Synthesis of alicyclic trans-β-amino acids from cis-β- hydroxycycloalkane-carboxylates

Article abstract of DOI:10.1055/s-2005-861875

A simple and efficient method is described for the preparation of both racemic and enantiopure trans-β-amino acids with a cycloheptane or cyclooctane skeleton, starting from racemic and enantiopure ethyl cis-2-hydroxycarboxylates. Georg Thieme Verlag Stut

Full text of DOI:10.1055/s-2005-861875

PAPER
1265
Synthesis of Alicyclic trans-b-Amino Acids from cis-b-Hydroxycycloalkane-
carboxylates
S
a
ynthesis of
Ali
o
cyclic trans-
r
b
-Amin
á
oAcids nd Kiss,a Enikő Forró,a Gábor Bernáth,a,b Ferenc Fülöp*a
Institute of Pharmaceutical Chemistry, University of Szeged, PO Box 121, 6701 Szeged, Hungary
Fax +(36)62545705; E-mail: fulop@pharma.szote.u-szeged.hu
b
Research Group for Heterocyclic Chemistry, Hungarian Academy of Sciences, University of Szeged, PO Box 121, 6701 Szeged,
Hungary
Received 7 October 2004; revised 24 January 2005
( )-2 can be easily prepared by reduction of the corre-
sponding 2-oxo-carboxylates. The cis-isomers were sepa-
rated from the minor amount of trans-isomers by
fractional distillation, and could be obtained in 99% puri-
ty.10 We expected that the conversion of the hydroxy
group of ethyl cis-2-hydroxycarboxylates ( )-1 and ( )-2
to a nitrogen-containing functional group in an SN2 man-
ner would lead by inversion of configuration to trans-b-
amino esters. For this reason, the hydroxy group of ( )-1
and ( )-2 was first tosylated to give ( )-3 and ( )-4
(Scheme 1). The nitrogen-containing functional group
was introduced by substitution of the tosyloxy group of
( )-3 and ( )-4, with sodium azide in DMF. Besides the
substitution products ( )-5 and ( )-6, the ethyl 1-cycloalk-
enecarboxylates as elimination components could be
identified in the crude products. In the seven-membered
system, the ratio of the substitution/elimination products
was 1:1. The amount of substitution product ( )-5 was
somewhat increased (1.2:1) when the reaction was per-
formed in the presence of tetrabutylammonium bromide
(TBAB) as phase-transfer catalyst. The reaction of ethyl
2-tosyloxycyclooctanecarboxylate ( )-4 with sodium
azide in DMF gave a substitution/elimination ratio of
1:2.7. With 12-crown-4 as catalyst in the reaction, a small
increase, in favor, of the substitution product was ob-
served (1:2.2). The yield of the elimination reaction was
moderated when the reaction was carried out in the NaN3/
DMF/TBAB system (1:1.3). When the transformations
were effected with the aim of preparing the 2-aminocyclo-
pentanecarboxylic acid, it was noteworthy that a larger
amount of substitution product was detected. In the trans-
formation of the ethyl 2-tosyloxycyclopentane-
carboxylate with NaN3 in DMF, the substitution/
elimination product ratio was 2:1. Interestingly, in the
case of the corresponding six-membered analog, only an
elimination reaction was observed.
Abstract: A simple and efficient method is described for the prep-
aration of both racemic and enantiopure trans-b-amino acids with a
cycloheptane or cyclooctane skeleton, starting from racemic and
enantiopure ethyl cis-2-hydroxycarboxylates.
Key words: natural products, drugs, antifungal agents, amino ac-
ids, chiral resolution
b-Amino acids, which have interesting biological activi-
ties, are key components of many natural products and an-
tibiotics. They are important building blocks for the
synthesis of peptide oligomers.1 Chiral cyclic b-amino ac-
ids have also received great attention in recent years.2 For
instance, trans-2-aminocyclopentanecarboxylic acid has
been used for the synthesis of b-peptide antibiotics, while
(1R,2S)-2-aminocyclopentanecarboxylic acid (cispenta-
cin) is a strong antifungal agent.3
Although good methods are available for the syntheses of
five- and six-membered cyclic trans-b-amino acids, very
few examples exist for the syntheses of seven- and eight-
membered analogs. trans-2-Aminocycloheptanecarboxy-
lic acid was prepared in low yield from 1-cycloheptene-
carboxylic acid by the addition of ammonia,4 while, N-
substituted trans-derivatives were obtained from Z-pro-
tected amino acids by a mixed anhydride method, using
isobutyl chloroformate and the corresponding amine, or
by benzylamine addition to 1-cycloheptenecarboxylic ac-
id.5 The Michael initiated ring closure (MIRC) reaction
has been successfully used for the preparation of
(1S,2S)-2-aminocycloheptanecarboxylic acid with (S)-
(–)-1-(trimethylsilylamino)-2-(methoxymethyl)pyrroli-
dine (SAMP) as chiral ammonia equivalent.6,7 The cis-de-
rivatives of the eight-membered b-amino acids have been
obtained from cyclooctadiene via its b-lactam8 or by re-
duction of 2-acetylamino-1-cyclooctenecarboxylate,9 but
the trans-counterpart has not been successfully synthe-
sized so far.
The azido group in ethyl 2-azidocycloalkylcarboxylates
( )-5 and ( )-6 was reduced to an amino group by catalyt-
ic hydrogenation in the presence of Pd/C in ethyl acetate,
giving the 2-amino esters ( )-7 and ( )-8. The reduction
could also be achieved by using the PPh3/H2O–THF sys-
tem, which gave approximately the same yield of amino
esters as described above.
In the present paper, we wish to report a simple new route
for the synthesis of trans-b-amino acids with cyclohep-
tane or cyclooctane skeletons in both racemic and optical-
ly pure forms. Ethyl 2-hydroxycarboxylates ( )-1 and
SYNTHESIS 2005, No. 8, pp 1265–1268
Advanced online publication: 17.03.2005
DOI: 10.1055/s-2005-861875; Art ID: T11304SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5
Subsequent hydrolysis of amino esters ( )-7 and ( )-8 and
crystallization of the crude solid products gave the desired
amino acids ( )-9 and ( )-10 as hydrochlorides.

1266
L. Kiss et al.
PAPER
COOEt
COOEt
OTs
COOEt
N3
from the acylated derivatives 11 and 12 by column chro-
matography on silica gel, eluting with EtOAc–hexane
(1:4).
a
b
n
n
n
OH
Following the reactions presented in Scheme 1, optically
active hydroxy esters (+)-1 and (+)-2 were transformed
analogously as for the racemic compounds to the required
amino acid hydrochlorides (–)-9 and (–)-10. The interme-
diate tosylates, azido esters, and amino esters were not
isolated. Since the optically active hydrochlorides of the
amino acids (–)-9 and (–)-10 have not been described in
the literature, 2-aminocycloheptanecarboxylic acid hy-
drochloride (–)-9 was desalted with propylene oxide to
give amino acid (–)-13. Although the absolute configura-
tions of the starting hydroxy esters had been proven, the
absolute configuration of (–)-9 was established as 1R,2R
by comparison of the optical rotation of 2-aminocyclo-
heptanecarboxylic acid (–)-13 with the literature data:7 it
was that expected from the transformation of (1R,2S)-(+)-
1. Accordingly, the absolute configuration of amino acid
(–)-10 was 1R,2R.
n = 1; ( )-1
n = 2; ( )-2
n = 1; ( )-5 36%
n = 2; ( )-6 34%
n = 1; ( )-3 80%
n = 2; ( )-4 73%
c
COOH
COOEt
NH2
d
n
n
NH2 . HCl
n = 1; ( )-7 60%
n = 2; ( )-8 50%
n = 1; ( )-9 82%
n = 2; ( )-10 74%
Scheme 1 Reagents and conditions: (a) TsCl, pyridine, r.t., 14 h; (b)
NaN3, DMF, r.t., 16 h; (c) H2, Pd/C, EtOAc, r.t., 2 h or PPh3, THF/
H2O, r.t., 6 h; (d) 6% HCl, r.t., 30 h.
The hydrolysis products ( )-9 and ( )-10 were identified
as trans-2-aminocycloheptanecarboxylic and trans-2-
aminocyclooctanecarboxylic acid hydrochlorides by
comparison of their NMR data with those of the cis-iso-
mers described earlier.8,11 Analysis of the NMR spectra of
the trans-isomers revealed a downfield shift of the signal
of H-2 in ( )-9 (Dd = 0.2 ppm) and an upfield shift of the
signal of H-1 in ( )-10 (Dd = 0.3 ppm) with respect to
those of the cis-isomers.
In summary, a new route has been developed for the syn-
thesis of trans-2-aminocycloalkanecarboxylic acids with
a cycloheptane or cyclooctane skeleton. This method also
permits enantioselective access to these compounds by
starting from optically active cis-2-hydroxycarboxylates.
The chemicals were purchased from Aldrich or Fluka. Melting
1
points were determined with a Kofler apparatus. H NMR spectra
were recorded on a Bruker DRX 400 spectrometer. Chemical shifts
are given in ppm relative to TMS as internal standard. Optical rota-
tions were measured with a Perkin-Elmer 341 polarimeter. Racemic
cis-hydroxy esters 1 (n = 1) and 2 (n = 2) were obtained from the
corresponding ethyl 2-oxo-cycloalkylcarboxylates.10 Vinyl acetate
was purchased from Fluka. Lipolase (lipase B from Candida Ant-
arctica was produced by submerged fermentation of a genetically
modified Aspergillus oryzae microorganism and adsorbed on a
macroporous resin), was purchased from Sigma-Aldrich (catalog
no. L4777). The progress of the enzymatic reaction of cis-( )-1 and
the ee of the unreacted (+)-1 was determined by using gas chroma-
tography on a Chromopak Chiralsil-Dex CB column (25 m). The al-
cohol in the sample was derivatized with propionic anhydride in the
presence of 4-dimethylaminopyridine and pyridine before the gas
chromatographic analysis [140 °C for 3 min to 180 °C (rate of tem-
perature rise 10 K/min; 100 kPa), tR (+)-1: 9.31(min) (antipode:
9.38)]. The progress of the enzymatic reaction of cis-( )-2 and the
ee of (+)-2 was determined by using HPLC with a Chiralcel OD-H
column (25 cm) [hexane–i-PrOH (95:5), 0.5 mL/min, 205 nm; tR
(+)-2 13.10 min (antipode: 15.90)]. The resulting trans-b-amino
acid enantiomers (–)-9 and (–)-10 were derivatized with TAGIT re-
agent and analyzed by HPLC on an NOVA-PAK C18 column15
[(3.9 × 150 mm), with 0.1% aq TFA–MeCN (70:30) for (–)-9 and
with 0.1% aq TFA–MeOH (55:45) for (–)-10, 0.8 mL/min, 250 nm;
tR (–)-9 9.23 min (antipode: 32.35), tR (–)-10: 22.60 (antipode:
13.68)].
COOEt
OH
COOEt
OH
EtOOC
AcO
1R
2S
1S
2R
n
a
n
n
+
n = 1; (+)-1
n = 2; (+)-2
n = 1; 11
n = 2; 12
n = 1; ( )-1
n = 2; ( )-2
b–e
COOH
COOH
1R
2R
1R
2R
f
n
n
NH2 . HCl
NH2
n = 1; (–)-9 80%
n = 2; (–)-10 81%
n = 1; (–)-13 75%
Scheme 2 (a) Lipolase, vinyl acetate, diisopropyl ether, 40 °C; (b)
TsCl, pyridine, r.t., 14 h; (c) NaN3, DMF, r.t., 16 h; (d) H2, Pd/C,
EtOAc, r.t., 2 h; (e) 6% HCl, r.t., 30 h; (f) propylene oxide, reflux, 2 h.
The method presented here suggested the possibility of
obtaining racemic amino acids 9 and 10 in optically pure
form by starting from optically active 2-hydroxycarboxy-
lates (+)-1 and (+)-2. The previous results on the enzymat-
ic resolution of 2-substituted cycloalkanols12 and N-
hydroxymethylated b-lactams8,13 suggested the selective
O-acylation of ( )-1 and ( )-2 (Scheme 2). The lipolase-
catalyzed highly R-selective O-acylation of ( )-1 and ( )-
2 (E > 200) by vinyl acetate (1.1 equiv) in diisopropyl
ether at 40 °C afforded the target (1R,2S)-hydroxy esters
(+)-1 and (+)-2. The products could be easily separated
Ethyl 2-Hydroxycycloalkanecarboxylates ( )-1 and ( )-2
The ethyl cis-2-hydroxycycloalkanecarboxylates ( )-1 and ( )-2
were prepared according to a literature process10 by Raney-Ni hy-
drogenation of the corresponding b-oxocarboxylates at r.t. in EtOH.
The resulting cis-trans (ca. 9:1) diastereomeric mixture was dis-
tilled in a high-performance fractional distillation apparatus to give
the pure cis 2-hydroxycarboxylates.10
Synthesis 2005, No. 8, 1265–1268 © Thieme Stuttgart · New York

PAPER
Synthesis of Alicyclic trans-b-Amino Acids
1267
Ethyl cis-2-Hydroxycycloheptanecarboxylate ( )-1
1H NMR (400 MHz, CDCl3): d = 1.27 (t, 3 H, CH3, J = 7.2 Hz),
1.38–1.60 (m, 4 H, CH2), 1.68–1.90 (m, 5 H, CH2), 1.92–2.05 (m, 1
H, CH2), 2.58–2.60 (m, 1 H, H-1), 2.8 (s, 1 H, OH), 4.14–4.21 (m,
3 H, OCH2 and H-2).
Amino Esters ( )-7 and ( )-8; General Procedure
Ethyl trans-2-azidocycloalkanecarboxylate (3 mmol) was dissolved
in EtOAc (50 mL) and hydrogenated in the presence of 10% Pd/C
(250 mg) at r.t. After 2 h, the catalyst was filtered off and the filtrate
was concentrated. The oily residue was purified by chromatography
(silica gel; CHCl3–MeOH, 10:1).
Ethyl cis-2-Hydroxycyclooctanecarboxylate ( )-2
1H NMR (400 MHz, CDCl3): d = 1.28 (t, 3 H, CH3, J = 7.2 Hz),
1.32–1.38 (m, 1 H, CH2), 1.52–1.62 (m, 5 H, CH2), 1.70–1.85 (m, 5
H, CH2), 2.02–2.10 (m, 1 H, CH2), 2.68–2.71 (m, 1 H, H-1), 3.1 (s,
1 H, O-H), 4.09–4.20 (m, 3 H, OCH2 and H-2).
Ethyl trans-2-Aminocycloheptanecarboxylate [( )-7]
Yield: 60%; colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.26 (t, 3 H, CH3, J = 7 Hz), 1.45–
1.98 (m, 10 H, 5 × CH2), 2.25–2.28 (m, 1 H, H-1), 3.16–3.18 (m, 1
H, H-2), 4.12–4.17 (m, 2 H, OCH2).
Tosylation; General Procedure
Anal. Calcd for C10H19NO2 (185.27): C, 64.83; H, 10.34; N, 7.56.
Found: C, 64.65; H, 10.26.
To a solution of ethyl cis-2-hydroxycycloalkanecarboxylate (10.5
mmol) in anhyd pyridine (30 mL), p-TsCl (15.7 mmol) was added
and the resulting mixture was stirred at r.t. for 14 h. The pH was ad-
justed to 3 by the addition of HCl (18%) dropwise at 0 °C and then
the mixture was extracted with EtOAc (3 × 30 mL). The combined
organic extracts were washed with water (3 × 150 mL), dried
(Na2SO4), and concentrated under reduced pressure.
Ethyl trans-2-Aminocyclooctanecarboxylate [( )-8]
Yield: 50%; colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.19 (t, 3 H, CH3, J = 7 Hz),
1.41–1.90 (m, 12 H, 6 × CH2), 2.40–2.50 (m, 1 H, H-1), 3.30–3.40
(m, 1 H, H-2), 4.14–4.17 (m, 2 H, OCH2).
Ethyl cis-2-Tosyloxycycloheptanecarboxylate [( )-3]
Yield: 80%; white solid (hexane); mp 55–58 °C.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, 3 H, CH3, J = 7.2 Hz),
1.40–1.95 (m, 10 H, 5 × CH2), 2.65–2.68 (m, 1 H, H-1), 3.22 (s, 1
H, ArCH3) 4.14–4.18 (m, 2 H, OCH2), 5.20–5.23 (m, 1 H, H-2),
7.31 (d, 2 H, ArH, J = 8.4 Hz), 7.77 (d, 2 H, ArH, J = 8.4 Hz).
Anal. Calcd for C11H21NO2 (199.3): C, 66.29; H 10.62; N, 7.03.
Found: C, 66.12; H, 10.50, N, 6. 97.
Amino Acids ( )-9/( )-10/(–)-9/(–)-10; General Procedure
The amino ester (1.08 mmol) was stirred at r.t. in 6% HCl (15 mL).
After 30 h, the mixture was concentrated under reduced pressure
and the residue was crystallized (EtOH–Et2O).
Anal. Calcd for C17H24O5S (340.44): C, 59.98; H, 7.11. Found: C,
59.77; H, 7.01.
trans-2-Aminocycloheptanecarboxylic Acid Hydrochloride
[( )-9]
Yield: 82%; white crystals; mp 207–209 °C.
1H NMR (400 MHz, D2O): d = 1.50–2.10 (m, 10 H, 5 × CH2), 2.73–
2.78 (m, 1 H, H-1), 3.71–3.78 (m, 1 H, H-2).
Ethyl cis-2-Tosyloxycyclooctanecarboxylate [( )-4]
Yield: 73%; white solid (hexane); mp 54–58 °C.
1H NMR (400 MHz, CDCl3): d = 1.23 (t, 3 H, CH3, J = 7.2 Hz),
1.35–2.00 (m, 12 H, 6 × CH2), 2.75–2.79 (m, 1 H, H-1), 3.22 (s, 1
H, ArCH3), 4.10–4.16 (m, 2 H, OCH2), 5.17–5.20 (m, 1 H, H-2),
7.31 (d, 2 H, ArH, J = 8.4 Hz), 7.76 (d, 2 H, ArH, J = 8.4 Hz).
Anal. Calcd for C8H16ClNO2 (193.57): C, 49.61; H, 8.33; N, 7.23.
Found: C, 49.65; H, 8.19; N, 7.12.
Anal. Calcd for C18H26O5S (354.47): C, 60.99; H, 7.39. Found: C,
60.81; H, 7.28.
trans-2-Aminocyclooctanecarboxylic Acid Hydrochloride
[( )-10]
Yield: 74%; white crystals; mp 210–212 °C.
1H NMR (400 MHz, D2O): d = 1.20–2.10 (m, 12 H, 6 × CH2), 2.72–
2.79 (m, 1 H, H-1), 3.71–3.80 (m, 1 H, H-2).
Azido Esters ( )-5 and ( )-6; General Procedure
The tosyl compound 3 or 4 (8.1 mmol), sodium azide (24.3 mmol)
and TBAB (8.1 mmol) were dissolved in DMF (40 mL). After stir-
ring for 16 h, water (100 mL) was added to the mixture, which was
then extracted with Et2O (3 × 40 mL). The combined ethereal phas-
es was washed with water (3 × 150 mL), dried (Na2SO4), and con-
centrated. The crude oily product was purified by chromatography
(silica gel; hexane–EtOAc, 15:1).
Anal. Calcd for C19H18ClNO2 (207.7): C, 52.05; H, 8.74; N, 6.74.
Found: C, 52.10; H, 8.61; N, 6.69.
Lipolase-Catalyzed Resolution of Ethyl cis-2-Hydroxycyclohep-
tanecarboxylate [( )-1]
Racemic cis-1 (4.00 g, 21.47 mmol) and vinyl acetate (2.22 mL,
23.64 mmol) in diisopropyl ether (80 mL) were added to the lipo-
lase (3 g), and the mixture was stirred at 40 °C for 14 h. The reaction
was stopped when 50% of the starting material was converted. The
enzyme was filtered and both starting material and product were re-
covered in 99% ee.
Ethyl trans-2-Azidocycloheptanecarboxylate [( )-5]
Yield: 36%; colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.14 (t, 3 H, CH3, J = 7.1 Hz),
1.38–1.90 (m, 10 H, 5 × CH2), 2.25–2.30 (m, 1 H, H-1), 3.68–3.73
(m, 1 H, H-2), 4.00–4.07 (m, 2 H, OCH2).
Anal. Calcd for C10H17N3O2 (211.27): C, 56.85; H, 8.11; N, 19.89.
Found: C, 56.96; H, 7.99; N, 19.70.
(1R,2S)-(+)-1
20
Yield: 1.79 g, 9.61 mmol; [a]D25 +36.8 (c 0.5, CHCl3), {lit.14 [a]D
+37 (c 1, CHCl3)}; 94%.
The 1H NMR data for (1R,2S)-(+)-1 was similar to those for ( )-1.10
Ethyl trans-2-Azidocyclooctanecarboxylate [( )-6]
Yield: 34%; colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.27 (t, 3 H, CH3, J = 7.1 Hz),
1.40–1.80 (m, 12 H, 6 × CH2), 2.48–2.51 (m, 1 H, H-1), 3.89–3.96
(m, 1 H, H-2), 4.12–4.22 (m, 2 H, OCH2).
(1S,2R)-(+)-11
Yield: (2.03 g, 8.89 mmol).
Anal. Calcd for C10H18O3 (186.25): C, 64.49; H, 9.74. Found: C,
64.38; H, 9.87.
Anal. Calcd for C11H19N3O2 (225.29): C, 58.64; H, 8.5; N, 18.65.
Found: C, 58.75; H, 8.39; N, 18.52.
Synthesis 2005, No. 8, 1265–1268 © Thieme Stuttgart · New York

1268
L. Kiss et al.
PAPER
Lipolase-Catalysed Resolution of Ethyl cis-2-Hydroxycyclooc-
tanecarboxylate [(+)-2]
Compound ( )-2 (5.00 g; 24.96 mmol) was subjected to the same
resolution as described for ( )-1, in a reaction time of 16 h.
References
(1) (a) Epand, R. F.; Raguse, T. L.; Gellman, S. H.; Epand, R.
M. Biochemistry 2004, 43, 9527. (b) Hayen, A.; Schmitt, M.
A.; Ngassa, F. N.; Thomasson, K. A.; Gellman, S. H. Angew.
Chem. Int. Ed. 2004, 43, 510. (c) Huck, B. R.; Fisk, J. D.;
Guzei, I. A.; Carlson, H. A.; Gellman, S. H. J. Am. Chem.
Soc. 2003, 125, 9035. (d) Raguse, T. L.; Lai, J. R.; Gellman,
S. H. J. Am. Chem. Soc. 2003, 125, 5592. (e) Schinnerl, M.;
Murray, J. K.; Langenhan, J. M.; Gellman, S. H. Eur. J. Org.
Chem. 2003, 4, 721. (f) Woll, M. G.; Fisk, J. D.; LePlae, P.
R.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124, 12447.
(2) Fülöp, F. Chem. Rev. 2001, 101, 2181.
(1R,2S)-(+)-2
Yield: 2.29 g, 11.43 mmol; [a]D25 +35.7 (c 0.5, CH2Cl2); ee 97%.
1
The H NMR data for (1R,2S)-(+)-2 were similar to those for ( )-
2.10
(1S,2R)-(+)-12
Yield: 2.71 g, 11.18 mmol.
(3) (a) Wang, X.; Espinosa, J. F.; Gellman, S. H. J. Am. Chem.
Soc. 2000, 122, 4721. (b) Bailey, S.; Davies, S. G.; Smith,
A. D.; Withey, J. M. Chem. Commun. 2002, 23, 2910.
(c) Langer, O.; Kaehling, H.; Zierler-Gould, K.; Bats, J. W.;
Mulzer, J. J. Org. Chem. 2002, 67, 6878. (d) Martinek, T.
A.; Tóth, G. K.; Vass, E.; Hollósi, M.; Fülöp, F. Angew.
Chem. Int. Ed. 2002, 41, 1717. (e) Aggarwal, V. K.;
Roseblade, S. J.; Barrel, J. K.; Alexander, R. Org. Lett. 2002,
4, 1227.
Anal. Calcd for C11H20O3 (200.28): C, 65.97; H, 10.07. Found: C,
65.88; H, 9.92.
(1R,2R)-2-Aminocycloheptanecarboxylic Acid Hydrochloride
[(–)-9]
Compound 9 was subjected to the same resolution as described for
( )-1.
Yield: 80%; white crystals; ee 94%; mp 208–209 °C; [a]D25 –4.1 (c
0.55, H2O).
The 1H NMR data were similar to those for ( )-9.
(4) Bernáth, G.; Göndös, G.; Kovács, K.; Sohár, P. Tetrahedron
1973, 29, 981.
(5) Bernáth, G.; Gera, L.; Göndös, G.; Pánovics, I.; Ecsery, Z.
(1R,2R)-2-Aminocyclooctanecarboxylic Acid Hydrochloride
[(–)-10]
Compound 10 was subjected to the same resolution as described for
( )-1.
Acta Chim. Acad. Sci. Hung. 1976, 89, 61.
(6) Enders, D.; Wiedemann, J.; Bettray, W. Synlett 1995, 369.
(7) Enders, D.; Wiedemann, J. Liebigs Ann. 1997, 699.
(8) Forró, E.; Árva, J.; Fülöp, F. Tetrahedron: Asymmetry 2001,
12, 643.
(9) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125,
9570.
25
Yield: 81%; white crystals; ee 97%; mp 211–213 °C; [a]D –10.8
(c 0.57, H2O).
The 1H NMR data were similar to those for ( )-10.
(10) (a) Bernáth, G.; Göndös, G.; Márai, P.; Gera, L. Acta Chim.
Acad. Sci. Hung. 1972, 74, 287. (b) Bernáth, G.; Göndös,
G.; Gera, L. Acta Phys. Chem. (Szeged) 1974, 20, 139.
(11) Forró, E.; Fülöp, F. Org. Lett. 2003, 5, 1209.
(12) (a) Forró, E.; Lundell, K.; Kanerva, L. T.; Fülöp, F.
Tetrahedron: Asymmetry 1997, 8, 3095. (b) Forró, E.;
Kanerva, L. T.; Fülöp, F. Tetrahedron: Asymmetry 1998, 9,
513. (c) Forró, E.; Fülöp, F. Tetrahedron: Asymmetry 1999,
10, 1985. (d) Forró, E.; Szakonyi, Z.; Fülöp, F. Tetrahedron:
Asymmetry 1999, 10, 4619. (e) Levy, M. L.; Dehli, J. R.;
Gotor, V. Tetrahedron: Asymmetry 2003, 14, 2053.
(13) Forró, E.; Fülöp, F. Tetrahedron: Asymmetry 2001, 12,
2351.
(1R,2R)-2-Aminocycloheptanecarboxylic acid [(–)-17]
(1R,2R)-2-Aminocycloheptanecarboxylic acid hydrochloride (–)-9
(1.55 mmol) was refluxed in propylene oxide for 2 h. The mixture
was then concentrated and crystallized (EtOH–Et2O, 1:2).
Yield 75%; [a]D25 –21 (c 0.5, H2O); white crystals; mp 273–275 °C.
1H NMR (400 MHz, CDCl3): d = 1.39–2.01 (m, 10 H, 5 × CH2),
2.39–2.44 (m, 1 H, H-1), 3.49–3.54 (m, 1 H, H-2).
Anal. Calcd for C8H15NO2 (157.21): C, 61.12; H, 9.62; N, 8.91.
Found: C, 61.01; H, 9.49; N, 8.70.
(14) Danchet, S.; Bigot, C.; Buisson, D.; Azerad, R. Tetrahedron:
Asymmetry 1997, 8, 1735.
Acknowledgment
(15) Antal, P.; Fülöp, F. J. Chromatogr., A 1995, 715, 219.
The authors acknowledge receipt of OTKA grants TS 040888 and
T 046440.
Synthesis 2005, No. 8, 1265–1268 © Thieme Stuttgart · New York