Carbocyclic α-amino acids: Asymmetric Strecker synthesis of a series of 2-alkylated 1-aminocyclopentanecarboxylic acids

Article abstract of DOI:10.1016/S0957-4166(00)00284-6

A series of 12 carbocyclic α-amino acids has been prepared from four different racemic 2-alkylated cyclopentanones and (R)-1-phenylethylamine as the chiral auxiliary by means of an asymmetric Strecker synthesis. The stereoselectivity was influenced by sol

Full text of DOI:10.1016/S0957-4166(00)00284-6

Tetrahedron: Asymmetry 11 (2000) 3231±3252
Carbocyclic a-amino acids: asymmetric Strecker synthesis of a
series of 2-alkylated 1-aminocyclopentanecarboxylic acids
Judith Wede, Franz-J. Volk and August W. Frahm*
Lehrstuhl fur Pharmazeutische Chemie, Albert-Ludwigs-Universitat Freiburg, Hermann-Herder-Straûe 9,
È
È
D-79104 Freiburg, Germany
Received 14 July 2000; accepted 18 July 2000
Abstract
A series of 12 carbocyclic a-amino acids has been prepared from four di€erent racemic 2-alkylated
cyclopentanones and (R)-1-phenylethylamine as the chiral auxiliary by means of an asymmetric Strecker
synthesis. The stereoselectivity was in¯uenced by solvent, temperature and size of the substituent at the
2-position of the cyclopentanones. For the methyl and ethyl substituted amino acids all four possible
stereoisomers could be obtained, whereas for the isopropyl and tertiary butyl compounds an unexpected
side reaction prohibited the isolation of the cis con®gured amino acids. The 1,3-induction mechanism
observed for the kinetically controlled a-amino nitrile formation in the 2-methyl and 2-ethyl series was
overlayed by a 1,2-induction in the respective 2-isopropyl and 2-tertiary butyl series. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
In the last few years a variety of interesting biological properties of carbocyclic a-amino acids
have been described. Ohfune et al. showed that cyclic threonine analogues when incorporated as
building blocks into peptides (e.g. Leu-enkephalin) can alter their biological e€ects.1 Moreover,
1-aminocyclopropane (ACPC), 1-aminocyclobutan (ACBC), and 1-aminocyclopentanecarboxylic
acid are reported as partial agonists at the strychnine insensitive glycine binding site of the
NMDA receptor complex.2 Recently, it was shown that ACPC acts concurrently as a glycine site
partial agonist and as a glutamate site antagonist,3 thus protecting against neural cell death and
exhibiting antipsychotic-like e€ects in animal models.4 Finally, a-quaternary a-amino acids such
as ACPC or a-methylaspartate are able to function as enzyme inhibitors by covalently binding to
pyridoxal phosphate dependent enzymes such as decarboxylases5a and transaminases.5b
* Corresponding author. E-mail: awfrahm@ruf.uni-freiburg.de
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00284-6

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In the course of our work on asymmetric synthesis of cyclic analogues of naturally occurring
a-amino acids we previously published the cyclohexane derived isoleucines6 I±IV and threonines7
V±VIII, respectively, (Scheme 1) by means of asymmetric Strecker reactions.8,9
In this paper we report on the preparation of a series of 12 homochiral 1-amino-2-alkylcyclo-
pentanecarboxylic acids from the racemic cyclopentanones 1.1-4 and (R)-1-phenylethylamine10 as
the chiral auxiliary. For the methyl and ethyl substituted a-amino acids all four possible diastereo-
and enantiomerically pure stereoisomers could be obtained, whereas in the isopropyl and tertiary
butyl series only the two trans con®gured a-amino acids were accessible according to our
experimental protocol.
Scheme 1. Cyclic isoleucines I±IV and cyclic threonines V±VIII
2. Results
2.1. ꢀ-Amino nitrile synthesis
The racemic starting ketones 1.2-4 were prepared according to literature procedures,11 while
1.1 is commercially available. For the synthesis of the a-amino nitriles 3.1-4 the 2-alkylated
ketones 1.1-4 were subjected to a two-step procedure previously developed in our group6,7
(Scheme 2) which includes azeotropic condensation with the chiral auxiliary (R)-1-phenylethyl-
amine to the corresponding ketimin mixtures 2.1-412 (each as a mixture of the E-aR,2R, E-aR,2S,
Z-aR,2R, and Z-aR,2S stereoisomers) in the ®rst step, followed by a Lewis-acid catalysed addition
of trimethylsilylcyanide (TMSCN) to the CˆN bond of the Schi€'s bases yielding the a-amino
nitriles 3.1-4.
In this step, a new stereogenic centre is formed at C-1 of the cyclopentane skeleton. Since the
stereochemistry of the chiral auxiliary is ®xed, theoretically up to four diastereomeric a-amino
nitriles can be obtained. In accordance with our earlier observations in the cyclohexane series,6,7
TMSCN addition to the ketimines 2.1-4. yielded oily mixtures of all four theoretically feasible
diastereomers A±D of the a-aminocarbonitriles 3.1-4 (Scheme 3) even under di€erent reaction
conditions, each exhibiting four sets of signals in the 13C NMR spectra. The relative proportions
of the nitriles in the 3.1-4 mixtures were assigned by comparison of the intensities of
corresponding 13NMR signals, a method we have established previously.6

J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
3233
Scheme 2. Synthesis of the a-amino acids 6.1-4
Scheme 3. The four theoretically feasible stereomers A±D
Although the selective synthesis of only a single a-amino nitrile failed, we could make interesting
observations changing the solvent from methanol to hexane and running the formation of the
amino nitriles 3.1-4 at 25ꢀC and ^10ꢀC, respectively. The results of these investigations are
summarised in Tables 1 and 2.

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Table 1
Stereochemical composition A±D of the a-amino nitrile mixtures 3.1-4 obtained from reactions in MeOH
Table 2
Stereochemical composition A±D of the a-amino nitrile mixtures 3.1-4 obtained from reactions in n-hexane

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It shows that, apart from the type of alkyl substituent at 2-position of the cyclopentane
skeleton, after 24 h at 25ꢀC in MeOH the trans con®gured a-amino nitrile A was obtained as the
major reaction product in 44±61%, whereas the second trans compound B and the cis nitrile C
was obtained in 23±24% and 14±28%, respectively. In all cases the second cis con®gured a-amino
nitrile D was the minor product in only 2±5%. Neither heating these nitrile mixtures for 3 h in
MeOH in a sealed tube nor re¯uxing them under the exact reaction conditions, i.e. in the presence
of zinc chloride and 1-PEA changed their stereochemical composition, thus indicating that at
25ꢀC the reaction is under thermodynamic control. However, after 3 h at ^10ꢀC in MeOH the
stereochemical outcome of the reaction changes. For the methyl (3.1) and ethyl (3.2) substituted
a-amino nitrile mixtures diastereomer A was still found as the major product (45%) along with
increased amounts of the cis nitrile C (21±28%), which becomes the major reaction product (47 or
59%) in the isopropyl (3.3) and tertiary butyl (3.4) series. Similarly, the second trans nitrile B is
either not formed at all (3.4) or only in negligible amounts of 4% for 3.3. Hence, at ^10ꢀC in
MeOH, the synthesis of the a-amino nitriles 3.1 and 3.2 still occurs with trans-diastereoselectivity,
whereas those of the respective 3.3 and 3.4 series is switched to cis-diastereoselectivity. This
reversal is in accordance with a decreased chemical yield of only 36%, i.e. 74% of the ketimine
mixture 2.4 remains unreacted. Increasing the reaction time from 3 h to 2 weeks, quantitative
yields of the tertiary butyl a-amino nitrile mixture can be obtained, and similarly the trans
compound A becomes the major product (55%). Consequently, the cis-diastereoselectivity
observed after 3 h in MeOH at ^10ꢀC in the 3.3 and 3.4 series is due to a kinetic resolution of the
ketimine mixture 2.3 and 2.4 with the respective aR,2R con®gured imines reacting faster com-
pared to the (aR,2S) con®gured ketimines.
As a model the use of hexane at 25ꢀC was studied for the methyl series, revealing the same
stereochemical composition (A:B:C:D=57:23:16:4) as in MeOH, whereas after 3 h at ^10ꢀC in
hexane we observed that for all four substituents the cis con®gured amino nitrile C becomes the
major product in quantities (47±66%). Furthermore, the amount of A decreases with the size of
the substituent from 43% for methyl to 5% for tertiary butyl. In parallel, the amount of the
second cis nitrile D increases from 5% to 28%. Under these conditions the tertiary butyl
substituted nitrile mixture was obtained in only 37%; however, after 1 week the yield increased to
83% with only small alterations in the stereochemical composition, i.e. the cis nitrile C remains
the dominating product. Therefore, by the choice of the solvent, we are able to run the a-amino
nitrile synthesis with either trans-diastereoselectivity (MeOH) or cis-diastereoselectivity (n-hexane)
in good to quantitative yields.
In order to quantify the e€ect of the additional stereogenic centre we also studied the a-amino
nitrile synthesis using benzylamine derived ketimines. As a result, we found that the trans/cis-
diastereoselectivity of the reaction remained unchanged but of course both the trans as well as the
cis amino nitriles were obtained as racemates. Hence, on the one side the use of 1-PEA in¯uences
the reaction in the sense that it proceeds with diastereo- and enantioselectivity and on the other
side it allows us to separate the subsequent a-amino amide mixtures 4.1-4 under achiral
conditions (vide infra).
2.2. Acidic hydrolysis
Subsequently, the a-amino nitrile mixtures 3.1-4 were subjected to hydrolysis, which was only
successful with conc. sulfuric acid. Therefore, the mixtures obtained in methanol were added
dropwise to precooled (^10ꢀC) sulfuric acid (Procedure I), whereas to those stemming from

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kinetically controlled reactions H2SO4 was added to the hexane solution without work-up at
^10ꢀC (Procedure II). The reactions were kept for 3 h at ^10ꢀC, 3 h at 0ꢀC and ®nally for 1 week
at 25ꢀC yielding the a-amino carboxamides 4.1-4 each as a diastereomeric mixture in 20±68%
chemical yield with essentially unchanged stereochemical distributions for the methyl and ethyl
series (Table 3).
Table 3
Structural and stereochemical distribution of the products obtained from the a-amino nitrile mixtures A±D of 3.1-4
with H2SO4 conc.
However, in the isopropyl and tertiary butyl series the outcome of the acidic hydrolysis di€ered
completely. Hence, for example as shown in Fig. 1 for the isopropyl series 4.3, GC±MS analysis
of the crude product mixtures revealed four peaks (Fig. 1B) with retention times of 2.7, 3.0, 9.8,
and 10.2 min, respectively. The mass peaks of m/z 230 (Fig. 1A), corresponding to M^44, for the
latter two are in accordance with their expected a-amino carboxamide structures and can be
explained with the spontaneous loss of the carboxamide functional group. The entities with
retention times of 2.7 and 3.0 min, respectively, showed mass peaks of m/z 125 [M^44] (Fig. 1/C),
corresponding to hydrogenolysed a-amino carboxamides, i.e. compounds with a primary a-
amino group. Since this hydrogenolysis of the 1-phenylethyl moiety goes along with the loss of
the third stereogenic centre the ®rst two peaks consequently correspond to the cis and trans con-
®gured a-amino carboxamides 5.3, each as non-racemic mixtures of two enantiomers, whereas
the two peaks with higher retention times turned out to stem from the two trans con®gured a-
amino carboxamides 4.3A and 4.3B, respectively.
Thus, it becomes evident that the acidic hydrolysis of the a-amino nitrile mixtures 3.3 and 3.4
runs in parallel with a complete hydrogenolysis of the cis con®gured diastereomers C and D, while
the respective trans con®gured ones, A and B, are only cleaved to a certain degree (Table 3).
2.3. Separation of the ꢀ-aminocarboxamide mixtures 4.1-4
The a-aminocarboxamide mixtures 4.1-4 were separated into diastereomerically pure
compounds by means of ¯ash chromatography and preparative HPLC. For the 4.1 and 4.2 series

J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
3237
Figure 1. GC±MS analyses of the crude 4.3 mixture

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J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
¯ash chromatography yielded two combined fractions. The ®rst one consisted of the stereomers A
and C, whereas the second one was a mixture of B and D. Separation of the A/C mixture was
achieved using HPLC in the reversed-phase mode, while the application of silica gel in normal-
phase mode was successful for the separation of the B/D mixtures. In the case of the 4.3 and 4.4
mixtures, ¯ash chromatography directly gave the two trans con®gured carboxamides A and B as
diastereomerically pure compounds.
2.4. Hydrogenolysis and ®nal hydrolysis
The diastereomerically pure a-amino carboxamides 4.1/A±D, 4.2/A±D, 4.3/A±B and 4.4/A±B,
respectively, were subjected to catalytic transfer hydrogenolysis, using ammonium format and
palladium on charcoal (10%). Re¯uxing for 1 h in methanol gave the corresponding a-amino
amides 5.X in 72±99% yield, which were ®nally hydrolysed with conc. HCl to the target a-amino
.
acid hydrochlorides 6.X HCl. For the removal of NH4Cl the crude products were chromato-
graphed over a strong acidic cation exchange resin using 1 M ammonia as the eluent, yielding the
12 a-amino acids (zwitterionic form) 6.1/A±D, 6.2/A±D, 6.3/A±B and 6.4/A±B in 55±92% yield.
2.5. Absolute stereochemistry
The absolute stereochemistry of all synthesised compounds was deduced stepwise. First,
compound 4.1A was determined as trans-(aR,1R,2R)-2-methyl-1-(1-phenylethylamino)cyclo-
pentanecarboxamide by X-ray analysis (three beam method13). Compound 4.1A (aR,1R,2R) was
hydrogenolysed to 5.1A (1R,2R) which, according to NMR data and speci®c rotation values,
turned out to be the enantiomer of 5.1B. Hence, the (1S,2S)-con®guration could be assigned to
5.1B and (aR,1S,2S) to its chemical precursor 4.1B. For the two cis con®gured compounds 4.1C
and 4.1D the absolute con®guration was derived in analogy to our previous observations, show-
ing that in all cases the major product from kinetically controlled reactions (±10ꢀC, hexane, 3 h)
posesses the same con®guration at C-1 as the chiral auxiliary used (`like-induction'). Thus, the
(aR,1R,2S)-con®guration was assigned to 4.1C and ®nally (aR,1S,2R) to 4.1D. The stereo-
chemical assignments made for the methyl series X.1 account also for the compounds of the ethyl
(X.2), isopropyl (X.3) and tertiary butyl (X.4) series.
3. Conclusions
The asymmetric Strecker synthesis starting from the racemic 2-substituted cyclopentanones
1.1-4 and (R)-1-phenylethylamine gave mixtures of all four possible a-amino nitriles 3.1-4/A±D the
stereochemical composition of which was a€ected by the solvent, the temperature and the 2-alkyl
substituent. Thus, the thermodynamically controlled reactions (MeOH or hexane, 25ꢀC, 24 h)
gave the trans con®gured a-amino nitriles A as major reaction products with trans/cis diastereo-
selectivities (A+B/C+D) ranging from 67:33 for the 3.3 series to 84:16 for the 3.4 series. In contrast,
the kinetically controlled formations (^10ꢀC, hexane, 3 h) yielded the cis con®gured nitriles C as
the dominant products with trans/cis diastereoselectivities of 48:52 (3.1) to 6:94 (3.4) according to
the spatial requirements of the respective alkyl substituents at 2-position. Therefore, regarding
the nucleophilic attack of the cyanide to the ketimine mixtures 2.1-4 the following conclusions
can be drawn.

J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
3239
In the methyl series 2.1 the re-face attack to the (E-aR,2R)- and to the (E-aR,2S)-con®gured
ketimines is hindered by the phenyl group of the 1-phenylethyl moiety, whereas the pseudo-
equatorial oriented methyl group at 2-position does not in¯uence the cyanide addition, which
therefore occurs with a high si-face selectivity (Fig. 2). The si-face attack to the (E-aR,2R)-imine leads
to the trans-(aR,1R,2R)-a-amino nitrile A (43%), the si-face attack to the (E-aR,2S)-imine to the
cis-(aR,1R,2S)-nitrile C (47%). In contrast, both the Z-con®gured ketimines are attacked from the
re-face, since in the respective lowest energy conformers the phenyl group hampers a nucleophilic
attack from the si-face (Fig. 3). The re-face attack on the (Z-aR,2R)-imine leads to the cis-
(aR,1S,2R)-a-amino nitrile D (5%), while the corresponding attack on the (Z-aR,2S)-imine leads to
the trans (aR,1S,2S)-nitrile B (5%).
Figure 2. Proposed nucleophilic attack to the E-aR,2R and E-aR,2S ketimines 2.1
Figure 3. Proposed nucleophilic attack to the Z-aR,2R and Z-aR,2S ketimines 2.1

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J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
In the tertiary butyl series 2.4, as well as in the isopropyl series 2.3, the 1,3-induction mechanism
from the 2.1 and 2.2 series is overlayed by a 1,2-induction mechanism, e.g. the cyanide addition
occurs anti to the bulky tertiary butyl group in all cases. For example, in the (E-aR,2S)-imine the
tertiary butyl group hampers the nucleophilic si-face attack, thus leading to a moderate re-face
selectivity of ꢁ6:1 (D:A=28:5), while for the (E-aR,2R)-imine the re-face is completely blocked
by both the tertiary butyl and the phenyl group of the 1-phenylethyl moiety (Fig. 4). This sterical
hindrance induces the very high si-face selectivity of 66:1, re¯ected in the formation of the cis
con®gured aR,1R,2R amino nitrile C as the predominating product.
Figure 4. Proposed nucleophilic attack to the E-aR,2S and E-aR,2R ketimines 2.4
Accordingly, the nucleophilic cyanide addition to the (Z-aR,2R)- and (Z-aR,2S)-imines gives
rise to the amino nitriles C (originates from the si attack) and D (originates from the re-attack),
respectively (Fig. 5).
In some cases, the original 1:1 ketimine mixtures 2.X [(aR,2R):(aR,2S)=50:50)] were converted
to a 2(R):2(S)ꢁ60:40 mixture of a-amino nitrile products 3.X. This indicates that an inter-
conversion, namely a C-2 epimerisation of the ketimines 2.X, takes place during the cyanide
addition step, although the epimerisation of about 5% is comparably low. Under the applied
reaction conditions, this epimerisation at C-2 of the cyclopentane occurs most likely via an
carbanion intermediate, since enamine intermediates could not be traced in the NMR spectra.
4. Experimental
Melting points were determined with a Reichert melting point apparatus and are uncorrected.
Elemental analyses were obtained with a Perkin±Elmer elemental analyzer PE 240 at the
Department of Biochemistry and Organic Chemistry, University of Freiburg. NMR experiments
were carried out at 300 MHz (1H) and 75.4 MHz (13C), respectively, with a Varian Unity 300

J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
3241
Figure 5. Proposed nucleophilic attack to the Z-aR,2S and Z-aR,2R ketimines 2.4
spectrometer. Chemical shifts are reported as ꢁ values using either TMS (1H) or the solvent peak
(13C) as the reference. Infrared spectra were recorded with a Perkin±Elmer PE 841 spectrometer.
Optical rotations values were measured in a 1 dm cell with a Perkin±Elmer 241 polarimeter.
GC±MS analyses were carried out with a Perkin±Elmer QMASS 910 spectrometer using a RTX-
351 column (Restek GmbH, Bad Soden, Germany). Flash chromatography was performed with
silica gel (Si 60, 0.04±0.063 mm, Sigma±Aldrich Chemie GmbH). Analytical and preparative
HPLC was carried out with Waters equipment, including photodiode-array detection, on silica
gel columns (Si 60, Bischo€ GmbH or Merck Eurolab GmbH) with n-hexane/ethyl acetate
mixtures as mobile phase and on reversed phase columns (RP-18 select AB, Macherey & Nagel
GmbH) using methanol/water mixtures as the eluent. Solvents were puri®ed according to
standard procedures. Starting materials were purchased from either Merck or Fluka companies
and were used without further puri®cation.
4.1. E/Z-2-(RS)-N-[(R)-1-Phenylethyl]cyclopentylidenamines 2.1-4 (mixtures of four
diastereomers)
A mixture of 2-alkylated cyclopentanone 1.1-4 (0.1 mol), (R)-(+)-1-phenylethylamine (0.1 mol,
12.1 g) and a catalytic amount of p-toluenesulfonic acid was dissolved in toluene (2.1-3) and
xylene (2.4), repectively, and re¯uxed for 24 h (2.1), 48 h (2.2), 72 h (2.3) and 240 h (2.4),
respectively, using a Dean±Stark apparatus. The solvent was evaporated in vacuo. The residues
of 2.1 and 2.2 were puri®ed by destillation in vacuo.
4.1.1. E/Z-2-(RS)-N-[(R)-1-Phenylethyl]-2-methylcyclopentylidenamine 2.1
Bp0.3=72±78ꢀC; IR (®lm): ꢂ=3083, 3061, 3027, 2963, 2930, 2866, 1675, 1601, 1491, 1448, 1418,
1368, 1179, 1068, 1008, 761, 700 cm^1.

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4.1.2. E/Z-2(RS)-N-[(R)-1-Phenylethyl]-2-ethylcyclopentylidenamine 2.2
Bp0.7=90±94ꢀC; IR (®lm): ꢂ=3090, 3062, 3027, 2963, 2930, 2873, 1674, 1603, 1492, 1449, 1420,
1367, 1179, 1069, 1009, 762, 699 cm^1.
4.1.3. E/Z-2(RS)-N-[(R)-1-Phenylethyl]-2-(1-methylethyl)cyclopentylidenamine 2.3
IR (®lm): ꢂ=3084, 3062, 3027, 2956, 2870, 1673, 1602, 1492, 1449, 1420, 1365, 1179, 1068,
1011, 761, 700 cm^1.
4.1.4. E/Z-2(RS)-N-[(R)-1-Phenylethyl]-2-(1,1-dimethylethyl)cyclopentylidenamine 2.4
IR (®lm): ꢂ=3082, 3060, 3030, 2963, 2868, 1667, 1602, 1492, 1449, 1420, 1361, 1177, 1080,
1010, 760, 699 cm^1.
4.2. 2-Alkyl-1-(1-phenylethylamino)cyclopentanecarbonitrile mixtures 3.1-4
4.2.1. Procedure I (`thermodynamic control')
To a solution of 10 mmol of the ketimine mixtures 2.1-4 and 75 mg of dry zinc chloride in 50
mL of methanol, 1.5 mL TMSCN (14 mmol) were added slowly at 0ꢀC. The reaction mixture was
either stirred for 3 h at 0ꢀC and then for 21 h at 25ꢀC or for 3 h at ^10ꢀC. The methanol was
evaporated and the residue was dried in vacuo yielding the a-amino nitriles 3.1-4 each as a
diastereomeric mixture of A±D.
4.2.2. Procedure II (`kinetic control')
To a solution of 10 mmol of the ketimine mixtures 2.1-4 and 75 mg of dry zinc chloride in 50
mL of n-hexane 1.5 mL TMSCN (14 mmol) were added dropwise at 25ꢀC and ^10ꢀC,
respectively. The resulting mixture was stirred for 24 h at 25ꢀC or for 3 h at ^10ꢀC. The solvent
was evaporated yielding diastereomeric mixtures of the a-amino nitriles 3.1-4 as pale yellow oils,
which were dried in vacuo and analysed without further puri®cation.
4.2.3. 2-Methyl-1-(1-phenylethylamino)cyclopentanecarbonitriles 3.1/A±D
IR (®lm): ꢂ=3329, 3083, 3061, 3028, 2964, 2872, 2220, 1672, 1603, 1492, 1451, 1371, 1314,
1277, 1205, 1028, 913, 846, 762, 701 cm^1; 1H NMR (CDCl3): 1.18 (A)/1.00 (B)/1.16 (C)/0.89 (D)
(d, J=6.3±6.8 Hz, 3H, 4Â2-CH3), 1.2±2.4 (A±D) (m, 8H, cycloaliphatic H and NH), 1.42 (A)/1.41
(B)/1.41 (C) (d, J=6.6±6.7 Hz, 3H, 3Âb-CH3), 4.15 (A)/4.09 (B)/4.08 (C) (q, J=6.7 Hz, 1H, 3Âa-
CH), 7.1±7.5 (A±D) (m, 5H, aromatic H); 13C NMR (CDCl3): 15.48 (A)/16.26 (B)/12.61 (C)/12.97
(D) (4Â2-CH3), 20.44 (A)/20.89 (B)/20.89 (C)/20.55 (D) (4ÂC-4), 25.78 (A)/25.35 (B)/26.23 (C)/
25.05 (D) (4Âb-CH3), 30.22 (A)/30.83 (B)/30.25 (C)/30.34 (D) (4ÂC-3), 37.69 (A)/35.50 (B)/35.50
(C)/36.69 (D) (4ÂC-5), 44.87 (A)/43.28 (B)/45.21 (C)/44.51 (D) (4ÂC-2), 55.98 (A)/55.62 (B)/55.19
(C)/54.98 (D) (4ÂC-a), 67.08 (A)/66.05 (B)/63.36 (C)/62.30 (D) (4ÂC-1), 120.70 (A)/122.57 (B)/
122.57 (C) (3ÂCN), 126.83 (A)/126.37 (B)/128.18 (C) (3ÂC-20/60), 127.00 (A)/127.11 (B)/126.76 (C)
(3ÂC-40), 128.22 (A)/128.44 (B)/128.22 (C) (3ÂC-30/50), 146.04 (A)/145.81 (B)/146.86 (C) (3ÂC-10).
4.2.4. 2-Ethyl-1-(1-phenylethylamino)cyclopentanecarbonitriles 3.2/A±D
IR (®lm): ꢂ=3330, 3090, 3063, 3029, 2965, 2875, 2221, 1674, 1603, 1493, 1452, 1372, 1307,
1
1277, 1203, 1028, 912, 763, 701 cm^1; H NMR (CDCl3): 1.01 (A)/0.83 (B)/1.06 (C)/0.85 (D) (t,
J=7.3±7.5 Hz, 3H, 4ÂCH2-CH3), 1.2±2.4 (A±D) (m, 10H, cycloaliphatic H, CH2-CH3 and NH),
1.42 (A)/1.41 (B)/1.40 (C) (d, J=6.6 Hz, 3H, 3Âb-CH3), 4.14 (A)/4.09 (B)/4.06 (C)/4.04 (D) (q,

J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
3243
J=6.6 Hz, 1H, 4Âa-CH), 7.1±7.5 (A±D) (m, 5H, aromatic H); 13C NMR (CDCl3): 12.52 (A)/
12.40 (B)/12.60 (C)/12.32 (D) (4ÂCH2-CH3), 20.73 (A)/20.81 (B)/20.73 (C)/20.98 (D) (4ÂC-4),
24.33 (A)/24.62 (B)/24.33 (C)/24.62 (D) (4ÂCH2-CH3), 25.90 (A)/25.36 (B)/26.38 (C) (3Âb-CH3),
28.00 (A)/28.55 (B)/28.13 (C)/27.93 (D) (4ÂC-3), 38.51 (A)/40.16 (B)/36.04 (C)/37.27 (D) (4ÂC-5),
52.06 (A)/50.86 (B)/52.64 (C)/52.13 (D) (4ÂC-2), 56.03 (A)/55.76 (B)/55.18 (C)/54.92 (D) (4ÂC-a),
66.73 (A)/65.68 (B)/62.91 (C)/61.94 (D) (4ÂC-1), 121.23 (A)/121.11 (B)/123.04 (C) (3ÂCN), 126.76
(A)/126.36 (B)/126.05 (C) (3ÂC-20/60), 126.92 (A)/127.08 (B)/126.67 (C)/127.18 (D) (4ÂC-40), 128.15
(A)/128.38 (B)/128.15 (C)/128.00 (D) (4ÂC-30/50), 146.18 (A)/145.69 (B)/147.02 (C) (3ÂC-10).
4.2.5. 2-(1-Methylethyl)-1-(1-phenylethylamino)cyclopentanecarbonitriles 3.3/A±D
IR (®lm): ꢂ=3333, 3080, 3062, 3028, 2959, 2870, 2220, 1673, 1603, 1493, 1449, 1367, 1304,
1276, 1202, 1027, 912, 843, 762, 701 cm^1; 1H NMR (CDCl3): 1.00 (A)/0.92 (B)/1.00 (C)/1.07 (D)
(d, J=6.6 Hz, 3H, 4ÂCH(CH3)2), 1.16 (A)/0.92 (B)/1.26 (C)/0.92 (D) (d, J=6.6 Hz, 3H,
4ÂCH(CH3)2), 1.3±2.5 (A±D) (m, 9H, cycloaliphatic H, CH(CH3)2 and NH), 1.41 (A)/1.41 (B)/
1.42 (C) (d, J=6.6 Hz, 3H, 3Âb-CH3), 4.16 (A)/4.09 (B)/4.10 (C)/4.03 (D) (q, J=6.6 Hz, 1H,
4Âa-CH), 7.1±7.5 (A±D) (m, 5H, aromatic H); 13C NMR (CDCl3): 21.34 (A)/20.73 (B)/20.65 (C)/
21.06 (D) (4ÂCH(CH3)2), 21.76 (A)/21.76 (B)/21.55 (C)/21.48 (D) (4ÂC-4), 22.19 (A)/22.19 (B)/
22.12 (C)/22.02 (D) (4ÂCH(CH3)2), 26.03 (A)/25.11 (B)/26.42 (C)/25.25 (D) (4Âb-CH3), 28.48
(A)/28.02 (B)/28.60 (C) (3ÂC-3), 31.14 (A)/30.67 (B)/28.69 (C)/28.85 (D) (4ÂCH(CH3)2), 40.10
(A)/41.45 (B)/37.67 (C)/38.84 (D) (4ÂC-5), 55.77 (A)/55.68 (B)/54.80 (C)/ 54.29 (D) (4ÂC-a),
57.29 (A)/56.36 (B)/57.42 (C)/57.71 (D) (4ÂC-2), 65.80 (A)/64.50 (B)/61.15 (C)/59.24 (D) (4ÂC-
1), 121.51 (A)/121.16 (B)/123.45 (C)/123.10 (D) (4ÂCN), 126.64 (A)/126.64 (B)/125.99 (C) (3ÂC-
20/60), 126.81 (A)/126.34 (B)/126.34 (C)/126.21 (D) (4ÂC-40), 128.13 (A)/128.41 (B)/128.13 (C)/
128.48 (D) (4ÂC-30/50), 146.35 (A)/145.42 (B)/147.02 (C)/145.10 (D) (4ÂC-10).
4.2.6. 2-(1,1-Dimethylethyl)-1-(1-phenylethylamino)cyclopentanecarbonitriles 3.4/A±D
IR (®lm): ꢂ=3329, 3080, 3063, 3028, 2962, 2869, 2220, 1666, 1603, 1492, 1449, 1363, 1276,
1
1209, 1028, 910, 761, 700 cm^1; H NMR (CDCl3): 1.16 (A)/1.04 (B)/1.19/ (C) 1.12 (D) (s, 9H,
4xC(CH3)3), 1.3±2.6 (A±D) (m, 8H, cycloaliphatic H and NH), 1.40 (A)/1.41 (B)/1.42 (C)/1.40 (D)
(d, J=6.6±6.8 Hz, 3H, 4Âb-CH3), 4.17 (A)/4.15 (B)/4.06 (C)/3.98 (D) (q, J=6.6±6.8 Hz, 1H,
4Âa-CH), 7.1-7.5 (A±D) (m, 5H, aromatic H); 13C NMR (CDCl3): 22.16 (A)/22.41 (B)/20.24 (C)/
20.70 (D) (4ÂC-4), 25.04 (A)/25.41 (B)/24.84 (C)/24.52 (D) (4ÂC-3), 26.62 (A)/26.41 (B)/26.66
(C)/25.74 (D) (4Âb-CH3), 28.41 (A)/28.27 (B)/29.91 (C)/29.66 (D) (q, 4ÂC(CH3)3), 32.72 (A)/
32.67 (B)/32.67 (C)/33.32 (D) (4ÂC(CH3)3), 40.99 (A)/42.64 (B)/37.76 (C)/38.70 (D) (4ÂC-5),
55.27 (A)/55.23 (B)/55.23 (C)/55.07 (D) (4ÂC-a), 61.30 (A)/59.72 (B)/59.51 (C)/59.72 (D) (4ÂC-
2), 63.06 (A)/61.94 (C)/62.80 (D) (3ÂC-1), 122.69 (A)/122.62 (B)/123.68 (C)/123.30 (D) (4ÂCN),
126.53 (A)/126.25 (B)/125.94 (C)/126.32 (D) (4ÂC-20/60), 126.70 (A)/126.98 (B)/126.62 (C)/126.68
(D) (4ÂC-40), 128.14 (A)/128.41 (B)/128.18 (C)/128.47 (D) (4ÂC-30/50), 146.77 (A)/145.85 (B)/
147.20 (C)/146.10 (D) (4ÂC-10).
4.3. 2-Alkyl-1-(1-phenylethylamino)cyclopentanecarboxamide mixtures 4.1-4
4.3.1. Procedure I (`thermodynamic control')
Diastereomeric a-amino nitrile mixtures 3.1-4 (40 mmol) (obtained from reactions in methanol
at 25ꢀC) were dissolved in 80 mL of concentrated H2SO4 and stirred for 3 h at ^10ꢀC, 3 h at 0ꢀC

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and 168 h at 25ꢀC. The mixture was poured onto ice (300 g) and ®ltered over silica gel. The
®ltrate was adjusted to pH 8 with concentrated NH3 and extracted Et2O (3Â200 mL). The
combined organic layers were washed with H2O (2Â200 mL), dried with Na2SO4, ®ltered, and the
Et2O was evaporated, yielding 67% of 4.1 (A:B:C:D=54:21:15:10), 62% of 4.2
(A:B:C:D=55:31:9:5), 20% of 4.3 (A:B=52:48) and 21% of 4.4 (A:B=61:39), respectively. The oily
mixtures were separated into diastereomerically pure a-amino amides by ¯ash chromatography
followed by preparative HPLC.
4.3.2. Procedure II (`kinetic control')
To 40 mmol of the diastereomeric a-amino nitrile mixtures 3.1-2 (obtained from reactions in
hexane at ^10ꢀC) dissolved in 200 mL of n-hexane, 80 mL of concentrated H2SO4 were added
slowly at ^10ꢀC. The mixture was stirred for 3 h at ^10ꢀC, 3 h at 0ꢀC and 168 h at 25ꢀC, poured
onto ice (300 g) and ®ltered over silica gel. The ®ltrate was adjusted to pH 8 with concentrated
NH3 and extracted with Et2O (3Â200 mL). The combined organic layers were washed with H2O
(2Â200 mL), dried with Na2SO4, ®ltered, and the Et2O was evaporated, yielding 62% of 4.1
(A:B:C:D=50:8:34:8) and 68% of 4.2 (A:B:C:D=47:5:38:10), respectively. The oily mixtures were
separated into diastereomerically pure a-amino amides by ¯ash chromatography followed by
preparative HPLC.
4.3.3. Flash chromatography of the ꢀ-aminocarboxamide mixtures 4.1 and 4.2
Stationary phase: Si 60 (230±400 mesh); mobile phase: petrolether (40±60ꢀC):ethyl acetate
(60:40); compound:stationary phase=1:100; fraction size=100 mL; detection: TLC (Si 60 F254
plats) with ninhydrine reagent; recovery rates: 4.1/A=63±74%, 4.1/B=71±82%, 4.1/C=66±69%,
4.1/D=61±62%, 4.2/A=66±79%, 4.2/B=62±81%, 4.2/C=65±67%, 4.2/D=73±98%.
4.3.4. Flash chromatography of the ꢀ-aminocarboxamide mixtures of 4.3 and 4.4
Stationary phase: Si 60 (230±400 mesh); mobile phase: petrolether (40±60ꢀC):ethyl acetate
(70:30); compound:stationary phase=1:100; fraction size=100 mL; detection: TLC (Si 60 F254
plats) with ninhydrine reagent; recovery rates: 4.3/A=81%, 4.3/B=94%, 4.4/A=52%, 4.4/
B=66%.
4.3.5. Analytical HPLC of the ꢀ-aminocarboxamide mixtures 4.1A/C and 4.2A/C
Stationary phase: Nucleosil1 RP-18 select AB (5 mm; 250±4); mobile phase: CH3OH:H2O
(65:35); ¯ow rate: 0.5 mL/min; detection: UV (254 nm).
4.3.6. Analytical HPLC of the ꢀ-aminocarboxamide mixtures 4.1B/D and 4.2B/D
Stationary phase: LiChrosorb1 Si 60 (5 mm, 250±4); mobile phase: n-hexane:ethyl acetate
(50:50); ¯ow rate: 0.6 mL/min; detection: UV (254 nm).
4.3.7. Preparative HPLC of the ꢀ-aminocarboxamide mixtures 4.1A/C and 4.2A/C
Diastereomeric ratios: 4.1: A:C=81:19 (procedure I) and 57:43 (procedure II); 4.2: A:C=94:6
(procedure I) and 68:32 (procedure II); stationary phase: Nucleosil1RP-18 select AB (5 mm, 250±
20); mobile phase: CH3OH:H2O (65:35); ¯ow rate: 6 mL/min; detection: UV (254 nm); recovery
rates: 4.1/A=89±93%, 4.1/C=69±81%, 4.2/A=65±66%, 4.2/C=45±68%.

J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
3245
4.3.8. Preparative HPLC of the ꢀ-aminocarboxamide mixtures 4.1B/D and 4.2B/D
Diastereomeric ratios: 4.1: B:D=94:6 (procedure I) and 64:36 (procedure II); 4.2: B:D=87:13
(procedure I) and 55:45 (procedure II); stationary phase: LiChrosorb1 Si 60 (5 mm, 250±10);
mobile phase: n-hexane:ethyl acetate (50:50); ¯ow rate: 3 mL/min; detection: UV (254 nm);
recovery rates: 4.1/B=77±96%, 4.1/D=92±99%, 4.2/B=70±80%, 4.2/D=55±80%.
4.3.9. (ꢀR,1R,2R)-2-Methyl-1-(1-phenylethylamino)cyclopentanecarboxamide 4.1A
Mp: 75ꢀC; ‰ꢀŠ2D5=+18.6 (c 0.56, CH3OH); IR: ꢂ=3473, 3023, 2962, 2869, 1650, 1608, 1494,
1
1452, 1379, 1305, 1274, 1208, 1142, 1100, 1026, 911, 763, 704 cm^1; H NMR (CDCl3): 0.90 (d,
J=6.8 Hz, 3H, 2-CH3), 1.30 (d, J=6.8 Hz, 3H, b-CH3), 1.36/1.85 (m, 2H, 3-CH2), 1.43/1.74 (m,
2H, 4-CH2), 1.62/2.14 (m, 2H, 5-CH2), 1.76 (m, 1H, 2-H), 3.85 (q, J=6.8 Hz, 1H, a-CH), 7.1±7.4
(m, 5H, aromatic H), 1.5 (s(b), 1H, NH(amine)), 5.6/7.2 (s(b), 2H, NH(amide)); 13C NMR
(CDCl3): 16.78 (2-CH3), 21.95 (C-4), 24.98 (b-CH3), 29.73 (C-5), 31.75 (C-3), 46.25 (C-2),
54.74 (C-a), 72.67 (C-1), 126.20 (C-20/60), 126.89 (C-40), 128.45 (C-30/50), 147.30 (C-10) 178.74
(C-6); C15H22N2O (246.36) calcd: C, 73.13; H, 9.01; N, 11.36; found: C, 73.14; H, 8.91; N,
11.29.
4.3.10. (ꢀR,1S,2S)-2-Methyl-1-(1-phenylethylamino)cyclopentanecarboxamide 4.1B
Colorless oil; ‰ꢀŠ2D5=+111.4 (c 0.6, CH3OH); IR: ꢂ=3453, 2965, 2874, 1673, 1558, 1492, 1453,
1374, 1216, 1132, 757, 701 cm^1; 1H NMR (CDCl3): 0.92 (d, J=6.8 Hz, 3H, 2-CH3), 1.23/1.61 (m,
2H, 4-CH2), 1.25/1.86 (m, 2H, 3-CH2), 1.35 (d, J=6.8 Hz, 3H, b-CH3), 1.85/2.20 (m, 2H, 5-CH2),
2.14 (m, 1H, 2-H), 3.74 (q, J=6.8 Hz, 1H, a-CH), 7.1±7.4 (m, 5H, aromatic H), 1.5 (s(b), 1H,
NH(amine)), 5.1/6.5 (s(b), 2H, NH (amide)); 13C NMR (CDCl3): 16.28 (2-CH3), 22.15 (C-4),
27.26 (b-CH3), 31.95 (C-5), 32.09 (C-3), 46.46 (C-2), 54.35 (C-a), 73.43 (C-1), 126.11 (C-20/60),
126.59 (C-40), 128.44 (C-30/50), 147.44 (C-10), 177.33 (C-6); C15H22N2O (246.36) calcd: C, 73.13;
H, 9.01; N, 11.36; found: C, 72.96; H, 8.90; N, 11.45.
4.3.11. (ꢀR,1R,2S)-2-Methyl-1-(1-phenylethylamino)cyclopentanecarboxamide 4.1C
Colorless oil; ‰ꢀŠ2D5=+33.7 (c 0.4, CH3OH); IR: ꢂ=3442, 2964, 2875, 1667, 1602, 1452, 1373,
1274, 1215, 1153, 1112, 1026, 911, 702 cm^1; 1H NMR (CDCl3): 0.95 (d, J=7.1 Hz, 3H, 2-CH3),
1.25/1.62 (m, 2H, 4-CH2), 1.31 (d, J=6.6 Hz, 3H, b-CH3), 1.35/1.87 (m, 2H, 3-CH2), 1.85/2.21
(m, 2H, 5-CH2), 2.15 (m, 1H, 2-H), 3.80 (q, J=6.6 Hz, 1H, a-CH), 7.1±7.4 (m, 5H, aromatic H),
1.4 (s(b), 1H, NH (amine)), 6.5/7.4 (s(b), 2H, NH (amide)); 13C NMR (CDCl3): 12.80 (2-CH3),
21.47 (C-4), 24.89 (b-CH3), 30.26 (C-5), 31.82 (C-3), 45.05 (C-2), 54.17 (C-a), 70.47 (C-1), 126.09
(C-20/60), 126.98 (C-40), 128.53 (C-30/50), 147.08 (C-10), 180.15 (C-6); C15H22N2O (246.36) calcd: C,
73.13; H, 9.01; N, 11.36; found: C, 72.88; H, 8.98; N, 11.32.
4.3.12. (ꢀR,1S,2R)-2-Methyl-1-(1-phenylethylamino)cyclopentanecarboxamide 4.1.D
Colorless oil; ‰ꢀŠ2D5=+90.0 (c 0.4, CH3OH); IR: ꢂ=3445, 2965, 1674, 1453, 1372, 1203, 1104,
1
762, 702 cm^1; H NMR (CDCl3): 0.94 (d, J=6.9 Hz, 3H, 2-CH3), 1.34 (d, J=6.3 Hz, 3H,
b-CH3), 1.40/2.02 (m, 2H, 3-CH2), 1.75/1.82 (m, 2H, 4-CH2), 2.02/2.41 (m, 2H, 5-CH2), 2.20 (m,
1H, 2-H), 3.73 (q, J=6.7 Hz, 1H, a-CH), 7.1±7.4 (m, 5H, aromatic H), 5.3/6.6 (s(b), 2H, NH (amide));
13C NMR (CDCl3): 12.97 (2-CH3), 21.67 (C-4), 27.09 (b-CH3), 31.53 (C-5), 32.11 (C-3), 44.66
(C-2), 53.57 (C-a), 71.85 (C-1), 126.10 (C-20/60), 126.68 (C-40), 128.55 (C-30/50), 147.46 (C-10),
178.85 (C-6); C15H22N2O (246.36) calcd: C, 73.13; H, 9.01; N, 11.36; found: C, 73.25; H, 9.06;
N, 11.48.

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4.3.13. (ꢀR,1R,2R)-2-Ethyl-1-(1-phenylethylamino)cyclopentanecarboxamide 4.2A
Colorless oil; ‰ꢀŠ2D5=+2.8 (c 0.75, CH3OH); IR: ꢂ=3446, 3340, 3026, 2962, 2875, 1670, 1601,
1451, 1373, 1275, 1202, 1137, 910, 762, 701 cm^1; 1H NMR (CDCl3): 0.76 (t, J=7.3 Hz, 3H, CH2-
CH3), 1.02/1.48 (m, 2H, CH2-CH3), 1.28 (d, J=6.3 Hz, 3H, b-CH3), 1.36/1.83 (m, 2H, 3-CH2),
1.44/1.74 (m, 2H, 4-CH2), 1.50 (m, 1H, 2-H), 1.61/2.11 (m, 2H, 5-CH2), 3.88 (q, J=6.6 Hz, 1H,
a-CH), 7.1±7.4 (m, 5H, aromatic H), 5.6/7.2 (s(b), 2H, NH (amide)); 13C NMR (CDCl3): 12.86
(CH2-CH3), 22.24 (C-4), 24.18 (CH2-CH3), 25.24 (b-CH3), 28.79 (C-3), 31.22 (C-5), 53.72 (C-2),
54.74 (C-a), 72.66 (C-1), 126.25 (C-20/60), 126.95 (C-40), 128.52 (C-30/50), 147.41 (C-10), 178.79 (C-
6); C16H24N2O (260.38) calcd: C, 73.20; H, 9.30; N, 10.75; found: C, 73.18; H, 9.18; N, 10.39.
4.3.14. (ꢀR,1S,2S)-2-Ethyl-1-(1-phenylethylamino)cyclopentanecarboxamide 4.2B
Colorless oil; ‰ꢀŠ2D5=+87.5 (c 0.36, CH3OH); IR: ꢂ=3450, 3330, 3030, 2962, 2873, 1679, 1556,
1
1492, 1450, 1372, 1275, 1200, 1131, 1028, 910, 762, 701 cm^1; H NMR (CDCl3): 0.90 (t, J=7.3
Hz, 3H, CH2-CH3), 1.11/1.56 (m, 2H, CH2-CH3), 1.38 (d, J=6.8 Hz, 3H, b-CH3), 1.41/1.94 (m,
2H, 3-CH2), 1.58 (m, 1H, 2-H), 1.67/1.90 (m, 2H, 4-CH2), 1.84/2.37 (m, 2H, 5-CH2), 3.77 (q, J=6.8
Hz, 1H, a-CH), 7.1±7.4 (m, 5H, aromatic H), 5.0/6.5 (s(b), 2H, NH (amide)); 13C NMR (CDCl3):
13.11 (CH2-CH3), 22.33 (C-4), 23.97 (CH2-CH3), 27.42 (b-CH3), 29.31 (C-3), 33.05 (C-5), 54.16 (C-2),
54.37 (C-a), 73.36 (C-1), 126.07 (C-20/60), 126.59 (C-40), 128.47 (C-30/50), 147.57 (C-10), 177.60 (C-6);
C16H24N2O (260.38) calcd: C, 73.20; H, 9.30; N, 10.75; found: C, 73.51; H, 9.46; N, 10.80.
4.3.15. (ꢀR,1R,2S)-2-Ethyl-1-(1-phenylethylamino)cyclopentanecarboxamide 4.2C
Colorless oil; ‰ꢀŠ2D5=^2.2 (c 0.57, CH3OH); IR: ꢂ=3442, 2963, 2864, 1674, 1453, 1372, 1205,
1111, 910, 763, 701 cm^1; 1H NMR (CDCl3): 0.85 (t, J=7.4 Hz, 3H, CH2-CH3), 1.10/1.23 (m, 2H,
CH2-CH3), 1.20/1.94 (m, 2H, 3-CH2), 1.29 (d, J=6.6 Hz, 3H, b-CH3), 1.60/1.60 (m, 2H, 4-CH2),
1.88/2.21 (m, 2H, 5-CH2), 1.94 (m, 1H, 2-H), 3.79 (q, J=6.6 Hz, 1H, a-CH), 7.1±7.4 (m, 5H,
aromatic H), 5.9/7.4 (s(b), 2H, NH (amide)); 13C NMR (CDCl3): 12.87 (CH2-CH3), 21.38 (C-4),
21.45 (CH2-CH3), 24.94 (b-CH3), 29.25 (C-3), 30.27 (C-5), 52.57 (C-2), 54.14 (C-a), 70.75 (C-1),
126.09 (C-20/60), 127.01 (C-40), 128.55 (C-30/50), 147.08 (C-10), 180.10 (C-6); C16H24N2O (260.38)
calcd: C, 73.20; H, 9.30; N, 10.75; found: C, 73.16; H, 9.20; N, 10.68.
4.3.16. (ꢀR,1S,2R)-2-Ethyl-1-(1-phenylethylamino)cyclopentanecarboxamide 4.2D
Colorless oil; ‰ꢀŠ2D5=+38.2 (c 0.27, CH3OH); IR: ꢂ=3445, 2962, 2877, 1672, 1556, 1453, 1371,
1274, 1206, 1105, 911, 756, 702 cm^1; 1H NMR (CDCl3): 0.90 (t, J=7.3 Hz, 3H, CH2-CH3), 1.26/
1.58 (m, 2H, CH2-CH3), 1.36/2.08 (m, 2H, 3-CH2), 1.37 (d, J=6.8 Hz, 3H, b-CH3), 1.73/1.85 (m,
2H, 4-CH2), 2.02 (m, 1H, 2-H), 2.02/2.38 (m, 2H, 5-CH2), 3.76 (q, J=6.6 Hz, 1H, a-CH), 7.1±7.4
(m, 5H, aromatic H), 5.3/6.7 (s(b), 2H, NH (amide)); 13C NMR (CDCl3): 12.85 (CH2-CH3), 21.57
(C-4), 21.67 (CH2-CH3), 27.16 (b-CH3), 29.60 (C-3), 31.97 (C-5), 52.09 (C-2), 53.53 (C-a), 72.05
(C-1), 126.05 (C-20/60), 126.67 (C-40), 128.57 (C-30/50), 147.53 (C-10), 178.98 (C-6); C16H24N2O
(260.38) calcd: C, 73.20; H, 9.30; N, 10.75; found: C, 72.42; H, 9.09; N, 10.49.
4.3.17. (ꢀR,1R,2S)-2-(1-Methylethyl)-1-(1-phenylethylamino)cyclopentanecarboxamide 4.3A
Colorless oil; ‰ꢀŠ2D5=+71.4 (c 0.65, CH3OH), IR: ꢂ=3446, 2958, 2871, 1671, 1602, 1452, 1370,
1275, 1200, 1026, 760, 701 cm^1; 1H NMR (CDCl3): 0.81 (d, J=6.8 Hz, 3H, CH(CH3)2), 0.90 (d,
J=6.8 Hz, 3H, CH(CH3)2), 1.30 (d, J=6.8 Hz, 3H, b-CH3), 1.44/1.74 (m, 2H, 4-CH2), 1.52/1.71
(m, 2H, 3-CH2), 1.55 (m, 1H, 2-H), 1.65/2.13 (m, 2H, 5-CH2), 1.78 (m, 1H, CH(CH3)2), 3.88 (q,
J=6.7 Hz, 1H, a-CH), 7.2±7.4 (m, 5H, aromatic H), 5.8/7.4 (s(b), 2H, NH (amide)); 13C NMR

J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
3247
(CDCl3): 20.19 (CH(CH3)2), 22.30 (C-4), 23.69 (CH(CH3)2), 25.56 (b-CH3), 26.58 (C-3), 28.44
(CH(CH3)2), 32.73 (C-5), 55.04 (C-a), 59.29 (C-2), 72.47 (C-1), 126.16 (C-20/60), 126.92 (C-40),
128.56 (C-30/50), 147.48 (C-10) 179.39 (C-6); C17H26N2O (274.41) calcd: C, 74.40; H, 9.56; N,
10.20; found: C, 73.89; H, 9.58; N, 10.16.
4.3.18. (ꢀR,1S,2R)-2-(1-Methylethyl)-1-(1-phenylethylamino)cyclopentanecarboxamide 4.3B
Colorless oil; ‰ꢀŠ2D5=+3.8 (c 0.61, CH3OH); IR: ꢂ=3329, 2960, 2870, 1673, 1608, 1561, 1449,
1
1383, 1275, 1201, 1130, 1026, 922, 760, 702 cm^1; H NMR (CDCl3): 0.87 (d, J=6.6 Hz, 3H,
CH(CH3)2), 1.03 (d, J=6.6 Hz, 3H, CH(CH3)2), 1.36 (d, J=6.8 Hz, 3H, b-CH3), 1.55 (m, 1H, 2-
H), 1.58 (m, 1H, CH(CH3)2), 1.58/1.83 (m, 2H, 3-CH2), 1.59/1.82 (m, 2H, 4-CH2), 1.80/2.22 (m,
2H, 5-CH2), 3.75 (q, J=6.8 Hz, 1H, a-CH), 7.2±7.4 (m, 5H, aromatic H), 5.3/6.8 (s(b), 2H, NH
(amide)); 13C NMR (CDCl3): 21.49 (CH(CH3)2), 22.58 (C-4), 23.44 (CH(CH3)2), 27.75 (b-CH3),
28.74 (C-3), 28.83 (CH(CH3)2), 34.92 (C-5), 54.07 (C-a), 59.06 (C-2), 72.78 (C-1), 124.48 (C-30/50),
125.88 (C-20/60), 126.49 (C-40), 147.98 (C-10) 178.65 (C-6); C17H26N2O (274.41) calcd: C, 74.40; H,
9.56; N, 10.20; found: C, 74.56; H, 9.40; N, 9.82.
4.3.19. (ꢀR,1R,2S)-2-(1,1-Dimethylethyl)-1-(1-phenylethylamino)cyclopentanecarboxamide 4.4A
Colorless oil; ‰ꢀŠ2D5=+65.7 (c 0.33, CH3OH); IR: ꢂ=3442, 3252, 2961, 2870, 1673, 1563, 1450,
1
1368, 1313, 1216, 1132, 1024, 910, 759, 701 cm^1; H NMR (CDCl3): 1.01 (s, 9H,C(CH3)3), 1.32
(d, J=6.8 Hz, 3H, b-CH3), 1.45/1.80 (m, 2H, 4-CH2), 1.63/2.08 (m, 2H, 5-CH2), 1.67 (m, 1H, 2-
H), 1.77/1.77 (m, 2H, 3-CH2), 3.87 (q, J=6.6 Hz, 1H, a-CH), 7.1±7.4 (m, 5H, aromatic H), 5.9/
7.5 (s(b), 2H, NH (amide)); 13C NMR (CDCl3): 21.30 (C-4), 26.19 (C-3), 26.19 (b-CH3), 28.94
(C(CH3)3), 33.18 (C(CH3)3), 33.34 (C-5), 55.41 (C-a), 63.86 (C-2), 71.07 (C-1), 125.92 (C-20/60),
126.72 (C-40), 128.54 (C-30/50), 147.98 (C-10), 179.82 (C-6); C18H28N2O (288.44) calcd: C, 74.95;
H, 9.79; N, 9.70; found: C, 74.96; H, 9.70; N, 9.15.
4.3.20. (ꢀR,1S,2R)-2-(1,1-Dimethylethyl)-1-(1-phenylethylamino)cyclopentanecarboxamide 4.4B
Colorless oil; ‰ꢀŠ2D5=^6.2 (c 0.66, CH3OH); IR: ꢂ=3450, 3336, 2960, 2870, 1678, 1552, 1450,
1
1369, 1313, 1201, 1130, 1027, 761, 701 cm^1; H NMR (CDCl3): 1.03 (s, 9H, C(CH3)3), 1.37 (d,
J=6.8 Hz, 3H, b-CH3), 1.67/1.94 (m, 2H, 4-CH2), 1.71 (m, 1H, 2-H), 1.75/1.75 (m, 2H, 3-CH2),
1.83/2.36 (m, 2H, 5-CH2), 3.80 (q, J=6.8 Hz, 1H, a-CH), 7.1±7.4 (m, 5H, aromatic H), 5.1/6.8
(s(b), 2H, NH (amide)); 13C NMR (CDCl3): 21.37 (C-4), 26.53 (C-3), 28.39 (b-CH3), 29.20
(C(CH3)3), 33.03 (C(CH3)3), 36.96 (C-5), 54.75 (C-a), 63.40 (C-2), 71.64 (C-1), 125.83 (C-20/60),
126.47 (C-40), 128.53 (C-30/50), 148.32 (C-10), 178.83 (C-6); C18H28N2O (288.44) calcd: C, 74.95;
H, 9.79; N, 9.70; found: C, 75.40; H, 9.93; N, 9.37.
4.4. 1-Amino-2-alkylcyclopentanecarboxamides 5.1-4
To a solution of 1 mmol of the diastereomerically pure a-amino carboxamides 4.1A±D, 4.2A±D,
4.3A±B and 4.4A±B, respectively, in 50 mL of CH3OH, 280 mg of Pd/C (10%) and 510 mg of
ammonium formiate were added and the mixture was re¯uxed for 1 h. The cooled solution was
®ltered over Celite and the solvent was evaporated yielding the oily a-amino amides which were
dried in vacuo. For microanalysis the oily a-amino amides were converted into their hydrochloride
salts using ether saturated with HCl gas.

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J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
4.4.1. (1R,2R)-1-Amino-2-methylcyclopentanecarboxamide 5.1A
Yield: 91%; colorless oil; ‰ꢀŠ2D5=^37.1 (c 1.0, CH3OH); IR: ꢂ=3336, 2963, 2875, 1658, 1459,
1
1383, 1355, 1208, 1125 cm^1; H NMR (CDCl3): 0.97 (d, J=6.8 Hz, 3H, 2-CH3), 1.47/2.46 (m,
2H, 5-CH2), 1.52/1.88 (m, 2H, 3-CH2), 1.70/1.83 (m, 2H, 4-CH2), 1.73 (m, 1H, 2-H), 1.6 (s(b),
2H, NH (amine)), 5.7/7.2 (s(b), 2H, NH (amide)); 13C NMR (CDCl3): 15.63 (2-CH3), 22.58 (C-4),
33.35 (C-3), 39.96 (C-5), 47.85 (C-2), 67.65 (C-1), 178.82 (C-6); C7H14N2O (142.20).
4.4.2. (1R,2R)-1-Amino-2-methylcyclopentanecarboxamide hydrochloride 5.1AÂHCl
Mp: 234ꢀC; C7H15N2OCl (178.52) calcd: C, 47.09; H, 8.47; N, 15.68; found: C, 47.19; H, 8.57;
N, 15.82.
4.4.3. (1S,2S)-1-Amino-2-methylcyclopentanecarboxamide 5.1B
25
1
Yield: 92%; colorless oil; ‰ꢀŠD =+37.7 (c 0.5, CH3OH); IR, H NMR and 13C NMR data are
identical with those of 5.1A.
4.4.4. (1S,2S)-1-Amino-2-methylcyclopentanecarboxamide hydrochloride 5.1BÂHCl
Mp: 238ꢀC; C7H15N2OCl (178.52) calcd: C, 47.09; H, 8.47; N, 15.68; found: C, 47.10; H, 8.46;
N, 15.83.
4.4.5. (1R,2S)-1-Amino-2-methylcyclopentanecarboxamide 5.1C
Yield: 90%; colorless oil; ‰ꢀŠ2D5=+16.8 (c 0.69, CH3OH); IR: ꢂ=3324, 2957, 2874, 1662, 1454,
1
1384, 1216, 1106 cm^1; H NMR (CDCl3): 0.88 (d, J=6.8 Hz, 3H, 2-CH3), 1.29/1.90 (m, 2H, 3-
CH2), 1.55/2.25 (m, 2H, 5-CH2), 1.6±1.8 (m, 2H, 4-CH2), 2.49 (m, 1H, 2-H), 1.3 (s(b), 2H, NH
(amine)), 5.9/7.5 (s(b), 2H, NH (amide)), 13C NMR (CDCl3): 12.83 (2-CH3), 21.71 (C-4), 31.41
(C-3), 40.05 (C-5), 42.01 (C-2), 66.76 (C-1), 179.92 (C-6).
4.4.6. (1R,2S)-1-Amino-2-methylcyclopentanecarboxamide hydrochloride 5.1CÂHCl
Mp: 235ꢀC; C7H15N2OCl (178.52) calcd: C, 47.09; H, 8.47; N, 15.68; found: C, 47.17; H, 8.57;
N, 15.83.
4.4.7. (1S,2R)-1-Amino-2-methylcyclopentanecarboxamide 5.1D
25
1
Yield: 72%; colorless oil; ‰ꢀŠD =^12.7 (c 0.4, CH3OH); IR, H NMR and 13C NMR data are
identical with those of 5.1C; C7H14N2O (142.20) calcd: C, 59.12; H, 9.93; N, 19.69; found: C,
58.87; H, 9.83; N, 19.42.
4.4.8. (1R,2R)-1-Amino-2-ethylcyclopentanecarboxamide 5.2A
Yield: 97%; oil; ‰ꢀŠ2D5=^44.8 (c 1.0, CH3OH); IR: ꢂ=3282, 2959, 2869, 1677, 1456, 1384, 1201,
1
1119 cm^1; H NMR (CDCl3): 0.82 (t, J=7.2 Hz, 3H, CH2-CH3), 1.09/1.48 (m, 2H, CH2-CH3),
1.38/1.85 (m, 2H, 3-CH2), 1.40 (m, 1H, 2-H), 1.42/2.30 (m, 2H, 5-CH2), 1.62/1.72 (m, 2H, 4-
CH2), 1.9 (s(b), 2H, NH (amine)), 6.3/7.2 (s(b), 2H, NH (amide)); 13C NMR (CDCl3): 13.07
(CH2-CH3), 22.61 ( C-4), 23.43 (CH2-CH3), 30.69 (C-3), 40.46 (C-5), 55.40 (C-2), 67.26 (C-1),
179.22 (C-6).
4.4.9. (1R,2R)-1-Amino-2-ethylcyclopentanecarboxamide hydrochloride 5.2AÂHCl
Mp: 244ꢀC; C8H17N2OCl (192.68) calcd: C, 49.86; H, 8.90; N, 14.53; found: C, 49.73; H, 8.89;
N, 14.61.

J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
3249
4.4.10. (1S,2S)-1-Amino-2-ethylcyclopentanecarboxamide 5.2B
25
1
Yield: 91%; oil; ‰ꢀŠD =+47.9 (c 1.0, CH3OH), IR, H NMR and 13C NMR data are identical
with those of 5.2A.
4.4.11. (1S,2S)-1-Amino-2-ethylcyclopentanecarboxamide hydrochloride 5.2BÂHCl
Mp: 246ꢀC; C8H17N2OCl (192.68) calcd: C, 49.86; H, 8.90; N, 14.53; found: C, 49.66; H, 8.90;
N, 14.64.
4.4.12. (1R,2S)-1-Amino-2-ethylcyclopentanecarboxamide 5.2C
Yield: 93%; oil; ‰ꢀŠ2D5=+17.9 (c 1.0, CH3OH); IR: ꢂ=3301, 2951, 2866, 1667, 1407, 1192, 1182
1
cm^1; H NMR (CDCl3): 0.84 (t, J=7.3 Hz, 3H, CH2-CH3), 1.11/1.30 (m, 2H, CH2-CH3), 1.20/
1.91 (m, 2H, 3-CH2), 1.48/2.15 (m, 2H, 5-CH2), 1.69/1.69 (m, 2H, 4-CH2), 2.26 (m, 1H, 2-H), 1.5
(s(b), 2H, NH (amine)), 6.3/7.5 (s(b), 2H, NH (amide)); 13C NMR (CDCl3): 12.62 (CH2-CH3),
21.47 (C-4), 22.00 (CH2-CH3), 29.08 (C-3), 40.34 (C-5), 49.06 (C-2), 66.31 (C-1), 180.39 (C-6).
4.4.13. (1R,2S)-1-Amino-2-ethylcyclopentanecarboxamide hydrochloride 5.2CÂHCl
Mp: 247ꢀC; C8H17N2OCl (192.68) calcd: C, 49.86; H, 8.90; N, 14.53; found: C, 49.64; H, 8.88;
N, 14.43.
4.4.14. (1S,2R)-1-Amino-2-ethylcyclopentanecarboxamide 5.2D
25
Yield: 89%; oil; ‰ꢀŠ =^14.3 (c 0.35, CH3OH); IR, 1H NMR and 13C NMR data are identical
D
with those of 5.2C.
4.4.15. (1S,2R)-1-Amino-2-ethylcyclopentanecarboxamide hydrochloride 5.2DÂHCl
Mp: 243ꢀC; C8H17N2OCl (192.68) calcd: C, 49.86; H, 8.90; N, 14.53; found: C, 49.73; H, 8.88;
N, 14,70.
4.4.16. (1R,2S)-1-Amino-2-(1-methylethyl)cyclopentanecarboxamide 5.3A
Yield: 99%; oil; ‰ꢀŠ2D5=^10.0 (c 1.0, CH3OH); IR: ꢂ=3300, 2960, 2871, 1665, 1469, 1385, 1366,
1
1204 cm^1; H NMR (CDCl3): 0.72 (d, J=6.6 Hz, 3H, CH(CH3)2), 0.84 (d, J=6.6 Hz, 3H,
CH(CH3)2), 1.36 (m, 1H, 2-H), 1.54/2.30 (m, 2H, 5-CH2), 1.60/1.90 (m, 2H, 3-CH2), 1.61/1.76 (m,
2H, 4-CH2), 1.80 (m, 1H, CH(CH3)2), 2.5 (s(b), 2H, NH (amine)), 6.6/7.4 (s(b), 2H, NH (amide));
13C NMR (CDCl3): 21.96 (CH(CH3)2), 22.49 (CH(CH3)2), 22.58 (C-4), 29.06 (C-100), 31.42 (C-3),
42.78 (C-5), 61.72 (C-2), 66.42 (C-1), 179.85 (C-6).
4.4.17. (1R,2S)-1-Amino-2-(1-methylethyl)cyclopentanecarboxamide hydrochloride 5.3AÂHCl
Mp: 237ꢀC; C9H19N2OCl (206.71) calcd: C, 52.29; H, 9.27; N, 13.54; found: C, 52.39; H, 9.80;
N, 13.21.
4.4.18. (1S,2R)-1-Amino-2-(1-methylethyl)cyclopentanecarboxamide 5.3B
25
1
Yield: 97%; oil; ‰ꢀŠD =+11.7 (c 1.0, CH3OH); IR, H NMR and 13C NMR data are identical
with those of 5.3A.
4.4.19. (1S,2R)-1-Amino-2-(1-methylethyl)cyclopentanecarboxamide hydrochloride 5.3BÂHCl
Mp: 236ꢀC; C9H19N2OCl (206.71) calcd: C, 52.29; H, 9.27; N, 13.54; found: C, 52.28; H, 9.33;
N, 13.47.

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4.4.20. (1R,2S)-1-Amino-2-(1,1-dimethylethyl)cyclopentanecarboxamide 5.4A
Yield: 80%; mp: 68ꢀC; ‰ꢀŠD25=^18.6 (c 1.0, CH3OH); IR: ꢂ=3438, 2957, 1668, 1477, 1397, 1368,
1215, 755 cm^1; 1H NMR (CDCl3): 0.94 (s, 9H, C(CH3)3), 1.56/2.32 (m, 2H, 5-CH2), 1.65 (m, 1H,
2-H), 1.68/1.86 (m, 2H, 4-CH2), 1.86/1.96 (m, 2H, 3-CH2), 2.2 (s(b), 2H, NH (amine)), 6.3/7.4
(s(b), 2H, NH (amide)); 13C NMR (CDCl3): 21.27 (C-4), 27.60 (C-3), 28.95 (C(CH3)3), 32.73
(C(CH3)3), 44.50 (C-5), 63.79 (C-2), 65.49 (C-1), 180.13 (C-6); C10H20N2O (184.28) calcd: C,
65.18; H, 10.95; N, 15.19; found: C, 65.04; H, 10.79; N, 14.76.
4.4.21. (1S,2R)-1-Amino-2-(1,1-dimethylethyl)cyclopentanecarboxamide 5.4B
25
ꢀ
1
Yield: 82%; mp: 65 C; ‰ꢀŠD =+19.8 (c 1.0, CH3OH); IR, H NMR and 13C NMR data are
identical with those of 5.4A; C10H20N2O (184.28) calcd: C, 65.18; H, 10.95; N, 15.19; found: C,
65.21; H, 10.98; N, 15.08.
4.5. 1-Amino-2-alkylcyclopentanecarboxylic acids 6.1-4
An amount of 1 mmol of the stereomerically pure a-amino carboxamides 5.1A±D, 5.2A±D,
5.3A±B, and 5.4A±B, respectively, were dissolved in 10 mL of concentrated hydrochloric acid and
re¯uxed at 80ꢀC for 10 h. The solution was evaporated to dryness, the residue was dissolved in
water and chromatographed using strong acid ion exchang resin (Merck Eurolab GmbH Art.
4765) and 1 M ammonia as the eluent. The combined fractions were concentrated in vacuo
yielding the a-amino acids 6.1A±D, 6.2A±D, 6.3A±B, and 6.4A±B in the zwitterionic form.
4.5.1. (1R,2R)-1-Amino-2-methylcyclopentanecarboxylic acid 6.1A
25
ꢀ
1
Yield: 92%; mp: 280 C (decomp); ‰ꢀŠD =^16.3 (c 0.63, CH3OH); H NMR (CD3OD) 1.08 (d,
J=6.7 Hz, 3H, 2-CH3), 1.69/1.89 (m, 2H, 3-CH2), 1.76/1.87 (m, 2H, 4-CH2), 1.78/2.46 (m, 2H, 5-
CH2), 2.00 (m, 1H, 2-H); 13C NMR (CD3OD): 15.06 (2-CH3), 24.35 (C-4), 34.96 (C-3), 36.29 (C-
5), 45.33 (C-2), 70.55 (C-1), 175.88 (C-6); C7H13NO2 (143.18) calcd: C, 58.72; H, 9.16; N, 9.77;
found: C, 58.61; H, 9.16; N, 9.72.
4.5.2. (1S,2S)-1-Amino-2-methylcyclopentanecarboxylic acid 6.1B
Yield: 91%; mp: 275ꢀC (decomp); ‰ꢀŠD25=+20.1 (c 0.47, CH3OH); 1H NMR and 13C NMR data
are identical with those of 6.1A; C7H13NO2 (143.18) calcd: C, 58.72; H, 9.16; N, 9.77; found: C,
58.53; H, 9.55; N, 9.85.
4.5.3. (1R,2S)-1-Amino-2-methylcyclopentanecarboxylic acid 6.1C
Yield: 91%; mp: 277ꢀC (decomp); ‰ꢀŠD25=^17.4 (c 0.49, CH3OH); 1H NMR (CD3OD): 1.00 (d,
J=7.2 Hz, 3H, 2-CH3), 1.40/1.98 (m, 2H, 3-CH2), 1.79/1.79 (m, 2H, 4-CH2), 1.82/2.39 (m, 2H, 5-
CH2), 2.50 (m, 1H, 2-H); 13C NMR (CD3OD): 13.25 (2-CH3), 23.50 (C-4), 33.06 (C-3), 37.17 (C-
5), 43.49 (C-2), 71.20 (C-1), 176.20 (C-6); C7H13NO2 (143.18) calcd: C, 58.72; H, 9.16; N, 9.77;
found: C, 58.62; H, 9.16; N, 9.61.
4.5.4. (1S,2R)-1-Amino-2-methylcyclopentanecarboxylic acid 6.1D
Yield: 87%; mp: 269ꢀC (decomp); ‰ꢀŠD25=+20.5 (c 0.49, CH3OH); 1H NMR and 13C NMR data
are identical with those of 6.1C; C7H13NO2 (143.18) calcd: C, 58.72; H, 9.16; N, 9.77; found: C,
58.59; H, 9.16; N, 9.58.

J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
3251
4.5.5. (1R,2R)-1-Amino-2-ethylcyclopentanecarboxylic acid 6.2A
25
ꢀ
1
Yield: 88%; mp: 267 C (decomp); ‰ꢀŠD =^20.9 (c 1.0, CH3OH); H NMR (CD3OD): 0.92 (t,
J=7.4 Hz, 3H, CH2-CH3), 1.29/1.67 (m, 2H, CH2-CH3), 1.59/1.98 (m, 2H, 3-CH2), 1.74/1.90 (m,
2H, 4-CH2), 1.78 (m, 1H, 2-H), 1.79/2.42 (m, 2H, 5-CH2); 13C NMR (CD3OD): 13.37 (CH2-
CH3), 24.19 (CH2-CH3), 24.22 (C-4), 32.08 (C-3), 36.63 (C-5), 52.84 (C-2), 70.60 (C-1),
175.81 (C-6); C8H15NO2 (157.21) calcd: C, 61.12; H, 9.62; N, 8.90; found: C, 60.67; H, 9.49;
N, 8.72.
4.5.6. (1S,2S)-1-Amino-2-ethylcyclopentanecarboxylic acid 6.2B
Yield: 84%; mp: 269ꢀC (decomp); ‰ꢀŠD25=+17.1 (c 0.51, CH3OH); 1H NMR and 13C NMR data
are identical with those of 6.2A; C8H15NO2 (157.21) calcd: C, 61.12; H, 9.62; N, 8.90; found: C,
60.57; H, 9.27; N, 8.67.
4.5.7. (1R,2S)-1-Amino-2-ethylcyclopentanecarboxylic acid 6.2C
25
Yield: 81%; mp: 271ꢀC (decomp); ‰ꢀŠ =^22.7 (c 0.52, CH3OH); 1H NMR (CD3OD): 0.96 (t,
D
J=7.4 Hz, 3H, CH2-CH3), 1.22/1.54 (m, 2H, CH2-CH3), 1.35/2.08 (m, 2H, 3-CH2), 1.81/1.81 (m,
2H, 4-CH2), 1.82/2.38 (m, 2H, 5-CH2), 2.35 (m, 1H, 2-H); 13C NMR (CD3OD): 13.32 (CH2-
CH3), 22.96 (CH2-CH3), 23.17 (C-4), 30.49 (C-3), 37.47 (C-5), 50.65 (C-2), 71.01 (C-1), 177.00 (C-
6); C8H15NO2 (157.21) calcd: C, 61.12; H, 9.62; N, 8.90; found: C, 60.58; H, 9.43; N, 8.73.
4.5.8. (1S,2R)-1-Amino-2-ethylcyclopentanecarboxylic acid 6.2D
Yield: 80%; mp: 273ꢀC (decomp); ‰ꢀŠD25=^20.1 (c 0.63, CH3OH); 1H NMR and 13C NMR data
are identical with those of 6.2C; C8H15NO2 (157.21) calcd: C, 61.12; H, 9.62; N, 8.90; found: C,
60.46; H, 9.42; N, 8.62.
4.5.9. (1R,2S)-1-Amino-2-(1-methylethyl)cyclopentanecarboxylic acid 6.3A
25
Yield: 80%; mp: 254ꢀC (decomp); ‰ꢀŠD =^19.9 (c 0.1, CH3OH); H NMR (CD3OD): 0.92 (d,
J=6.6 Hz, 3H, CH(CH3)2), 1.02 (d, J=6.6 Hz, 3H, CH(CH3)2), 1.62 (m, 1H, 2-H), 1.71/1.90 (m,
2H, 4-CH2), 1.72/1.96 (m, 2H, 3-CH2), 1.82/2.42 (m, 2H, 5-CH2), 1.89 (m, 2H, CH(CH3)2); 13C
NMR (CD3OD): 22.35 (CH(CH3)2), 23.13 (CH(CH3)2), 23.95 (C-4), 30.48 (CH(CH3)2), 32.25 (C-
3), 38.45 (C-5), 58.63 (C-2), 69.84 (C-1), 176.27 (C-6); C9H17NO2Â0.5 H2O (180.24) calcd: C,
59,97; H, 10.07; N, 7.76; found: C, 59.80; H, 9.56; N, 7.78.
1
4.5.10. (1S,2R)-1-Amino-2-(1-methylethyl)cyclopentanecarboxylic acid 6.3B
Yield: 66%; mp: 257ꢀC (decomp); ‰ꢀŠD25=+17.3 (c 0.22, CH3OH); 1H NMR and 13C NMR data
are identical with those of 6.3A; C9H17NO2 (171.24) calcd: C, 63.12; H, 10.01; N, 8.17; found: C,
62.93; H, 9.88; N, 7.98.
4.5.11. (1R,2S)-1-Amino-2-(1,1-dimethylethyl)cyclopentanecarboxylic acid 6.4A
25
ꢀ
1
Yield: 55%; mp: 259 C (decomp); ‰ꢀŠD =^22.1 (c 0.5, CH3OH); H NMR (CD3OD): 1.01 (s,
9H, C(CH3)3), 1.74/2.25 (m, 2H, 5-CH2), 1.76/1.85 (m, 2H, 4-CH2), 1.85 (m, 1H, 2-H), 1.91/1.91
(m, 2H, 3-CH2); 13C NMR (CD3OD): 22.46 (C-4), 29.13 (C-3), 29.86 (C(CH3)3), 34.08 (C(CH3)3),
42.95 (C-5), 64.41 (C-2), 67.62 (C-1), 181.69 (C-6); C10H19NO2 (185.26) calcd: C, 64.84; H, 10.35;
N, 7.55; found: C, 64.19; H, 9.92; N, 7.23.

3252
J. Wede et al. / Tetrahedron: Asymmetry 11 (2000) 3231±3252
4.5.12. (1S,2R)-1-Amino-2-(1,1-dimethylethyl)cyclopentanecarboxylic acid 6.4B
Yield: 70%; mp: 255ꢀC (decomp); ‰ꢀŠD25=+19.6 (c 0.26, CH3OH); 1H NMR and 13C NMR data are
identical with those of 6.4A; C10H19NO2 (185.26) calcd: C, 64.84; H, 10.35; N, 7.55; found: C, H, N.
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