1H), 2.50–
2.64 (m, 1H), 3.80 (q, J=6.72 Hz, 1H), 5.8 (br.s, 1H),
6.9 (br.s, 1H), 7.2–7.4 (m, 5H); 13C NMR (CDCl3) l
14.5 (q), 23.3 (t), 23.9 (q), 24.1 (t), 39.1 (d), 54.3 (d),
64.2 (s), 126.2 (d), 126.9 (d), 128.4 (d), 146.6 (s), 180.1
(s). Anal. calcd for C14H20N2O: C, 62.56; H, 7.87; N,
10.42. Found: C, 62.92; H, 7.45; N, 10.50%.
(CD3OD) data are identical with those of 5c; MS (CI,
isobutane, 200 eV): m/z (%) 129 (100) [M+], 111.9 (23)
[M+−17 (NH3)], 85 (7) [M+−44 (CONH2)].
4.8. General procedure for the hydrolysis of the a-amino
amides 5a–d
The stereochemically pure a-amino amide hydrochlo-
ride 5a–d (1 mmol) was dissolved in conc. hydrochloric
acid (10 ml) and heated under reflux at 100°C for 24 h.
The solution was evaporated to dryness. The residue
was dissolved twice in 10 ml of water and evaporated
again. The crude a-amino acid hydrochlorides 6a–d
were washed with small amounts of diethyl ether and
ethyl acetate and finally dried in high vacuum.
4.6.2.
(aS,1S,2R)-2-Methyl-1-(1-phenylethylamino)-
cyclobutanecarboxamide, ent-4c. Mp 206°C (HCl-salt,
decomp); [h]2D5=−3.0 (c 1.01, H3COH); 1H NMR
(CDCl3) and 13C NMR (CDCl3) data are identical with
those of 4c. Anal. calcd for C14H20N2O: C, 62.56; H,
7.87; N, 10.42. Found: C, 62.75; H, 7.51; N, 10.55%.
4.8.1. (1S,2S)-1-Amino-2-methylcyclobutanecarboxylic
acid hydrochloride, 6a. Mp >250°C (decomp.); [h]2D5=
1
+13.8 (c 0.105, water); H NMR (CD3OD) l 1.13 (d,
J=7.02 Hz, 3H), 1.84–2.0 (m, 1H), 2.12–2.32 (m, 2H),
2.52–2.64 (m, 1H), 2.78–2.92 (m, 1H); 13C NMR
(CD3OD) l 15.8 (q), 23.7 (t), 27.6 (t), 39.8 (d), 62.6 (s),
171.9 (s); MS (CI, isobutane, 200 eV): m/z (%) 130
(100) [M+], 113 (3) [M+−17 (NH3)], 85 (10) [M+−45
(COOH)]; HRMS (EI, 70 eV): m/z (%) 87 [M+1+−44
(CO2)], C5H13N1: calcd 87.1048, found 87.1051.
4.7. General procedure for the hydrogenolysis of the
a-amino amides 4a–c and ent-4c
To a solution of the diastereomerically pure a-amino
carboxamides 4a–c and ent-4c (230 mg, 1 mmol),
respectively, in methanol (30 ml), Pd/C (10%, 280 mg)
and ammonium formate (510 mg) were added and the
resulting mixture was heated under reflux for 2 h. The
catalyst was removed by filtration through Celite and
the solvent was evaporated yielding 5a–d as colorless
oils, which were converted into their hydrochloride salts
using ether saturated with HCl gas.
4.8.2. (1R,2R)-1-Amino-2-methylcyclobutanecarboxylic
acid hydrochloride, 6b. Mp >250°C (decomp.); [h]2D5=
−14.5 (c 0.112, water); 1H NMR (CD3OD) and 13C
NMR (CD3OD) data are identical with those of 6a; MS
(CI, isobutane, 200 eV): m/z (%) 130 (100) [M+], 113 (3)
[M+−17 (NH3)], 85 (10) [M+−45 (COOH)].
4.7.1. (1S,2S)-1-Amino-2-methylcyclobutanecarboxam-
ide hydrochloride, 5a. Mp 209°C (decomp); [h]2D5=+86.1
(c 1.015, H3COH); 1H NMR (CD3OD) l 1.09 (d,
J=7.02 Hz, 3H), 1.70–1.84 (m, 1H), 2.16–2.42 (m, 2H),
2.56–2.66 (m, 1H), 2.70–2.88 (m, 1H); 13C NMR
(CD3OD) l 16.0 (q), 23.5 (t), 26.7 (t), 39.6 (d), 63.2 (s),
172.2 (s); MS (CI, isobutane, 200 eV): m/z (%) 129
(100) [M+], 111.9 (23) [M+−17 (NH3)], 85 (7) [M+−44
(CONH2)]; HRMS (EI, 70 eV): m/z (%) 128 [M−1+],
C6H12N2O: calcd 128.0947, found 128.0949.
4.8.3. (1R,2S)-1-Amino-2-methylcyclobutanecarboxylic
acid hydrochloride, 6c. Mp >250°C (decomp.); [h]2D5=
1
+23.5 (c 0.190, water); H NMR (CD3OD) l 1.19 (d,
J=7.33 Hz, 3H), 1.81–2.0 (m, 1H), 2.16–2.38 (m, 2H),
2.63–2.76 (m, 1H), 3.02–3.16 (m, 1H); 13C NMR
(CD3OD) l 15.1 (q), 24.1 (t), 27.9 (t), 37.3 (d), 61.8 (s),
173.1 (s); MS (CI, isobutane, 200 eV): m/z (%) 130
(100) [M+], 113 (3) [M+−17 (NH3)], 85 (5) [M+−45
(COOH)]; HRMS (EI, 70 eV): m/z (%) 87 [M+1+−44
(CO2), C5H13N1: calcd 87.1048, found 87.1041.
4.7.2. (1R,2R)-1-Amino-2-methylcyclobutanecarboxam-
ide hydrochloride, 5b. Mp 206°C (decomp.); [h]2D5=
4.8.4. (1S,2R)-1-Amino-2-methylcyclobutanecarboxylic
acid hydrochloride, 6d. Mp >250°C (decomp.); [h]2D5=
−24.0 (c 0.088, water); 1H NMR (CD3OD) and 13C
NMR (CD3OD) data are identical with those of 6c; MS
(CI, isobutane, 200 eV): m/z (%) 130 (100) [M+], 113 (3)
[M+−17 (NH3)], 85 (5) [M+−45 (COOH)].
1
−86.8 (c 0.875, H3COH); H NMR (CD3OD) and 13C
NMR (CD3OD) data are identical with those of 5a; MS
(CI, isobutane, 200 eV): m/z (%) 129 (100) [M+], 111.9
(22) [M+−17 (NH3)], 85 (7) [M+−44 (CONH2)].

502
F.-J. Volk et al. / Tetrahedron: Asymmetry 14 (2003) 497–502
Stirton, C. H. Tetrahedron 1987, 43, 1857.
Acknowledgements
3. (a) Allan, R. D.; Hanrahan, J. R.; Hambley, T. W.;
Johnston, G. A.; Mewett, K. N.; Mitrovic, A. D. J. Med.
Chem. 1990, 33, 2905; (b) Lanthorn, T. H.; Hood, W. F.;
Watson, G. B.; Compton, R. P.; Rader, R. K.; Gaoni,
Y.; Moanhan, J. B. Eur. J. Pharmacol. 1990, 182, 397.
4. Gaoni, Y.; Chapman, A. G.; Parvez, N.; Pook, P. C. K.;
Jane, D. E.; Watkins, J. C. J. Med. Chem. 1994, 37,
4288.
The authors are indebted to Dr. (habil) E. Weckert,
HASYLAB at DESY, Hamburg, Germany for the X-
ray structure of compound 4a, and to V. Brecht for
carefully running the NMR experiments. Financial sup-
port by the Fonds der Chemischen Industrie, Frankfurt
a.M., Germany is gratefully acknowledged.
5. Fridkin, M.; Gaoni, Y.; Gershonov, E.; Granoth, R.;
Tzehoval, E. J. Med. Chem. 1996, 39, 4833.
6. (a) Gaoni, Y. Org. Prep. Proc. Int. 1995, 27, 185; (b)
Gaoni, Y. Tetrahedron Lett. 1988, 29, 1591.
7. van Leusen, D.; van Leusen, A. Synthesis 1980, 325.
8. Wede, J.; Volk, F.-J.; Frahm, A. W. Tetrahedron: Asym-
metry 2000, 11, 3231 and references cited therein.
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