The invention relates to a process for the manufacture of carbapenem and carbapenam derivatives which are intermediates for antibiotic compounds, some of which are β-lactamase inhibitors and some of which are antibiotics in their own right.

The invention provides a process for the preparation of compounds of the formula

(I):

(i)

wherein R' is hydrogen or optionally substituted: C,. ₆ alkyl, C,. ₆ alkylthio or C,. ₆ alkoxy;

R ² is hydrogen, halogen or optionally substituted: C,. ₆ alkyl, C ₃ _ ₆ alkenyl, arylC,. ₃ alkyl, aryl, heteroarylC,. ₃ alkyl, heteroaryl, heterocyclyl, heterocyclylC ₁ . ₃ alkyl, C _V7 cycloalkyl, C ₃ . ₇ cycloalkylC,. ₃ alkyl, C ₅ . ₇ cycloalkyenyl, C ₅ . ₇ cycloalkenylC, ₃ alkyl. C,. ₆ alkoxy, C _| . ₆ alkylthio, arylthio, aryloxy, heteroaryloxy, heteroarylthio, C,. ₆ alkoxycarbonylamino, aryloxycarbonylamino, arylC^alkoxycarbonylamino, heteroaryloxycarbonylamino, heteroarylC,_ ₃ alkoxycarbonylamino, C,. ₆ alkanesulphonylamino, arylsulphonylamino, arylC|. ₃ alkylsulphonylamino, heteroarylC^alkylsulphonylamino or heteroarylsulphonylamino or R ² is of the formula R ⁶ CONH- wherein R ⁶ is an organic group; or

R ¹ and R ² together form an optionally substituted C ₃ . ₆ alkylene chain wherein one methylene group is optionally replaced by -N(R ⁿ )-, -O- or -S-, (C ₃ . ₆ alkylene chains wherein one methylene group is optionally replaced by -N(R")-, -O- or -S- are hereafter referred to as C ₃ . ₆ heteroalkylene), wherein R" is hydrogen, C,. ₆ alkanoyl, phenylC _M alkyl or C,. ₆ alkyl; or R' and R ² together form a group of the formula:

R ^a

wherein R ^a and R ^b are independently hydrogen or optionally substituted C.^alkyl, aryl or heteroaryl; or R ^a and R ^b , together with the carbon atom to which they are attached, form an optionally substituted C ₄ . ₇ cycloalkyl, C ₄ . ₇ cycloalkenyl or heterocyclyl ring, each optionally fused to a benzene or heteroaryl ring;

R ³ is hydrogen, cyano or halo or optionally substituted: C,. ₆ alkyl or of the formula -S(O) _n R ⁷ (n is 0, 1 or 2) wherein R ⁷ is C,. ₆ alkyl, arylC,. ₃ alkyl, aryl, C ₃ . ₆ alkenyl, arylprop-2-enyl, heteroarylC,. ₃ alkyl, heteroaryl or heteroarylprop-2-enyl or, when n is 2, R ⁷ is NR ⁸ R ⁹ wherein R ⁸ and R ⁹ are independently hydrogen, or optionally substituted: C,. ₆ alkyl, C _3.6 alkenyl, arylC^alkyl, arylprop-2-enyl, heteroarylC,. ₃ alkyl, heteroarylprop-2-enyl, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form an optionally substituted heteroaryl ring or R ³ is optionally substituted: C,. ₆ alkoxy, C ₃ . ₆ alkenyloxy, arylC,. ₃ alkoxy, heteroarylC,_ ₃ alkoxy, arylprop-2-enyloxy, heteroarylprop-2-enyloxy, aryloxy or heteroaryloxy or R ³ is of the formula -COR ¹⁰ wherein R'° is hydrogen or optionally substituted: C, _.6 alkyl, C _3.6 alkenyl, arylC,. ₃ alkyl, arylprop-2-enyl, heteroarylC,.,alkyl, heteroarylprop-2-enyl, aryl or heteroaryl or R ¹⁰ is of the formula NR ⁸ R ⁹ wherein R ⁸ and R ⁹ are as hereinabove defined, or R ³ is of the formula -CO ₂ R" wherein R" is hydrogen or optionally substituted: C, _.6 alkyl, C ₃ . ₆ alkenyl, arylC,. ₃ alkyl, arylprop-2-enyl, heteroarylC, _.3 alkyl, heteroarylprop-2-enyl, aryl or heteroaryl; R ⁴ is hydrogen, halo, cyano or optionally substituted: C,^alkyl, C ₃ . ₆ alkenyl, arylC,. ₃ alkyl, heteroarylC _| . ₃ alkyl, prop-2-enyl, heteroarylprop-2-enyl, aryl, heteroaryl, C ₅ . ₇ cycloalkenyl, C ₅ . ₇ cycloalkenylC,. ₃ alkyl, heterocyclyl. heterocyclylC,. ₃ alkyl, C ₃ . ₇ cycloalkyl, C ₃ _ ₇ cycloalkylC,. ₃ alkyl or of the formula R ¹² or R ¹² C,. ₃ alkyl wherein R ¹² is a tricyclic ring system, or R ⁴ is of the formula -CO ₂ R ¹⁸ wherein R ¹⁸ is hydrogen or optionally substituted: C,. ₆ alkyl, C ₃ . ₆ alkenyl, arylC,_ ₃ alkyl, heteroarylC,. ₃ alkyl, arylprop-2-enyl, heteroarylprop-2-enyl, heteroaryl or aryl or R ⁴ is of the formula -CONR ^l3 R ¹⁴ wherein R ¹³ or R ¹⁴ are independently hydrogen or optionally substituted: arylC, _.3 alkyl, C, _.6 alkyl, C _3.6 alkenyl, heteroarylC, _.3 alkyl, heteroarylprop-2-enyl, arylprop-2-enyl, aryl or heteroaryl or R ¹³ and R ¹⁴ , together with the nitrogen atom to which they are attached, form an optionally substituted

heterocyclyl ring or R ⁴ is of the formula -S(O) _n R ¹⁷ wherein n is 0, 1 or 2 and R ¹⁷ is optionally substituted: C, _.6 alkyl, arylC, _.3 alkyl, C _3.6 alkenyl, heteroarylC,. ₃ alkyl, arylprop-2-enyl, C ₅ . ₇ cycloalkenyl, C _5.7 cycloalkenylC, _.3 alkyl. heteroarylprop-2-enyl, aryl, heteroaryl, C ₂ . ₆ alkynyl, C ₃ . ₇ cycloalkyl, C _3.7 cycloalkylC,. ₃ alkyl, heterocyclyl, heterocyclylC,. ₃ alkyl, heterocyclylium or heteroarylium or, when n is 2, R ¹⁷ is of the formula -NR ^I5 R ¹⁶ wherein R ¹⁵ and R ¹⁶ are independently hydrogen or optionally substituted: C alkyl, C ₃ . ₆ alkenyl, heteroarylC _| . ₃ alkyl, heteroarylprop-2-enyl, arylC,. ₃ alkyl, arylprop-2-enyl, aryl or heteroaryl or R ¹⁵ and R ¹⁶ , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or R ⁴ is of the formula -COR ¹⁸ wherein R ¹⁸ is as hereinabove defined or R ⁴ is of the formula -Se(O) _q R ⁷ (q is 0, I or 2) wherein, when q is 0, R ⁷ is as hereinabove defined and when q is 1 or 2, R ⁷ is optionally substituted: aryl or heteroaryl;

R ⁵ is cyano or of the formula -CO _; R ¹⁹ wherein R' ⁹ is hydrogen or optionally substituted: C, _.6 alkyl. arylC _M alkyl, heteroaryl, heteroarylC,. ₃ alkyl, C ₃ . ₆ alkenyl, arylprop-2-enyl or heteroarylprop-2enyl or R ⁵ is of the formula -COR ²⁰ wherein R ²⁰ is hydrogen or optionally substituted C,. ₆ alkyl. arylC,. ₃ alkyl, heteroarylC,. ₃ alkyl, aryl or heteroaryl; and wherein any functional groups are optionally protected; and salts thereof; which process includes the step of reacting the intermediate formed by heating a compound of the formula (II):

R ^<

(M)

in an inert solvent, with a compound of the formula R ³ -=-R ⁴ wherein R ³ and R ⁴ are as hereinabove defined and functional groups are optionally protected; and thereinafter, if necessary, removing any protecting groups.

The compounds of the formula (I) are useful as intermediates in the preparation of Δ ² carbapenems and may possess antibacterial properties and/or inhibit β-lactamase.

In another aspect the invention provides a process for the preparation of compounds of the formula (III):

(Ml)

wherein R ¹ , R ² and R ⁵ are as hereinabove defined and

R ²¹ is nitro or R ² ' is of the formula -Se(O) _q R ⁷ (q is 0) wherein R ⁷ is as hereinabove defined, or R ² ' is as hereinabove defined for R ³ ;

R ²² is nitro or R ²² is of the formula -Se(0) _q R ⁷ wherein q and R ⁷ are as hereinabove defined, or R ²² is as hereinabove defined for R ³ ; R ²³ and R ²⁴ are independently nitro, of the formula -OR ⁴³ wherein R ⁴³ is C,. ₆ alkyl. arylC,. ₃ alkyl or C _2.6 alkenyl, or as hereinabove defined for R ⁴ ; or R ² ' and R ²² , or R ²² and R ²⁴ . or R ²³ and R ²⁴ together form an optionally substituted C ₃ . ₇ alkylene chain wherein 1 or 2 methylene groups are optionally replaced by -N(R ⁿ )-, -O- or -S-, (C ₃ . ₇ alkylene chains wherein 1 or 2 methylene groups are replaced by -N(R")-, -O- or -S- are hereafter referred to as C ₃ .-heteroalkylene), wherein R" is as hereinabove defined, and wherein the chain optionally contains one double bond and is optionally fused to a benzene or a heteroaryl ring; provided 2 adjacent methylene groups are not replaced by -N(R ⁿ )-, -0- or -S-; or R ²¹ and R ²² or R ²¹ and R ²⁴ together form an optionally substituted methylene group: and any functional groups are optionally protected; provided that no more than two of R ^2I -R ²⁴ are nitro; and salts thereof; which process includes the step of reacting the intermediate formed by heating a compound of the formula (II); as hereinabove defined, in an inert solvent, with a compound of the formula:

wherein R ^2, -R ²⁴ are as hereinabove defined; and thereinafter, if necessary, removing any protecting groups.

The compounds of the formula (III) are useful as intermediates in the preparation of Δ ² carbapenems and may possess antibacterial properties and/or inhibit β-lactamase.

When compounds of the formular (II) are heated in an inert solvent, an intermediate is formed. This intermediate reacts with acetylenes and olefins to give products of the formulae (I) and (III) respectively. It is believed, but we do not wish to be bound by theory, that one type of intermediate formed in this reaction by heating the compound of formula (II) in an inert solvent is the stabilised ylide of formula (IVa). In this case the carbon dioxide that is lost in the reaction is lost in a step subsequent to the ring forming step.

IVa IVb

Other unrelated stabilised 1,3-dipolar species are known to arise by ring openning reactions of Δ ⁴ -oxazolidines (E. Vedejs and J.W.Grissom, J. Amer. Chem. Soc, 1986, 108, 6433).

It is further believed that another type of intermediate formed in this reaction by heating the compound of formula (II) in an inert solvent is the unstabilised ylide of formula (IVb). In this case the carbon dioxide that is lost in the reaction is lost in a step prior to the ring forming step.

Other unrelated unstabilised 1,3-dipolar species are known to arise from decarboxylation reactions of iminium salts derived from primary and secondary α-amino

acids (see E. Vedejs and F.G. West, Chem. Rev., 1986, 86, 941 ; E. Vedejs, Adv. Cycloaddition, 1988, 1, 33).

The relative importance of these two types of intermediate will depend upon the conditions of the reaction, such as temperature and solvent, and on the relative abilities of the co-reagent olefins and acetylenes to react with the different intermediates. For instance, milder reaction conditions and reactive co-reagents will favour the importance of the stabilised intermediate (IVa) whereas higher reaction temperatures and less reactive co-reagent will favour the importance of the unstabilised intermediate (IVb).

The normal outcome of the reaction does not depend upon the stage at which the decarboxylation occurs since the same bicyclic ring system arises regardless of the order of the decarboxylation-cycloaddition steps.

Under the preferred reaction conditions the stabilised 1 ,3-dipole (IVa) is believed to be the important reaction intermediate.

Preferably the intermediate is formed by reacting the compound of the formula (II) in an inert solvent in a temperature range of 50°C to 180°C.

More preferably the intermediate is formed by reacting the compound of the formula (II) in an inert solvent in a temperature range of 80°C to 1 10°C.

Preferably the inert solvent is acetonitrile, propionitrile. toluene, chloroform or o-dichlorobenzene. Most preferably the inert solvent is acetonitrile.

In another aspect the intermediate may be formed in the compound of the formula R ³ -s-R ^< or R ² '(R ²² )C=C(R ²³ )R ²⁴ as solvent. This could take the form of a 'melt' depending upon the nature of the reagents.

It is envisaged that there will be other ways of preparing the intermediate. The compounds of the formulae (I) and (III) can be converted into carbapenem compounds of the formula (V):

(V) and salts thereof; wherein R', R ² and R ⁵ are as hereinabove defined and either R ²⁵ is R ³ and R ²⁶ is R ⁴ or R ²⁵ is R ²¹ or R ²² and R ²⁶ is R ²³ or R ²⁴ , by methods known in the art. In circumstances where R ²³ or R ²⁴ is an eliminatable group, a compound of the formula

(V) may be prepared from a compound of the formula (III) in situ. Suitable eliminatable groups include benzene selenyl; the oxide of which readily eliminates.

The compounds of the formula (V) may be of value in the treatement of bacterial infections and/or inhibit β-lactamase in their own right. Carbapenem compounds of the formula (V) can be converted into carbapenem compounds of the formula (VI):

(VI) and pharmaceutically-acceptable salts thereof; wherein R ²⁷ , R ²⁸ , R ²⁹ and R ³⁰ are substituents known in the carbapenem art.

Suitable pharmaceutically-acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N- ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. There may be more than one or more cation or anion depending on the number of charged functions and the valency of the cations or anions.

Preferred pharmaceutically-acceptable salts are sodium and potassium salts. However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.

The process of the invention may also be used in the preparation of chemical compound libraries. It may be used to provide a common synthetic step at any convenient stage of library synthesis, such as at the penultimate or last stage. The libraries so prepared may comprise any convenient number of individual, and diverse, chemical compounds, such as from tens to hundreds, hundreds to thousands, thousands to tens ot thousands, tens of thousands to hundreds of thousands, hundreds of thousands to a million or more individual compounds. Suitable and preferred chemical moieties for inclusion in the library will be apparent to the chemist of ordinary skill.

Particular optional substituents for alkyl. alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R' and R ² include halo, trifluoromethyl, nitro. hydroxy, amino, C _M alkylamino. diC _M alkylamino, cyano, C,. ₆ alkoxy, carboxy, C,. ₆ alkylS(O) _p ( p is 0, 1 or 2), C,. ₆ alkyl (optionally substituted by hydroxy, amino, halo, nitro, cyano, hydroxyimino or C _M alkoxyimino), carbamoyl, C _M alkylcarbamoyl, di(C _M alkyl)carbamoyl, C,. ₆ alkenyl, C _2-6 alkynyl, C _M alkoxycarbonylamino, C _M alkanoylamino, C _M alkanoyl(N-C _M alkyl)amino, C _M alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C _M alkylaminosulphonyl, di(C _M alkyl)aminosulphonyl, C,. ₄ alkoxycarbonyl, C _M alkanoyioxy, C, _.6 alkanoyl, formylC _M alkyl, trifluoroC, ₃ alkylsulphonyl, hydroxyiminoC, _.6 alkyl, C _M alkoxyiminoC,. ₆ alkyl, C,. ₆ alkylcarbamoylamino. tπazolyl, tetrazolyl and an additional optional substituent on saturated carbon atoms is oxo.

Particular optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R ³ , R ²¹ and R ²² include halo, trifluoromethyl, nitro, hydroxy, amino, C _M alkylamino, diC _M alkylamino, cyano. C,. ₆ alkoxy, carboxy, C,. ₆ alkyl S(O) _p (p is 0, 1 or 2), C,. ₆ alkyl (optionally substituted by hydroxy, amino, halo, nitro, cyano, oxo (=O), hydroxyimino or C _M alkoxyimino), carbamoyl, C _M alkylcarbamoyl, di(C,. ₄ alkyl)carbamoyl, C ₃ . ₆ alkenyl, C _3.6 alkynyl, C _M alkoxycarbonylamino, C _M alkanoylamino, C _M alkanoyl(N-C, _.4 alkyl)amino, C,. ₄ alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C _M alkylaminosulphonyl, di(C _M alkyl)aminosulphonyl, C _μ4 alkoxycarbonyl, C,. ₄ alkanoyloxy, C, _.6 alkanoyl. formylC _M alkyl, trifluoroC _ι . ₃ alkylsulphonyl, hydroxyiminoC,. ₆ alkyl, C _l.4 alkoxyiminoC _U6 alkyl and C,. ₆ alkylcarbamoylamino.

Particular optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R ⁴ , R ²³ and R ²⁴ include halo, trifluoromethyl, nitro, hydroxy, amino, C _M alkylamino, diC _M alkylamino, cyano, C^alkoxy, carboxy, C,. ₆ alkylS(O) _p - (p is 0, 1 or 2), C^alkyl (optionally substituted by hydroxy, amino, halo, nitro, cyano, oxo (=O), hydroxyimino C _M alkoxyimino), carbamoyl, C _M alkylcarbamoyl, di(C _M alkyl)carbamoyl, C ₃ ^alkenyl, C alkynyl, C _M alkoxycarbonylamino, C _M alkanoylamino, C _M alkanoyl(N-C,. ₄ alkyl)amino, C _M alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C _M aIkylaminosulphonyl. di(C _M alkyl)aminosulphonyl, C _M alkoxycarbonyl, C _M alkanoyloxy, arylC _M alkanoyl, C,. ₆ alkanoyl, formylC _M alkyl, aryl. heteroaryl, arylC, _.3 alkyl, heteroarylC,. ₃ alkyl, arylprop-2-enyl, heteroarylprop-2-enyl, trifiuoroC _M alkylsulphonyl, hydroxyiminoC,. ₆ alkyl, C _| . ₄ alkoxyiminoC,. ₆ alkyl, C,. ₆ alkylcarbamoylamino, aryloxyalkanoyl, a group of the formula -N=C(R ^c )R ^d , -N(R ^e )C(R ^f )=NR ^B , -C(N(R")R')=NR ^J or -CON(R ^k )R ^p wherein R ^c is hydrogen, C, _.4 alkyl, amino, C _M alkylamino or di(C _M alkyl)amino; R ^d -R ^k are independently hydrogen or C _M alkyl; R ^p is hydrogen, C,. ₄ alkyl, aryl, heteroaryl, heterocyclyl, heterocyclylene, heterocyclyleneC _| . ₃ alkyl, cycloalkyl or cycloalky!C,. ₃ alkyl; and on saturated carbon atoms additional optional substituents are oxo. imino and C _M alkylimino.

Optional substituents for ring nitrogen atoms in heteroaryl groups include C _M alkyl and C _M alkanoyl.

Any aryl and heteroaryl groups in the optional substituents for R'. R ² , R\ R ⁴ , R ²¹ , R ²² . R ²³ and R ²⁴ may be optionally substituted by halo, C _M alkyl, trifluoromethyl, nitro, hydroxy, amino, C _M alkylamino, di-(C _M alkyl)amino, cyano, C _M alkoxy, carboxy, C _M alkanoyl or carbamoyl. A heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms wherein 1 , 2 or 3 ring atoms are selected from nitrogen, oxygen and sulphur or a bicyclic aryl ring system having 8 to 10 ring atoms wherein 1 , 2, 3 or 4 ring atoms are selected from nitrogen, oxygen and sulphur.

Particular heteroaryl rings include pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, 1,2,4-, 1,2,5- and 1 ,3,4-thiadiazolyl, thienyl, furyl and oxazolyl and 1 ,2,3- and 1 ,2,4-triazolyl. An aryl ring system is phenyl. naphthyl or a tricyclic aryl ring system.

Preferably an aryl ring system is phenyl.

A heterocyclylium ring is a positively charged saturated or partially saturated monocyclic ring system, having 5 or 6 ring atoms, or a positively charged bicyclic ring system, having 8 to 10 ring atoms, containing one ring nitrogen atom and 0-2 further hetero ring atoms selected from nitrogen, oxygen and sulphur.

A heteroarylium ring is a positively charged monocyclic aryl ring system, having 5 or 6 ring atoms, or a positively charged bicyclic aryl ring system, having 8 to 10 ring atoms, containing one ring nitrogen atom and 0 - 2 further hetero ring atoms selected from nitrogen, oxygen and sulphur. A heterocyclyl ring system is a saturated or partially saturated monocyclic ring system having 5 or 6 ring atoms or a saturated or partially saturated bicyclic ring system having 8 to 10 ring atoms, each containing 1 - 3 hetero ring atoms selected from nitrogen, oxygen and sulphur and wherein any ring sulphur and nitrogen atoms are optionally oxidized. For example, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, pyrazolinyl, pyrrolinyl and imidazolinyl.

Particular examples of tricyclic ring systems include optionally substituted bicyclic heteroaryl ring systems to which is fused a benzene ring. Specific examples of tricyclic rings include, dibenzofuran and dibenzothiophene.

A C ₃ . ₇ cycloalkyl group is a saturated monocyclic ring system having from 3 to 7 ring atoms.

A C _5.7 cycloalkenyl group is a monocyclic ring system having from 5 to 7 ring atoms and containing one double bond.

The term alkyl when used herein includes straight chain and branched chain substituents for example C _M alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

An organic group includes, for example, a group of the formula -C(=R ^q )R ^r - wherein R' is an optionally substituted heteroaryl group and R ^q is an oxyimino group. The oxyimino group may be, for example, of the formula =NOR ¹⁸ wherein R ¹⁸ is as hereinabove defined.

An organic group also includes C,. ₆ alkyl ₍ phenyl, heteroaryl, arylC _M alkyl and heteroarylC,. ₃ alkyl.

Optional substituents for carbon atoms in C,. ₆ and C ₃ . ₇ alkylene and heteroalkylene chains include halo, trifluoromethyl, nitro, oxo, hydroxy, amino, C,. ₄ alkylamino,

di(C _M alkyl)amino, cyano, C,^alkoxy, C _M alkyl-S(O) _p -(p is 0, 1 or 2), C _M alkanoyl and C _M alkyl optionally substituted by hydroxy, halo, nitro, cyano or amino;

Examples of C^alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; examples of carboxy C,. ₃ alkyl are carboxymethyl, 2-carboxyethyl, 1 -carboxyethyl and 3-carboxypropyl; examples of C|. ₆ alkoxycarbonylC,. ₃ alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples of tetrazolyC, _.3 alkyl are tetrazolylmethyl and 2-tetrazolylethyl; examples of C _M alkoxy are methoxy, ethoxy, propoxy and isopropoxy; an example of C ₃ . ₆ alkenyl is allyl; an example of C ₂ . ₆ alkynyl is propynyl; examples of C _M alkanoyl are formyl, acetyl, propionyl and butyroyl; examples of halo are fluoro, chloro, bromo and iodo; examples of C _M alkylamino are methylamino, ethylamino, propylamino and isopropylamino; examples of di(C _M alkyl)amino are dimethylamino, diethylamino and ethylmethylamino; examples of C _M alkylS(O) _p - are methylthio, methanesulphinyl and methanesulphonyl; examples of C _M alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl; examples of di(C _U4 alkyl)carbamoyl are dimethylcarbamoyi, diethylcarbamoyl and ethylmethylcarbamoyl; examples of C,. ₆ alkyl are methyl, ethyl, propyl and isopropyl; examples of C _M alkoxycarbonylamino are methoxycarbonylamino and ethoxycarbonylamino; examples of C _M alkanoylamino are acetamido and propionamido; examples of C _M alkanoyl(N-C,. ₄ alkyl)amino are N-methylacetamido and N-methylpropionamido; examples of C _M alkanesulphonamido are methanesulphonamido and ethanesulphonamido; examples of Cμ.alkylaminosulphonyl are methylaminosulphonyl and ethylaminosulphonyl: examples of di(C _M alkyl)aminosulphonyl are dimethylaminosulphonyl, diethylaminosulphonyl and ethylmethylaminosulphonyl; examples of C _M alkanoyioxy are acetoxy and propionyloxy; examples of formylC,. ₄ alkyl are formylmethyl and 2-formylethyl; and examples of C _M alkoxyimino are methoxyimino and ethoxyimino.

Examples of alkylene chains include trimethylene, but-1 ,4-diyI, pent-1 ,5-diyl and hex-l ,6-diyl.

Examples of C _3.6 heteroalkylene chains include -CH ₂ NHCH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ SCH ₂ -, -CH ₂ CH ₂ NHCH ₂ - and -O-CH ₂ CH ₂ CH ₂ -, Examples of C _3.7 alkylene and heteroaikylene chains optionally containing a double bond and optionally fused to a benzene or heteroaryl ring include:

(wherein X and Y are independently NH, oxygen, sulphur, methylene, -CO- or -CH(R ^m )- wherein R ^m is hydrogen, halo, nitro. amino, hydroxy, cyano or C _M alkyl), -CH ₂ CH ₂ CH=CH-, -CH ₂ CH=CHCH ₂ CH ₂ -, -CH ₂ NHCH ₂ CH ₂ -, -OCH ₂ CH=CHCH ₂ - and -SCH ₂ CH ₂ CH ₂ -.

The present invention relates to all tautomeric forms of the compounds disclosed. Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods. For example see 'Protective Groups in Organic Synthesis ^" , by T.W. Greene et. al., second edition, 1991.

The skilled chemist will appreciate that it is sometimes necessary to protect certain functional groups in certain reactions. For example, when the functional group is sensitive to the reaction conditions or would cause side-reactions.

Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake of convenience, in which "lower" signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. For example, it will be appreciated that polymer-supported protecting groups are included such as those employed in solid phase synthesis (see 'Polymer-supported Reactions in organic synthesis', by P. Hodge and D.C. Sherrington, 1980). Where specific examples of methods for the removal of protecting groups are given below, these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.

A carboxyl protecting group may be the residue of an ester- forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain

(l-12C)alkyl groups (eg. isopropyl. t-butyl); lower alkoxy lower alkyl groups (eg

methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (eg. acetoxy methyl, propionyloxymethyl, butyryloxymethyl, pivaloxyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1 -methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl, rj-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups (eg allyl and vinylethyl).

Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis or hydro genation.

Examples of hydroxyl protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl. p-nitrobenzyloxycarbonyl); tri lower alkylsilyl (eg trimethylsilyl, t-butyldimethylsilyl) and aryl lower alkyl (eg benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p_-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl): lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, g-nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups. Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as E-nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photo lyrically.

The invention relates to all enantiomeric and diasteromeric forms unless explicitly indicated otherwise. When R ² is significantly larger than R ¹ , the enantiomer with the

5-position stereochemistry as depicted in formulae (I) and (III) is obtained in significantly larger quantities relative to the other enantiomer.

The position of the substituents in the product is determined by the regiochemistry of the reaction. The reaction of the intermediate with a co-reagent olefm or acetylene generally gives both of the possible regioisomers. Where the substituents on the olefm or acetylene are electronically similar the major product will be the one that minimises steric interactions of the substituents at points where these substituents clash. Where electronic effects dominate the regiochemistry of the ring- forming process may be predicted by considering the magnitude of the interactions between the interacting orbitals as described by Houk (K.N. Houk, Ace. Chem. Res., 1975, 8, 361). The practical outcome is that alkylthio-, alkylseleno-, and carbonyl- and similar conjugating and electron withdrawing substituents preferentially form the 2-substituent of the product (R ²³ or R ²⁴ ), whereas hydrogen and alkyl substituents show little discrimination between either position.

The relative orientation of the substituents in the product is determined by the stereochemistry of the reaction. The indicated hydrogen (the ring junction C5) will be preferably cis to the sterically larger of the substituents R ¹ and R ² . The substituent R ⁵ will be preferably cis to the indicated hydrogen at C5. The relative orientation of the substituents on an olefinic co-reagent will be preferably retained in the product of cycloaddition so that R ²¹ and R ²³ will preferably be mutually cis in that product and R ²² and R ²⁴ will preferably be mutually cis in that product. Olefm substituents such as alkyl that show little electronic effect on the relative position (regiochemistry) of the substituents will preferably be cis to the indicated hydrogen at C5; alkylthio-, alkylseleno-, and carbonyl- and similar conjugating and electron withdrawing substituents will be preferably trans to the indicated hydrogen at C5. When R ¹ and R ² are different and enantiomerically enriched lactone (II) is used, the products of the reaction are similarly enantiomerically enriched and when enantiomerically pure lactone (II) is used, the products of the reaction are similarly enantiomerically pure. When R' and R ² are the same or when racemic lactone (II) is used, the products are also racemic.

A particular enantiomer may be isolated from a mixture of the enantiomers by resolution. For example, by reaction with an optically active form of a suitable organic base, for example, N,N,N-trimethyl(l-phenylethyl)ammonium hydroxide, followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, for example by fractional crystallisaton from a suitable solvent, for example a (l-4C)alkanol, whereafter the optically

active form of said compound of formula (I), (III), (V) or (VI) may be liberated by treatment with acid using a conventional procedure. Preferably R ¹ is no bigger than R ² More preferably R ² is bigger than R ¹ . Most preferably R' is hydrogen.

Preferably R ² is hydrogen, halo or optionally substituted: C,. ₆ alkyl, aryl, heteroaryl, arylC,. ₃ alkyl, heteroary!C,. ₃ alkyl, C,. ₆ alkoxy, C,. ₆ alkylthio or of the formula R ⁶ CONH-.

More preferably R ² is hydrogen or optionally substituted: C,. ₆ alkyl, phenylC, _.3 alkyl or phenyl, wherein the optional substituents are selected from hydroxy, halo, nitro. amino, C _M alkoxy or C,. ₄ alkylthio and the hydroxy and amino groups are optionally protected.

Most preferably R ² is hydrogen or C,. ₆ alkyl optionally substituted by protected hydroxy, or fluoro.

Preferably R ³ is hydrogen, cyano or optionally substituted C,. ₆ alkyl or R ³ is of the formula -CO ₂ R ³² wherein R ³² is optionally substituted: C,. _ή alkyl, aryl or arylC,. ₃ alkyl or R ³ is of the formula -CONR ³³ (R ³⁴ ) wherein R ³³ and R ³⁴ are independently hydrogen or optionally substituted: C, _.6 alkyl. arylC,. ₃ alkyl, or R ³³ and R ³⁴ , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or R ³ is of the formula -COR ³⁵ wherein R ³⁵ is optionally substituted: hydrogen, C,. ₆ alkyl, arylC _M alkyl or aryl. More preferably R ³ is hydrogen or optionally substitued: C,. ₆ alkyl or C _M alkoxycarbonyl.

Most prefereably, R ³ is hydrogen or C,. ₄ alkoxycarbonyl.

Preferably R ⁴ is cyano, C,. ₆ alkyl, arylC,. ₃ alkyl, heteroarylC,. ₃ alkyl, aryl, heteroaryl or of the formula -CO ₂ R ¹⁸ wherein R ¹⁸ is as hereinabove defined or R ⁴ is of the formula

-CONR ^l3 R ¹⁴ wherein R ¹³ and R' ⁴ are as hereinabove defined or R ⁴ is of the formula -COR ³⁵ wherein R ³⁵ is as hereinabove defined or R ⁴ is of the formula -SR ³⁶ wherein R ³⁶ is optionally substituted:C _|.6 alkyl, arylC _M alkyl, heterocyclyl, heterocyclylC,. ₃ alkyl, aryl, heteroarylC,. ₃ alkyl or heteroaryl or R ⁴ is of the formula -Se(O) _q R ⁷ (q is 0, 1 or 2) wherein, when q is 0, R ⁷ is as hereinabove defined and when q is 1 or 2, R ⁷ is optionally substituted: aryl or heteroaryl.

More preferably R ⁴ is cyano, C, _.6 alkyl, aryl or of the formula -CO ₂ R ³⁹ wherein R ³⁹ is hydrogen or optionally substituted: C _h alky 1, C ₃ ^alkenyl, arylC^alkyl, arylprop-2-enyl or aryl or R ⁴ is of the formula -CONR ⁴⁰ (R ⁴¹ ) wherein R ⁴⁰ and R ⁴¹ are independently hydrogen or optionally substituted: C^alkyl, arylC,. ₃ alkyl or R ⁴⁰ and R ⁴¹ , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or R ⁴ is of the formula -COR ³⁵ wherein R ³⁵ is as hereinabove defined or R ⁴ is of the formula -SR ³⁶ wherein R ³⁶ is as hereinabove defined or R ⁴ is of the formula -Se(O) _q R ⁷ wherein q is 0 and R ⁷ is as hereinabove defined.

Yet more preferably, R ⁴ is C,. ₆ aikyl, phenyl or of the formula -CO ₂ R ³⁹ wherein R ³⁹ is hydrogen or optionally substituted: C,. ₆ alkyl or arylC,. ₃ alkyl or R ⁴ is of the formula -COR ³⁵ wherein R ³⁵ is as hereinabove defined or R ⁴ is of the formula -SR ³⁶ wherein R ³⁶ is optionally substituted: C, _.6 alkyl, aryl or heteroaryl.

Yet more preferably, R ⁴ is C,. ₆ alkyl, phenyl or of the formula -C0 ₂ R ³⁹ wherein R ³⁹ is C,. ₆ alkyl or of the formula -SR ³⁶ wherein R ³⁶ is optionally substituted: C,. ₆ alkyl or phenyl or R ⁴ is of the formula -SR ³⁶ wherein R ³⁶ is aryl or heteroaryl.

Most preferably, R ⁴ is methyl, ethyl, phenyl or of the formula -CO ₂ R ³⁹ wherein R ³⁹ is methyl or ethyl or R ⁴ is of the formula -SR ³⁶ wherein R ³⁶ is pentyl, 2-(acetamido)ethyl or phenyl or R ⁴ is of the formula -SR ³⁶ wherein R ³⁶ is phenyl.

Preferably R ⁵ is cyano or of the formula -C0 ₂ R ³⁹ wherein R ³⁹ is as hereinabove defined, or R" is of the formula -COR ³⁵ wherein R ³⁵ is as hereinabove defined.

More preferably R ⁵ is of the formula -C0 ₂ R ³⁹ wherein R ³⁹ is as hereinabove defined.

Preferably R ²¹ is hydrogen, cyano or optionally substituted C,. ₆ alkyl, aryl or a group of the formula -SO ₂ R ³¹ wherein R ³ ' is as hereinabove defined or R ²¹ is of the formula -CO ₂ R ³² (wherein R ³² is as hereinabove defined) or R ² ' is of the formula -CONR ¹³ R ¹⁴ (wherein R ¹³ and R ¹⁴ are as hereinabove defined) or of the formula -COR ³⁵ (wherein R ³⁵ is as hereinabove defined) or R ²¹ , together with R ²² , forms an optionally substituted C ₄ . ₆ alkylene chain wherein one methylene group is optionally replaced by -N(R")-, -O- or -S-, (wherein R" is as hereinabove defined) and the chain optionally contains one double bond and is optionally fused to an aryl or heteroaryl ring.

More preferably R ²¹ is hydrogen or optionally substituted C,. ₆ alkyl. Most preferably R ²¹ is hydrogen.

Preferably R ²² is hydrogen, cyano, halo or optionally substituted: C,. ₆ alkyl, C, _.6 alkoxy, ary!C, _.3 alkoxy, heteroaryl C,. ₃ alkoxy, aryloxy, heteroaryloxy or of the formula -S(O) _n R ⁷ , -COR ¹⁰ or -CO ₂ R ³² (wherein n, R ⁷ , R ^!0 and R ³² are as hereinabove defined) or R ²² , together with R ²¹ or R ²⁴ , forms an optionally substituted C ₄ _ ₆ alkylene chain wherein one methylene group is optionally replaced by -N(R ^r )-, -O- or -S-, wherein R ⁿ is as hereinabove defined, and the chain optionally contains one double bond and is optionally fused to an aryl or heteroaryl ring. More preferably R ²² is hydrogen, cyano or optionally substituted C,. ₆ alkyl or aryl or a group of the formula -SO ₂ R ³¹ , -CO ₂ R ³² , -CONR ¹³ (R ¹⁴ ) or of the formula -COR ³⁵ (wherein R ¹³ , R ¹⁴ , R ³ ', R ³² and R ³⁵ are as hereinabove defined) or R ²² and R ²⁴ together form a chain as hereinabove defined.

Yet more preferably, R ²² is hydrogen or optionally substituted: C,. ₆ alkyl or aryl or arylsulphonyl or R ²² is of the formula -CO ₂ R ³⁹ or -COR ³⁹ wherein R ³⁹ is as hereinabove defined or R ²² and R ²⁴ together form a chain as hereinabove defined.

Most preferably, R ²² is hydrogen, methyl, phenylsulphonyl of the formula -CO ₂ R ³⁹ , wherein R ³⁹ is methyl or ethyl or R ²² and R ²⁴ together form a chain as hereinabove defined.

Preferably R ²³ is hydrogen, nitro, halo, cyano, C,. ₆ alkoxy, arylC,. ₃ alkoxy, aryloxy, heteroarylC, _.3 alkoxy, arylC, _.3 alkoxy or R ²³ is of the formula -C0 ₂ R ¹⁸ wherein R ¹⁸ is as hereinabove defined or R ²³ is of the formula -S(O) _n R ³⁶ wherein n is 0, 1 or 2 and R ³⁶ is as hereinabove defined or R ²³ is of the formula -COR ³⁷ wherein R ³⁷ is as hereinabove defined for R ¹⁸ or R ³⁷ is of the formula -NR ^,3 R ¹⁴ wherein R ¹³ and R ¹⁴ are as hereinabove defined or R ³⁷ is C,. ₆ alkyl, C _3.6 alkenyl, arylC, _.3 alkyl, heteroarylC _M alkyl, arylprop-2-enyl, aryl or heteroaryl or R ²³ forms a chain together with R ²¹ or R ²⁴ as hereinabove defined, or R ²³ is optionally substituted C, _.6 alkylseleno or arylseleno.

More preferably R ²³ is hydrogen, halo or C,. ₆ alkylthio, arylthio, C,. ₆ alkylseleno or arylseleno.

Preferably R ²⁴ is nitro, cyano or optionally substituted: C,. ₆ alkyl. arylC,. ₃ alkyl, heteroarylC, _.3 alkyl, aryl or heteroaryl or R ²⁴ is of the formula -CO ₂ R ¹⁸ wherein R ¹⁸ is as

hereinabove defined, or R ²⁴ is of the formula -CONR ¹³ R ⁴ wherein R ¹³ and R ¹⁴ are as hereinabove defined or R ²⁴ is of the formula -S(O) _n R ³⁶ wherein n and R ³⁶ are as hereinabove defined, or R ²⁴ , together with R ²² , forms an optionally substituted C ₃ „ ₆ alkylene chain wherein one methylene group is optionally replaced by -N(R ⁿ )-, -O- or -S-. wherein R ⁿ is as hereinabove defined and wherein the chain optionally contains one double bond and is optionally fused to a benzene or heteroaryl ring or R ²³ and R ²⁴ together form a C ₃ . ₄ alkylene chain.

More preferably, R ²⁴ is nitro, cyano, aryl or of the formula -CO ₂ R ³⁹ wherein R ³⁹ is as hereinabove defined or R ²⁴ is of the formula -CONR ⁴⁰ (R ⁴¹ ) wherein R ⁴⁰ and R ⁴¹ are as hereinabove defined or R ²⁴ is of the formula -COR ³⁵ wherein R ³⁵ is as hereinabove defined or R ²⁴ is of the formula -S(O) _π R ³⁶ is as hereinabove defined, or R ²⁴ , together with R ²² , forms a C,. ₅ alkylene chain and is optionally substituted by hydroxy, C,. ₆ alkoxy or oxo and optionally fused to a benzene or heteroaryl ring.

Yet more preferably R ²⁴ is optionally substituted aryllsulphonyl, arylthio, C,. ₆ alkylsulphonyl, C, _.6 alkylsulphinyl, C,. ₆ alkylthio, C,. ₆ alkylseleno or arylseleno or of the formula -CO ₂ R ⁴² . wherein R ⁴² is hydrogen, C,. ₆ alkyl or arylC,. ₃ alkyl or R ²⁴ , together with R ²² , forms a C, _.5 alkylene chain and is optionally substituted by hydroxy, C,. ₆ alkoxy or oxo and optionally fused to a benzene ring.

Most preferably R ²⁴ is optionally substituted phenylsulphonyl, phenylthio, methanesulphonyl, methanesulphinyl, methanethio or phenylseleno or of the formula

-CO ₂ R ⁴² . wherein R ⁴² is methyl or ethyl, or R ²⁴ , together with R ²² . forms a C,. _s alkylene chain and is optionally substituted by hydroxy, C,. ₆ alkoxy or oxo and optionally fused to a benzene ring.

Preferably the alkylene chain formed by R ²² and R ²⁴ is of the formula -C(=O)CH ₂ CH ₂ CH ₂ -, -C(O)N(R ⁿ )C(=0)-, -CH ₂ CH ₂ C(=O)-, -(CH ₂ ) ₄ C(=0)-, -(CH ₂ ) ₃ C(=O), -(CH ₂ ) ₄ - optionally fused to a benzene ring.

More preferably the alkylene chain formed by R ²² and R ²⁴ is of the formula -C(=O)CH ₂ CH ₂ CH ₂ -, -C(=0)N(R ⁿ )C(=O)-, -CH ₂ CH ₂ C(=0)-, -(CH ₂ ) ₄ C(=0)-, -(CH ₂ ) ₃ C(=O), -(CH ₂ ) ₄ -. Preferably R ⁴³ is methyl, ethyl, benzyl or allyl.

Preferred optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R ¹ and R ² include halo, trifluoromethyl, nitro, hydroxy, amino,

cyano, C,. ₆ alkoxy, carboxy, C, _.6 alkyIS(O) _p ( p is 0, 1 or 2), C,. ₆ alkyl. carbamoyl,

C _M alkylcarbamoyl, di(C _M alkyl)carbamoyl, C _M alkanoylamino,

C _M alkoxycarbonyl, C _M alkanoyloxy, C^alkanoyland oxo.

Preferred optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R ³ , R ²¹ and R ²² include halo, trifluoromethyl, nitro, hydroxy, amino, cyano, C^alkoxy, carboxy, C,. ₆ alkyl S(O) _p (p is 0, 1 or 2), C,. ₆ alkyl, carbamoyl,

C _M alkylcarbamoyl, di(C _M alkyl)carbamoyl, C _M alkanoylamino,

C,. ₄ alkanoyl(N-C _| . ₄ alkyl)amino, C _| . ₄ alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C _M alkylaminosulphonyl, C _M alkoxy carbonyl, C _M alkanoyloxy, C, _.6 alkanoyl, formylC,. ₄ alkyl, hydroxy iminoC _] . ₆ alkyl and C _M alkoxyiminoC,^,alkyl.

Preferred optional substituents for alkyl, alkenyl and aryl groups and ring carbon atoms in heteroaryl groups in R ⁴ , R ²³ and R ²⁴ include halo, trifluoromethyl, nitro. hydroxy. amino, C,. ₄ alkylamino. diC,. ₄ alkylamino, cyano, C, ^alkoxy, carboxy, C,. ₆ alkylS(O) _p - (p is 0, 1 or 2), C,. ₆ alkyl (optionally substituted by hydroxy, amino, halo, nitro, cyano, oxo (=O), hydroxyimino C _M alkoxyimino), carbamoyl, C _M alkylcarbamoyl, di(C _M alkyl)carbamoy],

C _l . ₄ alkoxycarbonylamino, C _M alkanoylamino, aminosulphonyl, C _M alkoxycarbonyl,

C _M alkanoyIoxy, C,. ₆ alkanoyl, formylC _M alkyl, hydroxyiminoC,. ₆ alkyl.

C _M aIkoxyiminoC, _.4 alkyI, C, _.6 alkylcarbamoylamino, a group of the formula -N=C(R ^c )R ^d ,

-N(R ^e )C(R ^f )=NR ^g , -C(N(R ^h )R')=NR ^J or -CON(R ^k )R' wherein R ^c is hydrogen or C _M alkyl; and R ^d -R ^p are as hereinabovedefined; and on saturated carbon atoms additional optional substituents are oxo. imino and

C,. ₄ alkylimino.

Preferred optional substituents for the alkylene chain formed by R ²² and R ²⁴ include oxo, hydroxy and C,. ₆ alkoxy. A compound of the formula (II) can be prepared by methods known in the carbapenem art. For example by the general methods of scheme 1.

A compound of the formula (XI) may be reacted to form a compound of the formula

(II) by the methods disclosed in Heterocycles Vol. 16, No. 9, 1981 and European patent application EP 078026 or methods analagous thereto. A compound of the formula (XI) may be prepared by reacting a compound of the formula (X) in a diazo exchange reaction with, for example. N-ethyl 2-azidobenzthiazolium

fluoroborate using the method disclosed in Heterocycles Vol. 16, No. 9, 1981 or methods analogous thereto.

Alternatively, a compound of the formula (XI) may be prepared by reacting a compound of the formula (IX), wherein L is acetoxy or preferably chloro, with compounds of the formula R ⁵ -C(=N ₂ )-CO ₂ H, wherein R ⁵ is as hereinabove defined, using the method described in EP 078026.

A compound of the formula (IX) wherein L is chloro may be prepared from a compound of the formula (IX) wherein L is acetoxy, by methods known in the art.

A compound of the formula R ⁵ -C(=N ₂ )-CO ₂ H may be prepared by the method disclosed in EP 078026 or by methods analogous thereto or by the method described in J. Chem. Research (S) 1993, 18-19 or by methods analogous thereto.

A compound of the formula (X) may be prepared from a compound of the formula (IX) by reacting the latter compound with a compound of the formula R ⁵ -CH ₂ CO ₂ H using the method described in Heterocycles Vol. 16, No. 9, 1981 or methods analogous thereto. Alternatively a compound of the formula (II) may be prepared by ozonolysis of a compound of the formula (XVI) (A.G. Brown, D. F. Corbett, J. Goodacre, J. B. Harbridge, T.T. Howarth, R.J. Ponsford, I. Stirling and T. J. King. J. Chem. Soc, Perkin Trans. I. 1984, 635).

A compound of the formula (XVI) may be prepared from a compound of the formula (XV), which in turn may be prepared from a compound of the formula (XIV), using methods described in (E. Hunt, GB Patent No 15299.3) or by methods analogous thereto.

A compound of the formula (XIV) may be prepared from a compound of the formula (XIII), which in turn may be prepared from a compound of the formula (XII), by methods described in German patent application DE 4,142,423 or by methods analogous thereto. A compound of the formula (XII) may be prepared from a compound of the formula

(IX).

A compound of the formula (II), wherein R' and R ² are hydrogen, may be prepared by ozonolysis of a compound of the formula (VII):

(VII) wherein R ⁵ is as hereinabove defined and any functional groups are optionally protected using the method described in GB Patent No 1,509,400, or methods analogous thereto.

A compound of the formula (I) may be prepared by reacting the intermediate, formed from the compounds of the formula (II), with a compound of the formula R ³ -≡-R ⁴ in situ.

A compound of the formula (III) may be prepared by reacting the intermediate, formed from a compound of the formula (II), with a compound of the formula

in situ.

A compound of the formula (II) may be converted to the intermediate, believed to be of formula (IVa) or (IVb) , by heating it in acetonitrile or in another inert solvent such as other lower alkylnitriles, for example propionitrile, an aromatic hydrocarbon, for example toluene, an ether for example di-isopropyl ether, a halogenated solvent, for example 1 ,1 ,2-trichloroethane or an aliphatic hydrocarbon such as decalin. in a temperature range of 70-160°C, until the lactone is converted, which is usually between 30 minutes and 24 hours, most usually between 1 and 6 hours.

A compound of the formula (I) may be converted into a compound of the formula (V) by base catalysed isomerisation. For example see 'S.M. Schmitt. D.B.R. Johnston, and B.G. Christensen, J. Org. Chem. 1980, 45, 1 135 and 1 142', and in a similar vein, ^ς M. W. Foxton, R.C. Mearman, C. E. Newall, and P. Ward, Tetrahedron Letts., 1981 , 22, 2497'.

A compound of the formula (I) may be converted into a compound of the formula (III), wherein one of R ²¹ and R ²² is hydrogen and the other is as defined for R ³ and one of R ²² and R ²³ is hydrogen and the other is as defined for R\ by catalytic hydrogenation. with palladium on carbon as the catalyst, for example.

A compound of the formula (III), wherein at least one of R ²³ and R ²⁴ is an eliminatable group, may be converted into a compound of the formula (V) by base-catalysed or thermal

elimination. An eliminatable group is a group which can be eliminated together with a hydrogen in the 3-position of the penam ring. Examples of base-catalysed eliminatable groups include arylsulphonyloxy, methanesulphonyloxy (for example see M. Miyashita, N. Chida, and A. Yoshikoshi, J. Chem. Soc, Chem. Commun., 1984, 195 and M. Shibuya, M. Kuretani, and S. Kubota, Tetrahedron, 1982, 38, 2659), chloro (for example see J. H. Bateson, P. M. Roberts, T. C. Smale, and R. Southgate, J. Chem. Soc, Chem. Commun., 1980, 185) bromo and arylsulphinyl. Examples of thermally eliminatable groups include the oxides of phenylselenyl (phenylselenyl is conveniently oxidised in situ), nitro and arylsulphinyl.

An example of double bond incorporation utilising a phenylselenyl moiety has been reported by Hanessian and co-workers in the synthesis of 5-methoxytribactams (S. Hanessian, M.J. Rozema, G. Bhaskar Reddy and J.F. Braganza. Bioorg. Med. Chem. Lett.. 1995, 5, 2535). Further manipulation via DBU mediated isomerisation was necessary to put the double bond in the correct position:

(d)

C0 ₂ Bn

(a) mCBBA (2eq), -78°C, CH ₂ C1 ₂ , 30mins, 80%; (b) NaBH ₄ (1.1 eq), -78°C, 30 min, 75%; (c) Mel (solvent), Ag ₂ O (3eq), rt, lOh, 63%; (d) DBU (leq), rt, CH ₂ C1 ₂ , 12h. 92%.

A compound of the formula (III), wherein neither R ²³ nor R ²⁴ is an eliminatable group, may be converted into a compound of the formula (VIII):

(VIII) wherein L is an eliminatable group by standard methods known in the art.

A compound of the formula (VIII) may then be converted to a compound of the formula (V) by base-catalysed or thermal elimination.

Scheme

The antibacterial properties of the carbapenems prepared using the process of the present invention may be demonstrated in vivo in conventional tests.

The invention will now be illustrated by the following examples:

Example 1. (±) p-Nitrobenzyl (2R. 3R. 7S, 8^-5-nhenyl-4.6,10-trioxo-1.5- diazatricvclo[6.2.0.0 ³ ' ⁷ ]-decane-2-carboxylate.

To a solution of/?-nitrobenzyl (2S, 5R)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2- carboxylate (86 mg, 0.28 mmol) in acetonitrile (1.5 cm ³ ) was added N-phenylmaleimide (55 mg, 0.32 mmol) and the solution heated in a sealed tube at 90 °C for 17 h. Solvent was removed under rotary evaporation and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (10 - 50% EtOAc : petroleum ether) afforded (±)p- nitrobenzyl (2Λ, 3R, IS, 8 _l S')-5-phenyl-4,6.10-trioxo-l ,5-diazatricyclo[6.2.0.0 ³ . ⁷ ]-decane-2- carboxylate as a pale yellow oil, which crystallised on standing (29 mg, 24%), m.p. 80 - 84 °C (Found: M ⁺ , 435.1067. C ₂₂ H ₁₇ N ₃ O ₇ requires M, 435.1066); v _max (CH ₂ C1 ₂ ) / cm" ¹ 1780, 1745, 1721, 1608, 1527 and 1418; δ _H (200 MHz) 2.98 (1 H. dd. J 16.7, 2.2), 3.51 (1 H, dd. J

16.7, 5.4), 3.85 (1 H, app. t, J 8.6), 4.09 (1 H. dd. J 8.6, 1.8). 4.38 (1 H, ddd, J 8.6. 5.4, 2.2), 5.18 ( 1 H, d, J 1.8), 5.33 (2 H, s), 7.16 - 7.63 (7 H, m) and 8.22 - 8.32 (2 H, m); m/z (E.I.) 435 (M ⁺ , 8%), 394 (M + H ⁺ - C ₂ H ₂ O, 9) and 255 (100).

p-Nitrobenzyl (2S, 5R)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylate was prepared by the following method:

/7-Nitro benzyl (Z)-(2R, 5Λ)-3(β-hydroxyethylidene)-7-oxo-4-oxa-l-azabicyclo[3.2.0] - heptane-2-carboxylate (p-nitrobenzyl clavulanate).

To a stirred suspension of lithium clavulanate (1.59 g, 7.76 mmol) in DMF (15 cm ³ ) under an atmosphere of nitrogen was added /?-nitrobenzyl bromide (1.85 g, 8.56 mmol). After 72 h the reaction mixture was partitioned between Et ₂ O (100 cm ³ ) and water (50 cm ³ ). The aqueous solution was further extracted with Et ₂ O (3 x 50 cm ³ ) and the ethereal solutions combined, washed with brine and dried (Na ₂ SO ₄ ). The solvent was removed under rotary evaporation and the residual oil purified by flash chromatography on Merck 60 9385) silica-gel (30 - 75% EtOAc : petroleum ether) to give p-nitrobenzyl clavulanate [Reference: A. G. Brown. D. F. Corbett. J. Goodacre, J. B. Harbridge. T. T. Howarth, R. J. Ponsford. I. Stirling and T. J. King, J. Chem. Soc, Perkin Trans. 1. 1984, 635] as a pale yellow oil, which crystallised on standing (1.22 g, 47%); δ _H 1.64 ( 1 H, br s). 3.1 1 (1 H, d, .7 16.5), 3.52 (1 H, dd, J 16.5. 2.7), 4.25 (2 H, d, J 7.0), 4.92 (1 H, td, J 7.0, 1.2), 5.13 ( 1 H, d, J 1.2), 5.30 (2 H, s), 5.71 (1 H, d, J 2.7), 7.52 (2 H, part of AA'BB. J 8.7) and 8.25 (2 II, part of AA'BB', J 8.7).

p-Nitrobenzyl (25, 5R)-3,7-dioxo-4-oxa-l-azabicycIo[3.2.0]-heptane-2-carboxylat e.

A stream of ozone was gently passed through a solution of/7-nitrobenzyl clavulanate ( 1.00 g, 2.99 mmol) in EtOAc (100 cm ³ ) at -78 °C for 45 min, after which time the reaction was complete by tic analysis and a colourless precipitate had formed. The reaction mixture was flushed with a stream of nitrogen whilst allowing it to warm to room temperature, whereupon a solution resulted. The colourless solution was washed successively with water (50 cm ³ ) and brine, dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give /?-nitrobenzyl (2S. 5R)-3J- dioxo-4-oxa-l -azabicyclo[3.2.0]-heptane-2-carboxylate as a colourless solid (0.91 g, 99%),

m.p. 131-133 °C (dec.) (EtOAc / petroleum ether) (Found: C, 51.4; H, 3.3; N, 9.1.

C ₁₃ H _{] 0} N ₂ O ₇ requires C, 51.0; H, 3.3; N, 9.15%); [α] ² _D ³ + 173.6 (c 1.05, CH ₂ C1 ₂ ); v _max / cnr ^l 1808 (br), 1761, 1609, 1527 and 1350; δ _H 3.36 (1 H, dd, J 17.5, 1.0), 3.73 (1 H, dd, J 17.5, 3.0), 5.00 (1 H, s), 5.32 (1 H, part of AB, J 13.2), 5.40 (1 H, part of AB, J 13.2), 5.83 (1 H, dd, J 3.0, 1.0), 7.56 (2 H, part of AA'BB', J 9.0), and 8.27 (2 H, part of AA'BB', J 9.0); δ _c (CD ₃ CN) 48.3, 60.2, 67.4, 86.0, 124.5, 129.4, 143.4, 148.8, 164.5, 169.3, and 174.1 ; m/z (CΛ., NH ₃ ) 324 (M + NH ₄ ⁺ , 18%), 280 (M + NH ₄ ⁺ - CO ₂ , 14) and 263 (M + H ^τ - CO ₂ , 100).

The title compound (±) p-nitrobenzyl (2R, 3R, 7S, 8^-5-phenyl-4,6,10-trioxo-l,5- diazatricyclo[6.2.0.0 ³ > ⁷ ]-decane-2-carboxylate was also prepared by the fusion of p- nitrobenzyl (2S, 57?)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylat e (181) (23 mg, 0.08 mmol) and N-phenylmaleimide (14 mg, 0.08 mmol) at 120 °C (bath temp.) for 45 min. Purification as above yielded (±) p-nitrobenzyl (2R, 3R, 75, 85)-5-phenyl-4,6,10-trioxo-l,5- diazatricycIo[6.2.0.0 ³ ' ⁷ ]-decane-2-carboxyIate as a pale yellow oil. which crystallised on standing (10.3 mg, 31%), for which spectral data were identical with those reported above.

Example 2. (±) Benzyl (2R. 3R. 75, 8.5)-5-phenyl-4,6,10-trioxo-l,5-diazatricvch)- [6.2.0.0 ³ ' ⁷ |decane-2-carboxylate.

To a solution of benzyl (25, 5/?)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxyIat e [Reference: A. G. Brown, D. F. Corbett, J. Goodacre, J. B. Harbridge, T. T. Howarth, R. j. Ponsford, I. Stirling and T. J. King, J. Chem. Soc, Perkin Trans. 1, 1984, 635.] (35.5 mg, 0.14 mmol) in propionitrile (3.0 cm ³ ) was added N-phenylmaleimide (26.4 mg, 0.15 mmol) and the solution heated at reflux for 19.5 h. Solvent was removed under rotary evaporation and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel ( 10 -

30% EtOAc : petroleum ether) afforded (±) benzyl (2R, 3R, IS, 85)-5-phenyl-4,6,10-trioxo- l,5-diazatricyclo[6.2.0.0 ³ _' ⁷ ]decane-2-carboxylate as a colourless oil, which crystallised on standing (30.5 mg, 57%), m.p. 148 - 149 °C (MeOH) (Found: C, 67.32; H, 4.76; N, 7.21; M ⁺ , 390.1226. C ₂₂ H ₁₈ N ₂ O ₅ requires C, 67.69; H, 4.65; N, 7.18%; M, 390.1216); v _max (CH ₂ C1 ₂ ) / cm- ¹ 1779, 1740, 1722, 1499, 1382, 1282 and 1 190; δ _H (400 MHz) 2.93 (1 H, dd, J 16.7, 2.1 ), 3.49 (1 H, dd, J 16.7, 5.3), 3.82 (l H, dd, J9.0, 8.2), 4.05 (1 H, dd, J 8.2, 1.6), 4.37 (1 H, ddd, J 9.0, 5.3, 2.1), 5.16 (1 H, d, J 1.6), 5.22 (1 H, part of AB, J 12.1), 5.25 (1 H, part of AB, J 12.1), 7.17 - 7.19 (2 H, m) and 7.38 - 7.50 (8 H, m); δ _c 41.7, 47.1, 55.1 , 55.4, 62.0, 68.1 , 126.3, 128.4, 128.8, 128.8, 129.4, 129.5, 130.9, 134.6, 168.4, 172.1, 174.3, and 174.5; m/z (E.I.) 390 (M ⁺ , 5%), 348 (M ⁺ - C ₂ H ₂ O, 16), 255 (92) and 91 (100).

Example 3. (±) (2R, 3*, 5J?)-2-Benzyloxycarbonyl-3-methoxycarbonyl-7-oxo-l- azabicvclo(3.2.01 heptane.

H

To a solution of benzyl (25, 5/?)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylat e (20.0 mg, 0.08 mmol) in propionitrile (1.5 cm ³ ) was added methyl acrylate (0.5 cm ³ ) and the solution heated at reflux for 18 h. Solvent was removed under rotary evaporation and purification of the residue by preparative tic (35% EtOAc : 65% petroleum ether) afforded (±) (2R, 3*, 5Λ)-2-benzyloxycarbonyl-3-methoxycarbonyl-7-oxo-l-azabicycl o[3.2.0] heptane as a colourless oil (4.5 mg, 19%) (Found: M ⁺ , 303.1 103. C ₁₆ H ₁₇ NO ₅ requires M, 303.1 107); v _max (CH ₂ Ch) ^{/ cm} ' ^{] 1773} _> 1740 and l649; δ _H 1.89 (1 H, ddd, J 13.0, 10.0, 8.4), 2.50 - 2.60 (1 H, m), 2.78 (1 H, dd, J 15.9, 2.0), 3.31 (1 H, dd, J 15.9, 4.8), 3.62 (1 H, dt, J 10.0, 7.1 ), 3.69 (3 H, s), 3.92 - 4.16 (1 H, m), 4.74 (1 H, d, J 7.1), 5.15 (1 H, part of AB, J 12.3), 5.24 (1 H, part of AB, J 12.3) and 7.35 (5 H, s); m/z (E.l.) 303 (M ⁺ , 1%), 261 (M ⁺ - C ₂ H ₂ O, 6), 168 (21 ) and 91 (100).

Example 4. (±) (IR. 2R, 3R, 5.SV2-Ben-ryIoxycarbonyl-3-methoxycarbonvI-4-methyl-7- oxo- 1 -azabicyclo[3.2.0] heptane.

To a solution of benzyl (25, 5i?)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylat e (100 mg, 0.38 mmol) in propionitrile (2.0 cm ³ ) was added methyl crotonate (1.0 cm ³ ) and the solution heated at reflux for 7.5 h. Solvent was removed under rotary evaporation and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (0 - 50% EtOAc : petroleum ether) afforded (±) (IR, 2R. 3R, 55)-2-benzyloxycarbonyl-3- methoxycarbonyl-4-methyl-7-oxo-l-azabicyclo[3.2.0]heptane as a colourless crystalline solid (58 mg, 48%), m.p. 91 - 91.5 °C (benzene / petroleum ether) (Found: C, 63.9; H, 6.0; N, 4.2. C ₁₇ H ₁₉ NO ₅ requires C, 64.3; H, 6.0; N, 4.4%); v _max (CH ₂ C1 ₂ ) / cm" ¹ 1773, 1741, 1282 and 1203; δ _H 1.20 (3 H, d, J 6.6), 2.10 - 2.16 (1 H, m), 2.71 (1 H, dd, J 15.6, 1.7). 3.21 (1 H, dd. J 10.6, 8.6). 3.26 (1 H, dd, J 15.6, 4.8), 3.50 (1 H, ddd, J 7.0. 4.8, 1.7), 3.67 (3 H. s). 4.70 (1 H, d, J 10.6), 5.12 (1 H, part of AB, J 12.5), 5.24 (1 H, part of AB, J 12.5) and 7.35 (5 H, s); δ _c 14.6, 41.9, 45.2, 52.4, 58.9, 60.1 , 61.4. 67.3, 128.0, 128.5, 128.6, 135.5. 169.9. 171.1. and 174.7; m/z (E.I.) 317 (M ⁺ , 1%), 275 (M ⁺ - C ₂ H ₂ 0, 7) and 91 (100).

Example 5. (±) (2R. 3*. 4*, 5,SV2-Benzyloxycarbonv--3,4-bis(ethoxycarbonvn-7-oxo-l- azabicvclo|3.2.01heptane.

To a solution of benzyl (25, 5Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylat e (175 mg, 0.67 mmol) in acetonitrile (2.0 cm ³ ) was added diethyl maleate (130 mg, 0.76 mmol) and the solution heated in a sealed tube at 95 °C for 18 h. Solvent was removed under rotary evaporation and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (10 - 30% EtOAc : petroleum ether 40 - 60 °C) afforded (±) (2R, 3*, 4*, 55)- 2-benzyloxycarbonyl-3,4-bis(ethoxycarbonyl)-7-oxo-l-azabicyc lo[3.2.0]heptane as a colourless oil (30.3 mg, 12%) (Found: M + H ⁺ , 390.1553. C ₂₀ H ₂₄ NO ₇ requires M. 390.1553); v _max (CH ₂ Cl ₂ ) / cm- 1 1782, 1742, 1422 and 1 196; δ _H (250 MHz) 1.15 (3 H. t, J 7.1), 1.24 (3 H, t, J 7.1), 2.73 (1 H, dd, J 16.3, 2.3), 3.23 (1 H, dd, J 16.3, 5.0), 3.55 (1 H, app. t, J6.9), 4.01 (1 H, dd. J7.8, 6.9), 4.10 (2 H, q, J7.1), 4.06 - 4.20 (1 H, m), 4.15 (2 H, q, J 7.1), 4.89 ( 1 H, d, J 7.8), 5.18 (1 H, part of AB, J 12.3), 5.25 (1 H, part of AB, J 12.3) and 7.29 - 7.40 (5 H, m); m/z {Cl. NH ₃ ) 407 (M + NH ₄ ⁺ , 53%), 390 (M + H ⁺ . 82) and 348 (M + H ⁺ - C ₂ H ₂ O, 100).

Example 6. (±) Benzyl (2R, 4*, 5.SV7-oxo-4-phenylsu-fonyl-l-azabicvclo[3.2.01heptane-2- carboxylate and (±) benzyl (2R, 3*, 54y)-7-oxo-3-phenylsulfonyl-l- azabicvclol3.2.0|heptane-2-carboxylate.

To a solution of benzyl (25, 5/?)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxyIat e (70 mg, 0.27 mmol) in propionotrile (4.0 cm ³ ) was added phenyl vinyl sulfone (60 mg, 0.36 mmol) and the solution heated at reflux for 3.5 h. Removal of solvent in vacuo and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (25 - 50% EtOAc : petroleum ether) gave (±) benzyl (2R, 4*, 55)-7-oxo-4-phenylsulfonyl-l - azabicyclo[3.2.0]heptane-2-carboxylate (Found: M + H ⁺ - C ₂ H ₂ O, 344.0957. C _{l g} H ₁₈ NO ₄ S requires M 344.0957); v _max (CH ₂ C1 ₂ ) / cm" ¹ 1780. 1744 and 1270; δ _H 2.33 ( 1 H, ddd. J 13.9, 8.6, 7.5), 2.62 (1 H, ddd, J 13.9. 8.6, 7.2), 2.95 (1 II, dd, J 15.8, 2.2), 3.34 (1 H, dd. J 15.8.

4.9), 3.97 - 4.03 (1 H, m), 4.39 (1 H, td, 78.6, 5.5), 4.77 (1 H. d, J 5.5), 4.96 (1 H, part of AB, J 12.5), 4.98 (1 H, part of AB, J 12.5), 7.19 - 7.22 (2 H, m), 7.34 - 7.36 (3 H, m), 7.48 - 7.53 (2 H, m), 7.60 - 7.65 (1 H, m) and 7.87 - 7.90 (2 H, m); m/z (C.I.) 344 (M + H ⁺ - C ₂ H ₂ O, 100%) and 91 (43) as a colourless oil (10 mg, 10%) followed by (±) benzyl {2R, 3*, 5^-7- oxo-3-phenylsulfonyl-l-azabicyclo[3.2.0]heptane-2-carboxylat e (Found: M + H ⁺ - C ₂ H ₂ O, 344.0957. C ₁₈ H ₁₈ NO ₄ S requires M, 344.0957); v _max (CH ₂ C1 ₂ ) / cm" ¹ 1780, 1745, 1657, 1604, 1284, 1244 and 1 152; δ _H 2.34 (1 H, ddd, J 13.6, 7.3, 2.4), 2.68 (1 H, ddd, J 13.6, 10.0, 8.0), 3.38 (1 H, dd, J 16.9, 5.7), 3.63 - 3.70 (1 H, m), 4.04 (1 H, dd, J 16.9, 3.2), 4.14 - 4.22 (1 H, m). 4.77 (1 H, dd, J 8.0, 2.4), 5.09 (1 H, part of AB, J 1 1), 5.13 (1 H, part of AB, J 1 1), 7.28 - 7.37 (5 H, m), 7.58 - 7.75 (3 H, m) and 7.87 - 7.90 (2 H, m); m/z (C.I.) 344 (M + H ⁺ - C ₂ H ₂ O, 2%) and 91 (100) as a colourless oil (25 mg, 24%). Each regioisomer was determined to be a single diastereoisomer.

Example 7. (±) Sodium (IR. 2R. 3R. 55)-3-methoxycarbonyl-4-rnethyl-7-oxo-l- azabicyclof3.2.01heptane-2--carboxylate.

To a stirred solution of (±) (IR, 2R, 3R, 54S)-2-benzyloxycarbonyl-3-methoxycarbonyl-4- methyl-7-oxo-l-azabicyclo[3.2.0]heptane (9.3 mg, 29 μmol) in ethyl acetate (1.0 cm ³ ) was added water (0.5 cm ³ ), sodium bicarbonate (3.2 mg, 32 μmol) and a catalytic amount of 10% palladium on carbon. After stirring vigorously under an atmosphere of hydrogen for 30 minutes, tic analysis of the organic solution showed complete consumption of the starting material. The reaction mixture was filtered through a pad of celite and the residue washed with water. The phases were separated and the organic solution further washed with water, and the combined aqueous solutions freeze-dried to afford (±) sodium (\R, 2R, 3R, 55)-3- methoxycarbonyl-4-methyl-7-oxo-l-azabicyclo[3.2.0]heptane-2- -carboxylate as a hygroscopic colourless solid (5.0 mg, 68%); δ _H 1.08 (3 H, d, J 6.8), 2.07 - 2.16 (1 H. m), 2.76

(l H, dd, J 16.1, 1.7), 3.06 (1 H, dd, J 10.3, 8.2), 3.21 (1 H, dd, J 16.1, 4.4), 3.52 (1 H, ddd, J

8.0, 4.4, 1.7), 3.70 (3 H, s) and 4.37 (1 H, d, J 8.2); m/z (FAB) 272 (M + Na ⁺ , 44%) and 250 (M + H\ 46).

Example 8. (±) Benzyl (25. 5.SV3-methylth-o-7-oxo-l-azabicvclo[3.2.01hept-3-ene-2- carboxylate.

To a solution of benzyl (25, 5/?)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylat e (171 mg, 0.65 mmol) in acetonitrile (2.0 cm ³ ) was added ketene dimethyl thioacetal monoxide [Reference R. Kaya and N. R. Beller, J. Org. Chem., 1981, 46, 196.] (155 mg, 1.14 mmol) and the solution heated in a sealed tube at 1 10 ^C C for 8 h. Solvent was removed under rotary evaporation and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (30% EtOAc : 70% petroleum ether) afforded (±) benzyl (25, 5^-3- methylthio-7-oxo-l-azabicyclo[3.2.0]hept-3-ene-2-carboxylate as a pale yellow oil (17.0 mg, 9%) [Reference S. M. Schmitt, D. B. R. Johnston and B. G. Christensen, J Org. Chem., 1980, 45, 1 135]; δ _H (CDC1 ₃ ) 2.34 (3 H, s), 2.85 (1 H. dd, J 16.0, 2.8), 3.39 (1 H. dd, J 16.0, 5.4). 4.62 (1 H, m), 5.15 (1 H, dd, J3.3, 1.8), 5.18 (1 H, part of AB, J 12), 5.19 (1 H, part of AB, J 12), 5.67 (1 H, app. t, J 1.8) and 7.34 - 7.38 (5 H, m); δ _H (DMSO -d ₆ ) 2.35 (3 H, s), 2.87 (1 H, dd, J 16.3, 2.7), 3.44 (1 H, dd, J 16.3, 5.5), 4.52 (I H, m), 5.00 (l H, dd, J 3.1 , 1.8), 5.16 (2 H. s), 5.93 (1 H, app. t, J 1.8) and 7.33 - 7.38 (5 H, m).

Example 9. (±) p-Nitrobenzyl (25. 5^-7-oxo-3-phenyl-l-azabicvclof3.2.01hent-3-ene-2- carboxylate.

H

To a solution ofp-nitrobenzyl (25, 5Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2- carboxylate (210 mg, 0.69 mmol) in propionitrile (5.0 cm ³ ) was added phenylacetylene (1.0 cm ³ ) and the solution heated at reflux for 2.5 h, during which time considerable darkening of the solution was observed. Solvent was removed under rotary evaporation to give a dark brown oil and purification by successive flash chromatography on Merck 60 (Art. 9385) silica-gel (10 - 40% EtOAc : petroleum ether) and preparative tic (30 - 40% EtOAc : petroleum ether; 2 elutions) afforded (±)/?-nitrobenzyl (25, 55)-7-oxo-3-phenyl-l- azabicyclo[3.2.0]hept-3-ene-2-carboxyiate as a colourless solid (18 mg, 6%), m.p. 1 19 - 120 °C (Found: M ⁺ , 364.1056. C ₂₀ H ₁₆ N ₂ O ₅ requires M, 364.1059); v _max (CH ₂ C1 ₂ ) / cm" ¹ 1778, 1750, 1607, 1526 and 1424; δ _H 2.97 (1 H, dd, J 16.1 , 2.9), 3.51 (1 H, dd. J 16.1, 5.7), 4.68 - 4.78 (1 H, m), 5.10 ( 1 H, part of AB, J 13.4), 5.23 ( 1 H, part of AB, J 13.4), 5.69 (1 H, dd, J 3.4, 1.9), 6.50 (1 H, app. t, J 1.9), 7.18 (2 H, part of AA'BB'. J 8.8), 7.34 - 7.45 (5 H, m) and 8.07 (2 H, part of AA'BB', J 8.8); m/z (E.I.) 364 (M ^~ , 68%), 336 (70), 184 (82) and 156 (100).

Example 10. (±) Benzyl (25, 55)-7-oxo-3-phenyl-l-azabicvclof3.2.0]hent-3-ene-2- carboxylate.

To a solution of benzyl (25, 5Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylat e (126 mg, 0.48 mmol) in acetonitrile (0.75 cm ³ ) was added phenylacetylene (56 mg, 0.55 mmol) and the solution heated in a sealed tube at 90 °C for 33 h. Solvent was removed under rotary evaporation and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (10 - 40% EtOAc : petroleum ether) afforded (±) benzyl (25, 54S>7-oxo-3-

phenyl-l-azabicyclo[3.2.0] hept-3-ene-2 -carboxy late as a colourless oil (18 mg, 12%) (Found:

M + H+, 320.1287. C ₂₀ H _{l 8} NO ₃ requires M, 320.1287); v _max (CH ₂ C1 ₂ ) / cm ^{" 1} 1777, 1744, 1605, 1497 and 1172; δ _H (200 MHz) 2.93 (1 H, dd, J 16.0, 2.9), 3.48 (1 H, dd, J 16.0, 5.6), 4.68 - 4.79 (1 H, m), 5.04 (1 H, part of AB, J 13), 5.12 (1 H, part of AB, J 13), 5.63 (1 H, dd, J3.4, 1.9), 6.49 (1 H, app. t, J 1.9) and 7.10 - 7.50 (10 H, m); m/z (Cl.) 320 (M + H ⁺ , 7%), 278 (M + H ⁺ - C ₂ H ₂ O, 100), 156 (57) and 91 (33).

Example 11. (±) (25, 5^-2-Benzyloxycarbonyl-4-methoxycarbonyl-3-methyl-7-oxo-l- azabicyclo[3.2.01hept-3-ene.

To a solution of benzyl (25, 5/?)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptanc-2-carboxylat e (132 mg, 0.51 mmol) in acetonitrile (2.0 cm ³ ) was added methyl 2-butynoate (54 mg, 0.55 mmol) and the solution heated in a sealed tube at 95 °C for 18 h. Solvent was removed under rotary evaporation and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (10 - 30% EtOAc : petroleum ether 40 - 60 °C) afforded (±) (25, 55)-2- benzyloxycarbonyl-4-methoxycarbonyl-3-methyl-7-oxo- 1 -azabicyclo[3.2.0]hept-3-ene as a colourless crystalline solid (1 1.2 mg, 7%), m.p. 143 - 146 °C (Found: M ⁺ - C ₂ H ₂ O, 273.0999. C _{! 5} H , ₅ NO ₄ requires M, 273.100 l); v _max (CH ₂ Cl ₂ ) / cm-' 1780 and 1747; δ _H 2.17 (3 H, dd, J

1.8, 0.9), 2.94 (1 H, dd, J 16.3, 2.9), 3.51 (1 H, dd, J 16.3, 5.5), 3.78 (3 H, s), 4.68 - 4.75 (1 H, m), 5.1 1 (1 H, dd, J 3.4, 0.9), 5.15 (1 H, part of AB, J 12.3), 5.22 (1 H, part of AB, J 12.3) and 7.36 (5 H, s); m/z (FAB) 316 (M + H ⁺ , 49%) and 274 (M + H ⁺ - C ₂ H ₂ 0, 100).

Example 12. (±) (2R. 5^-2-Benzyloxycarbonyl-3.4-bis(methoxycarbonyl)-7-oxo-l- azabicvclo[3.2.0jhept-3-ene.

To a solution of benzyl (25, 5Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylat e (128 mg, 0.49 mmol) in propionitrile (5.0 cm ³ ) was added dimethyl acetylenedicarboxylate (0.5 cm ³ ) and the solution heated at reflux for 6 h. Solvent was removed under rotary evaporation and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (20 - 30% EtOAc : petroleum ether) afforded (±) (2R, 5^-2-benzyloxycarbonyl-3,4- bis(methoxycarbonyl)-7-oxo-l-azabicyclo[3.2.0]hept-3-ene as a viscous pale yellow oil (81 mg, 46%) (Found: M + H ^* . 360.1083. C ₁₈ H ₁₈ N0 ₇ requires M. 360.1083); v _max (CH ₂ C1 ₂ ) / cm" ¹ 1790, 1741 (br), 1645 and 1032; δ _H 3.12 (1 H, dd. J 16.5, 2.9), 3.57 (1 H, dd. J 16.5. 5.9), 3.63 (3 H, s), 3.83 (3 H, s), 4.84 (1 H, ddd, J 5.9. 3.7. 2.9). 5.14 (1 H, part of AB, J 12.1), 5.20 (1 H, part of AB, J 12.1), 5.47 (1 H. d, J 3.7) and 7.34 - 7.37 (5 H, m); δ _c 44.9, 52.5, 52.7, 60.3, 67.0, 67.8, 128.4, 128.5, 134.6, 140.0, 140.2, 162.0. 162.4, 166.7, and 176.3; m/z (C.I., NH ₃ ) 377 (M + NH ₄ ⁺ , 95%), 360 (M + H ⁺ , 50), 318 (M + H ⁺ - C ₂ H ₂ 0, 100) and 91 (78).

Example 13. Ethyl (2R. 3R. 75. 85, 95)-ll(R)-/g/-/-butyldimethylsilyloxyethylI-5-nhenyl- 4,6,10-trioxo-l,5-diazatricvclo[6.2.0.0 ³ ' ⁷ ldecane-2-carboxylate.

To a solution of ethyl (25, 5R, 6/?)-6-[l (Λ)-/er/-butyldimethylsilyloxyethyl]-3,7-dioxo-4-oxa- l -azabicyclo[3.2.0]heptane-2-carboxylate in acetonitrile (2.0 cm ³ ) was added N- phenylmaleimide (49 mg, 0.28 mmol) and the solution heated at reflux for 15 h. Removal of

solvent in vacuo and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (10 - 25% EtOAc : petroleum ether) afforded ethyl (2R, 3R, IS, 85, 95)-[l(/?)- /er/-butyldimethylsilyloxy-ethyl]-5-phenyl-4,6,10-trioxo-l,5 -diazatricyclo[6.2.0.0 ³ _' ⁷ ]decane- 2-carboxylate as a colourless solid (25 mg, 20 %), m.p. 182 - 183 °C (EtOAc / petroleum ether) (Found: M + H ⁺ , 487.2264. C ₂₅ H ₃₅ N ₂ O ₆ Si requires M, 487.2264); [a]% -7.3 (c 0.62, CHC1 ₃ ); v _max (CH ₂ C1 ₂ ) / cm-' 1773, 1738 and 1721; δ _H 0.05 (3 H, s), 0.06 (3 H, s), 0.87 (9 H, s), 1.20 (3 H, d, J6.4), 1.32 (3 H. t, 77.1 ), 3.06 (1 H, app. t, J 2.1), 3.84 (1 H, dd, 79.4, 8.5), 4.13 (1 H, dd, 78.5, 1.5). 4.17 - 4.32 (3 H, m), 4.40 (1 H, dd, 79.4, 2.1), 5.09 (1 H, d, 7 1.5), 7.18 - 7.21 (2 H, m) and 7.43 - 7.52 (3 H, m); m/z (C.I.) 487 (M + H ⁺ , 18%), 471 (M ⁺ - Me, 1 1 ), 429 (M ⁺ - «Bu, 100) and (M + H ⁺ - 'ketene', 25).

The ethyl (25, 5R, 6R)-6-[l(R)-/er«'-butyldimethyIsilyloxyethyI]-3,7-dioxo-4-o xa-l- azabicyclo[3.2.0]heptane-2-carboxylaτe was prepared in the following way:

(35, 4R)-3-[l(R)-ter/-butyldimethy-siIyloxyethyl]-4-chJoro-2-azet idinone.

To a solution of (35, 4Λ)-3-[l(Λ)-/ι?r/-butyldimethylsilyloxyethyl]-4-methylthi o-2-azetidinone [Reference M. Murakami, T. Aoki, M. Matsuura and W. Nagata, 7. Antibiot. , 1990, 43, 1441 ] (1.32 g, 4.80 mmol) in CH ₂ C1 ₂ (10 cm ³ ) at -20 °C (bath temp.) was gently passed a stream of chlorine until consumption of the starting material was complete (as judged by tic analysis) and a yellow coloured solution just persisted. Solvents were removed in vacuo to give a colourless solid residue which was slurried in cold w-hexane. Filtration yielded (35, AR)-3- [l(R)-/err-butyldimethylsilyloxyethyl]-4-chloro-2-azetidinon e as a colourless solid (1.05 g, 83%), m.p. 75 - 77 °C (dec.) (lit. 84 - 85 °C) [Reference M. Endo, Can. J. Chem. , 1987, 65, 2140]; δ _H 0.06 (3 H, s), 0.08 (3 H, s), 0.86 (9 H, s). 1.28 (3 H, d, 76.4), 3.44 (1 H, m), 4.24 (1 H, qd, 76.4, 3.1), 5.69 (1 H, d. 7 1.3) and 6.32 (1 H, br s).

(35, 4R)-3-[l(R)-*W^buryldimethylsilyloxyethyl]-2-azetidinone-4-y l ethyl diazomalonate.

Into a solution of (35, 4/?)-3-[l(Λ)-<'er/-butyldimethylsilyloxyethyl]-4-chloro- 2-azetidinone (1.02 g, 3.87 mmol) in THF (5 cm ³ ) at room temperature under nitrogen was added potassium ethyl diazomalonate [Reference F. Kido, K. Yamaji, T. Abiko and M. Kato, 7 Chem. Res. (S), 1993, 18] (1.00 g, 5.10 mmol). After stirring vigorously for 4 h the mixture was partitioned between EtOAc (50 cm ³ ) and water (20 cm ³ ) and the aqueous solution further extracted with EtOAc (20 cm ³ ). The combined organic solutions were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to a pale yellow oil. Purification by flash chromatography on Merck 60 (Art. 9385) silica-gel (10 - 25% EtOAc : petroleum ether) afforded (35, 4i?)-3-[l(i?)-/er/-butyldimethylsilyloxyethyl]-2-azetidinone -4-yl ethyl diazomalonate as a colourless oil (0.64 g, 37%) (Found: M ⁺ - ^l Bu, 328.0980. C ₁₂ H ₁₈ N ₃ O ₆ Si requires M, 328.0965); [α] ² _D ' + 45.6 (c 2.28, CHC1 ₃ ); v _max (CH ₂ C1 ₂ ) / cm" ¹ 3410, 2145, 1791, 1756, 1732, 1692, 1422, 1321 and 1074; δ _H 0.06 (3 H. s), 0.08 (3 II, s), 0.87 (9 H. s), 1.27 (3 H, d, 76.4), 1.33 (3 H, t, 77.1 ), 3.23 (1 H, dd, 73.4, 1.2), 4.24 (1 H, qd, 76.4, 3.4), 4.33 (2 H, q, 77.1 ), 6.01 (1 H, d, 7 1.2) and 6.53 (1 H, br s); m/z (E.I.) 328 (M ⁺ - «Bu, 1 1%), 285 (M ⁺ - 'ketene', 5) and 75 (100).

Ethyl (25, 5R, 6R)-6-{l(R)-terNbutyldimethylsilyloxyethyI]-3,7-dioxo-4-oxa- l- azabicyclo[3.2.0]heptane-2-carboxylate.

To a solution of (35, 4Λ)-3-[l(Λ)-/ _< ?r/-butyidimethylsilyloxyethyl]-2-azetidinone-4-yl ethyl diazomalonate (100 mg, 0.26 mmol) in CH ₂ C1 ₂ (1.0 cm ³ ) was added Rh ₂ (OAc) ₄ (5 mol%) and the reaction mixture heated at reflux for 3 h. Removal of solvent in vacuo gave ethyl (25, 5R, 6/?)-6-[l(Λ)-rer/-butyldimethylsilyloxyethyl]-3,7-dioxo-4-o xa-l- azabicyclo^^.OJheptane^-carboxylate v^x ^H^l^ / cm- ¹ 1818, 1801 , 1743, 1420 and 1343; δ _H 0.07 (3 H, s), 0.09 (3 H, s), 0.88 (9 H, s), 1.32 (3 H, d, 76.2), 1.32 (3 H, t, 77.1), 3.42 (1 H, dd, 73.7, 0.7), 4.25 - 4.32 (1 H, m), 4.28 (1 H, q, 77.1 ), 4.87 (1 H, s) and 5.81 (1 H, d, 70.7)., which was used (above) without further purification.

Example 14. Benzyl (2R. 3R, 75. 85. 95)-H(R)-fer/-butyldimethylsilyloxyethvIl-5-phenyl- 4,6.10-trioxo-1.5-diazatricvclo[6.2.0.0 ³ ' ⁷ ldecane-2-carboxylate.

To a solution of the crude benzyl (25. 5R, 6Λ)-6-[ l(Λ)-<'er/-butyldimethylsilyloxyethyl]-3.7- dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylate in toluene (2.0 cm ³ ) was added N- phenylmaleimide (100 mg, 0.58 mmol) and the solution heated at reflux for 24 h. Removal of solvent in vacuo and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (10 - 20% EtOAc : petroleum ether) afforded benzyl (2R, 3R, 75, 85, 95)- [ 1 (Λ)-/er/-butyldimethylsilyloxyethyl]-5-pheny 1-4,6, 10-trioxo- 1 ,5- diazatricyclo[6.2.0.0 ³ - ⁷ ]decane-2-carboxylate as a colourless solid (77 mg, 25 %), m.p. 137 °C (EtOAc / petroleum ether) (Found: C, 65.93; H, 6.99; Ν, 5.04. C ₃₀ H ₃₆ Ν ₂ O ₆ Si requires C,

65.67; H, 6.61 ; N, 5.1 1%); [α] ^: _D ³ -12.8 (c 1.09, CHC1 ₃ ); v _max (CH ₂ C1 ₂ ) / cm ^{" 1} 1773, 1744 and 1721 ; δ _H 0.03 (3 H, s), 0.05 (3 H, s). 0.85 (9 H. s), 1.19 (3 H, d, 76.2), 3.05 (1 H, dd, 73.0, 2.2), 3.82 (1 H, dd.79.3, 8.2). 4.08 (1 H, dd, 7 8.2, 1.5), 4.25 (1 H, qd, 76.2, 3.0), 4.40 ( 1 H, dd, 79.3, 2.2), 5.15 (1 H, d, 7 1.5), 5.15 (1 H, part of AB, J 12), 5.25 (1 H, part of AB, J 12),

7.17 - 7.20 (2 H, m) and 7.34 - 7.51 (8 H, m); δ _c -5.3, -4.5, 17.8, 22.2, 25.5, 46.5, 55.2, 56.6, 61.4, 63.1, 64.3, 67.9, 126.2, 128.4, 128.6, 129.2, 129.3, 131.0, 134.6, 168.3, 172.4, 174.5 and 174.6; m/z (C.I.) 549 (M + H ⁺ , 23%), 533 (M ⁺ - Me, 8), 491 (M ⁺ - ^l Bu, 46), 349 (M + H ⁺ - 'ketene', 25) and 91 (100).

The benzyl (25, 5R, 6R)-6-[l(R)-^r/-butyIdimethylsilyloxyethyl]-3,7-dioxo-4-oxa- l- azabicyclo[3.2.0]heptane-2-carboxylate was prepared in the following way:

Potassium benzyl diazomalonate.

C0 ₂ K

N ₂ =<

CO ₂ Bn

To a stirred pale yellow solution of dibenzyl diazomalonate (29.6 g, 95.5 mmol) in benzyl alcohol (100 cm ³ ) at room temperature was added a solution of potassium hydroxide (5.35 g, 95.5 mmol) in benzyl alcohol (80 cm ³ ). A deep yellow viscous solution resulted immediately followed by dense precipitation within 5 min. After stirring for a further 30 min the mixture was diluted with Et ₂ O (200 cm ³ ) and filtered. The residue was washed well with Et ₂ O to give the mono potassium salt as a pale yellow solid (17.3 g, 70%), decomposes at 170 °C without melting (Found: C, 46.10; H, 2.60; N, 10.66. C _l0 H ₇ N ₂ O ₄ K requires C, 46.50; H, 2.73; N, 10.85%); v _max (mull) / cm"' 21 15, 1706. 1603, 1455, 1386, 1283 and 1096; δ _H (D ₂ O) 5.24 (2 H, s) and 7.35 - 7.45 (5 H, m).

Benzyl (35, 4R)-3-[l(R)-/er/-butyIdimethylsilyloxyethyl}-2-azetidinone-4 -yl diazomalonate.

To a solution of (35, 4/?)-3-[l(Λ)-/er/-butyldimethylsilyloxyethyl]-4-chloro-2-az etidinone (5.27 g, 20 mmol) in THF (40 cm ³ ) at room temperature under nitrogen was added potassium benzyl diazomalonate (5.16 g, 20 mmol). The mixture was stirred for 4 h and then partitioned between EtOAc (150 cm ³ ) and water (50 cm ³ ). The organic solution was washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to a viscous yellow oil. Crystallisation from petroleum ether afforded benzyl (35, 4R)-3-[l(R)-tert- butyldimethylsilyloxyethyl]-2-azetidinone-4-yl diazomalonate as a colourless solid (5.37 g, 60%>), m.p. 96 - 97.5 °C (Et ₂ O / petroleum ether) (Found: C, 56.38; H, 6.85; N, 9.37.

C ₂ ,H ₂₉ N ₃ O ₆ Si requires C, 56.35; H, 6.54; N, 9.39%); [αβ +43.7 (c 2.00, CHC1 ₃ ); v max (CH ₂ C1 ₂ ) / cm-' 3407, 2146, 1791, 1758, 1732 and 1694; δ _H 0.06 (3 H, s), 0.07 (3 H, s), 0.86 (9 H, s), 1.24 (3 11, d, J6.4), 3.21 (1 H, dd, J 3.3, 1.2), 4.22 (1 H, qd, J6.4, 3.3), 5.28 (2 H. s), 6.00 (1 H. d. J 1.2), 6.69 (1 H, br s) and 7.37 (5 H, s); m/z (E.I.) 390 (M ⁺ - ^l Bu. 1%) and 91 (100).

Benzyl (25, 5R, 6R)-6-[l(R)-/έ?rt-butyldimethylsilyIoxyethyl]-3,7-dioxo-4-o xa-l- azabicyclo[3.2.0]heptane-2-carboxylate.

To a solution of benzyl (35, 4R)-3-[l(Λ)-/<?r/-butyldimethylsilyloxyethyl]-2-azetidin one-4-yl diazomalonate (250 mg, 0.56 mmol) in CH ₂ C1 ₂ (2.0 cm ³ ) was added Rh ₂ (OAc) ₄ (5 mol%) and the reaction mixture heated at reflux for 3 h. Removal of solvent in vacuo gave benzyl (25, 5R, 65)-6-[l (Λ)-/er/-butyldimethylsilyloxyethyl]-3,7-dioxo-4-oxa-l- azabicyclo[3.2.0]heptane-2-carboxylate; v _max (CH ₂ C1 ₂ ) / cm" ¹ 1801 (br) and 1756; δ _H 0.05 (3 H, s), 0.07 (3 H. s), 0.86 (9 H, s), 1.30 (3 H, d, J 6.2), 3.42 ( 1 H, dd, J 3.7, 0.7), 4.29 (1 H, qd, J 6.2, 3.7), 4.92 (1 H, s), 5.24 (2 H, s), 5.78 (1 H, d, J 0.7) and 7.37 (5 H, s), which was used (above) without further purification.

Example 15. 3.4-c.j-(2R. 3*. 4*. 55. 6R>-2-Benzyloxycarbonyl-ri(R>-fert- butyldimethylsilyloxyethyl1-3.4-bis(methoxycarbonyl)-7-oxo-l -azabicvclof3.2.01heptane.

To a solution of benzyl (25, 5R, 65)-6-[l(Λ)-/er/-butyldimethylsilyloxyethyl]-3,7-dioxo-4- oxa-l-azabicyclo[3.2.0]heptane-2-carboxylate [prepared from benzyl (35, 4R)-3-[\(R)-tert- butyldimethylsilyloxyethyl]-2-azetidinone-4-yl diazomalonate (112 mg, 0.25 mmol) by the method of Example 14] in acetonitrile (2.0 cm ³ ) was added dimethyl maleate (52 mg, 0.36 mmol) and the solution heated in a sealed tube at 1 10 °C for 3 h. Removal of solvent in vacuo and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (20% EtOAc : 80% petroleum ether) afforded 3A-cis-(2R, 3*. 4*, 55, 6R)-2- benzyloxycarbonyl-[l(Λ)-/er/-butyldimethylsilyloxyethyl]-3, 4-bis(methoxycarbonyl)-7-oxo- l-azabicyclo[3.2.0]heptane as a colourless solid (25 mg, 19 %), m.p. 109 - 1 1 1 °C (Found: M + H ⁺ , 520.2374. C ₂₆ H ₃₈ NO ₈ Si requires M, 520.2367); [α] ² _D ' +37.1 (c 0.93, CHC1 ₃ ); v _max

(CH ₂ C1 ₂ ) / cm- ^l 1778, 1745 and 1422; δ _H 0.02 (3 H, s), 0.05 (3 H, s), 0.84 (9 H, s), 1.20 (3 H, d, J6.2). 2.95 (1 H, dd, J 4.1. 2.3), 3.60 (1 H, app. t. J 7.2), 3.65 (3 H, s), 3.69 (3 H, s), 4.02 (1 H, app. t. J 7.2), 4.14 (1 H, dd, J7.2, 2.3). 4.22 (1 H, qd, J 6.2, 4.1 ), 4.87 (1 H, d, J 7.2), 5.15 (1 H, part of AB, J 12.3), 5.25 (1 H, part of AB. J 12.3) and 7.31 - 7.37 (5 H, m); m/z (C.I.) 520 (M + H ⁺ , 1 1%), 504 (M ⁺ - Me, 15), 462 (M ⁺ - ^l Bu, 54), 320 (M + H ⁺ - 'ketene', 100) and 91 (71).

Example 16. 3A-trans-(2R. 3*. 4*. 55. 6R)-2-Benzyloxycarbonyl-[l(R)-/grf- butyldimethylsilyloxyethyl1-3.4-bis(methoxycarbonyl)-7-oxo-l -azabicvcIo[3.2.0|heptane isomers.

To a solution of the crude benzyl (25, 5R, 64S>6-[l(Λ)-/er/-butyldimethylsilyloxyethyl]-3.7- dioxo-4-oxa-l -azabicyclo[3.2.0]heptane-2-carboxylate in acetonitrile (4.0 cm ³ ) was added dimethyl fumarate (288 mg, 2.0 mmol) and the solution heated in a sealed tube at 1 10 °C for 3 h. 'H-nmr analysis of the crude reaction mixture revealed an approximate 3:1 mixture of cycloadduct isomers. Removal of solvent in vacuo and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (10 - 30% EtOAc : petroleum ether) afforded the minor isomer of 3A-trans-(2R, 3*, 4*, 55, 6/?)-2-benzyloxycarbonyl-[l(/?)-rm- butyldimethylsilyloxyethyl]-3,4-bis(methoxycarbonyl)-7-oxo-l -azabicyclo[3.2.0]heptane as a pale yellow oil (66 mg, 6%); (Found: M + H ⁺ , 520.2361. C ₂₆ H ₃₈ NO ₈ Si requires M,

520.2367); v _max (CH ₂ C1 ₂ ) / cm" ¹ 1777 and 1742; δ _H 0.04 (3 H, s), 0.05 (3 H, s), 0.86 (9 H, s),

1.12 (3 H, d, J6.2), 2.97 (1 H, dd, J 4.0, 3.1), 3.50 (3 H, s), 3.71 (1 H, dd, J 10.8, 7.5), 3.73 (3 H. s), 3.96 (1 H, dd, J 10.8, 9.3), 4.20 (1 H, qd, J 6.2, 4.0), 4.36 (1 H, dd, J 9.3, 3.1 ), 4.92 (1 H, d, J 7.5), 5.10 (1 II, part of AB, J 12), 5.12 (1 H, part of AB, J 12) and 7.35 (5 H, s); m/z (C.I.) 520 (M + H ⁺ , 51%), 504 (M ⁺ - Me, 23), 462 (M ⁺ - ^l Bu, 39), 320 (M + H ⁺ - 'ketene', 100), 288 (47) and 91 (70); followed by the major isomer of 3A-trans-(2R. 3*, 4*, 55, 6Λ)-2- benzyloxycarbonyl-[l(/?)-»'er/-butyldimethylsilyloxyethyl]- 3,4-bis(methoxycarbonyl)-7-oxo- l-azabicyclo[3.2.0]heptane as a pale yellow oil (213 mg, 21 %);(Found: M + H ⁺ , 520.2351. C ₂₆ H ₃₈ NO ₈ Si requires M, 520.2367); [α] ² _D ' +42.9 (c 1.19, CHC1 ₃ ); v _max (CH ₂ C1 ₂ ) / cm" ¹ 1780 - 1730 (br) and 1437; δ _H 0.03 (3 H, s), 0.06 (3 H, s), 0.85 (9 H, s), 1.22 (3 H, d, J6.0),

3.15 (1 H, dd, 75.0, 1.9), 3.26 (1 H, dd, 79.0, 7.5), 3.68 (3 H, s), 3.71 (3 H, s), 4.06 (1 H, dd, 77.5, 1.9), 4.10 (1 H, dd, 79.0, 6.8), 4.21 (1 H, qd, 76.0, 5.0), 4.69 (1 H, d, 76.8), 5.14 (1 H, part of AB, 7 12.3), 5.21 (1 H, part of AB, 7 12.3) and 7.35 (5 H, s); δ _c -5.2, -4.5, 17.8, 22.4, 25.5, 51.2, 52.2, 52.8, 55.5, 58.7, 61.0, 65.2, 65.7, 67.5, 128.1 , 128.3, 128.5, 135.0, 168.8, 170.3, 170.8, and 173.6; m/z (C.I.) 520 (M + H ⁺ , 12%), 504 (M ⁺ - Me, 24), 462 (M ⁺ - ⁽ Bu, 72), 320 (M + H ⁺ - 'ketene', 100). 288 (69) and 91 (80).

The benzyl (25, 5R, 6^-6-[l(R)-/.?rt-buryIdimethylsilyloxyethyl]-3,7-dioxo-4-oxa -l- azabicyclo[3.2.0]heptane-2-carboxylate used in this example was prepared as follows: To a solution of benzyl (35, 4R)-3-[l(R)-/er/-butyldimethylsiIyloxyethyl]-2-azetidinone-4 -yl diazomalonate (894 mg, 2.0 mmol) in CH ₂ C1 ₂ (20.0 cm ³ ) was added Rh ₂ (OAc) ₄ (2.5 mol%) and the reaction mixture heated at reflux for 24 h. Removal of solvent in vacuo gave benzyl (25, 5R, 65)-6-[l(Λ)-/er/-butyldimethylsilyloxyethyl]-3,7-dioxo-4-ox a-l - azabicyclo[3.2.0]heptane-2-carboxylate, which was used without further purification.

Example 17. Benzyl (25. 3R. 55. 65)-HrRWgr/-butyldimethylsilyloxyethyll-2-nhenylthio- 7-oxo-l-azabicyclol3.2.0]heptane-2-carboxylate.

To a solution of benzyl (25, 5R, 65)-6-[l(Λ)-/er/-butyldimethylsilyloxyethyl]-3,7-dioxo-4- oxa-l-azabicyclo[3.2.0]heptane-2-carboxylate [prepared from benzyl (35, 4R)-3-[\(R)-tert- butyldimethylsilyloxyethyI]-2-azetidinone-4-yI diazomalonate (447 mg, 1.0 mmol) by the method described in Example 16] in acetonitrile (3.0 cm ³ ) was added phenyl vinyl sulfide ( 1.0 cm ³ ) whereupon the mixture became turbid in appearance. After heating in a sealed tube at 1 10 ^C C for 1 1.5 h solvent was removed in vacuo and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (5 - 10% EtOAc : petroleum ether) afforded benzyl (25, 3R, 55, 65)-[l(Λ)-/gr/-butyldimethylsilyloxyethyl]-2-phenylthio-7-o xo-l - azabicyclo[3.2.0]heptane-2-carboxylate as a colourless oil (36 mg, 7 %) (Found: M + H ⁺ , 512.2270. C ₂₈ H ₃₈ NO ₄ SSi requires M, 512.2291); v _max (CH ₂ C1 ₂ ) / cm" ¹ 1766 and 1747; δ _H 0.05 (3 H, s, SiMe), 0.06 (3 H, s), 0.85 (9 H, s), 1.22 (3 H, d, 76.2), 1.79 (1 H, dt, 7 14.1 , 5.3), 2.57 (1 H, dt, 7 14.1 , 7.1), 3.12 (1 H, dd, 75.7, 2.4), 3.95 (1 H, ddd, 77.1 , 5.3, 2.4), 4.14 - 4.20 (1 H, m), 4.16 (1 H, ddd, 77.1, 5.3, 3.9), 4.44 (1 H, d, 73.9), 5.07 (2 H, s), and 7.28 -

7.44 (10 H, m); m/z (C.I.) 512 (M + H ⁺ , 1%), 496 (M ⁺ - Me, 4), 454 (M ⁺ - 'Bu, 8), 312 (M + H ⁺ - 'ketene', 38), and 11 1 (100).

Example 18. Benzyl (25. 5R. 6^-H(R)-fgr/-butyldimethylsilyloxyethyll-3-methylthio-7- oxo-l-azabicvclo[3.2.Q|hept-3-ene-2-carboxylate.

To a solution of benzyl (25. 5R, 65)-6-[l(Λ)-/e/Y-butyldimethylsilyloxyethyl]-3,7-dioxo-4- oxa- 1 -azabicyclo[3.2.0]heptane-2-carboxylate (232) [prepared from benzyl (35, 4R)-3-[ 1 (R)- /gr/-butyldimethylsilyloxyethyl]-2-azetidinone-4-yl diazomalonate (231) (894 mg, 2.0 mmol) by the method described in Example 16] in acetonitrile (4.0 cm ³ ) was added ketene dimethyl thioacetal monoxide [Reference: (a) R. Kaya and N. R. Beller, J. Org. Chem. , 1981, 46, 196] (310 mg, 2.3 mmol) and the solution heated in a sealed tube at 1 10 °C for 8 h. Solvent was removed in vacuo and purification of the residue by flash chromatography on Merck 60 (Art. 9385) silica-gel (10% EtOAc : 90% petroleum ether) afforded benzyl (25, 5R, 6^-[l (Λ)-/gr/- butyldimethylsilyloxyethyl]-3-methylthio-7-oxo-l-azabicyclo[ 3.2.0]hept-3-ene-2-carboxylate as a pale yellow oil (42 mg, 5%); v _max (CH ₂ C1 ₂ ) / cm-' 1771, 1750 and 1605; δ _H 0.07 (6 H, s), 0.88 (9 H, s), 1.24 (3 H, d, J6.2), 2.34 (3 H, s), 2.98 (1 H, dd, J 6.2, 2.6), 4.23 (1 H, app t, J 6.2), 4.56 - 4.59 (1 H, m), 5.12 (1 H, dd, J3.5, 1.7), 5.17 (2 H, s), 5.65 ( 1 H, app t, 7 1.7) and 7.36 (5 H, s).

Example 19. (±) p-Nitrobenzyl (25. 3R. 5^-7-oxo-3-phenylselenenyI-l- azabicvcloI3.2.0)heptane-2-carboxylate.

H

O i

CO ₂ PNB

Phenyl vinyl selenide (H.J. Reich, W.W. Willis Jr., and P.D. Clark, 7 Org. Chem., 1981, 46, 2775) (0.068 g, 0.37 mmol) and p-nitrobenzyl (25, 5Λ)-3,7-dioxo-4-oxa-l- azabicyclo[3.2.0]heptane-2-carboxylate (0.111 g, 0.36 mmol) were dissolved in preheated o- dichlorobenzene (2mL) at 180°C and the mixture was heated under reflux for 5 minutes. The clear yellow solution of product was allowed to cool, absorbed onto a silica-gel plug, washed with isohexane (150 mL) and then eluted with ethyl acetate (150 mL). The ethyl acetate solution was evaporated to give the product as a yellow oil that was further purified by normal phase hplc on silica-gel. Elution with 40% ethyl acetate: 60% isohexane gave (±) p- nitrobenzyl (25, 3R, 55)-7-oxo-3-phenylselenenyl-l-azabicyclo[3.2.0]heptane-2-car boxylate as a colourless wax (0.091 g, 58%) (Found: C, 53.8; H, 4.2, N, 6.2. C ₂₀ H _l8 N _: O<Se requires C, 53.9; H, 4.1 ; N, 6.3%) v _max (film/cm ^"1 2910, 1735, 1585, 1495, 1326; δ _H (270 MHz; CDC1 ₃ ) 1.69 (1 H, ddd, J 9.9, 7.9, 4.3), 2.65 (l H, m), 2.75 (1 H, dd, J 15.9, 2.2), 3.32 (1 H, dd, J 15.9, 5.0), 3.88 (1 H, m), 4.07 (1 H, dt, J 9.9, 6.8), 4.42 (1 H, d, J 7.1 ), 5.14 (1 H, part of AB, J 13.5), 5.19 (1 H, part of AB, J 13.5), 7.38-7.25 (3H, m), 7.46 (1 H, part of AA'BB'. J 9.1), 7.58, (2H, m), 8.21 ( 2H, part of AA'BB', J 9.1); m/z (+ve E.S.P) 469 (M+Na ^" . 20%), 447 (M+H\ 30%), 405 (M+H ⁺ -C ₂ H ₂ O, 100%).

Example 20. (±) p-Nitrobenzyl (5R)-7-oxo-l-azabicvc.o[3.2.0}hept-2-ene-2-carboxyIate.

A stirred solution in THF (1 mL) of (±) p-nitrobenzyl (25, 3R, 55)-7-oxo-3-phenylselenenyl- l-azabicyclo[3.2.0]heptane-2-carboxylate [prepared as described in Example 19, (0.029 g, 0.06 mmol)] was maintained at -5°C under an atmoshere of nitrogen and treated dropwise with aqueous H ₂ 0 ₂ (0.055 mL, 7.5%, 2 eq). After 10 min. a further portion of aqueous H ₂ 0 ₂

(0.1 10 mL, 7.5%, 4 eq) was added. The mixture was permitted to warm to room temperature and stirred for a further 10 min. The reaction mixture was partitioned between ethyl acetate (5 mL) and water (5 mL) and the aqueous phase was extracted with ethyl acetate (5 mL). The organic phases were combined, washed with brine , dried (sodium sulfate) and evaporated in vacuo to give a pale yelow oil. Rapid flash chromatography (4°C, 50% ethyl acetate: 50% petroleum ether, 40-60°C fraction) gave (+) /?-nitrobenzyl (5Λ)-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylate as pale yellow crystals, (0.014 g, 82%), which gave Η-nmr (270 MHz; CDC1 ₃ ) spectral data in agreement with those published previously for this product (W.L. Parker, M.L. Rathnum, J.S. Wells, W.H. Trejo, P.A. Principe, and R.B. Sykes, 7 Antibiot., 1982, 35, 653.).

Example 21. (±) p-Nitrobenzyl-(25. 3R.75.85)-4,10-dioxo-3-phenylselenenyl-l- azatricvclo[6.2.0.0 ³⁷ ldecane-2-carboxylate and (±) p-nitrohenzyl-(25. 35.7R.85.-4.10- dioxo-3-phenvIselenenyl-l-azatricvclol6.2.0.0 ^3,7 ldecane-2-carboxylate.

A solution of /7-nitrobenzyl (25. 5Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2- carboxylate (0.60 g, 1.96 mmol) and 2-phenylselenenyl-2-cyclopentenone [L. Engman and K.W. Tδrnroos, 7 Organomet. Chem., 1990, 391, 165; (1.39 g, 5.86 mmol, 3 eq)] in acetonitrile (7.0ml) was heated at 105 °C in a sealed tube for 41 h. Solvent was removed under reduced pressure and the residue was purified flash column chromatography on silica- gel (40%) EtOAc : 60% petroleum ether 60:40 fraction) to give a 3: 1 mixture of the diastereomers (±)/?-nitrobenzyl-(25, 3R, 75, 85)-4, 10-dioxo-3-phenylselenenyl-l- azatricyclo[6.2.0.0 ³ - ⁷ ]decane-2-carboxylate and (±)/?-nitrobenzyl-(25, 35, 7R, 85)-4,10-dioxo- 3-phenylselenenyl-l-azatricyclo[6.2.0.0 ^{3 7} ]decane-2-carboxylate as a pale cream foam (0.52 g, 54%); (Found: C, 55.5; H, 4.05; N, 5.75. C ₂₂ H ₂₀ N ₂ O ₆ Se requires C. 55.3: H 4.0; N 5.6%);

v _max (fιlm) / cm" ¹ 2954, 1772, 1747, 1521, 1346; m/z (C.I.) 500 (MH ⁺ , 1%) and 459 ([M+H- C ₂ H ₂ O] ⁺ , 15%).

The components of the mixture had characteristic 'H-nmr spectra: (±)/?-Nitrobenzyl (25, 3R, 75, 8Λ)-4-oxo-10-oxa-2-phenylselenenyl-l- azatricyclo[6.2.0.03,7]decane-2-carboxylate, δ _H (270 MHz:CDCl ₃ ) 1.95 - 2.65 (5 H, m), 2.84 (1 H. dd, J 15.8, 2.3), 3.43 (1 H, dd, J 15.8, 5.0), 3.83 (1 H, ddd, J 5.3, 5.0, 2.3), 4.80 (1 H s), 5.14 (2 H, AB, J 13.5), 7.26 - 7.61 (5 H, m), 7.61 - 7.67 (2 H, part of AA'BB'), 8.19 - 8.25 (2 H, part of AA'BB');

(±)/?-Nitrobenzyl (25, 35, IR, 8Λ)-4-oxo-10-oxa-2-ρhenylselenenyI-l- azatricyclo[6.2.0.03.7]decane-2-carboxylate, δ _H (270 MHz:CDCl ₃ ) 1.95 - 2.65 (5 H, m), 3.03 (1 H, m), 3.25 (1 H. dd, J 16.7, 5.7), 4.15 (1 H, ddd, J 8.8, 5.7, 2.5), 4.99 (1 H, s), 5.36 ( 2 H. AB, J 13.0), 7.26 - 7.61 (5 H, m), 7.61 - 7.67 (2 H, part of AA'BB'), 8.19 - 8.25 (2 H, part of AA'BB').

Example 22. (±) p-Nitrobenzyl-(25. 3R .85, 9.y)-4.1 l-dioxo-3-nhenylselenenyl-l- azatricvc■or7.2.0.0 ³⁸ lundecane-2-carboxylate and (±) p-nitrobenzyl-(25. 35. 8R. 95V4.11 dioxo-3-phenylseIenenyl-l-azatricvclo[7.2.0.0 ³⁸ lundecane-2-carboxyIate.

A solution ofp-nitrobenzyl (25, 5Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2- carboxylate (0.50 g, 1.63 mmol) and 2-phenylselenenyl-2-cyclohexenone [L. Engman and K.W. Tornroos, 7 Organomet. Chem., 1990, 391, 165; (0.49 g, 1.95 mmol, 1.2 eq)] in acetonitrile (5.0 mL) was heated under an atmosphere of nitrogen at 80 °C for 36 h. Solvent was removed under reduced pressure and the residue was purified flash column chromatography on silica-gel (40% EtOAc : 60% petroleum ether 60:40 fraction) to give (±) p-nitrobenzyl-(25, 3R, 85, 95)-4,l l-dioxo-3-phenylselenenyl-l-

azatricyclo [7.2.0.0 ^3-8 ]undecane-2-carboxy late ( 207 mg, 25%) as an oil which crystallised on trituration with CCL _, : M.p. 130-132 °C; (Found: C, 56.7; H, 4.35; N, 5.1. C ₂₄ H ₂₂ N ₂ O ₆ requires C, 56.2; H, 4.3; N, 5.5%); v _max (film) / cm ^"1 2948, 1773, 1744, 1682, 1521, 1346; δ _H (300 MHz:CDCl ₃ ) 1.70 -2.07 (4 H, m), 2.25 - 2.35 (2 H, m), 3.04 (1 H, dd, J 15.8, 2.0), 3.06 ( 1H, m), 3.54 (1 H, dd, J 15.8, 4.8), 3.85 (1 H, m), 4.77 ( 1 H, s), 5.07 (2 H, AB, J 13.6), 7.30 - 7.60 (7H, m), 8.16 (2 H, part of AA'BB', J 8.8); m/z (C.I.) 514 (M+H ⁺ , 8%) and 473 (M+H- C ₂ H ₂ O] ⁺ , 100%).and (+)p-nitrobenzyl-(25, 35, %R, 95)-4,l l-dioxo-3-phenylselenenyl-l - azatricyclo[7.2.0.0 ^3,8 ]undecane-2-carboxylate (58mg, 7%) as a colourless foam: (Found: C, 55.8; H, 4.5; N, 5.5. C ₂₄ H ₂₂ N ₂ O ₆ Se requires C, 56.2; H, 4.3; N. 5.5%); v _max (film) / cm ^'1 2952, 1774, 1745, 1698, 1521, 1345; δ _H (300 MHz:CDCl ₃ ) 1.69 - 1.80 (1 H, m), 1.84 - 2.16 (2 H, m), 2.17 - 2.33 (2 H, m), 2.95 (1 H, dd, J 16.7, 3.1), 2.96 - 3.12 (2 H, m), 3.20 (1 H, dd, J 16.7, 5.7), 4.15 (1 H, m), 5.30 (2 H, s), 5.54 (1 H, s), 7.22 - 7.56 (7 H, m), 8.21 (2 H part of AA'BB', J 8.8); m/z (C.I.) 514 (M+H\ 4%) and 473 ([M+H-C,H ₂ O]\ 45%).

Example 23. (±) p-NitrobenzvI (25. 3R. 9S. 105V4.12-dioxo-3-phenylselenenyl-l- azatricvclof8.2.0.0 ³⁹ ldodecane-2-carboxylate.

A solution ofp-nitrobenzyl (25, 5Λ)-3,7-dioxo-4-oxa-l-azabicyclo[3.2.0]heptane-2- carboxylate (0.20 g, 0.65 mmol) and 2-phenylselenenyI-2-cycloheptenone [D.J. Buckley and M.A.McKervey, 7 Chem. Soc, Perkin Trans. I, 1985, 2193; prepared here by the method of L. Engman and K.W. Tornroos, 7 Organomet. Chem., 1990, 391, 165; (0.208 g, 0.78 mmol, 1.2 eq)] in acetonitrile (4.0 mL) was heated under an atmosphere of nitrogen at 80 °C for 36 h. Solvent was removed under reduced pressure and the residue was purified flash column chromatography on silica-gel (40% EtOAc : 60% petroleum ether 60:40 fraction) to give (±) /7-nitrobenzyl (25, 3R, 95, 105)-4,12-dioxo-3-phenylselenenyl-l - azatricyclo[8.2.0.0 ^3,9 ]dodecane-2-carboxylate as a pale yellow waxy solid: (23.1 mg. 7% ) (Found: MH\ 528.0799. C ₂₅ H ₂₄ N ₂ 0 ₆ Se requires M. 528.0781 ); v _max (film) / cm ^"1 2923. 1772.

1745, 1680, 1520, 1345; δ„ (270 MHz:CDCl ₃ ) 1.42 -1.62, 1.82 - 2.04, 2.24 - 2.58 (8 H,m), 3.26 (1 H, dd, J 16.0, 2.8), 3.55 (1 H, m), 3.59 (1 H, dd, J 16.0, 5.4), 3.84 (1 H, m), 4.61 (1 H, s), 5.08 (2 H, AB, J 13.9), 7.31 - 7.93 (7 H, m), 8.12 - 8.23 (2 H, m); m/z (C.I.) 528 (M+H ⁺ , 2%) and 487 ([M+H-C ₂ H ₂ O]\ 22%).

RMT 1 1JUN96 96/036