PROCESS FOR THE PREPARATION OF COMPOUNDS CONTAINING AN AZACYCLIC RING SYSTEM

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of compounds containing an azacyclic ring system, and compounds prepared by the process. The present invention further relates to novel compounds containing an azacyclic ring system.

BACKGROUND

The development of small molecule ligands for the extensive array of therapeutically important drug targets presents an ongoing challenge to organic chemists.

The chemistry and biology of nicotinic acetylcholine receptors (nAChRs) is currently of interest in the field of drug development. These receptors have been implicated as playing a key role in conditions such as epilepsy, Alzheimer's disease and schizophrenia.

Methyllycaconitine is a selective and potent α7 nAChR antagonist. A range of small molecule analogues of methyllycaconitine suitable for therapeutic applications have been synthesised and evaluated at nAChR ligands (Barker, D.; Brimble, M. A.; McLeod, M. D. Tetrahedron 2004, 60, 5953-5963; Barker, D.; Brimble, M. A.; McLeod, M. D.; Savage, G. P. Org. Biomol. Chem. 2004, 2, 1659-1669).

It has been shown that compounds such as 1 act as antagonists in functional assays of nicotinic receptors (Barker, D.; Lin, D. H.-S.; Garland, J. E.; Chu, C. P. -Y.; Chebib, M.; Brimble, M. A.; Savage, G. P.; McLeod, M. D. Bioorg. Med. Chem. 2005, 13(14), 4565).

1

It would be desirable to identify other compounds active at nicotinic acetylcholine receptors.

The direct synthesis of azabicycles such as 2 from cyclic ketones under standard conditions is limited in scope, low yielding and, in many cases, fails to afford the desired azabicyclic ring systems (Jeyaraman, R.; Avila, S. Chem. Rev. 1981, 18, 149; House, H. O.; Wickham, P. P.; Muller, H. C. J Am. Chem. Soc. 1962, 84, 3139;

Ohki, E.; Oida, S.; Ohashi, Y.; Yoshida, A.; Kamoshita, K.; Takagi, H. Chem. Pharm.

Bull. 1914, 22, 1014; Bailey, B. R., Ill; Berlin, K. D.; Holt, E. M.; Scherlag, B. J.;

Lazzara, R.; Brachmann, J.; Van der Helm, D.; Powell, D. R.; Pantaleo, N. S.;

Ruenitz, P. C. J. Med. Chem. 1984, 27, 758; Afsah, E. M.; Metwally, M. A.; Khalifa, M. M. Monatsh. Chem. 1984, 115, 303; Kim, D.-L; Schweri, M. M.; Deutsch, H. M.

J. Med. Chem. 2003, 46, 1456). hi some cases, azabicycles have been prepared by lengthy indirect synthesis, such as the reaction of dialkyl cyclohexanone-2,6-dicarboxylate substrates followed by ester hydrolysis and decarboxylation (Weatherbee, C; Adcock, W. E.; Winter, D. J. Org. Chem. 1957, 22, 465; Blicke, F. F.; McCarty F. J. J. Org. Chem. 1953, 24,

1379; Shimizu, B.; Ogiso, A.; Iwai, I Chem. Pharm. Bull. 1963, 11, 766.; Takahashi, M.; Tanino, K.; Kuwajima, I. Chem. Lett. 1993, 1655).

It has recently been shown that the use of N,N-&z5(alkoxymethyl)alkylamine reagents as preformed Mannich reagents can yield azabicyclic ring systems derived from β-keto esters (Brocke, C; Brimble, M. A.; Lin, D. S.-H.; McLeod, M. D. Synlett

2004, 2359; Brimble, M. A.; Brocke, C. Eur. J. Org. Chem. 2005, 2385; Buckley, B. R.; Page, P. C. Bulman; Heaney, H.; Sampler, E. P.; Carley, S.; Brocke, C; Brimble, M. A. Tetrahedron 2005, 61, 5876).

In view of the biological activity of many compounds having azacyclic groups, it would be desirable to provide alternative processes for the preparation of azacyclic compounds.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a process for the preparation of a compound of formula (TiI):

R ¹

{ W !

(in)

wherein, in formula (III):

W is a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8 ring members, wherein the ring may be part of a polycyclic structure, and wherein the ring members may be substituted;

R ¹ is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl and -OR ^a , wherein R ^a is selected from optionally substituted alkyl and optionally substituted aryl;

R ^3a and R ^3b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ^C , -SR ⁰ ,

-SeR ^c , -OCOR ^e , -OCONR ^e ₂ , -NR ^e ₂ , -NR ^e COOR ^e , -NR ^e CONR ^e ₂ , -POR ^e ₂ , O Il

-POR ^e (OR ^e ) and ^~p (°R ^e )2; wherein R ^c is selected from optionally substituted alkyl, optionally substituted aryl and -SiR ^d ₃ , wherein each R ^d is independently

selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R ^e is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; or R ^3a or R ^3b is a group bound to the ring member of W which is adjacent to the carbon to which the R ^3a or R ^3b respectively is attached to form a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8 ring members; or a salt or solvate thereof; the process comprising reacting a compound of formula (T) with a compound of formula (II):

CO (II) wherein, in formulae (T) and (TT):

R ¹ is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl and -OR ^a , wherein R ^a is selected from optionally substituted alkyl and optionally substituted aryl;

R ^2a and R ^2b are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted aryl and -SiR ^b ₃ , wherein each R ^b is independently selected from optionally substituted alkyl and optionally substituted aryl; A ¹ and A ² are each independently selected from the group consisting of optionally substituted alkyl and optionally substituted aryl; or A ¹ and A ² taken together with the carbon atoms to which A ¹ and A ² are attached and the carbonyl carbon between these carbon atoms form a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8 ring members, wherein the ring may be part of a polycyclic structure, and wherein the ring members may be substituted; and

R ^3a and R ^3b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ⁰ , -SR ^C , -SeR ^c , -OCOR ^e , -0C0NR ^e ₂ , -NR ^e ₂ , -NR ^e COOR ^e , -NR ^e C0NR ^e ₂ , -POR ^e ₂ , O

-POR ^e (OR ^e ) and ^~~ ^(βR ^e ) ₂ - _} wherein R ^c is selected from optionally substituted alkyl, optionally substituted aryl and -SiR ^d ₃ , wherein each R ^d is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R ^e is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; or when A ¹ and A ² taken together with the carbon atoms to which A ¹ and A ² are attached and the carbonyl carbon between these carbon atoms form a saturated or unsaturated carbocyclic or heterocyclic ring, R ^3a or R ^3b may be a group bound to the ring member which is adjacent to the carbon to which the R ^3a or R ^3b respectively is attached to form a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8 ring members.

hi a second aspect, the present invention provides a compound of formula (III) produced by the process of the first aspect of the present invention, or a salt or solvate thereof.

Ih a third aspect, the present invention provides a process according to the first aspect of the present invention followed by the steps of:

(a) reducing the carbonyl group of the compound of formula (III), or a salt or solvate thereof, to form a compound of the following formula (IV):

(IV) or a salt or solvate thereof;

(b) and then derivatising the hydroxyl group by reaction with a reagent selected from compounds of the formula R ^m C(=O)OH, R ^m C(=O)OC(=O)R ^m or R ^m C(=O)Cl, to form a compound of the following formula (V):

(V) or a salt or solvate thereof; wherein:

W, R ¹ , R ^3a and R ^3b are as defined in the first aspect of the present invention for formula (III); and

R ^m is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, -SR ^h , -OR ^h and -NR^, wherein R ^h is optionally substituted alkyl or optionally substituted aryl, and each R ¹ is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl.

hi a fourth aspect, the present invention provides a compound of formula (V) produced by the process of the third aspect of the present invention, or a salt or solvate thereof.

In a fifth aspect, the present invention provides a process according to the first aspect of the present invention followed by the steps of:

(a) reducing the cafbonyl group of the compound of formula (UT), or a salt or solvate thereof, to form a compound of the following formula (IV):

αv) or a salt or solvate thereof;

(b) and then derivatising the hydroxyl group by reaction with a reagent of the formula O=C=N-R ^P , to form a compound of the following formula (VI):

(VI)

or a salt or solvate thereof; (c) and then, optionally, reacting the compound of formula (VI), or a salt or solvate thereof, with a reagent of the formula R ^q -X to form a compound of the following formula (VII):

(VII) or a salt or solvate thereof;

wherein:

W, R ¹ , R ^3a and R ^3b are as defined above for formula (III);

R ^p is optionally substituted alkyl or optionally substituted aryl;

X is Cl, Br or I; and

R ^q is optionally substituted alkyl.

In a sixth aspect, the present invention provides a compound of formula (VI) or (VII) produced by the process of the fifth aspect of the present invention, or a salt or solvate thereof.

In a seventh aspect, the present invention provides a compound of formula (Ilia):

(HIa) or a salt or solvate thereof; wherein:

R ¹ is selected from the group consisting of optionally substituted C ₂ -C ₂₀ alkyl, optionally substituted C ₅ -C _2O aryl and -OR ^a , wherein R ^a is selected from optionally substituted alkyl and optionally substituted aryl; R ^3a and R ^3b are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ^C , -SR ^C , -SeR ^c , -OCOR ^e , -OCONR ^e ₂ , -NR ^e ₂ , -NR ⁶ COOR ⁶ , -NR ^e C0NR ^e ₂ , -POR ^e ₂ , -POR ^e (OR ⁶ ) O and P(C ¹ R ⁶ )!; wherein R ^c is selected from optionally substituted alkyl, optionally substituted aryl and -SiR ^d ₃ , wherein each R ^d is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R ^e is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; and n is O, 1, 2 or 3; with the proviso that R ¹ is not an ethyl group which is substituted with a N-containing heterocyclic group or an ethyl group which is substituted with a phenyl group.

DEFINITIONS

In this specification, the term "halo" refers to fluoro, chloro, bromo or iodo.

In this specification, the term "alkyl" used either alone or in a compound word such as "arylalkyl", refers to a straight chain, branched or mono- or polycyclic alkyl. Typically, the alkyl is a C ₁ -C ₂₀ alkyl, e.g. C ₁ -C ₆ alkyl. Examples of straight chain and branched alkyl include methyl, ethyl, n-propyl, isopropyl, butyl, wø-butyl, sec-butyl, fert-butyl, amyl, ώo-amyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 1 ,2,2-trimethylρropyl, 1 , 1 ,2-trimethylproρyl.

Examples of cyclic alkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In this specification, the term "arylalkyl" refers to an alkyl substituted with an aryl group. An example of arylalkyl is benzyl.

In this specification, the term "cycloalkyl" refers to a monocyclic or polycyclic alkyl having 3 to 12 carbons.

In this specification, the term "alkenyl" refers to a straight chain, branched or cyclic alkenyl with one or more double bonds. Typically, the alkenyl is a C ₂ -C ₂ O alkenyl, e.g C ₂ -C ₆ alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, wø-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl,

1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. In this specification, the term "alkynyl" refers to a straight chain, branched or cyclic alkynyl with one or more triple bonds. Typically, the alkynyl is a C ₂ -C ₂₀ alkynyl, e.g. C ₂ -C ₆ alkynyl.

In this specification, the term "aryl" used either alone or in compound words such as "arylalkyl", refers to a radical of a single, polynuclear, conjugated or fused aromatic hydrocarbon or aromatic heterocyclic ring system. Examples of aryl include

phenyl, naphthyl, pyridyl, fiiranyl, thiophenyl and pyrazolyl. When the aryl comprises a heterocyclic aromatic ring system, the aromatic heterocyclic ring system may contain 1 to 4 heteroatoms each independently selected from N, O, S and Se and may contain up to 8 carbon atoms in the ring. hi this specification, the term "optionally substituted alkyl" refers to an alkyl group which may be substituted by one or more substituents (for example, one, two or three substituents). The optional substituents can be any group and may, for example, be an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heterocyclyl, an optionally substituted aryl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g. phosphine, alkyl phosphine, phosphate or phosphoramide), a silicon containing group (e.g. trialkylsilyl or trialkylsilyloxy) or a selenium containing group (e.g. alkylselenyl). The optional substituents may be substituted at any position on the alkyl provided that when the groups R ¹ , R ^a , R ^2a , R ^2b , R ^b , R ^3a , R ^3b , R ^c , A ¹ , A ² , R ^h , R ¹ , R ^p , R ^q and R ^m are an optionally substituted alkyl, and the substituent on the alkyl is selected from one or more of the following: halo, hydroxyl, alkoxyl, trialkylsilyloxy, alkylthio, alkylselenyl, sulfone, sulfoxide, sulfonamide, ester, thioester, amide, thioamide, urea, thiourea, carbonate and carbamate, then the substituent is not attached directly to the α-carbon of the alkyl. For example, if R ¹ in the compound of formula (III) (R ¹ being attached to the nitrogen atom of the azabicycle) is an ethyl group substituted with halogen, then the halogen is not attached directly to the carbon atom which is attached to the nitrogen atom of the azabicycle. In this specification, the term "optionally substituted aryl" refers to an aryl group which may be substituted by one or more substituents (for example, one, two or three substituents). The optional substituents can be any group and may, for example, be an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heterocyclyl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g. phosphine,

alkyl phosphine, phosphate or phosphoramide), a silicon containing group (e.g. trialkylsilyl or trialkylsilyloxy) or a selenium containing group (e.g. alkylselenyl).

In this specification, the term "optionally substituted alkenyl" refers to an alkenyl group which may be substituted by one or more substituents (for example, one, two or three substituents). The optional substituents can be any group and may, for example, be an optionally substituted alkyl, an optionally substituted alkynyl, an optionally substituted heterocyclyl, an optionally substituted aryl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioaniide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g. phosphine, alkyl phosphine, phosphate or phosphoramide), a silicon containing group (e.g. trialkylsilyl or trialkylsilyloxy) or a selenium containing group (e.g. alkylselenyl).

Li this specification, the term "optionally substituted alkynyl" refers to an alkynyl group which may be substituted by one or more substituents (for example, one, two or three substituents). The optional substituents can be any group and may, for example, be an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g. phosphine, alkyl phosphine, phosphate or phosphoramide), a silicon containing group (e.g. trialkylsilyl or trialkylsilyloxy) or a selenium containing group (e.g. alkylselenyl).

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have found that N,iV-bis(substituted)alkylamines of formula (II) function as effective reagents in the double Mannich annulation of ketone substrates of formula (I) providing efficient access to azacyclic compounds of formula (III). The present inventors have further found that compounds of

formula (III) are a useful scaffold in the synthesis of biologically active small molecule homocholine analogues.

The present invention provides a process for the preparation of compounds of formula (III):

απ) or a salt or solvate thereof, wherein W, R ^3a , R ^3b and R ¹ are as defined above for formula (III), by reacting a compound of formula (I) with a compound of formula (II) to form a compound of formula (III). The process of the invention provides an efficient means for the preparation of the compounds of formula (III). The process typically results in good yields of the compounds of formula (III).

The process of the invention is depicted in the following Scheme A:

(D (DO)

Scheme A

In formula (III), the ring W is a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8 ring members, wherein the ring may be part of a polycyclic structure, and wherein the ring members may be substituted. In some embodiments, the ring W is a 5, 6, 7 or 8-membered carbocyclic ring. In other embodiments, the ring W is a 5, 6, 7 or 8-membered heterocyclic ring containing one or more heteroatoms selected from N, O or S.

The ring members of the ring W, other than the carbons to which R and R are attached and the carbonyl carbon, may be substituted or unsubstituted. For example, when the ring member is a carbon, the carbon may be substituted with, for example, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g. phosphine, alkyl phosphine, phosphate or phosphoramide), a silicon containing group (e.g. trialkylsilyl or trialkylsilyloxy) or a selenium containing group (e.g. alkylselenyl).

In formula (III), R ^3a and R ^3b may be the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ⁰ , -SR ⁰ , -SeR ^c ,

-OCOR ^e , -OCONR ^e ₂ , -NR ^e ₂ , -NR ^e C00R ^e , -NR ^e CONR ^e ₂ , -POR ^e ₂ , -POR ^e (OR ^e ) or O P(PR ^e )2; wherein R ^c is optionally substituted alkyl, optionally substituted aryl or -SiR ^d ₃ , wherein each R ^d is independently selected and is optionally substituted alkyl or optionally substituted aryl; and wherein each R ^e is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; or R ^3a or R ^3b is a group bound to the ring member of W which is adjacent to the carbon to which the R ^3a or R ^3b respectively is attached (i.e. the ring member which is at the β position relative to the carbonyl carbon) to form a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8 ring members fused to ring W. Examples of R ^3a and R ^3b groups include hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, phenyl, benzyl, -F, -Cl, -Br, -I, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCOCH ₃ , -OCOCH ₂ CH ₃ , -SCH ₃ , -SeCH ₃ , -N(CH ₃ ) ₂ , -NHCOOCH ₃ , -NHCONHCH ₃ , -Si(CH ₃ ) ₃ and

-Si(CH ₂ CH ₃ ) ₃ , -PO(OCH ₃ ) ₂ and -PO(CH ₃ ) ₂ .

In formulae (II) and (III), R ¹ is optionally substituted alkyl, optionally substituted aryl or -0R ^a , wherein R ^a is optionally substituted alkyl or optionally substituted aryl. In some embodiments, R ¹ is optionally substituted alkyl. Examples of R ¹ groups include methyl, ethyl, n-propyl, isopropyl, butyl, iso-bntyl, tert-butyl,

pentyl, iso-pentyl, neopentyl, phenyl, naphthyl, benzyl, phenylethyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ and -OPh.

In formula (II), R ^2a and R ^2b may be the same or different and are optionally substituted alkyl, optionally substituted aryl or -SiR ^b ₃ , wherein each R ^b is independently selected and is optionally substituted alkyl or optionally substituted aryl. Examples of R ^2a and R ^2b groups include methyl, ethyl, propyl, isopropyl, benzyl, phenyl, -Si(CEb) ₃ , -Si(CH ₂ CH ₃ ) ₃ , -Si(CH ₃ ) ₂ ^t Bu and -Si(Ph) ₂ ^Bu.

In formula (I), A ¹ and A ² may be the same or different and are optionally substituted alkyl or optionally substituted aryl; or A ¹ and A ² taken together with the carbon atoms to which A ¹ and A ² are attached and the carbonyl carbon between these carbon atoms form a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8 ring members, wherein the ring may be part of a polycyclic structure, and wherein the ring members may be substituted; and R ^3a and R ^3b may be the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ⁰ , -SR ^C , -SeR ⁰ , -OCOR ⁶ , -0C0NR ^e ₂ , -NR ^e ₂ , -NR ⁶ COOR ⁶ ,

O -NR ⁶ CONR ^e ₂ , -P0R ^e ₂ , -P0R ⁶ (0R ⁶ ) or ^~p (OR ^e ) _2; wherein R° is optionally substituted alkyl, optionally substituted aryl or -SiR ₃ , wherein each R is independently selected and is optionally substituted alkyl or optionally substituted aryl; and wherein each R ^e is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; or when A and A taken together with the carbon atoms to which A ¹ and A ² are attached and the carbonyl carbon between these carbon atoms form a saturated or unsaturated carbocyclic or heterocyclic ring, R ^3a or R ^3b may be a group bound to the ring member which is adjacent to the carbon to which the R ^3a or R ^3b respectively is attached to form a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8 ring members.

In some embodiments, the compound of formula (I) depicted in Scheme A is an acyclic ketone compound in which A ¹ and A ² in formula (I) are each an optionally substituted alkyl or optionally substituted aryl. When the compound of formula (I) is an acyclic ketone compound, the resultant compound of formula (III) is a compound of formula (HF) having the following structure:

wherein in formula (HF):

R ¹ is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl and -OR ^a , wherein R ^a is selected from optionally substituted alkyl and optionally substituted aryl; and

R ^3a and R ³ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ^C , -SR ^C , -SeR ⁰ , -OCOR ^e , -OCONR ^e ₂ , -NR ^e ₂ , -NR ^e COOR ^e , -NR ^e CONR ^e ₂ , -POR ^e ₂ , O Il -POR ^e (OR ^e ) and ^~"p (OR ^e )2; wherein R ^c is selected from optionally substituted alkyl, optionally substituted aryl and -SiR ^d ₃ , wherein each R ^d is independently selected from optionally substituted alkyl and optionally substituted aryl; and wherein each R ^e is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl. In this reaction, two equivalents of the compound of formula (II) react with the compound of formula (I) to form the compound of formula (UI'). hi other embodiments, the compound of formula (T) depicted in Scheme A is a cyclic ketone compound in which A ¹ and A ² taken together with the carbon atoms to which A ¹ and A ² are attached and the carbonyl carbon between these carbon atoms form a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8 ring members, wherein the ring may be part of a polycyclic structure. In such embodiments, the ring members, other than the carbon atoms to which A ¹ and A ² are attached and the carbonyl carbon, may be unsubstituted or may be substituted with any group, provided that, if the ring members which are β to the carbonyl carbon are carbon, then the ring members are either unsubstituted or substituted with optionally

substituted alkyl or optionally substituted aryl. For example, when the ring member is a carbon, the carbon may be substituted with, for example, optionally substituted alkyl, optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heterocyclyl, an optionally substituted aryl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group (e.g. phosphine, alkyl phosphine, phosphate or phosphoramide), a silicon containing group (e.g. trialkylsilyl or trialkylsilyloxy) or a selenium containing group (e.g. alkylselenyl).

For example, the compound of formula (I) may be selected from the following formulae:

(Ia) (Ib)

(Ic) αφ

wherein:

R ^3a and R ^3b may be the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ^C , -SR ^C , -SeR ⁰ , -OCOR ^e , -OCONR ^e 2, -NR ^e ₂ , -NR ^e COOR ^e , -NR ^e CONR ^e ₂ , -POR ^e ₂ , -POR ^e (OR ^e ) or

O Il

P(OR ^e ) ₂ ; wherein R ^c is optionally substituted alkyl, optionally substituted aryl or -SiR ^d ₃ , wherein each R ^d is independently selected and is optionally

substituted alkyl or optionally substituted aryl; and wherein each R ^e is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; each G ¹ may be the same or different and is -C(R ^f ) ₂ -, =CR ^f -, =N-, -NR ^f -, -O-, -S-,

O O -Se-, -PR -, -— P-R ¹ or ---P-OR ¹ ; wherein each R is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; each G ² may be the same or different and is -C(Bl) ₂ -, =CR ^r -, =N-, -NR ^f -, -O-, -S-,

O O

-Se-, -PR -, —-P-R , — P-OR or a common carbon of a spiro compound; wherein each R ^r is independently selected and is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group, a silicon containing group or a selenium containing group; and wherein

R ^f is hydrogen, optionally substituted alkyl or optionally substituted aryl; and

— denotes a single bond or a double bond.

In some embodiments, the ring U in the compound of formula (Ia), (Ib), (Ic) or (Id) is a monocyclic ring which is carbocyclic, and R ^3a and R ^3b are each hydrogen, optionally substituted alkyl or optionally substituted aryl. For example, R ^3a and R ^3b may be selected from hydrogen, methyl and phenyl. hi some embodiments, the compound of formula (I) depicted in Scheme A is a cyclic ketone compound in which A ¹ and A ² taken together with the carbon atoms to

1 9 which A and A are attached and the carbonyl carbon between these carbon atoms form a saturated or unsaturated carbocyclic or heterocyclic ring which is fused to one or more other rings. In such embodiments, R ^3a or R ^3b may be a group bound to the ring member which is adjacent to the carbon to which R ^3a or R ^3b respectively is attached (i.e. the ring member at the β position relative to the carbonyl carbon), to form a saturated or unsaturated carbocyclic or heterocyclic ring having 5, 6, 7 or 8

ring members fused to the ring formed by A ¹ , A ² , the carbons to which A ¹ and A ² are attached and the carbonyl carbon.

Examples of such compounds of formula (I) include compounds of the following formulae (Ie-I), (Ie-2), (Ie-3), (Ie-4), (If-I), (If-2) or (If-3):

(Ie-I) (Ie-2)

wherein in formula (Ie-I), (Ie-2), (Ie-3) and (Ie-4): R ^3a is hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ^C , -SR ^C , -SeR ^c , -OCOR ^e , -OCONR ^e ₂ , -NR ^e ₂ , -NR ⁶ COOR ⁶ , -NR ^e C0NR ^e ₂ ,

O

-POR ^e ₂ , -POR ^e (OR ^e ) or ^~ P(OR ^e ) _2; wherein R ^c is optionally substituted alkyl, optionally substituted aryl or -SiR ^d ₃ , wherein each R ^d is independently selected and is optionally substituted alkyl or optionally substituted aryl; and wherein each R ^e is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl;

O O

G ¹ is -C(R ^f ) ₂ -, =CR ^f -, =N-, -NR ^f -, -0-, -S-, -Se-, -PR ^f -, ^P ^~ R ^f or ^P ^~ OR ^f ; wherein each R ^f is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl;

each G ² may be the same or different and is -C(RV, =CR ^r -, =N-, -NR ^f -, -O-, -S-,

^O ^O

-Se-, -PR ^f -, -^P-R ^f , -~-P-OR ^f or a common carbon of a spiro compound; wherein each R ^τ is independently selected and is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group, a silicon containing group or a selenium containing group; and wherein R ^f is hydrogen, optionally substituted alkyl or optionally substituted aryl;

G ³ is CR ^f , N, P or P=O; wherein R ^f is hydrogen, optionally substituted alkyl or optionally substituted aryl; m' is 3, 4, 5 or 6; and

— denotes a single bond or a double bond;

wherein in formula (If-I):

R ^3a and R ^3b may be the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ⁰ , -SR ⁰ , -SeR ⁰ , -0C0R ^e , -0C0NR ^e ₂ , -NR ^e ₂ , -NR ⁶ COOR ⁶ , -NR ^e C0NR ^e ₂ , -POR ^e ₂ , -POR ^e (OR ^e ) or

O Il

P(OR ^e ) ₂ ; wherein R ^c is optionally substituted alkyl, optionally substituted aryl or -SiR ^d ₃ , wherein each R ^d is independently selected and is optionally substituted alkyl or optionally substituted aryl; and wherein each R ^e is

independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; each G ² may be the same or different and is -C(SC) ₂ -, =CR ^r -, =N-, -NR ^f -, -O-, -S-,

O O

-Se-, -PR -, — p-R , ---P-OR. or a common carbon of a spiro compound; wherein each R ^r is independently selected and is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group, a silicon containing group or a selenium containing group; and wherein R is hydrogen, optionally substituted alkyl or optionally substituted aryl; each G ⁴ may be the same or different and is CR ^f , N, P or P=O; wherein R ^f is hydrogen, optionally substituted alkyl or optionally substituted aryl; m" is 1, 2, 3, 4, 5 or 6; ring V is an aromatic or non-aromatic ring; and

— denotes a single bond or a double bond, or when ring V is an aromatic ring, then • in ring V denotes a bond of the aromatic ring V;

wherein in formula (If-2):

R ,3a ^a and R >3b may be the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ^C , -SR ^C , -SeR ^c , -OCOR ^e ,

-OCONR ^e ₂ , -NR ^e ₂ , -NR ⁶ COOR ⁶ , -NR ^e CONR ^e ₂ , -POR ^e ₂ , -POR ⁶ (OR ⁶ ) or O Il

P(OR ^e ) ₂ - _w herein R ^c is optionally substituted alkyl, optionally substituted aryl or -SiR ^d ₃ , wherein each R ^d is independently selected and is optionally substituted alkyl or optionally substituted aryl; and wherein each R ⁶ is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl;

O O

G ¹ is -C(R ^f ) ₂ -, =CR ^f -, =N-, -NR ^f -, -O-, -S-, -Se-, -PR ^f -, ^P -R ^f or >p-OR ^f ; wherein each R ^f is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; each G ² may be the same or different and is -C(RV. =CR ^r -, =N-, -NR ^f -, -O-, -S-,

O O

-Se-, -PR -, -—P-R , --P-OR or a common carbon of a spiro compound; wherein each R ^r is independently selected and is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group, a silicon containing group or a selenium containing group; and wherein R ^f is hydrogen, optionally substituted alkyl or optionally substituted aryl; G ³ is CR ^r , N, P or P=O; wherein R ^r is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group, a silicon containing group or a selenium containing group;

G ⁴ is CR ^f , N, P or P=O; wherein R ^f is hydrogen, optionally substituted alkyl or optionally substituted aryl; m" is 1, 2, 3, 4, 5 or 6;

p is 0, 1 or 2; ring V is an aromatic or non-aromatic ring; and

— denotes a single bond or a double bond, or when ring V is an aromatic ring, then — in ring V denotes a bond of the aromatic ring V;

wherein in formula (If-3):

R ^3a and R ^3b may be the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ^C , -SR ^C , -SeR ^c , -OCOR ^e , -OCONR ^e ₂ , -NR ^e ₂ , -NR ^e COOR ^e , -NR ^e CONR ^e ₂ , -POR ^e ₂ , -POR ^e (OR ^e ) or

O

P(OR ^e ) ₂ - wherein R ^c is optionally substituted alkyl, optionally substituted aryl or -SiR ^d ₃ , wherein each R ^d is independently selected and is optionally substituted alkyl or optionally substituted aryl; and wherein each R ^e is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; each G ¹ maybe the same or different and is -C(R ^f ) ₂ -, =€R ^f -, =N-, -NR ^f -, -O-, -S-,

O O

-Se-, -PR ^f -, --P-R ^f or —-P-QR ^f ; wherein each R ^f is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; each G ² maybe the same or different and is -C(BJ) ₂ -, =CR ^r -, =N-, -NR ^f -, -O-, -S-,

O O -Se-, -PR -, --P-R ¹ , — -P-OR ¹ or a common carbon of a spiro compound;

wherein each R ^r is independently selected and is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group, a silicon containing group or a selenium containing group; and wherein R ^f is hydrogen, optionally substituted alkyl or optionally substituted aryl; each G ³ may be the same or different and is CR ^r , N, P or P=O; wherein R ^r is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, halo, hydroxyl, alkoxyl, carbonyl, nitro, carboxylic acid, carboxylic acid ester, amino, amido, imino, cyano, urea, thiol, alkylthio, thioester, thioamide, thiourea, sulfone, sulfide, sulphonamide, sulfoxide, a carbonate, a carbamate, a phosphorous containing group, a silicon containing group or a selenium containing group; m" is 1, 2, 3, 4, 5 or 6; p is 0 or 1; ring V is an aromatic or non-aromatic ring; and — denotes a single bond or a double bond, or when ring V is an aromatic ring, then — in ring V denotes a bond of the aromatic ring V.

In the formulae (Ie-I), (Ie-2), (Ie-3), (Ie-4), (If-2) and (If-3) wherein G ¹ is -C(R ^f ) ₂ - and each R ^f is an optionally substituted alkyl, the two optionally substituted alkyls may be linked to form a cyclic group, i.e. G ¹ is a common carbon of a spiro compound. m some embodiments of the formula (Ie-I), (Ie-2), (Ie-3) or (Ie-4), G ¹ is -C(R ^f ) ₂ - or =CR ^f -, each G ² is independently selected and is -C(R ¹ V or =CR ^r -, G ³ is CR ^f , and m' is 3, 4, 5 or 6. hi some embodiments of the formula (If-I), each G ² is independently selected and is -C(RV or =CR ^r -, each G ⁴ is CR ^f , and m" is 1, 2, 3, 4, 5 or 6.

In some embodiments of the formula (If-2), G ¹ is -C(R ^f ) ₂ - or =CR ^f -, each G ² is independently selected and is -C(R ¹ V or =CR ^r - ₃ G ³ is CR ^r , G ⁴ is CR ^f , m" is 1, 2, 3, 4, 5 or 6, and p is 0, 1 or 2.

Li some embodiments of the formula (If-3), each G ¹ is independently selected and is -C(R ^f ) ₂ - or =CR ^f -, each G ² is independently selected and is -C(R ^r ) ₂ - or =CR ^r -, each G ³ is CR ^r , m" is 1, 2, 3, 4, 5 or 6, and p is 0 or 1.

In some embodiments of the process depicted in Scheme A, the compound of formula (I) is a compound of the following formula (Ig):

(Ig) wherein:

R ^3a and R ³ may be the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ^C , -SR ⁰ , -SeR ^c , -OCOR ^e ,

-OCONR ^e ₂ , -NR ^e ₂ , -NR ⁶ COOR ⁶ , -NR ^e CONR ⁶ ₂ , -POR ⁶ ₂ , -POR ⁶ (OR ^e ) or O P(PR ^e )2; wherein R° is optionally substituted alkyl, optionally substituted aryl or -SiR ^d ₃ , wherein each R ^d is independently selected and is optionally substituted alkyl or optionally substituted aryl; and wherein each R ^e is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; and n is 0, 1, 2 or 3.

In some embodiments, R ^3a and R ^3b in formula (Ig) are each independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl. For example, R ^3a and R ^3b may be independently selected from hydrogen, methyl and phenyl. In some embodiments, n is 2 or 3.

In some embodiments, the compound of formula (II) is a compound of the following formula (Ha):

wherein:

R ¹ is ethyl, n-propyl, isopropyl or tert-butyl, and "Et" is ethyl.

For example, the compound of formula (Ha) may be a compound selected from the following compounds:

EtCT^ N^OEt k

5a: R ¹ = Et 5b: R ¹ = /-Pr 5c: R ¹ = f-βu 5d: R ¹ = n-Pr 5e: R ¹ = CH ₂ Ph

The process depicted in Scheme A may be carried out in the presence of a

Lewis acid, an acid chloride or an acid anhydride. The Lewis acid may be any Lewis acid. The acid chloride may be any acid chloride. The acid anhydride may be any acid anhydride. Examples of suitable acid chlorides include acetyl chloride and propionyl chloride. Examples of suitable acid anhydrides include acetic anhydride and propionic anhydride.

Typically, the process depicted in Scheme A is carried out in the presence of one or more Lewis acids. Any Lewis acid may be used. The Lewis acid may, for example, be hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, MgX ₂ , ZrX ₄ , TiX ₄ , SnX ₄ , AlX ₃ , ZnX ₂ , an alkylaluminium halide, a metal trihalomethanesulfonate, SiR ^g _n X _m or R ^g _p Si(OR ^g ) _q X _r ; wherein X is Cl, Br or I, each R ^g is independently selected and is optionally substituted alkyl or optionally substituted aryl, n is 0, 1, 2 or 3, m=4-n, r is 1, 2 or 3, q is 1, 2 or 3, p is 0, 1 or 2, and p+q+r=4.

Specific examples of suitable Lewis acids include MgCl ₂ , MgBr ₂ , MgI ₂ , TiCl ₄ , TiBr ₄ , TiI ₄ , SnCl ₄ , SnBr ₄ , SnI ₄ , SiCl ₄ , SiBr ₄ , SiI ₄ , ZrCl ₄ , ZnCl ₂ , ZnBr ₂ , ZnI ₂ ,

dimethylaluminium chloride, methylaluminium dichloride, AlCl ₃ , AlBr ₃ , AlI ₃ , magnesium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, BF ₃ , hafnium trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, scandium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, methyltrichlorosilane (MeSiCl ₃ ) and trimethylchlorosilane (Me ₃ SiCl). In preferred embodiments, the Lewis acid is methyltrichlorosilane (MeSiCl ₃ ) or trimethylchlorosilane (Me ₃ SiCl). The use of methyltrichlorosilane (MeSiCl ₃ ) or trimethylchlorosilane (Me ₃ SiCl) as the Lewis acid is advantageous as these Lewis acids are mild and, from a practical point of view, are easy to handle. The process depicted in Scheme A may be carried out in the presence of one or more aprotic solvents. The aprotic solvent may, for example, be acetonitrile (MeCN), iV,7V-dimethylformamide (DMF), dichloroethane, dichloromethane, chloroform (CHCl ₃ ), tetrahydrofuran (THF), diethylether, hexane, methyl acetate, ethyl acetate, pentane, benzene, toluene, xylene, carbon tetrachloride, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, dimethoxyethane, dioxane or

N-methylpyrrolidone. In some embodiments, the solvent is acetonitrile. The use of acetonitrile typically leads to higher yields and cleaner products than the use of at least some other aprotic solvents.

The temperature at which the reaction is carried out and the reaction time to form the compound of formula (III) will depend on the specific reagents used.

Generally, however, the compound of formula (I), the compound of formula (II) and a Lewis acid, an acid chloride or an acid anhydride are mixed in an aprotic solvent, and the mixture is stirred for a period of 12 to 48 hours at room temperature (e.g. about 25°C) under anhydrous conditions (e.g. under a nitrogen atmosphere). When the reaction is carried out in acetonitrile in the presence of the Lewis acid methyltrichlorosilane (MeSiCl ₃ ) or trimethylchlorosilane (Me ₃ SiCl), the mixture of the compound of formula (T) and the compound of formula (II) is typically stirred at room temperature for about 24 to about 48 hours.

An embodiment of the process depicted in Scheme A is set out below in Scheme B:

Scheme B

The yields obtained experimentally using various Lewis acids, numbers of equivalents of the Lewis acid, and reaction times are set out below. The experiments were conducted as described below for Example 1.1.1 with appropriate changes to the Lewis acids, the number of equivalents of the Lewis acid, and reaction times.

Other embodiments of the process depicted in Scheme A, with the reaction yields obtained in the Examples described below, are set out below in Scheme C:

Scheme C

Other embodiments of the process depicted in Scheme A, with the reaction yields obtained in the Examples described below, are set out below in Schemes D, E, F, G and H:

94% yield

Scheme D

Scheme E

5% yield

Scheme F

75% yield

Scheme G

11% yield

Scheme H

The reaction depicted in Scheme A, wherein the compound of formula (I) is a cyclic ketone and wherein the reaction is carried out in the presence of a Lewis acid, may, for example, be carried out as follows. The compound of formula (II) is added to a solution of the Lewis acid (3.0 eq) in an aprotic solvent, to which is added a solution of the compound of formula (I) (1.0 eq) in an aprotic solvent. The resultant mixture is stirred under nitrogen for about 24 to about 48 h. The reaction is quenched by the addition of ice water and partitioned between diethyl ether and water. The ether layer is then extracted with hydrochloric acid and the combined aqueous extracts washed with ether, cooled to 0 °C and the pH brought to 9 by the addition of concentrated ammonia solution. The organic material is then extracted with ether and the combined ether extracts are washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to afford the compound of formula (III).

The process depicted in Scheme A may, for example, be used to synthesise compounds of the following formula (Ilia):

(Ilia) or a salt or solvate thereof; wherein:

R ¹ is optionally substituted C ₂ -C ₂₀ alkyl, optionally substituted C ₅ -C ₂₀ aryl or -OR\ wherein R ^a is optionally substituted alkyl or optionally substituted aryl;

R ^3a and R ^3b may be the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aryl, halo, -OH, -OR ^C , -SR ⁰ , -SeR ⁰ , -OCOR ^e , -0C0NR ^e ₂ , -NR ^e ₂ , -NR ^e C00R ^e , -NR ^e CONR ^e ₂ , -POR ^e ₂ , -POR ^e (OR ^e ) or O

P(OR ^e ) ₂ - wherein R° is optionally substituted alkyl, optionally substituted aryl or -SiR ^d ₃ , wherein each R ^d is independently selected and is optionally substituted alkyl or optionally substituted aryl; and wherein each R ^e is independently selected and is hydrogen, optionally substituted alkyl or optionally substituted aryl; and n is O, 1, 2 or 3; with the proviso that R ¹ is not an ethyl group which is substituted with a N-containing heterocyclic group or an ethyl group which is substituted with a phenyl group.

In some embodiments, in formula (Ilia), R ¹ is optionally substituted C ₃ -C ₆ alkyl.

For example, the compound of formula (Ilia) may be a compound selected from the following:

3h: n=3, R ¹ = n-Pr 3i: n=2, R ¹ = CH ₂ Ph

Advantageously, the process depicted in Scheme A typically results in the production of the compounds of formula (111) in good yield and high purity. If desired, the compounds of formula (III) may be purified by techniques known in the art, such as silica gel chromatography. Acid addition salts of the compounds of formula (III) may be prepared by mixing a compound of formula (III) with an organic or inorganic acid. Exemplary acid addition salts include, for example, acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates and tonluenesulfonates (also known as tosylates).

The compound of formula (III) may be in the form of a solvate wherein one or more solvent molecules are associated with each molecule of the compound of formula (III).

The compounds of formula (III) are a useful scaffold for the synthesis of small molecule homocholine analogues as shown below in Schemes I, J and K.

The carbonyl group of a compound of formula (III), or a salt or solvate thereof, may be reduced to a hydroxyl group to form a compound of formula (IV), or a salt or solvate thereof, as shown below in Scheme I:

(in) (IV)

Scheme I

The hydroxyl group of the compound of formula (IV), or a salt or solvate thereof, may then be reacted with:

> a reagent selected from compounds of the formula R ⁱⁿ C(=O)OH, R ^m C(=O)OC(=O)R ^m or R ^m C(=O)Cl, to form a compound of formula (V), or

> a reagent of the formula O=C=N-R ¹³ , to form a compound of formula (VI), as shown below in Scheme J:

(VI) Scheme J

Optionally, the compound of formula (VI), or a salt or solvate thereof, may be reacted with a reagent R ^q -X to form a compound of formula (VII), or a salt or solvate thereof, as show below in Scheme K:

(VI) (VII)

Scheme K

In the formulae (III), (IV), (V), (VI) and (VII) in the above Schemes I, J and K, W, R ¹ , R ^3a and R ^3b are as defined above for formulae (III), (IV), (V), (VI) and (VII) in the Summary of the Invention. In the above Schemes I, J and K, R ^m is optionally substituted alkyl, optionally substituted aryl, -SR ^h , -OR ^h or -NR^, wherein R ^h is optionally substituted alkyl or optionally substituted aryl, and each R ¹ is independently selected from hydrogen, optionally substituted alkyl and optionally substituted aryl; R ^p is optionally substituted alkyl or optionally substituted aryl; X is Cl, Br or I; and R ^q is optionally substituted alkyl. Reduction of the carbonyl group in the compound of formula (III) or a salt or solvate thereof (depicted in Scheme I) can be carried out using standard reducing agents and standard techniques known in the art. For example, reduction can be carried out using standard reducing agents such as sodium borohydride, diisobutylaluminium hydride (DIBAL-H), or lithium tri-see-butylborohydride (sold by Aldrich as L-Selectride® (IM solution of lithium tri-sec-butylborohydride in tetrahydrofuran)) .

Similarly, reaction of the compound of formula (IV), or a salt or solvate thereof, with a reagent of the formula R ^m C(=O)OH, R ^m C(=O)OC(=O)R ^m or R ^m C(=O)Cl to form the compound of formula (V), or a salt or solvate thereof, can be carried out under the standard reaction conditions known in the art. For example, when the reagent is acetic anhydride, the reaction can be carried out in

dichloromethane in the presence of triethylamine and 4-dimethylaminopyridine (DMAP).

Examples of reagents R ^m C(=O)OH, R ^m C(=O)OC(=O)R ^m and R ^m C(=O)Cl include acetic acid, acetyl chloride, acetic anhydride, pivalic acid, pivaloyl chloride, pivalic acid anhydride, benzoic acid, benzoyl chloride, benzoic acid anhydride, 2-methoxybenzoic acid, 2-methoxybenzoyl chloride, 2-methoxybenzoic acid anhydride, 4-methoxybenzoic acid, 4-methoxybenzoyl chloride, 4-methoxybenzoic acid anhydride, cyclohexanecarboxylic acid, cyclohexanecarbonyl chloride (also known as cyclohexanecarboxylic acid chloride), cyclohexanecarboxylic acid anhydride, nicotinic acid, nicotinoyl chloride, nicotinic acid anhydride, phenylacetic acid, phenylacetyl chloride and phenylacetic acid anhydride.

Reaction of the compound of formula (IV), or a salt or solvate thereof, with a reagent O=G=N-R ^P to form a compound of formula (VI), or a salt or solvate thereof, can, for example, be carried out in pyridine as the solvent. For example, the compound of formula (IV) and the reagent O=C=N-R ^P may be added to pyridine, and the reaction mixture stirred for about 24 h at about room temperature.

Examples of the reagent of formula O=C=N-R ^P include CH ₃ -N=C=O, CH ₃ CH ₂ -N=C=O, CH ₃ CH ₂ CH ₂ -N=C=O, (CH ₃ ) ₂ CH-N=C=O, Ph-N=C=O, PhCH ₂ -N=C=O and PhCH ₂ CH ₂ -N=C=O. Reaction of the compound of formula (VI), or a salt or solvate thereof, with a reagent R ^q — X to form a compound of formula (VII), or a salt or solvate thereof, can be carried out with sodium hydride or potassium hydride as base in an aprotic solvent such as N,N-dimethylforrnarnide.

Examples of the reagent R ^q -X include optionally substituted C ₁ -C ₂₀ alkyl chlorides, optionally substituted C ₁ -C ₂₀ alkyl bromides and optionally substituted C ₁ -C ₂₀ alkyl iodides. For example, R ^q -X may be selected from CH ₃ I, CH ₃ CH ₂ I, CH ₃ CH ₂ CH ₂ I, BnCl, BnBr, BnI, PhCH ₂ CH ₂ I, CH ₂ =CHCH ₂ Cl, CH ₂ =CHCH ₂ Br, CH ₂ =CHCH ₂ I, BrCH ₂ COOCH ₃ and BrCH ₂ COOCH ₃ .

In some embodiments, the compound of formula (V) is:

9a: R ¹ =Et 9d 9e 9b: R ¹ =f-Bu 9c: R ¹ =π-Pr

When the R ¹ substituent of the tertiary amino group of the compounds of formula (V), (VI) and (VII), or a salt or solvate thereof, is an arylmethyl group wherein the aryl group is optionally substituted (e.g. benzyl or benzyl wherein the phenyl group is optionally substituted), or a diarylmethyl group wherein either or both aryl groups is optionally substituted (e.g. benzhydryl or benzhydryl wherein either or both phenyl groups is optionally substituted), the tertiary amino group may be selectively reduced under suitable conditions to form a secondary amino group to form compounds of formula (Va), (Via) and (Vila), respectively, or salts or solvates thereof, as shown below in Schemes Ll, L2 and L3:

(V) (Va)

R ¹ = -CH ₂ Ar R ¹ = -CHAr ₂

Scheme Ll

(VT) (Via)

Scheme L2

(vπ) (VHa)

R ¹ = -CH ₂ Ar R ¹ = -CHAr ₉

Scheme L3

In the formulae (V), (VI), (VII), (Va), (Via) and (Vila) in the above

Schemes Ll, L2 and L3, R ¹ is -CH ₂ Ar or -CHAr ₂ , wherein each Ar is an independently selected, optionally substituted aryl group (e.g. R ¹ is benzyl or benzhydryl), and W, R ^3a and R ^3b , R ^m , R ^p and R ^q are as defined above for formulae (V), (VI) and (VII) in the Summary of the Invention. Suitable reagents for the reduction reaction shown in Schemes Ll, L2 and L3 include, for example:

• H ₂ , Pd/C;

• H ₂ , Pd(OH) ₂ ;

• Pd/C, cyclohexene, HCl; • sodium, NH ₃ ;

• lithium, diethylamine;

• vinyl chloroformate, then acid treatment;

• 2,2,2-trichloroethoxycarbonyl chloride, then treatment with Zn and acetic acid, • 2-(trimethylsilyl)-ethoxycarbonyl chloride, and then treatment with tetrabutylammonium fluoride.

Other reagents known in the art for carrying out reduction reactions may be used. A person skilled in the art could select reagents and conditions suitable for the reduction reaction shown in Schemes Ll, L2 and L3 having regard to the other functional groups present in the compounds of formula (V), (VI) and (VlI).

Compounds of formulae (Va), (Via) and (Vila) may be transformed into a variety of acid addition salts with inorganic and organic acids. Such acid addition salts may be prepared by mixing a compound of formula (Va), (Via) or (Vila) with an organic or inorganic acid. Exemplary acid addition salts include, for example, acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates and tonluenesulfonates (also known as tosylates). An example of a reduction reaction of Scheme Ll is the following reaction shown in Scheme M:

Scheme M

Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in a number of debilitating disease states, including neurodegenerative disorders such as Alzheimer's disease, Schizophrenia and Parkinson's disease, epilepsy, smoking

cessation and many dementias. The role and function of nAChRs in the nervous system is currently poorly defined. Compounds active at these receptors may be used to further elucidate the role of the receptors in these neuropathologies and provide useful targets for therapies to mediate their symptoms. nAChR ligands as such represent an attractive therapeutic target with potential use for ligands that act as agonists, antagonists and modulators for pharmacology-based disease research and as therapeutics in the clinic.

The examples described below show that compounds of formula (V) have activity at neuronal nicotinic acetylcholine receptors (nAChRs). The present inventors hypothesise that this is due to the constrained homocholine motif present in the compounds of formula (V) being suitably oriented for binding and interacting with neuronal nAChR.

The invention is described below by reference to the following non-limiting examples. It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the following Examples without departing from the spirit or scope of the invention as broadly described. The Examples are, therefore, to be considered in all respects as illustrative and not restrictive.

EXAMPLES The following compounds are referred to below:

3a: n=2, R ¹ = Et 5a: R ¹ = Et 3b: n=2, R ¹ = /-Pr 5b: R ¹ = /-Pr 3c: n=2, R ¹ = t-Bu 5c: R ¹ = f-Bu 3d: n=2, R ¹ = /i-Pr 5d: R ¹ = n-Pr 3e: n=3, R ¹ = Et 5e: R ¹ = CH ₂ Ph 3f: n=3, R ¹ = /-Pr 3g: n=3, R ¹ = f-Bu 3h: n=3, R ¹ = n-Pr 3i: n=2, R ¹ = CH ₂ Ph

7a: R ¹ =Et, R ² =CH ₃ 7b: R ¹ =/-Pr, R ² =CH ₃ 7c: R ¹ =f-Bu, R ² =CH ₃ 7d: R ¹ =n-Pr, R ² =CH ₃ 7e: R ¹ =Et, R ² =Ph

8a: R ¹ =Et δc 8d 8b: R ¹ =f-Bu

9a: R ¹ =Et 9d 9e

9b: R ¹ =f-Bu

1. Preparation of compounds

1.1 General procedure for the preparation of 3a-3i, 7a-7e and 6a-6e

The following procedure was used to prepare the compounds 3a-3h, 7a-7e, and 6a-6e referred to below.

The appropriate A^N-tø(ethoxymethyl)alkylamine (1.5 eq) was added to a solution of chlorotrimethylsilane (3.0 eq) in dry acetonitrile (0.5 M), to which was added a solution of the appropriate cycloalkanone (1.0 eq, 4 mmol) in dry acetonitrile and the resultant mixture stirred under nitrogen for 48 h. The reaction was quenched by the addition of ice water (10 mL) and partitioned between diethyl ether (20 mL) and water (15 mL). The ether layer was then extracted with hydrochloric acid (0.5 M, 4 x 4 mL) and the combined aqueous extracts washed with ether (20 mL), cooled to 0 °C and the pH brought to 9 by the addition of concentrated ammonia solution (~2 mL). The organic material was then extracted with ether (3 x 50 mL) and the combined ether extracts washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to afford the title compound.

1.1.1 8-ethyl-8-aza-bicvclor4.3.ndecan-10-one 3a

The reaction was conducted according to the general procedure using 7V,N-&M(ethoxymethyl)ethylamme 5a (1.09 g, 6.77 mmol), chlorotrimethylsilane (1.89 g, 17.4 mmol), cycloheptanone 4a (0.637 g, 5.68 mmol) and acetonitrile (40 mL) to afford the title compound 3a (0.805 g, 78 %) as a yellow oil. v _max (NaCiycm ^"1 2967, 2923, 2853, 2801, 2771 (C-H), 1712 (C=O); ¹ H

NMR (200 MHz, CDCl ₃ ) δ _H 2.69 (2H, d, J 11.2, H7A, H9A), 2.43 (2H, m, Hl, H6), 2.24 (2H, q, J 7.0, CH ₂ CH ₃ ), 2.20 (2H, m, H7B, H9B), 1.91-1.37 (6H, m, H2, H3A, H4A, H5), 1.17 (2H, m, H3B, H4B), 0.92 (3H, t, J7.1, CH ₂ CH ₃ ); ¹³ C NMR (50 MHz, CDCl ₃ ) δ _c 213.8, 59.4, 51.6, 48.7, 31.6, 26.7, 12.8; m/z (EI) 182 (MH ⁺ , 100 %), 180 (M-H ⁺ ), 166 (M-Me ⁺ , 19), 72 (C ₄ H ₁₀ N ⁺ , 17), 58 (C ₃ H ₈ N ⁺ , 30). HRMS (EI) found 182.1537; C ₁₁ H ₂₀ NO (MH ⁺ ) requires 182.1540.

1.1.2 8-isopropyl-8-aza-bicvclof4.3.ndecan-10-one 3b

The reaction was conducted according to the general procedure using N,N-tø(ethoxymethyl)isopropylamine 5b (0.587 g, 3.35 mmol) and chlorotrimethylsilane (0.728 g, 6.70 mmol) in acetonitrile (4 mL) and cycloheptanone 4a (0.250 g, 2.23 mmol) in acetonitrile (17 mL) to afford the title compound 3b (0.370 g, 85 %) as a clear colourless oil.

V _max (NaCiycm ^"1 2962, 2918, 2853, 2799 (C-H), 1709 (C=O); ¹ HNMR (300 MHz ₅ CDCl ₃ ) δ _H 2.85 (IH, sept, J 6.6, CH(CHs) ₂ ), 2.77 (2H, dd, J 9.5, 1.6, H7A, H9A), 2.62-2.59 (2H, m, Hl, H6), 2.60 (2H, d, J 9.5, H7B, H9B), 1.97 (2H, m, H3A, H4A), 1.79 (2H, m, H2A, H5A), 1.58 (2H, m, H2B, H5B), 1.36 (2H, m, H3B, H4B), 1.01 (6H, d, J 6.6, CR ₂ (CHs) ₂ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 214.9, 54.4, 53.6,

49.4, 31.9, 27.1, 18.5; m/z (ESI+) 196 (MH ⁺ , 100 %). HRMS (ESI+) found 196.1696; C ₁₂ H ₂₁ NO (MH ⁺ ) requires 196.1696.

1.1.3 8-tβrt-butyl-8-aza-bicyclor4.3.11decan-10-one 3c

The reaction was conducted according to the general procedure using

N,N-bis(ethoxymethyl)tert~butylamine 5c (1.13 g, 5.71 mmol), chlorotrimethylsilane (1.81 g, 16.7 mmol), cycloheptanone 4a (0.476 g, 4.24 mmol) and acetonitrile (40 mL) to afford the title compound 3c (0.720 g, 81 %) as a yellow oil. v _max (NaCiycm ^"1 2966, 2939, 2918, 2851, 2797, 2760 (C-H), 1705 (C=O); ¹ H NMR (300 MHz ₅ CDCl ₃ ) δ _H 3.03 (2H, d, J 10.7, H7A, H9A), 2.60 (2H, m, Hl , H6), 2.51 (2H, dd, J 11.0, 2.6, H7B, H9B), 2.01 (2H, m, H2A, H5A), 1.80 (2H, m, H3A, H4A), 1.64-1.45 (2H, m, H2B, H5B), 1.42-1.31 (2H, m, H3B, H4B), 1.10 (9H, s, C(CHs) ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 215.3, 53.6, 52.9, 49.5, 31.7, 27.2, 26.8; m/z (ESI+) 210 (MH ⁺ , 55), 194 (M-Me ⁺ , 100). HRMS (ESI+) found 210.1844; Ci ₃ H ₂₃ NO (MH ⁺ ) requires 210.1853.

The resultant compound 3c was used without purification to prepare (10s)-8-tert-butyl-8-aza-bicyclo[4.3.1]decan-10-ol 8b as described below.

1.1.4 8-propyl-8-aza-bicvclo[4.3.11decan-10-one 3d

The reaction was conducted according to the general procedure using N,N-tø(ethoxymethyl)propylamine 5d (1.05 g, 6.03 mmol), chlorotrimethylsilane (1.30 g, 12.0 mmol), cycloheptanone 4a (0.445 g, 3.97 mmol) and acetonitrile (40 mL) to afford the title compound 3d (0.662 g, 85 %) as a yellow oil. v _max (NaCiycm- ¹ 2922, 2874, 2854, 2804, 2770, 2741 (C-H), 1709 (C=O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 2.84, (2H, d, J 11.3, H7A, H9A), 2.60 (2H, m, Hl, H6), 2.37 (2H, dd, J 11.6, 3.6, H7B, H9B), 2.29 (2H, t, J7.0, NCH ₂ CH ₂ CH ₃ ), 1.99 (2H, m, H2A, H5A), 1.80 (2H, m, H3A, H4A), 1.60 (2H, m, H2B, H5B), 1.52 (2H, q _t J 7.3, NCH ₂ CH ₂ CH ₃ ), 1.38 (2H, m, H3B, H4B), 0.95 (3H, t, JlA, NCH ₂ CH ₂ CH ₃ );

¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 214.6, 60.3, 60.1, 49.1, 31.9, 27.1, 20.9, 12.4; m/z (ESI+) 208 (28), 197 (18), 196 (MH ⁺ , 100). HRMS (ESI+) found 196.1701; C ₁₂ H ₂₁ NO (MH ⁺ ) requires 196.1696.

1.1.5 9-ethyl-9-aza-bicyclor5.3.1]undecan-l 1-one 3e

The reaction was conducted according to the general procedure using iV;N-tø(ethoxymethyl)ethylamine 5a (0.967 g, 6.0 mmol), chlorotrimethylsilane (1.3O g, 12.0 mmol), acetonitrile (32 mL), cyclooctanone 4b (0.504 g, 3.99 mmol) and acetonitrile (2 x 8 mL) to afford the title compound 3e (0.749 g, 96 %) as a viscous yellow oil. v _max (NaCiycm ^"1 2927, 2861, 2998 (C-H), 1712 (C=O); ¹ H NMR (200 MHz, CDCl ₃ ) δ _H 2.79 (2H, d, J 10.7, H8A, HlOA), 2.42 (2H, q, J7.1, CH ₂ CH ₃ ), 2.35-2.13 (6H, m, Hl, H2A, H3A, H5A, H6A, H7), 1.93-1.56 (5H, m, H2B, H4A, H5B, H8B, HlOB), 1.29-1.41 (3H, m, H3B, H4B, H5B), 1.05 (3H, t, J7.1, CH ₂ CH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 218.5, 58.5, 50.4, 49.5, 31.4, 30.6, 24.9, 12.9; mk (EI+) 196 (MH ⁺ , 100), 180 (M-Me ⁺ , 20), 98 (16), 72 (C ₄ H ₁₀ N ⁺ , 15), 58 (C ₃ H ₈ N, 41). HRMS (ESI+) found 196.1703; C ₁₂ H ₂₂ NO (MH ⁺ ) requires 196.1696.

1.1.6 g-isopropyl-g-aza-bicvclorS.S.llundecan-l 1-one 3f

The reaction was conducted according to the general procedure using N,N-&w(ethoxymethyl)isopropylamine 5b (1.07 g, 6.12 mmol) and chlorotrimethylsilane (1.30 g, 12.0 mmol) in acetonitrile (8 mL) and cyclooctanone 4b (0.505 g, 4.00 mmol) in acetonitrile (32 mL) to afford the title compound 3f (0.795 g, 95 %) as a pale yellow oil. v _max (NaCiycm- ¹ 2961, 2926, 2864, 2797 (C-H), 1703 (C=O); ¹ HNMR (300 MHz, CDCl ₃ ) δ _H 2.88 (IH, sept., J 6.6, CH(CH ₃ ) ₂ ), 2.73 (2H, d, J 11.0, H8A, HlOA),

2.58 (2H, dd, J 11.2, 2.2, H8B, HlOB), 2.37-2.16 (4H, m, Hl, H2A, H6A, H7), 1.92-1.72 (4H, m, H2B, H3A, H5A, H6B), 1.64 (IH ₃ m, H4A), 1.29-1.14 (3H, m, H3B, H4B, H5B), 1.03 (6H, d, J 6.6, CH(CH ^" ₃ ) ₂ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 218.9, 77.6, 54.4, 54.1, 51.2, 31.6, 25.0, 18.7; m/z (ESI+) 210 (MH ⁺ , 100). HRMS (ESI+) found 210.1855; C ₁₃ H ₂₃ NO (MH ⁺ ) requires 210.1853.

1.1.7 g-tgrt-butyl-g-aza-bicvclofS.S.llundecan-ll-one 3g

The reaction was conducted according to the general procedure using

N,N-6zs(ethoxymethyl)isopropylamine 5c (1.14 g, 6.04 mmol) and chlorotrimethylsilane (1.30 g, 12.0 mmol) in acetonitrile (8 mL) and cyclooctanone 4b (0.505 g, 4.00 mmol) in acetonitrile (32 mL) to afford the title compound 3g (0.692 g, 77 %) as a white crystalline solid. v _max (NaCiycm ^"1 2968, 2924, 2866, 2847, 2797 (C-H), 1701 (C=O); ¹ H

NMR (300 MHz, CDCl ₃ ) δ _H 2.99 (2H, d, J 10.8, H8A, HlOA), 2.46 (2H, dd, J 11.3, 2.6, H8B, HlOB), 2.35-2.18 (4H, m, Hl, H2A, H6A, H7), 1.90-1.63 (5H, m, H2B, H3A, H4A, H5A, H6B), 1.32-1.18 (3H, m, H3B, H4B, H5B), 1.10 (9H, s, C(CH ₃ ) ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 219.2, 53.5, 51.9, 51.2, 31.7, 31.2, 27.1, 25.0; m/z (ESI+) 224 (MH ⁺ , 100), 168 (18). HRMS (ESI+) found 224.2000; C ₁₄ H ₂₅ NO (MH ⁺ ) requires 224.2009.

1.1.8 g-propyl-g-aza-bicyclors.S.llυndecan-ll-one 3h

The reaction was conducted according to the general procedure using N,N-tø(ethoxymethyl)propylamine 5d (0.578 g, 3.30 mmol) and chlorotrimethylsilane (0.719 g, 6.62 mmol) in acetonitrile (4 mL) and cyclooctanone 4b (0.277 g, 2.20 mmol) in acetonitrile (16 mL) to afford the title compound 3h (0.266 g, 74 %) as a pale yellow oil.

v _max (NaCiycm ^"1 2959, 2928, 2870, 2800, 2770 (C-H), 1701 (C=O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 2.80 (2H, d, J 10.0, H8A, HlOA), 2.36-2.24 (8H, m, Hl, H2A, H6A, H7, H8B, HlOB, NCH ₂ CH ₂ CH ₃ ), 1.90 (2H, m, H3A, H5A), 1.76 (2H, m, H2B, H6B), 1.62 (IH, m, H4A), 1.48 (2H, m, NCH ₂ CH ₂ CH ₃ ), 1.30-1.18 (3H, m, H3B, H4B, H5B), 0.95 (3H, t, J 7.3, NCH ₂ CH ₂ CH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 218.6, 59.6, 59.0, 50.8, 31.7, 31.5, 24.9, 20.9, 12.2; m/z (ESI+) 210 (MH ⁺ , 100). HRMS (ESI+) found 210.1847; C ₁₃ H ₂₃ NO (MH ⁺ ) requires 210.1853.

1.1.9 8-benzyl-8-aza-bicvclor4.3.ndecan-10-one 3i

The reaction was conducted according to the general procedure using

N,iV-έw(ethoxymethyl)benzylamine 5e (2.68 g, 12.0 mniol), chlorotrimethylsilane (2.57 g, 23.6 mmol), cycloheptanone 4a (0.897 g, 8.00 mmol) and acetonitrile (80 mL) to afford the title compound 3i (0.647 g, 33 %) as a white solid after purification by column chromatography (1:9, EtOAc:Hexane). v _max (NaCiycm ^"1 2916, 2851, 2802, 2766 (C-H), 1713 (C=O); ¹ H NMR (300

MHz, CDCl ₃ ) δ _H 7.31 (5H, m, NCH ₂ PA), 3.52 (2H, s, NCH ₂ Ph), 2.85 (2η, d, J 11.1, H7A, H9A), 2.62 (2H, m, Hl, H6), 2.44 (2H, m, H7B, H9B), 2.06 (2H, m, H2A, H5A), 1.79 (2H, m, H3A, H4A), 1.59 (2H, m, H2B, H5B), 1.42 (2H, m, H3B, H4B); m/z (ESI+) 256 (MH ⁺ , 100), 244 (89). HRMS (ESI+) found 244.1697; C ₁₆ H ₂₂ NO (MH ⁺ ) requires 244.1696.

1.1.10 3-ethyl-l,5-dimethyl-3-aza-bicyclor3.3.Hnonan-9-one 7a

The reaction was conducted according to the general procedure using N,iV-όw(ethoxymethyl)ethylamine 5a (1.09 g, 6.8 mmol), chlorotrimethylsilane (1.89 g, 17.4 mmol), 2,6-dimethylcyclohexanone 4h (0.734 g, 5.82 mmol) and

acetonitrile (10 mL) to afford the title compound 7a (1.103 g, 97 %) as a clear colourless oil. v _max (NaCiycm ^"1 2970, 2926, 2754 (C-H), 1717 (C=O); ¹ H NMR (200 MHz, CDCl ₃ ) δ _H 3.08 (IH, m, H7A), 2.96 (2H, dd, J 11.7, 1.5, H2A, H4B), 2.20 (2H, q, J 7.1 CH ₂ CH ₃ ), 2.11 (2H ₅ dd, / 11.9, 2.0, H2B, H4B), 1.98 (2H, ddt, J12.7, 6.1, 1.5, H6A, H8A), 1.64 (2H, dtt, J 12.7, 6.3, 1.9, H6B, H8B), 1.35 (IH, m, H7B), 1.01 (3H, t, J7.1, CH ₂ CH ₃ ), 0.85 (6η, s, CCH ₃ ); ¹³ C NMR (50 MHz, CDCl ₃ ) δ _c 219.4, 67.4, 51.1, 47.3, 43.3, 21.6, 21.3, 13.1; m/z (ESI+) 219 (MNa ⁺ , 36), 196 (MH ⁺ , 100). HRMS (ESI+) found 218.1518; C ₁₂ H ₂₁ NONa (MNa ⁺ ) requires 218.1515.

1.1.11 3-isopropyl-l,5-dimethyl-3-aza-bicyclor3.3.11nonan-9-one 7b

The reaction was conducted according to the general procedure using N,N-tø(ethoxymethyl)isopropylamine 5b (1.08 g, 6.17 mmol) and chlorotrimethylsilane (1.34 g, 12.4 mmol) in acetonitrile (8 mL) and 2,6-dimethylcyclohexanone 4h (0.668 g, 4.12 mmol) in acetonitrile (32 mL) to afford the title compound 7b (0.863 g, 97 %) as a clear colourless oil. v _max (NaCiycm ^'1 2966, 2926, 2903, 2845, 2795, 2768, 2741 (C-H), 1720 (C=O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 3.07 (IH, m, H7A), 2.90 (2H, d, J 11.5, H2A, H4B), 2.73 (IH, sept., J 6.6 CH(CH ₃ ) ₂ ), 2.38 (2H, dd, J 11.6, 1.9, H2B, H4B), 2.00 (2H, ddt, J 12.8, 6.2, 1.7, H6A, H8A), 1.68 (2H, dtt, J 12.8, 6.4, 2.0, H6B, H8B), 1.33 (IH, m, H7B), 0.97 (6H ₃ d, J6.6, CH(CHs) ₂ ), 0.89 (6η, s, CCH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 219.6, 62.8, 53.5, 47.3, 43.2, 21.6, 21.3, 18.4; m/z (ESI+) 210 (MH ⁺ , 100). HRMS (ESI+) found 210.1853; C ₁₃ H ₂₃ NO (MH ⁺ ) requires 210.1851.

1.1.12 3-tert-butyl-l,5-dimethγl-3-aza-bicvcloF3.3.11nonan-9-one 7c

The reaction was conducted according to the general procedure using i\ζN-&z5(ethoxymethyl)tert-butylamine 5c (1.13 g, 5.99 mmol), chlorotrimethylsilane (1.30 g, 12.0 mmol), 2,6-dimethylcyclohexanone 4h (0.644 g, 3.97 mmol) and acetonitrile (40 mL) to afford the title compound 7c (0.759 g, 86 %) as a clear colourless oil.

Vmax (NaCiycm ^"1 2924, 2970, 2870, 2845, 2795, 2758, 2741 (C-H), 1720 (C=O); ¹ HNMR (300 MHz, CDCl ₃ ) δ _H 3.12 (IH, m, H7A), 3.10 (2H, dd, J9.7, 1.7, H2A, H4B), 2.33 (2H, dt, J 9.6, 1.9, H2B, H4B), 2.02 (2H, ddt, J 12.6, 6.4, 1.8, H6A, H8A), 1.70 (2H, dtt, J12.6, 6.5, 2.0, H6B, H8B), 1.33 (lH, m, H7B), 1.11 (9H, s, C(CH ₃ ) ₃ ), 0.90 (6η, s, CCH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 220.1, 60.6, 53.4, 47.3, 43.1, 26.5, 21.6, 21.4; m/z (EI) 224 (MH ⁺ , 22), 208 (M-Me ⁺ , 100). HRMS (ESI+) found 224.2014; C ₁₄ H ₂₅ NO (MH ⁺ ) requires 224.2009.

1.1.13 3-propyl-l,5-dimethyl-3-aza-bicvclor3.3.11nonan-9-one 7d

The reaction was conducted according to the general procedure using N,N-tø(ethoxymethyl)propylamine 5d (1.06 g, 6.03 mmol), chlorotrimethylsilane (1.30 g, 12.0 mmol), 2,6-dimethylcyclohexanone 4h (0.662 g, 4.08 mmol) and acetonitrile (40 mL) to afford the title compound 7d (0.823 g, 96 %) as a clear colourless oil.

V _max (NaCiycm ^"1 2964, 2926, 2874, 2847, 2802, 2772, 2758, 2739 (C-H), 1720 (C=O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 3.14 (IH, m, H7A), 2.99 (2H, dd, J 10.3, 1.5, H2A, H4B), 2.16 (2H, t, J7.1, NCH ₂ CH ₂ CH ₃ ), 2.12-1.98 (4H, m, NCH ₂ CH ₂ CH ₃ , H2B, H4B), 1.70 (2H, m, H6A, H8A), 1.57-1.32 (3H, m, H6B, H7B, H8B), 0.93 (3H, t, J 7.3, NCH ₂ CH ₂ CH ₃ ), 0.91 (6η, s, CCH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 219.5, 67.8, 59.4, 47.4, 43.3, 21.5, 21.3, 20.8, 12.2; m/z (EI) 210 (MH ⁺ , 100). HRMS (ESI+) found 210.1857; C ₁₃ H ₂₃ NO (MH ⁺ ) requires 210.1853.

1.1.14 3-ethyl-l,5-diphenyl-3-aza-bicyclo| ^" 3.3.11nonan-9-one 7e

The reaction was conducted according to the general procedure using N,N-&zs(ethoxymethyl)ethylamine 5a (0.586 g, 3.63 mmol), chlorotrimethylsilane (0.986 g, 9.08 mmol), 2,6-diρhenylcyclohexanone 4i (0.758 g, 3.03 mmol) and acetonitrile (11 mL) to afford the title compound 7e (0.338 g, 35 %) as a yellow liquid. v _max (NaCiycm ^"1 3055, 2968, 2922, 2855, 2802 (C-H), 1719 (C=O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 7.37-7.16 (1OH, m, ArH), 3.47 (IH, m, H7A), 3.39 (2H, m, H2A, H4A), 2.96 (2H, d, J 10.8, H6A, H8A), 2.68 (2H, dd, J 12.9, 6.0, H2B, H4B), 2.50-2.39 (2H, m, H6B, H8B), 2.45 (2H, q, J 6.9, CH ₂ CH ₃ ), 1.82 (IH, m, H7B), 1.15 (3H, t, J7.1, CH ₂ CH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 141.8, 128.1, 128.0, 127.7, 127.1, 67.2, 55.1, 52.0, 41.8, 21.8, 13.1; m/z (EI) 320 (MH ⁺ , 54), 319 (M ⁺ , 100). HRMS (EI) found 319.1933; C ₂₂ H ₂₅ NO (MH ⁺ ) requires 319.1936.

1.1.15 1 -methyl-3 -fert-butyl-3 -aza-bicyclo [3.3.1 ^" lnonan-9-one 6a

The reaction was conducted according to the general procedure using

λζiV-6z5(ethoxymethyl)tert-butylamine 5c (1.14 g, 6.02 mmol), chlorotrimethylsilane (1.30 g, 12.0 mmol), 2-methylcyclohexanone 4c (0.449 g, 4.00 mmol) and acetonitrile (40 mL) to afford the title compound 6a (0.790 g, 3.77 mmol, 94 %) as a clear colourless oil. v _max (NaCiycm ^"1 2972, 2924, 2854, 2793 (C-H), 1720 (C=O); ¹ H NMR (300

MHz, CDCl ₃ ) δ _H 3.27 (IH, dt, J 10.9, 2.6, H2A), 3.11 (IH, dd, J 10.9, 2.9, H4A), 2.97 (IH, m, H7A), 2.64 (IH, m, H2B), 2.38-2.31 (2H, m, H4B, H5), 2.15-1.92 (3H, m, H6A, H6B, H8A), 1.72 (IH, m, H8B), 1.44 (IH, m, H7B), 1.07 (9H, s, NC(CH ₃ ) ₃ ), 0.89 (3η, s, CCH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 220.3, 60.5, 53.9, 53.5, 48.5, 47.6,

42.9, 35.1, 26.6, 21.7, 21.5; m/z (ESI+) 210 (MHT", 100), 154 (21). HRMS (ESI+) found 210.1854; C ₁₃ H ₂₄ NO (MH ⁺ ) requires 210.1853.

1.1.16 l-allyl-S-fert-butyl-S-aza-bicvcloB.S.linonan-g-one 6b

The reaction was conducted according to the general procedure using

λζ7V-&z5(ethoxymethyl)tert-butylamme 5c (0.568 g, 3.00 mmol), chlorotrimethylsilane (0.652 g, 6.00 mmol), 2-allylcyclohexanone 4d (0.276 g, 2.00 mmol) and acetonitrile (20 mL) to afford the title compound 6b (0.351 g, 1.49 mmol, 75 %) as a yellow liquid. v _max (NaCiycm ^"1 3074, 2974, 2922, 2853, 2793 (C-H), 1717 (C=O) 1639,

912 (C=C); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 5.81 (IH, m, H2'), 5.04 (IH, s, H3A'), 4.97 (IH, m, H3B'), 3.25 (IH, dt, J 10.9, 2.7, H2A), 3.14 (IH, dd, J 11.0, 2.8, H4A), 2.85 (IH, m, H7A), 2.65 (IH, dd, J 11.0, 2.6, H2B), 2.42-2.30 (2H, m, H4A, H5), 2.06 (4H, m, H6A, H8A, Hl'), 1-72 (2H, m, H6B, H8B), 1.41 (IH, m, H7B), 1.08 (9H, s, C(CH ₃ ) ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 219.5, 134.5, 117.6, 58.3, 53.7, 53.5, 49.5, 48.3, 39.6, 39.5, 34.6, 26.5, 21.4; m/z (ESI+) 236 (MH ⁺ , 100), 180 (58). HRMS (ESI+) found 236.2005; C ₁₅ H ₂₆ NO (MH ⁺ ) requires 236.2009.

1.1.17 1 -(benzyloxy)-3 -tertbutyl-3 -aza-bicyclo [3.3.1 lnonan-9-one 6c

The reaction was conducted according to the general procedure using

N,N-bzs(ethoxymethyl)tørt-butylamine 5c (0.205 g, 1.01 mmol), chlorotrimethylsilane (0.325 g, 2.99 mmol), 2-benzyloxycyclohexanone 4e (0.288 g, 1.52 mmol) and

acetonitrile (10 mL) to afford the title compound 6c (16.2 mg, 0.0537 mmol, 5 %) as a clear colourless liquid. v _max (NaCiycm ^"1 2970, 2926, 2853, 2795 (C-H), 1728 (C=O), 1130 (C-O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 7.28 (5H, m, PACH ₂ O), 4.73 (IH, d, J 11.4, Hl 'A), 4.59 (IH, d, J 11.3, Hl 'B), 3.17 IH, dd, J 10.5, 2.6, H2A), 3.14 (IH, dt, J 11.0, 2.6, H4A), 2.79 (IH, m, H7A), 2.65 (2H, m, H2B, H4B), 2.48 (IH, m, H5), 2.18 (2H, m, H6A, H8A), 2.04-1.86 (2H, m, H6B, H8B), 1.51 (IH, m, H7B), 1.05 (9H, s, C(CH ₃ ) ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 215.5, 139.5, 128.4, 127.8, 127.5, 81.9, 66.5, 58.7, 53.6, 53.3, 49.2, 39.0 33.6, 26.5, 21.9; m/z (ESI+) 324 (MNa ⁺ , 19), 302 (100), 246 (35), 236 (20). HRMS (ESI+) found 324.1931 ; C ₁₉ H ₂₇ NO ₂ (MNa ⁺ ) requires 324.1934.

1.1.18 7-oxa-3-terώutyl-3-aza-bicyclo[ ^" 3.3.11nonan-9-one 6d

The reaction was conducted according to the general procedure using N,N-fe(ethoxymethyl)ter^butylamine 5c (0.568 g, 3.00 mmol), chlorotrimethylsilane (0.652 g, 6.00 mmol), tetrahydro-4H-pyran-4-one 4f (0.200 g, 2.00 mmol) and acetonitrile (20 mL) to afford the title compound 6d (351 mg, 01.49 mmol, 75 %) as a white solid. v _m a _x (NaCiycrn ¹ 2968, 2924, 2853 (C-H), 1738 (C=O), 1198 (C-O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 4.10 (2H, d, J 11.0, H2A, H4A), 3.83 (2H, dd, J 11.0, 4.0, H2B, H4B), 3.09 (2H, d, J 10.9, H6A, H8A), 2.94 (2H, dd, J 10.8, 5.9, H6B, H8B), 2.47 (2H, m, Hl, H5), 1.00 (9H, s, C(CH ₃ ) ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 213.0, 73.3, 53.7, 51.4, 49.8, 26.5; m/z (ESI+) 230 ([MH+MeOH] ⁺ , 100), 216 (15). HRMS (ESI+) found 230.1751; C ₁₁ H ₂₀ NO ₂ ([MH+MeOH] ⁺ ) requires 230.1751.

1.1.19 lO-propyl-lO-aza-tricvclorό.S.l.O^^dodeca^rVXS^-trien-n-one θe

The reaction was conducted according to the general procedure using 7V,iV-6w(ethoxymethyl)propylamine 5d (1.05 g, 6.00 mmol), chlorotrimethylsilane (1.30 g, 12.0 mmol), 2-indanone 4g (0.529 g, 4.00 mmol) and acetonitrile (40 mL) to afford the title compound 6e (90.2 mg, 0.453 mmol, 11 %) as a brown oil. v _max (NaCiycm ^"1 2961, 2932, 2872, 2795 (C-H), 1769 (C-O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 7.16 (4H, m, H3, H4, H5, H6), 3.25 (2H, d, J3.6, Hl, H8), 3.06 (2H, dd, J 11.0, 3.8, H9A, Hl IA), 2.58 (2H, d, J 10.7, H9B, Hl IB), 2.20 (2H, t, J 7.2, NCH ₂ CH ₂ CH ₃ ), 1.18 (2H, m, NCH ₂ CH ₂ CH ₃ ), 0.53 (3H, t, J 7.3, NCH ₂ CH ₂ CH ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 214.9, 139.5, 127.5, 122.3, 59.0, 57.2, 53.1, 20.1, 11.3; m/z (ESI+) 248 ([MHfMeOH] ⁺ , 100), 216 (21). HRMS (ESI+) found 248.1640; C ₁₄ Hi ₈ NO ([MH+MeOH] ⁺ ) requires 248.1645.

1.2 General procedure for the preparation of 8a, 8b, 8c and 8d The following procedure was used to prepare the compounds 8a, 8b, 8c and 8d referred to below.

Sodium borohydride (2 eq) was added to a stirred solution of the appropriate ketone (1 eq) in ethanol/water (4:1; 0.2 M) at 0 °C, and the reaction stirred for 2 h. Cone, hydrochloric acid was added dropwise to quench the excess sodium borohydride and the mixture concentrated in vacuo to remove ethanol. The aqueous solution was made basic by the addition of sodium hydroxide (3 M, pH 10) and the organic material extracted into ether (3x). The combined ether extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give crude alcohol. Purification by flash chromatography (EtOAc :Hexane) then afforded the title compound.

1.2.1 (lQsrV8-ethyl-8-aza-bicvclor4.3.ndecan-10-ol 8a

The reaction was conducted according to the general procedure using ketone 3a (1.06 g, 5.8 mmol), sodium borohydride (0.441 g, 11.7 rnmol) and ethanol/water (125 mL) to afford the title compound 8a (0.867 g, 4.73 mmol, 81 %) as a white solid after chromatography (1:4, EtOAc:Hexane). v _max (NaCiycm- ¹ 3393 (0-H) ₃ 2967, 2904, 2755 (C-H); ¹ H NMR (300 MHz, CD ₃ OD) δ _H 3.88 (IH, t, J5.4, HlO), 2.71 (2H, d, /10.9, H7A, H9A), 2.25 (2H, q, J7.2, NCH ₂ CH ₃ ), 1.95 (4H, m, H2A, H3A, H4A, H5A), 2.07 (2H, m, Hl, H6), 1.96 (2H, dd, J 11.6, 3.2, H7B, H9B), 1.68 (2H, m, H2B, H5B), 1.53 (2H, m, H3B, H4B), 1.04 (3H, t, J7.2, NCH ₂ CH ₃ ); ¹³ C NMR (50 MHz, CDCl ₃ ) δ _c 76.2, 60.4, 52.4, 38.8, 31.7, 27.4, 13.0; m/z (ESI+) 184 (MH ⁺ , 100). Found MH ⁺ 184.1696. C _n H ₂₂ NO requires MH ⁺ 184.1693.

1.2.2 αθ5)-8-tert-butyl-8-aza-bicvclor4.3.11decan-10-ol 8b

The reaction was conducted according to the general procedure using ketone 3c (1.00 g, 4.78 mmol), sodium borohydride (0.724 g, 19.2 mmol) and methanol/water (50 mL) to afford the title compound 8b (0.613 g, 2.90 mmol, 61 %) as a white crystalline solid after chromatography (1:19, EtOAc:Hexane). R _f 0.29 (1 : 19, EtOAc :Hexane); v _max (NaCl)/cm ⁴ 3273 (O-H), 2961, 2910,

2851, 2795, 2739 (C-H); ¹ H NMR (300 MHz, CD ₃ OD) δ _H 3.83 (IH, t, J 5.5, HlO), 2.88 (2H, ddJ8.6, 2.4, H7A, H9A), 2.19 (2H, dd, / 11.3, 2.6, H7B, H9B), 2.06 (2H, m, Hl, H6), 1.93 (4H, m, H2A, H3A, H4A, H5A), 1.70 (2H, m, H2B, H5B), 1.50 (2H, m, H3B, H4B), 1.05 (9H, s, C(CH ₃ ) ₃ ); ¹³ C NMR (75 MHz, CD ₃ OD) δ _c 76.9, 53.8 (2C), 39.9, 32.6, 28.2, 26.7; m/z (ESI+) 312 (16), 212 (MH ⁺ , 100), 156 (17). Found MH ⁺ 212.2009. C _n H ₂₅ NO requires MH ⁺ 212.2009.

1.2.3 (1 lsy9-tert-Tmtv\-9-B7αAAcγclo\53λλ\mάscm-l l-ol 8c

The reaction was conducted according to the general procedure using ketone 3g (118 mg, 0.528 mmol), sodium borohydride (39.9 mg, 1.06 mmol) and ethanol/water (10 mL) to afford the title compound 8c (106 mg, 0.472 mmol, 89 %) as a white solid after chromatography (1:19, EtOAc:Hexane). v _max (NaCiycm ^'1 3339 (O-H), 2964, 2908, 2787 (C-H); ¹ HNMR (300 MHz, CD ₃ OD) δ _H 3.83 (IH, m, HIl), 2.98 (2H, dJ ll.l, H8A, HlOA), 2.25 (2H, m, H8B, HlOB), 2.01-1.61 (HH, m, Hl, H2, H3, H4A, H5, H6, H7), 1.43 (IH, m, H4B), 1.09 (9H, s, NC(CHs) ₃ ); m/z (ESI+) 226 (MH ⁺ , 100). Found MH ⁺ 226.2161. C ₁₄ H ₂₇ NO requires MH ⁺ 226.2166.

1.2.4 r9^-3-tert-butyl-3-aza-bicvclor3.3.11nonan-9-ol 8d

The reaction was conducted according to the general procedure using ketone 7c (82.7 mg, 0.37 mmol), sodium borohydride (28.0 mg, 0.74 mmol) and ethanol/water (6 mL) to afford the title compound as a mixture of epimers (1:1.7, 9r:9s) which was separated to give 8d (40.2 mg, 0.178 mmol, 48 %) as a white crystalline solid.

V _max (NaCiycm ^'1 3354 (OH), 2968, 2947, 2922, 2903, 2854, 2789 (C-H) ; ¹ H NMR (300 MHz, CD ₃ OD) δ _H 2.89 (IH, s, H9), 2.84 (IH ₅ m, H7A), 2.84 (2H, d, J 11.4, H2A, H4A), 2.07 (2H, dd, J 11.7, 2.1, H2B, H4B), 1.64 (2H, ddt, J 13.2, 6.4, 2.0, H6A, H8A), 1.35-1.22 (3H, m, H6B, H7B, H8B), 1.02 (9H, s, NC(CHs) ₃ ), 0.81 (6η, s, CCH ₃ ); ¹³ C NMR (75 MHz, CD ₃ OD) δ _c 82.1, 59.9, 53.6, 36.9, 32.5, 26.6, 26.3, 22.1; m/z (ESI+) 226 (MH ⁺ , 100). Found MH ⁺ 226.2169. C ₁₄ H ₂₇ NO requires MH ⁺ 225.2166.

1.3 General procedure for the preparation of 9a, 9b, 9d and 9e

The following procedure was used to prepare the compounds 9a, 9b, 9d and 9e referred to below.

To a solution of the appropriate alcohol (1 eq) and DMAP (0.1 eq) in dichloromethane (0.1 M) was added triethylamine (2 eq) and acetic anhydride (4 eq) under nitrogen. The reaction mixture was heated at reflux for 24 h at which time the reaction was quenched by the addition of saturated sodium hydrogen carbonate solution (10 mL) and the organic material extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to give crude acetate which was subsequently purified by flash chromatography (EtOAc :Hexane) to give the title compound.

1.3.1 (105')8-ethyl-8-aza-bicvclor4.3.11decan-10-yl acetate 9a

The reaction was conducted according to the general procedure using alcohol 8a (67.0 mg, 0.366 mmol), DMAP (5.0 mg, 0.0409 mmol), triethylamine (0.10 mL, 0.0728 g, 0.719 mmol), acetic anhydride (0.14 mL, 0.151 g, 1.48 mmol) and dichloromethane (2.5 mL) to afford the title compound 9a (0.0696 g, 0.309 mmol, 85 %) as a clear colourless oil after chromatography (1:9, EtOAc:Hexane). v _max (NaCiycmf ¹ 2968, 2943, 2918, 2858, 2802, 2781, 2758 (C-H), 1740

(C=O), 1244 (C-O); ¹ H NMR (200 MHz, CDCl ₃ ) δ _H 4.95 (IH, t, J5.7, HlO), 2.69 (2H, dd, J 11.1, 2.1, H7A, H9A), 2.31-2.20 (2H, m, Hl, H6), 2.24 (2H, q, J7.2, NCH ₂ CH ₃ ), 2.07 (3H, s, OCOCH ₃ ), 2.08 (2H, dd, J 11.1, 3.1, H7B, H9B), 1.85 (4H, m, H2A, H3A, H4A, H5A), 1.60 (4H, m, H2B, H3B, H4B, H5B), 1.02 (9H, s, NCH ₂ CH ₅ ); ¹³ C NMR (50 MHz, CDCl ₃ ) δ _c 170.9, 78.2, 60.2, 52.5, 36.0, 32.1, 27.1, 21.7, 13.0; m/z (ESI+) 226 (MH ⁺ , 100), 224 (27). Found MH ⁺ 226.1804. C ₁₃ H ₂₃ NO ₂ requires MH ⁺ 226.1802.

1.3.2 riO^-8-tert-butvl-8-aza-bicvclor4.3.11decan-10-vl acetate 9b

The reaction was conducted according to the general procedure using alcohol 8b (0.112 g, 0.529 rnmol), DMAP (6.5 mg, 0.0532 rnmol), triethylamine (0.15 mL, 0.109 g, 1.08 mmol), acetic anhydride (0.20 mL, 0.216 g, 2.12 rnmol) and dichloromethane (2.5 mL) to afford the title compound 9b (0.129 g, 0.509 mmol, 96 %) as a clear colourless oil after chromatography (1:19, EtOAc :Hexane). v _raax (NaCiycm ^"1 2968, 2943, 2914, 2874, 2860, 2789 (C-H), 1738 (C=O) ₃ 1242 (C-O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 4.91 (IH, t, J5.6, HlO), 2.84 (2H, dd, J8.5, 2.5, H7A, H9A), 2.17 (4H, m, Hl, H6, H7B, H9B), 1.94 (3H, s, OCOCH ₃ ),

1.85 (4H, m, H2A, H3A, H4A, H5A), 1.58 (4H, m, H2B, H3B, H4B, H5B), 1.02 (9H, s, C(CH ₃ ) ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 170.9, 78.9, 53.3, 52.9, 36.3, 32.1, 27.3, 26.5, 21.8; m/z (ESI+) 255 (17), 254 (MH ⁺ , 100), 252 (25), 198 (23). Found MH ⁺ 254.2105. Ci ₅ H ₂₇ NO ₂ requires MH ⁺ 254.2115.

1.3.3 (I l^-g-tgrt-butyl-g-aza-bicvclorS.S.llundecan-l 1-yl acetate 9d

The reaction was conducted according to the general procedure using alcohol 8c (84.1 mg, 0.373 mmol), DMAP (5.0 mg, 0.041 mmol), triethylamine (75.7 mg, 0.748 mmol), acetic anhydride (152 mg, 1.49 mmol) and dichloromethane (3.7 mL) to afford the title compound 9d (69.1 mg, 0.258 mmol, 69 %) as a clear colourless oil after chromatography (1:19, EtOAc :Hexane). v _max (NaCiycm- ¹ 2966, 2916, 2868, 2795 (C-H), 1738 (C=O), 1242 (C-O); ¹ H NMR (200 MHz, CDCl ₃ ) δ _H 4.97 (IH, t, J5.4, Hl 1), 2.87 (2H, d, J 11.3, H8A, HlOA), 2.27 (2H, dd, J 11.5, 2.6, H8B, HlOB), 2.07 (5H, m, Hl, H7, OCOCH ₃ ),

1.68 (1OH, m, H2, H3, H4, H5, H6), 1.04 (9H ₅ s, NC(CHs) ₃ ); m/z (ESI+) 268 (MH ⁺ , 100). Found MH ⁺ 268.2268. C ₁₆ H ₃₀ NO ₂ requires MH ⁺ 268.2271.

1.3.4 r9^-3-fert-butyl-L5-diethyl-3-aza-bicvclor3.3.11nona-9-yl acetate 9e

The reaction was conducted according to the general procedure using alcohol 8d

(71.5 mg, 0.362 mraol), DMAP (4.4 mg, 0.036 mmol), triethylamine (73.4 mg, 0.725 mmol), acetic anhydride (148 mg, 1.45 mmol) and dichloromethane (3.6 mL) to afford the title compound 9e (88.9 mg, 0.332 mmol, 92 %) as a clear colourless oil after chromatography (1:9, EtOAc :Hexane). v _max (NaCl)/crn ¹ 2966, 2926, 2872, 2853 (C-H), 1738 (C=O), 1244 (C-O);

¹ H NMR (200 MHz, CDCl ₃ ) δ _H 4.97(1H, t, J 5.4, HIl), 2.87 (2H, d, J 11.3, H8A, HlOA), 2.27 (2H, dd, J 11.5, 2.6, H8B, HlOB), 2.07 (5H, m, Hl, H7, COOCH ₃ ), 1.68 (10η, m, η2, H3, H4, H5, H6), 1.04 (9H, s, NC(CH) ₃ ); m/z (ESI+) 268 (MH ⁺ , 100). Found MH ⁺ 268.2268. C ₁₆ H ₃₀ NO ₂ requires MH ⁺ 268.2271.

1.4 General procedure for the preparation of 9f, 9g and 9h

The following procedure was used to prepare the compounds 9f, 9g and 9h referred to below.

To a solution of the appropriate alcohol (1 eq) and the appropriate acid chloride (1.5 eq) in dichloromethane (0.25 M) at 0 ⁰ C was added triethylamine (2.1 eq) dropwise under nitrogen. The solution was warmed to room temperature and the reaction heated at reflux for 16 h at which time the reaction was quenched by the addition of saturated sodium hydrogen carbonate solution (10 mL) and the organic material extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to give crude acetate which was subsequently purified by flash chromatography (EtOAc :Hexane) to give the title compound.

1.4.1 C10s)8-fert-butγl-8-aza-bicyclor4.3.11 decan-10-yl 2-methoxybenzoate 9f

The reaction was conducted according to the general procedure using alcohol 8b (74.9 mg, 0.354 mmol), o-anisoyl chloride (90.5 mg, 0.531 mmol), triethylamine (76.4 mg, 0.755 mmol) and dichloromethane (1.5 mL) to afford the title compound 9f (98.6 mg, 0.285 mmol, 81 %) as a white solid after chromatography (l:9, EtOAc:Hexane). v _max (NaCiycm ^"1 2968, 2943, 2912, 2856, 2787, 2733 (C-H), 1724 (C=O), 1302 (C-O, ester), 1252 (C-O, ether); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 7.85 (IH, d, J7.2, H3') ₃ 7.46 (IH, t, J7.6, H4'), 7.00-6.96 (2H, m, H5', H6'), 5.19 (IH ₅ t, J 4.9, HlO), 3.89 (3H, s, ArOCH ₃ ), 2.89 (2η, d, J 10.4, H7A _S H9A), 2.35-2.31 (4H, m, Hl, H6, H7B, H9B), 2.32 (4H, m, H2A, H3A, H4A, H5A), 1.94 (2H, m, H2B, H5B), 1.65 (2H, m, H3B, H4B), 1.05 (9H, s, NC(CH ₅ ) ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 165.8, 159.5, 133.4, 131.9, 120.8, 120.2, 112.1, 79.1, 55.9, 53.1, 52.8, 36.3, 31.9, 27.0, 26.4; m/z (ESI+) 713 (48), 368 (25), 346 (MH ⁺ , 100), 290 (39). Found MH ⁺ 346.2369. C ₂₁ H _3I NO ₃ requires MH ⁺ 346.2377.

1.4.2 (lO^-δ-tgrt-butyl-δ-aza-bicvclo^.S.lldecan-lO-yl 4-methoxybenzoate 9g

The reaction was conducted according to the general procedure using alcohol 8b (75.0 mg, 0.355 mmol), ^-anisoyl chloride (90.4 mg, 0.530 mmol), triethylamine (76.4 mg, 0.755 mmol) and dichloromethane (1.5 mL) to afford the title compound 9g (119 mg, 0.344 mmol, 97 %) as a white solid after chromatography (l:9, EtOAc:Hexane). v _max (NaCiycm ^"1 2968, 2947, 2918, 2854, 2799, 2787 (C-H), 1709 (C=O), 1258 (C-O, ester), 1163 (C-O, ether); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 8.03 (2H, d,

J8.8, H2\ H6'), 6.93 (2H, d, J8.8, H3', H4'), 5.17 (IH, t, J 5.4, HlO) ₅ 3.86 (3H ₃ s, ArOCH ₃ ), 2.90 (2η, d, J 11.2, WJA, H9A), 2.34 (4H, m, Hl ₅ H6, H7B, H9B), 2.08-1.85 (4H, m, H2A, H3A, H4A, H5A), 1.78-1.55 (4H, m, H2B, H3B, H4B, H5B) ₅ 1.05 (9H, s,NC(CH ₃ ) ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 165.9, 163.4, 131.7, 123.6, 113.8, 78.9, 55.6, 53.2, 52.8, 36.4, 32.0, 27.3, 26.4; m/z (ESI+) 346 (MH ⁺ , 100), 290 (33). Found MH ⁺ 346.2369. C ₂₁ H ₃₁ NO ₃ requires MH ⁺ 346.2377.

1.4.3 (lO^-fert-butyl-δ-aza-bicvclo^.S.lJdecan-lO-yl cyclohexanecarboxylate 9h

The reaction was conducted according to the general procedure using alcohol 8b (100 mg, 0.473 mmol), cyclohexanecarbonyl chloride (106 mg,

0.721 mmol), triethylamine (98.3 mg, 0.971 mmol) and dichloromethane (2.0 mL) to afford the title compound 9h (105 mg, 0.336 mmol, 71 %) as a clear colourless oil after chromatography (1:9, EtOAc:Hexane). v _max (NaCiycmf ¹ 2968, 2918, 2854, 2789, 2733, 2667 (C-H), 1728 (C=O), 1170 (C-O); ¹ H NMR (300 MHz, CDCl ₃ ) δ _H 4.92 (IH, t, J5.7, HlO), 2.84 (2H, d, JIl.1, H7A, H9A), 2.31 (IH, tt, J11.2, 3.6, Hl'), 2.25 (2H, dd, Jll.l, 3.8, H7B, H9B), 2.20 (2H, m, Hl, H6), 1.99-1.92 (4H, m, H2A\ H3A, H4A, H6A') ₅ 1.84-1.74 (4H, m, H2A, H3A\ H5A, H5A'), 1.68-1.59 (3H, m, H3B, H4A', H4B), 1.55-1.41 (4H, m, H2B, H2B\ H5B, H6B') 1.34-1.21 (3H, m, H3B', H4B', H5B'), 1-02 (9H, s, NC(CHj) ₃ ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ _c 175.7, 78.1, 53.1, 52.7, 43.9, 36.2, 31.9, 29.3, 27.1, 26.4, 26.0, 25.7; m/z (ESI+) 322 (MH ⁺ , 100), 266 (28). Found MH ⁺ 322.2739. C ₂₀ H ₃₅ NO ₂ requires MH ⁺ 322.2341.

2. Pharmacology

Azacyclic esters 9a, 9b and 9d to 9g were prepared by the methods described above. Azacyclic esters 9a, 9b and 9d to 9g were evaluated for biological activity against neuronal nicotinic acetylcholine receptors (nAChR) expressed in Xenopus

laevis oocytes. Expression of α4β2, α3β4 and α7 cRNA inXenopus oocytes generated respective nicotinic receptors which showed dose-dependent ACh-activated inward currents when the cell was voltage clamped at -60 mV. Oocytes were first screened with a submaximal dose of ACh corresponding to the EC ₅₀ (α4β2, 100 μM; α3β4, 150 μM; α7, 300 μM) to determine the expression level for each cell. Cells expressing currents >50 nA were used in further screening. Azacyclic esters were then applied to determine agonist activity, antagonist activity was then assessed by incubation of the cell with azacyclic esters (3 min) followed by application combined with a submaximal dose of ACh ₃ a further application of ACh was made to allow for normalization of the data. Azacyclic esters (100 μM) were additionally screened against nude oocytes that had not been injected with cDNA to exclude intrinsic activity.

2.1. Biological evaluation of azacyclic esters 9a, 9b and 9d to 9g

On their own, esters 9a, 9b and 9d to 9g (100 μM) triggered no response, but when co-applied with ACh they acted as antagonists, reducing the response of ACh at α3β4 nAChR (Table Ia).

Table Ia. Percentage inhibition ³ by esters 9a, 9b and 9d to 9g (100 μM) of acetylcholine at nicotinic acetylcholine receptors: α3β4 (150 μM).

^a Data supplied as value ± SEM (n = 3)

2.2. Biological evaluation of azacyclic esters 9e, 9f and 9g

Esters 9e, 9f and 9g were found to antagonize each of the nAChRs, α3β4, α4β2 and oc7 (Table Ib). The IC ₅₀ (Inhibitory concentration at which 50 % of the response of ACh is blocked) were determined for these receptor subtypes, with the highest activity observed against the α3β4 nicotinic receptors.

Table Ib. IC ₅₀ values (μM) for the inhibition of neuronal nicotinic receptors by azacyclic esters 9e, 91 and 9g

Receptor 9e 9ϊ α4β2 2±1 45. 7 ±12.7 15.9 ±2 .0 α3β4 5.4 ±1. 1 8. 9 ±1.2 7.2 ±2. 8 α7 92.9 ±7 .3 49 .0 ±2.5 40.2 ±1 .1

2.3. Conclusion

The compounds screened above showed activity at neuronal nAChRs, with evidence of potency and subtype selectivity. The constrained homocholine motif present in these compounds is as such well oriented for binding and interacting with neuronal nAChR.

3. Pharmacology Experimental

3.1. Expression of nicotinic AChRs in Xenopus oocytes by cytoplasmic injection of cRNA

Xenopus laevis were anaesthetised with 0.17% ethyl 3-aminobenzoate and a lobe of an ovary was removed and rinsed with oocyte releasing buffer, OR2 (82.5 mM NaCl, 2 mM KCl ₅ 1 mM MgCl ₂ , 5 mM HEPES, pH 7.5). It was then treated with Collagenase A (2 mg/mL or OR2, Bohringer Manheim) for 2 h. The released oocytes were rinsed in modified frog Ringer solution (96 mM NaCl, 2 mM KCl, 1 mM MgCl ₂ , 1.8 mM CaCl ₂ , 5 mM HEPES, 2.5 mM pyruvate, 0.5 mM theophylline, 50 ng/mL gentamycin, pH 7.5). Stage V-VI oocytes were collected and stored in this buffer.

Rat cc4, α3, β4 and β2 pcDNA were provided by Associate Professor Jim Boutler (Neuropsychiatric Institute, University of California, Los Angeles, USA); Plasmid containing α3 and cc4 were linearised with ECORl; β2 and β4 were linearised with Hindi and Xho-I respectively. cRNA was synthesized using the 'mMessage mMachine' kit from Ambion (Austin, TX, USA). cRNA was mixed in a

ratio of 1 α3 : 1 β4 and 2 cc4 : 1 β2) and injected into defolliculated oocytes at a concentration of 50 ng/ 50 nl. Oocytes were stored for 1-5 days at 18 °C.

3.2. Electrophysiology

Receptor activity was measured by two electrode voltage clamp recording using a Geneclamp 500 amplifier (Axon Instruments, Foster City, CA, USA), a MacLab 2e recorder (AD Instruments, Sydney, NSW, Australia) and Chart Version 5.0.1 program. Oocytes were voltage clamped at -60 mV and continuously superfused with calcium free frog Ringer solution (115 mM NaCl, 2.5 niM KCl, 1.8 mM BaCl ₂ , 10 mM HEPES) supplemented with 1 μM atropine. For receptor activation measurements, the indicated concentrations of drug were added to the buffer solution. Test compounds were applied to oocytes at intervals of 10-12 min to minimize effects ofdesensitisation.

3.3. Data analysis

The amplitude of the current (J) recorded in response to each drug was normalized to the maximum amplitude (Im) of the current response to ACh (α4β2, 60 μM; α3β4, 150 μM).

INDUSTRIAL APPLICABILITY

The present invention provides a novel process for the preparation of compounds containing azacyclic ring systems, and novel compounds containing azacyclic ring systems. The process and compounds of the present invention may be used to prepare a variety of compounds having therapeutic activity, including activity at the neuronal nicotinic acetylcholine receptors.

Although the invention has been described with reference to particular examples, it will be appreciated by those skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. All such variations and/or modifications are to be considered within the scope of the present invention the nature of which is to be determined from the

foregoing description. It will be appreciated by those skilled in the art that the invention may be embodied in many forms. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

It is to be understood that a reference herein to a prior art document does not constitute an admission that the document forms part of the common general knowledge in the art in Australia or any other country.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.