Conformational analysis of four spiro[cyclohexane-1,3′-indolin]-2′-one derivatives

Conformational analysis of four spiro[cyclohexane-1,30-indolin]-

20-one derivatives

Judit Halasz, Benjamin Podanyi*, Andrea Santa-Csutor, Zsolt Bocskei,Kalman Simon, Miklos Hanusz, Istvan Hermecz

Chinoin Pharmaceutical and Chemical Works Company Ltd (a member of the Sanofi-Synthelabo Group),

To u. 1-5, H-1045 Budapest, Hungary

Received 16 January 2003; revised 20 March 2003; accepted 20 March 2003

Abstract

SR 121463 is a potent and selective, orally active vasopressin V2 receptor antagonist. During the synthesis of SR 121463, the

formation of the stereochemistry of the cyclohexyl moiety is one of the most important steps. Conformational analysis (via

NMR studies and, for cis-3, also via X-ray structure determination) of the isomers obtained in this step is reported.

q 2003 Elsevier Science B.V. All rights reserved.

Keywords: X-ray diffraction; NMR; Configuration; Conformation

1. Introduction

The importance of arginine vasopressin (AVP)

in the regulation of blood pressure and volume and

in the control of the fluid and electrolyte balances

is well established. AVP plays a major role as an

antidiuretic hormone regulating the water and

solute excretion by the kidney through specific

interaction with the renal V2 receptors [1,2].

Receptor-specific AVP V2 antagonists, known as

‘aquaretic agents’, could be of major therapeutic

value for the treatment of a number of water-

retaining disorders, such as SIADH (syndrome of

inappropriate antidiuretic hormone secretion), liver

cirrhosis, certain stages of congestive heart failure

and hypertension, and the nephritic syndrome

[3–6]. SR 121463 (Scheme 1) is the most potent

and selective, orally active V2 antagonist described

so far. The action of SR 121463 is purely aquaretic

[7], with no changes in urine Naþ and Kþ

excretion unlike the situation with other well

known diuretic agents such as furosemide or

hydrochlorothiazide. Total syntheses of SR

121463 were reported recently [8,9].

During the synthesis of SR 121463 [8,9], the

important intermediates 1 and 2 are the compounds

in which the stereochemistry of the cyclohexyl

moiety is formed (Scheme 2). Both the reduction of

oxo compound 1 and the ring opening of the cyclic

ketal moiety of 2 (Scheme 2) may yield isomers of

3 and 4, respectively, and theirs unambiguous

identification is needed. This can be achieved

only if the conformation of the spiro[cyclohexane-

1,30-indolin]-20-one ring system is established.

0022-2860/03/$ - see front matter q 2003 Elsevier Science B.V. All rights reserved.

doi:10.1016/S0022-2860(03)00226-6

Journal of Molecular Structure 654 (2003) 187–196

www.elsevier.com/locate/molstruc

* Corresponding author. Tel.: þ361-369-2500/2538; fax: þ361-

370-5597.

E-mail address: [email protected]

(B. Podanyi).

http://www.elsevier.com/locate/molstruc

Accordingly, we decided to perform detailed

investigations. The key intermediates in the syn-

thesis appear to be cis-3 or cis-4 [8,9] (Scheme 2).

The corresponding trans isomers of 3 and 4, which

are potential impurities, were also prepared as

model compounds for the NMR investigations.

Structural characterisation and conformational anal-

ysis of these four compounds are reported.

2. Experimental

2.1. Synthesis of compounds 3-4

2.1.1. cis-50-Ethoxy-4-hydroxyspiro[cyclohexane-

1,30-indolin]-20-one (cis-3)

50-Ethoxyspiro[cyclohexane-1,30-indoline]-4,20-

dione 1 [10] (38.89 g, 0.15 mol) was suspended in

methanol (500 ml). Solid NaBH4 (5.67 g, 0.15 mol)

was added in small portions with vigorous stirring and

water-cooling. A clear solution was formed, which

progressively transformed to a suspension. After

stirring for 15 min, the precipitate was removed by

filtration, and washed with water (100 ml) and

methanol (20 ml) to give the crude product (18.15 g,

46.3%, mp. 227–228 8C). Recrystallization from 96%

ethanol (400 ml) yielded pure cis-3 (14.11 g, mp.

228–229 8C) (lit. mp. 225 8C [11]).

2.1.2. trans-5 0-Ethoxy-4-hydroxyspiro[cyclohexane-

1,30-indolin]-20-one (trans-3)

The above methanolic mother liquor of cis-3 was

evaporated to dryness, the residue was suspended in

Scheme 1. SR 121463.

Scheme 2.

J. Halasz et al. / Journal of Molecular Structure 654 (2003) 187–196188

water (200 ml), the suspension was filtered and the

solid was washed thoroughly with water and some

methanol to give the crude trans isomer (17.25 g, mp.

165–195 8C). The purification was performed first by

crystallization from 96% ethanol (130 ml) and another

‘crop’ of cis-3 was removed (4.8 g, mp. 227–228 8C).

The evaporated filtrate was then further purified by

column chromatography on neutral Al2O3 (600 g),

with elution with chloroform: i-propanol (9:1). After

evaporation, the crude product (6.45 g) was recrystal-

lized from ethyl acetate to afford pure trans-3 (4.65 g,

mp. 185–186 8C) (lit. mp. 170 8C [11]).

2.1.3. cis-5 0-Ethoxy-4-(2-hydroxyethoxy)

spiro[cyclohexane-1,3 0-indolin]-2 0-one (cis-4)

To a stirred suspension of 50-ethoxyspiro[cyclo-

hexane-1,30-indoline]-4,20-dione cyclic 4-ethylene

ketal 2 [11] (40.4 g, 0.133 mol) in dichloromethane

(250 ml), a freshly prepared 0.29 M Zn(BH4)2

solution [12] (275 ml, 0.08 mol) and trimethylchlor-

osilane (43.5 ml, 0.35 mol) were added dropwise at

0 8C. The mixture was stirred at room temperature for

16 h, and then quenched by the addition of 1N HCl

solution (250 ml) and ethyl acetate (250 ml). The

organic layer was separated, washed twice with water,

and dried over MgSO4. After evaporation, the oily

residue was crystallized from diethyl ether, and

filtered off. Recrystallization from toluene (260 ml)

afforded cis-4 (19.3 g, mp. 125 8C) (lit. mp. 125 8C

[12]; 123–124 8C [13]).

2.1.4. trans-5 0-Ethoxy-4-(2-hydroxyethoxy)

spiro[cyclohexane-1,3 0-indolin]-2 0-one (trans-4)

A solution of 50-ethoxyspiro[cyclohexane-1,30-

indoline]-4,20-dione cyclic 4-ethylene ketal 2 [11]

(15.15 g, 0.05 mol) in dichloromethane (100 ml) was

added dropwise to a stirred solution formed from

LiAlH4 (1.9 g, 0.05 mol) in diethyl ether (100 ml) and

AlCl3 (26.6 g, 0.02 mol) in diethyl ether (150 ml) at -

5 8C. The mixture was left to warm to room

temperature and stirred for 2.5 h. The pH was set to

1 with 2N H2SO4 (150 ml) and extracted with ethyl

acetate (2 £ 250 ml). The organic extract was washed

with water, dried over Na2SO4 and evaporated. The

residue contained the cis and trans isomers in a ratio of

3:2. These were separated by column chromatography

on neutral Al2O3 (600 g), with elution with chloro-

form: i-propanol (9:1). After evaporation, the crude

product (4.1 g) was crystallized twice from ethyl

acetate to afford pure trans-4 (2.6 g, mp. 178-179 8C)

(lit. mp. 180 8C [11]).

2.2. NMR measurements, spectrum simulation

and AM1 calculations

The NMR spectra were recorded in pyridine-d5

and acetone-d6 on Bruker AVANCE DRX-400 and

DMX-800 NMR spectrometers, using standard Bru-

ker software. Spectrum simulation was carried out

with the gNMR program [14]. AM1 calculations were

performed with HyperChem software [15]. Starting

geometries were constructed by the Model Builder

function of the program setting the torsion angles for

the theoretical values of the two chair conformations

Table 1

Crystal data and experimental parameters for the X-ray diffraction

studies on cis-3

cis-3

Empirical formula C15H19NO3

Formula weight 261.31

Crystal system Monoclinic

Space group P21=a

Colour of crystal Colourless

Unit cell dimensions

a (A) 8.611(2)

b (A) 13.802(1)

c (A) 11.504(2)

a (8) 90

b (8) 99.15(1)

g (8) 90

Volume (A3) 1349.8(3)

Z 4

Density (calculated) 1.286 g cm23

Crystal size (mm) 0.5 £ 0.1 £ 0.1

m (Cu Ka) (mm21) 0.725

Scan type v=2u

Scan width ð1:57–0:30tan uÞ8

u range 3.89–75.17

Reflections collected 2881

Independent reflections 2687 ½RðintÞ ¼ 0:0501�

Absorption correction None

Data/restraints/parameters 2674/0/179

Final R indices ½I . 2sigmaðIÞ�

R1 0.0551

WR2 0.1315

Largest diff. peak 0.238

Largest diff. hole 20.217 eA23

J. Halasz et al. / Journal of Molecular Structure 654 (2003) 187–196 189

of the cyclohexyl ring. No restrains were used during

the calculations.

2.3. X-ray crystallography

Data on cis-3 were collected on an MSC Rigaku

AFC6s diffractometer. The crystal data and refine-

ment parameters are summarized in Table 1. Data

reduction, structure solution and refinement were

performed with teXsan [16], SHELXS-86 [17] and

SHELXL-93 [18], respectively. All hydrogen atoms

but H6 were generated.

3. Results and discussion

3.1. X-ray crystallography and theoretical

calculations

A single-crystal could be grown from one of

the two isomers of the hydroxy derivative 3 (mp.

228-229 8C) and its X-ray structure demonstrated that

it was the cis isomer. In the cis isomer, the 20-oxo

group of the indolinone ring and the OH group of the

cyclohexyl moiety are on the same side of the six-

membered ring, whereas they are on opposite sides in

the trans isomer. The ORTEP plot of cis-3 is

presented in Fig. 1. The cyclohexane ring has the

expected chair conformation, with the OH oxygen

atom in the equatorial, and the carbon of the amide

group in the axial position.

Two stable conformers of both isomers may exist

(Scheme 3), denoted eq and ax according to the

equatorial or axial steric position of the C-1 substituent

respectively. The upper structure (cis-eq) corresponds

to the conformation found in the solid state by X-ray

crystallography for cis-3. The recently reported

N-benzyl derivative of cis-3 was found to exhibit the

axial conformation in the crystal structure [8]. The

axial position of the OH in the solid state was explained

by the pairwise hydrogen-bonds formed by the hydroxy

groups and the amide carbonyls [8]. It is worthy of

mention that we observed a very similar dimer

formation for our cis-3 compound (Fig. 1). In cis-3,

Fig. 1. ORTEP diagram with intermolecular hydrogen-bonds of cis-3.


the N–H forms a second intermolecular hydrogen-

bond with the OH group [O2_a· · ·O1_b ¼ 2.791(4) A;

O2_a – H6_a…O1_b ¼ 168(1)8; N1_d· · ·O2_a ¼

2.874(4) A; N1_d–H7_d…O2_a ¼ 173(1)8. Sym-

metry transformation used to generate equivalent

molecules (a, b, c, d): a ðx; y; zÞ; b ð2x þ 2;2y þ

1; -z þ 2Þ; c ð2x þ 1;2y þ 1;2z þ 2Þ; d ðx þ 1; y; zÞ].

AM1 semiempirical energy calculations [15]

resulted in that the energy difference between the

two conformers is small; in solution, therefore, the

two conformers may exist in equilibrium. This

question was studied by NMR.

3.2. Assignment of the NMR spectra

The NMR spectra were measured in different

solvents in order to achieve the best 1H signal

separation. Pyridine-d5 appeared to be the most

appropriate solvent for the cis isomer of both

derivatives and trans-3, whereas acetone-d6 was so

for trans-4.

The 1H and 13C signal assignments (Table 2)

were based on the coupling patterns, and the

NOESY [19], HMQC [20] and HMBC [21] spectra.

The protons of the cyclohexyl ring are denoted a

or b, indicating their positions below or above the

reference plane of the cyclohexyl ring. The b-

hydrogens of the methylene groups, 2-H2 and 3-H2,

were identified on the basis of their cross-peaks

with 40-H in the NOESY spectra (Table 3).

The vicinal proton-proton coupling constants were

determined by first-order approximation from the

400 MHz proton spectrum of cis-4, and by first-order

analysis of the 1H NMR spectrum of trans-4,

Scheme 3. Conformational equilibria of 3 and 4.


Table 21H and 13C chemical shifts [ppm] and some proton-proton coupling constants (J [Hz]) of 3 and 4 in pyridine-d5

1H 13C

cis-3a trans-3a cis-4a trans-4a,b cis-3 trans-3 cis-4 trans-4c

1 4.20 4.20 3.66 3.60 67.9 67.7 76.1 76.5

2 a 2.68 2.46 2.49 2.23 30.1 30.6 26.4 27.7

b 2.18 2.18 2.04 1.77

3 a 2.31 2.18 2.21 1.69 31.4 31.0 30.9 31.4

b 1.87 2.04 1.74 1.82

20 – – – – 182.3 182.3 182.0 182.7

30 – – – – 46.9 47.8 46.9 48.5

3a0 – – – – 137.5 137.2 137.2 138.5

40 7.20 7.41 7.18 7.00 111.5 112.9 111.6 113.8d

50 – – – – 154.7 154.5 154.7 155.1

60 6.89 6.91 6.90 6.76 112.6 112.6 112.6 113.7d

70 6.98 7.03 6.99 6.83 109.5 109.7 109.5 111.0

7a0 – – – – 135e 135.2 135.2 135.9

80 3.97 3.86 3.98 4.00 63.9 63.7 63.8 65.3

90 1.33 1.29 1.34 1.34 14.7 14.7 14.7 15.9

OCH2 – – 3.81 3.60 – – 70.4 71.1

CH2OH – – 4.05 3.69 – – 61.8 63.1

OH 6.25 6.36 6.32 3.60 – – – –

NH 11.43 11.53 11.40 9.13 – – – –

a Coupling constants [Hz] of cis-3: J1,OH ¼ 4.2; J2a,2b ¼ 12.7; J3a,3b ¼ 13.8; J40 ,60 ¼ 2.6; J60 ,70 ¼ 8.5; J80 ,90 ¼ 6.9; coupling constants [Hz] of

trans-3: J1,OH ¼ 4.2; J40 ,60 ¼ 2.6; J60 ,70 ¼ 8.5; J80 ,90 ¼ 6.9; coupling constants [Hz] of cis-4: J2a,2b ¼ 13.1; J3a,3b ¼ 13.8; J40 ,60 ¼ 2.6;

J60 ,70 ¼ 8.5; J80 ,90 ¼ 6.9; JOCH2,CH2OH¼JCH2OH,OH ¼ 5.4; coupling constants [Hz] of trans-4b: J2a,2b ¼ 13.5; J3a,3b ¼ 13.0; J40 ,60 ¼ 2.3;

J60 ,70 ¼ 8.8; J80 ,90 ¼ 6.9.b Measured in acetone-d6 at 800 MHz.c Measured in acetone-d6.d Tentative assignment.e The correct chemical shift could not be determined because of overlapping with the solvent signal.

Table 3

Characteristic spatial proximities on the basis of the phase-sensitive NOESY spectra

Cross-peaks

cis-3 trans-3 cis-4

1-H 2-Ha; 2-Hb; 3-Hb 2-Ha; 2-Hb þ 3-Ha 2-Ha; 2-Hb; 3-Hb; OCH2

2-Ha 1-H; 2-Hb; 3-Ha 1-H; 2-Hb þ 3-Ha; 3-Hb 1-H; 2-Hb; 3-Ha; OCH2

2-Hb 1-H; 2-Ha; 3-Hb; 40-H 1-H; 2-Ha; 3-Hb; 40-H 1-H; 2-Ha; 3-Hb; OCH2; 40-H

3-Ha 2-Ha; 3-Hb 2-Ha; 3-Hb 2-Ha; 3-Hb

3-Hb 1-H; 2-Hb; 3-Ha; 40-H 2-Ha; 2-Hb þ 3-Ha; 40-H 1-H; 2-Hb; 3-Ha; 40-H

40-H 2-Hb; 3-Hb; 80-H2 2-Hb þ 3-Ha; 3-Hb; 80-H2 2-Hb; 3-Hb; 80-H2

60-H 80-H2 80-H2 80-H2

70-H NH

80-H2 40-H; 60-H 40-H; 60-H 40-H; 60-H

OCH2 – – 1-H; 2-Ha; 2-Hb

NH 70-H


measured at 800 MHz. For cis-3, the coupling

constants were determined by spectrum simulation,

performed with the gNMR program.

3.3. Identification of the isomers and qualitative

conformational analysis based on NOE measurements

NOE cross-peaks of the NOESY spectra are listed

in Table 3. The cross-peaks between 1-H and 3-Hb in

cis-3 and cis-4 prove that these compounds are cis

isomers, since these protons are not in steric proximity

in the conformers of the trans isomer. Further cross-

peaks of the 2D NOESY spectra, however, i.e. the

interactions between aromatic proton 40-H and 2-Hb,

and 3-Hb, prove the existence of both conformers in

solution. The former cross-peak relates to the cis-eq,

and the latter to the cis-ax conformer.

In the conformers of trans-3 obtained in the

calculations, 40-H showed spatial proximity to 3-Hb

in the trans-ax conformer, and to 2-Hb in the trans-eq

form. Cross-peaks due to these interactions were

observed in the NOESY spectrum, but the signals of

2-Hb and 3-Ha overlapped. The AM1 calculation

revealed that there can not be spatial proximity

between 3-Ha and 40-H in either conformer, and

consequently there can not be a NOESY cross-peak

between these protons, so the obtained cross-peak is

an indication of the 40-H,2-Hb spatial proximity.

According to the models obtained in the AM1

calculations, the distances between 40-H and 2-Hb in

the trans-eq, and between 40-H and 3-Hb in the

trans-ax conformers are nearly identical. The signal

corresponding to the trans-eq conformer is more

intense than the cross-peak of the trans-ax form,

indicating that the amount of the trans-eq form is

larger than that of the trans-ax form in the

conformational equilibrium.

3.4. Quantitative determination of the conformer ratio

from the coupling constants

The vicinal proton–proton coupling constants

were first determined from the 1H NMR spectrum,

and the coupling constants for both conformers were

Table 4

Determination of the ratio of the conformers from the coupling constant data (J [Hz])

Dihedral anglesa Jcalculatedb Jmeasured

c,d ‘eq’/’ax’ ratio

‘eq’ ‘ax’ ‘eq’ ‘ax’

cis-3c 3-Hb,2-Ha 174.8 63.5 13.59 2.38 10.4 72:28

3-Hb,2-Hb 55.9 255.2 3.77 4.01 3.8

3-Ha,2-Ha 57.0 254.6 3.62 4.10 3.8

3-Ha,2-Hb 261.9 2173.3 2.63 13.50 6.1 68:32

2-Hb,1-H 258.4 52.3 4.34 2.86 3.5

2-Ha,1-H 2176.3 264.8 11.33 3.22 8.9 70:30

cis-4c 3-Hb,2-Ha 175.6 63.6 13.61 2.36 10.2 70:30

3-Hb,2-Hb 56.7 254.8 3.64 4.05 3.9

3-Ha,2-Ha 57.4 254.1 3.48 4.15 4.1

3-Ha,2-Hb 261.5 2172.5 2.72 13.47 6.1 69:31

2-Hb,1-H 257.4 54.7 4.50 2.55 3.8

2-Ha,1-H 2175.5 263.3 11.30 3.41 8.7 67:33

trans24d 3-Hb,2-Ha 62.1 176.6 2.61 13.64 ,7 60:40

3-Hb,2-Hb 256.4 58.0 3.73 3.39 4.0

3-Ha,2-Ha 255.3 58.2 3.91 3.38 4.3

3-Ha,2-Hb 2173.8 260.4 13.54 2.92 9.3 61:39

2-Hb,1-H 177.8 61.3 11.44 3.73 8.0c 55:45

2-Ha,1-H 59.6 257.3 4.11 2.27 3.8c

a Determined from the results of the AM1 calculations.b Calculated via the modified Karplus equation [15].c Measured in pyridine-d5.d Measured in acetone-d6.


then calculated from the molecular geometry obtained

in the AM1 calculation by using the modified Karplus

equation [22]. In consequence of the fast interconver-

sion of the conformers, the measured coupling

constants are weighted averages. The ratio of the

two conformers can be calculated from the compari-

son of the measured and calculated coupling

constants.

From the coupling constants, the ratio of the two

conformers was calculated to be about ,7:3 for both

cis-3 and cis-4 (Table 4). The ratio of the conformers

was determined from the coupling constants between

protons with significantly different dihedral angles in

the two conformers. For both compounds, the 3-Hb,

2-Ha, 3-Ha,2-Hb and 2-Ha,1-H coupling constants

were significant, since these protons are antiperiplanar

in one conformer (dihedral angle ,1808) and gauche

oriented in the other conformer (dihedral angle ,608)

(Table 4).

Strong coupling appeared between 2-Hb and 3-Ha

in the spectrum of trans-3, which prevented determi-

nation of the coupling constants, but the splitting of

the 1-H signal for the trans-3 isomer is very similar to

that observed for the 1-H signal for the cis-3 isomer,

where the 1-H signal relates to the axial situation. If

the dominant conformer were trans-ax, where 1-H is

equatorial, the 1-H signals would differ significantly.

This suggests that in the dominant conformer of the

trans isomer this proton is in the axial position

(trans-eq conformer).

For trans-4, comparison of the measured and the

calculated coupling constants (Table 4) indicated that

the ratio of the trans-eq and trans-ax conformers was

about 55–60:45–40.

Fig. 2. 1H NMR spectra of cis-4 (a) and trans-4 (b) in acetone-d6 at 285 8C.


3.5. Low-temperature NMR measurements

The conformational equilibria of 3 and 4 were

also investigated in detail by means of dynamic

NMR measurements. At room temperature, the ring

inversion is fast and this yields only one signal set.

At low temperature, where the ring inversion is

sufficiently slow, two signal sets appear and the

intensities of the signals correspond to the popu-

lations of the conformers. The measurements were

carried out in acetone-d6. The proton spectra of

both isomers of 3 and 4 at about 285 8C showed

two NH and OH signals (two separated OH signals

also appeared for 4) and two aromatic signal sets.

Since the coupling constants and the intensities of

the NOESY cross-peaks demonstrate that the

dominant conformer of both isomers is the eq.

form, the integral values of the NH, OH or

aromatic signals lead to a cis-eq: cis-ax value of

79:21 in cis-3, and of 68:32 in cis-4 (Fig. 2),

while trans-eq: trans-ax is 86:14 in trans-3, and

62:38 in trans-4 (Fig. 2). The positions of the

amide group in the two conformers differ, which

can be reflected in the NH chemical shift; in the

cis isomers, the CyO is quasi-axial in the

‘equatorial’, and quasi-equatorial in the ‘axial’

conformer. In the trans isomer, the position of

the amide group is opposite to that in the cis

isomer. CyO is quasi-axial in the ‘axial’, and

quasi-equatorial in the “equatorial” conformer. In

cis-3 and cis-4, the NH chemical shift relating

to the cis-eq form is lower than that in the

corresponding ‘axial’ form [dðNHÞcis-eq ¼ 10:19 ppm

(cis-3) and dðNHÞcis-eq ¼ 9:84 ppm (cis-4); dðNHÞcis-ax ¼

10:42 ppm (cis-3) and dðNHÞcis-ax ¼ 10:09 ppm (cis-4)].

In trans-3 and trans-4, the chemical shift of the NH

signal of the major conformer is higher than that of

the minor conformer [dðNHÞtrans-eq ¼ 10:34 ppm

(trans-3) and dðNHÞtrans-eq ¼ 10:13 ppm (trans-4);

dðNHÞtrans-ax ¼ 10:04 ppm (trans-3) and dðNHÞtrans-ax ¼

9:87 ppm (trans-4)], which suggests that the CyO

group is quasi-equatorial in the major conformer.

These data further support that the dominant

conformer of both trans-3 and trans-4 is the

trans-eq form.

The conformational ratios obtained via the NMR

methods are summarized in Table 5.

4. Conclusions

The cis and trans isomers of 3 and 4, containing a

spiro[cyclohexane-1,30-indolin]-20-one ring system,

were identified by means of 2D NOESY measure-

ments. The conformational equilibria of the cis and

trans isomers of 3 and 4 in solution were investigated

by NMR spectroscopy. The dominant forms were

identified as the two chair conformers of the

cyclohexane ring, and the ratios of the conformers

were determined from the coupling constant data and

from low-temperature NMR measurements. In both

isomers, the conformer containing an equatorial OR

group in the cyclohexane ring is the dominant, but the

other conformer also exists in significant amounts.

References

[1] F. Morel, M. Imbert-Telboul, D. Charbardes, Kidney Int. 31

(1987) 512.

[2] C. de Rouffignac, B. Corman, N. Roinel, Am. J. Physiol. 244

(1983) 156 Renal Fluid Electrolyte Physiol., 13.

[3] F.A. Laszlo, F. Laszlo, D. De Wied, Pharmacol. Rev. 43

(1991) 73.

[4] S.C. Mah, K.G. Hofbauer, Drugs Future 12 (1987) 1055.

[5] M. Manning, W.H. Sawyer, J. Lab. Clin. Med. 114 (1989) 617.

[6] J.B. Sorensen, M.K. Andersen, H.H. Hansen, J. Int. Med. 238

(1989) 617.

[7] C. Serradeil-Le Gal, C. Lacour, G. Valette, G. Garcia, L.

Foulon, G. Galindo, L. Bankir, B. Pouzet, G. Guillon, C.

Barberis, D. Chicot, S. Jard, P. Vilain, C. Garcia, E. Marty, D.

Raufaste, G. Brossard, D. Nisato, J.P. Maffrand, G. Le Fur,

J. Clin. Invest. 98 (1996) 2729.

[8] H. Venkatesan, M.C. Davis, Y. Altas, J.P. Snyder, D.C. Liotta,

J. Org. Chem. 66 (2001) 3653.

[9] I. Hermecz, A. Santa-Csutor, Cs. Gonczi, G. Heja, E. Csikos,

K. Simon, A. Smelko-Esek, B. Podanyi, Pure Appl. Chem. 73

(2001) 1401.

Table 5

Conformational ratio of 3 and 4 determined from coupling constants

values and by dynamic NMR measurements

cis-3 trans-3 cis-4 trans-4

‘eq’ ‘ax’ ‘eq’ ‘ax’ ‘eq’ ‘ax’ ‘eq’ ‘ax’

Coupling

constants

,7 ,3 ,7 ,3 ,6 ,4

Dynamic

NMR

79 21 86 14 68 32 62 38


[10] L. Foulon, C. Serradeil-Le Gal, G. Valette, CT Int. Appl. WO

98 25,901, Chem. Abstr. 129 (1998) 67697.

[11] L. Foulon, C. Serradeil-Le Gal, G. Valette, CT Int. Appl. WO

97 15,556, Chem. Abstr. 127 (1997) 5010.

[12] T. Oishi, T. Nakata, in: L.A. Paquette (Ed.), Encyclopedia of

Reagents for Organic Synthesis, vol. 8, Wiley, New York,

1995, p. 5536.

[13] G. Heja, E. Csikos, Cs. Gonczi, J. Halasz, F. Hajdu, I.

Hermecz, L. Kis, L. Nagy, A. Santa-Csutor, K. Simon, T.

Szomor, Gy. Szvoboda, PCT Int. Appl. WO 01 05,759, Chem.

Abstr. 134 (2001) 115850.

[14] gNMR V4.1.0, P.H.M. Budzelaar, published by Cherwell

Scientific Limited, 1995–9.

[15] HyperChem for Windows version 6.02, Hypercube, Inc., 2000

[16] teXsan version 1.7, Crystal Structure Analysis Package,

Molecular Structure Corporation, 1995.

[17] SHELXS-86, G.M. Sheldrick, 1990.

[18] SHELXL-93, G.M. Sheldrick, 1993.

[19] J. Jeener, B.H. Meier, P. Bachmann, R.R. Ernst, J. Chem.

Phys. 69 (1979) 4546.

G. Wagner, K. Wuthrich, J. Mol. Biol. 155 (1982) 347.

[20] A. Bax, R.H. Griffey, J. Magn. Reson. 55 (1983) 301.

A. Bax, S.J. Subramanian, J. Magn. Reson. 67 (1986) 565.

[21] A. Bax, M.F. Summers, J. Am. Chem. Soc. 108 (1986) 2093.

[22] C.A.G. Haasnoot, F.A.A. de Leeuw, C. Altona, Tetrahedron

36 (1980) 2783.


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