Synthesis of 1-amino-4-hydroxycyclohexane-1-carboxylic acids

Article abstract of DOI:10.1039/a904132j

The synthesis of both stereoisomers of 1-amino-4-hydroxycyclohexane-1-carboxylic acid (1 and 2), a new family of constrained hydroxy-α,α-disubstituted-α-amino acids, is achieved through selective transformations of the functional groups of the correspondi

Full text of DOI:10.1039/a904132j

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Synthesis of 1-amino-4-hydroxycyclohexane-1-carboxylic acids
Alberto Avenoza,*a Carlos Cativiela,*b Miguel A. Fernández-Recioa and Jesús M. Peregrinaa
a Departamento de Química (Química Orgánica), Universidad de La Rioja, 26001 Logroño,
Spain. Fax: ϩ34 941 259431; E-mail: alberto.avenoza@dq.unirioja.es
b Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón,
Universidad de Zaragoza-C.S.I.C., 50009 Zaragoza, Spain. Fax: ϩ34 976 761210;
E-mail: cativiela@posta.unizar.es
Received (in Cambridge, UK) 24th May 1999, Accepted 27th September 1999
The synthesis of both stereoisomers of 1-amino-4-hydroxycyclohexane-1-carboxylic acid (1 and 2), a new family of
constrained hydroxy-α,α-disubstituted-α-amino acids, is achieved through selective transformations of the functional
groups of the corresponding enone cycloadduct provided by the Diels–Alder cycloaddition of Danishefsky’s diene to
methyl 2-acetamidoacrylate. The stereochemistry of intermediates 8 and 9 in the synthesis of hydroxy-α-amino acids
1 and 2 was unambiguously confirmed by X-ray structure determination.
Introduction
In recent years, there has been an increasing interest in α,α-
disubstituted-α-amino acids, due to their important role in
the synthesis of peptides with altered physical properties and
biological activity (pseudopeptides, peptidomimetics).1 In this
context, and as a part of our research program on the racemic
and asymmetric synthesis of conformationally constrained
α-amino acids, we have been interested in the synthesis of non-
proteinogenic hydroxy-α-amino acids.2
Glycobiology is a research speciality of growing importance
which has given rise to an increasing interest in carbohydrate
mimetics.3 The prospect of new hydroxylated α-amino acids
becoming available will lead to the synthesis of new glyco-
sylated hydroxyamino acids, and this area is our new research
focus.
Fig. 1 All isomers of hydroxycyclohexane-α-amino acids.
In the last few years, the syntheses of the monohydroxycyclo-
hexane-α-amino acids have received considerable attention
(Fig. 1).4–6 Recently, we have reported the synthesis of a con-
oxycyclohex-3-ene-r-1-carboxylate and methyl 1-acetamido-
strained homoserine analogue [(1S,3R)-1-amino-3-hydroxy-
cyclohexane-1-carboxylic acid], through direct hydroxylation,
via a dihydro-1,3-oxazine intermediate, from the unsaturated
amino acid derivative, obtained by Diels–Alder cycloaddition
of buta-1,3-diene with 8-phenylmenthyl 2-acetamidoacrylate.6b
In order to complete the stereoisomers of hydroxycyclo-
hexane-α-amino acids and to further advance on our experience
in the synthesis of constrained amino acids and the method-
ology involving the Diels–Alder reaction, we would now like to
report the extension of this methodology to the synthesis of the
two 1-amino-4-hydroxycyclohexane-1-carboxylic acids 1 and 2
as a new family of constrained hydroxyamino acids (Fig. 1).
t-2-methoxy-4-trimethylsilyloxycyclohex-3-ene-r-1-carboxylate,
corresponding to endo and exo attack respectively. This mixture
of products was treated with a 0.005 M HCl–THF (1:4)
solution to give a mixture of methyl 1-acetamido-t-2-methoxy-
4-oxocyclohexane-r-1-carboxylate and methyl 1-acetamido-4-
oxocyclohex-2-ene-1-carboxylate 4 in a ratio of 1:1. Enone 4
was obtained from the easy elimination of the methoxy group
of the endo-cycloadduct.8 Subsequent addition of DBU–
CH2Cl2 at 2 ЊC to the above reaction mixture gave the elimin-
ation of the methoxy group of the exo-cycloadduct, leaving
only the corresponding enone 4 with an excellent yield. This
enone was quantitatively hydrogenated in CH2Cl2 at room
temperature, using 10% palladium–carbon as a catalyst to give
ketone 5, which is the direct precursor of the desired hydroxy-
lated amino acids. The carbonyl group of compound 5 was
reduced using sodium borohydride in ethanol at 0 ЊC to give a
mixture of the equatorial and axial alcohols 6 and 7, respec-
tively, in an 80:20 ratio or by the action of -Selectride at
Ϫ78 ЊC in THF to give the same mixture of alcohols 6 and 7,
but now in a 10:90 ratio (Scheme 1).
The stereochemical outcome of ketone reductions with metal
hydrides depends strongly on the structure of the reagent and
on the ketone, particularly in the case of cyclic ketones.9
In our case, it is of crucial importance to know the most
stable chair conformation of the ketone 5, since in the reduction
reaction, the hydride attack on the same side in both conform-
ations will lead to opposite results (Scheme 2). Due to this fact,
several calculations were made on ketone 5 and on alcohols 6
Results and discussion
As there is a plane of symmetry in amino acids 1 and 2 there
was no need to use a chiral dienophile, therefore the most con-
venient dienophile to use was methyl 2-acetamidoacrylate 3.
The direct diene precursor of this kind of 4-hydroxycyclo-
hexane-α-amino acid is 2-methoxybuta-1,3-diene but the
results obtained from the Diels–Alder reaction with methyl
2-acetamidoacrylate 3 were poor; we therefore changed this
diene for another 2-hydroxy-functionalised one, which was
more reactive than the first.7 In our experiments the cyclo-
addition of Danishefsky’s diene to methyl 2-acetamidoacrylate
3 worked with excellent results when the reaction was carried
out in toluene at reflux for 72 h, allowing the obtention of the
mixture of methyl 1-acetamido-c-2-methoxy-4-trimethylsilyl-
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Scheme 1 Synthesis of alcohols 6 and 7 from dienophile 3.
Fig. 2 X-Ray crystallographic projection of 8 and 9.
atography. The mixture starting from NaBH4 reduction was
therefore treated with methanesulfonyl chloride in triethyl-
amine to give the methanesulfonate derivatives 8 and 9, which
were separated by silica gel column chromatography, eluting
with ethyl acetate. The stereochemistry of compounds 8 and 9
was unambiguously confirmed by X-ray analysis (Fig. 2).
To obtain the stereoisomer of 4-hydroxycyclohexane-α-amino
acid 2, in which the amino and hydroxy groups present an
anti relationship, we attempted the inversion of methane-
sulfonate derivative 8 by means of the addition of CsF in DMF,
achieving the inversion of the hydroxy group in the form of the
benzoate derivative 10. This compound was hydrolysed by the
action of a 6 M HCl aqueous solution heated under reflux,
giving the desired 1-amino-c-4-hydroxycyclohexane-r-1-carb-
oxylic acid as a hydrochloride derivative. Further addition of
propylene oxide in ethanol yielded the 4-hydroxycyclohexane-
α-amino acid 2 (Scheme 3).
To obtain the other stereoisomer, in which the amino and
hydroxy groups present a syn relationship, we tried the
hydrolysis of the major compound 8; however all attempts in
acid media were unsuccessful because a mixture of elimination
products was produced under these conditions. Consequently,
we decided to convert the mixture of alcohols 6 and 7 (starting
from NaBH4 reduction) into the corresponding acetate deriv-
atives 11 and 12, using acetic anhydride and scandium triflate as
the catalyst. This mixture was separated by column chrom-
atography and the major product 11 was hydrolysed in an acid
medium at reflux in order to obtain the desired 1-amino-t-4-
hydroxycyclohexane-r-1-carboxylic acid 1, according to the
protocol described for the synthesis of 4-hydroxy-α-amino acid
2. Alternatively, 4-hydroxy-α-amino acid 2 was obtained by
hydrolysis, in an acid medium, of acetate derivative 12 (starting
from -Selectride reduction of ketone 5 and further acetyl-
ation) (Scheme 3).
Scheme 2 Reduction of ketone 5.
and 7, obtained in these reductions. The lowest energy con-
formers of cyclohexanone 5 were calculated by molecular
mechanics and dynamics (MM/MD)10 and the relative energy
of the conformer 5a was 1.6 kcal molϪ1 lower than the con-
former 5b11 (Scheme 2).
The addition of the sodium borohydride to the carbonyl
carbon of conformer 5a takes place preferentially on the
opposite side to the acetamide group to give alcohol 6 (resulting
from the axial attack), in accordance with the Felkin–Ahn
model.12 By contrast, the preferential equatorial attack of bulky
hydride -Selectride to the carbonyl group gives axial alcohol
7 as the major compound.
Conclusion
In summary, we have developed a strategy to synthesize both cis
and trans constrained δ-hydroxy-α-amino acids with a cyclo-
hexane structure, in order to complete the family of hydroxy-
Alcohols 6 and 7 could not be separated by column chrom-
3376
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4-oxocyclohex-2-ene-1-carboxylate 4 in a ratio of 1:1. The
residue was dissolved in CH2Cl2 (40 mL) and DBU (0.525 mL,
3.5 mmol) was added. The reaction mixture was stirred for 24 h
at 2 ЊC and the solution was washed with a solution of HCl 0.5
M (60 mL). The aqueous phase was extracted with CH2Cl2
(5 × 20 mL) and the combined organic phases were dried over
anhydrous MgSO4, filtered and evaporated. The residue was
chromatographed on silica gel, eluting with ethyl acetate, to
yield 770 mg of enone 4 as a white solid (52%). Mp: 94–95 ЊC.
Calc. for C10H13NO4: C, 56.87; H, 6.20; N, 6.63; found C, 56.48;
H, 6.23; N, 6.58%. IR (CH2Cl2, cmϪ1): 3433 (NH), 1743
1
(COO ϩ CO), 1685 (CON). H-NMR (CDCl3): δ 1.98 (s, 3H,
MeCO), 2.40–2.59 (m, 4H, H5aЈ ϩ H5eЈ ϩ H6aЈ ϩ H6eЈ), 3.74
(s, 3H, MeOOC), 6.04 (d, 1H, H3, J2–3=12.0), 6.47 (br s, 1H,
NH), 7.05 (d, 1H, H2, J3–2 = 12.0). 13C-NMR (CDCl3): δ 22.7,
31.4, 33.5 (C5, C6, MeCO), 53.1 (MeOOC), 57.8 (C1), 129.9
(C3), 147.1 (C2), 170.2, 171.2 (COO, CON), 197.4 (CO).
Methyl 1-acetamido-4-oxocyclohexane-1-carboxylate (5)
A solution of enone 4 (211 mg, 1 mmol) in dry CH2Cl2 (10 mL)
was hydrogenated at atmospheric pressure for 24 h at 30 ЊC;
using 10% palladium–carbon (30 mg) as a catalyst. After the
removal of the catalyst and the solvent, the residue was chrom-
atographed on silica gel eluting with hexane–ethyl acetate (1:9),
to yield 204 mg of compound 5 as a white solid (95%). Mp:
133–134 ЊC. Calc. for C10H15NO4: C, 56.33; H, 7.09; N, 6.57;
found C, 56.67; H, 6.95; N, 6.25%. IR (CH2Cl2, cmϪ1): 3433
(NH), 1741 (COO), 1720 (CO), 1686 (CON). 1H-NMR
(CDCl3): δ 2.03 (s, 3H, MeCO), 2.32–2.49 (m, 8H, H2a ϩ H2e
ϩ H3a ϩ H3e ϩ H5a ϩ H5e ϩ H6a ϩ H6e), 3.74 (s, 3H, MeOOC),
6.34 (br s, 1H, NH). 13C-NMR (CDCl3): δ 22.7 (MeCO), 31.9,
36.4 (C2, C3, C5, C6), 52.4 (MeOOC), 57.4 (C1), 171.0, 173.2
(COO, CON), 209.5 (CO).
Scheme 3 Synthesis of hydroxy-α-amino acids 1 and 2 from alcohols 6
and 7.
cyclohexane-α-amino acids described in the literature. The
Diels–Alder cycloaddition of methyl acetamidoacrylate with
Danishefsky’s diene is the key step to achieve these cyclic
quaternary amino acids.
Reduction of cyclohexanone 5
Experimental
Method A. Sodium borohydride (91 mg, 2.4 mmol) was
added to a stirred solution of ketone 5 (170 mg, 0.80 mmol) in
dry ethanol (10 mL) kept under an inert atmosphere at 0 ЊC.
After 30 min at 0 ЊC, water (2 mL) and a 2 M HCl solution were
added dropwise. The solvent was evaporated and the residue
washed with CH2Cl2 (2 × 20 mL) and THF (2 × 20 mL). Evap-
oration of the solvent gave a diastereoisomeric mixture (157
mg, 91%) of alcohols 6 and 7, as a colourless solid, in a ratio
80:20, used without purification in the succeeding procedures.
The solvents were purified according to standard procedures.
Analytical TLC was carried out using Polychrom SI F254 plates.
Column chromatography was carried out using Silica gel 60
(230–400 mesh). 1H- and 13C-NMR spectra were recorded on a
Bruker ARX-300 spectrometer. 1H- and 13C-NMR spectra were
recorded in CDCl3 with TMS as the internal standard and in
CD3OD and D2O with TMS as external standard using a
coaxial microtube (chemical shifts are reported in ppm on the
δ scale, coupling constants in Hz). Melting points were deter-
mined on a Büchi SMP-20 melting point apparatus and are
uncorrected. Microanalyses were carried out on a CE Instru-
ments EA-1110 analyser and are in good agreement with the
calculated values. IR spectra were recorded on a Perkin Elmer
FT-IR Spectrum 1000 spectrometer.
Method B. Compound 5 (100 mg, 0.47 mmol) was dissolved
in dry THF (8 mL) and -Selectride (0.7 mL of 1 M solution
in THF, 0.7 mmol) was added dropwise, at Ϫ78 ЊC, under an
inert atmosphere. After 3 h stirring at the same temperature, the
reaction was quenched by the addition of a saturated NH4Cl
solution (2 mL). The resulting mixture was allowed to warm up
to room temperature, the solvent evaporated and the residue
washed with CH2Cl2 (2 × 10 mL) and THF (2 × 10 mL). Evap-
oration of the solvent gave an unpurified mixture (110 mg) of
compounds 6 and 7, in a 10:90 ratio, used without purification
in the succeeding procedures. The ratio of alcohols 6 and 7 was
Methyl 1-acetamido-4-oxocyclohex-2-ene-1-carboxylate (4)
Danishefsky’s diene (2.4 g, 14.0 mmol) was added to a solution
of methyl 2-acetamidoacrylate 3 (500 mg, 3.5 mmol) in dry
toluene (50 mL) kept under an inert atmosphere. After stirring
for 24 h, at reflux, another 3.5 mmol of 3 were added. After 2
more days stirring at the same temperature, the solvent was
evaporated in vacuo and a solution of 0.005 M HCl–THF (1:4)
(40 mL) was added to the residue. The reaction mixture was
stirred for 15 h at 20 ЊC, the solvent was eliminated and the
mixture was diluted with CH2Cl2 (30 mL). This solution was
washed with brine (2 × 20 mL) and an aqueous solution of
5% NaHCO3 (2 × 20 mL). The aqueous phases were washed
again with CH2Cl2 (20 mL) and AcOEt (20 mL), the com-
bined organic phases were dried over anhydrous MgSO4 and
filtered. Evaporation of the solvent gave a residue which
corresponded to a mixture of methyl 1-acetamido-t-2-methoxy-
4-oxocyclohexane-r-1-carboxylate and methyl 1-acetamido-
1
determined by the integration of the next H-NMR signals:
1H-NMR (CDCl3): δ 3.62–3.72 (m, 4H, MeOOC ϩ H3ax 6),
3.86–3.94 (m, 1H, H3eq 7), 5.96 (br s, 1H, NH 6), 6.09 (br s, 1H,
NH 7).
Methyl 1-acetamido-t-4-methylsulfonyloxycyclohexane-r-1-
carboxylate (8)
The mixture of alcohols 6 and 7 obtained from the reduction of
ketone 5 using method A (157 mg, 0.73 mmol) was dissolved in
dry CH2Cl2 (15 mL) under an inert atmosphere; triethylamine
(111 mg/0.153 mL, 1.09 mmol) and methanesulfonyl chloride
(124.8 mg/0.084 mL, 1.09 mmol) were added to this solution.
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After 36 h stirring at reflux, the solution was left to reach room
temperature and washed with an aqueous solution of 5%
NaHCO3, dried over anhydrous MgSO4 and filtered. After
evaporation of the solvent the residue was chromatographed on
a silica gel column, eluting with ethyl acetate, to obtain 110 mg
of compound 8 (52%) and 35 mg (16%) of compound 9, both
of them as white solids (62% overall from 5). Mp: 120–123 ЊC.
Calc. for C11H19NO6S: C, 45.04; H, 6.53; N, 4.77; S, 10.93;
found C, 46.29; H, 6.78; N, 4.47; S, 10.13%. IR (CH2Cl2, cmϪ1):
3436 (NH), 1740 (COO), 1683 (CON). 1H-NMR (CDCl3):
δ 1.80–1.93 (m, 2H, H3a ϩ H5a), 1.94–2.12 (m, 7H, H2a ϩ H3e ϩ
(3 × 20 mL) and the organic phase dried over anhydrous
MgSO4, filtered and evaporated. The residue was chromato-
graphed on a silica gel column, eluting with hexane–ethyl acet-
ate (3:7) to obtain 145 mg of compound 11 (57%) and 45 mg
(18%) of compound 12, both of them as white solids (75%
overall). Mp: 140–142 ЊC. Calc. for C12H19NO5: C, 56.02; H,
7.44; N, 5.44; found C, 55.32; H, 7.31; N, 5.42%. IR (CH2Cl2,
cmϪ1): 3439 (NH), 1734 (COO), 1682 (CON). 1H-NMR
(CDCl3): δ 1.47–1.62 (m, 2H, H3a ϩ H5a), 1.85–2.06 (m, 10H,
H
2a ϩ H3e ϩ H5e ϩ H6a ϩ MeCON ϩ MeCOO), 2.07–2.20 (m,
2H, H2e ϩ H6e), 3.68 (s, 3H, MeOOC), 4.66–4.76 (m, 1H, H4),
5.96 (br s, 1H, NH). 13C-NMR (CDCl3): δ 21.2, 23.1 (MeCOO,
MeCON), 26.5 (C3, C5), 29.6 (C2, C6), 52.4 (MeOOC), 57.7
(C1), 70.9 (C4), 170.1, 170.3, 173.8 (MeCOO, COOMe, CON).
H5e ϩ H6a ϩ MeCO), 2.13–2.22 (m, 2H, H2e ϩ H6e), 3.05 (s,
3H, MeSO2), 3.70 (s, 3H, MeOOC), 4.66–4.76 (m, 1H, H4), 6.73
(br s, 1H, NH). 13C-NMR (CDCl3): δ 23.1 (MeCO), 27.8 (C3,
C5), 29.6 (C2, C6), 38.6 (MeSO2), 52.5 (MeOOC), 57.3 (C1), 79.0
(C4), 170.2, 173.5 (COO, CON).
Methyl 1-acetamido-c-4-acetyloxycyclohexane-r-1-
carboxylate (12)
Methyl 1-acetamido-c-4-methylsulfonyloxycyclohexane-r-1-
carboxylate (9)
Compound 12 was obtained as a white solid in a similar way to
that described for compound 11, starting from the mixture of
alcohols 6 and 7 which came from the reduction of ketone 5
using method B (150 mg, 0.69 mmol). Isolated yield, 120 mg
(68%). Mp: 156–158 ЊC. Calc. for C12H19NO5: C, 56.02; H, 7.44;
N, 5.44; found C, 56.25; H, 7.23; N, 5.51%. IR (CH2Cl2, cmϪ1):
3437 (NH), 1732 (COO), 1682 (CON). 1H-NMR (CDCl3):
δ 1.68–1.91 (m, 6H, H2aϩ H3a ϩ H5a ϩ H6a ϩ H3e ϩ H5e), 1.97
(s, 3H, MeCO), 2.03 (s, 3H, MeCO), 2.12–2.23 (m, 2H,
Compound 9 was obtained as a white solid in a similar way to
that described for compound 8, starting from the mixture of
alcohols 6 and 7 obtained from the reduction of ketone 5 using
method B (110 mg, 0.47 mmol). Isolated yield, 102 mg (74%).
Mp: 138–139 ЊC. Calc. for C11H19NO6S: C, 45.04; H, 6.53; N,
4.77; S, 10.93; found C, 45.32; H, 6.45; N, 4.62; S, 11.01%.
IR (CH2Cl2, cmϪ1): 3436 (NH), 1740 (COO), 1684 (CON).
1H-NMR (CDCl3): δ 1.76–1.90 (m, 2H, H3a ϩ H5a), 1.91–2.07
(m, 7H, H2a ϩ H3e ϩ H5e ϩ H6a ϩ MeCO), 2.15–2.31 (m, 2H,
H
2e ϩ H6e), 3.70 (s, 3H, MeOOC), 4.87–4.93 (m, 1H, H4), 6.00
(br s, 1H, NH). 13C-NMR (CDCl3): δ 21.3, 23.2 (MeCON,
MeCOO), 25.7 (C3, C5), 28.0 (C2, C6), 52.4 (MeOOC), 58.1 (C1),
68.7 (C4), 170.3, 170.6, 174.0 (MeCOO, COOMe, CON).
H
2e ϩ H6e), 3.03 (s, 3H, MeSO2), 3.72 (s, 3H, MeOOC), 4.87–
4.95 (m, 1H, H4), 5.75 (br s, 1H, NH). 13C-NMR (CDCl3):
δ 23.3 (MeCO), 26.9 (C3, C5), 27.4 (C2, C6), 38.8 (MeSO2), 52.6
(MeOOC), 57.9 (C1), 77.0 (C4), 170.4, 173.6 (COO, CON).
1-Amino-c-4-hydroxycyclohexane-r-1-carboxylic acid (2)
Compound 10 (128 mg, 0.40 mmol) was suspended in a 6 M
HCl aqueous solution (10 mL) and heated under reflux for 24 h.
The solvent was evaporated in vacuo, the residue was dissolved
in water, washed with diethyl ether (2 × 10 mL) and the aque-
ous layer evaporated. This residue of amino acid hydrochloride
was dissolved in ethanol (3 mL) and propylene oxide (1 mL)
was added. The mixture was heated under reflux for 2 h and
after removal of the solvent, the residue was dissolved in
distilled water (2 mL) and eluted through a C18 reverse-phase
Sep-pak cartridge which, after removal of water, gave 52 mg
(82%) of 4-hydroxy-α-amino acid 2 as a white solid. Altern-
atively, and using the same conditions as above, amino acid 2
was obtained in 78% yield starting from compound 12. Calc. for
C7H13NO3: C, 52.82; H, 8.23; N, 8.80; found C, 53.44; H, 7.98;
N, 8.67%. IR (MeOH, cmϪ1): 1772 (CO). 1H-NMR (D2O):
Methyl 1-acetamido-c-4-benzoyloxycyclohexane-r-1-
carboxylate (10)
A mixture of caesium fluoride (216 mg, 1.77 mmol) and
benzoic acid (270 mg, 1.77 mmol) dissolved in dry DMF (8
mL), under an inert atmosphere, was stirred for 20 min at room
temperature. Compound 8 (104 mg, 0.35 mmol) dissolved in
dry DMF (2 mL) was then added. After 12 h stirring at 80 ЊC, a
mixture of ethyl acetate and ice–water (4:1) (50 mL) was added
to the solution and the organic phase was washed with an
aqueous solution of 5% NaHCO3 (20 mL) and brine (20 mL),
dried over anhydrous MgSO4, filtered and evaporated. The
residue was chromatographed on a silica gel column, eluting
with ether–ethyl acetate (9:1) to obtain 77 mg of compound 10
(68%) as an oilish solid. Calc. for C17H21NO5: C, 63.94; H, 6.63;
N, 4.39; found C, 62.97; H, 6.76; N, 4.13%. IR (CH2Cl2, cmϪ1):
3438 (NH), 1740, 1714 (COO), 1683 (CON). 1H-NMR
(CDCl3): δ 1.81–2.10 (m, 9H, H3a ϩ H5a ϩ H2a ϩ H3e ϩ H5e
ϩ H6a ϩ MeCO), 2.25–2.40 (m, 2H, H2e ϩ H6e), 3.75 (s, 3H,
MeOOC), 5.19–5.26 (m, 1H, H4), 5.98 (br s, 1H, NH), 7.41–
7.50 (m, 2H, m-arom), 7.52–7.61 (m, 1H, p-arom), 8.01–8.09
(m, 2H, o-arom). 13C-NMR (CDCl3): δ 23.2 (MeCO), 25.8 (C3,
C5), 28.1 (C2, C6), 52.5 (MeOOC), 58.2 (C1), 69.2 (C4), 128.4,
129.5 (o,m,-arom), 130.3 (ipso-arom), 133.0 (p-arom), 165.9,
170.3, 174.0 (PhCOO, MeCOO, CON).
δ
1.82–2.11 (m, 8H, H2a ϩ H2eϩ H3a ϩ H3e ϩ H5a ϩ H5e
ϩ H6a ϩ H6e), 4.80–4.85 (m, 1H, H4). 13C-NMR (D2O): δ 24.8,
27.8 (C2, C3, C5, C6), 53.9 (C1), 77.3 (C4), 177.3 (COO).
1-Amino-t-4-hydroxycyclohexane-r-1-carboxylic acid (1)
Amino acid 1 was obtained as an oil in a similar way to that
described for amino acid 2, starting from compound 11 (145
mg, 0.56 mmol). Isolated yield, 63 mg (70%). Calc. for
C7H13NO3: C, 52.82; H, 8.23; N, 8.80; found C, 53.20; H, 8.41;
N, 8.76%. IR (MeOH, cmϪ1): 1736 (CO). 1H-NMR (D2O):
δ 1.38–1.54 (m, 2H, H3aϩ H5a), 1.98–2.16 (m, 6H, H2a ϩ H2e
ϩ H3e ϩ H5e ϩ H6a ϩ H6e), 3.75–3.87 (m, 1H, H4). 13C-NMR
(D2O): δ 28.6, 29.8 (C3, C5, C2, C6), 60.4 (C1), 67.9 (C4), 177.1
(COO).
Methyl 1-acetamido-t-4-acetyloxycyclohexane-r-1-
carboxylate (11)
The mixture of alcohols 6 and 7 from the reduction of ketone 5
using method A (215 mg, 1 mmol) was dissolved in dry
acetonitrile, under an inert atmosphere, and acetic anhydride
(306 mg/0.284 mL, 3 mmol) and scandium triflate (1.87 mL of a
0.01 M solution, 18.7 µmol) were added to the solution. After
stirring for 16 h, at 50 ЊC, the reaction was left to reach room
temperature and was quenched adding saturated aq. NaHCO3
(20 mL). The mixture was extracted with dicloromethane
Crystal data for compound 8†
Single crystals of 8 were recrystallised from dichloromethane–
¯
hexane. C11H19NO6S (293.33), triclinic, space group P1,
† CCDC reference number 207/365. See http://www.rsc.org/suppdata/
p1/1999/3375 for crystallographic files in .cif format.
3378
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Krasnoff, D. W. Roberts, J. A. A. Renwick, L. S. Brinen and
a = 5.928 (6), b = 13.671 (15), c = 18.592 (2) Å, V = 1451.4 (3)
Å3, Z = 4. Mo-Kα radiation, λ = 0.71069 Å, graphite mono-
chromator, ω/2θ scan technique. A total of 6240 reflections
were measured, and merged to 6240 unique reflections. Tem-
perature of data collection at 293(2) K. Absorption coefficient
(µ, mmϪ1) 0.244. The structure was solved by direct methods.
Software used, SHELXL 97,13 SHELXS 97.14 Least-squares
(full matrix) refinement yielded R and Rw-values of 0.0765
and 0.1878 respectively. All calculations were performed on a
Pentium PC.
J. Clardy, J. Am. Chem. Soc., 1991, 113, 707; (m) V. J. Hruby, The
Peptides: Analysis, Synthesis, Biology, Academic Press: Orlando,
1985; (n) A. Abell, Advances in Amino Acid Mimetics and
Peptidomimetics, vol. 1, Jai Press Inc., Greenwich, 1997.
2 (a) A. Avenoza, C. Cativiela and J. M. Peregrina, Tetrahedron, 1994,
50, 10021; (b) A. Avenoza, J. H. Busto, C. Cativiela and J. M.
Peregrina, Tetrahedron Lett., 1995, 36, 7123; (c) A. Avenoza,
C. Cativiela, M. A. Fernández-Recio and J. M. Peregrina, Synthesis,
1997, 165; (d) A. Avenoza, C. Cativiela, M. París, J. M. Peregrina
and B. Saenz-Torre, Tetrahedron: Asymmetry, 1997, 7, 1123; (e)
A. Avenoza, J. H. Busto, C. Cativiela and J. M. Peregrina, An. Quím.,
Int. Ed., 1998, 94, 50.
3 (a) A. Varki, Glycobiology, 1993, 3, 97; (b) H. Lis and N. Sharon,
Eur. J. Biochem., 1993, 218, 1; (c) R. A. Dwek, Chem. Rev., 1996, 96,
683.
4 Racemic 2-hydroxycyclohexane-α-amino acids: H. N. Christensen
and M. E. Handlogten, Biochim. Biophys. Acta, 1977, 469, 216.
5 Enantiomerically pure 2-hydroxycyclohexane-α-amino acids: (a)
Y. Ohfune and M. Horikawa, J. Synth. Org. Chem. Jpn., 1997, 55,
982; (b) Y. Ohfune, K. Nanba, I. Takada, T. Kan, M. Horikawa and
T. Nakajima, Chirality, 1997, 9, 459.
Crystal data for compound 9†
Single crystals of 9 were recrystallised from dichloromethane–
hexane. C11H19NO6S (293.33), monoclinic, space group C2/c,
a = 34.154 (10), b = 8.581 (2), c = 9.984 (3) Å, V = 2923.26 (14)
Å3, Z = 4. Mo-Kα radiation, λ = 0.71069 Å, graphite mono-
chromator, ω/2θ scan technique. A total of 3355 reflections
were measured, and merged to 3355 unique reflections. Tem-
perature of data collection at 293(2) K. Absorption coefficient
(µ, mmϪ1) 0.260. The structure was solved by direct methods.
Software used, SHELXL 97,13 SHELXS 97.14 Least-squares
(full matrix) refinement yielded R and Rw-values of 0.0450
and 0.1252 respectively. All calculations were performed on a
Pentium PC.
6 Racemic and enantiomerically pure 3-hydroxycyclohexane-α-amino
acids: (a) A. Avenoza, C. Cativiela, M. A. Fernández-Recio and
J. M. Peregrina, Synlett, 1995, 891; (b) A. Avenoza, C. Cativiela,
M. A. Fernández-Recio and J. M. Peregrina, Tetrahedron:
Asymmetry, 1996, 7, 721; (c) K. Hammer, Ch. Romming and
K. Undheim, Tetrahedron, 1998, 54, 10837.
7 F. Fringelli and A. Taticchi, Dienes in the Diels–Alder Reaction, John
Wiley and Sons, Inc., New York, 1990.
8 S. Danishefsky, T. Kitahara, C. F. Yan and J. Morris, J. Am. Chem.
Soc., 1979, 101, 6996.
Acknowledgements
9 M. Hudlicky, Reductions in Organic Chemistry; 2nd edn., ACS
Monograph 188, American Chemical Society, Washington DC,
1996.
We are indebted to the DGES (project PB97–0998-C02-02)
and to the Universidad de La Rioja (project API-98/B02) for
their generous support. M. A. F.-R. would like to thank the
Ministerio de Educación y Cultura for a grant.
10 Molecular dynamics calculations utilizing the CVFF force field were
performed on an SGI O2 workstation using the Discover, Analysis
and Search & Compare modules of InsightII (97.2 version).
11 The energy values were obtained by further refinement through
molecular mechanics employing the Chem 3D Pro program
(available from Cambridge Scientific Computing Inc.) and using
MM2 force field: H. Burkert and N. L. Allinger, Molecular
Mechanics, American Chemical Society, Washington DC, 1982.
12 (a) M. Cherest and N. Prudent, Tetrahedron, 1980, 36, 1599; (b)
N. Greeves, in Comprehensive Organic Chemistry, eds. M. B. Trost
and I. Fleming, Pergamon Press, London, 1991, vol. 8, ch. 1.1.
13 G. M. Sheldrick, SHELXL 97, an integrated system for refining
crystal structures from diffraction data, University of Göttingen,
Germany, 1997.
References
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Paper 9/04132J
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