New synthesis of all four 1-amino-2-hydroxycyclohexanecarboxylic acids

Article abstract of DOI:10.1016/S0040-4020(01)00129-6

This report describes a new synthesis of the four stereoisomers of 1-amino-2-hydroxycyclohexanecarboxylic acids [(1S,2S)-, (1R,2R)-, (1S,2R)- and (1R,2S)-c₆Ser], four conformationally constrained serine (Ser) analogues, possessing a six-membere

Full text of DOI:10.1016/S0040-4020(01)00129-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2745±2755
New synthesis of all four
1-amino-2-hydroxycyclohexanecarboxylic acids
a,p
Alberto Avenoza, Jose I. Barriobero, Carlos Cativiela, Miguel A. Fernandez-Recio,
a
b,p
a
Â
Jesus M. Peregrina and Fernando Rodrõguez
Â
a
a
Â
Â
a
  Â
Departamento de Quõmica, Universidad de La Rioja, Grupo de Sõntesis Quõmica de La Rioja, U.A.ÐC.S.I.C., 26006 LogronÄo, Spain
b
  Â
Departamento de Quõmica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de ZaragozaÐC.S.I.C.,
50009 Zaragoza, Spain
Received 24 November 2000; revised 19 January 2001; accepted 31 January 2001
AbstractÐThis report describes a new synthesis of the four stereoisomers of 1-amino-2-hydroxycyclohexanecarboxylic acids [(1S,2S)-,
(1R,2R)-, (1S,2R)- and (1R,2S)-c6Ser], four conformationally constrained serine (Ser) analogues, possessing a six-membered carbocyclic
ring. Initially, we synthesised cis-c6Ser and trans-c6Ser in their racemic forms, using as key steps the Diels±Alder reactions of methyl
2-benzamidoacrylate with Danishefsky's diene and 1-methoxy-1,3-butadiene, respectively. The optically active forms were achieved by
resolution methods. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
from 2-hydroxycyclohexanone. These amino acids were
used to study the cellular entry of a-amino acids through
the plasma membrane of the Ehrlich cell.6
Due to the important role that l-serine (l-Ser) plays in
peptides,1±5 not only as an hydrophilic residue but also as
either an active site or a catalytic site of a variety of enzy-
matic transformations, in recent years there has been an
increasing interest in the synthesis of conformational
variants of l-Ser, with the aim of incorporating them into
peptides instead of l-Ser.
Later, Ohfune and co-workers,7,8 using an intramolecular
version of the asymmetric Strecker reaction, achieved the
synthesis of (1R,2S)- and (1R,2R)-c6Ser and these amino
acids were further incorporated into peptides9 (Fig. 1).
Particularly, (1R,2S)-c6Ser was used to synthesise a Leu-
enkephalin analogue that behaves as a potent agonist of
d-opioid receptors (10 times more potent than the native
Leu-enkephalin).10
In this context, 1-amino-2-hydroxycyclohexanecarboxylic
acid (c6Ser) has received considerable attention since high
rigidity is achieved in this molecule by having the a-carbon
of the amino acid incorporated into a six-membered ring.
The ®rst approach to this target molecule was carried out by
Christensen and co-workers,6 obtaining the serine analogues
cis- and trans-c6Ser as a mixture of stereoisomers and in a
racemic form via the Bucherer±Libe and Strecker reactions
More recently, Frahm and co-workers reported a new syn-
thesis of the four stereoisomers of c6Ser starting from
2-methoxycyclohexanone and (S)- or (R)-1-phenylethyl-
amine via an asymmetric Strecker synthesis.11
Figure 1. Structures of the four stereoisomers of 1-amino-2-hydroxycyclohexanecarboxylic acid (c6Ser).
Keywords: Diels±Alder reactions; cyclohexanes; amino acids and derivatives; resolution.
Corresponding authors. Tel.: 134-941-299655; fax: 1941-299621; e-mail: alberto.avenoza@dq.unirioja.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00129-6

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A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
Scheme 1. Reagents and conditions: (a) TsCl, DMSO±DMF (1:1), TEA, 25 to 258C, 1 h, 56%; (b) 1,3-butadiene, TiCl4, CH2Cl2, 5±258C, 48 h, 62%.
Scheme 2. Reagents and conditions: (a) (i) Danishefsky's diene, dioxane, re¯ux, 6 d; (ii) NaF, THF±H2O (4:1), room temperature, 15 h; (iii) column
chromatography, 48%; (b) 1,3-propanedithiol, BF3´Et2O, CH2Cl2, room temperature, 36 h, 77%; (c) Ni-Raney, H2, EtOH, room temperature, 1.5 h, 62%;
(d) 12N HCl, 1008C, 7 d, 84%; (e) 1-methoxy-1,3-butadiene, toluene, 858C, 6 d, 72%; (f) H2/Pd±C, MeOH, room temperature, 6 h, 99%.
As part of our research work towards the synthesis of
conformationally constrained a-amino acids with a cyclo-
hexane skeleton, in particular analogues of phenylalanine
(Phe), we have previously reported the synthesis12±14 of
the four stereoisomers of 1-amino-2-phenylcyclohexane-
carboxylic acid (c6Phe) and their use as conformational
probes.15,16 Moreover, we have recently obtained 3- and
4-hydroxycyclohexane-a-amino acids as a new family of
constrained hydroxy-a-amino acids, using a methodology
that involves the Diels±Alder reaction as a key step.17±19
We herein report the extension of this methodology to the
synthesis of all stereoisomers of c6Ser, with the aim of
contributing to the development of hydroxylated cyclo-
hexane-a-amino acids, analogues of naturally occurring
a-amino acids.
2.1. Synthesis of racemic trans-c6Ser
Initially, in order to obtain the racemic trans-c6Ser 1 and
with the similar idea previously described for the synthesis
of c6Phe,12±14 we assayed the Diels±Alder reaction of 1,3-
butadiene with the dienophile 3, which is easily available
from racemic methyl N-benzoylserinate 2 using a modi®ed
procedure described in the literature.20 After testing several
conditions, reaction was only observed when TiCl4 was used
as a catalyst, obtaining the product 4 (Scheme 1).
We decided to change the strategy, introducing the hydroxyl
group in the cyclohexane ring from the diene instead of
using oxygenated dienophiles. In the course of our research
on hydroxy-a,a-disubstituted-a-amino acids, we had
demonstrated that methyl 2-benzamidoacrylate 5 behaves
as an excellent dienophile with Danishefsky's diene in the
Diels±Alder cycloaddition.21 We are now interested in the
synthesis of the trans-methoxycyclohexanone 6a, a pivotal
product in the synthesis of racemic trans-c6Ser 1. As a result
of the Diels±Alder reaction, a mixture of two cycloadducts
was obtained: methyl 1-benzamido-c-2-methoxy-4-tri-
methylsilyloxy-3-cyclohexene-r-1-carboxylate and methyl
1-benzamido-t-2-methoxy-4-trimethylsilyloxy-3-cyclohexene-
r-1-carboxylate, corresponding to endo and exo attack
respectively. This mixture of products was treated with
NaF in the presence of THF/H2O to give a mixture of the
corresponding trans- and cis-methoxycyclohexanones 6a/
6b in a ratio 90:10 (Scheme 2).
2. Results and discussion
In this paper we present a very ef®cient strategy for the
synthesis and resolution of racemic trans- and cis-c6Ser.
The resolution method is based on the formation of the
corresponding diastereoisomers, which are easily separated
by column chromatography. Once separated, these dia-
stereoisomers are selectively cleaved to give, in high
yield, the four enantiomerically pure c6Ser isomers.
Ketone 6a was treated with 1,3-propanedithiol in the
presence of BF3´OEt2 as a catalyst to give the corresponding
spirothioacetal 7. Desulphurisation of 7 by hydrogenolysis
with Raney nickel gave the 2-methoxycyclohexane deriva-
tive 8, the direct precursor of the amino acid required. The
hydrolysis of derivative 8 was carried out in an acid
Scheme 3. Reagents and conditions: (a) 1,3-butadiene, AlClEt2, CH2Cl2,
room temperature, 4 d, 15%.

A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
2747
Scheme 4. Reagents and conditions: (a) (i) Danishefsky's diene, toluene, re¯ux, 72 h; (ii) 0.005N HCl±THF (1:4), room temperature, 15 h; (iii) DBU, CH2Cl2,
28C, 24 h, 55% (b) DBU, CH2Cl2, 58C, 24 h, 96%; (c) TMSTfO, CH2Cl2, room temperature, 1 h, 100%; (d) NaBH4, CeCl3´7H2O, MeOH, room temperature,
10 min, 83%; (e) NaBH4, THF, 2108C, 30 min, 62%; (f) MsCl, TEA, CH2Cl2, room temperature, 14 h, 95%.
medium, at re¯ux, and the cyclic a-hydroxy-a-amino acid
rac-trans-1 was obtained as a hydrochloride derivative in a
22% overall yield using four steps (Scheme 2). In order to
improve this yield, alternatively, compound 8 was obtained
in two steps from the same dienophile 5 by the Diels±Alder
reaction with 1-methoxy-1,3-butadiene and further hydro-
genation of 9a. The Diels±Alder reaction produced two
stereoisomers, corresponding to endo-selectivity: the 1,2-
adduct 9a and the 1,3-adduct 9b in a ratio 90:10 in favour
of 9a. The exo-adducts were not observed by NMR tech-
niques. This second path was optimised on a multigram
scale (4 g of starting material 5) and now, the overall
yield of rac-trans-c6Ser HCl was 59% in three steps
(Scheme 2).
cycloadducts 6a and 6b and carrying out the transformation
of the corresponding silyl enol ethers into ketones by treat-
ment with an aqueous solution of HCl (Scheme 4).
The hydroxy-functionalisation on this enone 13 took place
with a very good yield when trimethylsilyl tri¯ate
(TMSTfO) were used as a Lewis acid, allowing the direct
hydroxylation in a syn relationship to the amide group
through the oxazoline intermediate 14. All typical attempts
to transform the carbonyl group into methylene failed,
obtaining the starting material. Because of this, we assayed
the reduction of carbonyl group of oxazoline 14 with the
aim to carry out a dehydroxylation. Nevertheless, the reduc-
tion of the carbonyl group of oxazoline 14 with NaBH4
produced a mixture of allylic alcohols 15a/15b instead of
the oxazoline alcohols. Better yield of this mixture of
alcohols was obtained by reduction of enone 13 with
NaBH4 in the presence of CeCl3´7H2O. Treatment of this
mixture of alcohols 15a/15b with methanesulfonyl chloride
(MsCl) in triethylamine (TEA) and further puri®cation by
silica gel column chromatography allowed us to obtain the
unsaturated oxazoline 16, instead of the corresponding
methanesulphonate derivatives. Compound 16 comes from
allylic nucleophilic substitution of benzamide group on the
methanesulphonate intermediates formed in situ (Scheme
4).
2.2. Synthesis of racemic cis-c6Ser
To obtain rac-cis-c6Ser and taking into account the
excellent behaviour of 4-aryliden-2-phenyl-5(4H)-oxazo-
lones as dienophiles in the Diels±Alder reactions with
several dienes,22,23 we ®rstly assayed the cycloaddition of (Z)-
4-methoxymethylene-2-phenyl-5(4H)-oxazolone 10 with 1,3-
butadiene. After testing several conditions, reaction was
only observed when AlClEt2 was used as a catalyst, obtain-
ing the cycloaddition product 12 in a low yield (Scheme 3).
In this case, in order to obtain the corresponding cis-b-
hydroxycyclohexane-a-amino acid, we introduced the
hydroxyl group into the cyclohexane ring using an ef®cient
and easily applicable method,24 which involves the stereo-
selective intramolecular conjugate addition of the benza-
mide group to cyclohexenone 13. This enone was easily
available from the mixture of the Diels±Alder cycloadducts
6a and 6b, by elimination of both methoxy groups using
DBU in MeOH at 58C. Alternatively, enone 13 was directly
obtained from dienophile 5, without puri®cation of methoxy
Oxazoline 16 was used as precursor of rac-cis-c6Ser, so we
initially tried its hydrogenation and both with palladium and
with platinum we obtained a mixture of products (17 and
18), derived from hydrogenolysis reaction 17 and a further
isomerisation 18, instead of hydrogenation products25,26
(Scheme 5). Because of this, we carried out ®rst the
hydrolysis of oxazoline ring with tri¯uoroacetic acid
(TFA), to obtain compound 19, which could be acetylated
to afford compound 20. The hydrogenation of 20 in the
Scheme 5. Reagents and conditions: (a) H2/Pd±C (or Pt±C), CH2Cl2, 308C, 4 h, 92%; (b) TFA, THF±H2O (4:1), 508C, 14 h, 95%; (c) AcCl, TEA, CH2Cl2,
room temperature, 14 h, 80%; (d) H2/Pd±C, CH2Cl2, 358C, 14 h, 78%; (e) 6N HCl, 1008C, 24 h, 76%.

2748
A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
Scheme 6. Reagents and conditions: (a) (i) LiOH´H2O, MeOH±H2O (3:2), re¯ux, 7 h, 93%; (ii) DCC, DMAP, CH2Cl2, room temperature, 3 h, 91%;
(b) l-phenylalanine cyclohexylamide, NMP, 908C, 48 h, column chromatography: 36% of 23, 35% of 24; (c) TfOH, MeOH, 808C, 48 h, 91%; (d) (i) 12N
HCl, 1008C, 7 d, 90%; (ii) propylene oxide, EtOH, re¯ux, 2 h, 83%.
presence of platinum±carbon as a catalyst worked without
problems to give compound 21, which is the direct precursor
of rac-cis-c6Ser, so its hydrolysis gave with an excellent
yield the required rac-cis-1 as a hydrochloride derivative.
In this way, rac-cis-c6Ser´HCl was obtained from 5 on a
multigram scale with a 16% yield, in seven steps (Scheme
5).
rac-22. This compound was smoothly reacted with
l-phenylalanine cyclohexylamide in N-methylpyrrolidin-
2-one (NMP) as a solvent, at 908C. The corresponding
diastereoisomeric peptides (1S,2S,S)-23 and (1R,2R,S)-24
were obtained in good yields after column chromatography
using toluene±ethyl acetate (1:1) as an eluent. Each dia-
stereoisomeric peptide 23 and 24 was separately treated
with tri¯uoromethanesulphonic acid (TfOH) in MeOH at
808C to give the optically pure methyl esters (1S,2S)-8
and (1R,2R)-8. Finally, the concomitant hydrolysis of
the benzamide, methyl ester and methyl ether groups, in
the same conditions as described above for rac-8, gave the
optically pure (1S,2S)- and (1R,2R)-c6Ser as hydrochloride
derivatives. In order to assess the enantiomeric purity and to
determine the absolute con®guration of each amino acid,
each hydrochloride derivative was dissolved in EtOH and
propylene oxide was then added. After 2 h at re¯ux, the free
amino acids (1S,2S)-1 and (1R,2R)-1 were obtained and the
observed optical rotations were in agreement with those
described in the literature11 (Scheme 6).
2.3. Synthesis of (1S,2S)- and (1R,2R)-c6Ser
The strategy used to resolve the racemic trans-c6Ser 1 was
previously developed and reported by Obrecht to prepare
and resolve both cyclic and acyclic N-acylated a,a-disubsti-
tuted amino acids.27±29 In our case, the synthesis of the two
enantiomerically pure amino acids (1S,2S)-1 and (1R,2R)-1
started from rac-8 (Scheme 6). The methyl ester group of
rac-8 was hydrolysed by the action of LiOH and further
treatment of the corresponding carboxylic acid with N,N-
dicyclohexylcarbodiimide (DCC) in the presence of 4-
dimethylaminopyridine (DMAP) gave the spirooxazolone
Scheme 7. Reagents and conditions: (a) (S)-2-acetoxypropionyl chloride, TEA, CH2Cl2, room temperature, 2 h, column chromatography: 40% of 25, 50% of
26; (b) H2/Pt±C, ethyl acetate, room temperature, 3 h, 99%; (c) (i) 9N HCl, 858C, 4 d, 93%; (ii) propylene oxide, EtOH, re¯ux, 2 h, 85%.

A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
2749
2.4. Synthesis of (1S,2R)- and (1R,2S)-c6Ser
was added and the mixture was allowed to warm up to 258C.
After stirring for 1 h, the reaction was quenched by the
addition of water (25 mL). The aqueous solution was
extracted with CH2Cl2 (3£20 mL) and the combined
organic phases were dried over anhydrous Na2SO4, ®ltered
and evaporated. The residue was chromatographed on silica
gel, eluting with hexane±ethyl acetate (6:4), to yield 263 mg
of compound 3 as a white solid (56%). Mp: 129±1308C;
Anal. calcd for C18H17NO6S: C, 57.59; H, 4.56; N, 3.73;
S, 8.54; found: C, 57.30; H, 4.55; N, 3.64; S, 8.68; IR
(CH2Cl2, cm21): 3418 (NH), 1728 (COO), 1686 (CON);
1H NMR (CDCl3): d 2.44 (s, 3H, CH3Ph); 3.78 (s, 3H,
CH3O); 7.36±7.46 (m, 4H, Arom.); 7.47±7.53 (m, 2H,
Arom.1NH); 7.54 (s, 1H, H3); 7.76±7.81 (m, 2H, Arom.);
7.85 (d, 2H, Jˆ8.4 Hz, Arom.); 13C NMR (CDCl3): d 21.7
(CH3Ph); 52.6 (CH3O); 116.0 (C2); 127.5, 128.2, 128.6,
130.2, 131.8, 132.2, 133.0, 138.4 (Arom.); 146.3 (C3);
163.7, 165.0 (COO, CON).
On the other hand, the strategy used to resolve the racemic
cis-c6Ser 1 involves the reaction of rac-19 with (S)-2-acet-
oxypropanoyl chloride in the presence of TEA to give with
90% yield a diastereomeric mixture of (1S,2R,S)-25 and
(1R,2S,S)-26. These diastereoisomers were separated by
column chromatography using ethyl ether±hexane (7:3) as
an eluent. Each diastereoisomer 25 and 26 was separately
hydrogenated in the presence of platinum±carbon as a cata-
lyst and ethyl acetate as a solvent to give, respectively, the
compounds (1S,2R,S)-27 and (1R,2S,S)-28, which were
subjected to hydrolysis using 6N HCl at re¯ux to obtain
(1S,2R)- and (1R,2S)-c6Ser as hydrochloride derivatives.
In the same way described for optically active trans-c6Ser,
we obtained the free amino acids (1S,2R)-1 and (1R,2S)-1 in
order to assess their enantiomeric purity and to determine
their absolute con®guration (Scheme 7).
4.1.2. Methyl (E)-2-benzamido-3-hydroxy-2-propenoate
(4). A 1 M solution of TiCl4 in CH2Cl2 (0.53 mL,
0.53 mmol) was added to a solution of dienophile 3
(200 mg, 0.53 mmol) in dry CH2Cl2 (10 mL) at 58C, under
an inert atmosphere. After stirring at the same temperature
for 1 h, a solution of 1,3-butadiene (286 mg, 5.3 mmol) in
dry CH2Cl2 (2 mL) was added and the mixture was allowed
to warm up to 258C. After stirring for 48 h, the reaction was
quenched by the addition of solid Na2CO3´10H2O, ®ltered
and evaporated. The residue was chromatographed on silica
gel, eluting with hexane±ethyl acetate (1:1), to yield 75 mg
of compound 4 as an oil (62%). Anal. calcd for C11H11NO4:
C, 59.73; H, 5.01; N, 6.33; found: C, 60.03; H, 5.11; N, 6.21;
IR (CH21Cl2, cm21): 3418 (NH1OH), 1737 (COO), 1686
(CON); H NMR (CDCl3): d 3.83 (s, 3H, CH3); 7.05 (s,
1H, H3); 7.44±7.51 (m, 3H, Arom.1OH); 7.53±7.62 (m,
2H, Arom.1NH); 7.86±7.91 (m, 2H, Arom.); 13C NMR
(CDCl3): d 52.9 (CH3); 123.2 (C2); 127.6 (Arom.); 128.8
(Arom.1C3); 132.6 (Arom.); 162.9, 165.1 (COO, CON).
3. Conclusions
In summary, we have developed a new methodology for the
synthesis, on a multigram scale, of two types of racemic
constrained serines (trans- and cis-c6Ser) from methyl
2-benzamidoacrylate, using as a key step the Diels±Alder
reaction with oxygenated dienes. Moreover, we have
prepared, in a good yield, all four enantiomerically pure
amino acids (1S,2S)-, (1R,2R)-, (1S,2R)- and (1R,2S)-c6Ser
by resolution of the corresponding diastereoisomers. In a
future work, we will introduce these amino acids in small
peptides as restricted serine analogues and we will make
several structural studies.
4. Experimental
4.1. General procedure
4.1.3. Methyl 1-benzamido-c-2-methoxy-4-oxocyclo-
hexane-r-1-carboxylate (6a) and methyl 1-benzamido-t-
Solvents were puri®ed according to standard procedures.
Analytical TLC was performed using Polychrom SI F254
plates. Column chromatography was performed using silica
2-methoxy-4-oxocyclohexane-r-1-carboxylate
(6b).
1
gel 60 (230±400 mesh). H and 13C NMR spectra were
Danishefsky's diene (1 g, 6.0 mmol) was added to a solution
of methyl 2-benzamidoacrylate 5 (615 mg, 3.0 mmol) in dry
dioxane (25 mL) under an inert atmosphere. After stirring at
re¯ux for 24 h, another 3.0 mmol of 5 were added. The
reaction was stirred for another 24 h and then another
6.0 mmol of Danishefsky's diene were added. After stirring
at re¯ux for 6 d overall, the solvent was evaporated to give a
residue corresponding to a mixture of silyl enol ethers. This
mixture (2.1 g, 5.6 mmol) was dissolved in a mixture of
THF±H2O (4:1) (50 mL) and NaF (517 mg, 12 mmol) was
added. After stirring at 258C for 15 h, the reaction was
extracted with CH2Cl2 (3£50 mL) and the combined
organic phases were washed with brine (50 mL), dried
over anhydrous MgSO4, ®ltered and evaporated. The
residue was chromatographed on silica gel, eluting with
hexane±ethyl acetate (4:6), to yield 875 mg of ketone 6a
(48%) and 73 mg of ketone 6b (4%) as white solids.
recorded on a Bruker ARX-300 spectrometer at 300 MHz
(1H) and at 75 MHz (13C) in CDCl3 and CD3OD with TMS
as the internal standard and in D2O with TMS as the external
standard using a coaxial microtube (chemical shifts are
reported in ppm on the d scale, coupling constants in Hz).
Melting points were determined on a BuÈchi SMP-20 melting
point apparatus and are uncorrected. Optical rotations were
measured on a Perkin±Elmer 341 polarimeter in a 1 dm cell
of 1 mL capacity. Microanalyses were carried out on a CE
Instruments EA-1110 analyser and were in good agreement
with the calculated values. IR spectra were recorded on a
Perkin Elmer FT-IR Spectrum 1000 spectrometer.
4.1.1. Methyl (E)-2-benzamido-3-(p-toluenesulphonyloxy)-
2-propenoate (3). p-Toluenesulphonyl chloride (718 mg,
3.7 mmol) was dissolved in a mixture of DMSO±DMF
1:1 (15 mL) at 258C and a solution of methyl N-benzoyl-
serinate (280 mg, 1.2 mmol) in dry DMF (10 mL) was
added dropwise, under an inert atmosphere. After stirring
for 5 min at the same temperature, Et3N (1.26 g, 12.5 mmol)
6a. Mp: 128±1298C; Anal. calcd for C16H19NO5: C, 62.94; H,
6.27; N, 4.59; found: C, 63.09; H, 6.22; N, 4.53; IR (CH2Cl2,
cm21): 3414 (NH), 1720 (CO, COO), 1673 (CON); 1H NMR

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A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
(CDCl3): d 2.41±2.82 (m, 6H, 2H312H512H6); 3.30 (s, 3H,
1H NMR (CDCl3): d 1.87±2.21 (m, 3H); 2.48±2.57 (m,
1H); 3.32 (s, 3H, CH3O); 3.73 (s, 4H, CH3O2C1H2);
5.85±5.93 (m, 1H, H3); 6.02±6.13 (m, 2H, H41NH);
7.30±7.46 (m, 3H, Arom.); 7.60±7.67 (m, 2H, Arom.);
CH3O); 3.79 (s, 3H, CH3O2C); 3.98 (t, 1H, J2e±3aˆJ2e±3e
ˆ
5.2 Hz, H2e); 7.02 (br s, 1H, NH); 7.37±7.53 (m, 3H,
Arom.); 7.73±7.81 (m, 2H, Arom.); 13C NMR (CDCl3): d
26.3, 36.9, 41.2 (C3, C5, C6); 52.9 (CH3O2C); 57.7 (CH3O);
62.0 (C1); 80.1 (C2); 127.1, 128.6, 132.1, 133.9 (Arom.);
167.7, 172.0 (COO, CON); 208.1 (CO).
13C NMR (CDCl3):
d 21.5 (C6); 22.6 (C5); 52.3
(CH3O2C); 57.4 (CH3O); 60.7 (C1); 76.5 (C2); 121.9 (C3);
126.9, 128.5, 131.8, 133.6 (Arom.); 134.7 (C4); 166.5
(CON); 172.2 (COO).
6b. Mp: 134±1368C; Anal. calcd for C16H19NO5: C, 62.94;
H, 6.27; N, 4.59; found: C, 63.12; H, 6.24; N, 4.64; IR
(CH2Cl2, cm21): 3426 (NH), 1744, 1720 (CO, COO),
1677 (CON); 1H NMR (CDCl3): d2.35±2.94 (m, 6H,
2H312H512H6); 3.41 (s, 3H, CH3O); 3.82 (s, 3H,
CH3O2C); 4.05 (dd, 1H, J2a±3aˆ7.5 Hz; J2a±3eˆ4.2 Hz,
H2a); 6.80 (br s, 1H, NH); 7.39±7.59 (m, 3H, Arom.);
7.74±7.84 (m, 2H, Arom.); 13C NMR (CDCl3): d 27.5,
36.6, 41.8 (C3, C5, C6); 53.0 (CH3O2C); 57.3 (CH3O); 62.1
(C1); 80.8 (C2); 126.9, 128.6, 131.9, 133.9 (Arom.); 168.0,
171.8 (COO, CON); 206.9 (CO).
9b. Anal. calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84;
found: C, 66.73; H, 6.78; N, 4.99; IR (CH2Cl2, cm21): 3425
(NH), 1731 (COO), 1669 (CON); H NMR (CDCl3): d
1
1.98±2.17 (m, 3H); 2.89±2.97 (m, 1H); 3.39 (s, 3H,
CH3O); 3.75 (s, 3H, CH3O2C); 4.17±4.24 (m, 1H, H3);
5.64 (dd, 1H, J4±5ˆ10.2 Hz, J4±3ˆ1.5 Hz, H4); 5.93±5.99
(m, 1H, H5); 6.73 (br s, 1H, NH); 7.29±7.53 (m, 3H,
Arom.); 7.71±7.80 (m, 2H, Arom.); 13C NMR (CDCl3): d
22.1 (C6); 26.5 (C2); 52.6 (CH3O2C); 57.7 (CH3O);
60.9 (C1); 78.8 (C3); 123.5 (C4); 126.9, 128.3 (Arom.);
130.9 (C5); 131.4, 134.4 (Arom.); 167.7 (CON); 173.0
(COO).
4.1.4. Methyl 1-benzamido-c-2-methoxy-4-spiro-[20 (10,30-
dithiocyclohexane)]cyclohexane-r-1-carboxylate (7). 1,3-
Propanedithiol (89 mg, 0.82 mmol) was added to a solution
of ketone 6a (200 mg, 0.65 mmol) in dry CH2Cl2 (20 mL) at
258C, under an inert atmosphere. After stirring for 30 min,
BF3´OEt2 (13 mg, 0.09 mmol) was added and the mixture
was stirred for another 36 h at the same temperature. The
reaction was quenched by the addition of solid
Na2CO3´10H2O, ®ltered and evaporated. The residue was
chromatographed on silica gel eluting with hexane±ethyl
acetate (1:1), to yield 200 mg of compound 7 as a white
solid (77%). Mp: 136±1388C; Anal. calcd for
C19H25NO4S2: C, 57.69; H, 6.37; N, 3.54; S, 16.21; found:
C, 57.81; H, 6.32; N, 3.62; S, 16.07; IR (CH2Cl2, cm21):
4.1.6. Methyl 1-benzamido-c-2-methoxycyclohexane-r-1-
carboxylate (rac-8). Method A: A suspension of Raney Ni
catalyst in water (5 mL) was added to a solution of
compound 7 (220 mg, 0.56 mmol) in EtOH (30 mL). The
mixture was hydrogenated at atmospheric pressure, vigor-
ously stirring at 258C for 90 min. The catalyst was ®ltered
off through Celite, washed with EtOH (3£10 mL) and the
®ltrate evaporated. The residue was chromatographed on
silica gel eluting with hexane±ethyl acetate (6:4), to yield
101 mg of compound 8 as a white solid (62%). Method B: A
solution of compound 9a (1.0 g, 3.46 mmol) in MeOH
(30 mL) was hydrogenated at atmospheric pressure, using
palladium±carbon (10%) as a catalyst (100 mg), vigorously
stirring at 258C for 6 h. The catalyst was ®ltered off through
Celite and the solvent evaporated to yield 1 g of compound
8 as a white solid (99%). Mp: 132±1338C; Anal. calcd for
C16H21NO4: C, 65.96; H, 7.27; N, 4.81; found: C, 65.84; H,
7.32; N, 4.75; IR (CHCl3, cm21): 3411 (NH), 1729 (COO),
1
3410 (NH), 1731 (COO), 1670 (CON); H NMR (CDCl3):
d1.93±2.08 (m, 2H); 2.17±2.39 (m, 3H); 2.40±2.64 (m,
2H); 2.75±3.02 (m, 5H); 3.39 (s, 3H, CH3O); 3.82 (s, 3H,
CH3O2C); 4.41 (dd, 1H, J2a±3aˆ10.2 Hz, J2a±3eˆ4.5 Hz,
H2a); 7.20 (br s, 1H, NH); 7.38±7.56 (m, 3H, Arom.);
7.76±7.85 (m, 2H, Arom.); 13C NMR (CDCl3): d 25.5,
1
0
0
0
26.1, 26.4, 27.1, 33.5, 37.4 (C3, C5, C6, C4 , C5 , C6 ); 48.4
(C4); 52.7 (CH3O2C); 58.0 (CH3O); 63.9 (C1); 76.9 (C2);
126.8, 128.4, 131.5, 134.5 (Arom.); 166.7, 171.9 (COO,
CON).
1664 (CON); H NMR (CDCl3): d 1.38±1.51 (m, 2H);
1.55±1.78 (m, 3H); 1.84±1.99 (m, 1H); 2.04±2.18 (m,
1H); 2.39±2.51 (m, 1H); 3.31 (s, 3H, CH3O); 3.78 (s, 3H,
CH3O2C); 3.76±3.91 (m, 1H, H2); 6.68 (br s, 1H, NH);
7.37±7.56 (m, 3H, Arom.); 7.71±7.82 (m, 2H, Arom.);
13C NMR (CDCl3): d 20.7, 21.3, 25.3, 27.8 (C3, C4, C5,
C6); 52.5 (CH3O2C); 57.5 (CH3O); 62.9 (C1); 79.5 (C2);
126.9, 128.6, 131.6, 134.5 (Arom.); 166.6, 173.1 (COO,
CON).
4.1.5. Methyl 1-benzamido-c-2-methoxy-3-cyclohexene-
r-1-carboxylate (9a) and methyl 1-benzamido-c-3-meth-
oxy-4-cyclohexene-r-1-carboxylate (9b). 1-Methoxy-1,3-
butadiene (4 g, 19.52 mmol) and hydroquinone (10 mg)
were added to a solution of methyl 2-benzamidoacrylate 5
(4 g, 47.62 mmol) in toluene (40 mL) at 858C. After stirring
for 6 d, the reaction was allowed to cool down to 258C. The
formed precipitate was ®ltered and washed with cold diethyl
ether (2£30 mL), to yield 3.22 g of compound 9a as a white
solid (57%). The ®ltrate was evaporated and the residue was
chromatographed on silica gel eluting with hexane±ethyl
acetate (6:4), to yield a further 870 mg of compound 9a
(15, 72% overall) and 524 mg of compound 9b as an oil
(9%).
4.1.7. 1-Amino-c-2-hydroxycyclohexane-r-1-carboxylic
acid (rac-trans-1). Compound rac-8 (2 g, 6.87 mmol) was
suspended in a 12N HCl solution (25 mL). After stirring
under re¯ux for 7 d, the solvent was evaporated, the excess
of HCl removed in vacuo and the residue was dissolved in
distilled water (20 mL). The aqueous mixture was washed
with diethyl ether (4£20 mL) and evaporated to yield 1.2 g
of rac-trans-1´HCl as a white solid (91%). The hydro-
chloride was dissolved in ethanol (30 mL) and propylene
oxide (10 mL) was added. After stirring under re¯ux for
2 h, the precipitate was ®ltered off and washed with cold
EtOH to yield 819 mg of rac-trans-1 as a white solid
(75%). The ®ltrate was evaporated and the residue was
9a. Mp: 148±1508C; Anal. calcd for C16H19NO4: C, 66.42;
H, 6.62; N, 4.84; found: C, 66.65; H, 6.68; N, 4.99; IR
(CH2Cl2, cm21): 3433 (NH), 1752 (COO), 1670 (CON);

A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
2751
dissolved in distilled water (5 mL) and eluted through a C18
reverse-phase Sep-pak cartridge which, after removal of
water, gave another 105 mg (9%, 84% overall) of the
was washed with a saturated NaHCO3 solution (3£20 mL).
The aqueous phase was extracted with CH2Cl2 (20 mL) and
the combined organic phases were dried over anhydrous
Na2SO4, ®ltered and evaporated. The residue was chro-
matographed on silica gel eluting with hexane±ethyl acetate
(1:1), to yield 429 mg of enone 13 as a white solid (96%).
Mp: 126±1278C; Anal. calcd for C15H15NO4: C, 65.92; H,
5.53; N, 5.13; found: C, 65.84; H, 5.59; N, 5.05; IR (CH2Cl2,
1
amino acid. rac-trans-1´HCl: H NMR (CD3OD):d 1.41±
1.49 (m, 1H); 1.58±1.71 (m, 2H); 1.75±1.92 (m, 3H); 1.99±
2.18 (m, 2H); 3.72 (dd, 1H, J2a±3aˆ11.1 Hz, J2a±3eˆ4.8 Hz,
H2a); 13C NMR (CD3OD): d 22.1, 24.4, 31.3, 32.9 (C3, C4,
C5, C6); 65.1 (C1); 73.8 (C2); 171.6 (COO). rac-trans-1:
Anal. calcd for C7H13NO3: C, 52.82; H, 8.23; N, 8.80;
1
cm21): 3433 (NH), 1744 (CO), 1673 (CON); H NMR
1
found: C, 52.65; H, 8.36; N, 8.67; H NMR (D2O): d
(CDCl3): d 2.50±2.65 (m, 4H, 2H512H6); 3.82 (s, 3H,
CH3); 6.14 (d, 1H, J3±2ˆ10.0 Hz, H3); 6.98 (br s, 1H,
NH); 7.14 (d, 1H, J2±3ˆ10.0 Hz, H2); 7.41±7.48 (m, 2H,
Arom.); 7.50±7.58 (m, 1H, Arom.); 7.76±7.82 (m, 2H,
Arom.); 13C NMR (CDCl3): d 31.6, 33.7 (C5, C6); 53.4
(CH3); 58.5 (C1); 127.1, 128.6, 130.5, 132.2 (C3, Arom.);
133.0 (Arom.); 146.9 (C2); 167.0, 171.2 (COO, CON);
197.2 (CO).
1.22±1.39 (m, 1H); 1.42±1.99 (m, 6H); 2.04±2.18 (m,
1H); 3.63 (dd, 1H, J2a±3aˆ10.5 Hz, J2a±3eˆ4.8 Hz, H2a);
13C NMR (D2O): d 21.0, 22.7, 29.8, 31.5 (C3, C4, C5, C6);
64.1 (C1); 72.5 (C2); 174.0 (COO).
4.1.8. (cis and trans)-6-Ethyl-3-cyclohexene-1-spiro-{40-
[20-phenyl-50(40H)-oxazolone]} (12). A 1 M solution of
AlClEt2 in hexane (4.20 mL, 4.20 mmol) was added to a
solution of oxazolone 10 (850 mg, 4.20 mmol) in dry
CH2Cl2 (25 mL) at 258C, under an inert atmosphere. After
stirring for 1 h, a solution of 1,3-butadiene (2 g, 37.0 mmol)
in dry CH2Cl2 (2 ml) was added to the mixture. After stirring
for 48 h, another 37.0 mmol of 1,3-butadiene were added.
After stirring for another 48 h at the same temperature, the
reaction was quenched by the addition of solid
Na2CO3´10H2O, ®ltered and evaporated. The residue was
chromatographed on silica gel eluting with hexane±ethyl
acetate (8:2), to yield 166 mg of the mixture of oxazolones
4.1.10. Methyl cis-8-oxo-3-phenyl-2-oxa-4-azabicyclo-
[4.3.0]non-3-ene-5-carboxylate (14). TMSTfO (732 mg,
3.30 mmol) was added dropwise to a solution of enone 13
(300 mg, 1.10 mmol) in dry CH2Cl2 (30 mL) at 258C, under
an inert atmosphere. After stirring for 1 h, the reaction was
quenched by the addition of solid Na2CO3´10H2O, dried
over anhydrous Na2SO4, ®ltered and evaporated, to yield
300 mg of compound 14 as an oil (100%). Anal. calcd for
C15H15NO4: C, 65.92; H, 5.53; N, 5.13; found: C, 65.99; H,
1
5.42; N, 5.08; H NMR (CDCl3): d 2.14±2.51 (m, 4H,
1
12 as a yellow oil (15%). H NMR (CDCl3): d 0.78±0.93
2H612H7); 2.79 (dd, 1H, J9x±9nˆ17.4 Hz, J9x±1ˆ3.6 Hz,
H9x); 3.00 (dd, 1H, J9n±9xˆ17.4 Hz, J9n±1ˆ3.0 Hz, H9n);
3.87 (s, 3H, CH3); 5.43 (t, 1H, Jˆ3.3 Hz, H1); 7.38±7.47
(m, 2H, Arom.); 7.48±7.56 (m, 1H, Arom.); 7.92±7.98 (m,
2H, Arom.).
(m, CH2CH3); 0.93±1.10, 1.15±1.34 (m, CH2CH3); 1.97±
2.29, 2.31±2.50, 2.57±2.78 (m, H2, H5, H6); 5.61±5.77;
5.85±5.98 (m, H3, H4); 7.40±7.62 (m, Arom.); 7.95±8.10
(m, Arom.); 13C NMR (CDCl3): d 11.2, 11.4 (CH2CH3);
22.6, 23.5, 26.4, 27.1, 33.6, 35.3, 40.7, 40.8 (C2, C5, C6,
CH2CH3); 70.2, 72.1 (C1); 120.9, 121.9, 125.8, 125.9,
126.9, 127.2, 127.9, 128.0, 128.7, 128.8, 132.5, 132.6 (C3,
C4, Arom.); 160.3 (CON); 181.5 (COO).
4.1.11. Methyl 1-benzamido-t-4-hydroxy-2-cyclohexene-
r-1-carboxylate (15a) and methyl 1-benzamido-c-4-
hydroxy-2-cyclohexene-r-1-carboxylate (15b). Method
A: A 0.4 M solution of CeCl3´7H2O in MeOH (2.56 mL,
1.02 mmol) was added to a solution of enone 13 (280 mg,
1.02 mmol) in MeOH (20 mL) at 258C. NaBH4 (38.7 mg,
1.02 mmol) was then added to the mixture and after stirring
for 10 min at the same temperature, the reaction was
quenched by the dropwise addition of a 2N HCl solution.
The mixture was extracted with CH2Cl2 (3£25 mL) and the
combined organic phases were dried over anhydrous
Na2SO4, ®ltered and evaporated. The residue was chro-
matographed on silica gel, eluting with hexane±ethyl
acetate (3:7), to yield 234 mg of the mixture of alcohols
15a/15b in an approximate ratio of 6:4 as a white solid
(83%). Method B: NaBH4 (111 mg, 2.9 mmol) was added
to a solution of ketone 14 (160 mg, 0.59 mmol) in dry THF
(15 mL) at 2108C. After stirring for 30 min at the same
temperature, the reaction was quenched by the dropwise
addition of water. The mixture was extracted with CH2Cl2
(3£15 mL) and the combined organic phases were dried
over anhydrous Na2SO4, ®ltered and evaporated. The
residue was chromatographed on silica gel, eluting with
hexane±ethyl acetate (3:7), to yield 101 mg of the mixture
of alcohols 15a/15b in an approximate ratio of 7:3, as a
white solid (62%). Anal. calcd for C15H17NO4: C, 65.44;
H, 6.22; N, 5.09; found: C, 65.59; H, 6.13; N, 5.08;
1H NMR (CDCl3): d 1.68±2.51 (m); 3.76 (s, CH3);
4.1.9.
Methyl
1-benzamido-4-oxo-2-cyclohexene-1-
carboxylate (13). Method A: Danishefsky's diene
(6.5 mL, 33.4 mmol) was added to a solution of methyl
2-benzamidoacrylate 5 (1.7 g, 8.3 mmol) in dry toluene
(80 mL) under an inert atmosphere. After stirring at re¯ux
for 24 h, another 8.3 mmol of Danishefsky's diene were
added. After stirring for another 2 d at the same temperature,
the solvent was evaporated in vacuo and a 0.005N HCl±
THF (1:4) solution (40 mL) was added to the residue. The
reaction mixture was stirred for 15 h at 208C, the solvent
was evaporated and the residue was chromatographed on
silica gel, eluting with hexane±ethyl acetate (2:8). The
mixture of compounds 6a, 6b and 13 was dissolved in
CH2Cl2 (75 mL) and DBU (2.7 mL, 18.2 mmol) was
added. The reaction mixture was stirred for 24 h at 28C
and the solution was washed with 0.5N HCl (60 mL). The
aqueous phase was extracted with CH2Cl2 (5£30 mL) and
the combined organic phases were dried over anhydrous
Na2SO4, ®ltered and evaporated. The residue was chro-
matographed on silica gel eluting with hexane±ethyl acetate
(1:1), to yield 2.5 g of enone 13 as a white solid (55%).
Method B: A mixture of ketones 6a and 6b in a 90:10
ratio (500 mg, 1.63 mmol) was dissolved in CH2Cl2
(30 mL) and DBU (0.27 mL, 1.80 mmol) was added. The
reaction mixture was stirred for 24 h at 58C and the solution
0
4.16±4.26 (m, H41H4 ); 5.79 (d, J3±2ˆ9.9 Hz, H3); 5.95

2752
A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
0
0
0
0
0
0
(d, J3 ±2ˆ9.9 Hz, H3 ); 6.06 (dd, J2 ±3 ˆ9.9 Hz, J2 ±4
ˆ
26.8 (C5, C6); 53.9 (CH3); 60.3 (C1); 70.0 (C2); 122.7 (C3);
128.3, 128.4, 130.2, 131.1, 133.7 (Arom, C4); 165.3, 169.7
(COO, PhCOO).
0
3.0 Hz, H2 ); 6.13 (dd, J2±3ˆ9.9 Hz, J2±4ˆ3.7 Hz, H2);
6.68 (br s, NH); 7.08 (br s, NH0); 7.34±7.53 (m, Arom.);
7.71±7.81 (m, Arom.).
4.1.15. Methyl 1-acetamido-t-2-benzoyloxy-3-cyclohex-
ene-r-1-carboxylate (20). Tri¯uoroacetate 19 (550 mg,
1.41 mmol), Et3N (186 mg, 1.84 mmol) and acetyl chloride
(144 mg, 1.84 mmol) were dissolved in dry CH2Cl2 (35 mL)
at 258C, under an inert atmosphere. After stirring for 14 h,
the reaction was washed with a saturated NaHCO3 solution
(2£25 mL) and the organic phase was dried over anhydrous
Na2SO4, ®ltered and evaporated. The residue was chro-
matographed on silica gel eluting with hexane±ethyl acetate
(8:2), to yield 358 mg of compound 20 as a white solid
(80%). Mp: 131±1328C; Anal. calcd for C17H19NO5: C,
64.34; H, 6.03; N, 4.41; found: C, 64.02; H, 6.15; N, 4.22;
IR (CH2Cl2, cm21): 3441 (NH), 1742, 1727 (COO,
4.1.12. Methyl cis-3-phenyl-2-oxa-4-azabicyclo[4.3.0]-
nona-3,8-diene-5-carboxylate (16). Et3N (143 mg,
2.42 mmol) and MsCl (162 mg, 1.42 mmol) were added to
a solution of the mixture of alcohols 15a/15b (300 mg,
1.10 mmol) in dry CH2Cl2 (25 mL) at 258C, under an inert
atmosphere. After stirring for 14 h, the mixture was washed
with a saturated NaHCO3 solution (2£20 mL) and the
organic phase was dried over anhydrous Na2SO4, ®ltered
and evaporated. The residue was chromatographed on silica
gel, eluting with hexane±ethyl acetate (1:1), to yield 270 mg
of compound 16 as an oil (95%). Anal. calcd for C15H15NO3:
C, 70.02; H, 5.88; N, 5.44; found: C, 70.14; H, 5.87; N, 5.35;
1H NMR (CDCl3): d 1.93±2.32 (m, 4H, 2H612H7); 3.80 (s,
3H, CH3); 5.33 (d, 1H, J1±9ˆ3.6 Hz, H1); 5.94±6.00 (m, 1H,
H9); 6.12±6.20 (m, 1H, H8); 7.36±7.42 (m, 2H, Arom.);
7.43±7.51 (m, 1H, Arom.); 7.95±8.01 (m, 2H, Arom.);
13C NMR (CDCl3): d 20.8, 29.1 (C6, C7); 52.5 (CH3); 74.4
(C5); 76.7 (C1); 122.8 (C9); 127.3, 128.0, 128.2, 131.5
(Arom.); 133.5 (C8); 164.9, 173.0 (COO, C3).
1
PhCOO), 1685 (CON); H NMR (CDCl3): d 2.03 (s, 3H,
CH3CO); 2.09±2.20 (m, 3H); 2.76±2.82 (m, 1H); 3.66 (s,
3H, CH3O); 5.59±5.67 (m, 1H, H3); 5.92±5.96 (br s, 1H,
H2); 5.96±6.04 (m, 1H, H4); 6.06 (br s 1H, NH); 7.44±7.51
(m, 2H, Arom.); 7.57±7.63 (m, 1H, Arom.); 8.00±8.06 (m,
2H, Arom.); 13C NMR (CDCl3): d 22.0, 23.2, 26.2 (C5, C6,
CH3CO); 52.6 (CH3O); 60.0 (C1); 70.8 (C2); 123.3 (C3);
128.4, 129.5, 132.2, 133.3 (Arom, C4); 165.2, 170.4, 171.3
(COO, PhCOO, CON).
4.1.13. Methyl 1-benzamido-3-cyclohexene-1-carboxyl-
ate (17) and methyl 1-benzamido-2-cyclohexene-1-
carboxylate (18). A solution of compound 16 (150 mg,
0.58 mmol) in dry CH2Cl2 (15 mL) was hydrogenated at
atmospheric pressure, using palladium±carbon (10%) as a
catalyst (30 mg), vigorously stirring at 308C for 4 h. The
catalyst was ®ltered off through Celite and the solvent
evaporated to yield 139 mg of the mixture of compounds
17/18 in a ratio 4:6 as a white solid (92%). Anal. calcd for
C15H17NO3: C, 69.48; H, 6.61; N, 5.40; found: C, 69.55; H,
4.1.16. Methyl 1-acetamido-t-2-benzoyloxycyclohexane-
r-1-carboxylate (21).
A solution of compound 20
(350 mg, 1.10 mmol) in dry CH2Cl2 (10 mL) was hydro-
genated at atmospheric pressure, using platinum±carbon
(10%) as a catalyst (50 mg), vigorously stirring at 358C
for 14 h. The catalyst was ®ltered off through Celite and
the solvent was evaporated. The residue was chromato-
graphed on silica gel eluting with hexane±ethyl acetate
(4:6), to yield 273 mg of compound 21 as a white solid
(78%). Mp: 44±458C; Anal. calcd for C17H21NO5: C,
63.94; H, 6.63; N, 4.39; found: C, 63.37; H, 6.49; N, 4.31;
1H NMR (CDCl3): d 1.40±1.62 (m, 3H); 1.71±1.85 (m,
2H); 2.05 (s, 3H, CH3CO); 1.92±2.13 (m, 2H); 2.66±2.77
(m, 1H); 3.64 (s, 3H, CH3O); 5.40 (dd, 1H, J2a±3aˆ9.6 Hz,
J2a±3eˆ4.2 Hz, H2a); 5.94 (br s, 1H, NH); 7.42±7.49 (m, 2H,
Arom.); 7.55±7.62 (m, 1H, Arom.); 7.92±8.02 (m, 2H,
Arom.); 13C NMR (CDCl3): d 20.1, 22.3, 23.0, 27.0, 29.7
(C3, C4, C5, C6, CH3CO); 52.2 (CH3O); 62.0 (C1); 73.2 (C2);
128.2, 129.3, 129.5, 132.9 (Arom.); 164.9, 170.3, 171.5
(COO, PhCOO, CON).
1
0
6.64; N, 5.34; H NMR (CDCl3): d 1.57±2.72 (m, H4 1
0
0
H5 1H6 1H21H51H6); 3.76 (s, CH3); 5.61±5.69 (m, H4);
0
0
5.77±5.85 (m, H3); 5.86±5.93 (m, H2 ); 6.03±6.12 (m, H3 );
6.40 (br s, 1H, NH); 6.54 (br s, 1H, NH0); 7.33±7.54 (m,
Arom.); 7.67±7.81 (m, Arom.); 13C0NMR (CDCl3): d 18.5,
0
0
21.8, 24.7, 26.7, 30.3, 34.1 (C4 , C5 , C6 , C2, C5, C6); 52.5,
0
52.8 (CH3); 57.1, 58.1 (C11C1 ); 122.3, 125.7, 126.9, 127.0,
0
0
127.5, 128.5, 131.6, 133.5 (C3, C4, C2 , C3 , Arom.); 166.4,
167.0, 173.3, 174.0 (COO, CON).
4.1.14. Methyl 1-amino-t-2-benzoyloxy-3-cyclohexene-r-
1-carboxylate tri¯uoroacetate (19). Compound 16 (385
mg, 1.50 mmol) was dissolved in THF±H2O (4:1)
(30 mL) and tri¯uoroacetic acid (855 mg, 7.50 mmol) was
then added. After stirring for 14 h at 508C, the water was
removed by the addition of anhydrous Na2SO4. The
remaining ®ltrate was then evaporated without warming.
The oily residue was then dissolved in Et2O and the solvent
and the residual tri¯uoroacetic acid were distilled off in
vacuo. This operation was repeated to ensure the complete
removal of the tri¯uoroacetic acid, to give 550 mg of
tri¯uoroacetate 19 as a white solid (95%). Anal. calcd for
C17H18F3NO6: C, 52.45; H, 4.66; N, 3.60; found: C, 52.33;
4.1.17. 1-Amino-t-2-hydroxycyclohexane-r-1-carboxylic
acid (rac-cis-1). Compound 21 (250 mg, 0.78 mmol) was
suspended in a 6N HCl solution (20 mL) and stirred under
re¯ux for 24 h. The solvent was evaporated and the excess
of HCl was removed in vacuo. The residue was dissolved in
distilled water (15 mL) and washed with Et2O (2£20 mL).
The aqueous layer was evaporated to yield 125 mg of
rac-cis-1´HCl as a white solid (82%), which was dissolved
in ethanol (6 mL) and propylene oxide (2 mL) was added.
After stirring at re¯ux for 2 h, the amino acid precipitated
partially. The solvent was evaporated and the residue was
dissolved in distilled water (2 mL) and eluted through a C18
reverse-phase Sep-pak cartridge to yield, after removal of
water, 95 mg of the amino acid rac-cis-1 as a white solid
1
H, 4.58; N, 3.78; H NMR (CDCl3): d 2.25±2.50 (m, 4H,
2H512H6); 3.66 (s, 3H, CH3); 5.60±5.70 (m, 1H, H3); 5.92±
6.00 (m, 1H, H4); 6.05 (br s, 1H, H2); 7.28±7.40 (m, 2H,
Arom.); 7.48±7.58 (m, 1H, Arom.); 8.09±8.18 (m, 2H,
Arom.); 8.56 (br s, 3H, NH3); 13C NMR (CDCl3): d 20.3,
1
(76%). rac-cis-1´HCl: H NMR (D2O): d 1.15±1.40 (m,

A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
2753
3H); 1.50±1.80 (m, 2H); 1.81±1.90 (m, 3H); 4.13 (dd, 1H,
0
water (2£15 mL) and the combined aqueous phases were
extracted with ethyl acetate (2£15 mL). The combined
organic phases were washed with brine (2£15 mL), dried
over anhydrous Na2SO4, ®ltered and the solvent was evapo-
rated. The mixture of diastereoisomeric peptides was
chromatographed on silica gel eluting with toluene±ethyl
acetate (1:1), to yield 525 mg of the peptide (1S,2S,S)-23
as a white solid (36%) and 514 mg of the peptide (1R,2R,S)-
24 as a white solid (35%). (1S,2S,S)-23: Mp: 192±1948C;
Anal. calcd for C30H39N3O4: C, 71.26; H, 7.77; N, 8.31;
J2a±3aˆ10.8 Hz, J2a±3e ˆ5.1 Hz, H2a); 13C NMR (D2O): d
20.9, 24.8, 30.6, 32.8 (C3, C4, C5, C6); 67.0 (C1); 71.8
(C2); 175.8 (COO). rac-cis-1: Anal. calcd for C7H13NO3:
C, 52.82; H, 8.23; N, 8.80; found: C, 52.72; H, 8.18; N,
1
8.92; H NMR (D2O): d 1.10±1.50 (m, 3H); 1.55±1.80
(m, 2H); 1.82±2.00 (m, 3H); 4.02±4.09 (m, 1H, H2); 13C
NMR (D2O): d 21.5, 25.2, 31.1, 33.3 (C3, C4, C5, C6); 68.1
(C1); 72.1 (C2); 178.3 (COO).
4.1.18. trans-2-Methoxycyclohexane-1-spiro-{40 [20-phenyl-
50(40H)oxazolone]} (rac-22). A suspension of compound
rac-8 (500 mg, 1.72 mmol) and LiOH´H2O (722 mg,
17.2 mmol) in methanol±water (3:2) (25 mL) was stirred
under re¯ux for 7 h. The solvent was removed, the residue
was then dissolved in water and washed with CH2Cl2
(2£20 mL). The aqueous phase was acidi®ed with 2N HCl
and then extracted with CH2Cl2 (4£25 mL). The combined
last organic phases were dried over anhydrous Na2SO4,
®ltered and evaporated, to yield 444 mg of the 1-benza-
mido-c-2-methoxycyclohexane-r-1-carboxylic acid as a
white solid (93%). Mp: 49±518C; Anal. calcd for
C15H19NO4: C, 64.97; H, 6.91; N, 5.05; found: C, 64.91;
H, 6.93; N, 4.99; IR (CH2Cl2, cm21): 3430 (NH), 3119
found: C, 71.64; H, 7.62; N, 8.23; [a]25 (c 2.08,
D
CHCl3)ˆ232.1; IR (CH2Cl2, cm21): 3426, 3351 (NH),
1
1702, 1657 (CON); H NMR (CDCl3): d 1.02±1.42 (m,
5H); 1.43±1.93 (m, 12H); 2.19±2.36 (m, 1H); 3.15 (s, 4H,
CH3O1Hb1); 3.27 (dd, 1H, Jb2±b1ˆ14.1 Hz, Jb2±aˆ6.9 Hz,
0
Hb2); 3.64±3.82 (m, 1H, H1 ); 3.89±4.01 (m, 1H, H2); 4.66±
4.79 (m, 1H, Ha); 6.51 (br s, 1H, NHCOPh); 6.90 (d, 1H,
0
JNHCy-1 ˆ8.7 Hz, NHCy); 7.10±7.18 (m, 5H, Arom.); 7.34±
7.55 (m, 4H, Arom.1NHPhe); 7.63±7.72 (m, 2H, Arom.);
13C NMR (CDCl3): d 20.0, 21.2, 22.9, 25.1, 25.2, 25.6, 30.7,
0
0
0
0
0
32.5, 32.8 (C3, C4, C5, C6, C2 , C3 , C4 , C5 , C6 ); 37.0 (Cb);
0
48.5 (C1 ); 53.9 (Ca); 55.8 (CH3O); 61.8 (C1); 78.2 (C2);
126.6, 127.0, 128.4, 128.6, 129.4, 132.0, 133.8, 137.2
(Arom.); 167.4, 169.8, 172.3 (CON). (1R,2R,S)-24: Mp:
111±1138C; Anal. calcd for C30H39N3O4: C, 71.26; H,
1
(COOH), 1760 (COO), 1672 (CON); H NMR (CDCl3): d
1.42±1.82 (m, 5H); 1.89±2.04 (m, 1H); 2.10±2.24 (m, 2H);
3.40 (s, 3H, CH3O); 4.18±4.26 (m, 1H, H2); 6.93 (br s, 1H,
NH); 7.36±7.55 (m, 3H, Arom.); 7.74±7.85 (m, 2H,
Arom.); 10.46 (br s, 1H, COOH); 13C NMR (CDCl3): d
19.9, 20.9, 24.4, 28.6 (C3, C4, C5, C6); 57.1 (CH3O); 62.5
(C1); 77.7 (C2); 127.1, 128.5, 131.9, 133.8 (Arom.); 167.9
(CON); 174.9 (COOH). This carboxylic acid (444 mg,
1.6 mmol) and dimethylaminopyridine (192 mg, 1.6
mmol) were dissolved in CH2Cl2 (13 mL) at 08C. Dicyclo-
hexylcarbodiimide (335 mg, 1.6 mmol) was then added and
the mixture was allowed to warm up to 258C. After stirring
for 3 h, the solvent was evaporated and the residue was
chromatographed on silica gel eluting with hexane±ethyl
acetate (1:1), to yield 337 mg of the oxazolone rac-22 as a
white solid (91%). Mp: 82±848C; Anal. calcd for
C15H17NO3: C, 69.48; H, 6.61; N, 5.40; found: C, 69.86;
H, 6.43; N, 5.62; IR (CH2Cl2, cm21): 1805 (COO), 1657
7.77; N, 8.31; found: C, 71.89; H, 7.64; N, 8.42; [a]25 (c
D
1.02, CHCl3)ˆ257.4; IR (CH2Cl2, cm21): 3427, 3348
1
(NH), 1805, 1658 (CON); H NMR (CDCl3): d 0.92±2.02
(m, 17H); 2.09±2.22 (m, 1H); 3.08 (dd, 1H, Jb1±b2
14.1 Hz; Jb1±aˆ6.0 Hz, Hb1); 3.21 (s, 3H, CH3O); 3.26
ˆ
(dd, 1H, Jb2±b1ˆ14.1 Hz, Jb2±aˆ6.6 Hz, Hb2); 3.64±3.79
0
(m, 1H, H1 ); 3.87±3.94 (m, 1H, H2); 4.64±4.73 (m, 1H,
0
Ha); 6.35 (br s, 1H, NHCOPh); 6.62 (d, 1H, JNHCy-1
ˆ
7.8 Hz, NHCy); 7.00 (d, 1H, JNHPhe-aˆ7.8 Hz, NHPhe);
7.14±7.24 (m, 5H, Arom.); 7.39±7.48 (m, 2H, Arom.);
7.48±7.56 (m, 1H, Arom.); 7.68±7.77 (m, 2H, Arom.);
13C NMR (CDCl3): d 19.9, 21.2, 24.2, 25.0, 25.5, 28.0,
0
32.7, 32.9, 33.9 (C3, C4, C5, C6, C2 , C3 , C4 , C5 , C6 );
0
0
0
0
0
37.3 (Cb); 48.3 (C1 ); 54.0 (Ca); 58.8 (CH3O); 62.1 (C1);
78.6 (C2); 126.7, 127.0, 128.4, 128.6, 129.4, 132.0, 133.9,
136.8 (Arom.); 167.2, 169.6, 172.0 (CON).
1
(CON); H NMR (CDCl3): d 1.29±1.45 (m, 1H); 1.58±
1.72 (m, 1H); 1.76±2.02 (m, 5H); 2.03±2.14 (m, 1H);
4.1.20. Methyl (1S,2S)-1-benzamido-2-methoxycyclohex-
ane-1-carboxylate ((1S,2S)-8). Tri¯ic acid (0.11 mL,
2.37 mmol) was added to a solution of (1S,2S,S)-23
(400 mg, 0.79 mmol) in dry methanol (12 mL) at 08C,
under an inert atmosphere. The reaction mixture was
warmed up to 808C and after stirring for 48 h, the solvent
was evaporated. The residue was chromatographed on silica
gel eluting with hexane±ethyl acetate (1:1), to yield 210 mg
of the compound (1S,2S)-8 as a white solid (91%). Mp:
132±1338C; Anal. calcd for C16H21NO4: C, 65.96; H,
3.31 (s, 3H, CH3O); 3.49 (dd, 1H, J2a±3aˆ11.2 Hz, J2a±3e
ˆ
4.9 Hz, H2); 7.41±7.60 (m, 3H, Arom.); 7.95±8.06 (m, 2H,
Arom.); 13C NMR (CDCl3): d 19.8 (C3), 23.6, 25.5, 33.0
(C4, C5, C6); 58.0 (CH3O); 73.0 (C1); 82.3 (C2); 126.0,
127.8, 128.7, 132.5 (Arom.); 160.8 (CON); 177.3 (COO).
4.1.19. (1S,2S)-[1-Benzamido-2-methoxycyclohexane-1-
carboxamido]-(S)-phenylalanine cyclohexylamide ((1S,
2S,S)-23) and (1R,2R)-[1-benzamido-2-methoxycyclo-
hexane-1-carboxamido]-(S)-phenylalanine cyclohexyl-
amide ((1R,2R,S)-24). A solution of (S)-phenylalanine
cyclohexylamide (1.6 g, 6.66 mmol) in N-methylpyrro-
lidin-2-one (NMP) (3 mL) was added to a solution of
compound rac-22 (750 mg, 2.9 mmol) in NMP (3 mL)
under an inert atmosphere. After stirring for 48 h at 908C,
the reaction mixture was allowed to cool down to room
temperature and was then poured onto a mixture of ice
(12 g), 1N HCl (12 mL) and ethyl acetate (15 mL). After
stirring for 30 min, the organic phase was washed with
7.27; N, 4.81; found: C, 65.84; H, 7.32; N, 4.75; [a]25 (c
D
1.09, CHCl3)ˆ152.5. Spectral data for the compound
(1S,2S)-8 were identical to those described for rac-8.
4.1.21. Methyl (1R,2R)-1-benzamido-2-methoxycyclo-
hexane-1-carboxylate ((1R,2R)-8). As described for
(1S,2S)-8, compound (1R,2R)-8 (196 mg, 85%) was
obtained starting from (1R,2R,S)-24 (400 mg, 0.79 mmol).
Anal. calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81;
found: C, 65.80; H, 7.22; N, 4.79; [a]25 (c 1.00,
D
CHCl3)ˆ254.9. Analytical and spectral data for the

2754
A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
compound (1R,2R)-8 were identical to those described for
its enantiomer (1S,2S)-8.
calcd for C20H23NO7: C, 61.69; H, 5.95; N, 3.60; found: C,
61.61; H, 5.92; N, 3.71; [a]25 (c 0.87, CH3OH)ˆ1125.4;
D
IR (CH2Cl2, cm21): 3341 (NH), 1744, 1730 (COO), 1692
(CON); 1H NMR (CDCl3): d 1.45 (d, 3H, Jˆ6.9 Hz,
CH3CH); 2.06 (s, 3H, CH3CO); 2.08±2.26 (m, 3H); 2.81±
2.88 (m, 1H); 3.67 (s, 3H, CH3O); 5.21 (c, 1H, Jˆ6.9 Hz,
CH3CH); 5.56±5.62 (m, 1H, H4); 5.95±6.02 (m, 2H,
H21H3); 6.72 (br s, 1H, NH); 7.45±7.50 (m, 2H, Arom.);
7.58±7.63 (m, 1H, Arom.); 8.02±8.05 (m, 2H, Arom.); 13C
NMR (CDCl3): d 17.3 (CH3CH); 20.9 (CH3CO); 22.0, 26.3
(C5, C6); 52.9 (CH3O); 60.1 (C1); 70.8 (CH3CH); 71.4 (C2);
122.9 (C4); 128.6, 129.6 (Arom.); 132.7 (C3); 133.5
(Arom.); 165.1, 169.5, 170.8, 171.0 (COO, CON).
4.1.22. (1S,2S)-1-Amino-2-hydroxycyclohexane-1-carb-
oxylic acid ((1S,2S)-1). Compound (1S,2S)-8 (220 mg,
0.76 mmol) was suspended in a 12N HCl solution (5 mL)
and stirred under re¯ux for 7 d. The solvent was evaporated
and the excess of HCl removed in vacuo. The residue was
dissolved in distilled water (8 mL) and washed with Et2O
(4£10 mL). The aqueous layer was evaporated to yield
133 mg (90%) of (1S,2S)-1´HCl as a white solid, which
was dissolved in ethanol (3 mL) and propylene oxide
(1 mL) was added. After stirring under re¯ux for 2 h, the
amino acid precipitated partially. The solvent was evapo-
rated and the residue was dissolved in distilled water (2 mL)
and eluted through a C18 reverse-phase Sep-pak cartridge to
yield, after removal of water, 100 mg of the amino acid
(1S,2S)-1 as a white solid (83%). Anal. calcd for
C7H13NO3: C, 52.82; H, 8.23; N, 8.80; found: C, 52.70; H,
4.1.25. Methyl (1S,2R,S)-1-(20-acetoxypropanoylamido)-
2-benzoyloxycyclohexane-1-carboxylate ((1S,2R,S)-27).
A solution of compound (1S,2R,S)-25 (159 mg, 0.40
mmol) in deoxygenated ethyl acetate (15 mL) was hydro-
genated at atmospheric pressure, using platinum±carbon
(10%) as a catalyst (50 mg), vigorously stirring at 258C
for 3 h. The catalyst was ®ltered off through Celite and the
solvent evaporated, to yield 158 mg of compound (1S,2R,S)-
27 as a colourless oil (99%). Anal. calcd for C20H25NO7: C,
61.37; H, 6.44; N, 3.58; found: C, 61.46; H, 6.38; N, 3.61;
8.20; N, 8.89; [a]25 (c 0.62, H2O)ˆ14.5. Analytical and
D
spectral data for the amino acid and its hydrochloride were
identical to those described for rac-trans-1.
4.1.23. (1R,2R)-1-Amino-2-hydroxycyclohexane-1-carb-
oxylic acid ((1R,2R)-1). As described for (1S,2S)-1,
compound (1R,2R)-1 (75 mg, 82%) was obtained starting
from (1R,2R)-8 (170 mg, 0.58 mmol). Anal. calcd for
C7H13NO3: C, 52.82; H, 8.23; N, 8.80; found: C, 52.76; H,
[a]25 (c 1.25, CH3OH)ˆ277.3; IR (CH2Cl2, cm21): 3436
D
1
(NH), 1744, 1727, 1694, 1604 (COO, CON); H NMR
(CDCl3): d 1.37±1.85 (m, 5H); 1.49 (d, 3H, Jˆ6.9 Hz,
CH3CH); 1.92±2.20 (m, 2H); 2.06 (s, 3H, CH3CO); 2.75±
2.85 (m, 1H); 3.64 (s, 3H, CH3O); 5.21 (c, 1H, Jˆ6.9 Hz,
CH3CH); 5.38 (dd, 1H, J2±3aˆ9.9 Hz, J2±3eˆ4.5 Hz, H2);
6.61 (br s, 1H, NH); 7.41±7.47 (m, 2H, Arom.); 7.56±
7.60 (m, 1H, Arom.); 7.95±7.98 (m, 2H, Arom.); 13C
NMR (CDCl3): d 17.8 (CH3CH); 20.3, 22.9, 27.5, 29.8
(C3, C4, C5, C6); 20.9 (CH3CO); 52.8 (CH3O); 62.7 (C1);
71.0 (CH3CH); 74.3 (C2); 128.6, 129.5, 129.6, 133.5
(Arom.); 164.9, 169.3, 170.6, 171.3 (COO, CON).
8.21; N, 8.90; [a]25 (c 0.62, H2O)ˆ24.2. Analytical and
D
spectral data for the amino acid and its hydrochloride were
identical to those described for rac-trans-1.
4.1.24. Methyl (1S,2R,S)-1-(20-acetoxypropanoylamido)-
2-benzoyloxy-3-cyclohexene-1-carboxylate ((1S,2R,S)-
25) and methyl (1R,2S,S)-1-(20-acetoxypropanoyl-
amido)-2-benzoyloxy-3-cyclohexene-1-carboxylate ((1R,
2S,S)-26). Compound 19 (500 mg, 1.28 mmol) was
dissolved in dry CH2Cl2 (50 mL), at 258C under an inert
atmosphere, and then Et3N (0.36 mL, 2.57 mmol) and (S)-
2-acetoxypropanoyl chloride (0.32 mL, 2.57 mmol) were
added. After stirring for 2 h at the same temperature, the
reaction was washed with a 0.005N HCl solution (50 mL)
and the aqueous phase extracted with CH2Cl2 (2£50 mL).
The combined organic phases were dried over anhydrous
Na2SO4, ®ltered and the solvent was evaporated. The
mixture of diastereoisomers was chromatographed on silica
gel eluting with Et2O±hexane (7:3) to yield 200 mg of
the compound (1S,2R,S)-25 (40%) and 252 mg of the
compound (1R,2S,S)-26 (50%) as colourless oils.
(1S,2R,S)-25: Anal. calcd for C20H23NO7: C, 61.69; H,
4.1.26. Methyl (1R,2S,S)-1-(20-acetoxypropanoylamido)-
2-benzoyloxycyclohexane-1-carboxylate ((1R,2S,S)-28).
As described for (1S,2R,S)-27, compound (1R,2S,S)-28
(216 mg, 99%) was obtained starting from (1R,2S,S)-26
(218 mg, 0.56 mmol). Anal. calcd for C20H25NO7: C,
61.37; H, 6.44; N, 3.58; found: C, 61.42; H, 6.50; N, 3.52;
[a]25 (c 0.94, CH3OH)ˆ140.5; IR (CH2Cl2, cm21): 3433
D
1
(NH), 1744, 1730, 1695, 1605 (COO, CON); H NMR
(CDCl3): d 1.37±1.79 (m, 5H); 1.48 (d, 3H, Jˆ6.9 Hz,
CH3CH); 1.97±2.17 (m, 2H); 2.07 (s, 3H, CH3CO); 2.80±
2.85 (m, 1H); 3.65 (s, 3H, CH3O); 5.26 (c, 1H, Jˆ6.9 Hz,
CH3CH); 5.40 (dd, 1H, J2±3aˆ9.9 Hz, J2±3eˆ4.2 Hz, H2);
6.67 (br s, 1H, NH); 7.43±7.49 (m, 2H, Arom.); 7.57±
7.61 (m, 1H, Arom.); 8.00±8.03 (m, 2H, Arom.); 13C
NMR (CDCl3): d 17.2 (CH3CH); 20.2, 22.9, 27.5, 29.9
(C3, C4, C5, C6); 20.9 (CH3CO); 52.8 (CH3O); 62.9 (C1);
70.8 (CH3CH); 74.2 (C2); 128.6, 129.5, 129.6, 133.4
(Arom.); 164.9, 169.6, 170.6, 171.3 (COO, CON).
5.95; N, 3.60; found: C, 61.53; H, 5.99; N, 3.66; [a]25 (c
D
1.02, CH3OH)ˆ2138.8; IR (CH2Cl2, cm21): 3437 (NH),
1
1744, 1738 (COO), 1690 (CON); H NMR (CDCl3): d
1.47 (d, 3H, Jˆ6.9 Hz, CH3CH); 2.04 (s, 3H, CH3CO);
2.07±2.27 (m, 3H); 2.83±2.89 (m, 1H); 3.66 (s, 3H,
CH3O); 5.18 (c, 1H, Jˆ6.9 Hz, CH3CH); 5.60±5.64 (m,
1H, H4); 5.94 (m, 1H, H2); 6.02±6.06 (m, 1H, H3); 6.68
(br s, 1H, NH); 7.43±7.48 (m, 2H, Arom.); 7.57±7.63 (m,
1H, Arom.); 7.99±8.02 (m, 2H, Arom.); 13C NMR (CDCl3):
d 17.8 (CH3CH); 20.9 (CH3CO); 22.0, 26.3 (C5, C6); 52.9
(CH3O); 60.0 (C1); 70.7 (CH3CH); 71.5 (C2); 123.1 (C4);
128.6, 129.5 (Arom.); 132.7 (C3); 133.6 (Arom.); 165.2,
169.4, 170.8, 171.0 (COO, CON). (1R,2S,S)-26: Anal.
4.1.27. (1S,2R)-1-Amino-2-hydroxycyclohexane-1-carb-
oxylic acid ((1S,2R)-1). Compound (1S,2R,S)-27 (108 mg,
0.27 mmol) was suspended in a 9N HCl solution (10 mL).
After stirring at 858C for 4 d, the solvent was evaporated and
the excess of HCl was removed in vacuo. The residue was
washed with a mixture of THF±Et2O (2:3) (2£5 mL) to
obtain another residue, which was dried in vacuo to yield

A. Avenoza et al. / Tetrahedron 57 (2001) 2745±2755
2755
10. Horikawa, M.; Nakajima, T.; Ohfune, Y.; Shigeri, Y.;
Yoshikawa, S.; Yumoto, S. Bioorg. Med. Chem. Lett. 1998,
8, 2027±2032.
49 mg (93%) of (1S,2R)-1´HCl as a white solid. This hydro-
chloride was dissolved in ethanol (2 mL) and propylene
oxide (1 mL) was added. After stirring under re¯ux for
1 h, the amino acid precipitated and, once ®ltered, it was
lyophilised to obtain 33 mg of the amino acid (1S,2R)-1 as a
white solid (85%; 77% from (1S,2R,S)-27). Anal. calcd for
C7H13NO3: C, 52.82; H, 8.23; N, 8.80; found: C, 52.81; H,
11. Fondekar, K. P.; Volk, F.-J.; Frahm, A. W. Tetrahedron:
Asymmetry 1999, 10, 727±735.
Â
12. Avenoza, A.; Cativiela, C.; Dõaz-de-Villegas, M. D.;
Peregrina, J. M. Tetrahedron 1993, 49, 10987±10996.
Â
13. Avenoza, A.; Cativiela, C.; Parõs, M.; Peregrina, J. M. J. Org.
Chem. 1994, 59, 7774±7778.
14. Avenoza, A.; Cativiela, C.; Busto, J. H.; Peregrina, J. M.;
8.20; N, 8.86; [a]25 (c 1.17, H2O)ˆ15.8. Analytical and
D
spectral data for the amino acid and its hydrochloride were
identical to those described for rac-cis-1.
Â
Rodrõguez, F. Tetrahedron 1998, 54, 11659±11674.
Â
Â
4.1.28. (1R,2S)-1-Amino-2-hydroxycyclohexane-1-carb-
oxylic acid ((1R,2S)-1). As described for (1S,2R)-1,
compound (1R,2S)-1 (28 mg, 75%) was obtained starting
from (1R,2S,S)-28 (107 mg, 0.27 mmol). Anal. calcd for
C7H13NO3: C, 52.82; H, 8.23; N, 8.80; found: C, 52.76; H,
15. Jimenez, A. I.; Cativiela, C.; Avenoza, A.; Parõs, M.;
Peregrina, J. M.; Aubry, A.; Marraud, M. Tetrahedron Lett.
1998, 39, 7841±7844.
 Â
16. Jimenez, A. I.; Cativiela, C.; Gomez-Catalan, J.; Perez, J. J.;
Â
Â
Â
Aubry, A.; Parõs, M.; Marraud, M. J. Am. Chem. Soc. 2000,
8.15; N, 8.92; [a]25 (c 0.84, H2O)ˆ25.5. Analytical and
122, 5811±5821.
17. Avenoza, A.; Cativiela, C.; Fernandez-Recio, M. A.;
Peregrina, J. M. Synlett 1995, 891±892.
D
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spectral data for the amino acid and its hydrochloride were
identical to those described for rac-cis-1.
Â
18. Avenoza, A.; Cativiela, C.; Fernandez-Recio, M. A.;
Peregrina, J. M. Tetrahedron: Asymmetry 1996, 7, 721±728.
Acknowledgements
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19. Avenoza, A.; Cativiela, C.; Fernandez-Recio, M. A.;
Peregrina, J. M. J. Chem. Soc., Perkin Trans. 1 1999, 3375±
3379.
Â
Â
We are indebted to the Direccion General de Investigacion
Â
Â
Cientõ®ca y Tecnica, project PB97-0998, and to the
Universidad de La Rioja, project API-00-B02, for their
generous support. J. I. B. thanks the Gobierno de La Rioja
for his doctoral grant. M. A. F.-R. and F. R. thank the
20. Nakazawa, T.; Suzuki, T.; Ishii, M. Tetrahedron Lett. 1997,
38, 8951±8954.
Â
21. Avenoza, A.; Busto, J. H.; Cativiela, C.; Fernandez-Recio,
Â
M. A.; Peregrina, J. M.; Rodrõguez, F. Tetrahedron 2001,
Â
Ministerio de Educacion y Ciencia for their doctoral grants.
57, 545±548.
22. Avenoza, A.; Busto, J. H.; Cativiela, C.; Parõs, M.; Peregrina,
Â
J. M. J. Heterocycl. Chem. 1997, 34, 1099±1110.
23. Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M.;
Zurbano, M. M. The use of 4-hetaryliden- and 4-aryliden-
5(4H)-oxazolones as dienophiles in the Diels±Alder reaction;
Attanasi, O. A., Spinelli, D., Eds.; In Targets in Heterocyclic
Systems. Chemistry and Properties; Italian Society of Chem-
istry: Roma, 1999; vol. 3.
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