WO2000032552A1

WO2000032552A1 - Process for the preparation of functionalized chiral cyclopentanes involving transformation of azanorbornyl derivatives

Info

Publication number: WO2000032552A1
Application number: PCT/SE1999/002253
Authority: WO
Inventors: Pher Andersson; Pedro Pinho
Original assignee: Astrazeneca Ab
Priority date: 1998-12-02
Filing date: 1999-12-01
Publication date: 2000-06-08
Also published as: SE9804176D0; AU2016200A

Abstract

The present invention relates to a novel process for the preparation of functionalized chiral cyclopentanes comprising the steps of transforming an azanorbornyl derivative into a substituted enantiomerically pure cyclopentane. Furthermore, the invention relates to certain novel intermediates and certain novel cyclopentane derivatives obtainable using said process.

Description

PROCESS FOR THE PREPARATION OF FUNCTIONALIZED CHIRAL CYCLOPENTANES INVOLVING TRANSFORMATION OF AZANORBORNYL

DERIVATIVES

TECHNICAL FIELD

The present invention relates to a novel process for the preparation of functionalized chiral 5 cyclopentane derivatives comprising the steps of transforming an azanorbomyl derivative into an enantiomerically pure substituted cyclopentane. Furthermore, the invention relates to certain novel intermediates and certain novel cyclopentane derivatives obtainable using said process.

l o BACKGROUND OF THE INVENTION

Functionalized chiral cyclopentanes are of considerable significance in medicinal chemistry, particularly as mimics of ribose. A large number of compounds containing a functionalized chiral cyclopentane moiety have been prepared and evaluated pharmacologically, particularly for their antibiotic and antiviral effects (G.W. Koszalka, is S.M. Daluge and F.L. Boyd, Ann. Reports in Medicinal Chemistry, Vol. 33, pages 163 - 171).

A.K. Saksena (Tetrahedron Letters, 1980, 21, 133-136) has reported a method for the synthesis of functionalized cyclopentane derivatives that involves the ring cleavage of 0 3-trichloromethyl-2-azabicycloheptane derivatives using zinc.

M. Maggini, M. Prato and G. Scorrano (Tetrahedron Letters, 1990, 31, 6243-6246) describe a method for the synthesis of functionalized cyclopentane derivatives that involves the ring cleavage of 3-(benzylcarbamato)-2-azabicycloheptane derivatives using 5 catalytic hydrogenation.

We now disclose a new and rapid methodology that gives access to functionalized chiral cyclopentanes in very good yield. DISCLOSURE OF THE INVENTION

In a first aspect the invention relates to a process for the preparation of chiral cyclopentanes of general formula (1)

(1)

wherein

R represents a carboxylic acid derivative or a sulphonic acid derivative;

2 3

R and R independently represent H, Cl to 6 alkyl, aryl, OH, NH₂ or halogen;

and R represents H, Cl to 6 alkyl or aryl;

by transforming an azanorbomyl derivative of general formula (2)

(2)

wherein R , R , R and R are as defined above, and X represents halogen; by treatment with an alkali, alkaline earth or transition metal in an aprotic solvent. Scheme 1

Metal Aprotic solvent

(2) (1 )

Chiral cyclopentanes of general formula (1) may be alternatively depicted as shown in 5 general formula (la):

(1a)

It is a particular feature of the process shown in Scheme 1 that the group R represents a ^~ϊo carboxylic acid derivative or a sulphonic acid derivative. Thus, if instead R represents 1-phenylethyl, the reaction does not proceed in a regiospecific manner and a mixture of two products B and C are formed in approximately equal amounts (Scheme 2): Scheme 2

B

In formulae (1) and (2) above, it is preferred that R represents benzoyl, trifluoroacetyl, nitrobenzoyl, benzenesulphonyl, p-toluenesulphonyl (tosyl), nitrobenzenesulphonyl, methanesulphonyl or trifluoromethanesulphonyl. It is particularly preferred that R represents tosyl.

In the process shown in Scheme 1 it is preferred that the alkali, alkaline earth or transition metal is magnesium, lithium, sodium or potassium. It is particularly preferred that the metal is magnesium.

In the process shown in Scheme 1 it is preferred that the aprotic solvent is diethyl ether, tetrahydrofuran, NN-dimethylformamide, hexane or toluene, or a mixture thereof.

It will be readily apparent to the man skilled in the art that in the above process it may be

2 3 4 desirable or necessary for the groups R , R and R to be present in a suitably protected form. In particular hydroxyl and amine groups may need to be protected. Suitable protecting groups are described in the standard text "Protective Groups in Organic Synthesis", 2nd Edition (1991) by Greene and Wuts. Amine protecting groups that may be mentioned include alkyloxycarbonyl such as t-butyloxycarbonyl, phenylalkyloxycarbonyl such as benzyloxycarbonyl, or trifluoroacetate. Hydroxy groups may, for example, be protected as the corresponding acetal or acyl derivative. Methods for the addition and removal of such protecting groups are well known in the art and are described, for example, in the above mentioned text.

Compounds of formula (2) may be prepared using methodology that has been previously disclosed.

It is preferred that the necessary chiral templates (5) are obtained (Scheme 3) via a diastereoselective aza-Diels-Alder reaction between cyclopentadiene (3) and an in situ generated imine derivative (4) wherein the group R represents a chiral auxiliary (L. Stella et al, Tetrahedron Letters, 1990, 31, 2603-2606; Tetrahedron, 1992, 48, 9707-9718).

Scheme 3

(3) (4) (5)

Compounds of formula (5) may then be transformed into compounds of formula (2) by chemical manipulation of the alkene, R and R groups using reactions that are, in general, well known in the art.

Thus, for example, the alkene group may be removed by hydrogenation in the presence of a metal catalyst such as Pt, Pd or Rh. Alternatively, the alkene may be functionalised by reactions such as epoxidation, aziridination, dihydroxylation or diamination, for example, by catalytic dihydroxylation using osmium tetroxide. The stereochemistry of any hydroxy group thus introduced may be manipulated using Mitsunobo chemistry and/or the hydroxy substituents may be chemically transformed into a variety of other functional groups. In such ways a wide

2 3 variety of groups R and R may be introduced into eventual compounds of general formula (2) in a stereochemically controlled fashion.

The chiral group R may itself be chemically manipulated. Alternatively the group R may be removed to give the corresponding -NH- compound which can then be used to generate -NR - compounds of general formula (2).

In one preferred embodiment of the reaction shown in Scheme 3, R represents an ester

7 7 group CO₂R wherein R represents Cl to 3 alkyl. In such cases, reduction of the product (5) yields the corresponding hydroxymethyl compound (5; R = CH₂OH). This reduction may be performed using reducing agents that are well known in the art, for example, lithium aluminium hydride or sodium/alcohol. The hydroxymethyl compound may then be converted into the halomethyl compound (5; R = CH₂Hal) under standard conditions, for example, by treatment with triphenylphosphine and a carbon tetrahalide, or with triphenylphosphine and a halogen, or with a phosphorus halide or phosphorus oxyhalide.

In a particularly preferred embodiment of reaction shown in Scheme 3, the compound of formula (4) represents an in situ generated imine derivative (6) of ethyl glyoxylate and (S)- 1 -phenylethylamine:

C0₂Et

N Ph

(6)

whereby the product (5) represents the compound (7):

In one preferred further embodiment, hydrogenation and hydrogenolysis of compound (7) then affords the key chiral intermediate (8) (D. Guijarro, P. Pinho and P.G. Andersson, J. Org. Chem., 1998, 63, 2530-2535).

(8)

In another preferred further embodiment, compound (7) is dihydroxylated using osmium tetroxide in the presence of 4-methylmorpholine N-oxide as a co-oxidant to afford the diol (9)

(9)

The diol (9) is then protected as the dimethylacetal derivative by treatment with 2,2-dimethoxypropane and p-toluenesulphonic acid in methanol. Hydrogenolysis of the N-phenethyl group under literature conditions (D. Guijarro, P. Pinho and P.G. Andersson, J. Org. Chem., 1998, 63, 2530-2535) then affords the further key intermediate (10)

(10)

Normally the functionalised chiral cyclopentanes of formula (1) formed by the process of the present invention are further reacted to give cyclopentane derivatives of general formula (11) (Scheme 4):

Scheme 4

(1) (11)

wherein R⁸ is CH-OH, CHO, CO₂H, CONRV , CO₂R' ^] and R⁹ R¹⁰ and R¹ 'are Cl to 6 alkyl, aryl or Cl to 3 alkyl-aryl; using methods that will be readily apparent to the man skilled in the art.

Thus, the carbon-carbon double bond may be cleaved using, for example, ozone, or periodic acid, or lead tetraacetate, or potassium permanganate, and the resulting product may be further manipulated by reduction, esterification or amidation.

Functionalized chiral cyclopentanes of general formula (11) are of considerable importance as templates for the synthesis of carbocyclic ribose analogues. In a second aspect, the invention relates to certain key intermediates in the process, that is, the following azanorbomyl derivatives:

wherein Ts represents a p-toluenesulphonyl group.

And, in a third aspect, the invention relates to the following novel chiral cyclopentane derivatives:

wherein Ts represents a p-toluenesulphonyl group.

The invention is illustrated by the following non-limiting examples that are summarised in Schemes 5 and 6.

Scheme 5

(8)

Key: (/) TsCl, Et₃N, CH₂C1₂, room temperature, overnight, 92%; LiAIH₄, tetrahydrofuran, room temperature, 2 h, 95%; (if) CBr₄, Ph₃P, CH₂C1₂, room temperature, overnight, 60-70%; (Hi) Mg, BrCH₂CH₂Br, tetrahydrofuran, reflux, 24 h, 90%.

Scheme 6

(9)

Key: (f) (MeO)₂C(CH₃)₂, TsOH, MeOH, reflux, 1 h, 87%;

(tO H₂, Pd-C (10%), EtOH, room temperature, 48 h, 99%; TsCl, Et₃N, CH₂C1₂, room temperature, overnight, 90%; LiAIH4, tetrahydrofuran, room temperature, 2 h, 92%; CBr₄, Ph₃P, CH₂C1₂, room temperature, overnight, 60-70%;

(Hi) Mg, BrCH₂CH₂Br, tetrahydrofuran, reflux, 32 h, 89%.

All NMR data were recorded for solutions in CDC1,

Example 1

Ethyl (IS, 3R, 4R)-2-azabicyclo[2.2Jlheptane-3-carboxylate

The title compound was prepared following a literature procedure (D. Guijarro, P. Pinho and P.G. Andersson, J. Org. Chem., 1998, 63, 2530-2535).

Example 2

(IS, 3R, 4R)-2-tosyl-2-azabicyclo 2.2J1heptane-3-methanol

(a) Ethyl (IS, 3R, 4R)-2-tosyl-2-azabicyclo[2.2J]heptane-3-carboxylate The amino ester (Example 1) (5.4 g, 32 mmol) was dissolved in dichloromethane (20 mL) under argon. To this solution was added triethylamine (9.2 mL, 80 mmol) and the mixture was then cooled to 0 °C before dropwise addition of a solution of tosyl chloride (9J g, 48 mmol) in dichloromethane (20 mL). The ice-bath was then removed and the reaction mixture allowed to stir at room temperature overnight. Evaporation of the solvent afforded a residue that upon purification by flash chromatography on silica gel yielded ethyl (IS, 3R, 4R)-2-tosyl-2-azabicyclo[2.2J]heptane-3-carboxylate (9.5 g, 29 mmol, 92%) as a white solid, m.p. 87-88 °C. [α]_D ²⁵ + 84.8° (c = 1.60, dichloromethane); 'H-NMR δ 1.22 (3H, t, J= 7.2 Hz), 1.31 (IH, d, J= 9.6 Hz), 1.40 - 1.78 (3H, m), 1.94 - 2.05 (2H, m), 2.40 (3H, s), 2.70 (IH, br s), 3.94 (IH, s), 4.05 - 4.18 (3H, m), 7.28 (2H, d, J = 8.4 Hz) and 7.83 (2H, ά, J= 8.4 Hz); MS (El) ^m/z 324 (M⁺).

(b) (IS, 3R, 4R)-2-tosyl-2-azabicyclo[2.2.1 ]heptane-3-methanol The compound from Example 2(a) (9.4 g, 29 mmol) in dry tetrahydrofuran (20 mL) was added dropwise at 0 °C to a suspension of lithium aluminium hydride (2.2 g, 58 mmol) in dry tetrahydrofuran (20 mL) under argon. After addition was complete, the ice-bath was removed and the reaction mixture was stirred at room temperature for 2h. The mixture was then re-cooled to 0 °C and hydrolysis was performed by the careful dropwise addition of water (2.2 mL), 5% sodium hydroxide solution (2.2 mL) and water (6.6 mL). The mixture was then filtered through celite and the filter cake carefully washed with four portions of ether (10 mL). The combined organic layers were dried with magnesium sulphate and then evaporated to afford a residue that was purified by flash chromatography on silica gel to yield the title compound (7.7 g, 27 mmol, 95%) as a colourless oil. [α ]_D ²⁴ + 86.5° (c = 1.00, dichloromethane);

'H NMR δ 0.99 - 1.05 (IH, m), 1.25 - 1.40 (2H, m), 1.50 - 1.60 (2H, m), 1.81 (IH, br d, J= 8.0 Hz), 2.41 - 2.44 (IH, m), 2.42 (3H, s), 2.85 (IH, m), 3.25 (IH, t, J= 5.2 Hz), 3.50 - 3.56 (IH, m), 3.70 - 3.76 (IH, m) 4.18 (IH, s), 7.29 (2H, d, J= 8.0 Hz) and 7.76 (2H, d, J= 8.0 Hz); MS (EI) ^m/z 281 (M⁺).

Example 3

(IS, 3R, 4R)-2Josyl-2-azabicyclo|^"2.2J1heptane-3-methylbromide

To a solution of the product from Example 2 (7.5 g, 27 mmol) in dry dichloromethane (20 mL) was added under argon at room temperature a solution of carbon tetrabromide (13 g, 40 mmol) in dichloromethane (20 mL). The mixture was allowed to stir for 10 min before a solution of triphenylphosphine (8.5 g, 32 mmol) in dichloromethane (20 mL) was added dropwise. CAUTION: Fast addition will cause the solvent to boil. The reaction mixture was then stirred at room temperature for 24 h. The solvent was then evaporated and the resulting residue purified by flash chromatography on silica gel to yield the title compound (6.3 g, 18 mmol, 68%), m.p. 155-156 °C, preceded by decomposition; [α]_D ²⁵ + 106.2° (c = 1.07, dichloromethane); 'H-NMR δ 1.01 - 1.15 (lH, m), 1.29 1.40 (2H, m), 1.53 - 1.65 (2H, m), 1.78 (IH, br d, J= 8.8 Hz), 2.44 (3H, s), 2.77 (IH, br s), 3.03 - 3.09 (IH, m), 3.42 - 3.47 (IH, m), 3.69 - 3.73 (IH, m), 4.19 (IH, s), 7.31 (2H, d, = 8.0 Hz) and 7.75 (2H, d, J= 8.0 Hz); MS (El) ^m/z 344 (M⁺).

Example 4

(IS, 3R)-l-Tosylamino-3-vinylcyclopentane

Magnesium metal (3.0 g, 123 mmol), previously activated with iodine, was placed in a two-neck round bottom flask under argon and dry tetrahydrofuran (3 mL) was added. The mixture was stirred and heated to reflux and a solution of the product of Example 3 (6.0 g, 17 mmol) in dry tetrahydrofuran (20 mL) was added in one portion. After stirring for 15 minutes, 1,2-dibromoethane (4.4 mL, 51 mmol) was added and the mixture was heated under reflux for 24h. The reaction mixture was then cooled to 0 °C and quenched by the addition of saturated ammonium chloride solution. After separation of the phases and extraction of the water phase with dichloromethane, the combined organic layers were dried with magnesium sulphate. Solvent evaporation afforded a residue that was purified by flash chromatography on silica gel to yield the title compound (4J g, 15 mmol, 90%) as a white solid, m.p. 65-66 °C. [α]_D ²⁴ = - 8.9° (c = 1.00, dichloromethane); 'H-NMR δ 1.14 - 1.24 (IH, m), 1.38 - 1.45 (2H, m), 1.62 - 1.79 (IH, m), 1.80 - 1.90 (IH, m), 1.99 - 2.10 (IH, m), 2.34 - 2.42 (IH, m), 2.41 (3H, s), 3.57 - 3.63 (IH, m), 4.83 - 4.94 (2H, m), 5.65 - 5.75 (IH, m), 7.28 (2H, d, J= 8.0 Hz) and 7.76 (2H, d, J= 8.0 Hz); MS (El) ^m/z 264 (M⁺).

Example 5 Ethyl 2-[(S)-l-phenylethyll-2-azabicyclo[2.2J]heptane-5,6-dihydroxy-3-carboxylate

Ethyl 2-[(S)-l-phenylethyl]-2-azabicyclo[2.2J]hept-5-ene-3-carboxylate (D. Guijarro, P. Pinho and P.G. Andersson, J. Org. Chem., 1998, 63, 2530-2535) (2.3 g, 8.5 mmol) was dissolved in t-butyl alcohol (15 mL). To the stirred solution was then added osmium tetroxide (43 mg, 0. 17 mmol) and a 60% aqueous solution of 4-methylmorpholine N- oxide (15 mL, 87 mmol). After stirring for 24h the reaction was quenched by the addition of sodium disulphite, the solvent was then evaporated off and the resulting residue was partitioned between water and ethyl acetate. The organic extracts were dried with magnesium sulphate and evaporation of the solvent then afforded a residue that was purified by flash chromatography on silica gel to yield the title compound (2J g, 6.9 mmol, 81%) as an orange oil.

[α]_D ²⁴ + 3.6° (c = 0.92, dichloromethane);

'H-NMR δ 0.92 (3H, t, J= 7.2 Hz), 1.44 (3H, d, .7=6.4 Hz), 1.79 (IH, d, j= 10.8 Hz), 1.96 (IH, d, J= 10.8 Hz), 2.24 (IH, s), 2.50 (IH, s), 3.20 - 3.60 (2H, m), 3.53 - 3.61 (2H, m), 3.62 - 3.80 (2H, m), 3.84 (IH, d, J= 5.2 Hz), 4.30 (IH, d, J= 4.8 Hz) and 7.15 - 7.30 (5H, m);

MS (El) ^m/z 305 (M⁺).

Example 6

Ethyl 2-r(S)-l-phenylethyll-2-azabicyclo[2.2J1heptane-5,6- diol-3-carboxylate dimethylketal

The product from Example 5 (2.0 g, 6.5 mmol) was dissolved in methanol (20 mL) and warmed (not to reflux) under argon. To the hot solution were added ?-toluenesulphonic acid monohydrate (1.36 g, 7.2 mmol) and 2,2-dimethoxypropane (2.0 mL, 16 mmol). The mixture was stirred for 1 h after which it was diluted with cyclohexane. The solvent was reduced to a quarter of the original volume and the resulting residue was partitioned between water and ethyl acetate, sodium hydroxide solution was added until pH 10 and the resulting mixture stirred for 10 min. The organic layer was separated, washed with water and dried with magnesium sulphate. Solvent evaporation afforded the title compound (1.9 g , 5.6 mmol, 87%) as a pale yellow oil. [α]_D ²⁴ + 4.5° (c - 0.95, dichloromethane);

'H-NMR δ 0.92 (3H, t, J= 7.2 Hz), 1.34 (3H, s), 1.43 (3H, s), 1.45 (3H, ά, J= 6.4 Hz), 1. 74 (1 H, ά, J= 10. 8 Hz), 1.95 (IH, ά, J= 10. 8 Hz), 2.34 (IH, s), 2.41 (IH, s), 3.60 (IH, q, J= 6.4 Hz), 3.64 - 3.79 (2H, m), 4J6 (IH, d, J= 5.2 Hz), 4.5 5 (IH, d, J= 5.2 Hz) and 7J5 - 7.30 (5H, m); MS (El) ^m/z 345 (M⁺).

Example 7

3-Bromomethyl-2-tosyl-2-azabicyclo[2.2.1 ]heptane-5,6-diol dimethylketal

The product from Example 6 was hydrogenolysed to give ethyl 2- azabicyclo[2.2J]heptane-5,6-diol-3-carboxylate dimethylketal using a literature procedure (D. Guijarro, P. Pinho and P.G. Andersson, J. Org. Chem., 1998, 63, 2530-2535) (99% yield). The product was obtained as low melting yellow solid. [α]_D ²⁴² - 11.8° (c = 0.94, dichloromethane);

'H-NMR δ 1.20 - 1.32 (6H, m), 1.43(3H, s), 1.73 (IH, ά, J= 10.8 Hz), 2.10 (IH, m), 2.66 (IH, br s), 3.05 (IH, br s), 3.44 (IH, br s) and 4.05 - 4.25 (5H, m); ¹³C-NMR δ 14.2, 24.2, 25.5, 28.8, 44.5, 57.3, 57.6, 61.5, 80.6, 81.6, 110.2 and 173.8; MS (El) ^m/z 241 (M⁺).

The resulting amino ester was N-tosylated to give ethyl 2-tosyl-2- azabicyclo[2.2J]heptane-5,6-diol-3-carboxylate dimethylketal (90% yield) using the same procedure as described for Example 2(a). The product was obtained as a white solid, m.p.

69-70 °C.

[ ]_D ²⁵ + 47.9° (c = 1.00, dichloromethane);

'H-ΝMR δ 1.25 (6H, m), 1.39 (3H, s), 1.75 - 1.84 (2H, m), 2.41 (3H, s), 2.71 (IH, s), 3.85 (IH, s), 3.92 (IH, s), 4.05 - 4.15 (2H, m), 4.30 (IH, d, -/== 5.2 Hz), 4.63 (IH, d, J= 5.2 Hz),

7.28 (2H, d, J= 8.4 Hz) and 7.83 (2H, d, J= 8.4 Hz);

MS (El) ^m/z 395 (M⁺).

This Ν-tosyl derivative was reduced using lithium aluminium hydride under the same conditions as described for Example 2(b) to afford 3-hydroxymethyl-2-tosyl-2- azabicyclo[2.2.1]heptane-5,6-diol dimethylketal (92% yield) as a colourless oil.

[α]_D ²⁴ + 32.8° (c = 0.80, dichloromethane);

'H-ΝMR δ 1.17 (3H, s), 1.38 (3H, s), 1.62 (IH, d, J= 10.8 Hz), 1.82 (IH, d, J= 10.8 Hz),

2.43 (3H, s), 3.18 (IH, s), 3.20 (IH, t, J= 5.6 Hz), 3.50 - 3.54 (IH, m), 3.73 - 3.77 (IH, m), 4.00 (2H, br s), 4.29 (IH, d, J= 5.6 Hz), 7.31 (2H, ά, J= 8.0 Hz) and 7.76 (2H, d, J= 8.0

Hz);

MS (El) ^m/z 353 (M⁺). This hydroxymethyl compound was converted into 3-bromomethyl-2-tosyl-2- azabicyclo[2.2J]heptane-5,6-diol dimethylketal (67% yield) using the procedure described for Example 3. The product was obtained as a pale yellow oil.

[α]_D ²⁵ + 37.1° (c = 1.00, dichloromethane);

'H-NMR δ 1.19 (3H, s), 1.39 (3H, s), 1.56 (IH, d, j= 11.2 Hz), 1.86 (IH, d, J= 11.2 Hz),

2.44 (3H, s), 2.84 (IH, br s), 3.01 (IH, t, J =10.8 Hz), 3.39 - 3.44 (IH, m), 3.61 - 3.65 (IH, m), 4.01 (IH, br s), 4.08 (IH, m), 4.35 (IH, d, J= 5.6 Hz), 7.32 (2H, d, J= 8.4 Hz) and

7.74 (2H, d, .7= 8.4 Hz);

MS (EI) ^m/z 415 (M⁺).

Example 8

1 -Tosylamino-4-vinylcyclopentane-2,3-diol dimethylketal

The product from Example 7 was submitted to the same procedure as described for Example 4 to yield after flash chromatography the desired title compound (89% yield) as a yellow solid, m.p. 109- 110 °C. [α]_D ²⁵ + 14.5° (c = 0.7 1, dichloromethane);

'H-NMR δ 1.22 (3H, s), 1.40 (3H, s), 1.44 - 1.51 (IH, m), 2.18 - 2.27 (IH, m), 2.43 (3H, s), 2.60 - 2.70 (IH, m), 3.56 - 3.63 (IH, m), 4.38 - 4.45 (2H, m), 4.70 - 4.77 (IH, m), 5.06 - 5.12 (2H, m), 5.80 - 5.89 (IH, m), 7.30 (2H, d, J= 8.0 Hz) and 7.77 (2H, d, J= 8.0 Hz); MS (El) ^m/z 337 (M⁺).

Claims

A process for the preparation of chiral cyclopentanes of general formula (1)

(1 )

wherein

R represents a carboxylic acid derivative or a sulphonic acid derivative;

2 3

R and R independently represent H, Cl to 6 alkyl, aryl, OH, NH₂ or halogen;

and R represents H, Cl to 6 alkyl or aryl;

by transforming an azanorbomyl derivative of general formula (2)

(2)

wherein R , R , R and R are as defined above, and X represents halogen; by treatment with an alkali, alkaline earth or transition metal in an aprotic solvent.

2. A process according to Claim 1 wherein R represents benzoyl, trifluoroacetyl, nitrobenzoyl, benzenesulphonyl, p-toluenesulphonyl (tosyl), nitrobenzenesulphonyl, methanesulphonyl or trifluoromethanesulphonyl.

A process according to Claim 1 wherein R represents p-toluenesulphonyl.

4. A process according to any one of Claims 1 to 3 wherein the metal is magnesium, lithium, sodium or potassium.

5. A process according to Claim 4 wherein the metal is magnesium.

6. A process according to any one of Claims 1 to 5 comprising the further step of converting the compound of general formula (1) into a compound of general formula (11)

(1 ) (11 )

wherein R⁸ is CH₂OH, CHO, CO₂H, CONR⁹R¹⁰, CO₂R^! ' and R⁹ R¹⁰ and R¹ 'are Cl to 6 alkyl, aryl or Cl to 3 alkyl-aryl.

7. Azanorbomyl derivatives characterised by the following formulae:

8. Cyclopentanes characterised by the following formulae: