Carbocyclic α-amino acids: Asymmetric synthesis of all four 1-amino-2- hydroxycyclohexanecarboxylic acids

Article abstract of DOI:10.1016/S0957-4166(99)00045-2

Starting from racemic 2-methoxycyclohexanone and (S)- or (R)-1- phenylethylamine, respectively, the four stereoisomers of 1-amino-2- hydroxycyclohexanecarboxylic acid are obtained via an asymmetric Strecker synthesis with ee values ranging from 87 to 98%.

Full text of DOI:10.1016/S0957-4166(99)00045-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 727–735
Carbocyclic α-amino acids: asymmetric synthesis of all four
1-amino-2-hydroxycyclohexanecarboxylic acids †
Kamalesh Pai Fondekar, Franz-J. Volk and August W. Frahm ∗
Lehrstuhl für Pharmazeutische Chemie, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Straße 9, D-79104 Freiburg,
Germany
Received 18 December 1998; accepted 3 February 1999
Abstract
Starting from racemic 2-methoxycyclohexanone and (S)- or (R)-1-phenylethylamine, respectively, the four
stereoisomers of 1-amino-2-hydroxycyclohexanecarboxylicacid are obtained via an asymmetric Strecker synthesis
with ee values ranging from 87 to 98%. Their stereochemistry is established by NMR methods and by X-ray
analyses. Hydrogenolysis of a benzylic C–N bond by conc. sulphuric acid as well as cleavage of a methoxy ether
by conc. HCl are two intriguing reactions which are observed within the five-step procedure described herein.
© 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Recently, diverse biological effects of carbocyclic α-amino acids have been described. They act as
agonists and/or antagonists at both ionotropic and metabotropic glutamate receptors.1,2 Furthermore,
they are involved in enzymatic processes for plant growth and fruit ripening.3 They are also reported
to modify biological activities in a useful way when incorporated as building blocks into peptides
or proteins.4 These findings demand the development of straightforward syntheses of this type of α-
quaternary α-amino acids from readily available starting materials. As part of our research efforts towards
conformationally restricted analogues of naturally occurring α-amino acids, we previously described the
preparation of the four cyclic isoleucines 1a–d (Scheme 1) by means of asymmetric Strecker synthesis.5
More recently, Ohfune and co-workers reported the syntheses of the 5- and 6-membered carbocyclic
serine analogues 2a,b and 3a,b (Scheme 1) via an intramolecular version of the Strecker reaction.6
Herein we describe the stereoselective preparation of the 1-amino-2-hydroxycyclohexanecarboxylic
acids 10a,b, representing 2,4-propano analogues of the natural L -threonine (Scheme 2), starting from
s
∗
†
Corresponding author. E-mail: awfrahm@ruf.uni-freiburg.de
Dedicated to Professor Dr. P. Nickel on the occasion of his 65th birthday.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00045-2

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Scheme 1.
racemic 2-methoxycyclohexanone 4 and (S)-1-phenylethylamine 5 as the chiral auxiliary (Scheme 3).
Using (R)-1-PEA instead of (S)-1-PEA the amino acids 3a,b were obtained.
Scheme 2.
2. Results and discussion
The racemic starting ketone 4 was prepared as described previously.7 Azeotropic condensation of
(RS)-4 with an equimolar quantity of (S)-1-PEA 5 gave imines 6 as diastereomeric mixtures with E-
1
αS,2R-, E-αS,2S-, Z-αS,2R- and Z-αS,2S configuration and an E:Z ratio of ∼10:1 as derived from H
NMR in 93% yield. The crude imines 6 were then reacted with trimethylsilylcyanide (TMSCN)/ZnCl2
yielding the α-amino nitriles 7 in quantitative yields as a mixture of all four possible diastereomers 7a–d
(Scheme 4).
As observed earlier,5 the trans/cis diastereoselectivity of the α-amino nitrile formation was dependent
on the solvent (Table 1).
Thus, in MeOH (procedure A) the α-amino nitrile formation was under thermodynamic control
leading predominantly to the trans configured products 7b and 7c (trans:cis=74:26), whereas in hexane
(procedure B) it was kinetically controlled, with the cis configured compounds 7a and 7d being the major
products (trans:cis=25:75). The stereochemical compositions of the α-amino nitrile mixtures 7, outlined
in Table 1, are based on our previously established 13C NMR analyses.5 On treatment of the α-amino
nitrile mixture 7 with conc. sulphuric acid for 6 days a complex crude product was obtained, which was
then chromatographed on silica gel using petrol ether/ethyl acetate as the eluent yielding (i) a mixture
of the two trans configured α-amino amides 8b/c and (ii) the hydrogenolysed cis configured primary

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729
Scheme 3. Reaction conditions: (a) toluene, reflux; (b) (i) MeOH, TMSCN, ZnCl2 (5 mol%), 0°C (30 min), rt (3 h); (ii) hexane,
TMSCN, ZnCl2 (5 mol%), 0°C (30 min), rt (48 h); (c) conc. H2SO4, −10°C (3 h), 0°C (3 h), rt (7 days); (d) CC: silica gel, petrol
ether:ethyl acetate (1:1) then (1:3); (e) LPLC: Lobar®, MeOH:H2O (85:15); (f) EtOH, Pd/C (10%), 45°C, 5 bar H2, 24 h; (g)
+
12 M HCl, reflux, 7 days; Dowex 50WX.8.100 (NH4 form), 1 M NH3
Scheme 4.
α-amino amide 9a. Subsequent Lobar® purification of the 8b,c mixture to diastereomerically pure 8b
followed by catalytic hydrogenolysis of the benzylic C–N bond on Pd/C at 5 bar H2 and 45°C gave the
second primary α-amino amide 9b. In the final reaction step the primary α-amino amides 9a and 9b,
respectively, were refluxed with conc. HCl for 7 days, whereby the carboxamide was hydrolysed along
with the demethylation of the methoxy group and, after treatment with ion-exchange resin (activated
Dowex 50WX.8.100), the 1-amino-2-hydroxycyclohexanecarboxylic acids 10a and 10b were obtained.
Shorter reaction times and lower concentrations of HCl led to the selective hydrolysis of the carboxamide

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K. Pai Fondekar et al. / Tetrahedron: Asymmetry 10 (1999) 727–735
Table 1
Diastereoselective α-amino nitrile formation
Figure 1.
function.8 The respective enantiomers of 10a and 10b, the α-amino acids 3a and 3b were prepared by
the same reaction sequence starting from (RS)-4 and (R)-1-PEA instead of (S)-1-PEA.
The ee values of 95% and 98% for the trans α-amino acids 3b and 10b, respectively, are within the
range of the optical purity of the chiral auxiliary used in the reaction sequence. The lower ee values
of 88% and 87% for the cis α-amino acids 3a and 10a are due to the simultaneous hydrolysis and
hydrogenolysis of the 93:7 mixtures of the two cis configured α-amino nitriles 7a:7d and ent-7a:ent-7d,
respectively, on treatment with conc. sulphuric acid. Thus, the cis configured compounds 9a and ent-9a
as well as the corresponding α-amino acids 3a and 10a are obtained as enantiomeric mixtures with the
given ee values which were determined by means of chiral HPLC on a Chirobiotic T™ column, using
EtOH:H2O (30:70) as the eluent.9
2.1. Stereochemical assignments
The relative configuration of the primary α-amino amides 9a and 9b was deduced on the basis of NMR
spectroscopic data using the heteronuclear coupling constants between the carboxamide carbon C-7 and
3
the proton 2-H (Fig. 1). Thus, the JC-7/2-H value of 1.6 Hz for 9a correlates with cis configuration and
that of 6.3 Hz for 9b with trans configuration.
Furthermore, assuming ‘like-induction’ at C-1, we predicted 1S,2R configuration for 9a and 1S,2S
for 9b. In fact, this assignment was finally proved by the X-ray analysis of the primary α-amino amide
hydrochloride 9a·HCl.10
3. Experimental
Solvents were purified according to standard procedures. Melting points are uncorrected. Analytical
TLC was performed on Merck Si60 F254 (0.2 mm) precoated alumina foils. CC was carried out on Merck
silica gel (0.2–0.063 mm). Infrared spectra were recorded on a Perkin–Elmer IR 298 spectrometer. The
NMR spectra were obtained on a Varian XL 300 spectrometer at 300 MHz (1H) and 75.4 MHz (13C)

K. Pai Fondekar et al. / Tetrahedron: Asymmetry 10 (1999) 727–735
731
respectively. Chemical shifts are reported as δ values using either TMS (1H) or the solvent peak (13C) as
the reference. Optical rotation values are measured in a 1 dm cell with a Perkin–Elmer 214 polarimeter.
HPLC was performed on a Chirobiotic T™ column equipped with a Waters 515 pump and a Waters
2487 dual λ absorbance detector. Elemental analyses were carried out with a Perkin–Elmer elemental
analyser PE240 at the Department of Biochemistry and Organic Chemistry, University of Freiburg. MS
and HRMS were obtained with a Finnigan MAT312 (EI) and a Finnigan 44S mass spectrometer.
3.1. (RS)-2-Methoxycyclohexanone 4
Compound 4 was prepared from 2-chlorocyclohexanone following the procedure described in the
literature.7
3.2. E/Z-2-(RS)-[N-(S)-α-Phenylethyl]methoxycyclohexaneimine 6
An equimolar mixture of (RS)-2-methoxycyclohexanone 4 (12.7 g, 0.1 mol) and (S)-(−)-1-PEA 5 (12.1
g, 0.1 mol) was taken up in 100 mL of dry toluene and refluxed for 8 h using a Dean–Stark apparatus.
The solvent was then evaporated under reduced pressure and the residue was dried under high vacuum to
yield 21.5 g (93%) of 6 as a reddish oil. IR (film): 1658 (C_N), 1098 (C–O) cm−1; 13C NMR (CDCl3):
20.4(E), 20.5(E), 21.1(Z), 22.8(Z), 23.6(Z), 24.6(E), 24.7(E), 24.9(E), 24.9(E), 25.7(Z), 25.7(Z), 26.4(E),
26.5(Z), 27.0(Z), 27.4(E), 31.9(Z), 33.0(E), 33.1(E), 33.9(Z), 52.7(Z), 53.2(Z), 55.7(E), 55.8(E), 57.4(Z),
57.5(Z), 57.7(E), 57.8(E), 82.1(Z), 83.6(E), 83.6(E), 83.9(Z), 125.4(Z), 125.5(Z), 125.5(E), 126.0(E),
126.1(Z), 126.2(Z), 126.2(E), 126.3(E), 127.9(Z), 128.0(E), 128.1(E), 128.2(Z), 139.3(Z), 145.7(E),
145.8(E), 146.0 (Z), 171.0(E), 171.3(E).
3.3. 2-Methoxy-1-(α-phenylethylamino)cyclohexanecarbonitriles 7a–d
3.3.1. Procedure A
To a solution of 11.5 g (0.05 mol) 6 and 340 mg (5 mol%) of dry ZnCl2 in 150 mL methanol, 8.3 mL
(0.0625 mol) TMSCN were added slowly at 0°C over a period of 30 min. The reaction mixture was then
stirred for a further 3 h, filtered, concentrated under reduced pressure and dried under high vacuum to
yield 13.4 g (99%) diastereomeric mixture of the α-amino nitriles 7a–d. IR (film): 3347 (N–H), 2224
(C^N), 1101 (C–O) cm−1; 13C NMR (CDCl3): 21.9, 21.7, 18.8, 20.3 (C-4), 23.1, 22.7, 23.1, 22.1 (C-5),
26.4, 24.7, 25.7, 24.3 (C-3), 26.4, 26.0, 25.9, 24.5 (C-β), 34.1, 32.9, 34.8, 33.1 (C-6), 54.4, 54.9, 54.0,
53.9 (C-α), 56.5, 56.4, 57.5, 56.7 (OCH3), 63.6, 61.7, 60.2, 63.7 (C-1), 83.4, 82.4, 82.8, 83.9 (C-2),
120.2, 122.4, 120.3, 121.7 (C^N), 126.3, 126.3, 126.5, 126.0 (C-30), 126.5, 127.0, 126.6, 126.9 (C-40),
128.1, 128.4, 128.3, 128.5 (C-20), 147.5, 146.6, 145.5, 145.9 (C-10).
3.3.2. Procedure B
To a solution of 9.0 g (0.04 mol) 6 and 270 mg (5 mol%) of dry ZnCl2 in 150 mL of hexane, 6.7 mL
(0.05 mol) TMSCN was added slowly at 0°C over a period of 30 min. The reaction mixture was then
stirred for a further 48 h and then an equimolar volume of methanol (1.6 mL) was added. The resulting
mixture was stirred for 30 min more, filtered, concentrated under reduced pressure and dried under high
vacuum to yield 10.3 g (98%) diastereomeric mixture of the α-amino nitriles 7a–d.

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3.4. Hydrolysis of the 2-methoxy-1-(α-phenylethylamino)cyclohexanecarbonitriles 7a–d
A diastereomeric mixture of α-amino nitriles 7a–d (11.0 g, 0.04 mol) was added slowly to 80 mL
of conc. H2SO4 at −10°C and stirred for 3 h at same temperature. The solution was then stirred at
0°C for 3 h and at rt for 7 days. The reaction mixture was decomposed on ice (250 g), filtered, and
the filtrate was adjusted to pH 8 with conc. ammonia and then extracted with ethyl acetate (3×100
mL). The crude organic extracts were dried over anhyd. Na2SO4, concentrated under reduced pressure
and dried under high vacuum to yield 7.1 g of an oily residue. A quantity (5.0 g) of the above residue
was chromatographed over silica gel (350 g) and eluted with petrol ether (40–60°C):ethyl acetate (1:1)
to yield a diastereomeric mixture of unreacted α-amino nitriles 7a–d (360 mg, fraction A); continuing
elution with same polarity resulted in 1.8 g of a mixture of the two diastereomeric α-amino carboxamides
8b,c (fraction B). Further elution with petrol ether (40–60°C):ethyl acetate (1:3) yielded 630 mg of
diastereomerically pure 9a.
3.4.1. cis-(1S,2R)-1-Amino-2-methoxycyclohexanecarboxamide 9a
Mp: 92°C; 1H NMR (CDCl3): 1.0–1.8 (m, 9H, cycloaliphatic and amino-H), 1.94 (m, 1H, 3-H), 3.30
(s, 3H, -OCH3), 3.76 (dd, J=11.0, 4.5 Hz, 1H, 2-H), 5.9 (s(b), 1H, -NH (amido)), 7.7 (s(b), 1H, -NH
(amido)); 13C NMR (CDCl3): 20.2 (C-5), 23.6 (C-4), 25.5 (C-3), 34.0 (C-6), 56.7 (OCH3), 60.8 (C-1),
79.8 (C-2), 180.4 (C_O).
3.4.2. cis-(1S,2R)-1-Amino-2-methoxycyclohexanecarboxamide hydrochloride 9a·HCl
Compound 9a was converted into its hydrochloride salt using ether saturated with HCl gas. Mp: 207°C;
[α]D20=+7.7 (c 0.963, CH3OH); H NMR (CDCl3): 1.3–2.3 (m, 8H, cycloaliphatic -H), 3.42 (s, 3H, -
1
OCH3), 3.84 (dd, J=11.0, 5.1 Hz, 1H, 2-H); 13C NMR (CDCl3): 20.9 (C-5), 23.76 (C-4), 26.5 (C-3),
33.0 (C-6), 57.4 (OCH3), 65.4 (C-1), 79.7 (C-2), 174.2 (C_O); HRMS (EI, 70 eV): m/z (%) 140 (2)
[M+−32 (H3COH), C7H12N2O1: calcd 140.094963, found 140.094451], 128 (100) [M+−44 (CONH2),
C7H14N1O1: calcd 128.107539, found 128.107555], 96 (66), 79 (41), 69 (20); MS (ESI, 1 µL/min, spray
3.8 kV, 200°C, 30 psi): m/z (%) 173 (100) [M+].
3.4.3. cis-(1R,2S)-1-Amino-2-methoxycyclohexanecarboxamide hydrochloride ent-9a·HCl
Mp: 206°C; [α]D20=−7.5 (c 1.0, CH3OH); MS (ESI, 1 µL/min, spray 3.8 kV, 200°C, 30 psi): m/z (%)
173 (100) [M+].
3.4.4. trans-(αS,1S,2S)-2-Methoxy-1-(α-phenylethylamino)cyclohexanecarboxamide 8b
Compound 8b was isolated from the 8b,c mixture (fraction B) by means of LPLC [stationary phase:
Merck LobarB®, mobile phase: CH3OH:H2O (85:15), flow rate: 0.7 mL/min, fraction size: 4.2 mL,
detector: UV (254 nm)] and then converted into its hydrochloride salt using ether saturated with HCl
gas. 8b·HCl: mp: 234°C (dec.); [α]D20=+24.9 (c 1.0, CH3OH); H NMR (CD3OD): 1.2–1.8 (m, 6H,
1
cycloaliphatic-H), 1.72 (d, J=6.8 Hz, 3H, β-CH3), 2.20 (m, 1H, 3-H), 2.45 (m, 1H, 6-H), 3.42 (s, 3H,
-OCH3), 3.68 (dd, J=10.0, 3.7 Hz, 1H, 2-H), 4.68 (q, J=7.0 Hz, 1H, α-H), 7.4–7.65 (m, 5H, Ar–H); 13
C
NMR (CDCl3): 21.7 (C-5), 22.9 (C-4), 23.3 (C-3), 26.8 (C-β), 30.7 (C-6), 57.2 (C-α), 58.1 (OCH3), 70.1
(C-1), 81.5 (C-2), 129.1 (C-30), 130.3 (C-20), 130.7 (C-40), 139.3 (C-10), 169.5 (C_O). C16H25ClN2O2:
calcd C 61.43, H 8.05, N 8.95, found C 61.22, H 8.02, N 8.82.

K. Pai Fondekar et al. / Tetrahedron: Asymmetry 10 (1999) 727–735
733
3.4.5. trans-(αR,1R,2R)-2-Methoxy-1-(α-phenylethylamino)cyclohexanecarboxamide hydrochloride
ent-8b·HCl
Mp: 234°C (dec.); [α]D20=−23.5 (c 1.03, CH3OH); C16H25ClN2O2: calcd C 61.43, H 8.05, N 8.95,
found C 61.38, H 8.09, N 8.93.
3.4.6. trans-(1S,2S)-1-Amino-2-methoxycyclohexanecarboxamide hydrochloride 9b·HCl
In a Parr apparatus, 100 mg of Pd/C (10%) was suspended in 50 mL of EtOH. After evacuation, the
mixture was shaken under 5 bar H2 pressure for 1 h at 45°C. A solution of 200 mg (0.6 mmol) 8b·HCl in
EtOH (50 mL) was added and the reaction mixture was shaken for 24 h at 45°C under 5 bar H2 pressure.
The cooled solution was filtered through Celite and concentrated to yield 127 mg (95%) of 9b·HCl.
1
Mp: 195°C; [α]D20=−4.9 (c 0.657, CH3OH); H NMR (CD3OD): 1.4–1.76 (m, 5H, cycloaliphatic-H),
1.78 (m, 1H, 4-H), 2.08 (m, 1H, 3-H), 2.42 (m, 1H, 6-H), 3.49 (s, 3H, -OCH3), 3.61 (dd, J=9.3, 3.7 Hz,
1H, 2-H); 13C NMR (CD3OD): 22.4 (C-5), 22.9 (C-4), 26.4 (C-3), 32.0 (C-6), 57.6 (OCH3), 63.4 (C-1),
81.4 (C-2), 171.6 (C^O); HRMS (EI, 70 eV): m/z (%) 140 (2) [M+−32 (H3COH), C7H12N2O1: calcd
140.094963, found 140.094726], 128 (100) [M+−44 (CONH2), C7H14N1O1: calcd 128.107539, found
128.107555]; MS (ESI, 1 µL/min, spray 3.8 kV, 200°C, 30 psi): m/z (%) 173 (100) [M+].
3.4.7. trans-(1R,2R)-1-Amino-2-methoxycyclohexanecarboxamide hydrochloride ent-9b·HCl
Mp: 195°C; [α]D20=+5.5 (c 0.657, CH3OH); MS (ESI, 1 µL/min, spray 3.8 kV, 200°C, 30 psi): m/z
(%) 173 (100) [M+].
3.4.8. trans-(1S,2S)-1-Amino-2-methoxycyclohexanecarboxamide 9b (free base)
A colourless oil; 1H NMR (CDCl3): 0.8–2.3 (m, 10H, cycloaliphatic and amino-H), 3.20 (dd, J=10.4,
3.7 Hz, 1H, 2-H), 3.41 (s, 3H, -OCH3), 6.15 (s(b), 1H, -NH (amido)), 7.24 (s(b), 1H, -NH (amido));
13C NMR (CDCl3): 22.2 (C-5), 23.5 (C-4), 26.1 (C-3), 35.2 (C-6), 57.2 (OCH3), 60.3 (C-1), 85.8 (C-2),
177.7 (C^O).
3.5. 1-Amino-2-hydroxycyclohexanecarboxylic acids 10a,b and 3a,b (general procedure)
40 mg of 9a·HCl, 9b·HCl, ent-9a·HCl and ent-9b·HCl, respectively, were dissolved in 10 mL conc.
HCl, stirred for 2 h at rt and then refluxed for one week in an oil bath. Concentration under reduced
pressure followed by drying under high vacuum yielded the α-amino acid hydrochlorides 10a·HCl,
10b·HCl, 3a·HCl and 3b·HCl, respectively, which were dissolved in 5 mL distilled water and then
+
applied to a Dowex 50WX.8.100 ion-exchange column (10 g) in the NH4 -form. The column was first
washed with distilled water, and then the free α-amino acids were eluted with 100 mL of 1 M NH3. The
eluant was concentrated in vacuo. In order to complete the removal of NH3, the substances were taken
up in water, evaporated to dryness, and finally dried for 3 h on the oil pump yielding the α-amino acids
10a,b and 3a,b, respectively in quantitative yields.
3.5.1. cis-(1S,2R)-1-Amino-2-hydroxycyclohexanecarboxylic acid hydrochloride 10a·HCl
Yield: 86%; mp: >300°C (dec.); 1H NMR (CD3OD): 1.38 (m, 3H, 3-H, 4-H, 5-H), 1.68 (m, 1H, 5-H),
1.81 (m, 1H, 4-H), 1.93 (m, 1H, 5-H), 2.01 (m, 2H, 6-H), 4.12 (dd, J=10.7, 5.1 Hz, 1H, 2-H); 13C NMR
(CD3OD): 20.3 (C-5), 23.8 (C-4), 30.3 (C-3), 31.8 (C-6), 65.5 (C-1), 70.3 (C-2), 173.2 (C_O).

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3.5.2. cis-(1S,2R)-1-Amino-2-hydroxycyclohexanecarboxylic acid 10a
Mp: >270°C (dec.); [α]D20=+4.5 (c 1.085, H2O); 1H NMR (D2O; HOD, 4.80 ppm): 1.1–1.4 (m, 3H,
cycloaliph. H), 1.5–2.0 (m, 5H, cycloaliph. H), 4.05 (dd, J=11.2, 5.0 Hz, 1H, 2-H); 13C NMR (D2O):
19.1 (C-5), 22.7 (C-4), 28.7 (C-3), 30.9 (C-6), 65.7 (C-1), 69.7 (C-2), 175.7 (C_O); HRMS (EI, 70
eV): m/z (%) 159 (1) [M+, C7H13N1O3: calcd 159.089544, found 159.089704], 141 (7) [M+−18 (H2O),
C7H11N1O2: calcd 141.078979, found 141.078994], 114 (100) [M+−45 (CO2H)]; MS (ESI, 1 µL/min,
spray 3.8 kV, 200°C, 30 psi): m/z (%) 160 (100) [M++1].
3.5.3. cis-(1R,2S)-1-Amino-2-hydroxycyclohexanecarboxylic acid 3a (antipode of 10a)
Mp: >270°C (dec.); [α]D20=−4.0 (c 0.15, H2O) (lit.6: [α]D20=−33.1); MS (ESI, 1 µL/min, spray 3.8
kV, 200°C, 30 psi): m/z (%) 160 (100) [M++1].
3.5.4. trans-(1S,2S)-1-Amino-2-hydroxycyclohexanecarboxylic acid hydrochloride 10b·HCl
Yield: 89%; mp: >300°C (dec.); 1H NMR (CD3OD): 1.42 (m, 1H, 4-H), 1.60–1.76 (m, 2H, 3-H, 5-H),
1.76–1.96 (m, 3H, 4-H, 5-H, 6-H), 2.00–2.20 (m, 2H, 3-H, 6-H), 3.76 (dd, J=11.0, 4.9 Hz, 1H, 2-H); 13
NMR (CD3OD): 22.1 (C-5), 24.4 (C-4), 31.3 (C-6), 32.9 (C-3), 65.1 (C-1), 73.8 (C-2), 171.6 (C_O).
C
3.5.5. trans-(1S,2S)-1-Amino-2-hydroxycyclohexanecarboxylic acid 10b
Mp: >270°C (dec.); [α]D20=+3.1 (c 1.06, H2O); H NMR (D2O; HOD, 4.80 ppm): 1.1–2.2 (m, 8H,
cycloaliph. H), 3.6 (dd, J=10.2, 4.6 Hz, 1H, 2-H); 13C NMR (D2O): 21.0 (C-5), 22.5 (C-4), 29.9 (C-3),
31.6 (C-6), 64.1 (C-1), 72.3 (C-2), 174.0 (C_O); HRMS (EI, 70 eV): m/z (%) 159 (1) [M+, C7H13N1O3:
calcd 159.089544, found 159.089715], 141 (7) [M+−18 (H2O), C7H11N1O2: calcd 141.078979, found
141.078987], 114 (100) [M+−45 (CO2H)]; MS (ESI, 1 µL/min, spray 3.8 kV, 200°C, 30 psi): m/z (%)
160 (100) [M++1].
1
3.5.6. trans-(1R,2R)-1-Amino-2-hydroxycyclohexanecarboxylic acid 3b (antipode of 10b)
Mp: >270°C (dec.); [α]D20=−3.0 (c 0.965, H2O) (lit.6: [α]D20=−28.9); MS (ESI, 1 µL/min, spray 3.8
kV, 200°C, 30 psi): m/z (%) 160 (100) [M++1].
Acknowledgements
The authors are thankful to Dr. E. Weckert, Institut für Kristallographie, Universität Karlsruhe (TU),
Germany, for the X-ray analysis of compound 9a·HCl. KPF is grateful to DAAD for a short term
fellowship. Financial support by the Fonds der Chemischen Industrie, Frankfurt a.M., Germany is
gratefully acknowledged.
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