Synthesis of mono- and dihydroxy-substituted 2-aminocyclooctanecarboxylic acid enantiomers

Article abstract of DOI:10.1016/j.tetasy.2010.05.003

(1R,2S,6R)-2-Amino-6-hydroxycyclooctanecarboxylic acid (-)-10 was synthesized from (1R,2S)-2-aminocyclooct-5-enecarboxylic acid (+)-2 via an iodolactone intermediate, while (1R,2S,3R,4S)-2-amino-5,6- dihydroxycyclooctanecarboxylic acid (-)-12 was prepared

Full text of DOI:10.1016/j.tetasy.2010.05.003

Tetrahedron: Asymmetry 21 (2010) 957–961
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of mono- and dihydroxy-substituted
2-aminocyclooctanecarboxylic acid enantiomers
a
a
a
a
b
b
}
Márta Palkó , Gabriella Benedek , Eniko Forró , Edit Wéber , Mikko Hänninen , Reijo Sillanpää ,
Ferenc Fülöp a,c,
*
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary
b Department of Chemistry, University of Jyväskylä, FIN-40014 Turku, Finland
c Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
(1R,2S,6R)-2-Amino-6-hydroxycyclooctanecarboxylic acid (ꢀ)-10 was synthesized from (1R,2S)-2-amin-
ocyclooct-5-enecarboxylic acid (+)-2 via an iodolactone intermediate, while (1R,2S,3R,4S)-2-amino-5,6-
dihydroxycyclooctanecarboxylic acid (ꢀ)-12 was prepared by using the OsO4-catalysed oxidation of
Boc-protected amino ester (ꢀ)-5. The stereochemistry and relative configurations of the synthesized
compounds were determined by 1D and 2D NMR spectroscopy (based on 2D NOE cross-peaks and
3J(H,H) coupling constants) and X-ray crystallography.
Received 22 April 2010
Accepted 5 May 2010
Available online 3 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
involve oxidation of the double bond with KMnO4 or with catalytic
OsO4.26,28
The stereoselective synthesis of alicyclic b-amino acids,1,2 de-
rived from b-lactams,3,4 has attracted attention because of their
occurrence in many pharmacologically relevant compounds.5 They
can become important components for peptides with the aim of
modifying their biological activities.6 These compounds are to be
found in various natural and synthetic biologically active
molecules, for example, natural cispentacin and its synthetic 4-
methylene analogue (Icofungipen, PLD-118) exhibit antifungal
activity.7–11 These molecules are also useful starting materials; as
an example anatoxin-a,12–14 a nicotinic acetylcholine receptor ago-
nist, was efficiently synthesized from the b-lactam.15
Among the b-amino acids, hydroxy-functionalized counterparts
also play an important role in medicinal chemistry because of their
presence in many essential products, such as Paclitaxel (TaxolÒ)
and its synthetic derivative Docetaxel (TaxotereÒ), which exert sig-
nificant chemotherapeutic effects.16–18 Some cyclic derivatives
have antibiotic (oryzoxymycin) and antifungal activities.19–22
We earlier reported several methods for the mono- or dihydr-
oxylation of the cyclopentene and cyclohexene rings, but there is
no example involving mono- or dihydroxycyclooctane b-amino
acids in the literature. By iodolactonization23 and epoxidation24,25
of the double bond or via dihydrooxazine26 and oxazoline27 deriv-
atives, the corresponding monohydroxy b-amino acids can be effi-
ciently synthesized. For dihydroxylation, well-known routes
Our present work focuses on functionalization of the double
bond of N-protected cis-2-aminocyclooct-5-enecarboxylic acid
derivatives and analysis of the structures of the newly prepared
mono- and dihydroxy-substituted enantiopure and racemic
molecules.
2. Results and discussion
The racemic b-lactam ( )-1 was prepared by 1,2-cycloaddition
of chlorosulfonyl isocyanate (CSI) in dry CH2Cl2 at room tempera-
ture by modification of
a
literature process.29 The starting
(1R,2S)-2-aminocyclooct-5-enecarboxylic acid (+)-2 was synthe-
sized from ( )-1 by highly enantioselective Lipolase-catalysed ring
opening with 1 equiv of H2O in iPr2O at 70 °C.30
The enantiopure amino acid (+)-2 (ee >99%) was esterified in
the presence of EtOH and SOCl2 to furnish amino ester hydrochlo-
ride (ꢀ)-4, which was then reacted with tert-butoxy pyrocarbon-
ate, affording the N-Boc-protected amino ester (ꢀ)-5. An
alternative synthesis of ( )-5, which was used in the case of race-
mic compounds, comprised hydrolysis of ( )-1 with 22% ethanolic
HCl at room temperature to give ( )-4, which was then acylated by
the above method (Scheme 1).
The starting material in the iodolactonization reaction was cis-
2-tert-butoxycarbonylaminocyclooct-5-enecarboxylic acid (ꢀ)-6.
Enantiopure (ꢀ)-6 was prepared from (+)-2 with Boc2O, while
( )-6 was synthesized by the ring opening of ( )-1 with 18%
aqueous HCl and after acylation with di-tert-butyl dicarbonate.
The N-protected acid (ꢀ)-6 was reacted with I2/KI/aqueous
* Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.003

958
M. Palkó et al. / Tetrahedron: Asymmetry 21 (2010) 957–961
1S
O
R COOH
NH2
O
1
i
+
NH
8R
NH
2S
( )-1
(+)-2
ii
(–)-3
iv
1R
1R
1R COOEt
COOH
COOEt
NHBoc
iii
NHBoc
NH2.HCl
2S
2S
2S
(–)-6
(–)-4
(–)-5
Scheme 1. Reagents and conditions: (i) Lipolase, iPr2O, 70 °C; (ii) SOCl2, EtOH,
30 min, 0 °C, 3 h rt, 1 h, 4, 88%; (iii) Et3N, Boc2O, THF, 2 h, rt, 91%; (iv) dioxane/H2O,
Boc2O, 4 h, rt, 76%.
NaHCO3 in CH2Cl2 to give iodolactone (ꢀ)-7 regio- and diastereose-
lectively as a white crystalline product, in good yield. Reduction of
the iodo group with Bu3SnH in CH2Cl2 yielded lactone (ꢀ)-8 which,
after hydrolysis with microwave irradiation, gave (1R,2S,6R)-2-
amino-6-hydroxycyclooctanecarboxylic acid ((ꢀ)-10) in good
yield. When ring opening of the Boc–lactone (ꢀ)-8 was attempted
with hydrochloric acid, deprotected lactone (ꢀ)-9 was observed,
which was transformed to hydroxy-amino acid (ꢀ)-10 upon micro-
wave irradiation followed by heating in propylene oxide
(Scheme 2). The presence of the lactone ring in (ꢀ)7-(ꢀ)-9 was
confirmed by the cross-peak between H-6 and the carbonyl carbon
in the HMBC spectra. In the case of (ꢀ)-10, the NOE cross-peak be-
tween H-1 and H-6 suggests that the hydroxyl group should have a
cis configuration relative to the carboxyl group. A small NOE cross-
peak was also observed between H-2 and H-6, which indicates the
conformational flexibility of the compound and also proves the ori-
entation of the amino group. The stereochemistry of ( )-7 and ( )-9
was confirmed by X-ray diffraction (Figs. 1 and 2).
Figure 1. ORTEP plot of the X-ray structure of iodolactone ( )-7.
O
O
O
O
6R
1R
COOH
NHBoc
6S
I
1R
1R
i
ii
NHBoc
NHBoc
2S
2S
2S
5S
(–)-7
(–)-6
(–)-8
iv
iii
O
O
Figure 2. ORTEP plot of the X-ray structure of lactone ( )-9.
1R
6R
HO
COOH
NH2
v
vi
6R
1R
NH2. HCl
2S
2S
reochemistry. The stereochemistry of 12 was also confirmed by
X-ray diffraction (Fig. 3). From a racemic mixture, a single enantio-
mer crystallized out in a zwitterionic form in the crystal investi-
gated. However, the data did not permit confirmation of which
enantiomer this was.
(–)-10
(–)-9
Scheme 2. Reagents and conditions: (i) I2/KI, NaHCO3, CH2Cl2, 20 h, rt, 71%; (ii)
Bu3SnH, CH2Cl2, 20 h, 40 °C, 76%; (iii) microwave irradiation, H2O, 1 h, 150 °C, 67%;
(iv) 10% HCl/H2O, 24 h, 82%; (v) microwave irradiation, H2O, 1 h, 150 °C, 65%; (vi)
propylene oxide, 1 h, 4, 62%.
1R
6S
5R
6S
5R
1R
1R
HO
HO
COOEt
NHBoc
HO
HO
COOH
NH2
(1R,2S,5R,6S)-2-Amino-5,6-dihydroxycyclooctane-carboxylic
acid (ꢀ)-12 was obtained by OsO4-catalysed dihydroxylation. The
oxidation of N-Boc ester (ꢀ)-5 with catalytic OsO4 and N-methyl-
morpholine N-oxide (NMO) as the stoichiometric co-oxidant affor-
ded the desired product (ꢀ)-11 as a single diastereomer in good
yield. After deprotection of the compound, microwave irradiation
in water resulted in the corresponding dihydroxy-aminoacid (ꢀ)-
12 in good yield (Scheme 3). In the case of (ꢀ)-11, the all-cis stereo-
chemistry of the substituents can be proved by the NOE cross-
peaks between H-2 and H-5 and between H-1 and H-6. The pres-
ence of these NOE signals not only confirms the cis orientation of
the functional groups, but also indicates the conformational flexi-
bility of (ꢀ)-11. For (ꢀ)-12, a similar NOE pattern was observed
which indicates the all-cis orientation of the functional groups
and reveals that the microwave irradiation did not affect the ste-
COOEt
NHBoc
ii
i
2S
2S
(–)-11
2S
(–)-5
(–)-12
Scheme 3. Reagents and conditions: (i) 2.0% w/w solution of OsO4 in t-BuOH, NMO,
acetone, 4 h, rt, 91%; (ii) microwave irradiation, H2O, 1 h, 150 °C, 69%.
3. Conclusions
In summary, we have successfully synthesized either racemic
and enantiomeric 6-hydroxy- and 5,6-dihydroxy-2-aminocyclooc-
tanecarboxylic acid derivatives by using iodolactonization and
OsO4-catalysed dihydroxylation. All the racemic and enantiopure
derivatives produced can be used for further valuable transforma-

M. Palkó et al. / Tetrahedron: Asymmetry 21 (2010) 957–961
959
and washed with H2O (2 ꢁ 20 mL). The aqueous layer was ex-
tracted with EtOAc (2 ꢁ 25 mL). The combined organic phase was
dried (Na2SO4) and the solvents were evaporated off. The residue
was purified by column chromatography (n-hexane/EtOAc 5:1) to
afford a colourless oil (1.74 g, 91%), ½a D20
ꢂ
¼ ꢀ53:4 (c 1, EtOH). 1H
NMR (500 MHz, CDCl3, 27 °C): d = 1.28 (t, J = 7.1 Hz, 3H, CH2CH3),
1.43 (s, 9H, tBu), 1.72–1.82 (m, 2H, H-3, H-8), 1.86–1.94 (m, 1H,
H-3), 1.96–2.02 (m, 1H, H-4), 2.07–2.21 (m, 2H, H-7, H-8), 2.26–
2.34 (m, 1H, H-4), 2.44–2.51 (m, 1H, H-7), 2.81–2.85 (m, 1H, H-
1), 4.11–4.22 (m, 3H, H-2, CH2CH3), 4.99–5.05 (m, 1H, NH), 5.61–
5.72 (m, 2H, H-5, H-6) ppm. 13C NMR (125 MHz, CDCl3, 27 °C):
d = 14.2, 23.3, 24.6, 27.3, 28.4, 32.9, 48.0, 50.2, 60.4, 79.2, 129.2,
130.4, 155.0, 174.2 ppm. Anal. Calcd for C16H27NO4 (297.39): C,
64.62; H, 9.15; N, 4.71. Found: C, 64.57; H, 9.11; N, 4.84.
Figure 3. ORTEP plot of the X-ray structure of zwitterionic dihydroxy-substituted
amino acid 12.
4.4. (1R,2S)-2-tert-Butoxycarbonylaminocyclooct-5-enecarb-
oxylic acid (ꢀ)-6
tions, and they are good starting materials for the synthesis of pep-
tides and different heterocycles with potential biological activity.
Amino acid (+)-2 (0.98 g, 4.76 mmol) was dissolved in a mixture
of dioxane (10 mL) and water (5 mL), and 1 M NaOH (5 mL) and
tert-butoxypyrocarbonate (1.14 g, 5.24 mmol) were added to the
solution at 0 °C. The pH was adjusted to 8.5 with 1 M NaOH and
the mixture was stirred at room temperature for 5 h. The solvent
was then evaporated down to one-third volume, and the mixture
was diluted with EtOAc (30 mL) and acidified with 10% H2SO4
(pH 2.5). The mixture was extracted with EtOAc (3 ꢁ 15 mL), the
combined organic phase was dried (NaSO4), and the solvents were
evaporated off. The residue was recrystallized from iPr2O to give a
4. Experimental
4.1. General
The NMR spectra were recorded at ambient temperature in
CDCl3, DMSO-d6 or D2O with a Bruker AV 500 spectrometer at
500 MHz and at 125 MHz for 1H and 13C, respectively. Chemical
shifts are given in d (ppm) relative to TMS 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. Optical
rotations were measured with a Perkin Elmer 341 polarimeter.
Microwave reactions were performed in a CEM Discover LabMate
MW reactor.
white crystalline solid (0.97 g, 76%), mp 125–127 °C, ½a D20
¼ ꢀ59:0
ꢂ
(c 1, EtOH). 1H NMR (500 MHz, CDCl3, 27 °C): d = 1.45 (s, 9H, tBu),
1.79–1.88 (m, 2H, H-3, H-8), 1.93–2.00 (m, 1H, H-3), 2.00–2.21 (m,
3H, H-4eq, H-7eq, H-8), 2.27–2.36 (m, 1H, H-4ax), 2.44–2.52 (m,
1H, H-7ax), 2.97 (s, 1H, H-1), 4.16–4.22 (m, 1H, H-2), 5.09 (s, 1H,
NH), 5.68–5.74 (m, 2H, H-5, H-6) ppm. 13C NMR (125 MHz, CDCl3,
27 °C): d = 22.9, 24.6, 27.6, 28.4, 33.0, 48.2, 50.0, 80.1, 129.6, 130.7,
155.8, 177.9 ppm.. Anal. Calcd for C14H23NO4 (269.34): C, 62.43; H,
8.61; N, 5.20. Found: C, 62.36; H, 8.52; N, 5.14.
The ee value for the starting (1R,2S)-2-aminocyclooct-5-ene-
carboxylic acid (+)-2 was determined by using GC after double
derivatization.31
4.5. (1R,2S,5S,6S)-2-tert-Butoxycarbonylamino-5-iodo-7-oxabi-
cyclo[4.2.2]decan-8-one (ꢀ)-7
The ee values for the HCl salts of the final products were deter-
mined by HPLC. A Chirobiotic TAG 5
l
column (0.46 cm ꢁ 25 cm)
was used at room temperature; the mobile phase was MeOH con-
taining 0.1% TEA and 0.1% AcOH; flow rate 1 mL/min; detection at
216 nm; retention times (min): (ꢀ)-10, 28.08 (antipode: 30.92)
and (ꢀ)-12, 25.49 (antipode: 27.36).
To
a
solution of carboxylic acid derivative (ꢀ)-6 (1 g,
3.71 mmol) in CH2Cl2 (25 mL) were added NaHCO3 (0.5 M,
22 mL), KI (3.69 g, 22.26 mmol) and I2 (1.88 g, 7.42 mmol) at 0 °C.
The reaction mixture was stirred at room temperature for 20 h,
and saturated Na2S2O3 (25 mL) was then added. The mixture was
extracted with CH2Cl2 (3 ꢁ 15 mL), in the extract was dried
(Na2SO4), and the solvents were evaporated off. The residue was
recrystallized from iPr2O to give iodolactone (ꢀ)-7 (1.04 g, 71%),
4.2. Ethyl (1R,2S)-2-aminocyclooct-5-enecarboxylate
hydrochloride (ꢀ)-4
Thionyl chloride (0.86 g, 7.27 mmol) was added dropwise with
stirring to dry EtOH (5 mL) at ꢀ15 °C. Compound (+)-2 (1 g,
6.61 mmol) was added in one portion to this mixture, which was
then stirred at 0 °C for 30 min. After subsequent stirring at room
temperature for a further 3 h, the mixture was refluxed for 1 h
and then concentrated to give colourless crystals (1.5 g, 88%) mp
mp 105–107 °C, ½a D20
ꢂ
¼ ꢀ76:2 (c 1, EtOH). 1H NMR (500 MHz,
CDCl3, 27 °C): d = 1.31–1.40 (m, 1H, H-3ax), 1.43 (s, 9H, tBu),
2.00–2.14 (m, 3H, H-3eq, H-7, H-8), 2.26–2.37 (m, 2H, H-4ax, H-
8), 2.47–2.54 (m, 1H, H-4eq), 2.53–2.56 (m, 1H, H-7), 3.04 (dt,
J = 11.3, 2.5, 2.5 Hz, 1H, H-1), 3.82–3.89 (m, 1H, H-2), 4.55 (dt,
J = 12.0, 4.0, 4.0 Hz, 1H, H-5), 5.02–5.06 (m, 2H, NH, H-6) ppm.
13C NMR (125 MHz, CDCl3, 27 °C): d = 18.9, 22.5, 28.4, 31.7, 33.3,
34.2, 43.5, 55.4, 79.8, 82.7, 155.3, 172.0 ppm. Anal. Calcd for
108–110 °C, lit. mp 112–117 °C,29
½
a 2D0
ꢂ
¼ ꢀ1:5 (c 1, EtOH). The 1H
NMR data are in accordance with those reported in the literature.29
13C NMR (125 MHz, CDCl3, 27 °C): d = 14.3, 23.2, 23.7, 27.0, 30.3,
44.5, 52.0, 61.4, 128.8, 130.2, 172.9 ppm.
C14H22INO4 (395.23): C, 42.54; H, 5.61; N, 3.54. Found: C, 42.46;
H, 5.52; N, 3.56.
4.3. Ethyl (1R,2S)-2-tert-butoxycarbonylaminocyclooct-5-
enecarboxylate (ꢀ)-5
4.6. (1R,2S,6R)-2-tert-Butoxycarbonylamino-7-oxabicyclo[4.2.2]
decan-8-one (ꢀ)-8
To a suspension of (ꢀ)-4 (1.5 g, 6.42 mmol) in THF (50 mL) were
added Et3N (1.29 g, 12.84 mmol) and di-tert-butyl dicarbonate
(1.54 g, 7.06 mmol) at 0 °C. Stirring was continued for 3 h at room
temperature, after which the organic layer was diluted with EtOAc
At first, Bu3SnH (1.36 mL, 5.06 mmol) was added to a solution of
iodolactone (ꢀ)-7 (1 g, 2.53 mmol) in dry CH2Cl2 (35 mL) under ar-
gon. After stirring for 20 h at 40 °C, the solvent was evaporated off,

960
M. Palkó et al. / Tetrahedron: Asymmetry 21 (2010) 957–961
and the crude lactone was crystallized from n-hexane and recrys-
(1.18 g, 10.13 mmol) and (ꢀ)-5 (0.5 g, 1.68 mmol) in acetone
(20 mL) and the mixture was stirred at room temperature for a fur-
ther 4 h. When the reaction was complete (monitored by TLC), the
mixture was treated with saturated aqueous Na2SO3 (20 mL). The
aqueous layer was next extracted with EtOAc (3 ꢁ 20 mL), the
combined organic layer was dried (Na2SO4) and the solvent was re-
moved by evaporation under reduced pressure. Compound (ꢀ)-11
was purified by column chromatography on silica gel (n-hexane/
tallized from iPr2O (0.52 g, 76%), mp 102–105 °C, ½a D20
¼ ꢀ93:1 (c
ꢂ
0.5, EtOH). 1H NMR (500 MHz, CDCl3, 27 °C): d = 1.34–1.47 (m,
10H, tBu, H-3ax), 1.64–1.74 (m, 1H, H-4ax), 1.75–1.87 (m, 3H, H-
4eq, H-5, H-7), 1.98–2.06 (m, 1H, H-8), 2.07–2.20 (m, 3H, H-3eq,
H-5, H-7), 2.27 (ddd, J = 13.1, 11.4, 10.6 Hz, 1H, H-8), 2.99 (dt,
J = 11.2, 2.7, 2.7 Hz, 1H, H-1), 3.81–3.87 (m, 1H, H-2), 4.84 (dt,
J = 6.0, 3.0, 3.0 Hz, 1H, H-6), 5.14 (d, J = 7.6 Hz, 1H, NH) ppm. 13C
NMR (125 MHz, CDCl3, 27 °C): d = 20.7, 22.3, 22.7, 28.2, 31.8,
35.3, 43.2, 55.8, 78.6, 79.5, 154.9, 173.1 ppm. Anal. Calcd for
EtOAc, 1:1) to afford a colourless oil (0.5 g, 91%), ½a D20
¼ ꢀ27:2 (c
ꢂ
1, EtOH). 1H NMR (500 MHz, DMSO, 27 °C): d = 1.16 (t, J = 7.1 Hz,
3H, CH2CH3), 1.30–1.40 (m, 11H, tBu, H-4, H-7), 1.42–1.48 (m,
1H, H-3), 1.53–1.60 (m, 1H, H-8), 1.80–1.96 (m, 3H, H-3, H-4, H-
8), 1.98–2.06 (m, 1H, H-7), 2.62 (dt, J = 11.0, 3.5, 3.5 Hz, 1H, H-1),
3.60 (t, J = 6 Hz, 1H, H-6), 3.65 (br s, 1H, H-5), 3.91–4.04 (m, 3H,
CH2CH3, H-2), 4.22 (d, J = 3.3 Hz, 1H, OH), 4.30 (d, J = 4.6 Hz, 1H,
OH), 6.61 (d, J = 9.2 Hz, 1H, NH) ppm. 13C NMR (125 MHz, DMSO,
27 °C): d = 14.0, 20.3, 26.1, 27.7, 28.1, 28.2, 44.5, 50.1, 59.8, 71.5,
71.5, 77.5, 154.8, 173.9 ppm. Anal. Calcd for C16H29NO6 (331.40):
C, 57.99; H, 8.82; N, 4.23. Found: C, 57.81; H, 8.89; N, 4.12.
C14H23NO4 (269.34): C, 62.43; H, 8.61; N, 5.20. Found: C, 62.35;
H, 8.66; N, 5.15.
4.7. (1R,2S,6R)-2-Amino-7-oxabicyclo[4.2.2]decan-8-one hydro-
chloride (ꢀ)-9
A solution of lactone (ꢀ)-8 (0.6 g, 2.23 mmol) was dissolved in
aqueous HCl (10%; 20 mL) and the mixture was stirred for 24 h
at rt. The solvent was then evaporated off to afford the crude amino
lactone hydrochloride which was recrystallized from EtOH/Et2O
(0.33 g, 68%), mp 250–252 °C, ½a D20
ꢂ
¼ ꢀ23:9 (c 0.4, H2O). 1H NMR
4.10. (1R,2S,5R,6S)-2-Amino-5,6-dihydroxycyclooctane-
carboxylic acid (ꢀ)-12
(500 MHz, DMSO, 27 °C): d = 1.37 (ddd, J = 14.0, 11.5, 9.8 Hz, 1H,
H-3ax), 1.67–1.87 (m, 4H, H-4, H-4, H-5, H-7), 1.89–2.08 (m, 3H,
H-5, H-7, H-8), 2.09–2.16 (m, 1H, H-3eq), 2.20 (ddd, J = 12.7,
11.3, 8.9 Hz, 1H, H-8), 3.09 (dt, J = 11.1, 2.5, 2.5 Hz, 1H, H-1), 3.45
(ddd, J = 10.8, 4.6, 2.8 Hz, 1H, H-2), 4.81–4.84 (m, 1H, H-6), 8.08
(s, 3H, NH) ppm. 13C NMR (125 MHz, DMSO, 27 °C): d = 19.0,
21.0, 21.6, 29.1, 34.5, 40.5, 55.0, 78.3, 170.9 ppm. Anal. Calcd for
C9H16ClNO2 (205.09): C, 52.56; H, 7.84; Cl, 17,24; N, 6.81. Found:
C, 52.35; H, 7.66; Cl, 17,43; N, 7.05.
Dihydroxy ester (ꢀ)-11 (0.2 g, 0.9 mmol) was dissolved in water
(4 mL) in a 10-mL pressurized reaction vial and the reaction mix-
ture was stirred at 150 °C for 60 min at max. One hundred and fifty
watts microwave irradiation. After cooling, the mixture was di-
luted with acetone (5 mL) and the product crystallized out from
the solvent. The crude amino acid was recrystallized from H2O/ace-
tone to afford a pale-yellow crystalline solid (126 mg, 69%), mp
207–210 °C (dec), ½a D20
ꢂ
¼ ꢀ7:6 (c 0.5, H2O), ee >99%. 1H NMR
4.8. (1R,2S,6R)-2-Amino-6-hydroxycyclooctanecarboxylic acid
(ꢀ)-10
(500 MHz, D2O, 27 °C): d = 1.57–1.66 (m, 2H, H-4, H-7), 1.76–1.87
(m, 2H, H-3, H-8), 1.89–2.06 (m, 4H, H-3, H-4, H-7, H-8), 2.62
(dt, J = 10.1, 3.5, 3.5 Hz, 1H, H-1), 3.54 (ddd, J = 10.3, 5.0, 3.5 Hz,
1H, H-2), 3.84 (dt, J = 8.6, 2.2, 2.2 Hz, 1H, H-6), 3.92 (dt, J = 7.4,
2.3, 2.6 Hz, 1H, H-5) ppm. 13C NMR (125 MHz, D2O, 27 °C):
d = 22.3, 23.5, 25.9, 27.1, 43.8, 50.9, 71.1, 72.1, 181.0 ppm. Anal.
Calcd for C9H17NO4 (203.24): C, 53.19; H, 8.43; N, 6.89. Found: C,
53.01; H, 8.57; N, 6.78.
4.8.1. Method A
The lactone (ꢀ)-8 (178 mg, 0.66 mmol) was dissolved in water
(4 mL) in a 10-mL pressurized reaction vial, and the mixture was
then stirred at 150 °C for 60 min at max. One hundred and fifty watts
microwave irradiation. After cooling, the mixture was diluted with
acetone (6 mL) and the product crystallized out from the solvent.
The crude amino acid was recrystallized from H2O/acetone to afford
a pale-yellow crystalline solid (83 mg, 67%), mp 211–213 °C (dec).
4.11. Racemic compounds
All the reactions were first optimized for the racemic com-
pounds. The 1H and 13C NMR spectroscopic data and elemental
analyses on the racemic derivatives are in accordance with those
for the enantiomers.
4.8.2. Method B
Lactone (ꢀ)-9 (205 mg, 1 mmol) was dissolved in water (4 mL)
in a 10-mL pressurized reaction vial, and the reaction mixture was
then stirred at 150 °C for 60 min at max. One hundred and fifty
watts microwave irradiation. The solvent was evaporated off, the
residue was dissolved in propylene oxide (10 mL) and the mixture
was refluxed for 1 h. The product crystallized out from the solvent.
The crude amino acid was recrystallized from H2O/acetone to af-
ford a pale-yellow crystalline product (116 mg, 62%), mp 210–
*
*
4.11.1. (1R ,2S )-9-Azabicyclo[6.2.0]dec-4-en-10-one ( )-1
To a solution of 1,5-cyclooctadiene (30 g, 0.28 mol) in dry
CH2Cl2 (250 mL) was added dropwise a solution of CSI (39.63 g,
0.28 mol) in dry CH2Cl2 (150 mL) at room temperature. After stir-
ring for a further 72 h, the resulting liquid was poured into a stirred
solution of Na2SO3 (54.5 g, 0.43 mol) in water (148 mL), and the pH
was adjusted to 8–9 with 20% KOH solution. The mixture was stir-
red at room temperature for 3 h, after which the organic layer was
separated off and the aqueous phase was extracted with CH2Cl2.
The combined organic layers were dried (Na2SO4), filtered and con-
centrated. The resulting yellow solid was recrystallized from iPr2O
to give (17.78 g, 42%) of pure ( )-1, mp 110–113 °C, lit. 112–
113 °C.29 The 1H NMR, 13C NMR and elemental analysis data are
in accordance with those reported in the literature.30
212 °C (dec),
½
a 2D0
ꢂ
¼ ꢀ9:0 (c 0.4, H2O), ee >99%. 1H NMR
(500 MHz, D2O, 27 °C): d = 1.36–1.44 (m, 1H, H-4), 1.51–1.58 (m,
1H, H-5), 1.67–1.98 (m, 8H, H-3, H-3, H-4, H-5, H-7, H-7, H-8, H-
8), 2.62 (dt, J = 10.1, 3.7, 3.7 Hz, 1H, H-1), 3.46 (dt, J = 10.0, 4.0,
4.0 Hz, 1H, H-2), 3.82–3.87 (m, 1H, H-6) ppm. 13C NMR
(125 MHz, D2O, 27 °C): d = 19.1, 22.6, 28.9, 32.3, 34.3, 44.5, 51.2,
70.3, 180.9 ppm. Anal. Calcd for C9H17NO3 (187.24): C, 57.73; H,
9.15; N, 7.48. Found: C, 57.68; H, 9.22; N, 7.45.
4.9. Ethyl (1R,2S,5R,6S)-2-tert-butoxycarbonylamino-5,6-
dihydroxycyclooctanecarboxylate (ꢀ)-11
*
*
4.11.2. (1R ,2S )-2-Aminocyclooct-5-enecarboxylic acid
hydrochloride ( )-2ꢃHCl
OsO4 (1 mL, 0.08 mmol; a 2.0% w/w solution in tBuOH) was
A solution of b-lactam ( )-1 (1.5 g, 9.92 mmol) in H2O contain-
ing 18% of HCl (15 mL) was refluxed for 1 h. After removal of the
added to
a stirred solution of N-methylmorpholine N-oxide

M. Palkó et al. / Tetrahedron: Asymmetry 21 (2010) 957–961
961
solvent, amino acid hydrochloride ( )-2ꢃHCl was obtained, which
was recrystallized from EtOH to Et2O. Colourless crystals (1.67 g,
82%), mp 229–231 °C, lit. mp 218–220 °C.29 The 1H NMR, 13C
NMR and elemental analysis data are in accordance with those re-
ported in the literature.30
can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data Cen-
tre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (internat.) +44-
1223-336-033; E-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
*
*
4.11.3. Ethyl (1R ,2S )-2-aminocyclooct-5-enecarboxylate
hydrochloride ( )-4
The authors acknowledge the receipt of grants K 71938 and T
049407 from the Hungarian Scientific Research Fund (OTKA), and
a Bolyai Fellowship for E.F.
A solution of b-lactam ( )-1 (3 g, 19.84 mmol) in EtOH contain-
ing 22% HCl (30 mL) was stirred for 2 h at room temperature. After
removal of the solvent, amino ester hydrochloride 3 was obtained,
which was recrystallized from EtOH to Et2O. Colourless crystals
(4.13 g, 89%), mp 108–110 °C, lit. mp 112–117 °C.29 The 1H NMR,
13C NMR and elemental analysis data are in accordance with those
reported in the literature.30
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*
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*
*
*
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cyclo-[4.2.2]decan-8-one ( )-8. Pale-yellow crystals, mp 86–
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*
*
*
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*
*
*
*
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*
*
*
*
4.11.4.8. (1R ,2S ,5R ,6S )-2-Amino-5,6-dihydroxycyclooctane-
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The deposition numbers CCDC 769713–769715 contain the
supplementary crystallographic data for this paper. These data