Carbocyclic α,β-diamino acids: Asymmetric Strecker synthesis of stereomeric 1,2-diaminocyclohexanecarboxylic acids

Article abstract of DOI:10.1016/S0957-4166(02)00610-9

Asymmetric syntheses of trans-(R,R)- and (S,S)-1,2-diaminocyclohexanecarboxylic acids have been achieved with ee >99% while the respective cis-(R,S)- and (S,R)-stereoisomers were obtained as 1-amino-2-benzoylaminocyclohexanecarboxylic acids. The underlying second generation asymmetric synthesis proceeds via Strecker reaction with commercially available (R)- and (S)-1-phenylethylamine (1-PEA) as chiral auxiliaries, TMSCN as cyanide source and racemic 2-benzoylaminocyclohexanone. The key stereodifferentiating step of the cyanide addition to the chiral ketimine intermediates has been studied under the influence of protic and aprotic solvents. Hydrolysis of the nitriles to the carboxamides with conc. H₂SO₄ yielded dramatic changes in the product composition as a function of temperature and time. Hydrolysis of both the attendant amido groups are concomitant processes in case of the trans-configured carboxamides while the cis-stereoisomers undergo selective carboxamide hydrolysis, with the benzoyl protecting group remaining intact, leading to orthogonally protected α,β-diamino acids. The absolute configurations of the amino acids and their intermediates have been assigned based on detailed NMR spectroscopic analysis and X-ray data.

Full text of DOI:10.1016/S0957-4166(02)00610-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2241–2249
Carbocyclic a,b-diamino acids: asymmetric Strecker synthesis of
stereomeric 1,2-diaminocyclohexanecarboxylic acids
Kamalesh P. Pai Fondekar, Franz-J. Volk, S. M. Khaliq-uz-Zaman, Philippe Bisel and
August W. Frahm*
Lehrstuhl fu¨r Pharmazeutische Chemie, Albert-Ludwigs-Universita¨t Freiburg, Albertstrasse 25, D-79104 Freiburg, Germany
Received 21 August 2002; accepted 27 September 2002
Abstract—Asymmetric syntheses of trans-(R,R)- and (S,S)-1,2-diaminocyclohexanecarboxylic acids have been achieved with ee
>99% while the respective cis-(R,S)- and (S,R)-stereoisomers were obtained as 1-amino-2-benzoylaminocyclohexanecarboxylic
acids. The underlying second generation asymmetric synthesis proceeds via Strecker reaction with commercially available (R)- and
(S)-1-phenylethylamine (1-PEA) as chiral auxiliaries, TMSCN as cyanide source and racemic 2-benzoylaminocyclohexanone. The
key stereodifferentiating step of the cyanide addition to the chiral ketimine intermediates has been studied under the influence of
protic and aprotic solvents. Hydrolysis of the nitriles to the carboxamides with conc. H2SO4 yielded dramatic changes in the
product composition as a function of temperature and time. Hydrolysis of both the attendant amido groups are concomitant
processes in case of the trans-configured carboxamides while the cis-stereoisomers undergo selective carboxamide hydrolysis, with
the benzoyl protecting group remaining intact, leading to orthogonally protected a,b-diamino acids. The absolute configurations
of the amino acids and their intermediates have been assigned based on detailed NMR spectroscopic analysis and X-ray data.
© 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
receptors.4 They have also been used as tools in the
family- and subtype-classification of mGluRs.5
In recent years, the structural features of both a,a-di-
substituted a-amino acids and the b-amino acids have
gained increasing attention in the field of medicinal
chemistry due to a variety of interesting biological
properties they may account for.
b-Amino acids, such as the neurotoxin b-N-methyl-
amino-L-alanine (BMAA), are reported to function as
modulators of the glycine binding site of the NMDA
receptor complex.6 In addition, b-peptides, the short
oligomers of b-amino acids, can adopt all types of
secondary peptide structures (helix, sheets and turns)
and are considered as alternatives to a-amino acid
oligomers since the b-peptide backbone offers greater
opportunities for conformational rigidity than the a-
peptides do.7 We reasoned that chimeric compounds
bearing both the structural features of a,a-disubstituted
a-amino acids and of b-amino acids are of considerable
interest in various fields of medicinal chemistry.
a,a-Dialkyl a-amino acids are widely used in the iso-
steric replacement of proteinogenic amino acids in pep-
tides,1 favoring specific backbone conformations and,
thus, leading to stabilized secondary peptide struc-
tures.2 Moreover, this incorporation increases the sta-
bility of these peptides towards chemical and enzymatic
degradation. Hence, a,a-disubstituted a-amino acids
are building blocks for the design and synthesis of new
peptide hormones and enzyme inhibitors.3 Further-
more, a,a-dialkyl a-amino acids such as a-alkylated
phenylglycine derivatives, the respective carbocyclic
analogue 1-aminoindanedicarboxylic acid (AIDA), and
Since the asymmetric Strecker reaction8 has proved to
be a powerful and convenient experimental protocol for
the synthesis of b-substituted a-amino acids,9 we
planned the preparation of the stereoisomeric a,b-
diaminocyclohexanecarboxylic acids starting from the
N-protected cyclohexanone 1 or 1% and 1-phenylethyl-
amine as the chiral auxiliary. The results of these
investigations are discussed in this paper.
the
stereoisomeric
1-aminocyclopentane-1,3-dicar-
boxylic acids (ACPD), have been described as ligands
at both the ionotropic and metabotropic glutamate
* Corresponding author.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00610-9

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K. P. Pai Fondekar et al. / Tetrahedron: Asymmetry 13 (2002) 2241–2249
2. Results and discussion
over cis-(aR,1R,2S)-4c or 4%c in methanol, cis-4c or 4%c
predominates trans-4b or 4%b in hexane. The fourth
diastereomer cis-(aR,1S,2R)-4d or 4%d is formed neither
in methanol nor in hexane. The stereochemical compo-
sition of the a-amino nitrile mixtures 4a–c and 4%a–c
(obtained in quantitative yields) is presented in Table 1
and is derived from our previously established 13C
NMR analysis.9
The whole of this discussion is based on the compounds
obtained with the chiral auxiliary (R)-1-PEA. The
respective enantiomeric compounds (ent-Xa-c) were
synthesized via the same sequence upon replacement of
this chiral auxiliary with its antipode (S)-1-PEA.
Asymmetric synthesis of the 1,2-diamino acids was
designed with racemic 2-protected-amino-cyclohex-
anone 1 or 1% prepared from cyclohexene oxide follow-
Subsequently, the nitrile mixture 4a–c was hydrolyzed
to the corresponding carboxamides with conc. H2SO4 at
25°C in a reaction monitored by means of infrared
spectroscopy (Scheme 2(a)). The reaction was com-
pleted after 3 days. 13C NMR analysis of the crude
reaction mixture showed two sets of signals, both
devoid of the characteristic signal groups accounting
for the 1-phenylethyl moiety, thus indicating simulta-
neous hydrolysis and hydrogenolysis. Standard column
chromatography followed by low pressure liquid chro-
matography (LPLC) resulted in the separation of the
homochiral a-amino carboxamide cis-6c from the mix-
ture of the two trans-configured enantiomers 6a and 6b.
Furthermore, a trans spiro heterocyclic compound 6S
could be isolated and characterized by means of NMR
and HRMS analysis. This compound is assumed to
arise from a silica gel-catalyzed imine formation
between the primary amine and the acetone co-eluent,
followed by ring-closure via nucleophilic attack of the
amido-nitrogen on the imine carbon during column
chromatography. Refluxing the cis configured 6c for 2
days in conc. HCl gave only orthogonally protected 7c
as the sole product (Scheme 2(a)), which could neither
be hydrolyzed to N-unprotected a,b-diamino acid by
increasing reaction time up to 2 weeks nor by using
base-catalyzed hydrolysis with aqueous sodium hydrox-
ide, Claisen’s alkali (KOH, methanol, water) and
ing
a
procedure previously reported from our
laboratory.10 Condensation of 1 or 1% with a threefold
excess of (R)-1-PEA 2 under azeotropic removal of
water gave a mixture of only two diastereomeric (E)-
imines 3A/B or 3%A/B in a ratio of 1:1 (Scheme 1). In
contrast to our earlier studies no (Z)-isomers were
observed. The 3A/B or 3%A/B mixture was subsequently
subjected to Lewis acid-catalyzed cyanide addition
using trimethylsilylcyanide (TMSCN). Since an addi-
tional stereo center at C-1 is generated in this step, four
diastereomeric a-amino nitriles (two with cis and two
with trans configuration) are theoretically feasible. In a
series of earlier works we had observed dramatic
changes in the cis/trans diastereoselectivity as a factor
of the nature of the solvent.9 Indeed, while protic
solvents favored the thermodynamically more stable
trans isomers, aprotic solvents led to diastereomeric
mixtures with predominance of the cis isomer. In the
study presented herein, although variation of the
product composition was observed upon solvent and
temperature changes, the overall cis/trans diastereose-
lectivity was not reversed and under all conditions
investigated, the trans-(aR,1R,2R)-a-amino nitrile 4a or
4%a was the major reaction product. However, while the
formation of trans-(aR,1S,2S)-4b or 4%b is preferred
Scheme 1. R=H: 1–4 series; R=NO2: 1%–4% series. Reagents and conditions: (i) p-toluenesulfonic acid, toluene, reflux, 5 h; (ii)
TMSCN, ZnCl2, methanol (or hexane), 0°C, 3 h.
Table 1. Stereochemical distributions of the a-amino nitriles 4a–c and 4%a–c, respectively, obtained under different reaction
conditions
Reaction conditions [solvent, T, t]
4a/4%a aR,1R,2R (trans) 4b/4%b aR,1S,2S (trans) 4c/4%c aR,1R,2S (cis) 4d/4%d aR,1S,2R (cis)
MeOH; 0°C; 3 h
Hexane; 0°C; 3 h
Hexane; −20°C; 24 h
51/−
53/50
52/−
25/−
33/37
31/−
24/−
14/13
17/−
0/−
0/0
0/−

K. P. Pai Fondekar et al. / Tetrahedron: Asymmetry 13 (2002) 2241–2249
2243
Scheme 2. Reagents and conditions: (a) (i) conc. H2SO4, −10°C for 30 min and 25°C for 3 days; (ii) CC, EtOAc/acetone (1:1),
+
followed by LPLC; (iii) conc. HCl, 0°C, 2 h, then reflux for 2 days; (iv) Dowex 50WX.8.100 (NH4 form), 1 M NH3. (b) (i) conc.
H2SO4, −20°C, 10 days; (ii) CC, cyclohexane/EtOAc (1:1); (iii) Pd/C (10%), HCO2NH4, methanol, reflux, 2 h; (iv) conc. HCl, 0°C,
+
2 h, then reflux for 2 days; (v) Dowex 50WX.8.100 (NH4 form), 1 M NH3. (c) (i) conc. H2SO4, CH2Cl2, −10°C for 30 min then
3 days at rt; (ii) CC, EtOAc/acetone (1/1), followed by CC, EtOAc/cyclohexane/diethylamine (4/6/5 drops); (iii) Pd/C (10%),
HCO2NH4, methanol, reflux, 2 h; (iv) conc. HCl, 0°C, 2 h, then reflux for 2 days; (v) Dowex 50WX.8.100 (NH4+ form), 1 M NH3.

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K. P. Pai Fondekar et al. / Tetrahedron: Asymmetry 13 (2002) 2241–2249
KOH/ethylene glycol at high temperatures. After sev-
eral trials to change the protecting group (acetyl, Boc)
we reasoned that among the more reactive N-protecting
groups, not affected by conc. H2SO4 at room tempera-
ture, the p-nitro substituted benzoyl moiety should be
more suitable for final deprotection. Thus, the Strecker
sequence was repeated with this protecting group.
matography on a Dowex 50WX column. All of our
efforts to prepare the trans-configured 1-amino-2-ben-
zoylamino-cyclohexanecarboxylic acids considered to
be orthogonally protected trans a-amino acids, by selec-
tive hydrolysis of only the carboxamide group to the
respective carboxylic acid, preserving the 2-benzoyl-
amino group, failed. Hydrolysis of 6a with hydrochloric
acid under varying concentration and temperature con-
ditions gave only differing product compositions (pre-
sented in Table 2).
In order to obtain the non-hydrogenolyzed products,
the 13C NMR-monitored hydrolysis was performed at
−20°C. After 10 days the complete set of amino nitriles
had been consumed. Subsequent chromatographic sep-
aration of the reaction products yielded the two
diastereomerically pure trans-configured carboxamides
5a and 5b (Scheme 2(b)) with the intact 1-phenylethyl-
amino moiety.
Table 2. Product distribution of the acidic hydrolysis of
6a versus HCl concentration
Conditions
Time (h)
8a (%)
7a (%)
Conc. HCl/reflux
Conc. HCl/reflux
6N HCl/reflux
2N HCl/reflux
2N HCl/reflux
48
24
6
6
2
100
95
88
86
0
5
12
14
34*
The structure and the relative stereochemistry of the
minor diastereomer 5b was assigned by complete NMR
1
1
analysis (1H, 13C, H–1H COSY, H–13C HETCOR and
2D-INEPT). Finally, its absolute stereochemistry was
established as aR,1S,2S by single crystal X-ray analysis
(Fig. 1). Since the primary amino amides 6a and 6b
obtained from the hydrogenolysis of 5a and 5b, respec-
tively, showed opposite specific rotation values, the
absolute stereochemistry aR,1R,2R was assigned to the
second parent compound 5a. All of our efforts to
isolate any of the cis configured stereoisomer failed
under these conditions. Since benzoic acid could be
isolated from the crude reaction mixture, the 2-benzoyl-
amino group must have been hydrolysed and the result-
41
* 25% unreacted 6a.
Further lowering of the temperature of the nitrile
hydrolysis to −30°C did not allow the isolation of the
cis a-amino carboxamide 5c. However, chromato-
graphic separation of the complex mixture, obtained
after not less than 30 days, gave trans-5a (aR,1R,2R)
along with the 2-benzoylamino ketone 1 and 1-PEA.
Neither trans-5b nor any of the cis secondary a-amino
carboxamide were isolated, indicating that the cyanide
elimination reaction and subsequent imine hydrolysis
are successfully competing with cyanide hydrolysis
under these reaction conditions.
ing
cis-2-amino-1-(1-phenylethylamino)cyclohexane-
carbonitrile is probably further degraded. The catalytic
transfer hydrogenolysis of the trans configured com-
pounds 5a and 5b underwent smoothly with Pd/C and
ammonium formate in methanol to give the corre-
sponding trans-(1R,2R)-6a and trans-(1S,2S)-6b,
respectively, in 89–92% yield. Concomitant hydrolysis
of both the amide groups occurred upon refluxing 6a
and 6b, respectively, in concentrated HCl for 2 days
yielding the diamino acid hydrochlorides trans-
(1R,2R)-8a·2HCl and trans-(1S,2S)-8b·2HCl, respec-
tively. The respective free zwitterionic a-amino acids 8a
and 8b were obtained by means of ion-exchange chro-
The very sensitive hydrolysis of the amino nitrile mix-
ture was performed under slightly modified conditions
in the case of the 4%a–c mixture. Thus, the cyanide
mixture was taken up in CH2Cl2, added to pre-cooled
(−10°C) conc. H2SO4, and subsequently reacted at
room temperature leading to the isolation of 5%a, 5%b
and 6%c after standard workup and column chromatog-
raphy (Scheme 2(c)). Unfortunately, analogously to 6c,
Figure 1. ORTEP plot of the crystal structure of 5b.

K. P. Pai Fondekar et al. / Tetrahedron: Asymmetry 13 (2002) 2241–2249
2245
the intermediate 6%c could not be hydrolyzed to the
corresponding free diamino acid under any of the con-
ditions investigated.
with 2R configuration is theoretically impossible. Con-
sequently, the cis configured compound 4c must have
the absolute configuration aR,1R,2S and originates
along with the minor trans diastereomer 4b (aR,1S,2S)
from the imine 3A (E,aR,2S) contained also with 50%
in the (E)-imine mixture (Scheme 3). These findings
support our earlier observations of a ‘like induction’ at
C-1 during the addition of cyanide to ketimines.9,11
The determination of the absolute stereochemistry of
the theoretically feasible cyanide addition products 4a–
c, which were identified in the crude 13C NMR spec-
trum by three sets of signals, corresponding to three
amino nitriles, proved particularly challenging (Scheme
3). As was observed earlier for 2-substituted cyclo-
hexylimines in methanol,7,8,10 the addition of cyanide to
chiral imines occurs under thermodynamic control
resulting in the formation of a major trans-configured
diastereomer. Based on these findings, the major reac-
tion product (:50%) in methanol was tentatively
assigned the trans configuration. The same
diastereomer also predominates when the reaction is
carried out in a non-polar solvent (hexane). The second
major diastereomer in methanol becomes the minor in
hexane and the minor diastereomer in methanol
becomes second major in hexane. Accordingly, they
were assigned the trans- and cis-configuration, respec-
tively. Since nitrile hydrolysis at −20°C yielded a car-
boxamide mixture of (aR,1R,2R)-5a and (aR,1S,2S)-5b
with 5a as the major product, the absolute configura-
tions of their precursors, 4a and 4b, respectively, could
be assigned accordingly. Thus, the major trans
diastereomer 4a has aR,1R,2R configuration, whilst the
second trans diastereomer 4b has aR,1S,2S configura-
tion. Obviously the imine (E,aR,2R)-3B was consumed
completely for the formation of the major trans
diastereomer (aR,1R,2R)-4a in :50% yield. Hence, the
simultaneous formation of a cis-configured compound
Since the stereocenters are not affected in the following
steps we could assign the absolute configurations to the
a,b-diamino acids as follows: 1R,2R to 8a, 1S,2S to 8b,
1R,2S to 7c and 1S,2R to ent-7c. The ee values of the
trans-configured a,b-diamino acids were determined by
means of chiral HPLC according to a method devel-
oped in our laboratory (column: D-Penicillamine,
mobile phase: 0.3 mM CuSO4 in H2O, temp. 20°C, flow
rate:0.8 mL/min) and were found to be >99% for 8a
and 8b, respectively.11 The enantiomeric unity of 7c and
ent-7c is assumed since they arise from the respective
unique cis-a-amino nitrile formed in the stereodeter-
mining cyanide addition step as discussed earlier.
3. Conclusion
In conclusion, in this contribution we have reported on
the asymmetric Strecker synthesis of trans-(1R,2R)-
and (1S,2S)-1,2-diaminocyclohexanecarboxylic acids
with ee values >99% and enantiomerically pure, orthog-
onally protected cis-(1R,2S)- and (1S,2R)-1-amino-2-
benzoylaminocyclohexanecarboxylic acids.
Scheme 3. Mechanistic aspects of the cyanide addition to the ketimine mixture 3A/B.

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K. P. Pai Fondekar et al. / Tetrahedron: Asymmetry 13 (2002) 2241–2249
4. Experimental
(C), 147.5/149.4 (C), 163.8/163.9 (CO), 167.2/167.4 (CO).
4.1. General methods
4.4. Cyanide addition to the ketimine mixtures 3A/B
and 3%A/B, respectively
Melting points were determined with a Mel-Temp II
apparatus (Devices Laboratory USA) and are uncor-
Method A: To a solution of the mixed ketimines 3A/B
(8 g, 25 mmol) and anhydrous ZnCl2 (170 mg, 5 mol%)
in MeOH (140 mL), TMSCN (4 mL, 33 mmol) was added
at 0°C over a period of 30 min. The reaction mixture was
stirred for 3 h, filtered, concentrated and dried to yield
a mixture of the a-amino nitriles 4a–c (8.6 g, 99%) and
further reacted without purification.
1
rected. H and 13C NMR spectra were recorded at 300
and 75.4 MHz, respectively, on a Varian Unity 300
spectrometer. The chemical shifts are reported as l values
using the solvent peaks as reference. Optical rotations
were measured on a Perkin–Elmer 241 spectrometer.
Column chromatography was carried out with Merck
silica gel Si60 (0.2–0.063 mm). TLC was performed with
Si60 F254 TLC plates from Merck. Drying of organic
extracts during the workup of reactions was performed
over anhydrous Na2SO4. Evaporation of the solvents was
accomplished under reduced pressure with a rotatory
evaporator. Microanalysis and HRMS were performed
at the Department of Biochemistry and Organic Chem-
istry, University of Freiburg.
Method B: The above procedure was repeated with 3A/B
and 3%A/B, respectively, using hexane as a solvent,
yielding 99% of the a-amino nitrile mixture 4a–c and
4%a–c, respectively.
4.5. Hydrolysis of the amino nitriles mixtures 4a–c and
4%a–c, respectively
4.2. Preparation of the aminocyclohexanones, 1 and 1%
Method A: To 4.7 g (13.6 mmol) of the a-amino nitrile
mixture 4a–c pre-cooled (−10°C) conc. H2SO4 (20 mL)
was added slowly. The resulting mixture was stirred at
−10°C for 30 min and was then allowed to stir at 25°C
for 3 days. The crude product was decomposed on ice
and filtered. The filtrate was adjusted to pH 8 with conc.
ammonia and extracted with EtOAc. The organic
extracts were washed with water, brine, dried, filtered,
concentrated and finally dried under high vaccum to yield
an oily residue (2.6 g, 79%). The above residue was
separated on silica gel, eluted with a gradient of acetone/
EtOAc mixtures (1/1 to 9/1) resulting in the isolation of
6a/6b mixture (1.1 g) and further fractions containing 6S
and cis-6c/trans-6a/6b mixtures. The latter were further
separated by means of LPLC [stationary phase: Merck
LOBAR column, mobile phase: EtOAc–acetone (1:1),
flow rate: 1 mL/min, fraction size: 5 mL, detector: 254
nm] yielding pure 6c, which was further converted into
its hydrochloride salts with HCl saturated ether.
4.2.1. (RS)-2-Benzoylaminocyclohexanone, 1. Prepared
from cyclohexeneoxide according to literature proce-
dure.10 For NMR data see Ref. 10.
4.2.2. (RS)-2-p-Nitrobenzoylaminocyclohexanone, 1%.
Prepared according to Ref. 10: 1H NMR (CDCl3)
1.40–1.54 (m, 1H), 1.64–1.98 (m, 3H), 2.14–2.26 (m, 1H),
2.42–2.64 (m, 2H), 2.78–2.88 (m, 1H), 4.68 (m, J=5.5 Hz,
1H), 7.26 (brs., NH) 7.96 (d, J=8.8 Hz, 2H), 8.28 (d,
J=8.7 Hz, 2H); 13C NMR (CDCl3) 23.75 (CH2), 27.84
(CH2), 35.12 (CH2), 40.83 (CH2), 58.45 (CH), 123. 59
(CH), 123.59 (CH), 128.05 (CH), 128.05 (CH), 149.53
(CH), 164.51 (CO), 207.21 (CO).
4.3. Imine condensation
A solution of 1 or 1% (1.09 g, 5 mmol), p-toluenesulfonic
acid (15 mg) and (R)-1-phenylethylamine (0.43 g, 7
mmol) in dry toluene was heated under reflux using a
Dean–Stark apparatus. After 90 min 0.3 g (5 mmol) and
after a further 60 min 0.24 g (4 mmol) of (R)-1-
phenylethylamine were added and reflux was continued
for 3 h. The solvent was removed under reduced pressure
and the residue was dried under high vacuum to yield
crude imine which was used without further purification
for the next step.
Method B: To the a-amino nitrile mixture 4a–c (8.6 g,
24.8 mmol) pre-cooled (−20°C) conc. H2SO4 (80 mL) was
added slowly. The resulting mixture was stirred at −20°C
for 10 days. The crude product was decomposed on ice
and filtered. The filtrate was adjusted to pH 8 with conc.
ammonia and extracted with EtOAc. The organic
extracts were washed with water, brine, dried, filtered,
concentrated and finally dried in a high vaccum, yielding
the crude product (7.1 g, 78%). A quantity of this residue
(7 g) was separated on silica gel (700 g) using cyclohex-
ane/EtOAc (1:1) as the eluent to yield 5a (1.71 g, 19%),
a 5a/5b mixture (257 mg, 2.8%) and finally 5b (721 mg,
8%).
4.3.1. (E)-2-(RS)-[N-(R)-1-Phenylethyl]benzoylamino-
cyclohexaneimine 3A/B. For spectral data see Ref. 10.
4.3.2. (E)-2-(RS)-[N-(R)-1-Phenylethyl]p-nitrobenzoyl-
aminocyclohexaneimine 3%A/B. 1H NMR (CDCl3) 1.1–1.4
(m, 3H), 1.1.42/1.48 (d, J=6.6 Hz, 3H), 1.6–1.9 (m, 3H),
2.7–2.9 (m, 1H), 3.0–3.2 (m, 1H), 4.35 (m, 1H), 4.7 (m,
1H), 7.12–7.30 (m, 5H), 7.88 (m, 2H), 8.16 (m, 2H), 8.52
(brs., NH); 13C NMR (CDCl3) 23.8/24.0 (CH2), 25.0/22.2
(CH3), 26.9/27.6 (CH2), 29.0/29.1 (CH2), 34.9/35.0
(CH2), 54.9/55.0 (CH), 57.7/57.6 (CH), 123.6/123.6
(CH), 126.2/126.7 (CH), 126.7/126.8 (CH), 128.0/128.3
(CH), 128.4/128.4 (CH), 140.4/140.5 (C), 145.2/145.7
Method C: The same procedure was repeated with 8.6 g
(24.8 mmol) of 4a–c, 80 mL conc H2SO4 maintaining the
temperature between −30 to −35°C for 30 days. A crude
yield of 7.8 g was isolated. A quantity of 7 g of the residue
was separated on silica gel (600 g) and eluted with
cyclohexane–EtOAc (1:1) to yield racemic 1 (1.92 g),
diastereomerically pure 5b (1.01 g) and phenylethylamine
(2.4 g).

K. P. Pai Fondekar et al. / Tetrahedron: Asymmetry 13 (2002) 2241–2249
2247
1
Method D: The a-amino nitriles (3.6 g, 9.7 mmol)
mixture 4%a–c was dissolved in dry dichloromethane (20
mL) and added slowly to pre-cooled (−10°C) conc.
H2SO4 (15 mL). The resulting mixture was kept at
−10°C for 30 min and then allowed to stir at room
temperature for 3 days. The crude product was decom-
posed on ice and filtered. The filtrate was adjusted to
pH 8 with conc. ammonia and extracted with EtOAc.
The organic extract was washed with water, brine, dried
with MgSO4, filtered, concentrated and finally dried in
high vacuum to yield an oily residue (3.2 g, 86%). The
above residue was separated on silica gel column eluted
with EtOAc/acetone (1/1) yielding a mixture of 5%a/5%b
(1.02 g, 27%) along with 6%c (96 mg, 2.6%). The 5%a/5%b
mixture (1 g) was further purified on silica gel column
eluted with EtOAc/cyclohexane/diethylamine 4/6/5
drops mixture yielding the diastereomerically pure
trans-secondary amino amides 5%a (542 mg) and 5%b
(307 mg), respectively.
217°C; [h]2D0=−3.4 (c 0.93, MeOH); H NMR (CDCl3)
1.20–1.90 (m, 8H), 1.28 (d, J=6.6 Hz, 3H), 2.1 (brs,
1H), 3.95 (q, J=6.6 Hz, 1H), 4.24 (ddd, J=9.0, 8.8, 3.8
Hz, 1H), 6.01 (s, 1H), 6.66 (s, 1H), 7.18–7.40 (m, 6H),
7.90 (d, J=8.4 Hz, 2H), 8.24 (d, J=8.4 Hz, 2H); 13C
NMR (CDCl3) 22.05 (CH2), 23.20 (CH2), 26.36 (CH3),
29.31 (CH2), 32.43 (CH2), 53.34 (CH), 55.26 (CH),
63.76 (C), 123.66 (CH), 126.20 (CH), 126.95 (CH),
128.10 (CH), 128.43 (CH), 140.18 (C), 147.06 (C),
149.45 (C), 164.06 (CO), 178.26 (CO). HRMS calcd for
C21H24N3O3 (100%, M+−CONH2) 367.4479, found
367.4471.
4.5.6.
trans-(aR,1S,2S)-2-p-Nitrobenzoylamino-1-(1-
5%b. Mp
phenylethylamino)cyclohexanecarboamide,
>250°C (decomp.); [h]2D0=+50.0 (c 1.12, MeOH); 1H
NMR (CDCl3) 1.18 (d, J=6.4 Hz, 3H), 1.20–2.05 (m,
8H), 2.1 (brs, 1H), 4.14 (q, J=6.7 Hz, 1H), 4.50 (ddd,
J=11.2, 9.6, 5.0 Hz, 1H), 5.62 (s, 1H), 6.68 (s, 1H),
7.14–7.42 (m, 6H) 7.92 (d, J=8.8 Hz, 2H), 8.24 (d,
J=8.8 Hz, 2H); 13C NMR (CDCl3) 22.13 (CH2), 24.57
(CH2), 27.30 (CH3), 30.51 (CH2), 51.10 (CH), 52.17
(CH), 65.73 (C), 123.73 (CH), 125.99 (CH), 126.57
(CH), 128.12 (CH), 128.45 (CH), 139.96 (C), 148.57
(C), 149.56 (C)), 164.86 (CO), 178.54 (CO). HRMS
calcd for C21H24N3O3 (100%, M+−CONH2) 367.4479,
found 367.4481.
4.5.1.
trans-(aR,1R,2R)-2-Benzoylamino-1-(1-phenyl-
ethylamino)cyclohexanecarboxamide, 5a. Mp 92°C;
1
[h]2D0=−4.3 (c 1.02, MeOH); H NMR (CDCl3) 1.26 (d,
J=6.6 Hz, 3H), 1.20–1.90 (m, 8H), 2.30 (bs, 1H) 3.90
(q, J=6.6 Hz, 1H), 4.24 (ddd, J=8.9, 8.9, 3.7 Hz, 1H),
6.30 (s, 1H), 6.90 (s, 1H), 7.10–7.50 (m, 8H), 7.6 (d,
J=8.4 Hz, 1H), 7.70–7.78 (m, 2H); 13C NMR (CDCl3)
21.8 (CH2), 22.9 (CH2), 26.2 (CH3), 29.1 (CH2), 31.6
(CH2), 53.4 (CH), 54.6 (CH), 63.9 (C), 126.2 (CH),
126.7 (CH), 126.9 (CH), 128. 2 (CH), 128.4 (CH), 131.2
(CH), 134.5 (C), 147. 3 (C), 167.0 (CO), 178.5 (CO);
HRMS calcd for C21H25N2O (100%, M+−CONH2)
321.1967, found 321.1968.
4.5.7. cis-(1R,2S)-1-Amino-2-benzoylaminocyclohexane-
carboxamide hydrochloride, 6c·HCl. Mp 226–228°C
(decomp.); [h]2D0=−5.8 (c 1.36, MeOH); 1H NMR
(CD3OD) 1.52–1.84 (m, 5H), 2.00–2.24 (m, 3H), 4.64
(dd, J=5.5, 5.3 Hz, 1H), 7.67 (dd, J=8.1, 7.5 Hz, 3H),
7.83 (d, J=7.5, 1H); 7.99 (dd, J=14.0, 8.1 Hz, 1H); 13
C
4.5.2.
trans-(aR,1S,2S)-2-Benzoylamino-1-(1-phenyl-
NMR (CD3OD) 18.3 (CH2), 18.7 (CH2), 26.5 (CH2),
29.3 (CH2), 60.2 (CH), 69.4 (C), 123.4 (C), 129.8 (CH),
130.8 (CH), 136.4 (CH), 166.5 (CO), 174.1 (CO).
ethylamino)cyclohexanecarboxamide, 5b. Mp 170°C;
1
[h]2D0=+51.2 (c 1.01, MeOH); H NMR (CDCl3) 1.25
(d, J=6.6 Hz, 3H), 1.20–2.20 (m, 9H), 4.13 (q, J=6.6
Hz, 1H), 4.48 (ddd, J=11.0, 11.0, 5.1 Hz, 1H), 5.6 (bs,
1H), 6.9 (s, 1H), 7.07 (d, J=9.6 Hz, 1H), 7.18 (dd,
J=7.2, 7.2 Hz, 1H), 7.28 (dd, J=7.6, 7.2 Hz, 2H),
7.34–7.52 (m, 5H); 7.89 (dd, J=7.6, 1.7 Hz, 2H), 13C
NMR (CDCl3) 22.2 (CH2), 24.8 (CH2), 27.4 (CH3), 30.6
(CH2), 34.6 (CH2), 50.4 (CH), 52.2 (CH), 66.0 (C),
126.1 (CH), 126.5 (CH), 126.9 (CH), 128.4 (CH), 128.6
(CH), 131.5 (CH), 134.5 (C), 149.0 (C), 167.0 (CO),
178.7 (CO); HRMS calcd for C21H25N2O (100%, M+−
CONH2) 321.1967, found 321.1963.
4.5.8. cis-(1S,2R)-1-Amino-2-benzoylaminocyclohexane-
carboxamide hydrochloride, ent-6c·HCl. Mp 226–228°C
(decomp.); [h]2D0=+7.4 (c 0.76, MeOH).
4.5.9. 6-Benzoylamino-3,3-dimethyl-2,4-diazaspiro[4,5]-
dec-1-one, 6S. Mp 231°C; H NMR (CDCl3) 1.25 (s,
1
3H), 1.36 (m, 1H), 1.39 (s, 3H), 1.50–1.68 (m, 2H),
1.74–1.88 (m, 3H), 2.12–2.34 (m, 2H), 3.20 (bs, 1H),
4.12 (ddd, J=11.5, 8.6, 4.4 Hz, 1H), 6.31 (bs, 1H), 6.52
(d, J=7.6 Hz, 1H), 7.40–7.90 (m, 5H); 13C NMR
(CDCl3) 21.7 (CH2), 24.1 (CH2), 28.9 (CH2), 30.2
(CH3), 32.8 (CH3), 38.8 (CH2), 53.1 (CH), 66.0 (C),
70.7 (C), 127.0 (CH), 128.6 (CH), 131.7 (CH), 134.3
(C), 168.8 (CO), 177.1 (CO). Anal. calcd for
C17H23N3O2: C, 67.75; H, 7.69; N, 13.94; found: C,
67.71; H, 7.74; N, 13.80%. MS (EI, 70 eV) 301 (M+).
4.5.3.trans-(aS,1S,2S)-2-Benzoylamino-1-(1-phenylethyl-
amino)cyclohexanecarboxamide, ent-5a. Mp 92°C;
[h]2D0=+2.0 (c 1.02, MeOH); HRMS calcd for
C21H25N2O (100%, M+−CONH2) 321.1967, found
321.1967.
4.5.4.
trans-(aS,1R,2R)-2-Benzoylamino-1-(1-phenyl-
ethylamino)cyclohexanecarboxamide, ent-5b. Mp 170°C;
[h]2D0=−51.2 (c 1.00, MeOH); HRMS calcd for
C21H25N2O (100%, M+−CONH2) 321.1967, found
321.1966.
4.5.10.
cis-(1R,2S)-1-Amino-2-p-nitrobenzoylamino-
1
cyclohexanecarbamide, 6%c. H NMR (CDCl3) 1.20–2.36
(m, 8H), 4.15 (t, J=4.73 Hz, 1H), 5.61 (s, 1H), 6.80 (s,
1H), 7.96 (d, J=8.8 Hz, 2H), 8.24 (d, J=8.8 Hz, 2H);
13C NMR (CDCl3) 18.68 (CH2), 19.32 (CH2), 27.39
(CH2), 32.32 (CH2), 59.15 (C), 74.01 (CH), 123.71
4.5.5.
trans-(aR,1R,2R)-2-p-Nitrobenzoylamino-1-(1-
5%a. Mp
phenylethylamino)cyclohexanecarboamide,

2248
K. P. Pai Fondekar et al. / Tetrahedron: Asymmetry 13 (2002) 2241–2249
(CH×2), 128.04 (CH×2), 135.97 (C), 149.29 (C), 161.41
evaporated in vacuum, the crude product was dissolved
in water, evaporated to dryness, and finally dried for 24
h under high vacuum to yield 8a and 8b, respectively, as
yellowish solids (135 mg, 97%).
(CO), 178.52 (CO).
4.6. Hydrogenolytic cleavage of the chiral auxiliary
To a solution of 5a or 5b (or 5%a and 5%b, respectively)
(312 mg, 0.85 mmol) and Pd/C (10%, 215 mg) in
methanol (43 mL), ammonium formate (436 mg) were
added. The reaction mixture was heated under reflux
for 2 h, cooled, filtered over a pad of Celite, washed
with methanol, concentrated and dried in high vacuum
to yield a yellow oil. The crude product was purified on
a small silica gel column using EtOAC as a solvent to
yield 6a and 6b, respectively (or 6%a and 6%b, respec-
tively) (204 mg, 92%) as white solids.
4.7.1. trans-(1R,2R)-1,2-Diaminocyclohexanecarboxylic
acid, 8a. Mp >250°C; [h]2D0=+7.4 (c 1.00, H2O); 1H
NMR (D2O) 1.32–1.50 (m, 2H), 1.52–1.74 (m, 3H),
1.80–2.00 (m, 2H), 2.18 (m, 1H), 3.53 (dd, J=9.0, 4.9
Hz, 1H); 13C NMR (D2O) 20.3 (CH2), 21.1 (CH2), 26.8
(CH2), 31.9 (CH2), 51.9 (CH), 60.6 (C), 172.2 (CO).
HRMS calcd for C7H14N2O2 158.1055, found 158.1055.
4.7.2. trans-(1S,2S)-1,2-Diaminocyclohexanecarboxylic
acid, 8b. Yield: 98%; mp >250°C; [h]2D0=−8.0 (c 1.01,
H2O). HRMS calcd for C7H14N2O2 158.1055, found
158.1052.
4.6.1. trans-(1R,2R)-1-Amino-2-benzoylaminocyclohex-
anecarboxamide, 6a. Mp 44°C; [h]2D0=+15.3 (c 1.09,
1
MeOH); H NMR (CDCl3) 1.30–1.70 (m, 4H), 1.72–
4.8. Hydrolysis of the cis-carboxamide, 6c·HCl
1.86 (m, 2H), 2.10–2.30 (m, 4H), 4.06 (ddd, J=11.6,
9.5, 4.6 Hz, 1H), 5.78 (s, 1H), 7.03 (d, J=9.5 Hz, 1H),
cis-Carboxamide 6c·HCl (70 mg, 0.23 mmol) was dis-
solved in conc. HCl (10 mL) at 0°C. The mixture was
stirred at rt for 2 h and then heated under reflux for 2
days. Concentration under reduced pressure, followed
by drying under high vacuum, yielded a yellowish solid
which was dissolved in water (10 mL) and washed with
ether. The aqueous extract was concentrated and dried
in high vacuum to yield a yellowish white solid (62.6
mg, 89%).
7.28 (bs, 1H), 7.35–7.50 (m, 3H); 7.72–7.78 (m, 2H); 13
C
NMR (CDCl3) 22.1 (CH2), 24.8 (CH2), 30.5 (CH2), 38.3
(CH2), 57.5 (CH), 60.9 (C), 127.0 (CH), 128. 5 (CH),
131.5 (CH), 134.2 (C), 167.8 (CO), 178.3 (CO); HRMS
calcd for C13H17N2O (85%, M+−CONH2) 217.1341,
found 217.1341.
4.6.2. trans-(1S,2S)-1-Amino-2-benzoylaminocyclohex-
anecarboxamide, 6b. Yield: 89% as a white solid. Mp
44°C; [h]2D0=−14.2 (c 1.03, MeOH); HRMS calcd for
C13H17N2O (85%, M+−CONH2) 217.1341, found
217.1338.
4.8.1. cis-(1R,2S)-1-Amino-2-benzoylaminocyclohexane-
carboxylic acid hydrochloride, 7c·HCl. Mp 212°C (dec.);
1
[h]2D0=−9.9 (c 0.93. CH3OH); H NMR (CD3OD) 1.30–
1.68 (m, 5H), 1.80–2.08 (m, 3H), 4.49 (dd, J=5.0, 5.0
Hz, 1H), 7.44–7.74 (m, 5H); 13C NMR (CD3OD) 16.0
(CH2), 16.5 (CH2), 24.3 (CH2), 27.6 (CH2), 58.5 (CH),
68.1 (C), 121.5 (C), 128.0 (CH), 129.5 (CH), 135.1
(CH), 164.8 (CO), 175.3 (CO). MS 245 (100%, M+−
OH).
4.6.3.
trans-(1R,2R)-1-Amino-2-p-nitrobenzoylamino-
cyclohexanecarboxamide, 6%a. Mp 152°C; [h]2D0=+16.5
(0.82, MeOH); 1H NMR (CDCl3) 1.2–1.9 (m, 6H),
2.0–2.3 (m, 4H), 3.9–4.1 (m, 1H), 5.75 (s, 1H), 7.1–7.3
(m, 2H), 7.89 (d, J=8.8, 2H), 8.22 (d, J=8.8, 2H); 13C
(NMR) 22.06 (CH2), 24.48 (CH2), 30.23 (CH2), 38.23
(CH2), 57.91 (CH), 60.55 (C), 123.67 (CH), 128. 20
(CH), 139.85 (C), 149.56 (C), 165.57 (CO), 178.58 (CO).
HRMS calcd for C13H17N3O3 (100%, M+−CONH2)
263.2964, found 263.2963.
4.8.2. cis-(1S,2R)-1-Amino-2-benzoylaminocyclohexane-
carboxylic acid hydrochloride, ent-7c·HCl. Mp 212°C
(dec.); [h]2D0=+10.4 (c 1.61. CH3OH). MS 245 (100%,
M+−OH).
4.6.4.
trans-(1S,2S)-1-Amino-2-p-nitrobenzoylamino-
cyclohexanecarboxamide, 6%b. Mp 152°C; [h]2D0=−17.1
(0.97, MeOH). HRMS calcd for C13H17N3O3 (100%,
M+−CONH2) 263.2964, found 263.2958.
Acknowledgements
We wish to thank Professor Dr. E. Weckert (Hasylab,
Hamburg, Germany) for providing us with the X-ray
structure of compound 5b and V. Brecht for skilful
NMR measurements.
4.7. Hydrolysis of the trans-carboxamides 6a/6%a and
6b/6%b, respectively
The trans-carboxamide mixture (6a/6%a or 6b/6%b) (300
mg, 0.9 mmol) was dissolved in conc. HCl (15 mL) at
0°C, stirred at rt for 2 h and then heated under reflux
for 2 days. Concentration under reduced pressure fol-
lowed by drying under high vacuum yielded 8a·2HCl
and 8b·2HCl, respectively, which was dissolved in water
(5 mL) and then applied to a Dowex 50WX.8.100
ion-exchange column (10 g) pre-treated with HCl and
washed with distilled water. The free a,b-diamino acid
was eluted with 100 mL of 1 M NH3. The NH3 was
References
1. For reviews see: (a) Seebach, D.; Hoffmann, M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2708; (b) Wirth, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 225.
2. For review, see: Kaul, R.; Balaram, P. Bioorg. Med.
Chem. 1999, 7, 105–117.

K. P. Pai Fondekar et al. / Tetrahedron: Asymmetry 13 (2002) 2241–2249
2249
3. (a) Shrader, W. D.; Marlowe, C. K. Biorg. Med. Chem. Lett.
1995, 5, 2207; (b) Boyce, R. J.; Mulqueen, G. C.; Pattenden,
G. Tetrahedron 1995, 51, 7321; (c) Breveglieri, A.; Guerrini,
R.; Salvadori, S.; Bianchi, C.; Bryant, S. D.; Attila, M.;
Lazarus, L. H. J. Med. Chem. 1996, 39, 773; (d) Gershonov,
E.; Granoth, R.; Tzehoval, E.; Gaoni, Y.; Fridkin, M. J.
Med. Chem. 1996, 39, 4833; (e) Horikawa, M.; Shigeri, Y.;
Yumato, N.; Yoshikawa, S.; Nakaijima, T.; Ohfune, Y.
Bioorg. Med. Chem. Lett. 1998, 8, 2027; (f) Toth, G. H.;
Bakos, K.; Penke, B.; Pavo, I.; Varga, C.; Torok, G.; Peter,
A.; Fulop, F. Bioorg. Med. Chem. Lett. 1999, 9, 667.
4. (a) Bedingfield, J. S.; Kemp, M. C.; Jane, D. E.; Tse, H.
W.; Roberts, P. J.; Watkins, J. C. Br. J. Pharmacol. 1995,
116, 3323; (b) Pellicciari, R.; Luneia, R.; Costantino, G.;
Marinozzi, M.; Natalini, B.; Jakobsen, P.; Kanstrup, A.;
Lombardi, G.; Moroni, F.; Thomsen, C. J. Med. Chem.
1995, 38, 3717; (c) Trist, D. G. Pharm. Act. Helv. 2000, 74,
221.
(b) Duthaler, R. O. Tetrahedron 1994, 50, 1539–1650; (c)
Williams, R. M. Synthesis of Optically Active a-Amino
Acids, Vol. 7 of Organic Chemistry Series, Baldwin, J. E.;
Magnus, P. D., Eds.; Pergamon Press: Oxford, 1989;
Chapter 5, pp. 208–229. For recent work on Asymmetric
Strecker Synthesis, see: (a) Byrne, J.; Chavarot, M.; Cha-
vant, P.; Vallee, Y. Tetrahedron Lett. 2000, 41, 873–876;
(b) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi,
S. J. Am. Chem. Soc. 2000, 122, 762–766; (c) Ma, D.;
Guozhi, T.; Zou, G. Tetrahedron Lett. 1999, 40, 9385; (d)
Ma, D.; Guozhi, T.; Zou, G. Tetrahedron Lett. 1999, 40,
5753–5756; (e) Corey, E. J.; Grogan, M. Org. Lett. 1999,
1, 157–160; (f) Ma, D.; Tian, H.; Zou, G. J. Org. Chem.
1999, 64, 120–125; (g) Dominguez, C.; et al. Tetrahedron
Lett. 1998, 39, 9305–9308; (h) Vergne, C.; Bouillon, J.-P.;
Chastanet, J.; Bois-Choussy, M.; Zhu, J. Tetrahedron:
Asymmetry 1998, 9, 3095–3103.
9. (a) Volk, F. J.; Frahm, A. W. Liebigs Ann. Chem. 1996,
1893; (b) Pai Fondekar, K. P.; Volk, F. J.; Frahm, A. W.
Tetrahedron: Asymmetry 1999, 10, 727; (c) Wede, J.; Volk,
F.-J.; Frahm, A. W. Tetrahedron: Asymmetry 2000, 11,
3231–3252.
10. Schlichter, W. H.; Frahm, A. W. Arch. Pharm. 1993, 429.
11. Schlauch, M.; Volk, F.-J.; Pai Fondekar, K. P.; Wede, J.;
Frahm, A. W. J. Chromatogr. A 2000, 897, 145–152.
5. Acher, F.; Tellier, F.; Azerad, R.; Brabet, I.; Fagni, L.; Pin,
J.-P. J. Med. Chem. 1997, 40, 3119.
6. Allen, C. N.; Omelchenko, I.; Ros, S. M.; Spencer, P.
Neuropharmacology 1995, 34, 651.
7. For review, see: Gellman, S. H. Acc. Chem. Res. 1998, 31,
173.
8. For reviews on Asymmetric Strecker Synthesis, see: (a)
Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225–227;