Facile regio- and diastereoselective syntheses of hydroxylated 2-aminocyclohexanecarboxylic acids

Article abstract of DOI:10.1002/ejoc.200500062

By means of total regio- and diastereoselective functionalizations of cis- and trans-2-amino-4-cyclohexenecarboxyric acid derivatives 1, 9, 12 and 16, isomers of 2-amino-4-hydroxycyclohexanecarboxylic acid 8 and 11, and 2-amino-5-hydroxycyclohexanecarboxy

Full text of DOI:10.1002/ejoc.200500062

FULL PAPER
Facile Regio- and Diastereoselective Syntheses of Hydroxylated
2-Aminocyclohexanecarboxylic Acids
Ferenc Fülöp,*[a] Márta Palkó,[a] Eniko˝ Forró,[a] Máté Dervarics,[a] Tamás A. Martinek,[a]
and Reijo Sillanpää[b]
Dedicated to Professor András Lipták on the occasion of his 70th birthday
Keywords: Amino acids / Heterocycles / Diastereoselectivity / Structure elucidation
By means of total regio- and diastereoselective functionaliza-
tions of cis- and trans-2-amino-4-cyclohexenecarboxylic acid
derivatives 1, 9, 12 and 16, isomers of 2-amino-4-hydroxycy-
clohexanecarboxylic acid 8 and 11, and 2-amino-5-hydroxy-
cyclohexanecarboxylic acid 15 and 19 were prepared in good
yields, via 1,3-oxazine or γ-lactone intermediates. The
enantiomers of 8 and 15 were also prepared by the same
pathway, resulting in products with ee Ͼ 99%. The struc-
tures, stereochemistry and relative configurations of the syn-
thesized compounds were proved by NMR, using some key
vicinal couplings and characteristic NOEs.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
in many biologically active compounds (e.g. taxol and re-
lated molecules).[2,7] Our present aim was to introduce an
extra hydroxy group at position 4 or 5 of the cyclohexane
ring. For these syntheses, the readily available cis- and trans-
2-amino-4-cyclohexenecarboxylic acids were used. For the
derivatization, we considered two strategies: cyclization on
an acylamino derivative via 1,3-oxazine formation, or cycli-
zation on a carboxylic acid function via lactone formation
(iodolactonization protocol).
Introduction
The continuously increasing interest in cyclic β-amino
acids[1–3] is mainly connected with the importance of the
naturally occurring cispentacin,[4] which exhibits strong an-
ticandida activity. A further feature is the fact that
GellmanЈs group recently synthesized and investigated[5]
trans-2-aminocyclopentane- and trans-2-aminocyclohex-
anecarboxylic acid oligomers, which clearly display a stable
helical conformation. We have found that by inversion of
the relative configurations of the cis oligomers, the pre-
ferred conformation can be switched from a helix to a single
nonpolar strand.[6] Cyclic β-amino acids are widely used as
starting substances for the preparation of heterocycles.
Through their incorporation in place of an α-amino acid of
a naturally occurring pharmacologically active peptide, the
activities can be modified and the stabilities of the natural
peptides can be increased. Changes of configuration and
differences in ring size allow modification of the conforma-
tion of the peptides. They are also applicable in combinato-
rial syntheses.[7–10]
Results and Discussion
The starting cis-2-amino-4-cyclohexenecarboxylic acid
was prepared by hypochlorite-mediated Hoffman degrada-
tion of the carboxamide obtained by ammonolysis of cis-
1,2,3,6-tetrahydrophthalic anhydride.[12] The amino acid
was esterified in the presence of ethanol and thionyl chlo-
ride and then acylated with acetic anhydride, benzoyl chlo-
ride, or tert-butoxy pyrocarbonate, resulting in N-acylated
amino esters 1a-c, respectively.
With N-iodo- (NIS) or N-bromosuccinimide (NBS) (for
a related transformation, see, for example, ref.[13]), the N-
Boc derivative 1c gave oxazinone 2, while the N-acetyl and
N-benzoyl derivatives 1a and 1b furnished the correspond-
ing methyl- or phenyl-substituted oxazines 5a,b and 6a,b
regio- and diastereoselectively (Scheme 1). Not even traces
of other regio- or diastereomers were observed in the crude
product. Iodooxazinone 2 and bromooxazine derivatives
5a,b or 6a,b were dehalogenated with tributyltin hydride un-
der argon, resulting in compounds 3 and 7a,b, respectively.
In recent years, a number of new syntheses of function-
alized derivatives have been reported (see, for example,
ref.[11]). Among them, hydroxy-substituted β-amino acids
are of considerable importance because of their occurrence
[a] Institute of Pharmaceutical Chemistry, University of Szeged,
P. O. Box 121, 6701 Szeged, Hungary
Fax: +36-62-545705
E-mail: fulop@pharma.szote.u-szeged.hu
[b] Department of Chemistry, University of Jyväskylä,
40351 Jyväskylä, Finland
3214
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500062
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Diastereoselective Syntheses of Hydroxylated 2-Aminocyclohexanecarboxylic Acids
FULL PAPER
Scheme 1. (i) NIS, CH2Cl2, 14 h, room temp.; (ii) NBS, CH2Cl2, 14 h, room temp.; (iii) Bu3SnH, CH2Cl2, 20 h, 40 °C; (iv) 20% HCl, 30 h
reflux.
Acidic hydrolysis of 3 gave the stable oxazinonecarboxylic 10 to furnish the corresponding (r-1,t-2,t-4)-2-amino-4-hy-
acid derivative 4, which slowly decomposed on further heat- droxycyclohexanecarboxylic acid 11 (Scheme 2).
ing. Hydrolysis of oxazines 7a,b with 20% aqueous HCl,
Stereoselective iodolactonization[7] was the key step in
and removal of the HCl by ion-exchange chromatography the synthesis of 2-amino-5-hydroxycyclohexanecarboxylic
led to 8, the all-cis isomer of 2-amino-4-hydroxycyclohex- acid. The reactions of N-benzoyl- and N-Boc-protected cis-
anecarboxylic acid (Scheme 1).
2-amino-4-cyclohexenecarboxylic acid 12a,b with I2/KI in
The corresponding trans-2-amino-4-cyclohexenecarbox- slightly alkaline medium yielded the iodolactones 13a,b in
ylic acid was prepared by Hoffman degradation of the car- fairly good yields, with excellent regio- and diastereoselec-
boxamide obtained by ammonolysis of trans-1,2,3,6-tetra- tivity. The products were reduced with tributyltin hydride
hydrophthalic anhydride. The amino acid was esterified, to give lactones 14a,b. The acidic hydrolysis of benzoyl de-
and subsequent treatment with acetic anhydride resulted in rivative 14a did not give the desired amino acid; instead,
N-acetylamino ester 9. By a similar transformation as for decomposition took place. When the N-Boc lactone 14b
the cis isomer 1a, the trans-2-acetylamino-4-cyclohexene- was hydrolysed after ion-exchange chromatography, the all-
carboxylic acid 9 reacted via the iodooxazine intermediate cis isomer of 2-amino-5-hydroxycyclohexanecarboxylic acid
15 was obtained in 66% yield (Scheme 3).
By a similar transformation from trans-2-tert-butoxycar-
bonylamino-4-cyclohexenecarboxylic acid 16 via iodolac-
tone 17, the corresponding (r-1,t-2,c-5)-2-amino-5-hydroxy-
cyclohexanecarboxylic acid 19 was prepared (Scheme 4).
The cis compounds (+)-8 and (–)-15 were synthesized
from rac-7-azabicyclo[4.2.0]oct-3-en-8-one by CAL-B treat-
ment with one equivalent of H2O in isopropyl ether, as de-
scribed earlier.[14] The enantiopure β-lactam obtained was
transformed with 18% HCl into the (1S,2R)-2-amino-4-cy-
clohexenecarboxylic acid hydrochloride.[14] The syntheses of
the 4-hydroxy- and 5-hydroxyamino acid derivatives (+)-8
and (–)-15 were carried out similarly as for the racemic
compounds given in Scheme 1 and Scheme 3, resulting in
the products with ee Ͼ 99%.
Scheme 2. (i) NIS, CH2Cl2, 14 h, room temp.; (ii) Bu3SnH, CH2Cl2,
20 h, 40 °C; (iii) 20% HCl, 30 h reflux.
Scheme 3. (i) KI, I2, NaHCO3, CH2Cl2, 20 h, room temp.; (ii) Bu3SnH, CH2Cl2, 20 h, 40 °C; (iii) 20% HCl, 30 h room temp.
Eur. J. Org. Chem. 2005, 3214–3220
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F. Fülöp, M. Palkó, E. Forró, M. Dervarics, T. A. Martinek, R. Sillanpää
FULL PAPER
Scheme 4. (i) KI, I2, NaHCO3, CH2Cl2, 20 h, room temp.; (ii) Bu3SnH, CH2Cl2, 20 h, 40 °C; (iii) 20% HCl, 30 h, room temp.
The given stereochemistry and the relative configurations couplings: 3J(H-1,H-2) = 11.2 Hz and 3J(H-2,H-3ax) =
of the synthesized compounds were proved by using some 4.0 Hz. The H-5 signal has both large and small couplings:
3
key vicinal couplings and characteristic NOEs. For 8, there 3J(H-5,H-4ax/H-6ax) = 11.1 Hz and J(H-5,H-4eq/H-6eq)
3
3
are two small couplings, J(H-1,H-2) = 4.2 Hz and J(H- = 4.0 Hz. These suggest an axial H-5, which, together with
1,H-6ax) = 3.8 Hz, demonstrating an equatorial H-1. H-2 is the characteristic NOE signals between H-1, H-3ax and H-
3
in the axial position as it has a large coupling, J(H-2,H- 5 and the likely chair ring conformation, proves the relative
3ax) = 9.7 Hz. The H-4 signal has both large and small stereochemistry.
couplings: 3J(H-4,H-3ax/H-5ax) = 9.1 Hz and 3J(H-4,H-
The conformation might be sensitive to the solvent. The
3eq/H-5eq) = 4.1 Hz. These suggest an axial H-4, which, 1H, COSY and NOESY spectra of 15 and 19 were therefore
together with the characteristic NOE signals between H-2, recorded in [D4]methanol, too. In both cases, we found sim-
H-4 and H-6 and the likely chair ring conformation, proves ilar vicinal coupling and a similar NOE signal pattern as in
the relative stereochemistry.
D2O, leading to the conclusion that these molecules have
3
For 15, there are small and large couplings, J(H-1,H-2) the same predominant conformers in D2O and in [D4]meth-
3
= 4.2 Hz and J(H-1,H-6ax) = 12.1 Hz, indicating an axial anol. This finding corroborated our conclusions on the
H-1. H-2 is in the equatorial position as it has two small relative configurations and conformations. The relevant
couplings: 3J(H-2,H-3ax) = 4.2 Hz and 3J(H-1,H-2) = spectroscopic data obtained in [D4]methanol are as
3.8 Hz. The H-5 dddd multiplet exhibits both large and follows:
small couplings: 3J(H-5,H-4ax/H-6ax) = 10.1 Hz and 3J(H-
19: Axial H-1, concluded from small and large couplings:
3
5,H-4eq/H-6eq) = 4.1 Hz. These suggest an axial H-5, 3J(H-1,H-6ax) = 3.5 Hz and J(H-1,H-2) = 12.0 Hz. Axial
3
which, together with the characteristic NOE signals be- H-2 was indicated by the large and small couplings, J(H-
tween H-1, H-3ax and H-5 and the likely chair ring confor- 1,H-2) = 12.0 Hz and 3J(H-1,H-2) = 3.8 Hz. The H-5 signal
mation, proves the relative stereochemistry.
has both large and small couplings, 3J(H-5,H-4ax/H-6ax) =
3
For 19, there are large and small couplings: J(H-1,H-2) 10.8 Hz and 3J(H-5,H-4eq/H-6eq) = 4.0 Hz, which suggests
3
= 11.2 Hz and J(H-1,H-6ax) = 4.4 Hz, indicating an axial an axial H-5. There are characteristic NOE signals between
H-1. H-2 is in the axial position as it has large and small H-1, H-3ax and H-5.
Figure 1. Crystal structure of 15, showing the hydrogen bonding scheme. Thermal ellipsoids have been drawn at the 30% probability
level. Symmetry codes: i = x + 1/2, –y + 3/2, –z+2, ii = –x + 3/2, –y+1, z + 1/2 and iii = x + 1/2, –y + 3/2, –z+1.
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Eur. J. Org. Chem. 2005, 3214–3220

Diastereoselective Syntheses of Hydroxylated 2-Aminocyclohexanecarboxylic Acids
FULL PAPER
Ethyl cis-2-Benzoylamino-4-cyclohexenecarboxylate (1b): Ethyl cis-
2-amino-4-cyclohexenecarboxylate hydrochloride (2.04 g, 10 mmol)
was benzoylated according to the Schotten–Baumann method. Af-
ter separation, drying and evaporation of the toluene layer, an al-
most white crystalline product was obtained. After recrystallisation
from n-hexane/EtOAc, a white crystalline product, 1.76 g (65%),
15: Axial H-1, concluded from the small and large coup-
lings: J(H-1,H-2) = 3.9 Hz and J(H-1,H-6ax) = 11.0 Hz.
3
3
Equatorial H-2 was shown by its small coupling constants:
3
3J(H-1,H-2) = 3.9 Hz and J(H-1,H-2) = 4.2 Hz. The H-5
signal has both large and small couplings: 3J(H-5,H-4ax/H-
3
6ax) = 9.0 Hz and J(H-5,H-4eq/H-6eq) = 4.0, which sug-
1
was obtained. M.p. 105–106 °C. H NMR (DMSO): δ = 1.13 (t, J
gests an axial H-5. There are characteristic NOE signals
between H-1, H-3ax and H-5.
= 7.0 Hz, 3 H, CH3CH2), 2.30–2.40 (m, 3 H, H-2, H-5), 2.47 (s, 1
H, H-2), 2.93–2.99 (m, 1 H, H-1), 3.97-4.1 (m, 2 H, CH3CH2),
4.43–4.50 (m, 1 H, H-6), 5.65 (q, J = 9.8 Hz, 2 H, H-3, H-4), 7.44
X-ray diffraction studies confirmed the structure of 15.
All bonding parameters are in the usual ranges. The mol- (t, J = 7.3 Hz, 2 H, m-Ph), 7.52 (t, J = 7.3 Hz, 1 H, p-Ph), 7.78 (d, J
= 7.3 Hz, 2 H, o-Ph), 8.00 (d, J = 7.5 Hz, 1 H, NH) ppm. 13C NMR
ecular structure and extensive hydrogen bonding system of
(DMSO): δ = 14.4, 25.1, 29.5, 41.3, 45.6, 60.2, 124.8, 125.3, 127.8,
15 are presented in Figure 1.
128.4, 131.4, 135.1, 166.7, 173.0 ppm. C16H19NO3 (273.34): calcd.
C 70.31, H 7.01, N 5.12; found C 70.44, H 7.27, N 5.48.
Ethyl cis-2-(tert-Butoxycarbonylamino)-4-cyclohexenecarboxylate
(1c): Ethyl cis-2-amino-4-cyclohexenecarboxylate hydrochloride
Experimental Section
General Procedures: 1H NMR spectra were recorded at 400 MHz
(2.04 g, 10 mmol) was dissolved in a mixture of toluene (25 mL)
and 13C NMR spectra at 100 MHz in CDCl3 or in [D6]DMSO, at
ambient temperature, with a Bruker AM 400 spectrometer. Chemi-
cal shifts are given in δ (ppm) relative to TMS (CDCl3 or DMSO)
as an internal standard. Elemental analyses were performed with a
Perkin–Elmer CHNS-2400 Ser II Elemental Analyzer. Melting
points were measured with a Kofler melting point apparatus and
are uncorrected.
and NaOH solution (1 m, 25 mL), and tert-butoxypyrocarbonate
(2.4 g, 11 mmol) was then added with stirring. Stirring was contin-
ued for 1 h, after which the toluene layer was separated off, and
the aqueous layer was extracted with ethyl acetate (3×20 mL). The
combined organic phase was dried (Na2SO4), and the solvents were
evaporated. The residue was recrystallised from n-hexane/diisopro-
pyl ether to give a white solid (1.63 g, 61% yield), m.p. 70–72 °C.
1H NMR (DMSO): δ = 1.17 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.37
(s, 9 H, OtBu), 2.02 (d, J = 17.9 Hz, 1 H, H-5), 2.13 (d, J = 17.9 Hz,
1 H, H-2), 2.27 (d, J = 17.9 Hz, 1 H, H-5), 2.41 (d, J = 17.9 Hz, 1
H, H-2), 2.74-2.80 (m, 1 H, H-1), 3.94-4.11 (m, 3 H, H-6, CH3CH2),
5.54 (d, J = 10.4 Hz, 1 H, H-4), 5.61 (d, J = 10.4 Hz, 1 H, H-3),
6.49 (d, J = 8.3 Hz, 1 H, NH) ppm. 13C NMR (DMSO): δ = 14.4,
24.1, 28.5, 30.7, 41.4, 46.1, 60.1, 78.0, 124.4, 125.4, 155.4,
172.9 ppm. C14H23NO4 (269.35): calcd. C 62.43, H 8.61, N 5.20;
found C 62.84, H 8.32, N 5.55.
The ee values of the synthesized enantiomers were determined by
gas chromatography (GC) on Chromopak Chiralsil-Dex CB (CCD)
or Chirasil-l-Val (CLV) columns. (1S,2R)-Ethyl 2-amino-4-cyclo-
hexenecarboxylate: CCD column, after derivatization with acetic
anhydride in the presence of 4-dimethylaminopyridine and pyridine
[120 °C for 2 min Ǟ 190 °C (rate of temperature rise 10 °C/min;
100 kPa)], retention time (min): 10.86 (antipode: 10.77); (+)-1a and
(+)-14b: CCD column [120 °C for 2 min Ǟ 190 °C (rate of tem-
perature rise 10 °C/min; 100 kPa)], retention times (min) (+)-1a:
10.86 (antipode: 10.77), (+)-14b: 17.48 (antipode: 17.19); (+)-12b:
CLV column, after derivatization with diazomethane [100 °C for
10 min Ǟ 160 °C (rate of temperature rise 10 °C/min; 45 kPa)], re-
tention time (+)-12b: 26.61 (antipode: 26.49). The ee values of (+)-
8 and (–)-15 were determined on a CCD column after double
derivatization with (i) diazomethane; (ii) acetic anhydride in the
presence of 4-dimethylaminopyridine and pyridine [120 °C for
2 min Ǟ 190 °C (rate of temperature rise 10 °C/min; 100 kPa)],
retention times (min): (+)-8: 20.17 (antipode: 19.59); (–)-15: 18.34
(antipode: 17.82).
Ethyl trans-2-Acetylamino-4-cyclohexenecarboxylate (9): Starting
from ethyl trans-2-amino-4-cyclohexenecarboxylate hydrochloride,
the procedure described for 1a was followed to prepare 9: yield
1
58%, white solid, m.p. 68–69 °C. H NMR (DMSO): δ = 1.16 (t,
J = 7.0 Hz, 3 H, CH3CH2), 1.76 (s, 3 H, COCH3), 1.87–1.98 (m, 1
H, H-5), 2.19 (dt, J = 17.1, 4.3 Hz, 1 H, H-5), 2.25-2.29 (m, 2 H,
H-2, H-1), 2.55 (dt, J = 10.1, 7.5 Hz, 1 H, H-2), 4.11-4.19 (m,
CH3CH2, 3 H, H-6), 5.56–5.66 (m, 2 H, H-3, H-4), 7.85 (d, J =
8.3 Hz, 1 H, NH) ppm. 13C NMR (DMSO): δ = 14.4, 23.0, 27.6,
31.1, 44.6, 45.9, 60.2, 125.2, 125.1, 168.7, 173.6 ppm. C11H17NO3
(211.26): calcd. C 62.54, H 8.11, N 6.63; found C 62.63, H 8.42, N
6.91.
Ethyl cis-2-Acetylamino-4-cyclohexenecarboxylate (1a): To a sus-
pension of ethyl cis-2-amino-4-cyclohexenecarboxylate hydrochlo-
ride (2.04 g, 10 mmol) in toluene (40 mL) were added triethylamine
(2.04 g, 20 mmol) and acetyl chloride (0.94 g, 12 mmol), and the
mixture was stirred at room temperature for 2 h, and then washed
with water (2×10 mL). The aqueous layer was extracted with n-
hexane (3×20 mL). The combined organic phase was dried
(Na2SO4), and the solvents were evaporated. The residue was
recrystallised from n-hexane/diisopropyl ether to give a white solid
(1.15 g, 55% yield), m.p. 64–67 °C. 1H NMR (DMSO): δ = 1.14 (t,
J = 7.0 Hz, 3 H, CH3CH2), 1.77 (s, 3 H, COCH3), 2.00 (d, J =
17.6 Hz, 1 H, H-5), 2.15 (d, J = 18.6 Hz, 1 H, H-2), 2.27 (d, J =
General Procedure for the Synthesis of Iodo- and Bromooxazines (2,
5a,b, 6a,b and 10): A solution of N-acylamino ester 1a–c or 9
(3 mmol) in CH2Cl2 (40 mL) was treated with one equivalent of
NIS or NBS, and the reaction mixture was stirred for 14 h at room
temp. When the reaction was completed (monitored by TLC), the
mixture was treated with aqueous NaOH solution (10%,
3×20 mL). The aqueous solution was extracted with CH2Cl2
(3×40 mL), the combined organic layer was dried (Na2SO4), and
the solvents were evaporated. The residue was recrystallised from
n-hexane/diisopropyl ether.
1
17.6 Hz, 1 H, H-5), 2.71-2.76 (m, 1 H, H-2), 4.28-4.34 (m, 1 H, H- 2: Yield 80%, a white crystalline solid, m.p. 199–201 °C. H NMR
6), 5.56 (d, J = 10.3 Hz, 1 H, H-4), 5.64 (d, J = 10.3 Hz, 1 H, H- (DMSO): δ = 1.21 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.95 (ddt, J =
3), 7.59 (d, J = 7.6 Hz, 1 H, NH) ppm. 13C NMR (DMSO): δ =
14.9, 23.4, 24.6, 31.1, 41.8, 44.8, 60.6, 125.9, 125.1, 169.8,
1.8, 14.1, 4.0 Hz, 1 H, H-9eq), 2.00–2.16 (m, 2 H, H-7), 2.55 (d, J
= 14.1 Hz, 1 H, H-9ax), 2.85 (ddd, J = 1.5, 5.5, 11.1 Hz, 1 H, H-
173.4 ppm. C11H17NO3 (211.26): calcd. C 62.54, H 8.11, N 6.63; 6), 3.81 (br. s, 1 H, H-5), 4.01–4.16 (m, 2 H, CH3CH2), 4.58–4.63
found C 62.24, H 7.82, N 6.48.
(m, 1 H, H-1), 4.73-4.79 (m, 1 H, H-8), 7.69 (d, J = 5.0 Hz, 1 H,
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FULL PAPER
H-4) ppm. 13C NMR (DMSO): δ = 14.3, 25.3, 28.1, 28.7, 43.1,
46.6, 60.9, 75.4, 152.6, 171.6 ppm. C10H14INO4 (339.13): calcd. C
35.42, H 4.16, N 4.13; found C 35.13, H 4.27, N 3.98.
(DMSO): δ = 14.8, 18.7, 29.5, 30.9, 46.5, 47.4, 60.1, 72.6, 154.3,
173.1 ppm. C10H15NO4 (213.24): calcd. C 56.33, H 7.09, N 6.57;
found C 55.92, H 7.22, N 6.19.
5a: This compound was very sensitive to air and was used in the
dehalogenation step without further purification.
7a: Yield 60%, a colourless oil, from iodooxazine 5a, and 55%
from bromooxazine 5b. 1H NMR (DMSO): δ = 1.18 (t, J = 7.3 Hz,
3 H, CH3CH2), 1.45 (ddt, J = 4.8, 12.6, 4.8 Hz, 1 H, H-7), 1.55
(ddd, J = 1.5, 4.8, 13.3 Hz, 1 H, H-8), 1.59–1.73 (m, 2 H, H-9),
1.82 (s, CH3, 3 H, H-8), 1.93 (d, J = 13.3 Hz, 1 H, H-7), 2.67 (dt,
J = 12.1, 3.0 Hz, 1 H, H-6), 3.85 (s, 1 H, H-5), 3.97–4.11 (m, 2 H,
CH3CH2), 4.39 (s, 1 H, H-1) ppm. 13C NMR (DMSO): δ = 14.1,
17.9, 20.9, 27.8, 31.1, 45.5, 48.1, 59.7, 59.8, 69.2, 158.6, 172.6 ppm.
C11H17NO3 (211.26): calcd. C 62.54, H 8.11, N 6.63; found C
63.00, H 8.24, N 6.32.
5b: Yield 80%, a white crystalline solid, m.p. 113–114 °C. 1H NMR
(DMSO): δ = 1.21 (t, J = 7.05 Hz, 3 H, CH3CH2), 1.83–1.96 (m, 2
H, H-7, H-9), 2.04 (d, J = 3.2 Hz, 1 H, H-7), 2.62 (dt, J = 14.1,
1.3 Hz, 1 H, H-9), 3.04 (ddd, J = 3.0, 4.0, 12.3 Hz, 1 H, H-6), 4.12
(q, J = 7.3 Hz, 2 H, CH3CH2), 4.16–4.20 (m, 1 H, H-6), 4.74–4.78
(m, 1 H, H-1), 4.85–4.89 (m, 1 H, H-8), 7.41 (t, J = 7.8 Hz, 2 H,
m–Ph), 7.48 (t, J = 7.0 Hz, 1 H, p-Ph), 7.81 (d, J = 8.1 Hz, 2 H, o-
Ph) ppm. 13C NMR (DMSO): δ = 14.4, 24.4, 29.0, 29.3, 42.9, 48.8,
60.6, 73.3, 127.2, 128.5, 131.2, 132.8, 155.9, 172.0 ppm. 7b: Yield 65% from iodooxazine 6a, and 62% from bromooxazine
1
C16H18INO3 (399.23): calcd. C 48.14, H 4.54, N 3.51; found C
47.89, H 4.32, N 3.87.
6b, a white crystalline solid, m.p. 64–65 °C. H NMR (DMSO): δ
= 1.21 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.38–1.52 (m, 1 H, H-7),
1.63–1.74 (m, 2 H, H-7, H-8), 1.82–1.89 (m, 1 H, H-9), 1.93 (dt, J
= 13.3, 1.8 Hz, 1 H, H-9), 2.01–2.12 (m, 1 H, H-8), 2.82 (dt, J =
12.1, 3.5 Hz, 1 H, H-6), 4.10 (q, J = 7.0 Hz, 2 H, CH3CH2), 4.17–
4.20 (m, 1 H, H-5), 4.68–4.72 (m, 1 H, H-1), 7.39 (t, 7.5 Hz, 2 H,
m-Ph), 7.46 (t, J = 7.3 Hz, 1 H, p-Ph), 7.81 (d, J = 7.3 Hz, 2 H, o-
Ph) ppm. 13C NMR (DMSO): δ = 14.5, 18.2, 28.1, 31.5, 46.1, 49.0,
60.1, 70.3, 127.1, 128.4, 130.8, 133.8, 156.8, 173.0 ppm. C16H19NO3
(273.34): calcd. C 70.31, H 7.01, N 5.12; found C 70.39, H 6.87, N
5.43.
1
6a: Yield 83%, a white crystalline solid, m.p. 68–69 °C. H NMR
(DMSO): δ = 1.22 (t, 3 H, J = 7.0 Hz, CH3CH2), 1.70 (ddt, J =
1.5, 13.8, 4.0 Hz, 1 H, H-9), 1.86 (s, 3 H, Me-3), 1.99–2.05 (m, 2
H, H-7), 2.35 (dt, J = 13.8, 1.5 Hz, 1 H, H-9), 2.93 (ddd, J = 2.8,
6.0, 10.3 Hz, 1 H, H-6), 3.89–3.94 (m, 1 H, H-5), 4.00–4.15 (m, 2 H,
CH3CH2), 4.48-4.52 (m, 1 H, H-1), 4.64–4.68 (m, 1 H, H-8) ppm.
13C NMR (DMSO): δ = 16.8, 23.6, 29.5, 38.6, 45.3, 61.7, 63.7, 64.5,
74.9, 172.7, 174.2 ppm. C11H16BrNO3 (290.17): calcd. C 45.53, H
5.56, N 4.83; found C 45.89, H 5.72, N 4.37.
General Synthesis of Stereoisomeric 2-Amino-4-hydroxy Acids 8 and
11 and Oxazinonecarboxylic Acid 4: A solution of ester 3, or 7a,b
or the reaction mixture of 10 (1 mmol in 20 mL 20% HCl) was
refluxed for 30 h. The solvent was then evaporated to afford the
crude amino acid hydrochloride. The free amino acid base was lib-
erated by ion-exchange chromatography with Dowex 50.
6b: Yield 81%, a white crystalline solid, mp. 119–120 °C. 1H NMR
(DMSO): δ = 1.22 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.86 (ddt, J =
1.5, 13.8, 3.8 Hz, 1 H, H-9), 1.95–2.13 (m, 2 H, H-7), 2.49 (dt, J =
10.3, 1.5 Hz, 1 H, H-9), 3.07 (ddd, J = 2.8, 4.3, 11.8 Hz, 1 H, H-
6), 4.13 (q, J = 7.0 Hz, 2 H, CH3CH2), 4.20–4.24 (m, 1 H, H-5),
4.47–4.78 (m, 1 H, H-1), 4.78–4.83 (m, 1 H, H-8), 7.41 (t, J =
7.55 Hz, 2 H, m-Ph), 7.49 (t, J = 7.3 Hz, 1 H, p-Ph), 7.81 (d, J =
7.3 Hz, 2 H, o-Ph) ppm. 13C NMR (DMSO): δ = 14.4, 23.3, 27.6,
42.4, 48.6, 49.9, 60.6, 72.2, 127.2, 128.5, 131.2, 132.9, 155.6,
172.1 ppm. C11H18BrNO3 (252.24): calcd. C 54.56, H 5.15, N 3.98;
found C 54.41, H 5.49, N 4.22.
(r-6,c-1,c-5)-2-Oxa-3-oxo-4-azabicyclo[3.3.1]nonane-6-carboxylic
Acid (4): Yield 53% from 7a, and 35% from 7b, a white crystalline
solid, m.p. 222–226 °C. 1H NMR (DMSO): δ = 1.52–1.67 (m, 2 H,
H-5, H-6), 1.69–1.80 (m, 1 H, H-6), 1.82–1.98 (m, 3 H, H-3, H-5),
2.51–2.59 (m, 1 H, H-1), 3.79 (br. s, 1 H, H-2), 4.51 (br. s, 1 H, H-
4), 7.28 (d, J = 5.04 Hz, 1 H, OH) ppm. 13C NMR (DMSO): δ
= 18.4, 29.1, 30.1, 46.0, 46.7, 72.1, 153.8, 174.3 ppm. C8H11NO4
(185.18): calcd. C 51.89, H 5.99, N 7.56; found C 51.92, H 5.57, N
7.92.
10: This compound is sensitive to air and was used in the next step
1
without purification. H NMR (CDCl3): δ = 1.23 (t, J = 7.0 Hz, 3
H, CH3CH2), 1.64 (d, J = 14.1 Hz, 1 H, H-9), 1.90 (s, 3 H, Me),
2.24 (ddd, J = 3.5, 7.3, 16.4 Hz, 1 H, H-7), 2.44 (d, J = 16.4 Hz, 1
H, H-7), 2.53 (d, J = 14.1 Hz, 1 H, H-9), 2.73 (d, J = 6.1 Hz, 1 H,
H-6), 3.83 (s, 1 H, H-5), 4.11 (q, J = 7.0 Hz, 2 H, CH3CH2), 4.52
(r-1,c-2,c-4)-2-Amino-4-hydroxycyclohexanecarboxylic Acid (8):
Yield 52%, a white crystalline solid, m.p. 220–225 °C. 1H NMR
(s, 1 H, H-1), 4.53 (s, 1 H, H-8) ppm. 13C NMR (DMSO): δ = 14.8, (D2O): δ = 1.41 (s, 1 H, H5), 1.55–1.67 (m, 1 H, H-6), 1.78–1.91
20.5, 21.6, 27.5, 41.1, 46.3, 49.5, 61.1, 72.9, 158.9, 172.8 ppm.
(m, 2 H, H-3, H-5), 2.06 (dt, J = 12.6, 3.5 Hz, 1 H, H-3), 2.10–
2.22 (m, 1 H, H-6), 2.58 (dt, J = 4.4, 4.0 Hz, 1 H, H-2), 3.49 (dt,
J = 13.6, 4.1 Hz, 1 H, H-1), 3.88 (m, 1 H, H-4) ppm. 13C NMR
(D2O): δ = 22.9, 30.8, 34.7, 42.6, 49.0, 67.5, 180.3 ppm. C7H13NO3
(159.19): calcd. C 52.82, H 8.23, N 8.80; found C 52.99, H 8.48, N
8.70.
General Procedure for Dehalogenation of Iodo- and Bromooxazines
2, 5a,b, 6a,b and 10 to Oxazines 3, 7a and 7b: Tributyltin hydride
(0.8 mL, 3 mmol) was added to a solution of iodo- or bromooxa-
zine 2, 5a,b, 6a,b or 10 (1.48 mmol) in dry CH2Cl2 (65 mL) under
argon. The reaction mixture was stirred for 20 h at 40 °C. Except
in the case of air-sensitive 10, the solvent was evaporated, and the
residue was purified by column chromatography on silica gel (elu-
ent: n-hexane–EtOAc 10:1) to afford the 1,3-oxazine as a white
crystalline solid (3, 7b) or as an oil (7a). The reaction mixture of
10 was used without purification to form 11 upon addition of HCl
(20 mL 20%) and refluxing (see below).
(r-1,t-2,t-4)-2-Amino-4-hydroxycyclohexanecarboxylic Acid (11):
Yield 48%, a white crystalline solid, m.p. 230–232 °C. 1H NMR
(D2O): δ = 1.27-1.5 (m, 3 H, H-3, H-5, H-6), 2.02–2.08 (m, 1 H,
H-5), 2.14-2.26 (m, 2 H, H-2, H-6), 2.28-2.34 (m, 1 H, H-3), 3.35
(ddd, J = 4.0, 10.8, 12.1 Hz, 1 H, H-1), 3.76 (tt, J = 4.0, 10.8 Hz,
1 H, H-4) ppm. 13C NMR (D2O): δ = 25.7, 35.2, 41.0, 45.8, 50.5,
67.5, 180.5 ppm. C7H13NO3 (159.19): calcd. C 52.82, H 8.23, N
8.80; found C 52.54, H 8.73, N 8.49.
1
3: Yield 70%, a white crystalline solid, m.p. 150–153 °C. H NMR
(DMSO): δ = 1.20 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.53–1.66 (m, 2
H, H-7, H-8), 1.71–1.78 (m, 1 H, H-8), 1.86–1.91 (m, 2 H, H-9), cis-2-Benzoylamino-4-cyclohexenecarboxylic Acid (12a): 2-Amino-
1.91–1.97 (m, 1 H, H-7), 2.65 (ddd, J = 2.0, 4.5, 11.8 Hz, 1 H, H- 4-cyclohexenecarboxylic acid (1.41 g, 10 mmol) was dissolved in
6), 3.79 (br. s, 1 H, H-5), 4.00–4.13 (m, 2 H, CH3CH2), 4.49–4.55 NaOH solution (10%, 15 mL), benzoyl chloride (1.54 g, 11 mmol)
(m, 1 H, H-1), 7.37 (d, J = 5.0 Hz, 1 H, H-4) ppm. 13C NMR
was added dropwise, and the solution was stirred at room tempera-
3218
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 3214–3220

Diastereoselective Syntheses of Hydroxylated 2-Aminocyclohexanecarboxylic Acids
FULL PAPER
ture for 1 h. The solution was then acidified with aqueous HCl,
and 12a was precipitated, filtered off, washed with water and dried.
Yield 2.05 g, 84%, a white crystalline solid, m.p. 188–189 °C (n-
hexane–ethyl acetate). H NMR (DMSO): δ = 2.30 (m, 1 H, H-2),
2.55 (m, 1 H, H-2), 2.90 (dd, J = 6.0, 9.5 Hz, 1 H, H-1), 4.41–4.48
13b: Yield 84%, a white crystalline solid, m.p. 170–174 °C. 1H
NMR (DMSO): δ = 1.40 (s, 9 H, OtBu), 2.09 (dd, J = 5.8, 16.1 Hz,
1 H, H-3), 2.27 (ddd, J = 5.8, 12.3, 16.1, 1 H, H-3), 2.46 (ddd, J =
1.5, 5.8, 12.6 Hz, 1 H, H-8), 2.55 (d, J = 12.6 Hz, 1 H, H-8), 2.67
(d, J = 6.3 Hz, 1 H, H-1), 3.69–3.79 (m, 1 H, H-2), 4.66 (t, J =
1
(m, 1 H, H-6), 5.68 (d, J = 10.3 Hz, 1 H, H-3), 5.62 (d, J = 10.3 Hz, 5.3 Hz, 1 H, H-4), 4.82 (dd, J = 4.3, 5.3 Hz, 1 H, H-5), 7.17 (d, J
1 H, H-4), 7.52 (t, J = 7.3 Hz, 1 H, p-Ph), 7.45 (t, J = 7.3 Hz, 2 H, = 7.3 Hz, 1 H, NHCO) ppm. 13C NMR (DMSO): δ = 23.2, 28.5,
o-Ph), 7.79 (d, J = 7.30 Hz, 2 H, m-Ph), 7.97 (d, J = 8.2 Hz, 1 H,
NH), 12.28 (br. s, 1 H, OH) ppm. 13C NMR (DMSO): δ = 26.1,
30.2, 41.6, 46.1, 125.4, 126.1, 128.2, 129.0, 131.9, 135.6, 167.0,
175.3 ppm. C14H15NO3 (245.28): calcd. C 68.56, H 6.16, N 5.71;
found C 68.94, H 7.43, N 5.39.
33.2, 34.9, 44.2, 46.7, 78.8, 79.1, 155.2, 175.8 ppm. C12H18INO4
(367.19): calcd. C 39.25, H 4.94, N 3.81; found C 38.93, H 4.65, N
3.72.
17: Yield 82%, a white crystalline solid, m.p. 125–127 °C. 1H NMR
(DMSO): δ = 1.41 (s, 9 H, OtBu), 2.25–2.38 (m, 2 H, H-3, H-8),
2.41-2.48 (m, 1 H, H-3), 2.75 (t, J = 4.1 Hz, 1 H, H-8), 2.88 (d, J
= 12.8 Hz, 1 H, H-1), 3.75 (s, 1 H, H-5), 4.42 (s, 1 H, H-4), 4.94
(dd, J = 3.3, 5.8 Hz, 1 H, H-2), 6.93 (br. s, 1 H, NH) ppm.
13C NMR (DMSO): δ = 19.5, 28.0, 28.6, 33.3, 42.4, 46.0, 78.8, 81.2,
176.5 ppm. C12H18INO4 (367.19): calcd. C 39.25, H 4.94, N 3.81;
found C 39.37, H 5.22, N 3.68.
cis-2-tert-Butoxycarbonylamino-4-cyclohexenecarboxylic Acid (12b):
2-Amino-4-cyclohexenecarboxylic acid (1.41 g, 10 mmol) was dis-
solved in a mixture of dioxane (20 mL) and water (10 mL), tert-
butoxypyrocarbonate (2.4 g, 11 mmol) was added to the solution
at 0 °C, and the mixture was stirred at room temperature for 4 h.
The solvent was then evaporated down to half volume, and the
mixture was diluted with ethyl acetate (20 mL) and acidified with
H2SO4 (10%, pH = 2.5). The mixture was extracted with ethyl ace-
tate (3×20 mL), the combined organic layer was dried (Na2SO4),
and the solvents were evaporated. The residue was recrystallised
from diisopropyl ether to give a white crystalline solid. Yield 75%,
m.p. 58–60 °C. 1H NMR (CDCl3): δ = 1.44 (s, 9 H, OtBu), 2.21
(dd, J = 18.1 Hz, 6.04 Hz, 1 H, H-2), 2.36 (d, J = 18.1 Hz, 2 H,
H-5), 2.54 (d, J = 18.1 Hz, 1 H, H-2), 2.81–2.93 (m, 1 H, H-1),
4.11–4.23 (m, 1 H, H-6), 5.29 (d, J = 6.04 Hz, 1 H, NH), 5.55–5.70
(m, 2 H, H-3, H-4) ppm. 13C NMR (DMSO): δ = 26.8, 28.9, 31.8,
42.6, 46.8, 80.1, 125.3, 125.7, 156.1, 179.1 ppm. C12H19NO4
(241.29): calcd. C 59.73, H 7.94, N 5.80; found C 59.42, H 7.81, N
5.92.
Reduction of Iodolactones 13a,b and 17 to Lactones 14a,b and 18:
Tributyltin hydride (2.4 mL, 9 mmol) was added to a solution of
iodolactone 13a,b or 17 (4.5 mmol) in dry CH2Cl2 (65 mL) under
argon. After stirring for 20 h at 40 °C, the solvent was evaporated,
and the crude lactone was crystallized from n-hexane and recrystal-
lised from isopropyl ether/ethyl acetate.
14a: Yield 68%, a white crystalline solid, m.p. 188–190 °C. 1H
NMR (DMSO): δ = 1.79–2.12 (m, 5 H, H-3, H-4, H-8), 2.50–2.57
(m, 1 H, H-8), 2.88 (d, J = 5.8 Hz, 1 H, H-1), 4.20-4.29 (m, 1 H,
H-5), 4.94 (t, J = 4.8 Hz, 1 H, H-2), 7.60 (t, J = 7.3 Hz, 2 H, m-
Ph), 7.67 (t, J = 7.3 Hz, 1 H, p-Ph), 7.98 (d, J = 7.3 Hz, 2 H, o-
Ph), 8.50 (d, J = 7.0 Hz, 1 H, NH) ppm. 13C NMR (DMSO): δ =
23.9, 27.4, 35.6, 43.6, 48.3, 77.0, 127.8, 128.5, 131.7, 134.5, 166.8,
176.9 ppm. C14H15NO3 (245.28): calcd. C 68.56, H 6.16, N 5.71;
found C 68.49, H 6.33, N 5.49.
14b: Yield 75%, a white crystalline solid, m.p. 115–119 °C. 1H
NMR (DMSO): δ = 1.40 (s, 9 H, OtBu), 1.45–1.56 (m, 1 H, H-3),
1.57–1.65 (m, 1 H, H-3), 1.75–1.9 (m, 3 H, H-4, H-8), 2.29–2.37
(m, 1 H, H-8), 2.62 (d, J = 4.8 Hz, 1 H, H-1), 3.56–3.65 (m, 1 H,
H-5), 4.73 (t, J = 4.8 Hz, 1 H, H-2), 6.95 (d, J = 6.5 Hz, 1 H,
NH) ppm. 13C NMR (DMSO): δ = 24.3, 27.4, 28.5, 35.5, 43.8,
49.1, 76.7, 78.3, 155.1, 176.7 ppm. C12H19NO4 (241.29): calcd. C
59.73, H 7.94, N 5.80; found C 59.92, H 8.21, N 5.37.
trans-6-tert-Butoxycarbonylaminocyclohex-3-ene-carboxylic
Acid
(16): The procedure described for 12b was followed to prepare 16
from trans-6-aminocyclohex-3-ene-carboxylic acid. Yield 74%, a
white crystalline solid, m.p. 120–122 °C. 1H NMR (DMSO): δ =
1.36 (s, 9 H, OtBu), 1.88–1.97 (m, 1 H, H-2), 2.15–2.23 (m, 3 H,
H-2, H-5), 2.44–2.54 (m, 1 H, H-6), 3.6-3.72 (m, 1 H, H-1), 5.55–
5.63 (m, 2 H, H-3, H-4), 6.76 (d, J = 8.6 Hz, 1 H, NH) ppm.
13C NMR (DMSO): δ = 28.3, 28.6, 31.5, 44.6, 47.5, 77.8, 126.1,
125.3, 155.2, 175.5 ppm. C12H19NO4 (241.29): calcd. C 59.73, H
7.94, N 5.80; found C 59.39, H 7.49, N 5.53.
1
18: Yield 72%, a white crystalline solid, m.p. 82–86 °C. H NMR
General Procedure for the Synthesis of Iodolactones 13a,b and 17:
To a solution of carboxylic acid derivative 12a,b or 16 (5.75 mmol)
in CH2Cl2 (50 mL), were added NaHCO3 (0.5 n, 35 mL), KI (5.7 g,
34.5 mmol) and I2 (2.9 g, 11.5 mmol) at 0 °C. The reaction mixture
was stirred at room temperature for 20 h and then poured into a
saturated solution of Na2S2O3 (100 mL). The mixture was ex-
tracted with CH2Cl2 (3×50 mL), the combined organic layer was
washed with saturated NaCl solution, dried (Na2SO4), and the sol-
vents were evaporated. The residue was recrystallised from diiso-
propyl ether to give iodolactone 13a,b or 17.
(DMSO): δ = 1.40 (s, 9 H, OtBu), 1.53–1.61 (dd, J = 6.3, 14.6 Hz,
1 H, H-8), 1.66–1.85 (m, 2 H, H-3, H-4), 2.05–2.18 (m, 2 H, H-4,
H-8), 2.69 (t, J = 4.3 Hz, 1 H, H-1), 3.69–3.78 (m, 1 H, H-5), 4.81
(t, J = 4.3 Hz, 1 H, H-3), 7.48 (1 H, br. s, NH) ppm. 13C NMR
(DMSO): δ = 24.0, 24.8, 28.6, 31.0, 43.1, 45.6, 78.1, 78.56,
177.3 ppm. C12H19NO4 (241.29): calcd. C 59.73, H 7.94, N 5.80;
found C 59.56, H 7.83, N, 5.52.
General Procedure for 2-Amino-5-hydroxycarboxylic Acids 15 and
19 from Lactones 14b and 18: Lactone 14b or 18 (0.72 g, 3 mmol)
was dissolved in aqueous HCl (of 20%, 20 mL), and the solution
was stirred at room temperature for 10 h. The solvent was evapo-
rated, and the amino acid base was liberated from the residual hy-
drochloride by ion-exchange chromatography on Dowex 50.
13a: Yield 78%, a white crystalline solid, m.p. 185–189 °C. 1H
NMR (DMSO): δ = 2.22 (dd, J = 5.3, 15.8 Hz, 1 H, H-3), 2.51–
2.80 (m, 3 H, H-8, H-3), 2.81 (d, J = 12.4 Hz, 1 H, H-1), 4.23–4.31
(m, 1 H, H-2), 4.75 (t, J = 4.8 Hz, 1 H, H-4), 4.89 (t, J = 4.8 Hz,
1 H, H-5), 7.48 (t, J = 7.3 Hz, 2 H, m-Ph), 7.55 (t, J = 7.3 Hz, 1 (r-1,c-2,c-5)-2-Amino-5-hydroxycyclohexanecarboxylic Acid (15):
H, p-Ph), 7.83–7.87 (d, J = 7.3 Hz, 2 H, o-Ph), 8.53 (d, J = 7.0 Hz,
1 H, NH) ppm. 13C NMR (DMSO): δ = 23.4, 33.4, 34.6, 43.9, 46.0,
79.3, 127.8, 128.6, 131.8, 134.3, 166.9, 175.9 ppm. C14H14INO3
(371.18): calcd. C 45.30, H 3.80, N 3.77; found C 44.92, H 3.61, N
3.87.
Yield 66%, a white crystalline solid, mp, 255–256 °C. 1H NMR
(D2O): δ = 1.43–1.54 (m, 1 H, H-4), 1.61 (q, J = 11.8 Hz, 2 H, H-
6), 1.78 (tt, J = 4.3, 13.6 Hz, 1 H, H-3), 1.85–1.93 (m, 1 H, H-4),
2.02 (ddt, J = 4.3, 14.9, 4.3 Hz, 1 H, H-3), 2.15 (d, J = 13.6 Hz, 1
H, H-6), 2.62 (dt, J = 12.1, 3.8 Hz, 1 H, H-1), 3.64 (dt, J = 4.2,
Eur. J. Org. Chem. 2005, 3214–3220
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F. Fülöp, M. Palkó, E. Forró, M. Dervarics, T. A. Martinek, R. Sillanpää
FULL PAPER
3.8 Hz, 1 H, H-2), 3.75–3.84 (m, 1 H, H-5) ppm. 13C NMR (D2O):
δ = 25.5, 27.9, 32.4, 43.7, 47.9, 68.2, 180.5 ppm. C7H13NO3
(159.19): calcd. C 52.82, H 8.23, N 8.80; found C 52.67, H 8.49, N
8.31.
[1]
[2]
F. Fülöp, Chem. Rev. 2001, 101, 2181–2204.
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F. Fülöp “The Chemistry of 2-Aminocyclopentanecarboxylic
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ell, X. Huang, J. J. Barchi, S. H. Gellman, Nature 1997, 387,
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13071–13072; c) D. H. Appella, S. L. Durell, J. J. Barchi, S. H.
Gellman, J. Am. Chem. Soc. 1999, 121, 2309–2310; d) J. J. Bar-
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S. H. Gellman, J. Am. Chem. Soc. 2000, 122, 2711–2718.
(r-1,t-2,c-5)-2-Amino-5-hydroxycyclohexanecarboxylic Acid (19):
Yield 62%, a white crystalline solid, m.p. 275–280 °C. 1H NMR
(D2O): δ = 1.32–1.44 (m, 2 H, H-4, H-6), 1.53 (ddt, J = 3.5, 12.8,
3.5 Hz, 1 H, H-3), 2.01–2.14 (m, 2 H, H-3, H-4), 2.31–2.40 (m, 2
H, H-1, H-6), 3.24 (dt, J = 3.8, 11.2 Hz, 1 H, H-2), 3.73 (tt, J =
4.0, 11.2 Hz, 1 H, H-5) ppm. 13C NMR (D2O): δ = 27.7, 32.0, 36.9,
46.8, 51.5, 68.8, 179.8 ppm. C7H13NO3 (159.19): calcd. C 52.82, H
8.23, N 8.80; found C 52.55, H 8.43, N 8.21.
[5]
(1S,2R,4R)-2-Amino-4-hydroxycyclohexanecarboxylic Acid (+)-(8):
The same synthesis was followed as for the racemic compound ( )-
8, starting from (1S,2R)-2-amino-4-cyclohexenecarboxylic acid hy-
1
drochloride, via intermediate 5a. The H NMR spectroscopic data
on the intermediates and products were similar to those for the
racemates. Representative data on the enantiomers isolated:
(1S,2R)-Ethyl 2-Amino-4-cyclohexenecarboxylate: Colourless crys-
tals, m.p. 125–128 °C, [α]2D0 = +19 (c, 1.0, EtOH), ee Ͼ 99%.
(+)-1a. A colourless oil, [α]2D0 = +58 (c, 0.6, MeOH), ee Ͼ 99%.
(+)-7a. A colourless oil, [α]2D0 = +28 (c, 0.4, MeOH).
(+)-(8). Colourless crystals, m.p. 140–145 °C, [α]2D0 = +17 (c, 0.23,
H2O), ee Ͼ 99%.
[6]
[7]
T. A. Martinek, G. K. Tóth, E. Vass, M. Hollósi, F. Fülöp,
Angew. Chem. Int. Ed. 2002, 41, 1719–1721.
a) K. Gademann, T. Hintermann, J. V. Schreiber, Current Med.
Chem. 1999, 6, 905–925; b) A. F. Abdel-Magid, J. H. Cohen,
C. A. Maryanoff, Current Med. Chem. 1999, 6, 955–969; c) E.
Juaristi, H. Lopez-Ruiz, Current Med. Chem. 1999, 6, 983–
1004.
[8]
[9]
(1S,2R,5R)-2-Amino-5-hydroxycyclohexanecarboxylic Acid (–)-(15):
The same synthesis was followed as for the racemic compound ( )-
15, starting from (1S,2R)-2-amino-4-cyclohexenecarboxylic acid
hydrochloride, via intermediate 13b. The 1H NMR spectroscopic
data on the intermediates and products were similar to those for
the racemates. Representative data on the enantiomers isolated:
(+)-(12b). Colourless crystals, m.p. 118–123 °C, [α]2D0 = +19.4 (c,
0.5, MeOH), ee Ͼ 99%.
(+)-(13b). Colourless crystals, m.p. 185–190 °C, [α]2D0 = +92.5 (c,
0.6, MeOH).
a) S. G. Davies, O. Ichihara, I. A. S. Walters, Synlett 1993, 461–
462; b) S. G. Davies, O. Ichihara, I. Lenoir, I. A. S. Walters, J.
Chem. Soc. Perkin Trans. 1 1994, 1411–1415; c) S. G. Davies,
G. Bhalay, Tetrahedron: Asymmetry 1996, 7, 1595–1596.
F. Fülöp, G. Bernáth, K. Pihlaja, Adv. Heterocyclic Chem.
1998, 69, 349–477.
[10] a) S. Gedey, J. Van der Eycken, F. Fülöp, Org. Lett. 2002, 4,
1967–1969; b) S. Gedey, P. Vainiotalo, I. Zupkó, P. A. M.
de Witte, F. Fülöp, J. Heterocycl. Chem. 2003, 40, 951–956; c)
S. Gedey, J. Van der Eycken, F. Fülöp, Lett. Org. Chem. 2004,
1, 215–217.
[11] a) P. Wipf, X. Wang, Tetrahedron Lett. 2000. 41, 8747–8751; b)
F. Fringuelli, F. Pizzo, M. Rucci, L. Vaccaro, J. Org. Chem.
2003, 68, 7041–7045; c) K. Tatsuta, M. Takahashi, N. Tanaka,
K. Chikauchi, J. Antibiot. 2000, 53, 1231–1234; d) Y. Ichikawa,
M. Ohbayashi, K. Hirata, R. Nishizawa, M. Isobe, Synlett
2001, 1763–1766; e) K. Wright, M. Crisma, C. Toniolo, R.
Török, A. Péter, M. Wakselman, J. P. Mazaleyrat, Tetrahedron
Lett. 2003, 44, 3381–3384; f) I. B. Masesane, P. G. Steel, Tetra-
hedron Lett. 2004, 45, 5007–5009.
[12] G. Bernáth, G. Stájer, A. E. Szabó, F. Fülöp, P. Sohár, Tetrahe-
dron 1985, 41, 1353–1365.
[13] a) A. Avenoza, C. Cativiela, M. A. Fernandez-Recio, M. J. Per-
egrina, Tetrahedron: Asymmetry 1996, 7, 721–728; b) A. Av-
enoza, C. Cativiela, M. A. Fernandez-Recio, M. J. Peregrina,
Synthesis 1997, 165–167.
[14] E. Forró, F. Fülöp, Tetrahedron: Asymmetry 2004, 15, 2875–
2880.
[15] Z. Otwinowski, W. Minor, Methods in Enzymology, vol. 276,
Macromolecular Crystallography, Part A (Eds.: C. W. Carter,
R. M. Sweet), pp. 307–326, Academic Press, New York, 1997.
[16] G. M. Sheldrick, SHELX-97, University of Göttingen, Ger-
many (1997).
(+)-(14b). Colourless crystals, m.p. 135–140 °C, [α]2D0 = +104 (c, 0.1,
MeOH), ee Ͼ 99%.
(–)-(15). Colourless crystals, m.p. 247–250 °C, [α]2D0 = –26 (c, 0.15,
H2O), ee Ͼ 99%.
X-ray Data Collection and Processing: Crystallographic data for 15
were collected at 173 K on a Nonius Kappa CCD area-detector
diffractometer, using graphite monochromatized MoKα radiation
(λ = 0.71073 Å). The data collection was performed using φ and ω
scans. The data were processed using DENZO-SMN v0.93.0.[15]
The structures were solved by direct methods with the SHELXS
program[16] and full-matrix least-squares refinements on F2 were
performed using the SHELXL-97 program.[16] All heavy atoms
were refined anisotropically. The OH and NH hydrogens were re-
fined anisotropically. The CH hydrogen atoms were included at
fixed distances with fixed displacement parameters from their host
atoms. Figure 1 was drawn with ORTEP-III for Windows.[17]
Acknowledgments
[17] L. J. Farrugia, J. Appl. Cryst. 1997, 30, 565.
Received: January 26, 2005
We thank the Hungarian Research Foundation (OTKA No. T
049407 and TS 04888) for financial support.
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Eur. J. Org. Chem. 2005, 3214–3220