Carbocyclic serine analogues: Regio- and diastereoselective syntheses of new 1-amino-2,5-dihydroxycyclohexanecarboxylic acids

Article abstract of DOI:10.1016/S0040-4020(01)00534-8

Spirooxazolones 3, obtained by Diels-Alder reaction between oxazolone 1 and dienes 2, are the key starting materials for the preparation of β-hydroxycyclohexenamino acid derivatives 4-6. The regio- and diastereoselective functionalization of cyclohexyl ring with a second hydroxy group to give the new 1-amino-2,5-dihydroxycyclohexanecarboxylic acids 11, 19 and the 2,4-dihydroxy derivative 20 was achieved when starting from compounds 4-6. In fact, the iodo-oxazination reaction on compounds 4, followed by reduction of the iodine atom, led to the dihydroxyamino acids 11 in which the cis relationship exists between the two hydroxy groups. The iodo-lactonization reaction, followed by reduction of the iodine atom, allowed for the formation of the trans dihydroxy derivatives 19 starting from the acids 5.

Full text of DOI:10.1016/S0040-4020(01)00534-8

TETRAHEDRON
Pergamon
Tetrahedron 57 52001) 6429±6438
Carbocyclic serine analogues:
regio- and diastereoselective syntheses of new
1-amino-2,5-dihydroxycyclohexanecarboxylic acids
Francesca Clerici, Maria Luisa Gelmi,p Andrea Gambini and Donatella Nava
Á
Istituto di Chimica Organica, Facolta di Farmacia e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi
Á
Etero e Carbociclici, Universita di Milano, Via Venezian 21, I-20133 Milano, Italy
Received 24 January 2001;revised 1 March 2001;accepted 12 April 2001
AbstractÐSpirooxazolones 3, obtained by Diels±Alder reaction between oxazolone 1 and dienes 2, are the key starting materials for the
preparation of b-hydroxycyclohexenamino acid derivatives 4±6. The regio- and diastereoselective functionalization of cyclohexyl ring with
a second hydroxy group to give the new 1-amino-2,5-dihydroxycyclohexanecarboxylic acids 11, 19 and the 2,4-dihydroxy derivative 20 was
achieved when starting from compounds 4±6. In fact, the iodo-oxazination reaction on compounds 4, followed by reduction of the iodine
atom, led to the dihydroxyamino acids 11 in which the cis relationship exists between the two hydroxy groups. The iodo-lactonization
reaction, followed by reduction of the iodine atom, allowed for the formation of the trans dihydroxy derivatives 19 starting from the acids 5.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
3,4,5-tryhydroxy derivatives8 and the 2,3,4,5-tetrahydroxy
one.9 The synthesis of the polyhydroxycyclohexanecarboxylic
acid opens the interesting ®eld of carbohydrate mimetics. The
replacement of the oxygen atom on the pyranosyl ring with
the methylene group is of particular interest since the resulting
carbocyclic ring has a greater metabolic stability.
Our previous researches were focused on the synthesis of
carbocyclic constrained amino acids characterized by the
presence of a heteroatom on the b-position.1±3 Recently,
we have reported on a high diastereoselective approach to
1-amino-6-hydroxy-3-cyclohexenecarboxylic acids 7,
which bear a hydroxy group at the b-carbon and in which
the serine skeleton is included, when starting from 4-chloro-
methylene-554H)-oxazolone and dienes.2
b-Hydroxycyclohexenylamino acid derivatives are our
key starting materials for the preparation of the dihydroxy
derivatives.
As mentioned before, the 4-chloromethylene-554H)-oxazo-
lone has been used for the synthesis of these compounds.
Efforts to ®nd a more ef®cient synthon are in progress and
the methyleneoxazolone 1,3 functionalized at the double
bond with a carbonate group, has been found a more con-
venient starting material. As it will be described further on, the
use of the compound 1 allowed the ®nal amino acid deriva-
tives 7 to be obtained in a better overall yield 550%, two steps)
than with the chloromethylene-oxazolone 533%, four steps).
The importance of constrained amino acids is due to their
potential biological properties related to their structural
features and the interest in the preparation of new
compounds is increasing as shown in recent literature.1±4
Clearly the presence of substituents on the ring plays a
crucial role in the enzymatic interactions. So the possibility
to realize regio- and stereocontrolled syntheses is of great
interest to clarify these interactions.4h,5
In continuing our study, we now report on the preparation
of new 1-amino-2,5-dihydroxycyclohexanecarboxylic acid
derivatives.
Starting from 1-amino-6-hydroxy-3-cyclohexenecarboxylic
acid derivatives the new amino-2,5-dihydroxycyclohexane-
carboxylic acids were prepared in which the cis or trans
relationship exists. The goal of our syntheses is the pos-
sibility to control the stereochemistry of four centers using
very simple stereocontrolled reactions.
To our knowledge, only few examples of 1-aminopoly-
hydroxycyclohexanecarboxylic acid derivatives are reported
in the literature: the 3,4-6 and 2,6-dihydroxy derivatives,7
Keywords: oxazolones;Diels±Alder;amino-2,5-dihydroxycyclohexane-
carboxylic acids;stereochemistry;serine analogues.
Corresponding author. Tel.: 139-2-706-303-48;fax: 139-2-706-384-73;
e-mail: marialuisa.gelmi@unimi.it
2. Results and discussion
p
Ethyl 2-phenyl-5-oxo-oxazol-4-methylenecarbonate 5Z-1)
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020501)00534-8

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F. Clerici et al. / Tetrahedron 57 /2001) 6429±6438
Scheme 1.
was reacted with 2,3-dimethylbutadiene 52a) in dichloro-
methane at 2208C and in presence of ethylaluminum
dichloride. After 5 h, the H NMR analysis of the crude
the cycloaddition process. In fact, only traces of the other
regioisomer were detected.
1
mixture revealed the formation of the cycloadduct 3a.
Reaction workup resulted in partial transformation of 3a
into the corresponding ester 4a and acid 5a, which could
be separated by chromatography 5Scheme 1).
Selective hydrolysis of the functional groups was achieved
in different ways or starting directly from the crude cyclo-
addition reaction mixture or from the isolated products.
Cycloadducts 3a,b were transformed into the corresponding
acids 5a,b in good yield by reaction in wet tetrahydrofuran
and in presence of a catalytic amount of hydrogen chloride.
The corresponding hydroxyacids 6a,b, in which the hydroxy
group has been deprotected, were obtained from compounds
5a,b with sodium hydroxide in ethanol. It is possible to
attain directly compounds 6a,b when starting from oxazo-
lone 3a,b or ester 4a 5Scheme 1).
In order to avoid such a mixture of compounds, the crude
reaction mixture can be directly treated with ethanol or
water giving the corresponding ester 4a or acid 5a, respec-
tively, which were obtained in about 70% yield.
The reaction of 2-methylbutadiene 52b) and oxazolone 1,
operating as described before, gave the cycloadduct 3b
which was transformed into ester 4b or acid 5b in 65 or
60% yield, respectively.
The structure of compounds 3, 4, 5 and 6 was con®rmed by
spectroscopic data. In the IR spectra of the compounds 3, the
characteristic absorption of the lactone group 51800 cm21
is present. According to the structure of cyclohexenyl ring,
)
As shown, the cycloaddition reaction proceeded with high
diastereoselectivity and the cis relationship between the
nitrogen and oxygen atoms, such as in the starting dieno-
phile, was maintained. Furthermore, when starting from the
2-methylbutadiene 2b, the diastereoisomeric compound 3b
was obtained con®rming the high regioselective control in
1
the H NMR spectra of compounds 3±6 show an AB or
ABX system 5CH2 groups a to the CNH) and an ABX
system associated to CH2 protons a to the CHOR group.
As an example, the H NMR spectrum of compound 5a is
1
detailed to demonstrate the con®guration of substituents.

F. Clerici et al. / Tetrahedron 57 /2001) 6429±6438
6431
ing in basic conditions.10 Acids 6a,b were reacted with
sodium peroxide in water at 508C and the amino acids
7a,b were isolated in satisfactory yield 5Scheme 1).
The regio- and diastereoselective functionalization of C-5
with a hydroxy group to give the corresponding 1-amino-
2,5-dihydroxycyclohexanecarboxylic acids was achieved
when starting from compounds 4±6. The stereochemical
control on C-5 was favored by the presence both of the
benzoylamino group and carboxylic group which were
utilized in the iodo-oxazination11 and iodo-lactonization12
reactions, respectively.
Starting from compounds 4a,b, the iodo-oxazine derivatives
9a,b were obtained in good yield by reaction in dichloro-
methane with N-iodosuccinimide at room temperature,
according to the mechanism reported in the literature.11
The reduction of compounds 9a,b with tributyltin hydride
allowed one to obtain compounds 10a,b, as single diastereo-
isomers, in 75±70% overall yield 5Scheme 2).
The structure of compounds 9±10 was assigned by 1H
NMR, COSY and NOE experiments. COSY and hetero-
correlated 5C/H) experiments allowed to assign the chemi-
cal shift to all protons and to establish the regiochemistry of
the iodo-oxazination reaction. Particularly, the formation of
1
the oxazine ring was con®rmed by H NMR spectra of
Scheme 2.
compounds 10 in which the signal associated with the NH
proton is absent and the multiplicity of Me-8 5d, dˆ1.17±
1.06 region) reveals the saturation of the double bond. The
conformational rigidity of the backbone allows us to estab-
lish the con®guration of compounds 10. Considering that the
nitrogen and oxygen atoms in the oxazine ring should be in
the axial position, that the ethoxycarbonyloxy group and the
nitrogen atom are cis, as demonstrated before, and that the J
values between H-6 55.78±5.35 d region) and H-7 are 11±
10 and 6±4 Hz, it was possible to assign unequivocally the
axial con®guration of H-6. This result is decisive to assign
the con®guration of Me-8 group. The NOE experiment on
compound 10a showed evidence of close proximity between
H-6 55.35 d), H-7 52.05±1.95 d) and H-9 52.12 d), con®rm-
ing the equatorial position of the Me-8 group.
Signals at 5.57 and 2.75, 2.25 d 5ABX system, Jˆ18.2, 6.2,
6.3 Hz) associated with H-6 and H-5 protons, respectively,
and at 3.00, 2.88 d 5AB system, Jˆ17.4 Hz), associated
with H-2, are present. A strong positive NOE effect was
observed between H-2 proton 5dˆ3.00) and H-6 and
between this last and H-5 5dˆ2.75). A positive effect was
also observed between H-5 5dˆ2.25) and NH proton
5dˆ6.92). Considering these spectroscopic data and on the
basis of molecular model analysis, it can be assumed that the
conformation of the compound 5a is a twisted chair in which
the OR group is in the equatorial position and the benzoyl-
amino group is in the axial one, thus con®rming the cis
relationship between the two substituents.
According to these results, we concluded that the iodo-
oxazination reaction was regioselective and anti-diastereo-
selective. This is in agreement with similar cases reported in
the literature.11 Furthermore, the reduction of iodine atom
proceeded with retention of the con®guration and produced
a single diastereoisomer. As a further con®rmation of this
con®gurational assignment 5see below), both the carbonate
and ester groups in 10a were hydrolyzed in ethanol and in
the presence of sodium hydroxide, giving compound 21
5Scheme 4).
The regiochemistry of the cycloaddition reaction in the case
of monomethyl derivatives was established considering the
multiplicity of the methylene protons and by a NOE experi-
ment on compound 3b in which a positive Overhauser effect
was observed between the methyl group and H-7 5dˆ2.60±
2.50) and between the ole®nic proton at dˆ5.40 and H-10
5dˆ2.14).
Acidic hydrolysis of the benzoylamino group of compounds
5a,b did not allow one to obtain the expected amino acids
7a,b. In fact, operating in hydrochloric acid 520%) at re¯ux
for 16 h, benzoic acid and the substituted benzoic acids 8a,b
were isolated 5Scheme 1). Their formation is explained by
water elimination, probably favored by a previous acid-
catalyzed isomerization of the double bond, giving a cyclo-
hexadiene intermediate from which, after ammonia elimi-
nation, benzoic acid derivatives 8 are formed.
The hydrolysis of compounds 10a and b in acidic conditions
5HCl 20%, 16 h) resulted in the formation of the amino acids
7a and 11b, respectively 5Scheme 2).
The formation of 7a, besides the expected dihydroxy
compound 11a, has to be ascribed to the transformation of
10a into a hydroxy intermediate which was transformed into
7a on water elimination favored by the formation of the tetra
substituted ole®n.
The preparation of the amino acids 7 was achieved operat-

6432
F. Clerici et al. / Tetrahedron 57 /2001) 6429±6438
Scheme 3.
To overcome this problem, the oxazine derivative 10a was
tentatively reduced with sodium borohydride in ethanol, by
a modi®cation of the procedure described in the literature.13
Unfortunately, the reduction reaction resulted in the forma-
tion of the compound 12 in 86% yield in which the ester
function was reduced to alcohol.
The structure of compound 12 was established by 1H NMR
and COSY experiments. The chemical shifts 5dˆ4.50, 3.86,
3.28) and the multiplicity of the signals 5ABX system,
Jˆ10.3, 6.0, 5.4 Hz) con®rmed the presence of the
CH2OH group.
To control the trans relationship between the two hydroxy
groups, the iodo-lactonization reaction was used. Starting
from 5a and by reaction in ethanol, sodium hydrogencarbo-
nate and in presence of a solution of I2/I2, the iodolactone
13a was obtained which was reduced to the lactone 14a
541% overall yield) with tributyltin hydride 5Scheme 3).
In the case of 5b a mixture of the regioisomeric iodolactones
13b and 15 was found operating with the same reagents both
at room temperature 51:2 ratio) and at re¯ux 51:3.5 ratio).
Reduction of these compounds allowed us to obtain lactones
14b and 16 5Scheme 3).
Scheme 4.

F. Clerici et al. / Tetrahedron 57 /2001) 6429±6438
6433
It is known that the intramolecular iodo-lactonization
reaction normally shows a preference for the formation of
®ve-membered over six-membered rings and anti stereo-
speci®c addition is generally observed.12 In the present
case, the formation of the six-membered lactone 15 can be
justi®ed considering that the carboxylic group reacts with the
more stable tertiary carbon of the iodonium intermediate.
In conclusion, by simple reactions, it was possible to
prepare the 1-amino-2,5-dihydroxycyclohexanecarboxylic
acids in which the trans or cis relationship between the
two hydroxy groups can be chosen. Furthermore, the high
diastereoselectivity of the reactions used allowed for the
satisfactory control of the stereochemistry of four centers.
The structure of compounds 13±16 was con®rmed by
spectroscopic data. The IR spectra showed absorptions at
1780±1760 and 1740 cm21, typical for the ®ve- and six-
membered lactones, respectively. The chemical shifts of
signals of methyl groups linked to the oxygen-bearing and
iodine-bearing carbons are, respectively, in the dˆ1.87±
1.64 region and dˆ2.20±2.09 region. Compounds 14a,b
present a characteristic doublet associated with Me-4
5dˆ1.10±1.00) which is absent in compound 16, thus
con®rming the formation of the ®ve- and six-membered
lactone rings, respectively. The con®guration of the methyl
group on C-4 of compound 14b was con®rmed by NMR
data and the chemical shifts have been assigned unequivo-
cally by the COSY and hetero-correlation 5C/H) experi-
ments. The molecular model analysis suggested that two
conformations are possible for the bicyclic ring but the J
values of H-2 are very small suggesting that a con®guration
is preferred in which this proton is in the equatorial position.
Signi®cantly, a strong NOE effect was observed between
H-4 52.18 d) and H-8 52.49 d) allowing the axial position
to be assigned to H-4.
3. Experimental
3.1. General
Melting points were determined using an Electrothermal
1
9100 apparatus. H and 13C NMR spectra were recorded
in CDCl3 as the solvent with Bruker Avance 300 and Varian
Gemini 200 instruments. Coupling constants values 5J) are
given in hertz. Mass spectra were obtained by electron
impact ionization at 70 eV from a Finningan INCOS 50
instrument using the direct exposure probe 5DP). Ethanol-
free CH2Cl2 was used in all experiments. Oxazolone 13 is a
known compound.
3.2. General procedures for the Diels±Alder reaction
To a stirred solution of oxazolone 5Z)-1a 51.56 g, 6 mmol)
and diene 2 524 mmol) in anhydrous CH2Cl2 510 mL) under
the nitrogen atmosphere at 2208C, was added EtAlCl2
53.3 mL, 6 equiv., 1.8 M in toluene). The stirring was
continued at 2208C for 5 h. The reaction was monitored
by 1H NMR. The reaction mixture was worked up as
described below. 5i) The solvent was evaporated and the
crude reaction mixture was chromatographed [n-pentane/
AcOEt 520:1)] giving two fractions containing, respectively,
the pure cycloadduct 3 53a: 35%, 3b: 47%), the ester 4 54a:
30%, 4b: 13%). Elution with AcOEt/MeOH allowed us to
obtain a third fraction containing the acid 5 55a: 8%, 5b:
7%). 5ii) Anhydrous EtOH 520 mL) was added to the crude
reaction mixture and the solution was stirred for 12 h after
which a solid was separated, ®ltered and washed with EtOH
510 mL). The organic solution was evaporated and the reac-
tion mixture was chromatographed 5n-pentane/CH2Cl2 1:0
to 0:1). Ester 4 54a: 70%, 4b: 65%) was isolated as pure
compound. 5iii) The solvent was evaporated and the crude
reaction mixture was taken up with THF 520 mL) and a
catalytic amount of HCl 537%) was added. After 2 h, a
solid was separated, ®ltered off and washed with THF
510 mL). The organic solvent was eliminated in vacuum.
The solid was dissolved in AcOEt 510 mL) and extracted
with a solution of NaHCO3 55£3 mL). The aqueous solution
was acidi®ed with HCl 510%, Congo red) and extracted with
CH2Cl2 53£10 mL). After drying over Na2SO4 and recrys-
tallization, the pure acid 5 55a: 68%, 5b: 60%) was obtained.
5iv) The solvent was evaporated and the crude reaction
mixture was taken up with THF 520 ml) and a solution of
NaOH 520 mL, 10%) was added. The stirring was continued
for 48 h after which THF was evaporated and the aqueous
layer was extracted with AcOEt 510 mL). Then the aqueous
solution was acidi®ed with HCl 510%, Congo red) and
extracted with CH2Cl2 54£10 mL). After drying over
Na2SO4 and recrystallization, pure acid 6a 568%) was
isolated.
This result is a further con®rmation that the reduction of the
iodine group occurs with retention of the con®guration.
The lactones 14a,b and 16 were quantitatively transformed
into the dihydroxyamino acids 17a,b and 18, respectively,
by reaction in tetrahydrofuran and in presence of sodium
hydroxide 5Scheme 3). The acid 17a was readily trans-
formed in solution into the lactones 22a 5Scheme 4) as
1
demonstrated by TLC and H NMR analyses and its mass
spectroscopy analysis 5M1ˆ289). Compound 17b was more
stable in solution but was transformed into 22b by heating
5Scheme 4).
Interestingly, it is possible to obtain the hydroxy analogous
of 10a and 14a, namely 21 and 22, when directly starting
from the hydroxy acid 6a. By heating of this compound in a
HCl solution 520%) for 10 min, a mixture of 21 and 22 53:2
ratio) was isolated in 62% overall yield 5Scheme 4).
This result allows us to avoid the two-step reaction
described before 5i.e. the iodo-oxazination or iodo-lactoni-
zation reaction followed by reduction) and to our knowledge
represents the ®rst example of direct oxazination and
lactonization reactions.
Starting from 6b operating in the same reaction conditions,
the formation of the above compounds was not observed.
Finally, the compounds 17a,b and 18 were debenzoylated
giving the expected 1-amino-2,5-dihydroxycyclohexane-
carboxylic acids 19a,b and 20. Acidic conditions 5HCl
20%) were achieved in the case of 17b and sodium peroxide
in water was preferred in the case of 17a and 18.

6434
F. Clerici et al. / Tetrahedron 57 /2001) 6429±6438
3.3. General procedure for hydrolysis of spirooxazolone
3,4-dimethylcyclohex-3-ene carboxylic acid /5a). Mp
1558C 5CH2Cl2/iPr2O);IR nmax 3700±3000, 1730, 1700,
1
Cycloadduct 3 51 mmol) was dissolved in THF 55 mL) in the
presence of a catalytic amount of HCl 537%). The solution
was stirred at room temperature for 1 h. Solvent was evapo-
rated and the solid was taken up with in CH2Cl2 510 mL) and
dried over Na2SO4. After solvent evaporation and after
recrystallization, the pure acid 5 was obtained 55a: 94%,
5b: 93%).
1620 cm21; H NMR d 10.0 5bs, 1H, exch.), 7.77±7.42
5m, 5H), 6.92 5s, 1H, exch.), 5.57, 2.75, 2.25 5ABX system,
Jˆ18.2, 6.2, 6.3 Hz, 3H), 4.22 5q, Jˆ7.1 Hz, 2H), 3.00, 2.88
5AB system, Jˆ17.4 Hz, 2H), 1.67 5s, 6H), 1.23 5t, Jˆ
7.1 Hz, 3H); 13C NMR d 14.6, 18.8, 18.9, 34.9, 36.4,
62.6, 65.1, 75.0, 121.5, 122.9, 127.7, 129.1, 132.7, 133.7,
155.2, 169.6, 173.4. Anal. calcd: C, 63.51;H, 6.41;N, 3.88.
Found: C, 63.83;H, 6.41;N 4.14.
3.4. General procedure for hydrolysis of carbonate
3.4.6. /1Sp, 6Rp)-1-Benzoylamino-6-ethoxycarbonyloxy-
4-methylcyclohex-3-ene carboxylic acid /5b). Mp 2188C
5CH2Cl2). IR nmax 3305, 3300±2800, 1740, 1710,
Ester 4a 5389 mg, 1 mmol) or acid 5 51 mmol) was
suspended in EtOH 56 mL) and a solution of NaOH 510%,
6 mL) was added. The solution was stirred at room tempera-
ture for 24 h. After solvent evaporation, the residue was
taken up with an aqueous solution of HCl 510 mL, 10%)
and extracted with AcOEt 53£15 mL). The organic layers
were dried over Na2SO4. After recrystallization, the pure
compound 6 56a: 90% from 4a;94% from 5a; 6b: 96%
from 5b) was isolated.
1
1620 cm21; H NMR d 10.0 5bs, 1H, exch.), 7.79±7.00
5m, 5H), 6.90 5s, 1H, exch.), 5.50, 2.80, 2.27 5ABX system,
Jˆ18.7, 6.5, 6.0 Hz, 3H), 5.36 5bs, 1H), 4.25 5q, Jˆ7.1 Hz,
2H), 3.03±2.85 5m, 2H), 1.75 5s, 3H), 1.32 5t, Jˆ7.1 Hz,
3H); 13C NMR d 14.5, 23.1, 30.8, 34.0, 61.1, 64.8, 75.1,
118.2, 127.5, 128.8, 129.8, 132.0, 134.6, 155.3, 168.1,
172.5. Anal. calcd: C, 62.24;H, 6.09;N, 4.03. Found: C,
62.55;H, 6.17;N, 4.12.
3.4.1. Ethyl /5Sp, 6Rp)-8,9-dimethyl-4-oxo-2-phenyl-3-
oxa-1-azaspiro[4.5]deca-1,8-dien-6-carbonate /3a). Mp
3.4.7. /1Sp, 6Rp)-1-Benzoylamino-6-hydroxy-3,4-dimethyl-
cyclohex-3-enecarboxylic acid /6a). Mp 2028C 5CH2Cl2);
IR nmax 3400, 3300, 1700, 1600 cm21; 1H NMR d 5CDCl3/
DMSO-d6) 7.86±7.44 5m, 5H), 6.70 5s, 1H, exch.), 5.50±
4.20 5bs, 2H, exch.), 4.29, 2.36, 2.15 5ABX system, Jˆ11.0,
9.1, 5.8 Hz, 3H), 2.82, 2.57 5AB system, Jˆ17.6 Hz, 2H),
1.60 5s, 6H); 13C NMR 5DMSO-d6) d 18.6, 18.8, 37.7, 63.7,
69.2, 122.1, 122.3, 127.7, 128.5, 131.6, 134.7, 167.8, 173.3.
Anal. calcd: C, 66.42;H, 6.62;N, 4.84. Found: C, 66.40;H,
6.43;N, 4.58.
1
1198C 5iPr2O);IR nmax 1800, 1740, 1640 cm21; H NMR
d 8.20±7.20 5m, 5H), 5.19 5dd, Jˆ9.2, 7.1 Hz, 1H), 4.13 5q,
Jˆ7.1 Hz, 2H), 2.82, 2.14 5AB system, Jˆ17.3 Hz, 2H),
2.65±2.45 5m, 2H), 1.74, 1.67 5two s, 6H), 1.24 5t, Jˆ
7.1 Hz, 3H); 13C NMR d 14.6, 18.6, 19.5, 33.9, 41.4,
64.7, 72.2, 76.0, 121.6, 124.1, 126.4, 128.8, 129.1, 133.2,
154.5, 161.9, 179.2. Anal. calcd: C, 66.46;H, 6.16;N, 4.08.
Found: C, 66.30;H, 6.21;N, 4.00.
3.4.2. Ethyl /5Sp, 6Rp)-8-methyl-4-oxo-2-phenyl-3-oxa-1-
azaspiro[4.5]deca-1,8-dien-6-carbonate /3b). Mp 1108C
3.4.8. /1Sp, 6Rp)-1-Benzoylamino-6-hydroxy-4-methyl-
cyclohex-3-enecarboxylic acid /6b). Mp 1688C 5CH2Cl2/
5iPr2O);IR nmax 1800, 1720, 1630 cm21 1H NMR d
;
1
Et2O);IR nmax 3400, 3300, 1720, 1620 cm21; H NMR d
8.09±7.43 5m, 5H), 5.40 5bs, 1H), 5.19 5dd, Jˆ8.9,
7.1 Hz, 1H), 4.14 5q, Jˆ7.1 Hz, 2H), 2.80 5d, Jˆ17.5 Hz,
1H), 2.60±2.50 5m, 2H), 2.14 5dd, Jˆ17.5, 3.8 Hz, 1H), 1.80
5s, 3H), 1.24 5t, Jˆ7.1 Hz, 3H); 13C NMR d 14.4, 23.4, 32.8,
35.5, 64.7, 71.2, 75.9, 116.4, 126.2, 128.7, 129.1, 132.5,
133.2, 154.4, 161.9, 179.3. Anal. calcd: C, 65.64;H, 5.81;
N, 4.25. Found: C, 65.48;H, 5.88;N 4.22.
5DMSO-d6) 12.98±11.00 5bs, 1H exch.), 7.78±7.42 5m, 6H),
6.00±5.00 5bs, 1H exch.), 5.22 5bs, 1H), 4.07, 2.26, 2.08
5ABX system, Jˆ17.5, 7.6, 5.1 Hz, 3H), 2.84, 2.64 5AB
system, Jˆ17.0 Hz, 2H), 1.62 5s, 3H); 13C NMR d
5DMSO-d6) 23.5, 32.0, 37.0, 63.54, 69.8, 118.3, 128.1,
129.0, 131.3, 132.1, 135.4, 168.3, 173.9. Anal. calcd: C,
65.44;H, 6.22;N, 5.09. Found: C, 65.09;H, 6.40;N, 4.88.
3.4.3. Ethyl /1Sp, 6Rp)-1-benzoylamino-6-ethoxycarbonyl-
oxy-3,4-dimethylcyclohex-3-enecarboxylate /4a). Oil;IR
3.5. General procedures for hydrolysis of benzoylamino
group
n
max 3350, 1730, 1620 cm21; 1H NMR d 7.77±7.39 5m, 5H),
6.76 5s, 1H, exch.), 5.32, 2.54, 2.29 5ABX system, Jˆ18.0,
8.9, 7.2 Hz, 3H), 4.25±4.15 5m, 4H), 3.03, 2.85 5AB system,
Jˆ17.6 Hz, 2H), 1.70 5two s, 6H), 1.30, 1.22 5two t, Jˆ7.2,
7.1 Hz, 6H);Anal. calcd: C, 64.77;H, 6.99;N, 3.60. Found:
C, 64.50;H, 7.15;N, 3.47.
5i) Operating in a sealed tube, the compound 5 51 mmol) was
suspended in a solution of HCl 54 mL, 20%). The solution
was heated at 1008C for 16 h. The reaction mixture was
extracted with Et2O 52£10 mL). After drying over
Na2SO4, a mixture of benzoic acid and the derivative 8
1
3.4.4. Ethyl /1Sp, 6Rp)-1-benzoylamino-6-ethoxycarbonyl-
oxy-4-methylcyclohex-3-enecarboxylate /4b). Oil;IR
51:1 ratio, H NMR) was obtained which were separated
by chromatography 5CH2Cl2/Et2O). 8a: 94%;mp 166 8C
5H2O); 8b: 95%;mp 180 8C 5H2O). 5ii) Compound 6
51 mmol) was suspended in H2O 520 mL) and Na2O2
5374.4 mg, 4.8 mmol) was added. The mixture was heated
at 508C for 24 h. The aqueous solution was acidi®ed with
HCl 510%, Congo red) and extracted with CH2Cl2
52£10 mL). The aqueous layer was evaporated to dryness
and the crude mixture was taken up with EtOH 52 mL) and
inorganic salts were ®ltered. EtOH was evaporated. The
1
nmax 3350, 1730, 1720, 1620 cm21; H NMR d 7.77±7.38
5m, 5H), 6.66 5s, 1H, exch.), 5.41±5.37 5m, 2H), 4.26±4.14
5m, 4H), 2.96 5bs, 2H), 2.60 5dd, Jˆ18.3, 4.5 Hz, 1H), 2.26
5dd, Jˆ17.4, 5.4 Hz, 1H), 1.69 5s, 3H), 1.28, 1.25 5two t,
Jˆ7.2, 7.1 Hz, 6H);Anal. calcd: C, 63.99;H, 6.71;N, 3.73.
Found: C, 63.71;H, 6.77;N, 3.53.
3.4.5. /1Sp, 6Rp)-1-Benzoylamino-6-ethoxycarbonyloxy-

F. Clerici et al. / Tetrahedron 57 /2001) 6429±6438
6435
solid was dissolved in a minimum amount of H2O and
desalted on a column of Amberlite IR-120 5PLUS) ion-
exchange resin. The column was eluted with H2O until the
eluate was shown to be free of halide ion. The amino acid
was then eluted with a solution of pyridine 520% in H2O).
The solvent was evaporated and pure compound 7 57a: 74%,
7b: 78%) was isolated.
3.7.1. Ethyl /1Rp, 5Sp, 6Rp, 8Sp)-6-ethoxycarbonyloxy-
1,8-dimethylcyclohex-2-oxa-3-phenyl-4-azabicyclo[3.3.1]-
non-3-ene-5-carboxylate /10a). Mp 1358C 5Et2O);IR nmax
1720, 1630 cm21; 1H NMR d 8.10±7.32 5m, 5H), 5.35 5dd,
Jˆ11.4, 4.9 Hz, 1H), 4.40±4.10 5m, 4H), 2.12, 1.88 5AB
system, Jˆ13.4 Hz, 2H), 2.05±1.95 5m, 1H), 1.90±1.70
5m, 1H), 1.39 5s, 3H), 1.35±1.20 5m, 7H), 1.06 5d, Jˆ
6.6 Hz, 3H); 13C NMR 14.5, 14.6, 15.3, 25.3, 32.9, 38.7,
41.3, 61.9, 62.5, 64.4, 76.1, 79.6, 128.3, 128.3, 131.1, 133.7,
155.3, 158.0, 172.5. Anal. calcd: C, 64.78;H, 6.94;N, 3.59.
Found: C, 64.68;H, 7.10;N, 3.61. m/z 389 5M1).
3.5.1. /1Sp, 6Rp)-1-Amino-6-hydroxy-3,4-dimethylcyclo-
hex-3-enecarboxylic acid /7a). Mp dec. 5EtOH). IR nmax
3215, 1660 cm21; 1H NMR 5D2O/CF3CO2D)2 d 4.30, 2.41,
1.87 5ABX system, Jˆ17.6, 9.9, 7.0 Hz, 3H), 2.75, 2.19 5AB
system, Jˆ18.3 Hz, 2H), 1.54 5s, 6H); 13C NMR 5D2O/
CF3CO2D) d 17.0, 17.4, 34.4, 36.7, 63.2, 66.6, 120.1,
123.5, 172.4. Anal. calcd: C, 58.35;H, 8.17;N, 7.56.
Found: C, 58.02;H, 8.27;N, 7.24.
3.7.2. Ethyl /1Rp, 5Sp, 6R, 8Sp)-6-ethoxycarbonyloxy-8-
methylcyclohex-2-oxa-3-phenyl-4-azabicyclo[3.3.1]non-
3-ene-5-carboxylate /10b). Mp 1238C 5Et2O);IR nmax
1
1725, 1625 cm21; H NMR d 8.01±7.34 5m, 5H), 5.39
5dd, Jˆ11.3, 4.4 Hz, 1H), 4.40±4.38 5m, 1H), 4.39±4.12
5m, 4H), 2.20±1.56 5m, 4H), 1.48±1.20 5m, 7H), 1.17 5d,
Jˆ6.2 Hz, 3H); 13C NMR d 14.1, 14.2, 17.7, 31.3, 31.4,
37.3, 59.9, 61.5, 63.9, 73.6, 79.4, 127.8, 127.9, 130.8,
133.2, 154.8, 157.1, 172.2. Anal. calcd: C, 63.99;H, 6.71;
N, 3.73. Found: C, 64.18;H, 6.95;N, 3.55.
3.5.2. /1Sp, 6Rp)-1-Amino-6-hydroxy-4-methylcyclohex-
3-enecarboxylic acid /7b). Mp dec. 5EtOH). IR nmax
1
3200, 1650 cm21; H NMR 5D2O/CF3CO2D) d 5.35 5bs,
1H), 4.44 5dd, Jˆ9.4, 6.7 Hz, 1H), 2.82 5d, Jˆ18.7 Hz,
1H), 2.59±1.90 5m, 4H), 1.68 5s, 3H); 13C NMR d 21.8,
31.4, 33.6, 62.7, 67.1, 113.3, 114.7, 172.9. Anal. calcd: C,
56.13;H, 7.65;N, 8.18. Found: C, 55.83;H, 7.91;N, 7.88.
3.7.3. /1Rp, 5Sp, 6Rp, 8Sp)-5-Hydroxymethyl-1,8-dimethyl-
3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-6-ole /12).
Oxazine derivative 10a 5389 mg, 1 mmol) was dissolved
in EtOH 53 mL, 96%) and THF 53 mL). The solution was
cooled at 2258C after which NaBH4 5185 mg, 5 mmol) was
added. The solution was stirred for 16 h. After solvent elimi-
nation, the reaction mixture was taken up with AcOEt
520 mL) and washed with H2O 52£5 mL). Pure compound
12 5247 mg, 86%) was isolated from the dried organic layer
5Na2SO4) after crystallization: mp 1958C 5CH2Cl2). IR nmax
3600±3000, 1620 cm21; 1H NMR 5DMSO-d6) d 7.89±7.36
5m, 5H), 4.50, 3.86, 3.28 5ABX system, Jˆ10.3, 6.0, 5.4 Hz,
3H), 4.13, 5d, Jˆ6.8 Hz, 1H, exch.), 3.79±3.70 5m, 1H),
1.80, 1.41 5AB system, Jˆ13.4 Hz, 2H), 1.68±1.63 5m,
2H), 1.29 5s, 3H), 0.92 5d, Jˆ6.4 Hz, 3H); 13C NMR
5DMSO-d6) d 15.9, 25.7, 37.5, 38.3, 41.0, 59.4, 66.8,
71.9, 77.4, 127.8, 128.7, 131.0, 134.6, 155.8. Calcd: C,
69.79;H, 7.69;N, 5.09. Found: C, 70.38;H, 7.79;N, 5.20.
3.6. General procedure for the iodo-oxazination reaction
To a stirred solution of ester 4 51 mmol) in anhydrous
CH2Cl2 55 mL), the NIS 5247 mg, 1.1 mmol) was added at
room temperature. After 1 h, the organic solution was
washed with a solution of Na2S2O4 52£5 mL, 5%), H2O
55 mL) and dried over Na2SO4 giving pure compound 9
59a: 94%, 9b: 90%).
3.6.1. Ethyl /1Rp, 5Sp, 6Rp, 8Rp)-6-ethoxycarbonyloxy-8-
iodo-1,8-dimethylcyclohex-2-oxa-3-phenyl-4-azabicyclo-
[3.3.1]non-3-ene-5-carboxylate /9a). Oil;IR nmax 1710,
1
1630 cm21; H NMR d 8.08±7.35 5m, 5H), 5.78, 2.52,
1.58 5ABX system, Jˆ14.6, 11.4, 4.7 Hz, 3H), 4.42±4.15
5m, 4H), 3.09, 1.85 5AB system, Jˆ14.1 Hz, 2H), 2.16 5s,
3H), 1.74 5s, 3H),1.40±1.22 5m, 6H). Anal. calcd: C, 48.94;
H, 5.09;N, 2.72. Found: C, 49.04;H, 5.19;N, 2.81.
3.7.4. /1Sp, 2Rp, 4Sp, 5Rp)-1-Amino-2,5-dihydroxy-4-
methylcyclohexanecarboxylic acid /11b). Operating in a
sealed tube, the compound 10b 5361 mg, 1 mmol) was
suspended in a solution of HCl 54 mL, 20%). The solution
was heated at 1008C for 16 h. The reaction mixture was
extracted with Et2O 52£10 mL) and H2O was evaporated
in vacuum to dryness. Pure amino acid hydrochloride 11b
5207 mg, 92%) was isolated. Mp 3008C dec. 5EtOH/propyl-
ene oxide);IR nmax 3400±3100, 1590 cm21; 1H NMR 5D2O)
d 4.15 5dd, Jˆ12.1, 5.1 Hz, 1H), 3.95, 2.10, 1.98 5ABX
system, Jˆ15.5, 3.0, 2.7 Hz, 3H), 1.92±1.75 5m, 2H),
1.45±1.32 5m, 1H), 0.93 5d, Jˆ7.4 Hz, 3H); 13C NMR
5D2O) d 17.0, 31.3, 34.0, 36.2, 65.0, 68.6, 69.7, 175.4.
Anal. calcd: C, 50.78;H, 7.99;N, 7.40. Found: C, 51.10;
H, 8.14;N, 7.21.
3.6.2. Ethyl /1Rp, 5Sp, 6Rp, 8Rp)-6-ethoxycarbonyloxy-8-
iodo-8-methylcyclohex-2-oxa-3-phenyl-4-azabicyclo[3.3.1]-
non-3-ene-5-carboxylate /9b). Oil;IR
nmax 1715,
1630 cm21; H NMR d 8.08±7.37 5m, 5H), 5.72, 2.55,
1.51 5ABX system, Jˆ15.4, 11.3, 4.4 Hz, 3H), 4.62±4.58
5m, 1H), 4.43±4.15 5m, 4H), 3.18 5dd, Jˆ13.9, 1.4 Hz, 1H),
2.19 5dd, Jˆ13.9, 4.01 Hz, 1H), 2.27 5s, 3H),1.38±1.24 5m,
6H). Anal. calcd: C, 47.92;H, 4.83;N, 2.79. Found: C,
47.58;H, 5.00;N, 2.89.
1
3.7. General procedure for preparation of compounds 10
To a stirred solution of iodo-oxazine 9 51 mmol) in anhy-
drous CH2Cl2 55 mL) under nitrogen atmosphere, the
Bu3SnH 5344 mL, 1.1 mmol) was added. The solution was
re¯uxed for 2 h and after solvent evaporation, the crude
reaction mixture was chromatographed 5CH2Cl2/Et2O, 1:0
to 0:1) giving compound 10 which was crystallized 510a:
80%, 10b: 78%).
3.8. General procedure for the iodo-lactonization
reaction
To a mixture of compound 5 51 mmol) and NaHCO3
584 mg, 1 mmol) in EtOH 57 mL), a solution of I2/I2

6436
F. Clerici et al. / Tetrahedron 57 /2001) 6429±6438
5H2O: 7 mL, I2: 572 mg, 2.2 mmol, KI: 1.1 g, 6.6 mmol)
was added. The mixture was stirred at room temperature
for 24 h 5compound 5b) or re¯uxed for 1.30 h 5compounds
5a,b). After cooling, a solid was separated. The solvent was
evaporated and the residue was taken up with CH2Cl2 and
washed with a solution of Na2S2O4 52£5 mL, 5%), H2O
55 mL) and dried over Na2SO4. The crude reaction mixture
was chromatographed 5CH2Cl2/Et2O, 1:0 to 0:1) giving
compound 13. In the case of 5b, a second fraction contain-
ing lactone 15 was isolated. After crystallization, pure
compounds 13a 5268 mg, 55%), 13b 5102 mg, 22%, 258C;
85 mg, 18%, re¯ux) and 15 5205 mg, 43%, 258C;294 mg,
62%, re¯ux) were isolated.
1.8 Hz, 1H), 2.47 5d, Jˆ11.7 Hz, 1H), 2.17±1.60 5m, 3H),
1. 56 5s, 3H), 1.40 5t, Jˆ7.3 Hz, 3H), 1.00 5d, Jˆ6.2 Hz,
3H). Anal. calcd: C, 63.15;H, 6.41;N, 3.88. Found: C,
63.10;H, 6.38;N, 3.94.
3.9.2. Ethyl /1Sp, 2Rp, 4Rp, 5Sp)-1-benzoylamino-4-
methylcyclohex-7-oxo-6-oxa-bicyclo[3.2.1]oct-2-yl-carbo-
nate /14b). Mp 1348C 5CH2Cl2/iPr2O). IR nmax 3220, 1780,
1740, 1620 cm21; 1H NMR d 7.84±7.41 5m, 6H), 5.13±5.10
5m, 1H), 4.69 5d, Jˆ6.2 Hz, 1H), 4.32 5q, Jˆ7.3 Hz, 2H),
3.51±3.39 5m, 1H), 2.44 5d, Jˆ11.7 Hz, 1H), 2.22±2.04 5m,
2H), 1.88±1.71 5m, 1H), 1.40 5t, Jˆ7.3 Hz, 3H), 1.10 5d, Jˆ
6.6 Hz, 3H). 13C NMR d 14.6, 18.4, 31.5, 33.4, 33.9, 64.0,
65.8, 74.5, 80.8, 127.4, 128.9, 132.4, 133.4, 156.8, 166.7,
173.1. Anal. calcd: C, 62.24;H, 6.09;N, 4.03. Found: C,
62.01;H, 6.27;N, 3.82.
3.8.1. Ethyl /1Sp, 2Rp, 4Sp, 5Sp)-1-benzoylamino-4-iodo-
4,5-dimethyl-7-oxo-6-oxa-bicyclo[3.2.1]oct-2-yl-carbonate
/13a). Mp 1898C 5CH2Cl2/Et2O). IR nmax 3310, 1765, 1710,
3.9.3. Ethyl /1Sp, 4Sp, 5Rp)-4-benzoylamino-1-methyl-3-
oxo-2-oxa-bicyclo[2.2.2]oct-5-yl-carbonate /16). Mp
1558C 5CH2Cl2/iPr2O). IR nmax 3325, 1740, 1729,
1
1630 cm21; H NMR d 7.83±7.42 5m, 5H), 7.59 5s, 1H,
exch.), 5.20±5.10 5m, 1H), 4.39 5q, Jˆ7.3 Hz, 2H), 3.40
5d, Jˆ12.1 Hz, 1H), 3.30 5dd, Jˆ12.1, 1.4 Hz, 1H), 2.87
5dd, Jˆ17.6, 1.4 Hz, 1H), 2.47 5dd, Jˆ17.6, 4.8 Hz, 1H),
2.20 5s, 3H), 1.87 5s, 3H), 1.40 5t, Jˆ7.3 Hz, 3H). Anal.
calcd: C, 46.83;H, 4.55;N, 2.87. Found: C, 46.60;H,
4.33;N, 2.61.
1
1660 cm21; H NMR d 7.84±7.40 5m, 5H), 7.02 5s, 1H,
exch.), 5.46 5dt, Jˆ9.7, 2.0 Hz, 1H), 4.22 5q, Jˆ7.3 Hz,
2H), 3.10±3.00 5m, 1H), 2.58±2.50 5m, 1H), 2.40±2.30
5m, 1H), 2.11±2.05 5m, 2H), 1.97 5dd, Jˆ15.3, 2.2 Hz,
1H), 1.49 5s, 3H), 1.32 5t, Jˆ7.3 Hz, 3H); 13C NMR d
14.6, 21.4, 25.3, 31.2, 41.2, 60.3, 65.3, 73.2, 80.5, 127.5,
128.9, 132.1, 134.8, 155.4, 167.4, 171.6. Anal. calcd: C,
62.24;H, 6.09;N, 4.03. Found: C, 63.11;H, 6.13;N, 3.78.
3.8.2. Ethyl /1Sp, 2Rp, 4Sp, 5Sp)-1-benzoylamino-4-iodo-4-
methyl-7-oxo-6-oxa-bicyclo[3.2.1]oct-2-yl-carbonate /13b).
Mp 1668C 5CH2Cl2/Et2O). IR nmax 3300, 1770, 1700,
1
1650 cm21; H NMR d 7.87±7.41 5m, 5H), 7.66 5s, 1H,
exch.), 5.20±5.10 5m, 1H), 4.87 5d, Jˆ6.2 Hz, 1H), 4.31
5q, Jˆ7.3 Hz, 2H), 3.61±3.45 5m, 1H), 3.30 5d, Jˆ
12.5 Hz, 1H), 2.90 5d, Jˆ17.6 Hz, 1H), 2.40 5dd, Jˆ17.6,
4.8 Hz, 1H), 2.20 5s, 3H), 1.40 5t, Jˆ7.3 Hz, 3H). Anal.
calcd: C, 45.68;H, 4.26;N, 2.96. Found: C, 45.40;H,
4.38;N, 3.21.
3.10. General procedure for hydrolysis of lactone
Lactone 14 or 16 51 mmol) was suspended in THF 510 mL).
H2O 50.4 mL) and NaOH 5152 mg, 4 mmol) were added and
the mixture was stirred at room temperature for 1 h. The
water solution was extracted with CH2Cl2 51£10 mL) and
then acidi®ed with HCl 510%, Congo red) and extracted
with AcOEt 53£10 mL). After drying over Na2SO4 and
recrystallization pure acid 17 517a: 95%; 17b: 97%) or 18
593%) was isolated.
3.8.3. Ethyl /1Rp, 4Sp, 5Rp, 7Rp)-4-benzoylamino-7-iodo-
1-methyl-3-oxo-2-oxa-bicyclo[2.2.2]oct-5-yl-carbonate
/15). Mp 1698C 5CH2Cl2/Et2O). IR nmax 3350, 1740,
1
1660 cm21; H NMR d 7.82±7.40 5m, 5H), 7.14 5s, 1H,
3.10.1. /1Sp, 2Rp, 4Rp, 5Sp)-1-Benzoylamino-2,5-dihy-
droxy-4,5-dimethylcyclohexanecarboxylic acid /17a).
exch), 5.39±5.31 5m, 1H), 4.40±4.30 5m, 1H), 4.30 5q,
Jˆ7.3 Hz, 2H), 3.53±3.38 5m, 1H), 3.23 5dd, Jˆ14.6,
2.2 Hz, 1H), 2.70 5dd, Jˆ15.8, 3.3 Hz, 1H), 2.62±2.50
5dq, Jˆ15.8, 9.5, 2.6 Hz, 1H), 1.64 5s, 3H), 1.35 5t, Jˆ
7.3 Hz, 3H). Anal. calcd: C, 45.68;H, 4.26;N, 2.96.
Found: C, 45.51;H, 4.30;N, 3.15.
1
Mp 2508C 5CH2Cl2). IR nmax 3315, 1705, 1640 cm21; H
NMR 5MeOD) d 7.87±7.44 5m, 5H), 4.35±4.34 5m, 1H),
2.58 5d, Jˆ14.4 Hz, 1H), 2.00±1.84 5m, 3H), 1.72±1.63 5m,
1H), 1.23 5s, 3H), 0.97 5d, Jˆ6.4 Hz, 3H); 13C NMR
5DMSO-d6) d 13.2, 27.8, 33.5, 34.7, 41.7, 62.9, 64.7,
70.2, 127.4, 128.5, 131.8, 134.4, 167.6, 176.5. Anal.
calcd: C, 62.53;H, 6.89;N, 4.56. Found: C, 62.32;H,
6.60;N, 4.76.
3.9. General procedure for the preparation of
compounds 14 and 16
Bu3SnH 50.27 mL, 1 mmol) was added to a solution of the
iodolactone derivative 13 or 15 51 mmol) in CH2Cl2
510 mL) under a nitrogen atmosphere. The reaction mixture
was re¯uxed for 6 h and, after solvent evaporation, the crude
reaction mixture was recrystallized from CH2Cl2/i-Pr2O
giving pure compound 14 514a: 75%, 14b: 74%) or 16
580%).
3.10.2. /1Sp, 2Rp, 4Rp, 5Sp)-1-Benzoylamino-2,5-dihy-
droxy-4-methylcyclohexanecarboxylic acid /17b). Mp
1878C 5CH2Cl2). IR nmax 3310, 1700, 1630 cm21 1H
;
NMR 5MeOD) d 7.83±7.46 5m, 5H), 4.28 5dd, Jˆ6.4,
6.3 Hz, 1H), 3.91±3.86 5m, 1H), 2.67 5d, Jˆ13.6 Hz, 1H),
2.40±2.32 5dd, Jˆ13.6, 9.0 Hz), 2.17±2.13 5m, 1H), 1.86±
1.83 5m, 2H), 1.06 5d, Jˆ7.1 Hz, 3H); 13C NMR 5MeOD) d
12.9, 32.1, 32.9, 34.5, 64.2, 67.95, 67.99, 127.2, 128.6,
131.8, 134.9, 169.7, 174.9. Anal. calcd: C, 61.42;H, 6.53;
N, 4.78. Found: C, 61.28;H, 6.70;N, 4.51.
3.9.1. Ethyl /1Sp, 2Rp, 4Rp, 5Sp)-1-benzoylamino-4,5-
dimethylcyclohex-7-oxo-6-oxa-bicyclo[3.2.1]oct-2-yl-
carbonate /14a). Mp 1238C 5Et2O). IR nmax 3250, 1780,
1
1725, 1620 cm21; H NMR d 7.85±7.42 5m, 6H), 5.18±
5.03 5m, 1H), 4.32 5q, Jˆ7.3 Hz, 2H), 3.19 5dd, Jˆ11.7,
3.10.3. /1Sp, 2Rp, 4Sp)-1-Benzoylamino-2,4-dihydroxy-4-

F. Clerici et al. / Tetrahedron 57 /2001) 6429±6438
6437
methylcyclohexanecarboxylic acid /18)Mp 1058C dec.
66.42;H, 6.62;N, 4.84. Found: C, 66.19;H, 6.87;N,
4.69. m/z 289 5M1).
5CH2Cl2/iPr21O). IR nmax 3475±3100, 1700, 1690,
1620 cm21; H NMR 5DMSO-d6) d 12.30 5s, 1H, exch.),
7.81±7.20 5m, 5H), 7.20 5s, 1H, exch.), 5.24 5d, Jˆ7.9 Hz,
1H, exch.), 4.24 5s, 1H, exch.), 4.07 5dd, Jˆ11.4, 4.8 Hz,
1H), 2.63 5d, Jˆ13.2 Hz, 1H), 2.21±2.00 5m, 1H), 1.78±
1.50 5m, 2H), 1.38±1.21 5m, 2H), 1.11 5s, 3H); 13C NMR
5DMSO-d6) d 30.9, 33.1, 43.0, 64.4, 68.3, 69.4, 127.1,
128.3, 131.2, 135.1, 167.6, 174.0. Anal. calcd: C, 50.78;
H, 7.99;N, 7.40. Found: C, 50.43;H, 8.10;N, 7.22.
3.11.2. /1Sp, 2Rp, 4Rp, 5Sp)-N-/2-Hydroxy-4,5-dimethyl-7-
oxo-6-oxabicyclo[3.2.1]oct-1-yl)-benzamide /22a). Mp
2508C 5CH2Cl2);IR nmax 3300±3150, 1775, 1625 cm21
;
1H NMR d 8.14±7.46 5m, 5H), 7.22 5s, 1H, exch.), 4.19±
4.17 5m, 1H), 3.46 5d, Jˆ11.4 Hz, 1H), 2.35±2.13 5m, 1H),
2.08 5dd, Jˆ11.4, 1.6 Hz, 1H), 2.00 5dq, Jˆ15.0, 5.6,
1.7 Hz, 1H), 1.53 5s, 3H), 1.41 5dq, Jˆ15.0, 11.5, 3.7 Hz,
1
1H), 1.00 5d, Jˆ6.2 Hz, 3H); H NMR 5CD3OD) d 8.06±
3.10.4. /1Sp, 2Rp, 4Rp, 5Sp)-1-Amino-2,5-dihydroxy-4,5-
dimethylcyclohexanecarboxylic acid /19a). Compound
19a was obtained as described for 7a in 70% yield. Mp
7.44 5m, 6H), 4.10±4.05 5m, 1H), 2.88 5dd, Jˆ11.0, 1.5 Hz,
1H), 2.56 5d, Jˆ11.2 Hz, 1H), 2.35±1.88 5m, 2H), 1.52 5s,
3H), 0.97 5d, Jˆ6.6 Hz, 3H); 13C NMR d 15.1, 22.7, 33.0,
37.0, 43.1, 67.0, 71.7, 88.3, 127.4, 128.5, 128.9, 169.8,
175.0. Anal. calcd: C, 66.42;H, 6.62;N, 4.84. Found: C,
66.21;H, 6.84;N, 4.73.
1
1528C 5acetone/Et2O). IR nmax 3500±3100, 1590 cm21; H
NMR 5D2O/DCl) d 4.09±4.06 5m, 1H), 2.64 5d, Jˆ12.1 Hz,
1H), 2.20 5dd, Jˆ12.1, 1.9 Hz, 1H), 1.98±1.87 5m, 2H),
1.52±1.46 5m, 1H), 1.43 5s, 3H), 0.82 5d, Jˆ6.6 Hz, 3H).
Anal. calcd: C, 53.19;H, 8.43;N, 6.89. Found: C, 53.00;H,
8.67;N, 6.61.
3.11.3. /1Sp, 2Rp, 4Rp, 5Sp)-N-/2-Hydroxy-4,5-dimethyl-7-
oxo-6-oxabicyclo[3.2.1]oct-1-yl)-benzamide /22b). Mp
1878C 5CH2Cl2);IR nmax 3300±3200, 1770, 1620 cm21
;
1H NMR 5CD3OD) d 7.86±7.48 5m, 6H), 4.65 5d, Jˆ
6.4 Hz, 1H), 4.06±4.04 5m, 1H), 3.14 5ddd, Jˆ11.1, 6.6,
1.7 Hz, 1H), 2.51 5d, Jˆ11.1 Hz, 1H), 2.25±1.88 5m, 2H),
157±1.51 5m, 1H), 1.03 5d, Jˆ6.8 Hz, 3H). Anal. calcd: C,
66.42;H, 6.62;N, 4.84. Found: C, 66.21;H, 6.84;N, 4.73.
3.10.5. /1Sp, 2Rp, 4Rp, 5Sp)-1-Amino-2,5-dihydroxy-4-
methylcyclohexanecarboxylic acid /19b). Compound
19b was obtained as described for 11b in 92% yield. Mp
1
2608C dec. 5acetone);IR nmax 3450±3000, 1600 cm21; H
NMR 5D2O) d 4.72 5d, Jˆ6.3 Hz, 1H), 4.00±3.98 5m, 1H),
2.51 5d, Jˆ11.7 Hz, 1H), 2.37 5ddd, Jˆ11.7, 6.2 Hz, 1.8,
1H), 2.04±1.81 5m, 2H), 1.47±1.31 5m, 1H), 0.81 5d,
Jˆ6.6 Hz, 3H); 13C NMR 5D2O) d 18.3, 30.1, 33.9, 34.5,
62.8, 65.9, 84.0,174.3. Anal. calcd: C, 42.58;H, 7.15;N,
6.21. Found: C, 42.23;H, 7.44;N, 6.00.
Acknowledgements
We thank MURST for ®nancial supports.
3.10.6. /1Sp, 2Rp, 4Sp)-1-Amino-2,4-dihydroxy-4-methyl-
cyclohexanecarboxylic acid /20). Compound 20 was
obtained as described for 7a in 60% yield. Mp 2368C
References
1
5EtOH);IR nmax 3500±3000, 1595 cm21; H NMR 5D2O,
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