A new strategy for the regio- and stereoselective hydroxylation of trans-2-aminocyclohexenecarboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2006.02.133

A simple and novel method for the introduction of an extra hydroxy group into an aminocyclohexanecarboxylic acid via stereoselective epoxidation and regioselective opening of the oxirane ring is presented. This method permits the preparation of the enanti

Full text of DOI:10.1016/j.tetlet.2006.02.133

Tetrahedron Letters 47 (2006) 2855–2858
A new strategy for the regio- and stereoselective hydroxylation
of trans-2-aminocyclohexenecarboxylic acid
*
}
´
´
Lorand Kiss, Eniko Forro and Ferenc Fulo¨p
¨
Institute of Pharmaceutical Chemistry, University of Szeged, PO Box 427, H-6701 Szeged, Hungary
Received 20 January 2006; revised 14 February 2006; accepted 23 February 2006
Available online 13 March 2006
Dedicated to Professsor Pal Sohar on his 70th birthday
Abstract—A simple and novel method for the introduction of an extra hydroxy group into an aminocyclohexanecarboxylic acid via
stereoselective epoxidation and regioselective opening of the oxirane ring is presented. This method permits the preparation of the
enantiomerically pure hydroxylated amino acid.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
plished stereoselectively from cis- and trans-2-amino-
cyclohexenecarboxylic acids by iodolactonization or
via the corresponding oxazine derivatives.7
In recent years, significant interest has been demon-
strated in conformationally constrained alicyclic b-amino
acids as a consequence of their pharmacological poten-
tial. These compounds are found in a large number of
natural products, b-lactams and antibiotics. They are
also considered as important building blocks for the
synthesis of peptide oligomers.1 The presence of a polar
side chain in a peptide oligomer not only exerts strong
influence on the formation of its secondary structure,
but can also have an enormous effect on its biological
activity in an amphiphilic structure.2 Apart from this,
the hydroxy-functionalized derivatives (taxol, bestatin
and related molecules) are of considerable interest, in
view of their promising biological properties as potential
therapeutic agents.3 Among the alicyclic hydroxy-b-
amino acids, the natural oryzoxymycin exhibits moder-
ate activity against Xanthomonas oryzae.4 Whilst a
number of methods have been developed for the diaste-
reo- and enantioselective preparation of cyclic b-amino
acids, only a few examples are available for the synthesis
of hydroxy-substituted 2-aminocyclohexanecarboxylic
acids.3e,5 One short method is the base-induced fragmen-
tation of b-amino esters with an oxanorbornene or oxa-
norbornane skeleton.6 The introduction of a hydroxy
group onto the cyclohexane ring can also be accom-
Epoxidation of a mono N-protected alkene (carbamate
or amide) with peracids is known to proceed with a high
degree of cis selectivity (presumably via a hydrogen-
bonding interaction in the transition state).8 Conse-
quently, transformation of a 2-aminocyclohexenecarb-
oxylic acid through epoxidation may be expected to
lead, stereoselectively, to the hydroxylated derivative
of the alicyclic amino acid. For this reason, the Z- and
Boc-protected trans-b-amino esters 1a and 1b were sub-
mitted to epoxidation (Scheme 1).
The reactions were carried out in the presence of
m-chloroperbenzoic acid (MCPBA) as the oxidant in
CH2Cl2. In both cases, the reaction furnished in a diaste-
reoselective manner, only the cis-epoxides 2a and 2b as
single diastereomers (Scheme 1). The stereochemistry
of the rigid ring system of 2a was established using
NMR spectroscopy and molecular modelling. Both the
4S,5R (a cis epoxide ring relative to NHZ) and the
COOEt
NHR
COOEt
NHR
O
1a,b
2a,b
Keywords: Cyclic b-amino acids; Epoxidation; Hydroxylated amino
Scheme 1. Epoxidation of ethyl trans-2-amino-4-cyclohexenecarboxyl-
ate (a: R = Z, b: R = Boc). MCPBA, CH2Cl2, rt, 6 h, 2a: 59%; 2b:
65%.
acids; Selective synthesis; Enzymatic resolution.
*
Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705;
e-mail: fulop@pharm.u-szeged.hu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.133

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L. Kiss et al. / Tetrahedron Letters 47 (2006) 2855–2858
Table 1. Calculated geometry and measured characteristic NMR spectral parameters for 2a and 2b
Atom pair
Dihedral angle
for 4R,5S (deg)
Dihedral angle
for 4S,5R (deg)
Measured
3J (Hz)
Distances
for 4R,5S (A)
Distances
for 4S,5R (A)
NOESY
cross-peak rel. int.
˚
˚
H4–H3eq
H4–H3ax
H5–H6eq
H5–H6ax
66
52
18
18
99
65
52
2.1
1.5
5.5
2.58
2.48
2.36
2.82
2.36
2.82
2.57
2.48
2.30
2.25
3.11
1.00
100
<0.5
HO
COOH
HO
COOH
NH2
COOEt
HO
COOEt
i
ii
iii
O
NHZ
NHZ
NHZ
2a
3
4
5
Scheme 2. Synthesis of rac-(r-1,t-2,t-5)-2-amino-5-hydroxycyclohexanecarboxylic acid. Reagents and conditions: (i) NaBH4, EtOH, rt, 2 h, 66%; (ii)
NaOH, MeOH/H2O, rt, 3 h, 89%; (iii) H2, Pd/C, MeOH, rt, 6 h, 91%.
1
R
1
R
COOEt
NHZ
5
S
1R
COOH
NH2
1
R
COOEt
HO
COOH
NH2
i
ii
iii-vi
NH2×HCl
2R
2
R
2R
2
R
6
7
8
9
Scheme 3. Synthesis of (1R,2R,5S)-2-amino-5-hydroxycyclohexanecarboxylic acid. Reagents and conditions: (i) SOCl2, EtOH, 70 ꢁC, 4 h, 89%; (ii)
Z-Cl, Et3N, THF, rt, 16 h, 91%; (iii) MCPBA, CH2Cl2, rt, 6 h, 56%; (iv) NaBH4, EtOH, rt, 2 h, 66%; (v) NaOH, MeOH/H2O, rt, 3 h, 87%; (vi) H2,
Pd/C, MeOH, rt, 6 h, 86%.
4R,5S (a trans epoxide ring relative to NHZ) forms were
modelled at the HF/3-21G* level. The calculated geo-
metrical features around H4 and H5 and the character-
istic NMR spectral parameters are listed in Table 1.
Comparison of the pattern of the experimental para-
meters with the calculated geometrical features of the
corresponding diastereomers strongly supports the 4S,5R
relative configuration (a cis oxirane ring relative to the
NHZ group).
constants observed for H4 and the NOE interactions
HO-H6eq and HO-H3eq revealed the axial arrangement
(S relative configuration) of the OH substituent. Alka-
line hydrolysis of the ester group of compounds 3 and
subsequent deprotection of the amino group by catalytic
hydrogenation in MeOH afforded 2-amino-5-hydroxy-
cyclohexanecarboxylic acid 5.
The reactions were also performed for enantiomeric
substances (Scheme 3). The (1R,2R) enantiomer 6 was
prepared from the corresponding racemic ester by
enzyme-catalyzed kinetic resolution, using 2,2,2-trifluo-
roethyl chloroacetate as the acyl donor with lipase PS
in diethyl ether.9
The attack on the double bond occurred from the side of
the alkoxycarbonylamine moiety, the oxirane ring being
formed on the amide side of the cyclohexane skeleton.
The selectivity of the epoxidation reaction was determined
by 1H NMR and GC analyses of the crude products.
In conclusion, a new and effective approach to the
hydroxy-functionalized b-amino acids has been developed
based on a diastereoselective epoxidation and hydroxyl-
ation involving regioselective opening of the oxirane
ring. We are currently studying the application of these
transformations for the synthesis of other hydroxylated
b-amino acids in both racemic and optically pure forms.
This nitrogen-mediated directing effect in the epoxida-
tion reactions suggested a stereocontrolled route to the
hydroxy-substituted aminocyclohexanecarboxylic acid.
Furthermore, the reductive opening of the oxirane ring
of 2a, with NaBH4 in EtOH at room temperature, pro-
ceeded regioselectively, affording only compound 3, in
which the hydroxy group is in position 5 on the cyclo-
hexane ring of the alicyclic amino ester (Scheme 2).
The other regioisomer (4-OH derivative) was not
detected in the reaction mixture.
2. Experimental
The experimental details are given only for enantiomeric
substances. For the synthesis of racemates, the same
conditions were used.
The relative configuration and the position of the hydr-
oxy group on the cyclohexane skeleton were determined
by means of NMR analyses. For compound 3, the
COSY connectivity pattern unequivocally supported
the constitution depicted in Scheme 2. The vicinal cou-
plings and the clear 1,3-diaxial NOE interactions proved
the chair conformation with trans-diequatorial COOEt
and NHZ substituents. The exclusively small coupling
2.1. Ethyl (1R,2R)-2-amino-4-cyclohexenecarboxylate
hydrochloride (7)
To a solution of (1R,2R)-2-amino-4-cyclohexenecarb-
oxylic acid 6 (1 g, 7.1 mmol) (for the synthesis of the

L. Kiss et al. / Tetrahedron Letters 47 (2006) 2855–2858
2857
racemic and enantiomeric compounds, see Refs. 10 and
9, respectively) in EtOH (15 mL), SOCl2 (0.9 mL,
12.5 mmol) was added dropwise at ꢀ10 ꢁC over a period
of 30 min, and the mixture was stirred for 3 h at room
temperature and then for 1 h under reflux. The mixture
was concentrated giving the crude product, which was
used further without purification. White solid, mp 97–
98 ꢁC, yield 89%, ½aꢁ ꢀ120 (c 0.75, EtOH). H NMR
(400 MHz, D2O): dD 1.30 (t, 3H, J = 7.1 Hz, CH3),
2.15–2.50 (m, 4H, CH2), 2.92–2.98 (m, 1H, H-1), 3.77–
3.81 (m, 1H, H-2), 4.22–4.27 (m, 2H, OCH2), 5.68 (m,
1H, CH), 5.77 (m, 1H, CH); Anal. Calcd for
C9H16ClNO2: C, 52.68; H, 7.80; N, 6.83; Cl, 17.29.
Found: C, 52.60; H, 7.54; N, 6.76; Cl, 16.98.
solution was washed with H2O, dried (Na2SO4) and con-
centrated. The crude oily product was chromatographed
over silica gel (n-hexane/EtOAc 1:2). White solid, mp
25
68–70 ꢁC, yield 66%, ½aꢁD ꢀ4.5 (c 0.35, EtOH). 1H
NMR (CDCl3): d = 1.19 (t, 3H, J = 7.1 Hz, CH3),
1.68–1.95 (m, 6H, CH2), 2.75–2.77 (m, 1H, H-1), 3.81–
3.83 (m, 1H, H-2), 4.07–4.15 (m, 3H, OCH2 and H-5),
25
1
4.96–4.98 (d, 1H, J = 5.5 Hz, N-H), 5.08 (s, 2H,
OCH2), 7.30–7.35 (m, 5H, Ar-H); Anal. Calcd for
C17H23NO5: C, 63.55; H, 7.16; N, 4.36. Found: C,
63.43; H, 7.11; N, 4.30.
2.5. (1R,2R,5S)-2-(Benzyloxycarbonylamino)-5-hydroxy-
cyclohexanecarboxylic acid [(ꢀ)-4]
2.2. Ethyl (1R,2R)-2-(benzyloxycarbonylamino)-4-
cyclohexenecarboxylate (8)
To a solution of amino ester (ꢀ)-3 (300 mg, 0.93 mmol)
in THF (25 mL), NaOH (130 mg, 3.25 mmol) in H2O
(15 mL) was added. After stirring for 24 h, 10% HCl
was added at 0 ꢁC until pH 5, and the mixture was then
extracted with CHCl3 (3 · 40 mL). The combined
To a solution of amino ester 7 (1.2 g, 5.85 mmol) and
Et3N (1.8 mL, 17.8 mmol) in THF (40 mL), benzyl chlo-
roformate (1.5 g, 8.8 mmol) was added at 0 ꢁC. After
stirring for 16 h, the mixture was taken up in EtOAc
(60 mL), and the solution was washed with H2O, dried
organic layers were dried (Na2SO4) and concentrated.
25
White solid, mp 65–68 ꢁC, yield 86%, ½aꢁD ꢀ3.5 (c 0.37,
EtOH). 1H NMR (DMSO): d = 1.23–1.63 (m, 6H,
CH2), 2.63–2.66 (m, 1H, H-1), 3.50–3.54 (m, 1H, H-2),
3.82 (m, 1H, H-5), 4.54 (d, 1H, J = 5.5 Hz, N-H), 4.99
(s, 2H, OCH2), 7.26–7.37 (m, 5H, Ar-H), 12.06 (1H,
COOH); Anal. Calcd for C15H19NO5: C, 61.43; H,
6.48; N, 4.78. Found: C, 61.39; H, 6.49; N, 4.59.
over Na2SO4 and concentrated under reduced pressure.
25
White solid (n-hexane), mp 70–73 ꢁC, yield 91%, ½aꢁD
ꢀ18 (c 0.3, EtOH). 1H NMR (400 MHz, CDCl3): d
1.23 (t, 3H, J = 7.1 Hz, CH3), 2.00–2.04 (m, 1H, CH2),
2.30–2.35 (m, 1H, CH2), 2.51–2.56 (m, 2H, CH2),
2.71–2.73 (m, 1H, H-1), 4.11–4.17 (m, 3H, OCH2,
H-2), 4.93 (d, 1H, J = 5.5 Hz, N-H), 5.11 (s, 2H,
OCH2), 5.61–5.65 (m, 1H, H-5), 5.68–5.70 (m, 1H, H-
4), 7.33–7.39 (m, 5H, Ar-H); Anal. Calcd for
C17H21O4N: C, 67.32; H, 6.98; N, 4.62. Found: C,
67.24; H, 6.90; N, 4.51.
2.6. (1R,2R,5S)-2-Amino-5-hydroxycyclohexanecarboxy-
lic acid (9)
A solution of amino acid (ꢀ)-4 (295 mg, 1.5 mmol) and
10% Pd/C (80 mg) in MeOH (30 mL) was stirred under
H2 for 2 h. The Pd was then filtered off and the filtrate
was concentrated under reduced pressure. The residue
was crystallized from MeOH/Et2O. White crystals, mp
2.3. Ethyl (1R,2R,4S,5R)-2-(benzyloxycarbonylamino)-
4,5-epoxycyclohexanecarboxylate [(ꢀ)-2a]
25
1
272–275 ꢁC, yield 87%, ½aꢁD ꢀ18.5 (c 0.33, H2O). H
NMR (D2O): d = 1.60–1.92 (m, 5H, CH2), 2.15–2.19
(m, 1H, CH2), 2.57–2.62 (m, 1H, H-1), 3.30–3.32 (m,
1H, H-2), 4.15–4.17 (m, 1H, H-5); Anal. Calcd for
C7H13NO3: C, 52.83; H, 8.18; N, 8.80. Found: C,
52.60; H, 8.06; N, 8.69.
To a solution of amino ester 7 (5.85 mmol) in CH2Cl2
(40 mL), MCPBA (7 mmol) was added at 0 ꢁC. After
stirring for 5 h, CH2Cl2 (90 mL) was added and the mix-
ture was washed with saturated NaHCO3 solution in
H2O. The organic layer was then dried (Na2SO4) and
concentrated under reduced pressure. The crude product
was chromatographed over silica gel (n-hexane/EtOAc
Acknowledgements
3:1). White solid (n-hexane), mp 82–85 ꢁC, yield 59%,
25
½aꢁD ꢀ24.7 (c 0.35, EtOH). 1H NMR (CDCl3): d =
This work was supported by the Hungarian Research
Foundation (OTKA T 049407 and T 046440) and the
National Research and Development Office, Hungary
(GVOP-311-2004-05-0255/3.0). We thank Dr. Tamas
A. Martinek for the NMR analyses.
1.13 (t, 3H, J = 7.1 Hz, CH3), 1.82–1.88 (m, 1H, CH2),
2.11–2.22 (m, 3H, CH2), 2.56–2.58 (m, 1H, H-1), 3.08
(m, 1H, H-5), 3.17 (m, 1H, H-4), 3.99–4.06 (m, 3H,
OCH2 and H-2), 5.01 (s, 2H, OCH2), 5.28–5.30 (d,
1H, J = 5.5 Hz, N–H), 7.18–7.24 (m, 5H, Ar-H); Anal.
Calcd for C17H21NO5: C, 63.95; H, 6.58; N, 4.39.
Found: C, 63.77; H, 6.65; N, 4.32.
´
References and notes
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