DERIVATIVES OF MUPIROCIN

Abstract: The application discloses C-1 heteroaryl ketone derivatives of monic and isomonic acids, their use in antibacterial and antimycoplasmal therapy, and processes for the preparation thereof.

Description: Derivatives of Mupirocin This invention relates to a novel class of compounds having antibacterial and antimycoplasmal activity, to processes for their preparation and to their use in human and veterinary medicine, and also to intermediates for use in the preparation of such compounds. Mupirocin, the compound of formula (A) : exhibits good activity against Gram positive bacteria, H.influenzae. Lecrionella and mycoplasma. It is marketed as a topical formulation by Beecham Group p.I.e. under the Trade Mark 'Bactroban' . Mupirocin (formerly known as pseudomonic acid) is rapidly hydrolysed in vivo to monic acid A, the compound of formula (B) : which is inactive. Various proposals have been made to improve the metabolic stability of mupirocin with respect to enzymatic hydrolysis, by modifying of the C-1 ester functional group, including, for instance, C-1 heterocyclic derivatives (EP-A-0 087 953 and EP-A-0 123 578, Beecham Group) and C-1 amides (EP-A-0 001 914, Beecham Group) . In addition, derivatives of monic acids A, B and C characterised in having a ketone functionality at C-1, including inter alia heterocyclic ketones in which the heterocyclic group is a 5- or 6- membered ring containing a nitrogen, oxygen or sulphur atom are disclosed in EP-A-0 029 665 (Beecham Group) . The examples provided are however mainly alkyl ketones, with no example of a heterocyclic ketone given. More recently, Klein et al reported (in a poster presented at the Third Annual Chemical Congress of North America, Toronto, June 1988) the preparation of the C-1 fur-2-yl, ρyrid-2-yl and N-methylimidazol-2-yl ketones. These are characterised by having the heteroaryl group linked to the ketone carbonyl group by a ring carbon atom which is adjacent to the heteroatom. The limited data provided on these derivatives data showed that these compounds were less active than the analogous butyl and phenyl ketones which in turn were less active than methyl pseudomonate. No results of in. vivo activity were reported, the inference being that in vitro activity had not been sufficient to warrant in vivo investigation. It has now been surprisingly found that with other types of heteroaryl ketone, enhanced antibacterial activity may be obtained. Improvements to in vitro activity and in vivo stability may be observed. Accordingly, the present invention provides a compound of formula (I) : OH in which R is hydrogen and R 2 is -COR 3 or R 1 is -COR 3 and R is hydrogen, in which R 3 denotes a heteroaryl group, and excluding the compounds in which R 3 comprises a fur-2-yl, pyrid-2-yl or imidazol-2-yl ring. Suitably the heteroaryl group includes single and fused rings, each ring suitably comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms. A fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring. Suitable fused heteroaryl rings include bicyclic systems. Examples of suitable rings for use in R 3 include, for example, fur-3-yl, thienyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thiatriazolyl, pyrid-3-yl, ρyrid-4-yl, quinolinyl, isoquinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl. -> Preferred examples of rings for use in R J include thien-2-yl, thien-3-yl, fur-3-yl, pyrrol-3-yl, thiazol-5-yl, isothiazol-5-yl, pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl. pyrimidin-5-yl, and quinolin-3-yl. Preferably, when R 3 comprises a 5- or 6- membered heteroaryl ring having a nitrogen or oxygen heteroatom, R is bonded to the ketone carbonyl group of -COR 3 by a ring carbon atom which is not adjacent to said ring heteroatom. Advantageously said ring carbon atom is located β- to the ring heteroatom. Surprisingly however when R° comprises a thienyl group, good biological activity is observed with both thien-2-yl and thien-3-yl i.e. when thienyl is bonded to the carbonyl group via a ring carbon either α- or β- to the ring heteroatom. Preferably in a ring in R , an acidic hydrogen arising from the presence in the ring of an NH moiety, for instance, when -z> _ R J is pyrazolyl, may be replaced by a substituent. Preferably when the heteroaryl group of R J is substituted, the substitutent (other than fluorine) is located on a ring carbon which is not α- to a ring heteroatom. When used herein, the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents. When used herein, the term 'heterocyclyl' includes aromatic and non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents. Suitably the heterocyclic ring comprises from 4 to 7, preferably 5 to 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. When used herein, the term 'halogen' refers to fluorine, chlorine, bromine or iodine. Substituents for groups hereinbefore defined as be ng optionally substituted, for instance alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl or heterocyclyl, include: (a) halogen, cyano, azido, nitro, phthalimido, formyl, carboxy, carboxylate salts, sulpho, sulphonate salts, or oxo; (b) amino, imino, hydrazino, hydrazono, ureido, guanidino, carbamoyl, or sulphonamido, in each of which groups a nitrogen may be further optionally substituted by one or two groups (which may be the same or different) selected from the groups listed in subparagraphs (d) , (e) and (f) ; (c) hydroxy, oxyimino, hydroxyimoyl, benzohydroxyimoyl, or mercapto, in each of which groups hydrogen may be replaced by one of the groups listed in subparagraphs (d) , (e) and (f); (d) a group R^ wherein RP denotes aryl or heterocyclyl; (e) a group R^ wherein R^ denotes (C^g)alkyl, (C 3 _ 7 )cycloalkyl, (C 2 _g)alkenyl, (C 3 _ 8 )cycloalkenyl, or (C2_g)alkynyl, each of which may be optionally substituted by up to three groups (which may be the same or different) chosen from the groups listed in subparagraphs (a) , (b) , (c) , (d) and (f) ; and (f) groups RPC0-, RPOCO-, R^CO-, R^OCO-, RPSO-, R p S0 2 -, R^SO-, and R^SO ? - wherein RP and R^ are as defined in subparagraphs (d) and (e) respectively. Suitable substituents for an alkyl, cycloalkyl, alkenyl or alkynyl group include for example, halogen, cyano, azido, nitro, carboxy, (C 1 _g)alkoxycarbonyl, carbamoyl, mono- or di- (Cι_g)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C- j ^g)alkylsulphamoyl, amino, mono- or di- (C-^_g)alkylamino, acylamino, ureido, (C^_g)alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (C-^.g)alkoxy, acyloxy, oxo, acyl, 2-thenoyl, (C 1 _g)alkylthio, (C-^g)alkylsulphinyl, (C 1 _g) alkylsulphonyl, hydroxyimino, (C^_g)alkoxyimino, hydrazino, hydrazono, benzohydroximoyl, guanidino, amidino, or iminoalkylamino. Suitable substituents for an aryl group include, for example, halogen, cyano, (C^g)alkyl, phenyl, (C^_g)alkoxy, halo(C^. )alkyl, hydroxy, amino, mono- or di- (C-L_g)alkylamino, acylamino, nitro, carboxy, (C^_g)alkoxycarbonyl, (C^_g).alkoxycarbonyl(C-^_g)alkyl, (C^g)alkylcarbonyloxy, ( ^g)alkylthio, (C^_g)alkylsulphinyl, (C^.g)alkylsulphonyl, sulphamoyl, mono- or di- (C^_g)alkylsulphamoyl, carbamoyl, and mono- or di- (C^_g) alkylcarbamoyl. Suitable substituents for a heteroaryl group include, for example, halogen, (C^_ )alkyl, (C^.g)cycloalkyl, (C^_g)alkoxy, halo( ^g)alkyl, hydroxy, amino, mono- or di-(C^_g)alkylamino, carboxy, (C^_g)alkoxycarbonyl, (C^_g)alkoxycarbonyl(C^_g)alkyl, aryl, oxo, non-aromatic heterocyclyl, (C 1 _g)alkylthio, (C-^g)alkylsulphinyl, or (C^_g)alkylsulphonyl. Suitable substituents for a heterocyclyl group include, for example, halogen, (C- j ^g) alkyl, (C-^g)alkoxy, halo(C^.g)alkyl, hydroxy, amino, mono- or di- (C 1 _g)alkylamino, carboxy, (C^g) alkoxycarbonyl, ( -L.-.g)alkoxycarbonyl (C-^.g)alkyl, aryl or oxo. A compound of formula (I) of this invention incorporates a tri-substituted carbon-carbon double bond and may therefore exist as a E- (natural) or Z- (or iso) diastereoisomer. It is to be understood that both diastereoisomers of the compound of formula (I) are included within the scope of this invention, as well as mixtures of the two diastereoisomers. If general it is found that greater activity is associated with the E-isomer of a particular compound of formula (I) and it is therefore preferable to employ this isomer. Accordingly, in a further aspect, the present invention provides compounds of formulae (la) (the E-isomer) and (lb) (the Z-isomer) : in which R 3 is as hereinbefore defined. Compounds of formula (la) may conveniently be named ' (l-normon-2-yl) etones' . Normonyl is the trivial name for the 3-[ (2S,3R,4R,5S)-5-[ (2S,3S,4S,5S)-2,3- epoxy-5-hydroxy-4-methylhexyl]-3,4-dihydroxytetrahydro- pyran-2-yl]-2-methylprop-l(E)-enyl radical, as shown in formula (II) : OH By analogy, compounds of formula (lb) may conveniently be named ' (l-norisomon-2-yl)ketones' . It will be appreciated that in compounds of formula (I) , substituents of the heteroaryl group R J may contain one or more chiral centres. The present invention encompasses all such resultant isomeric possibilities. Since the compounds of formula (I) of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis) . Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical " it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I) . Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form. When some of the compounds of this invention are allowed to crystallise, or are recrystallised, from organic solvents. solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. Examples of compounds within this invention include the following: (Fur-3-yl)-1-(normon-2-yl) ketone; (l-Methylpyrazol-4-yl)-1- (normon-2-yl) ketone; (4-Bromo-l-methyltriazol-5-yl) -1- (normon-2-yl) ketone; (2-Methoxyρyrid-5-yl)-1-(normon-2-yl) ketone; Pyrid-3-yl-l-(normon-2-yl) ketone; (l-Methyltriazol-5-yl)-1-(normon-2-yl) ketone; (2-Methoxypyrimidin-5-yl)-1- (normon-2-yl) ketone; (2-Dimethylaminopyrimidin-5-yl)-1-(normon-2-yl) ketone; (2-Methylthiopyrid-5-yl)-1-(normon-2-yl) ketone; (2-Methylsulphinylpyrid-5-yl)-1- (normon-2-yl) ketone; [2- (Piperidin-1-yl)pyrimidin-5-yl]-1- (normon-2-yl) ketone; (2-Dimethylaminopyrid-5-yl)-l- (normon-2-yl) ketone; (l-Propylpyrazol-4-yl)-1-(normon-2-yl) ketone; (2-Acetylfur-4-yl)-1- (normon-2-yl) ketone; [2- (Morpholin-4-yl)-pyrimidin-5-yl]-1 (normon-2-yl) ketone; [2- (l-Methylpiperazin-4-yl)-pyrimidin-5-yl]-1-(normon-2-yl) ketone; [2-(5,7-Dimethoxyquinolin-3-yl) ]-1-(normon-2-yl) ketone; (l-Cyclohexylpyrazol-4-yl)-1-(normon-2-yl) ketone; [2-(Piperidin-l-yl)pyridin-5-yl]-l-(normon-2-yl) ketone; (Thien-3-yl)-1-(normon-2-yl) ketone; (Thien-2-yl)-1-(normon-2-yl) ketone; [5-Methoxy- (thien-2-yl) ]-1-(normon-2-yl) ketone; [2-(Methylmercapto)thiazol-5-yl) -1-(normon-2-yl) ketone; [2-(Piperidin-1-yl)thiazol-5-yl]-l-(normon-2-yl) ketone; (Isothiazol-5-yl)-1-(normon-2-yl) ketone; [2- (Hydroxymethyl)thien-5-yl]-l- (normon-2-yl) ketone; (2-Formylthien-5-yl)-1- (normon-2-yl) ketone; (Pyrrol-3-yl)-l- (normon-2-yl) ketone; [5-Bromo- (thien-2-yl) ]-1-(normon-2-yl) ketone; [2- (Methylsulphinyl)thiazol-5-yl]-1- (normon-2-yl) ketone; [5-(Dimethylaminoi inomethyl)thien-2-yl]-1- (normon-2-yl) ketone; [2-Bromo(pyrid-5-yl) ]-1- (normon-2-yl) ketone; (Pyrid-4-yl)-1-(normon-2-yl) ketone; [2-(Piρeridinyl)pyrimidin-5-yl]-l-(norisomon-2-yl) ketone; (2-Dimethylaminopyrid-5-yl)-l- (norisomon-2-yl) ketone; a. d (Fur-3-yl)-1- (norisomon-2-yl) ketone. Compounds of the present invention may be prepared by methods known for the preparation of α,β-unsaturated ketones. Some of these processes will be more appropriate than others. Suitably, compounds of formula (I) may be prepared by a process which comprises treating the acid of formula (III) : in which Z 1 , Z 2 and Z 3 are the same or different and each is hydrogen or a hydroxyl-protecting group, or an activated derivative thereof, with an organometallic reagent; and thereafter, and if necessary, removing any hydroxyl-protecting groups. Suitable organometallic reagents include: (i) a Grignard reagent of the formula R 3 MgX in which R 3 is as defined with respect to formula (I) and X represents chlorine, bromine or iodine, which reaction may optionally be carried out in -the presence of copper(I) iodide as catalyst; r> o (ii) an organolithium reagent of formula R J Lι in which R J is as defined with respect to formula (I) ; (in) an organomanganous reagent of the formula R J MnCl in which R J is as defined with respect to formula (I) ; and: • 3 , (IV) an organocerium reagent R- , Lι-CeX3, in which R J is as defined with respect to formula (I) and X represents chlorine, bromine or iodine. The reaction with the organometallic reagent may be conveniently carried out in an ethereal or hydrocarbon solvent, the choice of which is dependent upon the specific requirements of the organometallic reagent. Preferably, the Grignard reagent is generated and used in diethyl ether or tetrahydrofuran. The reaction is generally carried out in an inert atmosphere such as argon or nitrogen and at ambient temperature or below. The period for which the reaction is allowed to proceed depends upon the particular starting materials employed. The course of the reaction may be followed by conventional methods such as thin layer chromatography and the reaction may be terminated when an optimum quantity of product is present in the reaction mixture. Compounds of formula (III) will be recognised by the skilled man as monic acid (E-isomer) or isomonic acid (Z-isomer) , or hydroxyl protected derivatives thereof, as described in GB 1 587 058 (Beecham Group) . Suitable activated derivatives of the acid of formula (III) include thio-esters of formula (IV) : in which Z 1 , Z 2 and Z 3 are as hereinbefore defined and the moiety ✓ % N represents a 5- or 6-membered heterocyclic ring which may contain in addition to the nitrogen atom, one or two further heteroatoms selected from oxygen, nitrogen and sulphur and which may be substituted or fused to a benzene ring which may itself be substituted. Preferred thio-esters are of formula (IVa) : in which Z , Z~- and Z J are as hereinbefore defined. A compound of formula (IVa) may be prepared by treating of a compound of formula (III) with 2,2'-dipyridyl disulphide in the presence of triphenylphosphine, by analogy with the method described by E.J. Corey and D.A Clark in Tetrahedron Letters, 1979, 31, 2875. Other suitable activated derivatives of the acid of formula (III) include mixed anhydrides of the formula (V) : in which Z , Z , and Z 3 are as hereinbefore defined, and R 4 is (C-^.g)alkyl; and of the formula (VI) : in which Z 1 , Z 2 , and Z 3 are as hereinbefore defined, and R 5 and R° are the same or different and each denotes an aryl group, for instance phenyl, or a (C 1 _g)alkoxy group, for instance ethoxy. A compound of formula (V) may be obtained by treating a compound of formula (III) with for instance a suitable derivative of the formula R 3 0COCl using the method described by Crimmin M.J. et al.. J.C.S. Perkin I, 1989, 2047. A compound of formula (VI) may be obtained by treating a compound of formula (III) with CLPOR 5 R° using the method described by Baxter A.J.G. et al., Tetrahedron Letters, 1980, 2i, 5071. Further suitable activated derivatives of the acid of formula (III) include amides of the formula (VII) : CHCONOR R 8 (VII) in which Z 1 , Z 2 and Z 3 are as hereinbefore defined, R and R 8 are the same or different, and each is (C- j ^g)alkyl, or the substituents R 7 and R 8 form a (C 2 _7)alkylene chain; and of the formula (VIII) in which Z 1 , Z 2 , and Z 3 are as hereinbefore defined and R 9 and R 1 , together with the nitrogen atom to which they are bonded, form an imidazolyl or triazolyl ring. A preferred compound of formula (VII) is the N-methoxy- N-methylamide (i.e. R and R° is each methyl) as described in PCT/GB90/01932 (Beecham Group) . The reaction of an N-methoxy-N-methylamide with an organolithium or a Grignard reagent to form a ketone is described by Nahm and Weinreb in Tetrahedron Letters, 1981, 3815. A preferred amide of formula (VIII) is the imidazol-1-yl derivative. The reaction of an α,β-unsaturated acid or its imidazolyl derivative with a Grignard reagent is described in Chem. Ber., 1965, .95.1284. Amides of formulae (VII) and (VIII) may suitably be obtained from monic acid or isomonic acid by treatment thereof with iso-butyl chloroformate in tetrahydrofuran, in the presence of triethylamine, at a temperature of from -5 to 20°C, for about 30 min, to form an intermediate mixed anhydride (monic/isomonic acid isobutyl carbonic anhydride) . This intermediate may then be reacted with an amine HN(OR 7')RR° in dichloromethane at about 20°C for about 2h or an amine HNR^R-^.HCl in the presence of triethylamine and p-dimethylaminopyridine, in THF, at about 20°C, to form the compound of formula (VII) in which Z 1 ,Z 2 and Z 3 is each hydrogen (with R 3 ,R 7 ,R 8 , R 9 and R 10 as hereinbefore defined) . The hydroxyl groups thereof may be protected by treatment with a suitable hydroxyl protecting agent such as chlorotrimethylsilane, in a solvent such as THF in the presence of triethylamine and 4-dimethylamino pyridine as a catalyst. Suitably a thio-ester of formula (IV) i£ treated with an • 3 oorrggaannoommaa;nganous reagent of formula R^MnCl, as hereinbefore defined. Suitably an amide of formula (VII) or (VIII) is treated with an organolithium reagent of formula R 3 Li as hereinbefore defined. Preferably, a compound of formula (I) is prepared by a process which comprises treating a compound of formula (VII) as hereinbefore defined, with an organolithium reagent of formula R 3 Li as hereinbefore defined. Suitable organometallic reagents may be prepared according to conventional procedures. Suitable organomanganous reagents of the formula R MnCl may be conveniently prepared by addition of an organolithium reagent R J Lι to a solution of manganous chloride and lithium chloride in dry THF, or a suspension of anhydrous manganous chloride in dry THF. An excess of R 3 MnCl is preferably employed. Alternatively, a Grignard reagent may be used in place of the organolithium reagent, to generate the 3 organomanganous reagent R^MnCl. Other organomanganous reagents which may be used instead of R 3 MnCl include: (i) (R ) MnLi or (R 3 ) MnMgX in which X is as hereinbefore defined, as described in Synthetic Communications, 1979, 9_, 639; (ii) R 3 MnI in ether; as described in Synthetic Communications, 1979, I., 639; and (iii) R MnBr in ether, as described in Tetrahedron Letters, 1976, 3155. As in the case of R J MnCl, the above organomanganous reagents may be prepared in. situ when required. Organocerium reagents may be generated in situ by treating an organolithium compound of the formula R 3 Li, in which R 3 is as hereinbefore defined, with cerium (III) halide, by analogy with the procedure described by Imamoto e_t al; J.Chem. Soc Chem. Commun, 1982, 1042. Further processes for the preparation of compounds of formula (I) are described in EP-A-0 029 665 (Beecham Group) and include treating an allylic alcohol of formula (IX) : CHCHOHR 3 (IX) in which R 3 , Z 1 , Z 2 and Z 3 are as hereinbefore defined, with an oxidising agent which converts allylic alcohols into α,β-unsaturated ketones, and thereafter, and if necessary, removing any hydroxyl-protecting groups. Suitable such oxidising agents include activated manganese dioxide, pyridinium dichromate and pyridinium chlorochromate. Conveniently, the oxidation reaction is carried out in a non-polar organic solvent such as, for example, benzene or toluene. Compounds of formula (IX) are novel and useful intermediates in the aforementioned process. Accordingly, the invention further provides compounds of formula (IX) as hereinbefore defined. An allylic alcohol of formula (IX) may be prepared by treatment of the corresponding aldehyde of formula (X) : in which Z~- , Z 2 and Z 3 are as hereinbefore defined, with an organometallic reagent as hereinbefore defined, and thereafter, and if necessary, removing any hydroxyl-protecting groups. An aldehyde of formula (X) may be treated with a Grignard reagent of formula R 3 MgX or, more preferably, with an organoceriu reagent R 3 Li-CeX3, as hereinbefore defined. An aldehyde of formula (X) may be prepared by treatment of a amide of formula (VII) , as hereinbefore defined, with a suitable reducing agent such as diisobutyl-aluminium hydride, and thereafter, and if necessary, removing any hydroxyl-protecting group. It is found that in practice, such treatment of the E-isomer of an amide of formula (VII) in which R 7 and R 8 is each methyl leads to a mixture of the E- and Z-isomers of the aldehyde of formula (X) . These isomers may be readily separated by conventional chromatography, thereby affording a convenient source of starting material for the subsequent preparation of Z-isomer compounds of formula (I) . Other suitable methods of preparation of an aldehyde of formula (X) are described in EP-A-0 029 665 (Beecham Group) . A compound of formula (I) may also be prepared by treating a ketone of formula (XI) : in which Z 1 , Z 2 and Z 3 are as hereinbefore defined, with a terminal alkyne of the formula (XII) : HC≡C-R 3 (XII) 3 in which R J is as hereinbefore defined, to form an intermediate which is treated with tris (triphenylsilyloxy)vanadate and triphenylsilanol, as described by H. Pauling in Helvetica, 1976, 5?, 1233 and G.L. Olson, Helvetica, 1976, 59.567; and thereafter, and if necessary, removing any hydroxyl-protecting groups. Such a reaction may lack stpreoselectively and accordingly may lead to the formation oz. Doth the E- and Z-isomers of the compound of formula (I) , which may then be readily separated by conventional separation procedures such as chromatography. The preparation of a compound of formula (XI) is described in GB 1 587 060 (Beecham Group) . The skilled man will readily appreciated that the final obtention of either the E- or the Z-isomer of a compound of formula (I) , as required, may be conveniently effected by selecting, as starting material, a precusor containing a double bond which already has the desired E- or Z-stereochemistry. Alternatively processes may be used in which the double bond sterochemistry and, perhaps also the double bond itself, is generated during the course of the reaction. In addition, a compound of formula (lb) may be converted into the corresponding compound of formula (la) or vice-versa by suitable isomerisation procedures, such as those described by Sonnet in Tetrahedron, 1980, 3_6, 557 and include photo-chemical and addition-elimination methods. When used herein, the term 'hydroxyl protecting group' refers to any such group known in the art which may be removed without disruption of the remainder of the molecule. Suitable hydroxyl-protecting groups include those described in 'Protective Groups in Organic Synthesis', T.W. Greene, Wiley-Interscience, New York 1981. The hydroxyl groups of the compounds of formulae (III) to (XI) may be protected at any stage of the above processes, using conventional methods. The hydroxyl protecting group may be removed by methods known in the art, including enzymatic methods. Particularly suitable hydroxyl protecting groups are silyl groups since these are readily removed under mild conditions. Such groups are introduced using conventional silylating agents, including halosilanes and silazanes, of the formulae below: L 3 SiY L 3 SiO-C=NSiL 3 L 2 SiY 2 LL 3 wherein Me denotes methyl and fc Bu denotes t-butyl, Y is halogen and each group L is independently selected from hydrogen, (C^_g)alkyl, (C 1 _g)alkoxy, aryl or aryl(C 1 _ 4 )alkyl. A preferred silyating agent is trimethylsilyl chloride. Particularly suitable protecting groups are trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred protecting groups are trimethylsilyl groups because of their ease of removal. -23- The glycol function of the compounds of formulae (III) to (XI) may be protected by forming a cyclic derivative using a compound of formula (XIII) : wherein R 1 i 1 X is hydrogen or (C^g)alkyl and each of R1.?, R1 J " and R 14 is (C^ )alkyl. In the cyclic derivative Z 1 and Z 2 together are a moiety: R 11 OR 15 wherein R 1 ^ is (C 1 _g)alkyl. Suitably R 11 is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen. The groups R 12 , R 13 and R 14 are suitably methyl, ethyl, n- or iso-propyl, or n-, iso-, sec- or t-butyl; most suitably methyl. Similarly the hydroxyl groups of a compound of formula (I) may be protected prior to conversion to a further compound of formula (I) as described above. In each case the hydroxyl protecting groups described above may be removed by mild acid hydrolysis followed by alkaline hydrolysis, for instance, as described by J.P. Clayton, K. Luk and N.H. Rogers, in 'Chemistry of Pseudomonic Acid, Part II', J.C.S. Perkin Trans. I, 1979, 308. This invention also provides a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug' ) together with a pharmaceutically or veterinarily acceptable carrier or excipient. The compositions may be formulated for administration by any route, and would depend on the disease being treated. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils) , for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p_-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. For topical application to the skin the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as 'Harry's Cosmeticology' 7th Ed., ed Wilkinson J.B. and Moore R.J., George Goodwin, London, 1982, and the British Pharmacopoeia. Suppositories will contain conventional suppository bases, e.g. cocoa-butters or other glyceride. For parenteral administration, fluid unit dosage forms are prepared utilizing the drug and a sterile vehicle. The drug, depending on the vehicle and concentration used, can be suspended in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability the composition can be frozen after filling into the vial and water removed under vacuum. The dry lypophilized powder is then sealed in the vial. The drug can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug. For topical application to the ear, the drug may be made up into a suspension in a suitable liquid carrier, such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils. For topical application to the eye, the drug is formulated as a suspension in a suitable, sterile aqueous or non-aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edetate; preservatives including bactericidal and fungicidal agents, such as phenylmercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included. The dosage employed for compositions administered topically will, of course, depend on the size of the area being treated. For the ears and eyes each dose will typically be in the range from 10 to 100 mg of the drug. Veterinary compositions for intramammary treatment of mammary disorders in animals, especially bovine mastitis, will generally contain a suspension of the drug in an oily vehicle. The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the drug, depending on the method of administration. Where the compositions are in unit dose form, each dosage unit will preferably contain from 50-500 mg, of the drug. The dosage as employed for treating an adult human (of typical weight about 70 kg) will preferably range from 100 mg to 3 g, per day, for instance 250 mg to 2 g of the drug per day, depending on the route and frequency of administration. Alternatively, the drug may be administered to non-human animals as part of the total dietary intake. In this case the amount of drug employed may be less than 1% by weight of the diet and in preferably no more than 0.5% by weight. The diet for animals may consist of normal foodstuffs to which the drug may be added or the drug may be included in a premix for admixture with the foodstuff. A suitable method of administration of the drug to a non-human animal is to add it to the non-human animal's drinking water. In this case a concentration of the drug in the drinking water of about 5-500 μg/ml, for example 5-200 μg/ml, is suitable. The compounds of this invention are useful for the treatment of bacterial and mycoplasma-induced infections in non-human and human animals, such as the treatment of respiratory tract infections, otitis, meningitis, skin and soft tissue infections in human animals, mastitis in cattle, and respiratory infections in non-human animals such as pigs and cattle. Accordingly in a further aspect, the present invention provides a method for treating the human or non-human animal which method comprises administering an effective amount of a compound of formula (I) as hereinbefore defined, to a human or non-human animal in need of such therapy. Alternatively, a pharmaceutical composition as hereinbefore described may be employed in the treatment. In particular aspects of the treatment there are provided methods for treating bacterial infections of human or non-human animals, especially respiratory infections in human or non-human animals. The compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus, for instance H.influenzae Ql; Branhamella,for instance B.Catarrhalis 1502; Streptococci, for instance S.pyoqenes CN10 and S.pneumonia PU7; and Staphylococci, for instance S.aureus Oxford, and against mycoplasma. In addition, compounds of this invention are active against Staphylococci organisms such as S■ aureus and S. epidermis which are resistant (including multiply-resistant) to other anti¬ bacterial agents, for instance, β-lactam antibiotics such as, for example, methicillin; macrolides; aminoglycosides and lincosamides. The compounds of this invention are also active against mycoplasma-induced infections, in particular infections caused by Mycoplasma fermentans, which has been implicated as a co-factor in the pathogenesis of AIDS. Accordingly in a further aspect, the present invention provides a method of treating humans infected with M. fermentans, in particular humans also infected with HIV, which method comprises treating humans in need of such therapy with an anti-mycoplasmal effective amount of a compound of formula (I) . In a further aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for antibacterial and/or antimycoplasmal therapy in human and non-human animals. No adverse toxicological effects are expected from the administration of a compound of formula (I) . The following Examples illustrate the invention, but are not intended to .imit the scope in any way. N-Methoxy-N-methyl-6,7, 13-O-tris (trimethylsilyl)monamide N,0_-Dimethyl hydroxylamine hydrochloride (1.95g, 20mmol) was dissolved in dichloromethane and aqueous sodium hydroxide (20ml:10ml, 2.5M). The aqueous layer was re-extracted with dichloromethane (10ml) and the combined organic layers washed with saturated brine (5ml) . The organic layer was dried (MgS0 4 ) and added to monic acid isobutyl carbonic anhydride (lOmmol) After stirring at 20°C for Ih the reaction mixture was dilv 2d with dichloromethane and washed with saturated aqueous scxum hydrogen carbonate and brine. The combined aqueous solutions were extracted with ethyl acetate, and the combined organic solutions dried (MgSO^) and concentrated to give the amide, (3.0g) . This was taken up in tetrahydrofuran (50ml) and treated with triethylamine (8.4ml, 60mmol) and chlorotrimethylsil---....e (6.3ml, 50mmol) . After 10 minutes a catalytic amount of 4-N,N-dimethylaminopyridine was added. After 2h at room temperature the reaction was diluted with diethyl ether, filtered, and the filtrate evaporated. The residue was taken up in hexane, refiltered, and washed with water and brine. After drying and evaporation the residue was taken up in hexane (20ml) and allowed to crystallise at 0-20°C, to give the required product as a colourless crystalline solid (3.0g, 50%) mp 78-79°C. 6,7.13-O-Tris (trimethylsilyl)monaldehvde Di-isobutylaluminium hydride (1.0M in hexane) (20.00ml, 20.00mmol) was added dropwise to a solution of N- methoxy-N-methyl-6,7,13-0-tris (trimethylsilyl)monamide (ll.OOg, 18.24mmol) in THF (150ml) cooled to -78°C whilst maintaining the temperature below -70°C. After 3h at -70°C, methanol (20ml) and saturated sodium sulphate solution (20ml) were added. The precipitated solids were removed by filtration, the filtrate dried (MgS0 4 ) and evaporated to dryness under reduced pressure. Purification by flash 5 chromatography using hexane/ethyl acetate (4:1) as eluent gave initially the Z-isomer (Vide infra) , followed by the E-isomer, the title compound, (4.90g, 50%) as a colourless oil; V maχ (liquid film) 2960, 2900, 1675, 1250, 1120cm- 1 ; δ R (CDC1 3 ) 0.06-0.17 (27H, m, 9 x SiCH 3 ) , 0.90 (3H, d, J 7.1Hz, 1017-H 3 ), 1.19 (3H, d, J 6.4Hz, I4-H3) , 1.32-1.41 (IH, m, 12-H), 1.46-1.62 (2H, m, 9-Hz) , 1.74-1.83 (IH, m, 8-H) , 2.10 (IH, dd, J 15.2 and 10.8Hz, 4-H) , 2.20 (3H, s, 15-H 3 ) , 2.56-2.73 (3H, m, 4, 10 and 11-H) , 3.38 (IH, dd, J 9.1 and 2.5Hz, 6-H) , 3.53 (IH, d, J ll.OHz, 16-H) , 3.76-3.93 (4H, m, 155, 7, 13 and 16-H) , 5.96 (IH, d, J 8.0Hz, 2-H) , 10.00 (IH, d, J 8.0Hz, 1-H) ; m/z (E.I.) 544 (M + , 2%), 117 (100%). 6,7,13-O-Tris(trimethylsilyl)isomonaldehyde 20 Di-isobutylaluminium hydride (1.0M in hexane) 40.00ml, 40.00mmol) was added dropwise to a solution of N-methoxy-N- methyl-6,7,13-O-tris(trimethylsilyl)monamide (12.00g, 20.00mmol) in THF (150ml) cooled to -78°C whilst maintaining 25 the temperature below -70°C. After 3h at -70°C, methanol (40ml) and saturated sodium sulphate solution (50ml) were added. The precipitated solids were removed by filtration, the filtrate dried (MgS0 4 ) and evaporated to dryness under reduced pressure. Purification by flash chromatography using 30 hexane/ethyl acetate (8:1) as eluent gave the title compound (2.03g, 19%) as a colourless oil; δ H (CDCI3) 0.06-0.17 (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.1Hz, 17-H 3 ) , 1.19 (3H, d, J 6.4Hz, 14-H 3 ), 1.32-1.41 (IH, m, 12-H) , 1.46-1.62 (2H, m, 9-H 2 ), 1.74-1.83 (IH, m, 8-H) , 2.01 (3H, s, 15-H 3 ) , 2.53- 352.66 (4H, m, 4-H 2 , 10-H, 11-H) , 3.39 (IH, d, J 8.6Hz, 16-H) , 3.51 (IH, d, J 11.3Hz, 6-H) , 3.55-3.81 (4H, m, 5-H, 7-H, 13-H, 16-H), 5.93 (IH, d, J 8.1Hz, 2-H) , 9.91 (IH, d, J 8.2Hz, 1-H) ; m/z. (NH 3 D.C.I.) 430 (MH + , 100%). Example 1 (Fur-3-yl)-1- (normon-2-yl)ketone a) (Fur-3-yl)-1- (6,7, 13-0-tris-trimethylsilvnormon-2- yl) ketone 3-Bromofuran (1.37g, 9.30mmol) in THF (20ml) was added dropwise to n-butyllithium (1.6M in hexane) (6.60ml, 10.22mmol) in THF (10ml) whilst maintaining the temperature below -60°C. After 20mins at -70°C N-methoxy-N-methyl-6,7, 13-O-tris (trimethylsilyl)monamide (4.10g, 6.81mmol) in THF (10ml) was added dropwise whilst maintaining the temperature below -65°C. After lh at -70°C and lh at -60°C acetic acid (0.53ml) was added followed by water (100ml) . Extraction with ethyl acetate, drying (MgS0 4 ), evaporation to dryness under reduced pressure, and purification by flash chromatography using hexane/ethyl acetate (6:1) as eluent gave the title compound (3.67g, 88%) as a white foam; δ H (CDC1 3 ) 0.09-0.17 (27H, , 9 x SiCH 3 ) , 0.89 (3H, d, J 7.0Hz, 17-H 3 ) , 1.19 (3H, d, J 6.3Hz, 14-H 3 ) , 1.36-1.41 (IH, m, 12-H) , 1.55 (2H, br.s, 9-Hz) , 1.77-1.86 (IH, m, 8-H) , 2.08 (IH, dd, J 14.6 and 10.5Hz, 4-H) , 2.24 (3H, s, 15-H 3 ), 2.59 (IH, d, J 14.4Hz, 4-H) , 2.66-2.70 (2H, m, 10 and 11-H) , 3.39 (IH, dd, J 9.0 and 2.4Hz, 6-H) , 3.55 (IH, d, J 11.4Hz, 16-H), 3.80-3.92 (4H, m, 5,7,13 and 16-H) , 6.48 (IH, s, 2-H), 6.79 (IH, d, J 1.3HZ, 5'-H), 7.40 (IH, t, J 1.6Hz, 5'-H), 7.99 (IH, s, 2'-H); m/z. (L.C.M.S. thermospray) 628 (MNH 4 + , 40%), 141 (100%); (Found: M + , 610.3154. C 30 H 54 O 2 Si 3 requires M, 610.3177). b) (Fur-3-yl) -1- (normon-2-yl) ketone The above ketone (0.26g, 0.43mmol) and 4-dimethylaminopyridine dihydrochloride (6.6 x 10- mol) in 5 methanol (5ml) were stirred at room temperature for 20min. Saturated sodium hydrogen carbonate solution (10ml) then water (20ml) were added. Extraction with ethyl acetate, drying (MgS0 ) evaporation to dryness under reduced pressure and purification by flash chromatography using 8% methanol ιo in dichloromethane as eluent gave the title compound (0.122g, 73%) as a white foam; v maχ (KBr) 3424, 2969, 2924, 1655, 1609 1156cm- 1 ; λ maχ (EtOH) 258nm (^ 11,420); δ H (CDC1 3 ) 0.93 (3H, d, J 7.1Hz, 17-H 3 ) , 1.22 (3H, d, J 6.3Hz, 14-H 3 ), 1.29-1.41 (IH, m, 12-H) , 1.71-1.77 (2H, m, 9-Hz) , 151.96-2.04 (IH, m, 9-H) , 2.27 (3H, s, 15-H 3 ) , 2.35 (IH, dd, J 14.6 and 9.0Hz, 4-H) , 2.64-2.73 (2H, , 4 and 11-H) , 2.78-2.83 (IH, m, 10-H) , 3.51 (IH, dd, J 8.6 and 1.8Hz, 6-H) , 3.59 (IH, dd, J 11.5 and 1.8Hz, 16-H) , 3.74-3.96 (4H, m, 5,7,13 and 16-H) , 6.51 (IH, s, 2-H) , 6.80 (IH, d, J 201.8Hz, 4'-H), 7.42 (IH, t, J 1.8Hz, 5'-H), 8.01 (IH, s, 2'-H); δ c (CDC1 3 ), 12.7 (C-17) , 20.1 (C-15) , 20.8 (C-14) , 31.6 (C-9), 39.7 (C-8) , 42.8 (C-12) , 43.3 (C-4) , 55.6 (C-10), 61.3 (C-ll), 65.4 (C-16) , 68.9 (C-6) , 70.4 (C-7) , 71.4 (C-13), 75.1 (C-5) , 109.0 (C-4'), 123.2 (C-2) , 129.6 25 (C-3'), 144.1 (C2' or 5'), 147.0 (C2' or 5'), 156.7 (C-3), 185.7 (C-1); m/z. (E.I.) 394 (M + , 7%), 95 (100%); (Found: M + , 394.2002. C 21 H 30 O 7 requires M, 394.1992). Subsequent recrystallisation from ethyl acetate gave white 30 micro-crystals (m.p.95-96°C) ; [Found: C, 62.5; H, 7.7. C 21 H 30°7* 1 / 2H 2° requires C, 62.5; H, 7.7%]. Example 2 (l-Methylpyrazol-4-yl)-1-(normon-2-yl) ketone 5 a) (l-MethylPyrazol-4-yl)-1- (6,7, 13-O-tris-tri- methylsilylnormon-2-yl) ketone 4-Bromo-l-methylpyrazole (0.97g, 6.0mmol) in THF (10ml) was added to n-butyllithium (1.6M in hexane) (3.44ml, 5.5mmol) 10 in THF (25ml) whilst maintaining the temperature at -70 to -65°C. After ten minutes at -70°C N-methoxy-N-methyl-6,7,13-O-tris (trimethylsilyl)- monamide (0.60g, lmmol) in THF (10ml) was added dropwise maintaining the temperature below -65°C. After 1.5h at -70°C acetic 15 acid (0.32ml) was added followed by water (150ml) . The solution was extracted with ethyl acetate, dried (MgS0 4 ) , evaporated to dryness under reduced pressure and purified by flash chromatography usin- ethyl acetate/hexane (2:1) as eluent to give the title c mpound (0.36g, 58%) as a white 20 foam; δ H (CDC1 3 ) 0.09-0.16 (27H, m, 9 x SiCH 3 ) , 0.90 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.4Hz, 14-H 3 ) , 1.32-1.45 (IH, m, 12-H) , 1.50-1.62 (2H, , 9-H 2 ) , 1.77-1.86 (IH, m, 8-H) , 2.10 (IH, dd, J 14.6 and 10.6Hz, 4-H) , 2.25 (3H, s, 15-H 3 ), 2.60 (IH, d, J 14.6Hz, 4-H) , 2.63-2.72 (2H, m, 10 25 and 11-H), 3.39 (IH, dd, J 8.9 and 2.4Hz, 6-H) , 3.55 (IH, d, J 11.3Hz, 16-H), 3.80-3.93 (4H, m, 5,7,13 and 16-H) , 3.93 (3H, s, NCH 3 ), 6.51 (IH, s, 2-H) , 7.87 (IH, s, 3' or 5'-H), 7.90 (IH, s, 3'- or 5'-H); m/z. (E.I.). 62.4 (M + , 6%), 117 (100%); (Found: M + , 624.3428. C 30 H 5 gN 2 OgSi 3 requires M, 30 624.3446) . b) (l-Methylpyrazol-4-yl) -1- (normon-2-yl) ketone The above ketone (0.35g, 0.56mmol) and 4-dimethylaminopyridine dihydrochloride (l.lmg) in methanol 5 (7ml) were stirred at room temperature for 0.5h. Saturated sodium hydrogen carbonate solution (10ml) and water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 10% 10 methanol in dichloromethane as eluent gave the title compound (0.16g, 70%) as a white foam; v maχ (KBr) 3423, 2969, 2925, 1648, 1543, 1451, 1216, 1111cm- 1 ; λ j ^ (EtOH) 269.5nm (^ 19,180); δ H (CDC1 3 ) 0.94 (3H, d, J 7.0Hz, 17-H 3 ), 1.22 (3H, d, J 6.3Hz, 14-H 3 ) , 1.28-1.41 (IH, m, 1512-H) , 1.70-1.77 (2H, , 9-Hz) , 1.98-2.12 (IH, m, 8-H) , 2.26 (3H, s, 15-H 3 ) , 2.35 (IH, dd, J 14.5 and 8.8Hz, 4-H) , 2.64-2.83 (3H, m, 4, 10 and 11-H) , 3.48-3.51 (IH, m, 6-H) , 3.58-3.63 (IH, m, 16-H) , 3.75-3.96 (4H, , 5,7,13 and 16-H) , 3.93 (3H, s, NCH 3 ), 6.54 (IH, s, 2-H) , 7.87 (IH, s, 3' or 205'-H), 7.90 (IH, s, 3' or 5'-H); δ c (CDC1 3 ) 12.8 (C-17) , 20.1 (C-15), 20.8 (C-14), 31.7 (C-9) , 39.3 (NCH3) , 39.8 (C-3), 42.8 (C-12), 43.3 (C-4), 55.6 (C-10) , 61.2 (C-ll) , 65.4 (C-16), 68.9 (C-6) , 70.5 (C-7) , 71.2 (C-13) , 175.1 (C-5), 123.4 (C-2) , 126.0 (C-4), 132.8 (C-3' or 5'), 140.4 25 (C-3' or 5'), 156.4 (C-3), 185.2 (C-1); m/z. (E.I.) 408 (M + , 9%), 109 (100%); (Found: M + , 408.2264. C 21 H 32 N 2 0g requires M, 408.2260) . Example 3 30 (4-Bromo-l-methyltriazol-5-yl)-1-(normon-2-yl) ketone 4-Bromo-l-methyltriazole (0.97g, 6.0mmol) in THF (10ml) was added dropwise to n-butyllithium (1.6M in hexane) (3.44ml, 355.5mmol) in THF (25ml) cooled to -70°C, whilst maintaining the temperature above -60°C. N-methoxy-Nmethyl-6,7,13-O-tris (trimethylsilyl)monamide (0.60g, lmmol) in THF (5ml) was added dropwise at -65°C. After 2h at -70°C and lh at -50°C the solution was warmed to 0°C over lh and kept at that temperature for lh. Acetic 5 acid (0.32ml) was added followed by saturated sodium hydrogen carbonate solution (10ml) . Extraction with ethyl acetate (3 x 50ml), drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (4:1) as eluent 10 gave impure (4-bromo-l-methyl- triazol-5-yl)-1-(6,7,13-0-tris-trimethylsilyl-normon2-yl) ketone (0.085g). Further elution with 6% methanol in dichloromethane gave the required ketone (0.13g, 25%) . The protected ketone was treated with 4-dimethylaminopyridine 15 dihydrochloride (0.25mg) in methanol (3ml) at room temperature for 1.5h. Saturated sodium hydrogen carbonate solution (10ml) was added and the solution extracted with ethyl acetate. Drying (MgS0 4 ), evaporation to dryness under reduced pressure and purification by flash chromatography 20 using 6% methanol in dichloromethane as eluent gave the title compound (0.013g, 50%) as a white foam, giving an overall yield of 28%; V maχ (KBr) 3423, 2968, 2923, 1656, 1607, 1439, 1287, 1111, 1083cm- 1 ; λ m&χ (EtOH) 278nm (E j n 14,128); δ R (CDCI3) 0.94 (3H, d, J 7.0Hz, 17-H 3 ) , 1.22 25 (3H, d, J 6.3Hz, I4-H3), 1.27-1.38 (IH, m, 12-H) , 1.65-1.82 (2H, m, 9-H 2 ), 2.02-2.10 (IH, m, 8-H) , 2.30 (3H, s, 15-H3) , 2.42 (IH, dd, J 15.0 and 9.3Hz, 4-H) , 2.70 (IH, dd, J 6.2 and 2.6Hz, 11-H) , 2.75-2.83 (2H, m, 4 and 10-H) , 3.48-3.56 (IH, m, 6-H), 3.60 (IH, d, J lO.OHz, 16-H) , 3.80-3.86 (3H, 30 m, 5,7, and 13-H) , 3.91 (IH, dd, J 11.8 and 2.8Hz, 16-H) , 4.27 (3H, s, N-CH3), 6.94 (IH, s, 2-H) ; δ c (CDCI3) 12.8 (C-17), 20.9 (C-15), 21.1 (C-14) , 31.6 (C-9) , 39.1 (NCH3, 39.8 (C-8), 42.8 (C-12) , 43.6 (C-4), 55.6 (C-10) , 61.3 (C-ll), 65.5 (C-16), 68.9 (C-6) , 70.4 (C-7) , 71.4 (C-13) , 3574.8 (C-5), 122.6 (C-5'), 123.2 (C-2) , 134.0 (C-4), 162.8 (C-3), 180.0 (C-1); m z (E.I.) 489 (M + , 1%), 487 (M + , 1%), 43 (100%); (Found: M + , 487.1343. C 20 H 30 3 O Br requires M, 487.1318) . Example 4 (2-Methoxypyrid-5-yl)-1-(normon-2-yl) ketone 5 a) (2-Methoxypyrid-5-yl)-1-(6,7,13-O-tris-trimethylsilyl normon-2-yl) ketone n-Butyllithium (1.6M in hexane) (3.27ml, 8.22mmol) was added dropwise to 5-bromo-2-methoxypyridine (0.99g, 5.72mmol) in 10 THF (40ml) cooled to -85°C, maintaining the temperature below -80°C. After a further lh at -85°C, cerium trichloride (1.29g, 5.24mmol) was added and reaction mixture maintained at -80°C for lh. 6,7,13-O-Tris- (trimethylsilyl)monaldehyde in THF (10ml) was added dropwise 15 at -80°C. After 1.5h at -85°C, acetic acid (0.30ml) then water (40ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (2:1) as eluent gave the impure 20 diastereomeric alcohols (1.77g, 78%) as a colourless oil. Manganese dioxide (2.21g, 25.4mmol) and benzene (25ml) were added and the reaction mixture heated to reflux under Dean and Stark conditions for 0.5h. The solids were removed by filtration and washed with dioxane. The filtrates were 25 combined and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate (6:1) as eluent gave the title compound (1.25g, 71%) as a colourless oil; δ H (CDCI3) 0.10-0.16 (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.0Hz, 17-H 3 ) , 1.20 (3H, d, J 6.3Hz, 30 14-H 3 ), 1.33-1.44 (IH, m, 12-H) , 1.53-1.64 (2H, m, 9-H 3 ) , 1.75-1.91 (IH, m, 8-H) , 2.14 (IH, dd, J 15.1 and 11.0Hz, 4-H), 2.23 (3H, s, 15-H 3 ) , 3.40 (IH, dd, J 8.9 and 2.3Hz, 6-H), 3.57 (IH, d, J 11.4Hz, 16-H) , 3.81-4.00 (4H, m, 5,7,13 and 16-H), 4.00 (3H, s, OCH 3 ) , 6.74 (IH, s, 2-H) , 6.78 (IH, 35 d, J 8.8Hz, 3'-H), 8.15 (IH, dd, J 8.7 and 1.2Hz, 4'-H), 8.78 (IH, d, J 2.2Hz, 6'-H); m/z. (F.A.B. 3-NOBA/Na) 674 (MNa + , 37%), 652 (M + , 5%), 136 (100%). b) (2-Methoχypyrid-5-yl) -1- (normon-2-yl) ketone The above ketone (0.30g, 0.46mmol) and 4-dimethylaminoρyridine dihydrochloride (4.0mg, 2.1 x 510- 5 mol) in methanol (4ml) were stirred at room temperature for lh. Saturated sodium hydrogen carbonate solution (5ml) and water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ), evaporation to dryness under reduced pressure and purification as eluent gave the title 10 compound (0.135g, 68%) as a white foam; V maχ (KBr) 3421, 2969, 2916, 1656, 1601, 1250cm- 1 ; ^ x (EtOH) 287.5 (E J JJ 19,290); δ H (CDC1 3 ) 0.94 (3H, d, J 7.1Hz, 17-H 3 ) , 1.22 (3H, d, J 6.3Hz, 14-H 3 ), 1.29-1.42 (IH, m, 12-H) , 1.72-1.75 (2H, m, 9-Hz), 1.96-2.10 (IH, m, 8-H) , 2.23 (3H, s, 15-H 3 ) 152.39 (IH, dd, J 14.7 and 9.0Hz, 4-H) , 2.68-2.85 (3H, m, 4, 10 and 11-H) , ? 49-3.53 (IH, m, 6-H) , 3.60 (IH, dd, J 11.8 and 2.0Hz, 16-R , 3.76-4.00 (4H, m, 5,7,13 and 16-H) , 4.00 (3H, s, OCH 3 ), 6.75 (IH, s, 2-H) , 6.79 (IH, d, J 8.6Hz, 3'-H), 8.15 (IH, dd, J 8.6 and 2.4Hz, 4'-H), 8.77 (IH, d, J 202.3Hz, 6'-H); δ c )CD 3 OD) 17.3 (C-17) , 20.3 (C-15) , 20.4 (C-14), 33.0 (C-9), 41.7 (C-8), 43.6 (C-12) , 44.3 (C-4), 54.6 (OCH3), 56.8 (C-10), 61.2 (C-ll) , 66.4 (C-16) , 70.0 (C-6), 70.6 (C-7), 71.6 (C-13) , 76.3 (C-5), 111.8 (C-4'), 123.0 (C-2), 129.9 (C-5'), 139.8 (C-3'), 150.0 (C-6'), 159.3 25 (C-3), 167.8 (C-2'), 190.7 (C-1); m/z. (F.A.B. thioglycerol) 458 (M + , 7%), 36 (100%). Example 5 30 Pyrid-3-yl-l- (normon-2-yl) ketone a) Pyrid-3-yl-l-(6,7,13-Q-tris-trimethylsilylnormon-2- yl) ketone 353-Bromopyridine (0.275g, 1.74mmol) in THF (3ml) was added dropwise to n-butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) at -70°C. After ten minutes 6,7,13-O-tris(trimethylsilyl)monaldehyde (0.63g, l.lδmmol) in THF (5ml) was added dropwise maintaining the temperature below -65°C. After 2h at -65°C the solution was warmed to 5 -30°C over 0.5h. Acetic acid (0.10ml) and water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane (2:1) as eluent gave impure diastereomeric 10 alcohols (0.39g, 54%). The alcohols (0.37g, 0.59mmol) and manganese dioxide (0.60g, 6.9mmol) in benzene (10ml) were heated to reflux under Dean and Stark conditions for 2h. The solids were removed by filtration and washed with dioxane. Evaporation of the filtrates to dryness under 15 reduced pressure and purification by flash chromatography using hexane/ethyl acetate (3:1) as eluent gave the title compound (0.254g, 65%) as a colourless oil; V maχ (liquid film) 2960, 2900, 1660, 1610, 1580, 1245cm- 1 ; δ H (CDCI3) 0.10-0.16 (27H, m, 9 x SiCH 3 ) , 0.89 (3H, d, J 7.1Hz, 17-H 3 ) , 201.19 (3H, d, J 6.3Hz, 14-H 3 ) , 1.36-1.46 (IH, m, 12-H) , 1.52-1.62 (2H, m, 9-H 2 ) , 1.77-1.86 (IH, m, 8-H) , 2.16 (IH, dd, J 14.9 and 10.9Hz, 4-H) , 2.26 (3H, s, 15-H 3 ) , 2.64-2.71 (3H, , 4,10 and 11-H) , 3.39 (IH, dd, J 9.0 and 2.3Hz, 6-H) , 3.56 (IH, d, J 11.3Hz, 16-H) , 3.80-3.99 (4H, , 5,7,13, and 2516-H), 6.80 (IH, s, 2-H) , 7.39 (IH, dd, J 7.8 and 4.9Hz, 5'-H), 8.1 (IH, dt, J 7.8 and 1.9Hz, 4'-H), 8.72 (IH, dd, J 4.8 and 1.5Hz, 6'-H), 9.21 (IH, d, J 1.6Hz, 2'-H)l m/z. (E.I.) 671 (M + , 13%), 117 (100%); (Found: M + , 661.3351. c 31 H 55 N0 6 Si 3 sq ires M, 661.3357). 30 b) Pyrid-3-yl-l-(normon-2-yl) ketone The above ketone (0.233g, 0.375mmol) and 4-dimethylaminopyridine dihydrochloride (13.5mg, 6.9 x 3510- J mmol) in methanol (5ml) were stirred at room temperature for 4h. Saturated sodium hydrogen carbonate solution (10ml) and water (10ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ), evaporation to dryness under reduced pressure and purification by flash chromatography 5 using 8% methanol in dichloromethane as eluent gave the title compound (0.10g, 66%) as a white foam; v maχ (KBr) 3423, 2969, 2933, 1659, 1608, 1419, 1254, 1111, 1049cm- 1 ; λ j ^ (EtOH) 271nm (^ 14,100); δ H (CD 3 OD) 0.95 (3H, d, J 7.1Hz, 17-H 3 ), 1.20 (3H, d, J 6.4Hz, 14-H 3 ) , 1.33-1.43 (IH, 10 m, 12-H) , 1.71 (2H, t, J 6.6Hz, 9-H 2 ) , 1.91-2.04 (IH, m, 8-H) , 2.26 (3H, s, 15-H 3 ) , 2.39 (IH, dd, J 14.3 and 10.6Hz, 4-H), 2.69-2.82 (3H, m, 4,10 and 11-H) , 3.41 (IH, dd, J 9.0 and 2.9Hz, 6-H) , 3.61 (IH, d, J 11.7Hz, 16-H) , 6.92 (IH, s, 2-H), 7.57 (IH, dd, J 8.0 and 5.0Hz, 5'-H), 8.33-8.37 (IH, 15 , 4'-H), 8.70 (IH, dd, J 4.9 and 1.7Hz, 6'-H), 9.07 (IH, d, J 1.5Hz, 2-H); δ c (CD 3 OD) 12.3 (C-17) , 20.4 (C-15) , 20.6 (C-14), 33.1 (C-9), 41.9 (C-8) , 43.8 (C-12) , 44.6 (C-4), 56.9 (C-10), 61.3 (C-ll) , 66.5 (C-16) , 70.1 (C-6), 70.7 (C-7), 71.7 (C-13), 76.4 (C-5), 122.8 (C-2), 125.3 (C-5'), 20136.2 (C-3'), 137.5 (C-4'), 150.1 (C-2' or 6'), 153.2 (C-2' or 6), 161.6 (C-3), 190.9 (C-1); m/z. (E.I.). 405 (M + , 1%), 106 (100%); (Found: M + , 405.2211. C 22 H 31 NOg requires M, 405.2230) . 25 Example 6 (l-Methyltriazol-5-yl)-1- (normon-2-yl) ketone a) (l-Methyltriazol-5-yl)-1-(6,7,13-O-tris-tri- 30 methylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.88ml, 3.0mmol) was added dropwise to a solution of 1-methyltriazole (0.25g, 3.0mmol) in THF (10ml) maintaining the temperature below -60°C. 35 After lh at -65°C cerium trichloride (0.74g, 3.0mmol) was added. After a further lh at -65°C N-methoxy-N-methyl-6,7,13-O-tris(trimethylsilyl)monamide (0.60g, lmmol) in THF (5ml) was added dropwise maintaining the temperature below -60°C. After 2h at -65°C the solution was allowed to warm to 0°C over lh. Acetic acid (0.16ml) 5 was added followed by water (50ml) and ethyl acetate (50ml) . The organic layer was separated, dried (MgS0 4 ) and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate (4:1) as eluent gave the required ketone (0.19g, 31%) as a colourless 10 oil; δ H (CDC1 3 ) 0.11-0.18 (27H, m, 9 x SiCH 3 ) , 0.90 (3H, d, J 7.1Hz, 17-H 3 ), 1.21 (3H, d, J 6.4Hz, 14-H 3 ) , 1.35-1.43 (IH, , 12-H) , 1.52-1.63 (2H, , 9-H 2 ) , 1.76-1.88 (IH, m, 8-H) , 2.15 (IH, dd, J 10.7 and 14.7Hz, 4-H) , 2.31 (3H, s, 15-H 3 ), 2.64-2.73 (3H, m, 4,10 and 11-H) , 3.40 (IH, dd, J 15 9.1 and 2.3Hz, 6-H) , 3.58 (IH, d, J 11.4Hz, 16-H) , 3.82-3.95 (4H, m, 5,7,13 and 16-H) , 4.34 (3H, s, NCH 3 ) , 6.61 (IH, s, 2-H), 8.11 (IH, s, 4'-H); m/z. (E.I.). 625 (M + , 4%), 117 (100%); (Found: M + , 625.342). C 29 H 55 N 3 OgSi 3 requires M, 625.3399) . 20 b) (l-Methyltriazol-5-yl)-1- (normon-2-yl) ketone The above ketone (0.18g, 0.288mmol) and 4-dimethylaminopyridine dihydrochloride (l.Omg, 5.1 x 2510-°mmol) in methanol (7ml) were stirred at room temperature for ten minutes. Saturated sodium hydrogen carbonate solution (10ml) was added and the solution extracted with ethyl acetate (3 x 30ml). Drying (MgS0 4 ) , evaporation-to dryness under reduced pressure and purification by flash 30 chromatography using 10% methanol in dichloromethane as eluent gave the required compound (0.080g, 68%) as a white foam; V maχ (KBr) 3427, 2967, 2927, 1660, 1610, 1111, 1051cm- 1 ; ^ ax (EtOH) 273.5nm (^ 16,800); δ R (CDC1 3 ) 0.94 (3H, d, J 7.1Hz, 17-H 3 ), 1.23 (3H, d, J 6.3Hz, 14-H 3 ) , 351.27-1.41 (IH, m, 12-H) , 1.71-1.81 (2H, m, 9-H 2 ) , 1.97-2.10 (IH, m, 8-H), 2.32 (3H, s, 15-H 3 ) , 2.38 (IH, dd, J 9.2 and 14.8Hz, 4-H), 2.69-2.83 (3H, m, 4,10 and 11-H) , 3.49 (IH, dd, J 8.9 and 2.9Hz, 6-H) , 3.63 (IH, d, J 11.5Hz, 16-H) , 3.73-4.00 (4H, m, 5,7,13 and 16-H) , 4.34 (3H, s, NCH 3 ) , 6.64 (IH, s, 2-H), 8.13 (IH, s, 4 , -H); δ c (CD 3 OD) 12.2 (C-17) , 20.3 (C-15), 20.4 (C-14) , 32.9 (C-9) , 28.3 (NCH 3 ) , 41.8 (C-9), 43.6 (C-12), 44.5 (C-4), 56.8 (C-10) , 61.1 (C-ll) , 66.3 (C-16), 69.9 (C-6), 70.6 (C-7) , 71.5 (C-13) , 76.3 (C-5), 123.7 (C-2), 137.1 (C-5'), 137.4 (C-4'), 163.4 (C-3), 181.2 (C-1); m z (E.I.) 409 (M + , 4%), 224 (100%); (Found: M + , 409.2207. C 20 H 31 N 3 Og requires M, 409.2213). Example 7 (2-Methoxypyrimidin-5-yl)-1-(normon-2-yl) ketone a) (2-Methoχyρyrimidin-5-yl)-1-(6,7,13-O-tris- trimethylsilylnormon-2-yl) ketone n.-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added dropwise to 5-bromo-2-methoxypyrimidine (0.33g, 1.74mmol) in THF (10ml) maintaining the temperature below -85°C. After lh at -85°C cerium trichloride (0.43g, 1.74mmol) was added. After lh at -90°C, 6,7,13-O-tris (trimethylsilyl)monaldehyde (0.63g, 1.16mmol) in THF (5ml) was added dropwise maintaining the temperature below -85°C. After 3h at -85°C acetic acid (0.10ml) then water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (1:1) as eluent gave the diastereomeric alcohols (0.56g, 74%) as a pale yellow oil. Manganese dioxide (0.93g, 10.7mmol) and benzene (10ml) were added and the mixture heated to reflux under Dean and Stark conditions for 0.5h. The solids were removed by filtration, washed with dioxane and the combined filtrates evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate (4:1) as eluent gave the title compound (0.29g, 52%) as a colourless oil; δ H (CDC1 3 ) 0.11-0.17 (27H, m, 9 x SiCH 3 ) , 0.91 (3H, d, J 7.0Hz, I7-H3), 1.20 (3H, d, J 6.3Hz, 14-H 3 ) , 1.31-1.46 (IH, m, 12-H), 1.52-1.64 (2H, , 9-H 2 ) , 1.77-1.90 (IH, m, 8-H) , 2.13 (IH, dd, J 14.7 and 9.7Hz, 4-H) , 2.27 (3H, s, 15-H 3 ) , 2.64-2.72 (3H, m, 4,10 and 11-H) , 3.40 (IH, dd, J 9.0 and 2.1Hz, 6-H) , 3.58 (IH, d, J 11.3HZ, 16-H) , 3.81-4.00 (4H, m, 5,7,13 and 16-H) , 4.09 (3H, s, OCH3) , 6.70 (IH, s, 2-H) , 9.05 (2H, s, 3' and 5'-H); m/z (E.I.) 652 (M + , 4%), 73 (100%); (Found: M + , 652.3396. C 31 H 5 gN 2 0 7 Si 3 requires M, 652.3395) . b) (2-Methoxypyrimidin-5-yl)-1- (normon-2-yl) ketone The above ketone (0.27g, 0.414mmol) and 4-dimethylaminopyridine dihydrochloride (6.0mg, 0.03mmol) in methanol (4ml) were stirred at room temperature for 0.5h. Saturated sodium hydrogen carbonate solution (10ml) and water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (0.155g, 86%) as a white foam; v maχ (KBr) 3380, 2922, 1661, 1610, 1588, 1248cm- 1 ; λ^-^ (EtOH) 296.5nm (^ 21,465); δ R (CD3OD) 0.94 (3H, d, J 7.1Hz, 17-H 3 ) , 1.19 (3H, d, J 6.5Hz, I4-H3), 1.36-1.44 (IH, m, 12-H) , 1.67-1.73 (2H, m, 9-H 2 ), 1.89-2.04 (IH, m, 8-H) , 2.25 (2H, s, 15-H 3 ) , 2.25 (3H, s, 15-H3) , 2.38 (IH, dd, J 14.3 and 8.4Hz, 4-H) , 2.68-2.83 (3H, m, 4,10 and 11-H) , 3.40 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.60 (IH, d, J 10.7HZ, 16-H) , 3.73-3.92 (4H, m, 5,7,13 and 16-H) , 4.08 (3H, s, OCH 3 ) , 6.86 (IH, s, 2-H) , 9.09 (2H, s, 4' and 6'-H); δ c (CD 3 OD) 12.2 (C-17) , 20.3 (C-15), 20.4 (C-14), 32.9 (C-9), 41.7 (C-8) , 43.6 (C-3), 44.5 (C-4), 56.1 (OCH 3 ) , 56.8 (C-10) , 61.2 (C-ll) , 66.4 (C-16), 70.0 (C-6), 70.6 (C-7) , 71.6 (C-13) , 76.3 (C-5), 122.3 (C-2), 127.9 (C-5'), 161.4 (C-4'), 161.6 (C-3), 167.8 (C-2'), 188.3 (C-1); m/z. (E.I.) 436 (M + , 2%), 137 (100%); (Found: M + , 436.2213. C 2 H 32 N 2 0 7 requires M, 436.2210) . Example 8 (2-Dimethylaminopyrimidin-5-yl)-1-(normon-2-yl) ketone a) (2-Dimethylaminopyrimidin-5-yl)-1-(6,7, 13-0- tristrimethylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added dropwise to 5-bromo-2-dimethylaminopyrimidine in THF (10ml) whilst maintaining the temperature below -85°C. After lh at -90°C cerium trichloride (0.43g, 1.74mmol) was added. After a further lh at -90°C 6,7,13-O-tris (trimethylsilyl)monaldehyde (0.63g, 1.16mmol) in THF (3ml) was added dropwise whilst maintaining the temperature below -85°C. After 2.5h at -90°C acetic acid (0.10ml) then water (10ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ), evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (1:1) as eluent gave the diaste.eomeric alcohols (0.21, 27%) as a colourless oil. Manganese dioxide (0.43g, 4.95mmol) and benzene (5ml) were added and the mixture heated to reflux under Dean and Stark conditions for 0.5h. The solids were removed by filtration, washe with dioxane and the combined filtrates evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate (4:1) as eluent gave the title compound (0.083g, 40%) as a pale yellow oil; δ H (CDCI3) 0.11-0.16 (27H, m, 9 x SiCH 3 ) , 0.90 (3H, d, J 7.1Hz, 12-H 3 ), 1.20 (3H, d, J 6.3Hz, 14-H 3 ) , 1.36-1.44 (IH, m, 12-H) , 1.62-1.73 (2H, m, 9-H 2 ) , 1.79-1.84 (IH, m, 8-H), 2.12 (IH, dd, J 15.0 and 10.9Hz, 4-H) , 2.21 (3H, s, 15-H 3 ), 2.60-2.71 (3H, m, 4,10 and 11-H) , 3.27 [6H, s, N(CH 3 ) 2 ], 3.389 (IH, dd, J 9.0 and 2.4Hz, 6-H) , 3.56 (IH, d, J 11.2Hz, 16-H), 3.80-3.96 (4H, m, 5,7,13 and 16-H) , 6.63 (IH, s, 2-H) , 8.87 (2H, s, 4' and 6'-H); m/z. (E.I.) 6.64 (M + , 10%) 150 (100%); (Found: M + , 665.3713. C 32 H 59 N 3 OgSi 3 requires M, 665.3712) . 5 b) (2-Dimethylaminopyrimidin-5-yl)-1-(normon-2-yl) ketone The above ketone (0.08g, 0.12mmol) and ιo 4-dimethylaminoρyrimidine dihydrochloride (1.5mg, 7.7 x 10- 6 mol) in methanol (5ml) were stirred at room temperature for 1.5h. Saturated sodium hydrogen carbonate solution (5ml) and water (10ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness 15 under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (0.0416g, 77%) as a white foam; V maχ (KBr) 3430, 2924, 1651, 1593, 1559, 1266cm- 1 ; λ^^ (EtOH) (316nm (^ 21,615) and 260nm (^ 7,864); δ R 20 (CD3OD) 0.94 (3H, d, J 7.1Hz, 17-H 3 ) , 1.19 (3H, d, J 6.4Hz, I4-H3), 1.37-1.45 (IH, m, 12-H) , 1.62-1.79 (2H, m, 9-H 2 ) , 1.93-2.03 (IH, m, 8-H) , 2.19 (3H, s, 15-H 3 ) , 2.35 (IH, dd, J 14.8 and 10.0Hz, 4-H) , 2.71-2.84 (3H, m, 4,10 and 11-H) , 3.25 [6H, s, N(CH 3 ) 2 ], 3.41 (IH, dd, J 8.9 and 3.0Hz, 6-H) , 253.60 (IH, d, J 11.5Hz, 16-H) , 3.76-3.92 (4H, m, 5,7,13 and 6-H) , 6.74 (IH, s, 2-H) , 8.83 (2H, s, 4' and 6'-H), δ c (CD3OD) 12.3 (C-17), 20.3 (C-14 and C-15) , 33.0 (C-9), 37.6 [N(CH 3 ) 2 ], 41.7 (C-8) , 43.7 (C-12) , 44.2 (C-4), 56.9 (C-10), 61.3 (C-ll), 66.4 (C-16) , 70.0 (C-6), 70.0 (C-6), 3070.7 (C-7), 71.6 (C-13) , 76.3 (C-5), 121.9 (C-4'), 122.7 (C-2), 158.6 (C-3), 160.1 (C-3'), 163.5 (C-2'), 189.5 (C-1); m/z. (E.I.) 449 (M + , 5%), 150 (100%); (Found: M + , 449.2534. C 23 H 35 N 3°6 requires M, 449.2526) . Exa ple 9 (2-Methylthiopyrid-5-yl)-1- (normon-2-yl) ketone a) (2-Methylthiopyrid-5-yl)-l-(6,7,13-Q-tris-tri- methylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (3.27ml, 5.22mmol) was added dropwise to 5-bromo-2-methylthiopyridine (1.06g, 5.22mmol) in THF (45ml) at -85°C. After lh at -85°C cerium trichloride (1.29g, 5.22mmol) was added and after a further lh at -85°C 6,7, 13-O-tris (trimethylsilyl)monaldehyde (1.89g, 3.47mmol) in THF (7ml) was added dropwise whilst maintaining the temperature below -85°C. After lh at -85°C acetic acid (0.30ml) and water (50ml) were added sequentially and the solution extracted with ethyl acetate. Drying (MgS0 4 ) and purification by flash chromatography using hexane/ethyl acetate (2:1) as eluent gave the impure diastereomeric alcohols (1.53g, 66%) as a colourless oil. Manganese dioxide (2.46g, 28.3mmol) and benzene (20ml) were added and the mixture heated to reflux under Dean and Stark conditions for 0.5h. The solids were removed by filtration, washed with dioxane and the combined filtrates evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate (6:1) as eluent gave the title compound (1.03, 68%) as a colourless oil; δ H (CDC1 3 ) 0.11-0.17 (27H, m, 9 x SiCH 3 ) , 0.91 (3H, d, J 7.1Hz, 17-H 3 ), 1.20 (3H, d, J 6.3Hz, 14-H 3 ) , 1.35-1.43 (IH, m, 12-H), 1.62-1.79 (2H, m, 9-H 2 ) , 1.75-1.85 (IH, m, 8-H) , 2.14 (IH, dd, J 15.0 and ll.OHz, 4-H) , 2.24 (3H, s, 15-H 3 ) , 2.60 (3H, s, SCH 3 ), 2.60-2.71 (3H, m, 4,10 and 11-H) , 3.40 (IH, dd, J 9.0 and 2.4Hz, 6-H) , 3.58 (IH, d, J 11.4Hz, 16-H) , 3.80-3.95 (4H, m, 5,7,13 and 16-H), 6.75 (IH, s, 2-H) , 7.23 (IH, d, J 8.3Hz, 3'-H), 8.02 (IH, dd, J 8.4 and 2.2Hz, 4'-H), 8.97 (IH, d, J 1.7Hz, 6'-H); m/z. (E.I.) 667 (M + , 20%), 117 (100%); (Found: M + , 667.3223. C 32 H 57 NOgSi 3 requires M, 667.3214). b) (2-Methylthiopyrid-5-yl) -1- (normon-2-yl) ketone The above ketone (1.02g, 1.53mmol) and 4-dimethylaminopyrimidine dihydrochloride (13.6mg, 0.07mmol) 5 in methanol (5ml) were stirred at room temperature for lh. Saturated sodium hydrogen carbonate solution (10ml) and water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography ιo using 8% methanol in dichloromethane as eluent gave the title compound (0.55g, 80%) as a white foam; v maχ (KBr) 3426, 2924, 1654, 1580, 1114cm- 1 ; λ j ^ (EtOH) 318.4nm (ε m 22,080) and 284.Onm ^ 9,628); δ R (CD 3 OD) 0.94 (3H, d, J 7.0Hz, 17-H 3 ), 1.19 (3H, d, J 6.4Hz, I4-H3) , 1.33-1.47 15 (IH, m, 12-H) , 1.68-1.73 (2H, m, 8-H 2 ) , 1.90-2.05 (IH, m, 8-H) , 2.23 (3H, s, I5-H3), 2.37 (IH, dd, J 14.3 and 9.6Hz, 4-H) , 2.59 (3H, s, SCH3) , 2.69-2.83 (3H, m, 4,10 and 11-H) , 3.41 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.60 (IH, d, J 11.3Hz, 16-H), 3.74-3.93 (4H, m, 5,7,13 and 16-H) , 6.87 (IH, s, 202-H) , 7.36 (IH, d, J 8.4Hz, 3'-H), 8.10 (IH, dd, J 8.4 and 2.3Hz, 4'-H), 8.93 (IH, d, J 17Hz, 6'-H); δ c (CD3OD) 12.3 (C-17), 13.5 (SCH3), 20.4 (C-15) , 20.5 (C-14) , 33.0 (C-9), 41.8 (C-8), 43.7 (C-12) , 44.3 (C-4), 56.9 (C-10) , 61.3 (C-ll), 66.4 (C-16) , 70.0 (C-6), 70.7 (C-7) , 71.6 (C-13) , 2576.4 (C-5), 121.8 (C-5"), 122.9 (C-2), 131.6 (C-4'), 136.6 (C-3'), 150.6 (C-6'), 160.3 (C-3), 166.6 (C-2), 99.6 (C-1); m/z. (E.I.) 451 (M + , 7%), 152 (100%); (Found: M + , 451.2033. C 23 H 33 N0 6 S requires M, 451.2029). 30 Example 10 (2-Methylsulphinylpyrid-5-yl)-1-(normon-2-yl) ketone m-Chloroperoxybenzoic acid (85%) (0.050g, 0.242mmol) was 35 added to the ketone of example 9 (0.10g, 0.22mmol) in dichloromethane (3ml) and saturated sodium hydrogen solution (2ml) . After 2h at room temperature water (10ml) was added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 8% methanol in dichloromethane as eluent gave the title compound (0.0369g, 536%) as a white foam; v maχ (KBr) 3419, 2968, 1661, 1609, 1573, 1242, 1041cm- 1 ; λ^^ (EtOH) 281.5nm (ε m 14,857) and 237nm (^ 7,863); δ R CD3OD) 0.94 (3H, d, J 7.6Hz, 17-H 3 ) , 1.19 (3H, d, J 6.4Hz, 14-H 3 ) , 1.37-1.45 (IH, m, 12-H) , 1.67-1.73 (2H, m, 9-H 2 ), 1.93-2.02 (IH, m, 8-H) , .27 (3H, 10 two s, I5-CH3) , 2.41 (IH, dd, J 4.3 and 9.6Hz, 4-H) , 2.71 (IH, dd, J 7.5 and 2.7Hz, 11-H) , 2.80-2.84 (2H, m, 4 and 10-H) , 2.90 and 2.91 (3H, two s, SOCH3) , 3.42 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.61 (IH, d, J 11.5Hz, 16-H) , 3.75-3.93 (4H, m, 5,7,13 and 16-H) , 6.94 (IH, s, 2-H) , 8.06 (IH, dd, J 15 8.2 and 6.7Hz, 3'-H), 8.54 (IH, dd, J 8.2 and 2.1Hz, 4'-H), 9.13 (IH, d, J 2.1Hz, 6'-H); δ c (CD 3 OD) 12.3 (C-17) , 70.3 (C-15), 20.6 (C-14), 33.0 (C-9), 41.1 (SCH 3 ) , 41.6 (C-8) , 43.7 (C-12), 44.6 (C-4), 56.7 (C-10) , 61.2 (C-ll) , 66.4 (C-16), 70.0 (C-6), 70.7 (C-7) , 71.6 (C-13) , 76.3 (C-5), 20 120.3 (C-4'), 122.7 (C-2), 136.0 (C-5'), 139.1 (C-3'), 150.8 (C-6'), 162.5 (C-3), 169.5 (C-2'), 190.0 (C-1); m/z (F.A.B. thioglycerol) 468 (MH + , 24%) , 126 (100%) . Example 11 25 Ϊ2- (Piperidin-l-yl)pyrimidin-5-yll-l-(normon-2-yl) ketone a) T2-(Piperidin-1-yl)-ρyrimidin-5-yll-1-(6,7,13-0- tris-trimethylsilylnormon-2-yl) ketone 30 n-Butyllithium (1.6M in hexane) (1.78ml, 2.85mmol) was added dropwise to 5-bromo-2- (piperidin-l-yl)pyrimidine (0.67g, 2.76mmol) in THF (25ml) maintaining the temperature below -90°C. After lh at -90°C cerium trichloride (0.68g, 352.76mmol) was added and after a further 2h at -90°C and lh at -75°C acetic acid (0.16ml) and water (40ml) were added. The solution was extracted with ethyl acetate, the combined extracts dried (MgS0 4 ) and evaporated to dryness under reduced pressure. Purification by flash chromatography 5 using hexane/ethyl acetate (2:1) as eluent gave the diastereomeric alcohols (0.71g, 55%). The alcohols (0.54g, 0.76mmol) and manganese dioxide (0.89g, 10.2mmol) in benzene (20ml) were heated to reflux under Dean and Stark conditions for lh. The solids were removed by filtration, washed with 10 dioxane, and the combined filtrates evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate (5:1) as eluent gave the title compound (0.45g, 83%) as a colourless oil; δ H (CDC1 3 ) 0.11-0.17 (27H, , 9 x SiCH 3 ) , 0.90 (3H, d, J 9.0Hz, 1517-H 3 ), 1.20 (3H, d, J 6.3Hz, 14-H 3 ) , 1.31-1.44 (IH, m, 12-H) , 1.51-1.91 (9H, m, 8-H, 9-H 2 , 2 x 3"-H 2 and 4"-H 2 ), 2.11 (IH, dd, J 5.0 and ll.OHz, 4-H) , 2.21 (3H, s, 15-H 3 ) , 2.59-2.71 (3H, m, 4,10 and 11-H) , 3.41 (IH, d, J 11.4Hz, 16-H), 3.80-4.03 (8H, m, 5,7,13 and 16-H, and 2 x 2"-H 2 ), 208.77 (IH, s, 4" and 6"-H); m/z (E.I.) 705 (M + , 12%), 190 (100%) . b) [2-(Piperidin-1-yl)-pyrimidin-5-yll-1-(normon)2-yl) ketone 25 The above ketone (0.44g, 0.62mmol) and 4-dimethylaminopyridine (8.0mg, 4.1 x 10- 5 mol) in methanol (20ml) were stirred at room temperature for 1.5h. Saturated sodium hydrogen carbonate solution (20ml) and water (20ml) 30 were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (0.250g, 83%) as a white foam; v maχ (KBr) 3427, 352933, 1653, 1591, 1527, 1249cm- 1 ; λ maχ (EtOH) 322nm (^ 25,545), 259.5 (^ 8,466) and 236nm (^ 6,751); δ R (CD 3 0D) 0.94 (3H, d, J 7.1Hz, 17-H 3 ) , 1.20 (3H, d, J 6.4Hz, 14-H 3 ), 1.37-1.45 (IH, m, 12-H) , 1.57-1.67 (8H, m, 9-H 2 , 2 x 3"-H 2 and 4-H 2 ) , 1.94-2.02 (IH, , 8-H) , 2.19 (3H, s, 14-H 3 ), 2.35 (IH, dd, J 14.3 and 9.5Hz, 4-H) , 2.70-2.76 (2H, m, 4 and 11-H) , 2.80-2.84 (IH, , 10-H) , 3.40 (IH, dd, J 9.0 and 3.0Hz, 11-H) , 2.80-2.84 (IH, m, 10-H) , 3.40 (IH, dd, J 59.0 and 3.0Hz, 6-H) , 3.61 (IH, d, J 11.4Hz, 16-H) , 3.76-3.92 (8H, m, 5,7,13 and 16-H, and 2 x 2"-H 2 ), 6.73 (IH, s, 2-H) , 8.81 (2H, s, 4" and 6"-H); δ c (CD 3 OD) 12.1 (C-17) , 20.3 (C-15), 20.3 (C-14), 20.3 (C-14) , 25.6 (C-4"), 26.9 (C-3"), 33.0 (C-9), 41.7 (C78) , 43.6 (C-12) , 44.2 (C-4 ) , 1046.1 (C-2"), 56.8 (C-10) , 61.2 (C-ll) , 66.4 (C-16) , 70.0 (C-6), 70.6 (C-7), 71.6 (C-13) , 76.3 (C-5), 121.9 (C-4'), 122.7 (C-2), 158.4 (C-3), 160.3 (C-3'), 162.6 (C-2'), 189.3 (C-1); m/z. (E.I.) 489 (M + , 21%), 190 (100%); (Found: M + , 489.2837. C 2 H 39 N 3 0g requires M, 489.2839) . 15 Example 12 (2-Dimethylaminopyrid-5-yl)-1-(normon-2-yl) ketone 20 a) (2-Dimethylaminopyrid-5-yl)-1-(6,7, 13-O-tris- trimethylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.09ml, 1.76mmol) was added dropwise to 5-bromo-2-dimethylaminopyridine (0.35g, 251.74mmol) in THF (25ml) at -90°C. After lh at -85°C cerium trichloride (0.43g, 1.74mmol) was added. After lh at -85°C 6,7,13-O-tris(trimethylsilyl)monaldehyde (0.63g, 1.16mmol) in THF (5ml) was added whilst maintaining the temperature below -85°C. After 2h at -85°C and lh at -75°C acetic acid 30 (0.10ml) then water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness and reduced pressure and purification by flash chromatography using ethyl acetate/hexane (1:1) as eluent gave the diastereomeric alcohols (0.48g, 62%) as a pale 35 yellow foam. Manganese dioxide (0.60g, 6.90mmol) and benzene (10ml) were added and the mixture heated to reflux under Dean and Stark conditions for 30mins. The solids were removed by filtration, washed with dioxane and the combined filtrates evaporated to dryness under reduced pressure. 5 Purification by flash chromatography using hexane/ethyl acetate (3:1) as eluent gave the title compound (0.36g, 75%) as a white foam; δ R (CDC1 3 ) 0.10-0.16 (27H, , 9 x SiCH 3 ) , 0.91 (3H, d, J 9.0Hz, 17-H 3 ) , 1.20 (3H, d, J 6.3Hz, 14-H 3 ) , 1.33-1.46 (IH, m, 12-H) , 1.53-1.62 (2H, m, 9-H 2 ) , 1.79-1.90 10 (IH, , 8-H) , 2.11-2.19 (IH, m, 4-H) , 2.19 (3H, s, 15-H 3 ) , 2.59-2.71 (3H, m, 4,10 and 11-H) , 3.18 [6H, s, N(CH 3 ) 2 ], 3.40 (IH, d, J 9.0Hz, 6-H) , 3.57 (IH, d, J 11.4HZ, 16-H) , 3.80-3.96 (4H, m, 5,7,13 and 16-H) , 6.51 (IH, d, J 9.0Hz, 3'-H), 6.70 (IH, s, 2-H) , 8.05 (IH, dd, J 9.0 and 2.1Hz, 154'-H), 8.80 (IH, d, J 2.0Hz, 6'-H); m/z. (E.I.) . 649 [(M-CH 3 ) + , 30%], 141 (100%). b) (2-Dimethylaminopyrid-5-yl)-1-(normon-2-yl) ketone 20 The above ketone (0.35g, 0.53mmol) and 4-dimethylaminopyridine dihydrochloride (0.030g, 0.15mmol) in methanol (10ml) were stirred at room temperature for 8h and at 0°C for 16h. Saturated sodium hydrogen carbonate solution (10ml) and water (20ml) were added and the solution 25 extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (0.196g, 83%) as a pale - yellow foam; V maχ (KBr) 3428, 2967, 2922, 1648, 1603, 1396, 30 1266cm- 1 ; λ^^ (EtOH) 340nm (^ 24,050); δ R (CD3OD) 0.94 (3H, d, J 7.1Hz, 17-H3), 1.19 (3H, d, J 6.3Hz, 14-H 3 ) , 1.33-1.47 (IH, m, 12-H) , 1.68-1.74 (2H, m, 9-H 2 ) , 1.92-2.03 (IH, m, 8-H), 2.16 (3H, s, 15-H 3 ) , 2.34 (IH, dd, J 14.4 and 9.6Hz, 4-H) , 2.69-2.85 (3H, m, 4,10 and 11-H) , 3.17 [6H, s, 35 N(CH 3 ) 2 ], 3.41 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.62 (IH, d, J 11.4Hz, 16-H), 3.74-3.93 (4H, m, 5,7,13 and 16-H) , 6.69 (IH, d, J 9.2Hz, 3'-H), 6.78 (IH, s, 2-H) , 8.04 (IH, dd, J 9.2 and 2.4Hz, 4'-H), 8.71 (IH, d, J 2.3Hz, 6'-H); δ c (CD 3 0D) 12.2 (C-17), 20.2 (C-15) , 20.3 (C-14), 33.0 (C-9) , 38.4 [N(CH 3 ) 2 ], 41.6 (C-8) , 43.7 (C-12) , 44.0 (C-4), 56.8 (C-10), 51.2 (C-ll), 66.4 (C-16) , 70.0 (C-6), 70.6 (C-7) , 71.6 (C-13), 76.3 (C-5), 106.6 (C-4 f ) , 123.3 (C-2), 124.1 (C-5'), 138.2 (C-3'), 151.5 (C-6'), 156.7 (C-2'), 161.8 (C-3), 191.2 (C-1); m/z. (E.I.) 448 (M + , 4%), 149 (100%); (Found: M + , 448.2585. C 24 H 3 gN 2 0g requires M, 448.2573). Example 13 (l-Propylpyrazol-4-yl)-1-(normon-2-yl) ketone a) 4-Bromo-l-propylpyrazole Bromine (1.42ml, 27.3mmol) in glacial acetic acid (3.5ml) was added dropwise to 1-propylpyrazole (3.0g, 27.3mmol) and sodium acetate (371g, 27.3mmol) in glacial acetic acid (10ml) and water (25ml) . After lh at room temperature the solution was extracted with ethyl acetate, the extracts dried (MgS0 4 ) and evaporated to dryness under reduced pressure. Distillation at reduced pressure gave the title compound (4.00g, 77%) (b.p. 86-90°C ca.lOmm Hg) as a colourless liquid; δ R (CDCI3) 0.91 (3H, t, J 7.3Hz, CH3) , 1.07 (2H, sextet, J 7.3Hz, CH 2 CH 2 CH 3 ) , 4.06 (2H, t, J 7.3Hz, CH 2 CH 2 CH 3 ) 7.40 (IH, s, 3 or 5-H) , 17.45 (IH, s, 3 or 5-H) ; δ c (CDC1 3 ) 11.0 JCH 3 ), 23.6 (CH 2 CH 2 , 54.5 (CH 2 CH 2 CH 3 ) , 92.6 (C-4), 129.1 (C-3 or 5), 139.6 (C-3 or 5); m/z.190 (M + , 54%), 188 (M + , 56%), 161 (100%); (Found: M + , 187.9943. CgH 9 N 2 Br requires M 187.9949). b) (l-PropylPyrazol-4-yl)-l-(6,7,13-tris-0-tri- methylsilylnormon-2-yl) ketone 4-Bromo-l-propylpyrazole (0.57g, 3.00mmol) in THF (5ml) was 5 added dropwise to n-butyllithium (1-6M in hexane) (1.88mmol, 3.00mmol) in THF (20ml) at -70°C. Added a further 40mins at -70°C N-methoxy-N-methyl 6,7,13-0tris- Λ (trimethylsilyl)monamide (0.60g, l.OOmmol) in THF (5ml) was added dropwise whilst maintaining the temperature below 10 -60°C. After 4h at -70°C acetic acid (0.10ml) was added and the products poured into water (50ml) . The solution was extracted with ethyl acetate, dried (MgS0 4 ) and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane/ethyl acetate (3:1) as eluent 15 gave the title compound (0.57g, 88%) as a white foam; δ R (CDC1 3 ) 0.10-0.16 (27H, m, 9 x SiCH3) , 0.89-0.95 (6H, m, CH 2 CH 2 CH 3 and 17-H 3 ) , 1.20 (3H, d, J 6.4Hz, 14-H3) , 1.35-1.42 (IH, , ' 12-H) , 1.53-1.62 (2H, , 9-H 2 ) , 1.74-1.97 ) (3H, m, 8-H and 2"-H 2 ), 2.10 (IH, dd, J 14.6 and 10.6Hz, 204-H) , 2.25 (3H, s, 15-H 3 ) , 2.63-2.72 (3H, m, 4,10 and 11-H) , 3.40 (IH, dd, J 8.9 and 2.3Hz, 6-H) , 3.56 (IH, d, J 11.4Hz, 16-H), 3.80-3.94 (4H, m, 5,7,13 and 16-H) , 4.09 (2H, t, J 7.0Hz, 1"-H 2 ), 6.52 (IH, s, 2-H) , 7.89 (IH, s, 3' or 5'-H), 7.92 (IH, s, 3' or 5'-H); m/z (F.A.B. 3-NOBA/Na) . 675 (MNa + , 25100%) , 653 ( MH + , 58%) . c) (l-Propylpyrazol-4-yl)-1-(normon-2-yl) ketone The above ketone (0.56g, 0.86mmol) and 304-dimethylaminopyridine dihydrochloride (2.2mg, 11.3 x 10- 6 mol) in methanol (14ml) were stirred at room temperature for 30mins. Saturated sodium hydrogen carbonate solution was added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced 35 pressure and purification by flash chromatography using 9% methanol in dichloromethane as eluent gave the title co pound (0.32g, 86%) as a white foam; v maχ (KBr) 3422, 2969, 2933, 2877, 1647, 1606, 1540, 1224, 1270, 1109, 1048cm- 1 ; X m&χ (EtOH) 270.5nm ^ 20,137); δ R (CD3OD) 0.90 (3H, t, J 7.3Hz, 3"-H 3 ), 0.94 (3H, d, J 7.3Hz, 17-H3) , 1.19 5 (3H, d, J 6.3Hz, 14-H 3 ), 1.34-1.47 (IH, m, 12-H) , 1.70 (IH, t, J 6.5Hz, 17-H 2 ), 1.81-1.96 (3H, m, 2'-H 2 and 8-H) , 2.24 (3H, s, I5-H3), 2.31 (IH, dd, J 14.2 and 9.6Hz, 5-H) , 2.69-2.84 (3H, m, 4,10 and 11-H) , 3.39 (IH, dd, J 9.0 and 3.0Hz, 6-H), 3.58 (IH, d, J 11.4HZ, 16-H) , 3.76-3.92 (4H, m, 105,7,13 and 16-H) , 4.14 (3H, t, J 7.0Hz, 1"-H 2 ), 6.66 (IH, s, 2-H), 17.96 (IH, s, 3' or 5'-H), 18.23 (IH, s, 3' or 5'-H); δ c (CD3OD) 11.1 (CH 2 CH 2 CH 3 ) , 12.2 (C-17) , 20.1 (C-15), 20.3 (C-14), 24.3 (CH 2 CH 2 CH 3 ) , 32.9 (C-9) , 41.7 (C-8), 43.6 (C-12), 44.3 (C-4), 54.7 (CH 2 CH 2 CH 3 ) , 56.8 15 (C-10), 61.1 (C-ll), 66.3 (C-16) , 70.0 (C-6), 70.6 (C-7) , 71.6 (C-13), 76.3 (C-5), 124.4 (C-2), 126.5 (C-4'), 133.9 (C-3' or 5'), 141.1 (C-3' or 5'), 158.7 (C-3), 187.0 (C-1) ; m/z. (E.I.). 436 (M + , 3%) 137 (100%); (Found: M + , 436.2571. C 23 H 3 N 2 0g requires M, 436.2573) . 20 Example 14 (2-Acetylfur-4-yl)-1- (normon-2-yl) ketone 25 a) 4-Bromo-2- (1-triethylsilyloxyethen-l-yl) furan Triethylamine (2.94g, 4.06ml, 29.2mmol) and triethylsilyl trifluoromethanesulphonate (5.76g, 4.93ml, 1.83mmol) were added sequentially to 2-acet"- " '-4,5dibromofuran (3.93g, 3014.6mmol) in THF (100ml) cooled to 0°C. After 2h, water was added and the solution extracted wit ethvl acetate. Drying (MgS0 4 ) and evaporation to dryness under reduced pressure gave the crude silylenol ether (5.61g, 100%) as a pale yellow liquid. n-Butyllithium (1.6M in hexane) (9.12ml, 3514.6mmol) was added dropwise to the crude silylenol ether (5.61g, 14.0mmol) in THF (40ml) whilst maintaining the te perature below -60°C. After 40mins, at -70°C the products were poured into a pH 7 buffer solution. Extraction with ethyl acetate, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using dichloromethane/hexane (10:1) as eluent gave the title compound (2.20g, 4%) as a pale yellow liquid; V maχ (liquid film) 2960, 2918, 2880, 1555, 1310, 1150, 1010, 925cm- 1 ; δ R (CDC1 3 ) 0.69-0.79 (6H, m, 3 x CH 2 CH 3 ) , 0.97-1.04 (9H, , 3 x CH 2 CH 3 ), 4.39 (IH, d, J 1.8Hz, olefinic H) , 4.86 (IH, d, J 1.8Hz, olefinic H) , 6.45 (IH, s, 3-H) , 7.33 (IH, s, 5-H); δ c (CDCI3) 4.7 (CH 2 ) , 6.8 (CH3) , 90.4 (C-2'), 100.9 (C-4), 109.9 (C-3), 140.3 (C-5), 146.9 (C-2 or 1'), 152.9 (C-2 or 1'); m/z (C.I. NH3) 305 (MH + , 97%), 303 (MH + , 90%), 190 (100%) . b) [2- (1-Triethylsilyloxyethen-l-yl) fur-4-yll- 1-(6,7,13-Q-tris-trimethylsilylnormon-2-yl) ketone The above bromofuran (0.50g, 1.65mmol) in THF (3ml) was added dropwise to n-butyllithium (1.6M in hexane) (1.03ml, 1.65mmol) at -70°C. After a further 40mins. at -70°C N-methoxy-N-methyl-6,7,13-O-tris(trimethylsilyl)monamide (0.60g, l.OOmmol) in THF (5ml) was added dropwise. After 4h at -65°C acetic acid (0.10ml) then water (30ml) were added. Extraction with ethyl acetate, drying (MgS0 4 ) , evaporation to dryness under reduced pressure, and purification by flash chromatography using hexane/ethyl acetate (10:1) as eluent gave the title compound (0.13g, 17%) as a colourless oil; δ R (CDCI3) 0.10-0.16 (27H, m, 9 x SiCH 3 ) , 0.75 (6H, q, J 7.8Hz, 3 x CH 2 CH 3 ), 0.90 (3H, d, J 7.1Hz, 17-H3) , 1.00 (9H, t, J 7.8Hz, 3 x CH 2 CH 3 ) , 1.20 (3H, d, J 6.3Hz, I4-H3) , 1-33-1.43 (IH, m, 12-H) , 1.62-1.72 (2H, m, 9-H 2 ) , 1.77-1.88 (IH, m, 8-H) , 2.09 (IH, dd, J 10.6 and 14.5Hz, 4-H) , 2.25 (2H, s, I5-H3), 2.60 (IH, d, J 14.5Hz, 4-H) , 2.62-2.71 (2H, m, 10 and 11-H) , 3.39 (IH, dd, J 8.9 and 2.3Hz, 6-H) , 3.55 (IH, d, J 11.4Hz, 16-H), 3.80-3.93 (4H, m, 5,7,13 and 16-H) , 4.42 (1H, d, J 1.5Hz, olefinic H) , 4.89 (IH, d, J 1.5Hz, olefinic H), 6.47 (IH, s, 2-H), 6.78 (IH, s, 3-H) , 7.90 H, s, 5-H) . c) (2-Acetylfur-4-yl)-l- (normon-2-yl) ketone 5 The above ketone (0.13g, 0.17mmol) and 4-dimethylaminopyridine dihydrochloride (0.50g, 2.5 x 10- 6 mol) in methanol (4ml) were stirred at room temperature for 20min. Saturated sodium hydrogen carbonate solution was ιo added and the solution extracted with ethyl acetate. The combined extracts were dried (MgS0 4 ) and evaporated to dryness under reduced pressure. THF (52ml) was added and the resulting solution treated with tetra-n-butyl-ammonium fluoride trihydrate (0.054g, 0.17mmol) at 0°C. After 40mins 15 at 0o C water (50ml) was added and the solution extracted with ethyl acetate. Drying (MgS0 ), evaporation to dryness under reduced pressure and purification by flash chromatography using 9% methanol in dichloromethane as eluent gave the title compound (0.031g, 42%) as a white 20 foam; V maχ (KBr) 3447, 2967, 2924, 1683, 1659, 1609, 1572, 1250cm- 1 ; λ naχ (EtOH) 277.5nm (^ 17,260); δ R (CD 3 0D) 0.94 (3H, d, J 7.1Hz, 17-H 3 ), 1.19 (3H, d, J 6.4Hz, 14-H 3 ) , 1.36-1.45 (IH, m, 12-H) , 1.68-1.75 (2H, m, 9-H 2 ), 1.92-2.01 (IH, m, 8-H) , 2.26 (3H, s, 15-H3) , 2.34 (IH, dd, J 14.3 and 25 9.5Hz, 4-K) , 2.50 (3H, s, COCH3) , 2.70-2.76 (2H, m, 4 and 11-H), 2.80-2.83 (IH, m, 10-H) , 3.39 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.59 (IH, d, J ll.lHz, 16-H) , 3.75-3.85 (2H, m, 13 and 16-H) , 3.87-4.00 (2H, , 5 and 7-H) , 6.70 (IH, s, 2-H), 7.61 (IH, s, 3'-H), 8.46 (IH, s, 5'-H); δ c (CD3OD) 30 12.3 (C-17), 20.4 (C-15 and 14), 26.2 (COCH3) , 33.0 (C-9), 41.6 (C-8), 43.8 (C-12) , 44.5 (C-4), 56.9 (C-10) , 61.3 (C-ll), 66.5- (C-16), 70.1 'C-6), 70.7 (C-7) , 71.7 (C-13) , 76.4 (C-5), 117.0 (C-3'), 123.8 (C-2), 132.3 (C-4'), 151.8 (C-5'), 154.6 (C-1), 161.0 (C-3), 186.0, 188.7; m z (E.I.) 35436 (M + , 2%), 47 (100%); (Found: M + , 436.2088. C 23 H 32 O g requires M, 436.2097) . Example 15 f2-(Morpholin-4-yl)-pyrimidin-5-vπ-l (normon-2-yl) ketone 5 n-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added dropwise to 5-bromo-2-morpholinopyrimidine (0.43g, 1.74mmol) in THF (20ml) whilst maintaining the temperature at -80 to -85°C. After lh at -85°C cerium (III) chloride (0.43g, 1.74mmol) was added. After a further lh at -85°C 10 6,7,13-O-tris (trimethylsilyl)- monaldehyde (0.63g, 1.16mmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -80°C. After 3h at -85°C acetic acid (0.96ml) then water (50ml) were added. Extraction with ethyl acetate, drying (MgS0 4 ) and evaporation to dryness 15 under reduced pressure gave the crude alcohol which was dissolved in benzene (20ml) and treated with manganese dioxide (300g, 34.5mmol) under Dean and Stark conditions for 30mins. Filtration, washing of the filtered solids with dioxane and evaporation to dryness under reduced pressure 20 gave, after flash chromatography using hexane/ethyl acetate (3:1) as eluent, the protected ketone (0.46g, 56%) . Methanol (10ml) and 4-dimethylaminopyridine dihydrochloride (8.0mg, 0.04mmol) were added and the resulting solution stirred at room temperature for 30mins. Saturated sodium 25 hydrogen carbonate solution (10ml) was added and the solution extracted with ethyl acetate. Drying (MgS0 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 8% methanol in dichloromethane as eluent gave the title compound (0.26g, 30 84%) as a white foam; V maχ (KBr) 3433, 2966, 2921, 1864, 1653, 1591, 1525, 1448, 1246, 1114cm- 1 ; ^ ax (EtOH) 315nm (^ 23,209), 264nm (^ 7,962) and 231nm (^ 5,693); δ R (CD 3 OD) 0.95 (3H, d, J 7.0Hz, 17-H 3 ) , 1.20 (3H, d, J 6.3Hz, 14-H 3 ), 1.34-1.47 (IH, m, 12-H) , 1.70 (2H, t, J 6.2Hz, 359-H 2 ), 1.92-2.01 (IH, m, 8-H) , 2.20 (3H, s, 15-H 3 ) , 2.34 (IH, dd, J 14.4 and 9.5Hz, 4-H) , 2.70-2.84 (3H, m, 4,10 and 11-H), 3.40 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.60 (IH, d, J ll.,6Hz, 16-H), 3.72-3.95 (12H, m, 5,7,13 and 16-H, 2 x 2"-H 2 and 2 x 3"-H 2 ), 6.76 (IH, s, 2-H) , 8.87 (2H, s, 4' and 6'-H); δ c (CD 3 OD) 12.2 (C-17) , 20.3 (C-15) , 20.3 (C-9), 41.7 (C-8), 43.6 (C-12) , 44.2 (C-4), 45.5 (C-3"), 56.8 (C-10), 61.2 (C-ll), 66.4 (C-16) , 67.6 (C-2"), 70.0 (C-6), 570.6 (C-7), 71.6 (C-13), 76.3 (C-5), 122.6 (C-2), 122.8 (C-5), 158.9 (C-3), 160.2 (C-4 ' ) , 163.0 (C-2"), 189.2 (C-1); m/z 491 (M + , 7%), 192 (100%); (Found: M + , 491.2632, C 25 H 37 N 3°7 requires M, 491.2632 ) . 10 Example 16 \2- (l-Methylpiperazin-4-yl)-pyrimidin-5-yll-1- (normon2-yl) ketone 15 a) 5-Bromo-2- (l-methylpiperazin-4-yl)pyrimidine N-Methylpiperazine (0.5g, 5.68mmol) and 5-bromo-2- chloropyrimidine (l.OOg, 5.17mmol) in methanol (25ml) were heated to reflux for lh. The products were neutralised with 20 saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and recrystallisation from aqueous methanol gave the title compound (0.76g, 86%) as white crystals (mp.68-9°C); v maχ (KBr) 2955, 2926, 1579, 1528, 25 1491, 1449, 1360, 1308, 1760cm- 1 ; δ R (CDCI3) 2.34 (3H, s, NCH3), 2.45 (4H, t, J 5.1Hz, 2 x 2"-H 2 ), 3.80 (4H, t, J 5.1Hz, 2 x 3"-H 2 ), 8.28 (2H, s, 4 and 6-H) ; δ c (CDC1 3 ) 43.9 (N-CH 3 ), 46.2, 54.8, 105.7 (q) , 157.8, 159.9(q); m/z.258 (M + , 5%), 256 (M + , 13%), 70 (100%). 30 b) f2- (l-Methylpiperazin-4-yl)-pyrimidin-5-yll-1- (6,7,13-0-tris-trimethylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added 5 dropwise to 5-bromo-2-(l-methylpiperazin-4-yl)pyrimidine (0.44g, 1.74mmol) in THF (20ml) at -85°C. After lh at -85°C, cerium trichloride (0.43g, 1.74mmol) was added and the solution kept at -85°C for a further lh. 6,7,13-tris(trimethylsilyl)monaldehyde (0.63g, 101.16mmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -80°C and after 3h at -85°C acetic acid (0.10ml) then water (50ml) were added. Extraction with ethyl acetate, drying (MgS0 4 ) and evaporation to dryness under reduced pressure gave the crude alcohols which were 5 dissolved in benzene (20ml) and treated with manganese dioxide (3.00g, 34.5mmol) under Dean and Stark conditions for 30mins. Filtration, washing of the filtered solids with dioxane, evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/ 0 hexane (2:1) as eluent gave the title compound (0.33g, 40%) as a pale yellow oil; δ R (CDC1 3 ) 0.10-0.16 (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.3Hz, 17-H 3 ) , 1.19 (3H, d, J 6.3Hz, 14-H 3 ), 1.34-1.41 (IH, m, 2-H) , 1.50-1.58 (2H, m, 9-H 2 ) , 1.74-1.86 (IH, , 8-H) , 2.01 (IH, dd, J 14.9 and ll.OHz, 54-H) , 2.21 (3H, s, I5-H3), 2.36 (3H, s, N-CH3) , 2.43-2.52 (4H, m, 2 x 2"-H 2 ), 2.59-2.71 (3H,m, 4,10 and 11-H) , 3.38 (IH, dd, J 9.0 and 2.5Hz, 6-H) , 3.56 (IH, d, J 11.3Hz, 16-H), 3.79-4.03 (8H, m, 5,7,13, 16-H and 2 x 3"-H 2 ), 6.62 (IH, s, 2-H) , 18.85 (2H, s, 4'-H); m/z.720 (M + , 3%), 117 0 (100%); (Found: M + 720.4126. C 35 Hg 4 N 4 0gSi 3 requires M, 720.4134) . Example 17 12- (5,7-Dimethoxycruinolin-3-yl) 1-1-(normon-2-yl) ketone 5 a) 3-Bromo-5,7-dimethoxycruinoline Bromine (4.00g, 1.28ml, 25.0mmol) was added dropwise to α-bromoacrolein (3.38g, 25.0mmol) in acetic acid (60ml) at 5-10°C. After 20mins. 3,5-dimethoxyaniline (3.83g, 1025.0mmol) was added and the solution heated to reflux for lh. Evaporation to low volume under reduced pressure, addition of water, extraction with dichloromethane, evaporation to dryness under reduced pressure and purification by flash chromatography using dichloromethane 15 as eluent gave the title compound (0.45g, 7%) as a pale yellow solid; V maχ (KBr) 2960, 1625, 1582, 1451, 1416, 1352, 1332, 1269, 1219, 1208, 1157, 1110cm- 1 ; δ R (CDCI3) 3.93 (3H, s, OCH3), 3.96 (3H, s, OCH3), 6.53 (IH, d, J 7.2Hz, 6 or 8-H) , 6.97 (IH, d, J 7.2Hz, 6 or 8-H) , 8.56 (IH, d, J 202.0-Hz, 4-H) , 8.79 (IH, d, J 2.0Hz, 2-H) ; δ c (CDCI3) 55.6 (OCH 3 ), 55.8 (OCH 3 ), 99.0, 99.6, 113.9(q) , 117.7 (q) , 132.4, 148.5(q), 151.7, 155.1, 161.5(q) ; m/z 269 (M + , 98%), 267 (M + , 100%); (Found: M + , 266.9896. C 11 H 10 NO 2 Br requires M, 266.9895) . 25 b) r2-(5.7-Dimethoxycruinolin-3-yl) 1-1- (6.7, 13-0- tris-trimethylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.05ml, 1.68mmol) was added 30 dropwise to the above quinoline in THF (20ml) whilst maintaining the temperature below -85°C. After lh at -85°C cerium (III) chloride (0.40g, 1.65mmol) was added and after a further lh at -85°C acetic acid (0.10ml) then water (20ml) were added. Extraction with ethyl acetate, drying 35 (Na,S0 4 ) and evaporation to dryness under reduced pressure gave the crude alcohols. Manganese dioxide (3.00g, 34.5mmol) and benzene (25ml) were added to the crude alcohols and the mixture was heated to reflux under Dean and Stark conditions for lh. Filtration, washing the filtered solids with dioxane, evaporation of the combined filtrates to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (2:1) as eluent gave the title compound (0.35g, 41%) as a pale yellow foam; δ R (CDC1 3 ) 0.10g, 0.20 (27H, m, 9 x SiCH 3 ) , 0.91 (3H, d, J 7.2Hz, I7-H3), 1.20 (3H, d, J 6.3Hz, 4-H 3 ) , 1.36-1.43 (IH, m, 12-H) , 1.52-1.64 (2H, m, 9-H 2 ) , 1.80-1.90 (IH, m, 8-H) , 2.21 (IH, dd, J 15.0 and ll.OHz, 4-H) , 2.28 (3H, s, 15-H 3 ) , 2.67-2.73 (3H, m, 4,10 and 11-H) , 3.44 (IH, dd, J 9.0 and 2.3Hz, 6-H), 3.01 (IH, d, J 11.4HZ, 16-H) , 3.82-4.00 (4H, m, 5,7,13 and 16-H) , 3.97 (3H, s, OCH3) , 4.01 (3H, s, OCH3) , 6.55 (IH, d, J 2.0Hz, 6' or 8'-H), 6.98 (4,5, 2-H) , 7.09 (IH, d, J 2.0Hz, 6' or 8'-H), 9.01 (IH, d, J 2.0Hz, 4-H) , 9.34 (IH, d, J 2.0Hz, 2'-H); m/z. (E.I.) 731 (M + , 8%), 73 (60%); (Found: M + , 731.3710. C 37 HgN0 8 Si 3 requires M, 731.3705) . c) \2-(5,7-Dimethoxyαuinolin-3-yl) 1-1-(normon-2-yl) ketone The above ketone (0.35g, 0.48mmol) and 4-dimethylaminopyridine dihydrochloride (0.028g, 0.14mmol) in methanol (10ml) were stirred at room temperature for 7h. Saturated sodium hydrogen carbonate solution was added and the solution extracted into ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 7% methanol in dichloromethane as eluent gave the title compound (0.19g, 76%) as a white solid [mp.l50-51°C (MeOH) ] ; v maχ (KBr) 3423, 2967, 2927, 1653, 1617, 1453, 1431, 1414, 1282, 1251, 1151, 1108, 1045cm- 1 ; ^^ (EtOH) 344.5nm (^ 9,909) and 279.5nm (E JJJ 29,1985); δ R (CD 3 OD) 0.94 (3H, d, J 7.1Hz, 17-H 3 ) , 1.19 (3H, d, J 6.3Hz, 14-H 3 ), 1.33-1.47 (IH, m, 12-H) , 1.73 (2H, t, J 6'Hz, 9-H 2 ), 1.96-2.04 (IH, m, 8-H) , 2.26 (3H, s, 15-H 3 ), 2.42 (IH, dd, J 14.4 and 9.6Hz, 4-H) , 2.71 (IH, dd. J 8.6 and 2.4Hz, 11-H) , 2.78-2.85 (2H, m, 10 and 4-H) , 3.44 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.66 (IH, d, J 11.6Hz, 16-H), 3.72-3.93 (4H, m, 5,7,13 and 16-H) , 3.97 (3H, OCH 3 ) , 4.04 (3H, s, OCH 3 ), 6.70 (IH, d, J 2.0Hz, 6' or 8'-H), 6.99 5 (d, J 2.0Hz, 6' or 8'-H), 7.00 (IH, s, 2-H) , 8.99 (IH, d, J 2.0Hz, 4'-H), 9.20 (IH, d, J 2.0Hz, 2'-H); δ c (CD3OD) , 12.3 (C-17), 20.3 (C-15), 21.5 (C-4), 32.0 (C-9), 41.9 (C-8) , 43.7 (C-12), 44.4 (C-4), 56.3 (C-10) , 56.7 (OCH3) , 56.9 (OCH3), 61.2 (C-ll), 66.5 (C-16) , 70.1 (C-6), 70.7 (C-7) , 1071.7 (C-13), 76.4 (C-5), 99.8 (C-6' or 8'), 100.0 (C-6' or 8'), 116.4 (quat.), 122.8 (C-2), 129.6 (quat.), 132.9 (C-4'), 150.8 (C-2'), 152.1 (quat.), 158.3 (C-3), 160.1 (quat.), 165.4 (quat.), 190.6 (C-1); m/z. (E.I.) 515 (M + 5%), 216 (100%); (Found: M + , 515.2514. C 28 H 37 N0 8 requires M, 15515.2519) . Example 18 (l-Cvclohexylpyrazol-4-yl)-1-(normon-2-yl) ketone 0 a) 4-Bromo-l-cvcloheχylpyrazole Bromine (0.49ml, 9.40mmol) in acetic acid (3ml) was added dropwise to sodium acetate (1.28g, 9.40mmol) and 51-cyclohexylpyrazole (1.41g, 9.40mmol) in acetic acid (25ml) at room temperature. After 4h at room temperature the solution was evaporated to low volume and then basified with ammonium hydroxide solution. Extraction with ethyl acetate, drying (MgS0 ) , evaporation to dryness under reduced 0 pressure and recrystallisation from hexane gave the title compound (1.48g, 66%) as white needles (mp.55-56°C) ; v maχ (KBr) 2938, 2855, 1652, 1448, 1381, 950cm- 1 ; δ R (CDC1 3 ) 1.14-1.50 (3H, m, cyclohexyl) , 1.56-1.80 (3H, m, cyclohexyl) , 1.84-1.95 (2H, m, cyclohexyl), 2.08-2.19 (2H, 5 m, cyclohexyl), 4.08 (IH, tt, J 3.9 and 11.6Hz, 1"-H), 7.42 (IH, s, 3 or 5-H) , 7.44 (IH, s, 3 or 5-H) ; δ c (CDC1 3 ) , 25.3 (C-3' and C-4'), 33.4 (C-2'), 61.9 (C-1'), 82.3 (C-4), 126.7 (C-3 or C-5), 137.0 (C-3 or C-5); m/z. (M + , 80%), 228 (M + , 85%), 147 (100%); (Found: M + , 228.0264. C 9 H 13 N 2 Br requires M, 228.0262) . 5 b) (l-CvclohexylPyrazol-4-yl)-l-(6,7,13-tris-Q-tri- methylsilylnormon-2-yl) ketone The above bromopyrazole (0.92g, 4.0mmol) in THF (5ml) dropwise was added to n-butyllithium (1.6M in hexane) 10 (2.5ml, 4.0mmol) in THF (25ml) maintaining the temperature below -70°C. After lh at -70°C N-methoxy-N- methyl-6,7,13-O-tris (trimethylsilyl)monamide (1.20g, 2.0mmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -70°C. After 3h at -70°C acetic acid 15 (0.13ml) was added and the products poured into water. Extraction with ethyl acetate, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (4:1) as eluent gave the title co pund (0.99g, 74%) as a colourless oil; δ R 20 (CDC1 3 ) 0.10-0.16 (27H, m, 9 x SiCH 3 ) , 0.90 (3H, d, J 7.1Hz, 17-H 3 ), 1.20 (3H, d, J 6.3Hz, 14-H 3 ) , 1.30-1.95 (14H, 8 x cyclohexyl, 9-H 2 , 8 and 12-H) , 2.10-2.23 (3H, m, 4-H and 2 x cyclohexyl), 2.25 (3H, s, 15-H 3 ) , 2.60 (IH, d, J 14.5Hz, 4-H) , 2.65-2.73 (2H, m, 10 and 11-H) , 3.40 (IH, dd, J 2.4 25 and 8.9Hz, 6-H) , 3.55 (IH, d, J 11.4Hz, 16-H) , 3.80-3.94 (4H, m, 5,7,13 and 16-H) , 4.10 (IH, tt, J 3.9 and 11.6Hz, l'-H), 6.52 (IH, s, 2-H), 7.91 (IH, s, 3' or 5'-H), 7.94 (IH, s, 3' or 5'-H); m/z. (E.I.) 692 (M + , 7%), 117 (100%); (Found: M + , 692.4072. C 35 Hg 4 N 2 0gSi 3 requires M, 692.4072). 30 c) (l-Cvclohexylpyrazol-4-yl)-1- (normon-2-yl) ketone The above protected ketone (0.98g, 1.42mmol) and 4-dimethylaminopyridine dihydrochloride (4.0mg, 2.0 x 3510 ~5 mol) in methanol (25ml) were stirred at room temperature for 30min. Saturated sodium hydrogen carbonate solution was added and the resulting solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the 5 title compound (0.61g, 9%) as a white foam; v maχ (KBr) 3421, 2931, 2859, 1648, 1604, 1535, 1227cm- 1 ; λ j ^ (EtOH) 280.5nm ( ^ 19,644); δ R (CD3OD) 0.94 (3H, d, J 7.1Hz, 17-H 3 ), 1.19 (3H, d, J 6.4Hz, I4-H3), 1.32-2.13 (14H, m, 10 x cyclohexyl, 9-H 2 , 7 and 12-H) , .24 (3H, s, 15-H 3 ) , 2.32 (IH, dd, J 9.6 10 and 14.2Hz, 4-H) , 2.69-2.84 (3H, m, 4,10 and 11-H) , 3.39 (IH, dd, J 9.0 and 3.0Hz, 16-H) , 3.58 (IH, d, J 11.4Hz, 16-H), 3.73-3.91 (4H, m, 5,7,13 and 16-H) , 4.18 (IH, tt, J 3.6 and 11.5Hz, l'-H), 6.67 (IH, s, 2-H' ) , 7.94 (IH, s, 3' or 5'-H), 8.26 (IH, s, 3' or 5'-H); δ c (CD 3 OD) 12.3 (C-17) , 1520.4 (C-15), 20.7 (C-14), 26.3 (C-3' and 4'), 33.0 (C-9), 34.3 (C-2'), 41.8 (C-8) , 43.7 (C-12) , 44.4 (C-4), 56.7 (C-10), 61.2 (C-ll), 62.9 (C-1'), 66.4 (C-16) , 70.1 (C-6), 70.7 (C-7), 71.7 (C-13), 76.4 (C-5), 124.6 (C-2), 126.4 (C-3'), 131.7 (C-3' or 5'), 140.7 (C-3' or 5'), 158.7 (C-3), 20187.1 (C-1); m/z (E.I.) 476 (M + , 20%), 177 (100%); (Found: M + , 476.2899. C 24 H 40 N 2 Og requires M, 476.2886) . Example 19 25 12-(Piperidin-1-yl)pyridin-5-yll-1-(normon-2-yl) ketone a) 5-Bromo-2-(piperidin-1-yl)pyridine Bromine (8.16g, 2.62ml, 51.9mmol) in acetic acid (20ml) was 30 added dropwise to 2-(piperidin-1-yl)pyridine (8.41g, 51.9mmol) and sodium acetate (6.94g, 51.9mmol) (100ml) at room temperature. After 2 days at room temperature the solution was evaporated to low volume, water (50ml) added and the solution extracted with ethyl acetate. Drying 35 (MgS0 4 ), evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (8:1) as eluent gave the title compound (7.50g, 60%) as a pale yellow liquid; δ R (CDCI3) 1.55-1.71 (6H, m, piperazinyl-H) , 6.53 (IH, d, J 9.2Hz, 3-H) , 7.47 (IH, dd, J 9.3 and 2.5Hz, 4-H) , 8.16 (IH, d, J 2.5Hz, 6-H) ; δ c (CDCI3) 524.5 (C-4'), 25.3 (C-3'), 46.2 (C-2'), 106.4 (C-5), 108.3 (C-3), 139.4 (C-4), 148.3 (C-6), 158.0 (C-2); m/z.242 (M + , 90%), 240 (M + , 96%), 84 (100%); (Found: M + , 240.0261. C 10 H 13 N 2 Br requires M, 240.0262). 10 b) r2-(Piperidin-1-yl)pyridin-5-yl1-1-(6,7,13-0- tris-trimethylsilylnormon-2-yl) ketone N-Butyllithium (1.6M in hexane) (1.96ml, 3.14mmol) was added dropwise to the above bromopyridine (0.76g, 3.14mmol) in THF 15 (25ml) whilst maintaining the temperature at -80 to -85°C. After lh at -85°C cerium (III) chloride (0.77g, 3.14mmol) was added and the solution kept at -85°C for a further lh. 6,7,13-O-tris (trimethylsilyl)monaldehyde (1.14g, 2.09mmol) in THF (10ml) was added dropwise maintaining the temperature 20 below -80°C and after 3h at -85°C acetic acid (0.18ml) then water (50ml) were added. Extraction wi.th ethyl acetate, drying (MgS0 4 ) and evaporation to dryness under reduced pressure gave the crude alcohols which were dissolved in benzene (30ml) and treated with manganese dioxide (6.00g, 25 69mmol) under Dean and Stark conditions for 30mins. Filtration, washing of the filtered solids with dioxane, evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane (2:1) as eluent gave the title compound 30 (0.87g, 59%) as a yellow oil; δ R (CDCI3) 0.10-0.15 (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.0Hz, 17-H 3 ) , 1.19 (3H, d, J 6.2Hz, 14-H 3 , 1.42-1.49 (IH, , 12-H) , 1.52-1.90 (9H, m, 9-Hz, 8-H, 3", 4" and 5"-H 2 ), 2.08 (IH, m, dd, J 15.0 and 10.9Hz, 4-H), 2.18 (3H, s, 15-H 3 ) , 2.58-2.70 (3H, m, 4,10 35 and 11-H) , 3.39 (IH, dd, J 8.9 and 3.1Hz, 6-H) , 3.55 (IH, d, J 11.6Hz, 16-H), 3.63-3.74 (4H, m, 2" and 6"-H 2 ), 3.79-3.95 (14H, m, 5, 7, 13 and 16-H) , 6.60 (IH, d, J 9.0Hz, 3'-H), 6.68 (IH, s, 2-H) , 8.01 (IH, dd, J 9.0 and 2.2Hz, 4'-H), 8.77 (IH, d, J 2.2Hz, 6'-H); m/z. (E.I.) 704 (M + , 8%), 189 (100%); (Found: M + , 704.4087. C 3 gHg 4 N 2 0gSi 3 requires M, 5704.4072) . c) r2-(Piperidin-l-yl)Pyridin-5-yl1-l-(normon-2-yl) ketone 10 The above protected ketone (0.86g, 1.21mmol) was treated with hydrochloric acid (0.4M) (10.8ml) in THF (27ml) at room temperature for 2mins. Saturated sodium hydrogen carbonate solution was added and 15 the solution extracted with ethyl acetate. Drying (MgS0 4 ), evaporation to dryness under reduced pressure and purification by flash chromatography using 9% methanol in dichloromethane as eluent gave the titlecompound (0.50g, 84%) as a pale yellow foam; V maχ (KBr) 3420, 2931, 2857, 20 1734, 1595, 1242cm- 1 ; λ^^ (EtOH) 344nm (^ 24,430); δ R (CD 3 0D) 0.95 (3H, d, J 7.0Hz, 17-H 3 ) , 1.20 (3H, d, J 6.4Hz, 14-H 3 ), 1.34-1.47 (IH, m, 12-H) , 1.63-1.80 (8H, m, 9, 3", 4" and 5"-H 2 ), 1.90-2.01 (IH, m, 8-H) , 2.16 (3H, s, 15-H 3 ), 1 33 (IH, dd, J 14.4 and 9.6Hz, 4-H) , 2.69-2.85 (3H, 25 m, 4, 10 and 11-H) , 3.41 (IH, 'id, J 8.9 and 3.0Hz, 6-H) , 3.61 (IH, d, J 11.5Hz, 16-H) , 3.69-3.73 (4H, m, 2" and 6"-H 2 ), 3.76-3.93 (4H, m, 5, 7, 13 and 16-H) , 6.76 (IH, s, 2-H), 6.80 (IH, d, J 9.2Hz, 3'-H), 8.01 (IH, dd, J 9.2 and 2.4Hz, 4'-H), 8.69 (IH, d, J 2.4Hz, 6'-H); δ c (CD 3 OD) 12.2 30 (C-17), 20.2 (C-15), 20.3 (C-14), 25.6 (C-4"), 26.7 (C-3"), 33.0 (C-9), 41.6 (C-8) , 43.7 (C-12) , 44.0 (C-4), 47.0 (C-2"), 56.6 (C-10) , 61.2 (C-ll) , 66.4 (C-16), 70.0 (C-6), 70.6 (C-7), 71.6 (C-13), 76.4 (C-5), 107.0 (C-3'), 123.4 (C-2), 124.3 (C-5'), 138.5 (C-4'), 151.8 (C-6'), 156.7 35 (C-2'), 161.5 (C-3), 191.0 (C-1); m z (E.I.) 488 (M + , 18%), 189 (100%) . Example 20 (Thien-3-yl)-1- (normon-2-yl)ketone 53-Bromothiophene in THF (10ml) was added dropwise to n-butyl lithium (1.6M in hexane) in THF (20ml) as -70°C over 10 minutes. After a further 20 min at -70°C N-methoxy-N- methyl-6,7,13-0-tris (trimethylsilyl)monamide (1.20g, 2.00mmol) in THF (10ml) was added dropwise whilst 10 maintaining the temperature below -65°C. After 1.5h at -70°C acetic acid (0.23ml) then water were added and the aqueous phase extracted with ethyl acetate. Drying (Na 2 S0 4 ) and evaporation to dryness under reduced pressure gave the crude protected ketone which was dissolved in methanol 15 (25ml) and 4-dimethylaminopyridine dihydrochloride (5.0mg, 0.026mmol) was added. After stirring at room temperature for 30 min, saturated sodium hydrogen carbonate solution was added and the solution extraction with ethyl acetate. Drying (Na 2 S0 4 ) , evaporation to dryness under reduced 20 pressure and purification by flash chromatography using 7% methanol in dichloromethane as eluent gave the title compound (0.68g, 84%) as a white foam; vmax (KBr) 3465, 3308, 2968, 2920, 2888, 1657, 1598, 1246cm "1 ; λ^^ (EtOH) 267nm (^ 11,960); δ R (CD 3 OD) 0.94 (3H, d, J 7.1Hz, 17-H 3 ) , 251.19 (3H, d, J 6.3Hz, 14-H 3 ) , 1.33-1.47 (IH, m, 12-H) , 1.68- 1.73 (2H, m, 9-H 2 ) , 1.92-2.02 (IH, m, 8-H) , 2.23 (3H, s, 15- H 3 ), 2.35 (IH, dd, J 9.5 and 14.3Hz, 4-H) , 2.69-2.84 (3H, m, 4, 10 and 11-H) , 3.40 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.59 (IH, d, J 11.5Hz, 16-H), 3.73-3.92 (4H, m, 5, 7, 13 and 16- 30 H), 6.85 (IH, s, 2-H), 7.44 (IH, dd, J 5.0 and 2.7Hz, 4'-H), 7.55 (IH, dd, J 5.0 and 1.3Hz, 5'-H), 8.26 (IH, dd, J 2.7 and 1.3Hz, 2'-H); δC(CD 3 OD) 12.2 (C-17) , 20.2 (C-15) , 20.3 (C-14), 32.9 (C-9), 41.7 (C-8), 43.6 (C-12) , 44.3 (C-4), 56.8 (C-10), 61.2 (C-ll) , 66.3 (C-16) , 70.0 (C-6), 71.6 (C- 3513), 76.4 (C-5), 124.0 (C-2), 127.5, 128.0, 133.3, 145.3 (C- 3'), 187.2 (C-1); m/z 410 (M + , 6%), 178 (100%); (Found: M, 410.1760. C 21 H 30 O 6 S requires M 410.1763). Example 21 (Thien-2-yl)-1- (normon-2-yl)ketone 5 a) (Thien-2-yl)-1- ( 6,7, 13-O-tris-trimethylsilyl- (normon-2-yl)ketone; n-Butyl lithium (1.6M in hexane) (1.00ml, 1.60mmol) was added dropwise to 2-bromothiophene (0.24g, 1.5mmol) in THF 10 (4ml) whilst maintaining the temperature below -65°C. After 15 ins at -70°C, N-methoxy-N-methyl-6,7,13-O-tris- (trimethylsilyl)monamide (0.60g, l.OOmmol) in THF (15ml) was added dropwise whilst maintaining the temperature below -65°C. After 15 mins at -70°C, acetic acid (0.14g) was 15 added followed by water (20ml) . Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure, and purification by flash chromatography using ethyl acetate/hexane (10-30%) as eluent gave the title compound (0.25g, 38%) as a white foam; δ R (CDCI3) 0.09-0.17 20 (27H, m, 9 x SiCH 3 ) , 0.90 (3H, d, J 7.0Hz, 17-H 3 ) , 1.20 (3H, d, J 6.3Hz, 14-H 3 ), 1.30-1.41 (IH, m, 12-H) , 1.56 (2H, br.s, 9-H 2 ), 1.73-1.83 (lh, m, 8-H) , 2.10 (IH, dd, J 14.6 and 10.6Hz, 4-H) , 2.24 (3H, s, I5-H3) , 2.59 (IH, d, J 14.6HZ, 4- H) , 2.70-2.74 (2H, m, 10 and 11-H) , 3.41 (IH, dd, J 8.9 and 252.4Hz, 6-H) , 3.56 (IH, d, J 11.3HZ, 16-H) , 3.78-3.95 (4H, m, 5,7,13 and 16-H) , 6.70 (IH, s, 2-H) , 7.10 (IH, t, J 3.7Hz 4'-H), 7.60 (IH, dd, J 4.2 and 0.9Hz, 3'-H), 7.69 (IH, dd, J 2.7 and 0.8Hz, 5'-H) . 30 b) Thien-2-yl)-1-(normon-2-yl)ketone The above ketone (0.23g, 0.38mmol) and hydrochloric acid (0.4H) (3.0ml, 1.2 x 10~ 3 mol) in THF (15ml) were stirred at room temperature for 2 min. Saturated sodium hydrogen 35 carbonate solution (7.5ml) was then added. Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 0-6% methanol in dichloromethane as eluent gave the title compound (0.112g, 71%) as a white foam; vmax (KBr) 3440, 2970, 2926, 1639, 1602, 1246, 1184cm "1 ; ^ (EtOH) 5296nm (^ 14,044); δ R (CDC1 3 ) 0.93 (3H, d, J 7.1Hz, 17-H 3 ) , 1.22 (3H, d, J 6.3Hz, 14-H 3 ) , 1.29-1.41 (IH, m, 12-H) , 1.71- 1.77 (2H, m, 9-H 2 ) , 1.96-2.04 (IH, m, 8-H) , 2.30 (3H, s, 15- H 3 ), 2.35 (IH, dd, J 14.6 and 9.0Hz, 4-H) , 2.59-2.73 (2H, , 4 and 11-H) , 2.78-2.84 (IH, m, 10-H) , 3.48 (IH, dd, J 8.9 10 and 2.0Hz, 6-H) , 3.59 (IH, dd, J 11.3 and 1.8Hz, 16-H) , 3.74-3.98 (4H, m, 5,7,13 and 16-H) , 6.76 (IH, s, 2-H) , 7.10 (IH, t, J 3.7Hz, 4'-H), 7.60 (IH, dd, J 4.2 and 0.9Hz, 3'- H) , 7.69 (IH, dd, J 2.7 and 0.8Hz, 5'-H). δ c (CDCI3) , 12.6 (C-17), 20.7 (C-14), 20.7 (C-15) , 31.5 (C-9), 39.6 (C-8) , 1542.7 (C-12), 43.3 (C-4), 55.6 (C-10) , 61.2 (C-ll) , 65.4 (C- 16), 68.8 (C-6), 70.3 (C-7) , 71.2 (C-13), 74.9 (C-5), 121.8 (C-2), 128.0, 131.3, 133.2 (C3' , C4' and C5' ) 146.6 (C2'), 157.6 (C-3), 183.7 (C-1), m/z. (E.I.) 410 (M + , 1%) 111 (100%); (Found: M + , 410.1768. C 21 H 30 OgS requires M, 20410.1763) . Example 22 5-Methoxy- (thien-3-yl)-1-(normon-2-yl) ketone 25 a) 5-Methoxy-(thien-2-yl)-1-(6,7,13-O-tris-trimethyl silylnormon-2-yl) ketone n-Butyl lithium (1.6M in hexane) (1.00ml, 1.60mmol) was 30 added dropwise to diisolpropylamine (0.18g, 1.78mmol) in THF (4ml) whilst maintaining the temperature at 020°C. After 10 mins at -20°C, 2-methoxythiophene (0.17g, 1.50mmol) was added dropwise whilst maintaining the temperature below -65°C. After 15 mins at -70°C, cerous chloride (0.37 C C, 351.50mmol) was added whilst maintaining the temperature below -65°C. After a further 45 mins at -70°C, N-methoxy- N-methyl-6,7, 13-O-tris-(trimethylsilyl)monamide (0.60g, l.OOmmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -65°C. After 1.25h at -70°C acetic acid (0.14g) was added followed by water (20ml) . Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness 5 under reduced pressure and purification by flash chromatography using ethyl acetate/hexane (10-30%) as eluent gave the title compound (0.08g, 13%) as a white foam; δ R 0.09-0.17 (27H, m, 9 x SiCH 3 ) , 0.91 (3H, d, J 7.0Hz, 17-H 3 ) , 1.19 (3H, d, J 6.3Hz, 14-H 3 ) , 1.33-1.41 (IH, , 12-H) , 1.70 10 (2H, br.s, 9-H 2 ), 1.80-1.88 (IH, m, 8-H) , 2.08 (IH, dd, J 14.6 and 10.7Hz, 4-H) , 2.18 (3H, s, 15-H 3 ) , 2.59 (IH, d, J 13.9, and 4-H) , 2.68-2.80 (2H, m, 10 and 11-H) , 3.41 (IH, dd, J 12.0 and 3.0Hz, 6-H) , 3.59 (IH, d, J 11.3, 16-H) , 3.80-3.92 (4H, m, 5,7,13 and 16H) , 3.95 (3H, s, OCH 3 ) , 6.72 15 (IH, s, 2-H) , 6.34 (IH, d, J 4.3Hz, 3'-H), 7.58 (IH, d, J 4.3Hz, 4'-H). b) (5-Methoxythien-2-yl)-1-(normon-2-yl)ketone 20 The above ketone (0.08g, 0.13mmol) and hydrochloric aciα (0.4M) (3ml, 1.2 x 10 "3 mol) in THF (15ml) were stirred at room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (7.5ml) was added. Extraction with diethyl ether drying (MgS0 ) , evaporation to dryness under 25 reduced pressure and purification by flash chromatography using 0-6% methanol in dichloromethane as eluent gave the title compound (0.040g, 69%) as a white foam; y ^x (KBr) 3426, 2970, 2887, 1638, 1598, 1242, 1051cm "1 ; λ^^ (EtOH) 333nm (^ 14,424); δ R (CDC1 3 ) 0.93 (3H, d, J 7.1Hz, 17-H 3 ) , 30 1.20 (3H, d, J 6.4Hz, 14-H 3 ) , 1.35-1.47 (IH, m, 12-H) , 1.67- 1.75 (2H, m, 9-H 2 ) , 1.92-2.03 (IH, m, 8-H) , 2.20 (3H, s, 15- H 3 ), 2.35 (IH, dd, J 13.5 and 9.5Hz, 4-H) , 2.64-2.73 (2H, m, 4 and 11-H) , 2.78-2.83 (IH, m, 10-H) , 3.41 (IH, dd, J 12.0 and 3.0Hz, 6-H) , 3.59 (IH, dd, J 10.7 and 1.8Hz, 16-H) , 353.74-3.95 (4H, m, 5,7,13 and 16-H) , 3.97 (3H, s, OCH 3 ) 6.77 (IH, s, 2-H) , 6.35 (IH, d, J 4.3Hz, 3'-H), 7.62 (IH, d, J 4.3Hz, 4'-H); δ c (CDCI3) , 12.2 (C-17) , 20.0 (C-15) , 20.3 (C- 14), 33.0 (C-9), 41.7 (C-8) , 43.7 (C-12) , 44.2 (C-4), 56.9 (C-10), 60.9 (OCH3), 61.2 (C-ll), 66.4 (C-16) , 69.9 (C-6), 70.7 (C-7), 71.6 (C-13), 76.4 (C-5), 107.0 (C-3'), 121.9 (C- 52), 133.9 (C-4'), 134.1 (C-2 ) , 157.5 (C-3), 175.9 (C-5'), 185.2 (C-1); m/z (E.I.) 440 (M + , 5%), 141 (100%); (Found: M + , 440.1871. C 22 H 32 0 7 S requires M, 440.1869). Example 23 0 Tl-(Methylmercapto)thiazol-5-vn-l-(normon-2-yl)ketone Tetrabutylammonium hydroxide (1.0M in methanol) (5.00ml, 5.0mmol) and iodomethane (0.739, 5.0mmol) were add dropwise to 2-mercaptothiazole (0.59g, 5.0mmol) in THF (5ml) at room temperature. After 1.5h and evaporation to dryness under reduced pressure, the reaction mixture was triturated with hexane and diethyl ether (1:1), taking the solid up in dichlormethane. The combined extracts were dried (MgS0 4 ) , evaporated to dryness under reduced pressure and purified by flash chromatography using diethyl ether in hexane (0.25%) as eluent to give 2-methylmercaptothiazole (0.23g, 34%) . n.-Butyl lithium (1.6M in hexane) (0.60ml, l.OOmmol) was added dropwise to 2-methylmercaptothiazole (0.13g, l.OOmmol) in THF (5ml) whilst maintaining the temperature below -65°C. After 30 mins at -70°C, N-methoxy- N-methyl-6,7,13-O-tris (trimethylsilyl)monamide (0.6g, l.OOmmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -65°C. After 1.5h at -70°C, acetic acid (0.14g) was added followed by water (20ml) . Extraction with diethyl ether, drying (MgSo 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate in hexane (0-25%) as eluent gave the trimethylsilyl protected title compound (0.48g, 72%) as a white foam. This was then stirred with hydrochloric acid (0.4M) (3ml, 1.2 x 10 "3 mol) in THF (15ml) at room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (7.5ml) was added. Extraction with diethyl ether drying (MgS0 4 ) evaporation to dryness under reduced pressure and purification by flash chromatography 5 using 0-10% methanol in dichloromethane as eluent gave the title compound (0.231g, 70%) as a white foam; v maχ (KBr) 3428, 2970, 2879, 1642, 1605, 1255, 1047 cm_ χ , λ^^ (EtOH) 330nm (e^ 22,251); δ R (CDCI3) 0.93 (3H, d, J 7.1Hz, 17-H 3 ) , 1.22 (3H, d, J 6.4Hz, 14-H 3 ) , 1.31-1.45 (IH, m, 12-H) , 1.65- 101.75 (2H, m, 9-H 2 ) , 1.90-2.04 (IH, m, 8-H) , 2.27 (3H, s, 15- H 3 ), 2.35 (IH, dd, J 11.8 and 9.5Hz, 4-H) , 2.67-2.85 (6H, m, 4, 10 and 11-H) , 2.75 (3H, s, SCH3) 3.41 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.59 (IH, dd, J 10.9 and 1.8Hz, 16-H) , 3.74- 3.96 (4H, m, 5,7,13 and 16-H) , 6.67 (IH, s, 2-H) , 8.31 (IH, 15 s, 3'-H); δ c (CDCI3), 12.2 (C-17) , 16.7 (S-CH3) , 20.3 (C- 15), 20.4 (C-14), 33.0 (C-9), 41.8 (C-8), 43.7 (C-12) , 44.4 (C-4), 56.9 (C-10), 61.2 (C-ll) , 66.4 (C-16) , 69.9 (C-6), 70.7 (C-7), 71.6 (C-13), 76.4 (C-5), 122.3 (C-2'), 143.1 (C- 2'), 147.3 (C-3'), 161.0 (C-3), 171.5 (C-5'), 183.5 (C-1); 0 m/z. (E.I.) 457 (M + , 457.1595. C 21 H 31 NOgS 2 requires M, 457.1593) . Example 24 5 2- (Piperidin-1-yl) thiazol-5-vπ -1- (normon-2-yl) ketone a) 2- (Piperidin-1-yl) thiazole Chloroacetaldehyde (45% w/w in water) (0.92g, 5.25mmol) in 0 ethanol (22ml) was added dropwise over 10 minutes to 1- piperidinethiocarboxamide (0.91g, 6.3mmol) in ethanol (11ml) . After refluxing for 2h, iced water (55ml) was added, followed by dropwise addition of ammonia (18M) until the reaction mixture was found to be basic. Extraction with 5 diethyl ether, evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane (0-30%) as eluent gave the title compound (0 .43g, 49%) ; δ R (CDC1 3 ) 1. 67 ( 6H, m, b-H 4 and c-H 2 ) , 3 . 48 (4H, m, a-H 4 ) , 6.51 (IH, d, J 3. 6Hz , 5' H) , 7. 19 (IH, d, J 3. 6Hz, 4 ' -H) . 5 b) f2- (Piperidin-1-yl)thiazol-5-yll-1- (normon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.5ml, 2.40mmol) was added dropwise to 2-piperidin-l-yl thiazole (0.40g, 2.4mmol) in 10 THF (7ml) whilst maintaining the temperature below -65°C. After lh at -70°C N-methoxy-N-methyl-6,7,13-O-tris (tri¬ methylsilyl)monamide (0.98g, 1.60mmol) in THF (8ml) was added dropwise, maintaining the temperature below -65°C. After 1.5h at -70°C acetic acid (0.22g) was added, followed 15 by water (25ml) . Extraction with diethyl ether, drying (MgS0 ) , evaporation to dryness under reduced pressure and partial purification by flash chromatography using ethyl acetate/hexane (15-50%) as eluent gave [2-(piperidin-1- yl)thiazol-5-yl]-l-(6,7,13-0-tris-trimethylsilylnormon-2-yl) 20 ketone (0.251g) as a light brown foam. The above impure ketone (0.251g, <0.3mmol) and hydrochloric acid (0.4M) (8ml, 3.1 x 10 ~ mmol) in THF (24ml) were stirred at room temperature for 2mins. Saturated sodium hydrogen carbonate solution (12ml) was added. Extraction with diethyl ether, 25 drying (MgS0 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 0-10% methanol in dichloromethane as eluent gave the title compound (0.107g, 13%) as a cream foam; u max (KBr) 3423, 2937, 2861, 1640, 1594, 12523, 1051cm "1 ; λ^^ (EtOH) 356nm 30 (^ 24,935); δ R (CD3OD) 0.93 (3H, d, J 7.1Hz, 17-H 3 ) , 1.22 (3H, d, J 6.4Hz, I4-H3), 1.34-1.46 (IH, m, 12-H) , 1.63-1.72 (8H, m, 9-H 2 , b-H 4 and c-H 2 ) , 1.90-2.04 (IH, m, 8-H) , 2.20 (3H, s, 15-H 3 ), 2.31 (IH, dd, J 14.3 and 9.5Hz, 4-H) , 2.67- 2.85 (3H, m, 4, 10, and 11-H) , 3.40 (IH, dd, J 8.9 and 353.0Hz, 6-H) , 3.54-3.66 (5H, m, 16-H and a-H 4 ) , 3.73-3.92 (4H, m, 5,7,13 and 16-H) , 6.67 (IH, s, 2-H) , 7.94 (IH, s, 4'-H); δ c (CDC1 3 ), 12.3 (C-17) , 20.1 (C-15) , 20.3 (C-14), 24.9 (C-c), 26.2 (C-b) , 33.0 (C-9), 41.8 (C-8) , 43.8 (C-12) , 44.2 (C-4), 50.8 (C-a) , 56.9 (C-10) , 61.3 (C-ll) , 66.4 (C-16), 70.0 (C-6), 70.0 (C-7) , 71.6 (C-13), 76.4 (C-5), 122.4 (C-2), 131.7 (C-5'), 148.7 (C-4'), 156.9 (C-3), 176.5 (C-2'), 184.4 (C-1); m/z. (E.I.) 494 (M + , 3%), 195 (100%); 5 (Found: M + , 494.2470. C 25 H 38 N 2 0 4 S requires M, 494.2451). Example 25 (Isσthiazol-5-yl)-1-(normon-2-yl) ketone 10 a) (Isothiazol-5-yl)-1- (6,7,13-O-tris-trimethylsilyl- normon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.00ml, 1.60mmol) was added 15 dropwise to isothiazole (0.12g, 1.5mmol) in THF (4ml) whilst maintaining the temperature below -65°C. After 15mins at -70°C, 6,7,13-O-tris(trimethylsilyl)monaldehyde (0.54g, l.Ommol) in THF (4ml) was added dropwise, maintaining the temperature below -65°C. After 30mins. at -70°C acetic acid 20 (O.lOg) was added, followed by water (20ml) . Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane (0-30%) as eluent gave the diastereomeric alcohols (0.36g, 38%) as a yellow oil; δ R 25 (CDC1 3 ) 0.09-0.17 (27H, m, 9 x SiCH 3 ) , 0.90 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.3Hz, 14-H 3 ) , 1.30-1.41 (2H, m, 8 and 12-H) , 1.56 (2H, m, 9-H 2 ), 1.80 (4H, m, 15-H 3 and OH), 1.96-2.05 (IH, dd, J 14.0 and 2.8Hz, 4-H) , 2.49 (IH, d, J 16.7Hz, 4-H) , 2.63-2.73 (2H, m, 10 and 11-H) , 3.39 (IH, dd, 30 J 8.7 and 2.1Hz, 6-H) , 3.56 (IH, d, J 11.4Hz, 16-H) , 3.73- 3.93 (4H, m, 5,7,13 and 16-H) , 5.54 (IH, d, J 3.5Hz, 2-H) , 5.85 (IH, d, J 8.5Hz, 1-H) , 7.6 (IH, s, 4'-H), 8.38 (IH, s, 3'-H) . Manganese dioxide (l.OOg, 3wt equivalents) and benzene (15ml) were added to the above alcohols (0.36g, 350.57mmol) and the reaction mixture heated to reflux under Dean and Stark conditions for 30mins. The solids were removed by filtration and washed with dioxane. The filtrates were combined and evaporated to dryness under reduced pressure. Purification by flash chromatography using ethyl acetate/hexane (0-30%) as eluent gave the title compound (0.02g, 5%) as a white foam; δ R (CDC1 3 ) 0.09-0.19 (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.0Hz, 17-H 3 ) , 1.20 (3H, d, J 6.3Hz, 14-H 3 ), 1.33-1.43 (IH, m, 12-H) , 1.59 (IH, , 8-H) , 1.78-1.85 (2H, m, 9-H 2 ) , 2.10 (IH, dd, J 14.6 and 10.2Hz, 4-H), 2.30 (3H, s, 15-H 3 ), 2.59-2.71 (3H, m, 4,10 and 11-H) , 3.40 (IH, dd, J 9.0 and 2.4Hz, OH), 3.56 (IH, d, J 11.3Hz, 16-H), 3.77-3.95 (4H, m, 5,7,13 and 16-H) , 6.66 (IH, s, 2-H) , 7.65 (IH, d, J 1.7Hz, 4'-H), 18.56 (IH, d, J 1.7Hz, 3'-H). b) (Isothiazol-5-yl)-1-(normon-2-yl) ketone The above ketone (18.3mg, 0.03mmol) and hydrochloric acid (0.4M) (1.5ml, 0.5mmol) in THF (7.5ml) were stirred at room temperature for 2mins. Saturated sodium hydrogen carbonate solution (3.75ml) was then added. Extraction with ethyl acetate, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 0-10% methanol in dichloromethane as eluent gave the title compound (ll.Omg, 92%) as a white foam; δ R (CD 3 OD) 0.93 (3H, d, J 7.1Hz, 17-H 3 ) , 1.19 (3H, d, J 6.4Hz, 14-H 3 ) , 1.35-1.45 (IH, m, 12-H) , 1.64-1.74 (2H, m, 9-H 2 ) , 1.91-2.01 (IH, m, 8-H) , 2.30 (3H, s, 15-H 3 ) , 2.35 (IH, dd, J 14.3 and 9.6Hz, 4-H) , 2.70 (IH, dd, J 7.6 and 2.2Hz, 4-H) , 2.80 (2H, m, 10 and 11-H) , 3.40 (IH, dd, J 12.1 and 3.1Hz, 6-H) , 3.60 (IH, d, J 11.2Hz, 16-H), 3.73-3.95 (4H, m, 5,7,13 and 16-H) , 6.83 (IH, s, 2-H), 7.84 (IH, d, J 1.8Hz, 4'-H), 8.60 (IH, d, J 1.7Hz, 3'-H) . Example 26 Ϊ2- (Hvdroxymethyl)thien-5-yll-1-(normon-2-yl) ketone 5 Bromine (0.51ml, lOmmol) was added dropwise to 2-thiophene methanol (1.14g, lOmmol) in acetic acid (30ml) . After stirring for 30mins. with efficient cooling, water (30ml) was added. Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and puri- 10 fication by flash chromatography using ethyl acetate/hexane (10-30%) as eluent gave 2-bromo-5-hydroxy-methylthiophene (0.547g, 2.8mmol, 28%) as a brown oil; δ R (CDCI3) 1.70 (IH, s, OH), 4.75 (2H, s, CH 2 ), 6.76 (IH, d, J 3.8Hz, 4'-H), 6.90 (IH, d, J 3.8Hz, 3'-H). This was taken up in diethyl ether 15 (10ml) and treated with triethylamine (0.8ml, 5.6mmol) and chlorotrimethylsilane (0.5ml, 4.2mmol). After lOmins. a catalytic amount of 4-N,N-dimethylaminopyridine was added. After 45mins. at room temperature the reaction was diluted with diethyl ether, filtered and the filtrate evaporated. 20 The residue was taken up in hexane and refiltered. Evaporation of the filtrate gave the required protected alcohol (0.63g, 2.37mmol, 85%) as a brown oil; l> max (CHCI3) 2960, 2937, 2865, 1607, 1460, 1450, 1382, 1258, 1175, 1072, 873, 851cm "1 . n-Butyllithium (1.6M in hexane) (1.5ml, 252.37mmol) was added dropwise to this material in THF (6.5ml) whilst maintaining the temperature below -65°C. After 5mins. at -70°C, N-methoxy-N-methyl-6,7,13-O-tris (trimethylsilyl)- monamide 0.95g, 1.58mmol) in THF (8ml) was added dropwise, maintain g the temperature below -65°C. After 1.5h at -70°C 30 acetic acid (0.21g) was added, followed by water (25ml) . Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and partial purification by flash chromatography using ethyl acetate/hexane (10-30%) as eluent gave tetra-trimethylsilyl-protected ketone as a 35 brown oil (0.277g, 0.38mmol, 16%) . The above impure material and hydrochloric acid (0.4M) (4.75ml, 1.9mmol) in THF (24ml) were stirred at room temperature for 2mins. Saturated sodium hydrogen carbonate solution (12ml) was added. Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 0-10% methanol in dichloromethane as 5 eluent gave the title compound (97.6mg, 58%) as a white foam; υ maχ (KBr) 3421, 2969, 2877, 1639, 1602, 1257, 1049cm "1 ; ^ ax (EtOH) 306.5nm (^ 16,691); δ R (CD3OD) 0.94 (3H, d, J 7.0Hz, 17-H 3 ), 1.20 (3H, d, J 6.4Hz, I4-H3) , 1.35- 1.45 (IH, , 12-H) , 1.64-1.73 (2H, m, 9-H 2 ) , 1.90-1.98 (IH, 10 m, 8-H), 2.22 (3H, s, 15-H 3 ) , 2.31 (IH, dd, J 14.4 and 9.6Hz, 4-H) , 2.67-2.84 (3H, m, 4,10 and 11-H) , 3.39 (IH, dd, J 9.0 and 3.1Hz, 6-H) , 3.60 (IH, d, J 10.7Hz, 16-H) , 3.74- 3.94 (4H, m, 5,7,13 and 16-H) , 6.82 (IH, s, 2-H) , 7.06 (IH, d, J 3.8Hz, 3'-H), 7.72 (IH, d, J 3.8Hz, 4'-H); δ c (CD3OD) , 1512.5 (C-17), 20.5 (C-15) , 20.6 (C-14), 33.2 (C-9), 42.0 (C-8), 44.0 (C-12), 44.6 (C-4), 57.1 (C-10) , 60.6 (C-CH 2 ) , 61.5 (C-ll), 66.7 (C-16) , 70.2 (C-6), 71.0 (C-7) , 71.9 (C-13), 76.6 (C-5), 122.0 (C-2), 126.7 (C-3' or 4'), 133.4 (C-3' or 4'), 147.0 (C-2' or 5'), 158.3 (C-2' or 5'), 159.7 0 (C-3), 185.7 (C-1); m/z. (E.I.) 441 (M + , 16%), 141 (100%); (Found: M + , 440.1841. C 22 H 32 0 7 S requires M, 440.1869). Example 27 5 (2-Formylthien-5-yl)-1- (normon-2-yl) ketone [2-(Hydroxymethyl)thien-5-yl]-1-(6,7,13-O-tristrimethyl- silylnormon-2-yl) ketone was obtained as one of the major products (23%) from the reaction of N-methoxy-N-methyl- 0 6,7,13-O-tris(trimethylsilyl)monamide and trimethylsilyl- protected 2-bromo-5-methylhydroxythiophene (see Example 26) . Manganese dioxide (1.40g, 3 weight equivalents) and THF (40ml) were added to this impure material (1.02g, approx. lmmol) and the reaction mixture stirred at room temperature for 2.75h. The solids were removed by filtration and washed with THF. The filtrates were combined and evaporated to dryness under reduced pressure. Partial purification by flash chromatography using ethyl 5 acetate/hexane (0-30%) as eluent gave (2-formyl thien-5-yl)- 1- (6,7,13-0-tris-trimethylsilylnormon-2-yl) ketone (93.8mg, 14%) as a colourless foam. The above impure ketone (46.6mg, 0.071mmol) and hydrochloric acid (0.4M) (3ml, 1.2mmol) in THF (15ml) were stirred at room temperature for 2mins. 10 Saturated sodium hydrogen carbonate solution (7.5ml) was added. Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 0-10% methanol in dichloromethane as eluent gave the title compound (200mg, 15 64%) as a colourless foam; υ maχ (KBr) 3446, 2969, 2924, 1673, 1645, 1605, 1245, 1207, 1050cm "1 ; λ maχ (CH 3 CN) 310nm (E JJJ 19,275); δ R (CD 3 OD) 0.94 (3H, d, J 7.1Hz, 17-H 3 ) , 1.20 (3H, d, J 6.4Hz, 14-H 3 ), 1.31-1.47 (IH, m, 12-H) , 1.65-1.75 (2H, m, 9-H 2 ), 1.90-2.04 (IH, m, 8-H) , 2.20 (3-hemiacetal-H, 0 s, 15-H 3 ), 2.28 (3-aldehyde-H, s, 15-H 3 ) , 2.31-2.43 (IH, dd, J 14.3 and 9.6Hz, 4-H) , 2.64-2.71 (IH, dd, J 7.6 and 2.2Hz, 4-H) , 2.75-2.84 (2H, m, 10 and 11-H) , 3.41 (IH, dd, J 9.0 and 3.1Hz, 6-H) , 3.62 (IH, d, J 11.6Hz, 16-H) , 3.73-3.92 (4H, , 5,7,13 and 16-H) , 5.71 [1-hemiacetal-H, s, 5 CH(OD) (OCD 3 ) ], 6.84 (1-hemiacetal-H, s, 2-H) , 6.90 (1- aldehyde-H, s, 2-H) , 17.13 (1-hemiacetal-H, d, J 3.9Hz, 3'-H), 7.70 (1-hemiacetal-H, d, J 3.9Hz, 4'-H), 7.90 (2- aldehyde-H, m, 3' and 4'-H), 9.94 (1-aldehyde-H, s, CHO) ; m/z. (E.I.) 438 (M + , 0.5%), 139 (100%); (Found: M + , 438.1706. 0 C 22 H 30 O 7 S requires M, 438.1712). Example 28 f2- (Piperidin-l-yl)pyrimidin-5-yl1-l-(normon-2-yl) ketone a) f2- (Piperidin-1-yl)-pyrimidin-5-yll-1-(6,7,13-0- tristrimethylsilylnormon-2-yl) ketone n-Butyllithium (1.6M in hexane) (3.47ml, 5.53mmol) was added dropwise to 5-bromo-2-(ρiperidin-l-yl)pyrimidine (1.34g, 5.53mmol) in THF (80ml) maintaining the temperature below -85°C. After lh at -85°C cerium trichloride (1.36g, 5.53mmol) was added. After lh at -85°C N-methoxy-N-methyl- 6,7,13-O-tris (trimethylsilyl)monamide (3.60g, 6.00mmol) in THF (20ml) was added dropwise whilst maintaining the temperature below -85°C. After 3h at -85°C acetic acid (0.32ml) was added followed by water (200ml) . Extraction with ethyl acetate, drying (Na 2 S0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (6:1) as eluent gave the title compound (l.OOg, 48%) as a colourless oil; (all spectroscopic details were identical to those of Example 11a) . b) [2-(Piperidin-1-yl)-pyrimidin-5-yll-1- (normon-2-yl) ketone As for Example lib using the above ketone (0.99g) giving the title compound (0.51g, 74%) as a pale yellow foam; (all ~ spectroscopic data were identical to those of Example lib) . Example 29 (2-Dimethylaminopyrimidin-5-yl)-1-(normon-2-yl) ketone 5 a) (2-Dimethylaminopyrimidin-5-yl)-1- (normon-2-yl) ketone n-Butyllithium (1.6M in hexane) (2.81ml, 4.50mmol) was added dropwise to 5-bromo-2-dimethylaminopyrimidine (0.91g, 104.50mmol) in THF (30ml) at -85°C. After lh at -85°C cerium trichloride (1.68g, 4.50mmol) was added. After lh at -75°C N-methoxy-N-methyl-6,7,13-O-tris(trimethylsilyl)monamide (1.36g, 2.25mmol) in THF (10ml) was added dropwise at -85°C. After 3h at -85°C acetic acid (0.26ml) then water (50ml) 15 were added. Extraction with ethyl acetate, drying (Na S0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (4:1) as eluent gave the impure protected ketone (1.13g, 76%) as a colourless oil. This oil was dissolved in 0 THF (57ml) and hydrochloric acid (0.4N) (11.3ml) and the solution stirred at room temperature for 2mins. then saturated sodium hydrogen carbonate solution (12ml) was added. Extraction with ethyl acetate, drying (Na 2 S0 4 ) , evaporation to dryness under reduced pressure and 5 purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (0.56g, 74%) as a white foam; (all spectroscopic data were identical to those of Example 8b) Example 30 (2-Dimethylaminopyrid-5-yl)-1-(normon-2-yl) ketone a) (2-Dimethylaminopyrid-5-yl)-1-(6,7,13-O-tristri methyl-silyl(normon-2-yl) ketone n-Butyllithium (1.6M in hexane) (6.25ml, lO.OOmmol) was added dropwise to 5-bromo-2-dimethylaminopyrimidine (2.01g, lO.OOmmol) in THF (80ml) at -85°C. After lh at -85°C cerium trichloride (2.47g, lO.OOmmol) was added. After lh at -85°C N-methoxy-N-methyl-6,7,13-O-tris (trimethylsilyl)monamide (3.00g, 4.97mmol) in THF (20ml) was added dropwise at -85°C. After 3h at -85°C acetic acid (0.57ml) then water (100ml) were added. Extraction with ethyl acetate, drying (Na 2 S0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (3:1) as eluent gave the title compound (2.69g, 66%) as a pale yellow oil; (all spectroscopic data were identical to those of Example 12a) . b) (2-Dimethylaminopyrid-5-yl)-1-(normon-2-yl) ketone The above ketone (2.69g, 3.30mmol) in THF (190ml) was treated with hydrochloric acid (0.4N) (37.5ml) at room temperature for 2mins. Saturated sodium hydrogen carbonate solution (40ml) was added and the solution extracted with ethyl acetic. Drying (Na 2 S0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (1.65g, 91%) as a pale yellow foam; (all spectroscopic data were identical to those of Example 12b) . Example 31 (Pyrrol-3-yl)-1-(normon-2-yl) ketone 5 a) (l-Triisopropylsilylpyrrol-3-yl)-1-(6,7,13-0- tristrimethylsilylnormon-2-yl) ketone t-Butyllithium (1.7M in pentane) (6.57ml, 10.52mmol) was added dropwise to 3-bromo-l-triisopropylsilylpyrrole (1.54g, ιo 5.26mmol) in THF (25ml) at -78°C. After lh at -78°C N-methoxy-N-methyl-6,17,13-O-tris(trimethylsilyl)monamide (1.80g, 3.00mmol) in THF (10ml) was added dropwise at -75°C. After 3h at -75°C acetic acid (0.36ml) then water (60ml) were added. Extraction with ethyl acetate, drying (MgS0 4 ), 15 evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate (8:1) as eluent gave the title compound (1.42g, 62%) as a colourless oil; δ R (CD 3 OD) 0.10-0.18 (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.1Hz, 17-H 3 ) , 1.10 [18H, m, 203 x CH(CH 3 ) 2 ], 1.20 (3H, d, J 6.3Hz, 14-H 3 ) , 1.37-1.70 [6H, m, 12-H, 9-H 2 and 3 x CH(CH 3 ) 2 ], 1.75-1.90 (IH, m, 8-H) , 2.09 (IH, dd, J 14.6 and 9.2Hz, 4-H) , 2.23 (3H, s, 15-H 3 ) , 2.59 (IH, d, J 14.6Hz, 4-H) , 2.63-2.71 (2H, , 10 and 11-H) , 3.41 (IH, dd, J 8.9 and 2.4Hz, 6-H) , 3.54 (IH, d, J 11.3Hz, 2516-H), 3.80-3.94 (4H, m, 5,7,13 and 16-H) , 6.59 (IH, s, 2-H) , 6.70-6.75 (2H, m, 2 x pyrrole-H) , 7.37-7.40 (IH, m, pyrrole-H) ; m/z. (E.I.) 755 (M + , 5%), 73 (100%); (Found: M + , 765.4687. C 39 H 75 NOgSi 4 requires M, 765.4672). 30 (b) (Pyrrol-3-yl)-1- (normon-2-yl) ketone The above ketone (0.47g, 0.61mmol) in THF (19ml) was treated with hydrochloric acid (0.4N) (3.70ml) at room temperature for 2mins. Saturated sodium hydrogen carbonate solution was 35 added, the solution extracted with ethyl acetate, the combined organic fractions dried (MgS0 4 ) and evaporated to dryness under reduced pressure to give the crude N-protected pyrrol-3-yl ketone. THF (10ml) and tetrabutylammonium fluoride trihydrate (0.21g, 0.67mmol) were added and the solution stirred at room temperature for lOmins. Evaporation to dryness under reduced pressure and purification by flash chromatography using 10% methanol in dichloromethane as eluent gave the title compound (0.22g, 92%) as a white foam; υ max (KBr) 3400 ' 2968 ' 2931/ 1643 ' 1595 ' 1501cm ""1; λ ax (EtOH) 293nm (shoulder) (ε m 7,630) and 259.5 ε^ 12,597); δ R (CDC1 3 ) 0.94 (3H, d, J 7.0Hz, 17-H 3 ) , 1.22 (3H, d, J 6.3Hz, I4-H3), 1.33-1.50 (IH, m, 12-H) , 1.65-1.78 (2H, m, 9-H 2 ) , 1.93-2.06 (IH, m, 8-H) , 2.21 (3H, s, 15-H 3 ) , 2.31 (IH, dd, J 14.6 and 9.3Hz, 4-H) , 2.67-2.85 (3H, m, 4,10 and 11-H) , 3.41 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.60 (IH, d, J 11.4Hz, 16-H) , 3.75-3.94 (4H, m, 5,7,13 and 16-H) , 6.62-6.65 (2H, m, 2-H and pyrrole-H) , 6.72-6.78 (IH, m, pyrrole-H), 7.44-7.48 (IH, m, pyrrole-H), 10.65 (IH, br.s, N-H) ; δ c (CDCI3/CD3OD) 12.5 (C-17), 19.8 (C-15) , 20.5 (C-14), 31.6 (C-9), 39.7 (C-8), 42.6 (C-12), 42.8 (C-4), 55.8 (C-10) , 60.9 (C-ll) , 65.3 (C-16), 68.5 (C-6), 70.3 (C-7) , 70.9 (C-13), 75.1 (C-5), 108.4 (C-4'), 119.6 (C-2' or 5' ) , 123.9 (C-2), 124.2 (C-2' or 5'), 127.2 (C-3'), 153.6 (C-3), 188.2 (C-1); m/z. (E.I.) 393 (M + , 5%), 94 (100%); (Found: M + , 393.2166. C 21 H 31 NOg requires M, 393.2151) . Example 32 5-Bromo-(thien-2-yl)-1-(normon-2-yl)ketone a) 5-Bromo- (thien-2-yl)-1- (6,7,13-O-tris-trimethyl- silylnormon-2-yl)ketone n-Butyllithium (1.6M in hexane) (5.00ml, δ.OOmmol) was added dropwise to 2-bromothiophene (1.22g, 7.50mmol) in THF (20ml) whilst maintaining the temperature below -65°C. After 15 mins. at -70°C N-methoxy-N-methyl-6,7,13-0- tris(trimethylsilyl) onamide (3.00g, 5.00mmol) in THF (25ml) was added dropwise maintaining the temperature below -65°C. 5 After 30 mins. at 70°C, acetic acid (0.70g) was added followed by water (100ml) . Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using diethyl ether in hexane (0-20%) as eluent gave the title 10 compound (O.llg, 3%) as the minor product (white foam) . [See example 21 for major product]; δ R (CDCI3) 0.06-0.--./ (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.1Hz, 17-H 3 ) , 1.20 (3H, d, J 6.3Hz, I4-H3), 1.34-1.45 (IH, m, 12-H) , 1.60 (2H, br.s, 9-H 2 ), 1.75-1.85 (IH, m, 8-H) , 2.10 (IH, dd, J 15.4 and 1511.2Hz, 4-H), 2.28 (3H, s, 15-H 3 ) , 2.58-2.75 (3H, m, 10,11 and 4-H) , 3.39 (IH, dd, J 9.0 and 2.4Hz, 6-H) , 3.56 (IH, d, J 11.4Hz, 16-H), 3.77-3.95 (4H, m, 5,17,13 and 16-H), 6.63 (IH, s, 2-H) , 7.06 (IH, d, J 4.0Hz, 4'-H), 7.42 (IH, d, J 4.1Hz, 3'-H). 0 b) 5-Bromo-(thien-2-yl)-1-(normon-2-yl)ketone The above ketone (O.llg, 0.16mmol) and hydrochloric acid (0.4M) (3.0ml, 1.2 x 10 "3 mol) in THF (15ml) were stirred at 5 room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (7.5ml) was then added. Extraction with diethyl ether, drying (MgS0 4 ), evaporation to dryness under reduced pressure and purification by flash chromatography using methanol in dichloromethane (0-6%) as eluent gave the 0 title compound (0.05g, 58%) as a white foam; ^ ax (EtOH) 308nm (^ 26,220); δ R (CD3OD) 0.95 (3H, d, J 7.1Hz, 17-H 3 ) , 1.20 (3H, d, J 6.4Hz, 14-H 3 ) , 1.35-1.45 (IH, m, 12-H) , 1.70 (2H, br.s, 9-H 2 ), 1.90-2.02 (IH, m, 8-H) , 2.25 (3H, s, 15-H 3 ), 2.33 (IH, dd, J 14.3 and 9.6Hz, 4-H) , 2.70 (IH, dd, 5 J 7.5 and 2.1Hz, 4-H) , 2.75-2.85 (2H, m, 10 and 11-H) , 3.38 (IH, dd, J 9.1 and 3.0Hz, 6-H) , 3.60 (IH, d, J 11.5Hz, 16-H), 3.76-3.93 (3H, m, 5,7,13 and 16-H) , 6.78 (IH, s, 2-H), 7.21 (IH, d, J 4.0Hz, 4'-H), 7.61 (IH, d, J 4.1Hz, 3'-H); m/z. (E.I.) 489 (MH + , 3%), 111 (100%); (Found: M + , 488.0825. C 1 H 29 0gSBr requires M, 488.0868). 5 Example 33 12-(Methylsulphinyl)thiazol-5-yll-1-(normon-2-yl) etone ιo Saturated aqueous sodium hydrogen carbonate solution (1.40ml) was added to [2-(methylmercapto)thiazol-5-yl]-l- (normon-2-yl) ketone (0.05g, 0.lOmmol) in dichloromethane (2.75ml) at room temperature. After cooling to 0°C, m- chloroperoxybenzoic acid (0.03g, 0.15mmol) was added. After 152.5h at 0°C, dichloromethane (20ml) was added. The aqueous layer was evaporated to dryness under reduced pressure and triturated exhaustively with ethyl acetate and diethyl ether. Evaporation to dryness under reduced pressure of the combined organic layers and purification by flash 20 chromatography using methanol in dichloromethane (0-8%) as eluent, gave the title compound (0.02g, 31%) ' ; ^ ax (EtOH) 298nm (^ 23,440); δ R (CD 3 OD) 0.95 (3H, d, J 7.1Hz, 17-H 3 ) , 1.20 (3H, d, J 6.5Hz, 14-H 3 ) , 1.35-1.46 (IH, m, 12-H) , 1.67- 1.75 (2H, br.s, 9-H 2 ) , 1.90-2.02 (IH, , 8-H) , 2.29 (3H, s, 2515-H 3 ), 2.39 (IH, dd, J 14.2 and 9.6Hz, 4-H) , 2.70 (IH, d, J 7.6Hz, 4-H) , 2.76-2.84 (2H, m, 10 and 11-H) , 3.06 (3H, s, SOCH3), 3.40 (IH, dd, J 8.9 and 3.0Hz, 6-H) , 3.60 (IH, d, J 11.5Hz, 16-H), 3.72-3.92 (4H, m, 5,7,13 and 16-H) , 6.85 (IH, s, 2-H) , 8.57 (IH, s, 4'-H); m/z. (D.C.I.) 474 (MH + , 2%), 91 30 (100%) . Example 34 f5-(Dimethylaminoiminomethyl)thien-2-yll-1-(normon-2-yl)- ketone 5 a) [5- (Dimethylaminoiminomethyl)thien-2-yl]-l-(6,7, 13- O-tris-trimethylsilylnormon-2-yl)ketone 1, 1,N,N-Dimethylhydrazine (0.42g, 7.00mmol) was added to 5- 10 bromo 2-thiophene carboxaldehyde (0.88g, 5.00mmol) in ethanol (25ml) at room temperature. After 2h and evaporation to dryness under reduced pressure, the reaction mixture was purified by flash chromatography using diethyl ether in hexane (5-20%) as eluent to give 2-bromo-5-dimethyl- 15 aminoi inomethyl thiophene (0.67g, 58%). n-Butyllithium (1.6M in hexane) (1.0ml, 1.50mmol) was added dropwise to 2- bromo-5-dimethylaminoiminomethyl thiophene (0.37g, 1.60mmol) in THF (5ml) whilst maintaining the temperature below -85°C. After 10 mins. at -90°C N-methoxy-N-methyl-6,7,13-0- 20 tris(trimethylsilyl)monamide (0.6g, l.OOmmol) in THF (5ml) was added dropwise whilst maintaining the temperature below -85°C. After 1.75h, allowing the temperature to increase to -65°C, acetic acid (0.13g) was added, followed by water (15ml). Extraction with diethyl ether, drying (MgS0 4 ), 25 evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate in hexane (10-30%) as eluent gave the title compound (0.13g, 18%) as a colourless oil; δ R (CDC1 3 ) 0.09-0.18 (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.1Hz, 17-H 3 ) , 1.20 (3H, d, J 6.3Hz, 3014-H 3 ), 1.30-1.42 (IH, m, 12-H) , 1.56 (2H, br.s, 9-H 2 ) , 1.78-1.88 (IH, m, 8-H) , 2.13 (IH, dd, J 14.6 and 10.5Hz, 4-H), 2.28 (3H, s, 15-H 3 ) , 2.59-2.72 (3H, m, 10,11 and 4-H) , 3.04 [6H, s, N(CH 3 ) 2 ], 3.40 (IH, dd, J 8.9 and 2.3Hz, 6-H) , 3.55 (IH, d, J 11.4Hz, 16-H) , 3.78-3.95 (4H, m, 5,7,13 and 3516-H), 6.70 (IH, s, 2-H) , 7.03 (IH, d, J 3.9Hz, 3' or 4'-H), 7.57 (2H, d, J 3.9Hz, 3' or 4'-H and CH=N) . b) r5- (Dimethylaminoiminomethyl)thien-2-yll-1- (normon- 2-yl)ketone 5 The above ketone (0.13g, O.lδmmol) and hydrochloric acid (0.4M) (3.0ml, 1.2 x 10 "3 mol) in THF (15ml) were stirred at room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (7.5ml) was then added. Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to drynes under ιo reduced pressure and purification by flash chromatography using methanol in dichloromethane (0-8%) as eluent gave the title compound (73.4mg, 85%) as a yellow foam; υ max (KBr) 3427, 2965, 2924, 2327, 1637, 1598, 1448, 1257, 1050cm "1 ; 20,871); δ R (CD3OD) 0.93 (3H, d, J 157.1Hz, I7-H3), 1.20 (3H, d, J 6.4Hz, 14-H 3 ) , 1.35-1.44 (IH, m, 12-H) , 1.68-1.75 (3H, br.s, 9-H 2 ) , 1.94-2.02 (IH, m, 8-H) , 2.24 (3H, s, 15-H 3 ) , 2.31 (IH, dd, J 14.5 and 9.5Hz, 4-H) , 2.69-2.84 (3H, m, 10,11 and 4-H) , 3.00 [6H, s, N(CH 3 ) 2 ], 3.41 (IH, dd, J 8.8 and 3.2Hz, 6-H) , 3.60 (IH, d, 0 J 10.8Hz, 16-H), 3.74-3.93 (4H, m, 5,7,13 and 16-H) , 6.81 (IH, s, 2-H), 7.02 (IH, D, J 4.1Hz, 3' or 4'-H), 7.36 (IH, s, CH=N), 7.66 (IH, D, J 4.0Hz, 3' or 4'-H); m/z. (E.I.) 480 (M + , 20%), 181 (100%); (Found: M + , 480.2265. C 24 H 3 gN 2 OgS requires M, 480.2294). 5 Example 35 2-Bromo-(pyrid-5-yl)-1-(normon-2-yl)ketone 0 a) 2-Bromo-(pyrid-5-yl)-1-(6,7,13-O-tris-trimethyl- silylnormon-2-yl)ketone n-Butyllithium (1.6M in hexane) (3.75ml, 6.00mmol) was added dropwise to 2,5 dibromopyridine (1.42g, 6.0mmol) in THF (16ml) whilst maintaining the temperature below -85°C. After 10 mins. at -90°C N-methoxy-N-methyl-6,7,13-0- tris (trimethylsilyl) onamide (1.82g, 3.00mmol) in THF (20ml) was added dropwise maintaining the temperature below -85°C. 5 After 30 mins. allowing the temperature to increase to -70°C, acetic acid (0.56g) was added, followed by water (60ml). Extraction with dietf/l ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using ethyl acetate in ιo hexane (10-30%) as eluent gave the title compound (0.92g, 44%) as a white foam; δ R (CDCI3) 0.09-0.17 (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.0Hz, 17-H 3 ) , 1.20 (3H, d, J 6.3Hz, 14-H 3 ), 1.30-1.43 (IH, m, 12-H) , 1.58 (2H, br.s, 9-H 2 ) , 1.76-1.86 (IH, m, 8-H) , 2.13 (IH, dd, J 14.7 and 10.6Hz, 154-H), 2.23 (3H, s, 15-H 3 ) , 2.60-2.72 (3H, m, 4,10 and 11-H) , 3.39 (IH, dd, J 9.0 and 2.4Hz, 6-H) , 3.57 (IH, d, J 11.3Hz, 16-H), 3.76-3.95 (4H, m, 5,7,13 and 16-H), 6.70 (IH, s, 2-H) , 7.57 (IH, d, J 8.3Hz, 3'-H), 8.07 (IH, dd, J 8.3 and 2.5Hz, 4'-H), 8.90 (IH, d, J 2.3Hz, 6'-H). 20 b) 2-Bromo- (pyrid-5-yl)-1-(normon-2-yl)ketone The above ketone (0.47g, 0.70mmol) and hydrochloric acid (0.4M) (6.0ml, 2.4 x 10~ 3 mol) in THf (30ml) were stirred at 25 room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (15ml) was then added. Extraction with diethyl ether, drying (MgS0 4 ), evaporation to dryness under reduced pressure and purification by flash chromatography using methanol in dichloromethane (0-8%) as eluent gave the 30 title compound (0.322g, 94%) as a white foam; υ maχ (KBr) 3433, 2924, 1657, 1607, 1087cm "1 ; λ maχ (EtOH) 280.5nm (B m 19,001); δ R (CD3OD) 0.93 (3H, d, J 7.1Hz, 17-H 3 ) , 1.21 (3H, d, J 6.4Hz, 14-H 3 ), 1.34-1.47 (IH, m, 12-H) , 1.66-1.76 (2H, , 9-H 2 ), 1.91-2.03 (IH, m, 8-H) , 2.24 (3H, s, 15-H 3 ) , 352.38 (IH, dd, J 14.2 and 9.6Hz, 4-H) , 2.70 (IH, dd, J 7.6 and 2.2Hz, 4-H) , 2.73-2.83 (2H, m, 10 and 11-H) , 3.40 (IH, dd, J 9.0 and 3.0Hz, 6-H) , 3.60 (IH, d, J 11.1Hz, 16-H) , 3.73-3.93 (4H, m, 5,7,13 and 16-H) , 6.88 (IH, s, 2-H) , 7.73 (IH, d, J 8.3Hz, 3'-H), 8.18 (IH, dd, J 8.3 and 2.5Hz, 4'-H), 8.86 (IH, d, J 2.3Hz, 6'-H); δ c (CD 3 OD) , 12.3 (C-17) , 20.3 (C-15), 20.5 (C-14), 33.0 (C-9), 41.9 (C-8) , 43.8 (C-12), 44.6 (C-4), 56.9 (C-10) , 61.2 (C-ll) , 66.4 (C-16) , 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.3 (C-5), 122.6 (C-2), 129.6 (C-3'), 135.2 (C-5'), 139.6 (C-4'), 146.6 (C-2'), 151.1 (C-6'), 162.1 (C-3), 190.0 (C-1); m/z. (E.I.) 484 (MH + , 22%), 43 (100%). Example 36 (Pyrid-4-yl)-1-(normon-2-yl)ketone a) (Pyrid-4-yl)-1-(6,7,13-O-tris-trimethylsilyl-normon- 2-yl) etone Sodium hydrogen carbonate was added to 4-bromopyridine hydrochloride (0.58g, 3.00mmol) in water (5ml) until pH >7. Extraction with diethyl ether, drying (MgS0 4 ) and evaporation to dryness under reduced pressure gave 4- bromopyridine (0.28g, 59%) as a colourless oil. This material (0.28g, 1.77mmol) in THF (2ml) was added dropwise to n-butyllithium (1.6M in hexane) (1.10ml, 1.76mmol) in THF (2ml) whilst maintaining the temperature below -65°C. After 15 mins. at -70°C N-methoxy-N-methyl-6,7,13-0- tris(trimethylsilyl)monamide (0.60g, l.OOmmol) in THF (3ml) was added dropwise maintaining the temperature below -65°C. After 45 mins. at -70°C acetic acid (0.14g) was added followed by water (20ml) . Extraction with diethyl ether, drying (MgS0 4 ) , evaporation to dryness under reduced pressure and purification by flash chromatography using diethyl ether in hexane (0-15%) as eluent gave the title compound (0.04g, 4%) as a colourless oil; (CDC1 3 ) 0.09-0.17 (27H, m, 9 x SiCH 3 ), 0.90 (3H, d, J 7.1Hz, 17-H 3 ) , 1.20 (3H, d, J 6.4Hz, 14-H 3 ), 1.37-1.47 (IH, , 12-H) , 1.70 (2H, br.s. 9-H 2 ), 1.92-2.02 (IH, m, 8-H) , 2.10 (IH, dd, J 14.3 and 9.5Hz, 4-H) , 2.28 (3H, s, 15-H 3 ) , 2.66 (IH, d, J 7.6Hz, 4-H), 2.73-2.81 (2H, m, 10 and 11-H) , 3.41 (IH, dd, J 9.0 and 3.1Hz, 6-H) , 3.59 (IH, d, J 11.6Hz, 16-H) , 3.75-3.95 5 (4H, m, 5,7,13 and 16-H) , 6.89 (IH, s, 2-H) , 7.85 (2H, dd, J 4.6 and 1.6Hz, 2' and 6'-H), 8.72 (2H, dd, J 4.5 and 1.5Hz, 3' and 5'-H) . b) (Pyrid-4-yl)-1- (normon-2-yl)ketone 10 The above ketone (0.04g, 0.07mmol) and hydrochloric acid (0.4M) (3.0ml, 1.2 x 10 "3 mol) in THF (15ml) were stirred at room temperature for 2 mins. Saturated sodium hydrogen carbonate solution (7.5ml) was then added. Extraction with 15 diethyl ether, drying (MgS0 ) evaporation to dryness under reduced pressure and purification by flash chromatography using methanol in dichloromethane (0-6%) as eluent gave the title compound (0.02g, 59%) as a white foam; υ maχ (KBr) 3415, 2970, 2887, 1662, 1610, 1412, 1243, 1056cm "1 ; ^ ax 20 (EtOH) 272nm (^ 22,752); δ R (CD 3 OD) 0.93 (3H, d, J 7.1Hz, 17-H 3 ), 1.20 (3H, d, J 6.4Hz, 14-H 3 ) , 1.39-1.48 (IH, m, 12-H), 1.68-1.74 (2H, m, 9-H 2 ) , 1.96-2.03 (IH, m, 8-H) , 2.29 (3H, s, 15-H 3 ), 2.40 (IH, dd, J 14.3 and 9.5Hz, 4-H) , 2.71 (IH, dd, J 7.6 and 2.2Hz, 4-H) , 2.77 (2H, m, 10 and 11-H) , 253.41 (IH, dd, J 9.0 and 3.1Hz, 6-H) , 3.60 (IH, d, J 11.6Hz, 16-H), 3.76-3.95 (4H, m, 5,7,13 and 16-H) , 6.93 (IH, s, 2-H) , 7.85 (2H, dd, J 4.6 and 1.6Hz, 2' and 6'-H), 8.73 (2H, dd, J 4.6 and 1.6Hz, 3' and 5'-H); m/z. (E.I.) 405 (M + , 17%), 106 (100%); (Found: M + , 405.2150. C 22 H3 1 NOg requires M, 30405.2151. Example 37 f2-(Piperidinyl)pyrimidin-5-yll-(l-norisomon-2-yl) ketone 5 a) [ (2-Piperidinyl)pyrimidin-5-vn-l-(6,7,13-O-tris- trimethylsilyl-norisomon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.09ml, 1.74mmol) was added dropwise to 2-bromo-5-ρiperidinyl pyrimidine (0.42g, 10 1.74mmol) in THF (10ml) at -70°C. After 45 mins. at -70°C cerium (III) chloride (0.43g, 1.74mmol) was added at -70°C. After 1 hour at -70°C 6,7,13-O-tris (trimethylsilyl)iso- monaldehyde (0.63g, 1.16mmol) in THF (5ml) was added dropwise maintaining the temperature below -65°C. After 152 hours at -70°C acetic acid (0.1ml) and water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) and evaporating to dryness under reduced pressure gave the impure diastereomeric alcohols. The alcohols and manganese (IV) oxide (1.64g, 18.9mmol) in benzene (40ml) 20 were heated to reflux under Dean and Stark conditions for 3 hours. The solids were removed by filtration and washed with dioxane and dichloromethane. Evaporation of the filtrates to dryness under reduced pressure and purification by flash chromatography using hexane/ethyl acetate as eluent 25 gave the title compound (0.52g, 63%) as a yellow oil; δ R (CD 3 OD) 0.05-0.16 (27H, m, 9 x SiCH 3 ) , 0.90 (3H, d, J 7.0Hz, 17-H 3 ), 1.19 (3H, d, J 6.3Hz, 14-H 3 ) ' 1-15-1.40 (IH, m, 12-H) , 1.45-1.90 (9H, m, 9-H 2 , 8-H and 6 x piperidinyl-H) , 2.05 (3H, s, 15-H3), 2.69-2.74 (2H, m, 10-H, 11-H) , 2.76- 302.89 (2H, m, 4-H 2 ) , 3.45-3.51 (2H, m, 6-H, 16-H) , 3.81-3.93 (8H, m, 5-H, 7-H, 13-H, 16-H and 4 x piperidinyl-H), 6.68 (IH, s, 2-H), 8.82 (2H, s,-3'-H, 5'-H); m/z. (E.I.) 705. (M + , 7%), 73 (100%); [Found: M + , 705.4010. C 35 Hg 3 3 0gSi3 requires M, 705.4025) . 35 b) T (2-Piperidinyl)pyrimidin-5-vn-1- (norisomon-2-yl) ketone Hydrochloric acid (0.4N) (4.2ml) was added to the above 5 ketone (0.52g, 0.14mmol) in THF (22ml) at room temperature. After 2 minutes at room temperature saturated sodium hydrogencarbonate solution (10ml) was added and the solution was then extracted with ethyl acetate. Drying (MgS0 4 ) , evaporating to dryness under reduced pressure and ιo recrystallisation from methanol gave the title compound (0.27g, 75%) as white micro-needles (m.p.155-6%) ; υ maχ (KBr) 3471, 2969, 2921, 2866, 1655, 1591, 1527, 1250, 1215, 1017, 798, 748cm "1 ; λ maχ (EtOH) 327.5nm (^ 24,607); δ R (CDCI3) 0.95 (3H, d, J 7.0Hz, 17-H 3 ) , 1.21 (2H, d, J 6.3Hz, I4-H3) , 151.24-1.33 (IH, m, 12-H) , 1.54-1.82 (8H, m, 6 x piperidinyl-H and 9-H 2 ), 2.00-2.06 (IH, m, 8-H) , 2.12 (3H, s, 15-H 3 ) , 2.40 (IH, br.s, 13-OH), 2.66 (IH, dd, J 8.1 and 2.2, 11-H) , 2.69- 2.83 (3H, m, 10-H, 4-H and 7-OH) , 3.03 (IH, dd, J 13.5 and 4.4Hz, 4-H) , 3.50 (IH, ddd, J 3.1, 2.7 and 9.7Hz, 6-H) , 3.64 0 (IH, d, J 11.5Hz, 16-H), 3.72-4.02 (8H, m, 5-H, 7-H, 13-H, 16-H and 4 x piperidinyl-H), 5.85 (IH, d, J 2.7Hz, 6-OH) , 6.71 (IH, s, 2-H), 8.83 (2H, s, 3' and 5'-H); δ c (CDCI3) 12.7 (C-17), 20.7 (C-14), 24.7, 25.9, 27.7 (C-15) , 31.9 (C-9), 36.9 (C-4), 39.0 (C-8) , 42.9 (C-12) , 45.3, 56.0 5 (C-10), 61.4 (C-ll), 65.8 (C-16) , 67.6 (C-6), 70.3 (C-7) , 71.3 (C-13), 76.3 (C-5), 119.9, 122.2 (C-2), 158.7 (C-3), 159.7 (C-3'), 161.6, 188.6 (C-1); m/z. (E.I.) 489 (M + , 2%), 190 (100%); [Found: M + , 489.2832. C 2 H 39 N 3 0 4 requires M, 489.2839] . 0 Example 38 2-Dimethylaminopyrid-5-yl-l-(norisomon-2-yl) ketone 5 a) 2-Dimethylaminopyrid-5-yl-l-(6,7,13-O-tris- trimethylsilylnorisomon-2-yl) ketone n-Butyllithium (1.6M in hexane) (1.14ml, 1.82mmol) was added dropwise to 5-bromo-2-dimethylaminopyridine (0.37g, 101.82mmol) in THF (10ml) at -70°C. After 45 mins. at -70°C cerium (III) chloride (0.45g, 1.82mmol) was added at -70°C. After 1 hour at -70°C 6,7,13-O-tris (trimethylsilyl) iso- onaldehyde (0.50g, 0.92mmol) in THF (5ml) was added dropwise maintaining the temperature below -65°C. After 2 15 hours at -70°C acetic acid (0.07ml) and water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) evaporating to dryness gave the impure diastereomeric alcohols. The alcohols and manganese (IV) oxide (3.28g, 37.8mmol) in benzene (25ml) were heated to 0 reflux under Dean and Stark conditions for 1 hour. The solids were removed by filtration and washed with dioxane and dichloromethane. Evaporation of the filtrates to dryness under reduced pressure and purification by flash chromatography using ethyl acetate/hexane (1:3) gave the 5 title compound (0.26g, 43%) as a yellow oil; δ R (CD3OD) 0.10-0.15 (27H, m, 9 x SiCH 3 ) , 0.39 (3H, d, J 7.1Hz, 17-H 3 ) , 1.20 (3H, d, J 6.3Hz, 14-H 3 ) , 1.31-1.41 (IH, m, 12-H) , 1.52- 1.65 (2H, m, 9-H 2 ) , 1.80-1.95 (IH, m, 8-H) , 2.04 (3H, s, I5-H3), 2.63-2.67 (2H, m, 10-H, 11-H) , 2.76-2.85 (2H, m, 04-H) , 3.05-3.10 (IH, m, 4-H) , 3.18 [6H, s, N(CH 3 ) 2 ], 3.42- 3.51 (2H, m, 6-H, 16-H) , 3.77-3.95 (4H, m, 5-H, 7-H, 13-H, 16-H), 6.50 (IH, d, J 9.1Hz, 3'-H), 6.68 (IH, s, 2-H) , 8.05 (IH, dd, J 9.1 and 2.0Hz, 4'-H), 8.77 (IH, d, J 2.0Hz, 6'-H); m/z. (E.I.) 664 (M + , 1%), 175 (100%). 5 b) 2-Dimethylaminopyrid-5-yl-l-(norisomon-2-yl) ketone Hydrochloric acid (0.4N) (2.3ml) was added to the above ketone, (0.25g, 0.38mmol) in THF (12ml) at room temperature. 5 After 2 mins. at room temperature saturated sodium hydrogencarbonate solution (5ml) was added and the solution was then extracted with ethyl acetate. Drying (MgS0 4 ) , evaporating to dryness under reduced pressure and purification by flash chromatography using 9% methanol in 10 dichloromethane as eluent gave the title compound (0.122g, 72%) as a pale yellow foam; υ maχ (KBr) 3400, 2968, 2951, 1643, 1595, 1501, 1431, 1374, 1320, 1250, 1050, 811cm "1 ; λ maχ (EtOH) 343.5nm (^ 25,214); δ R (CDCI3) 0.95 (3H, d, J 7.0Hz, I7-H3), 1.21 (3H, d, J 6.2Hz, I4-H3) , 1.20-1.35 (IH, 15 m, 12-H), 1.54-1.66 (IH, m, 9-H) , 1.73-1.86 (IH, m, 9-H) , 1.98-2.06 (IH, , 8-H) , 2.12 (3H, d, J 0.6Hz, 15-H 3 ), 2.41 (IH, br.s, 13-OH), 2.63-2.73 (2H, m, 4-H and 11-H) , 2.79 (IH, ddd, J 6.3, 5.8 and 2.2Hz, 10-H) , 2.86 (IH, s, 7-OH) , 3.02 (IH, dd, J 4.6 and 13.4Hz, 4-H) , 3.19 [6H, s, N(CH 3 ) 2 ], 203.52 (IH, dd, J 3.1 and 9.7Hz, 6-H) , 3.64 (IH, d, J 11.5Hz, 16-H), 3.72-3.88 (2H, m, 13-H, 5-H) , 3.94 (IH, dd, J 2.4 and 11.5Hz, 16'-H), 3.95-4.05 (IH, m, 7-H) , 6.10 (IH, s, 6-OH) , 6.51 (IH, d, J 9.1Hz, 3'-H); 6.81 (IH, d, J 0.6Hz, 2-H) , 8.02 (IH, dd, J 9.1 and 2.3Hz, 4'-H), 8.79 (IH, d, J 2.3Hz, 256'-H); δ c (CDCI3) 12.8 (C-17) , 20.7 (C-14), 27.6 (C-15) , 31.9 (C-9), 36.9 (C-4), 38.2 [N(CH 3 ) 2 ], 39.0 (C-8) , 43.0 (C-12), 56.1 (C-10), 61.6 (C-ll) , 65.9 (C-16) , 67.4 (C-6), 70.4 (C-7), 71.4 (C-13), 76.3 (C-5), 105.3 (C-4'), 122.4 (C-2'), 123.1 (C-2), 137.5 (C-3'), 151.3 (C-6'), 157.0 30 (C-3), 160.7 (C-5'), 190.1 (C-1); m/z. (E.I.) 448 (M + , 3%) ; [Found: M + , 448.2571. C 24 H 3g N 2 0g requires M, 448.2573]. Example 39 Fur-3-yl-l-(norisomon-2-yl) ketone 53-Bromofuran (0.27g, 1.82mmol) in THF (2ml) was added dropwise to n-butyllithium (1.6M in hexane) (1.14g, 1.82mmol) at -70°C. After 60 mins. at -70°C 6,7,13-0- tris(trimethylsilyl) isomonaldehyde (0.50g, 0.92mmol) in THF (5ml) was added dropwise maintaining the temperature below 10 -65°C. After lh at -70°C acetic acid (0.07ml) and water (20ml) were added and the solution extracted with ethyl acetate. Drying (MgS0 4 ) and evaporating to dryness under reduced pressure gave the impure diastereomeric alcohols. The alcohols and manganese (IV) oxide (3.28g, 37.8mmol) in 15 benzene (30ml) were heated to reflux under Dean and Stark conditions for 2 hours. The solids were removed by filtration and washed with dioxane and dichloromethane. Evaporation of the filtrates to dryness under reduced pressure and purification by flash chromatography using 20 hexane/ethyl acetate (6:1) as eluent gave the crude protected title compound (O.lOg, 18%) as a yellow oil. Hydrochloric acid (0.4N) (1.0ml) was added to the above crude ketone in THF (5ml) at room temperature. After 2 mins. saturated sodium hydrogencarbonate solution (5ml) was added 25 and the solution extracted with ethyl acetate. Drying (MgS0 4 ) , evaporating to dryness under reduced pressure and purification by flash chromatography using 7% methanol in dichloromethane as eluent gave the title compound (0.030g, 18%) as a colourless foam; υ max (KBr) 3431, 2972, 2926, 301652, 1605, 1300, 1156, 1043, 1873, 804, 739cm "1 ; ^ ax (EtOH) 269.5nm (^ 9,565); δ R (CDCI3) 0.95 (3H, d, J 7.0Hz, 17-H 3 ), 1.21 (3H, d, J 6.3Hz, 14-H 3 ) , 1.23-1.38 (IH, m, 12-H) , 1.55-1.85 (2H, m, 9-H 2 ) , 1.95-2.10 (IH, m, 8-H) , 2.11 (3H, s, 15-H 3 ), 2.67 (IH, dd, JJ 2.1 and 8.1Hz, 11-H) , 2.76- 352.85 (3H, m, 4-H, 7-OH and 10-H) , 3.00 (IH, dd, J 4.5 and 13.5Hz, 4-H) , 3.48 (IH, dd, J 2.8 and 9.4Hz, 6-H) , 3.64 (IH, d, J 11.5Hz, 16-H), 3.72-3.88 (2H, m, 13-H, 5-H) , 3.93 (IH, dd, J 2.5 and 11.5Hz, 16'-H), 3.95-4.05 (IH, m, 7-H) , 5.42 (1H, br.s, 6-OH) , 6.58 (IH, s, 2-H) , 6.79 (IH, d, J 1.4Hz, furyl-H), 7.43-7.48 (IH, , furyl-H), 8.07 (IH, s, furyl-H); m/z. (E.I.) 394 (M + , 1%), 95 (100%); [Found: M + , 394.1994. C 21 H 30°7 requires M, 394.1992]. Biological Activity The Examples were tested for antibacterial activity against a range of bacterial strains important in human infections (H. influenzae Ql; 13. catarrhalis 1502; Strep. pyoqenes CN 10; Strep, pneumoniae PU7 and Steph. aureus Oxford) in a conventional microbiological assay, using serial dilutions in nutrient agar with 5% chocolate horse blood. The MICs were determined after incubation for 18h at 37° values in the range 0.06 to 32 μg ml A were observed.

Claims: Claims OH in which R 1 is hydrogen and R is -COR J or R x is -COR J and R is hydrogen, in which R J denotes a heteroaryl group, and 3 excluding the compounds in which R comprises a fur-2-yl, pyrid-2-yl or imidazol-2-yl ring. 2. A compound as claimed in claim 1 of the formula (la) OH in which R J is as defined n claim 1. 3. A compound as claimed in claim 1 of the formula (lb) in which R 3 is as defined in claim 1. 10 4. A compound as claimed in any one of claims 1 to 3 in which R 3 comprises a fur-3-yl, thienyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, benzimidazolyl, 15 oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thiatriazolyl, pyrid-3-yl, pyrid-4-yl, quinolinyl, isoquinolinyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl ring. 205. A compound as claimed in claim 4 in which R 3 comprises a thien-2-yl, thien-3-yl, fur-3-yl, pyrrol-3-yl, thiazol-5-yl, isothiazol-5-yl, pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl or quinolin-3-yl ring. 25 6. A compound as claimed in any one of claims 1 to 3 in which R J comprises a 5- or 6- membered heteroaryl ring 3 having a nitrogen or oxygen heteroatom, and in which R J is bonded to the ketone carbonyl group of -COR J by a ring carbon atom which is not adjacent to said ring heteroatom. 30 7. A compound as claimed in claim 6 in which the ring carbon atom is located β- to the ring heteroatom. 8. (Fur-3-yl)-l-(normon-2-yl) ketone. 9. (l-Methylpyrazol-4-yl)-l-(normon-2-yl) ketone. 5 10. (4-Bromo-l-methyltriazol-5-yl)-l-(normon-2-yi) ketone. 11. (2-Methoxypyrid-5-yl)-l-(normon-2-yl) ketone. 12. Pyrid-3-yl-l-(normon-2-yl) ketone. 10 13. (l-Methyltriazol-5-yl)-l-(normon-2-yl) ketone. 14. (2-Methoxypyrimidin-5-yl)-1-(normon-2-yl) ketone. 1515. (2-Dimethylaminopyrimidin-5-yl)-1-(normon-2-yl) ketone. 16. (2-Methylthiopyrid-5-yl)-1-(normon-2-yl) ketone. 20 17. (2-Methylsulphinylpyrid-5-yl)-1-(normon-2-yl) ketone. 18. [2-(Piperidin-1-yl)pyrimidin-5-yl]-1-(normon-2-yl) ketone. 2519. (2-Dimethylaminopyrid-5-yl)-1-(normon-2-yl) ketone. 20. (l-Proρylpyrazol-4-yl)-1-(normon-2-yl) ketone. 21. (2-Acetylfur-4-yl)-l-(normon-2-yl) ketone. 30 22. [2-(Morpholin-4-yl)-pyrimidin-5-yl]-1(normon-2-yl) ketone. 23. [2-(l-Methylpiperazin-4-yl)-pyrimidin-5-yl]-1-(normon- 2-yl) ketone. 24. [2-(5,7-Dimethoxyquinolin-3-yl) ]-1-(normon-2-yl) 5 ketone. 25. (l-Cyclohexylpyrazol-4-yl)-1-(normon-2-yl) ketone. 26. [2-(Piperidin-l-yl)pyridin-5-yl]-l-(normon-2-yl) 10 ketone. 27. (Thien-3-yl)-1-(normon-2-yl) ketone. 28. (Thien-2-yl)-1-(normon-2-yl) ketone. 15 29. [5-Methoxy- (thien-2-yl) ]-l-(normon-2-yl) ketone. 30. [2-(Methylmercapto)thiazol-5-yl)-1-(normon-2-yl) ketone. 20 31. [2-(Piperidin-1-yl)thiazol-5-yl]-1- (normon-2-yl) ketone. 32. (Isothiazol-5-yl)-1-(normon-2-yl) ketone. 25 33. [2-(Hydroxymethyl)thien-5-yl]-l-(normon-2-yl) ketone. 34. (2-Formylthien-5-yl)-1-(normon-2-yl) ketone. 3035. (Pyrrol-3-yl)-l-(normon-2-yl) ketone. 36. [5-Bromo-(thien-2-yl) ]-l-(normon-2-yl) ketone. 37. [2- (Methylsulphinyl) thiazol-5-yl] -1- (normon-2-yl) 35 ketone . 38. [5- (Dimethylaminoiminomethyl)thien-2-yl]-1- (normon-2- yl) ketone. 39. [2-Bromo (pyrid-5-yl) ]-l- (normon-2-yl) ketone. 5 ~ " 40. (Pyrid-4-yl)-1- (normon-2-yl) ketone. 41. [2- (Piperidinyl)pyrimidin-5-yl]-l- (norisomon-2-yl) ketone. 10 42. (2-Dimethylaminopyrid-5-yl) -1-(norisomon-2-yl) ketone. 43. (Fur-3-yl) -1- (norisomon-2-yl) ketone. 1544. A process for preparing a compound formula (I) as defined in claim 1 which process comprises: (i) treating an acid of formula (III) : in which Z 1 x , Z^ 2 and Z " J are the same or different and each is hydrogen or a hydroxyl protecting group, or an activated derivative thereof, 30 with an organometallic reagent; (ii) treating an allylic alcohol of formula (IX) : in which R 3 is as defined in claim 1 and, Z 1 , Z 2 and Z 3 are as hereinbefore defined, with an oxidising agent which converts allylic alcohols into α,β-unsaturated ketones, or (iii) treating a ketone of formula (XI) : in which Z 1 , Z 2 and Z 3 are as hereinbefore defined, with a terminal alkyne of the formula (XII) : HC≡C-R- (XII) 3 in which R J is as hereinbefore defined. to form an intermediate which is treated with tris (triphenylsilyloxy) vanadate and triphenylsilanol; and thereafter, and if necessary, removing any hydroxyl protecting groups. 45. A process for preparing a compound of formula (lb) as defined in claim 3 which process comprises isomerising a corresponding compound of formula (la) as defined in claim 2 and in which each or any of the hydroxyl groups thereof may be optionally protected with a hydroxyl protecting group, and thereafter and if necessary, removing any hydroxyl protecting groups, or vice versa. 46. A compound of formula (IX) as defined in claim 44 47. A pharmaceutical or veterinary composition which comprises a compound as defined in any one of claims 1 to 43 together with a pharmaceutically or veterinarily acceptable carrier or excipient. 48. A compound as defined in any one of claims 1 to 43 for use in therapy. 49. A compound as defined in any one of claims 1 to 43 for use in antibacerial therapy. 50. A compound for use in anti-mycoplasmal therapy of formula (I) : in which R 1 is hydrogen and R 2 is -COR 3 or R 1 is -COR 3 and R is hydrogen, in which R J is a heteroaryl group. 51. A compound as claimed in claim 50 for use in the therapy of mycoplasma fermentans induced infection. 52. A compound as claimed in claim 51 for use in anti- 5 mycoplasmal therapy of humans infected with mycoplasma fermentans and also infected with HIV. 53. The use of a compound as defined in any one of claims 1 to 43 for the manufacture of a medicament for 10 antibacterial therapy in human and non-human animals. 54. The use of a compound of formula (I) : OH 20 in which R 1 is hydrogen and R 2 is -COR 3 or R 1 is -COR 3 and R A is hydrogen, in which R J is a heteroaryl group, for the manufacture of a medicament for anti-mycoplasmal therapy of human and non-human animals. 2555. A method of treating a human or non-human animal which method comprises administering an antibacterial effective amount of a compound as defined in any one of claims 1 to 43 to a human or non-human animal in need of such therapy. 3056. A method of treating a human or non-human animal which method comprises administering an antimycoplasmal effective amount of a compound of formula (I) : OH in which R! is hydrogen and R 2 is -COR 3 or R 1 is -COR 3 and R 2 is hydrogen, in which R 3 is a heteroaryl group, 10 to a human or non-human animal in need thereof. 57. A method as claimed in claim 56 in which the infection is caused by Mycoplasma fermentans. 1558. A method as claimed in claim 57 in which the animal is a human animal who is further infected with HIV. 59. A compound of formula (I) substantially as hereinbefore defined with reference to any one of the 0 Examples. 60. A process for preparing a compound of formula (I) substantially as hereinbefore defined with reference to any one of the Examples. 5 61. A compound of formula (I) as defined in any one of claims 1 to 43 whenever produced by a process as defined in claim 44 or claim 45.

Inventors: HANNAN PETER CHARLES THOMAS, O'HANLON PETER JOHN, PEARSON NEIL DAVID, HANNAN, PETER, CHARLES, THOMAS, O'HANLON, PETER, JOHN, PEARSON, NEIL, DAVID
Applicants: BEECHAM GROUP PLC
Application year: 1991
Main classification: C07D417
IPC codes: A61K31, A61P31, C07D405, C07D407, C07D409, C07D413, C07D417