Chemical compounds

Novel semisynthetic .beta.-lactam intermediates of use in the production of cephalosporins, penicillins and related .beta.-lactam antibiotic compounds are provided. The novel compounds are prepared from .beta.-lactams obtained by cleavage of the 1,2-sulphur-carbon bond of a penicillin 1-oxide (with subsequent internal or external trapping of the sulphur atom to leave a residual substituent as the .beta.-lactam nitrogen) by removal of the said residual substituent by an oxidative cleavage reaction.

This invention relates to a process for the production of novel 
semisynthetic intermediates or relay compounds of use in the production of 
cephalosporins, penicillins and related .beta.-lactam antibiotic 
compounds. 
The first total synthesis of a cephalosporin antibiotic was achieved by R. 
B. Woodward (J.A.C.S. 1966, 88, (4), 852) starting from L(+)-cysteine and 
proceeding via about eight synthetic steps to a .beta.-lactam (i) which 
was then converted into a cephem (iii) by the following reaction sequence. 
##STR1## 
The compound (i) thus constitutes a valuable intermediate in the 
preparation of cephalosporins and other .beta.-lactam antibiotics; by 
reaction with an analogous aldehyde reagent it is also possible to convert 
(i) into a penicillin and it will be appreciated that in this way 
penicillins having varying substitution in the 5-membered ring can be 
produced. Similarly by replacing the 2,2,2-trichloroethyl 
3,3-diformylacrylate reagent by suitably substituted alternatives, a 
series of cephalosporin analogues can be prepared. 
R. B. Woodward started from L(+)-cysteine in order to achieve a total 
synthesis. However, this material is relatively expensive and even more 
significantly, its conversion into a .beta.-lactam of the required 
sterochemical configuration requires extremely careful control of the 
stereochemistry at several points. 
The present invention is based on the finding that the 1,2-bond of a 
penicillin 1-oxide can be cleaved with subsequent trapping of the sulphur 
atom to yield .beta.-lactam compounds which can be converted into a wide 
range of bicyclic structures such as cephams, cephems and penams. When the 
penicillin 1-oxide is cleaved with a trivalent phosphorus reagent, the 
sulphur atom will be internally trapped by the carbonyl group of the 
6-acylamido group present to form a thiazoline unless the reaction is 
effected in the presence of an acylating agent in which case the sulphur 
atom will be externally trapped to yield an S-acyl compound. Externally 
trapped compounds can also be prepared by cleaving the penicillin 1-oxide 
with a thiophilic sulphur nucleophile, and in particular a thiol, whereby 
the S atom is incorporated in a disulphide bond. Such disulphides can be 
converted if desired into corresponding thioethers. 
All these conversions are described in copending Applications by Underwood 
and Hewitt; Underwood and Long; Barton, Underwood, Looker, Hewitt and 
Taylor; Barton, Sammes, Hewitt, Looker and Underwood; and Barton, 
Underwood, Looker and Hewitt: all filed on July 30, 1971, Ser. Nos. 
167,847, now abandoned; 167,874, now Pat. No. 3,900,487; 167,848, now U.S. 
Pat. No. 3,872,086; 167,875, now abandoned and 167,849, now U.S. Pat. No. 
3,927,013, respectively. One advantage of these procedures is that by 
starting from penicillins it is possible to effect a conversion to 
compounds closely similar to Woodward's compound (i) more readily and in 
fewer stages than the production of (i) from L-(+)-cysteine and the 
.beta.-lactam retains the required steric configuration whereas close and 
difficult steric control is required in the Woodward syntheses. 
Furthermore, penicillins, particularly penicillins G and V, are generally 
cheaper to produce, e.g. by fermentation, than L-(+)-cysteine. 
The thiazolines prepared according to the present invention may be 
subsequently converted, by reduction and N-protection, into thiazolidines 
closely analogous to Woodward's compound (i) and which differ therefrom 
merely by the replacement of the gem-dimethyl grouping by hydrogen and a 
residue derived from the original 6-acylamido group. The reduction may, 
for example, be effected with aluminium amalgam and water as described in 
copending application Ser. No. 167,874, now U.S. Pat. No. 3,900,487. Such 
compounds may be reacted in exactly the same way as Woodward's compound 
(i) to give Woodward's compounds (ii) and (iii). Woodward's compound (iii) 
can be converted into an active antibiotic by N-acylation, e.g. with the 
group PhCH.sub.2 CO, and reductive cleavage of the 4-ester group. 
Compounds in which the sulphur atom of penicillin derivatives has been 
externally trapped may be reacted at the sulphur and .beta.-lactam 
nitrogen atoms by the methods now described in copending applications Ser. 
Nos. 167,848 now U.S. Pat. No. 3,872,086; 167,875 now abandoned and 
167,849 now U.S. Pat. No. 3,927,013 to give bicyclic structures, such as 
cephems and penams, having antibiotic activity. 
In both internal and external trapping, the penicillin 1-oxides are cleaved 
to yield compounds of the formula III 
##STR2## 
[wherein R.sup.2 is a group 
##STR3## 
where R.sup.4 is hydrogen or a carboxyl blocking group and R.sup.1a and 
R.sup.3a represent groups R.sup.1 and R.sup.3 respectively where R.sup.1 
is a blocked amino group including a group of formula --NHCOR (where --COR 
is an acyl group containing 1 to 21 carbon atoms) and R.sup.3 is an acyl 
group, an aliphatic, aromatic or araliphatic group or a group --SR.sup.5 
(where R.sup.5 is an aliphatic, araliphatic, cycloaliphatic or aromatic 
group containing from 1 to 20 carbon atoms) or a group of formula 
##STR4## 
(where R.sup.1 and R.sup.2 are as defined above) or R.sup.1a and R.sup.3a 
together represent the group 
##STR5## 
where R is the residue of an acyl group --COR which acyl group has from 1 
to 21 carbon atoms, the carbon atom of the group 
##STR6## 
being bonded to the sulphur atom of the compound of formula III]. 
It will be noted that the compounds of formula III carry a side-chain at 
the .beta.-lactam nitrogen and in order to functionalise the .beta.-lactam 
nitrogen atom as in Woodward's compound (ii), this side-chain must be 
removed. We have found that this can readily be achieved by oxidative 
cleavage. 
According to one feature of the present invention there is provided a 
process for the preparation of compounds of the general formula 
##STR7## 
[wherein R.sup.1a and R.sup.3a represent groups R.sup.1 and R.sup.3 
respectively where R.sup.1 is a blocked amino group including a group of 
formula --NHCOR (where --COR is an acyl group containing 1 to 21 carbon 
atoms) and R.sup.3 is an acyl group, an aliphatic, aromatic or araliphatic 
group or a group --SR.sup.5 (where R.sup.5 is an aliphatic, araliphatic, 
cycloaliphatic or aromatic group containing from 1 to 20 carbon atoms) or 
a group of formula 
##STR8## 
(where R.sup.1 is as defined above) or R.sup.1a and R.sup.3a together 
represent the group 
##STR9## 
where R is the residue of an acyl group --COR which acyl group has from 1 
to 21 carbon atoms, the carbon atom of the group 
##STR10## 
being bonded to the sulphur atom of the compound of formula I] which 
comprises subjecting to oxidative cleavage a compound of formula 
##STR11## 
as hereinbefore defined. The definition "acyl" for R.sup.3 includes groups 
such as sulphonyl, sulphinyl and phosphoryl. 
According to a further feature of the present invention there are provided 
compounds of the general formula 
##STR12## 
wherein R.sup.1a is a blocked amino group including a group of formula 
--NHCOR (where --COR is an acyl group containing 1 to 21 carbon atoms) and 
R.sup.3a is an acyl group or R.sup.1a and R.sup.3a together represent the 
group 
##STR13## 
where R is the residue of an acyl group --COR which acyl group has 1 to 21 
carbon atoms, the carbon atom of the group 
##STR14## 
being bonded to the sulphur atom of the compound of formula I. Compounds 
of formula I in which R.sup.3 is other than an acyl group are described 
and claimed in copending Applications Ser. Nos. 167,848 and 167,875. An 
alternative procedure for the preparation of compounds of formula I in 
which R.sup.1a and R.sup.3a form a group 
##STR15## 
is set out in the copending Application by Underwood and Hewitt of even 
date herewith (Part 2/4). 
The oxidative cleavage of the side-chain R.sup.2 in compounds of formula 
III in general proceeds either by allylic oxidation of compounds of 
formula III in which R.sup.2 is the group 
##STR16## 
or oxidation of compounds in which R.sup.2 is 
##STR17## 
to a derivative carrying an oxygen function at the carbon atom attached to 
the .beta.-lactam nitrogen. The reagents used will thus be appropriate to 
such oxidations. In both types of oxidation the introduction of an oxygen 
function causes instability of the whole side-chain. 
For the oxidation of compounds of formula III in which R.sup.2 is 
##STR18## 
preferred oxidising agents include ozone or a permanganate, e.g. an alkali 
metal or alkaline earth metal permanganate such as potassium permanganate, 
permanganates being preferably reacted in the presence of magnesium 
sulphate as a buffer. These reagents have the advantage of showing no 
tendency to oxidise the thiazoline sulphur atom and ozone has the merit of 
producing a gaseous product, oxygen, which does not require special 
separation. 
Other useful reagents include manganates and vanadates e.g. alkali metal or 
alkaline earth metal salts such as barium manganate or sodium vanadate. 
Chlorate oxidising agents can be used in the presence of manganese 
dioxide, the effective oxidising agent being, in fact, a permanganate, 
Osmium tetroxide can also be used as well as lead tetraacylates such as 
lead tetraacetate. 
The allylic oxidation may be effected using molecular oxygen. 
Alternatively, compounds in which R.sup.2 is a group 
##STR19## 
can be oxidised by a reagent of the type described for the oxidation of 
the conjugated isomer under isomerising conditions to effect preliminary 
isomerisation. 
A base used to effect isomerisation of compounds wherein 
##STR20## 
compounds wherein R.sup.2 is 
##STR21## 
as a separate reaction or during oxidation, may be an inorganic base, such 
as an alkali metal or alkaline earth metal hydroxide or an alkali metal 
carbonate or alumina, or an organic base such as a tertiary amine, e.g. a 
trialkylamine such as N-ethylpiperidine or triethylamine, a heterocyclic 
base such as pyridine or collidine, or an alkali metal alkoxide. Inorganic 
bases will be reacted in aqueous or aqueous alcoholic media while nitrogen 
bases will in general be used in organic solvents such as hydrocarbons or 
chlorinated hydrocarbons, e.g. methylene chloride. Alkoxides will be used 
mainly in alcoholic solvents. 
Oxidation of the decarboxylated product of formula III in which R.sup.2 is 
the group 
##STR22## 
may be effected using any of the reagents described for the oxidation of 
the conjugated isomer of formula III in which R.sup.2 is 
##STR23## 
The oxidation is preferably effected in a solvent for the starting 
material. In general, a polar organic solvent is preferred, for example, a 
cyclic ether such as dioxan or tetrahydrofuran, a substituted amide 
solvent such as dimethylformamide or dimethylacetamide or, most 
preferably, an alkanol e.g. an alkanol containing 1-6 carbon atoms such as 
methanol, ethanol, or butanol. Water is often advantageously present. 
Where ozone is used, a hyroxylic solvent is required to decompose the 
ozonide initially formed although the oxidation can be effected in a 
non-hydroxylic solvent and hydrolysis effected during work-up. Inert 
solvents for the compound of formula III, for example hydrocarbons or 
chlorinated hydrocarbons, may also be present, together with a solvent 
facilitating oxidation such as a hydroxylic solvent. 
The course of the reaction can be followed by thin layer chromatography and 
by the absence in the required product of the high-field signals in the 
n.m.r. due to the methyl groups in the side-chain R.sup.2. Generation of 
the N-H group in the 1-position is denoted by appearance of a band in the 
infra red absorption of about 3440 cm.sup.-1. 
As stated above, R.sup.1a in compounds of formula I may be a blocked amino 
group including groups of formula --NHCOR, e.g. the 6-acylamino groups 
present in penicillins and protected amino groups, that is groups which 
can readily be converted into free amino groups, for example by 
hydrolysis, reduction or hydrogenolysis. 
Where R.sup.1a is a protected amino group this may conveniently be one of 
the groups set out in the following table: 
______________________________________ 
Usual Name and 
Type Example Analogues etc. 
______________________________________ 
Urethane 
##STR24## Benzyloxycarbonyl, p-Methoxy 
Urethane 
##STR25## t-Butoxycarbonyl 
Urethane 
##STR26## Diphenylmethoxy- carbonyl 
Urethane 
##STR27## 1-Adamantyloxy- carbonyl 
Arylmethyl- amino 
##STR28## Trityl 
Onium NH.sub.3 .sup.+ 
Urethane HN . CO . OCH.sub.2 CCI.sub.3 
.beta.,.beta.,.beta.-trichloroethoxy 
carbonyl 
______________________________________ 
Where R.sup.1a is a group --NHCOR or together with R.sup.3a is a group 
##STR29## 
R may be defined generally as hydrogen or an organic group containing 1 to 
20 carbon atoms. Thus the following main classes are especially suitable 
for the group RCO--: 
(i) R.sup.u C.sub.n H.sub.2n --CO where R.sup.u is aryl (carbocyclic or 
heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, 
cyclohexadienyl, or a non-aromatic or mesoionic heterocyclic group, and n 
is an integer from 1-4. Examples of this group include phenylacetyl; 
substituted phenylacetyl e.g. fluorophenylacetyl, nitrophenylacetyl, 
aminophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, 
methylphenylacetyl, or hydroxyphenylacetyl; 
N,N-bis(2-chloroethyl)aminophenylpropionyl; thienyl-2- and -3-acetyl; 
4-isoxazolyl and substituted 4-isoxazolylacetyl; pyridylacetyl; 
tetrazolylacetyl or a sydnoncacetyl group. The substituted 4-isoxazolyl 
group may be a 3-aryl-5-methyl isoxazol-4-yl group, the aryl group being 
e.g. phenyl or halophenyl e.g. chloro- or bromo- phenyl. An acyl group of 
this type is 3-o-chlorophenyl-5-methyl isoxazol-4-yl-acetyl. 
(ii) C.sub.m H.sub.2m+1 CO-- where m is an integer from 1-7. The alkyl 
group may be straight or branched and, if desired, may be interrupted by 
an oxygen or sulphur atom or substituted by e.g. one or more halogen 
atoms, a cyano group, a carboxy group, an alkoxycarbonyl group, a hydroxy 
group or a carboxycarbonyl group (--CO.COOH). Examples of such groups 
include cyanacetyl, hexanoyl, heptanoyl, octanoyl, butylthioacetyl, 
chloroacetyl and trichloroacetyl groups. 
(iii) C.sub.p H.sub.2p-1 CO-- where p is an integer from 2-7. The alkenyl 
group may be straight or branched and, if desired, may be interrupted by 
an oxygen or a sulphur atom. An example of such a group is 
allylthioacetyl. 
(iv) 
##STR30## 
where R.sup.s is as defined above for R.sup.u or may be benzyl, and 
R.sup.v and R.sup.w which may be the same or different each represent 
hydrogen, phenyl, benzyl, phenethyl or lower alkyl. Examples of such 
groups include phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxy 
propionyl, 2-phenoxybutyryl, 2-methyl-2-phenoxypropionyl, p-cresoxyacetyl 
and p-methylthiophenoxyacetyl. 
(v) 
##STR31## 
where R.sup.s R.sup.v and R.sup.w have the meanings defined under (iv). 
Examples of such groups include S-phenylthioacetyl, 
S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl, and 
S-benzylthioacetyl. 
(vi) R.sup.s Z(CH.sub.2).sub.q CO-- where R.sup.s is as defined above, Z is 
an oxygen or sulphur atom and q is an integer from 2-5. An example of such 
a group is S-benzylthiopropionyl. 
(vii) R.sup.u CO-- where R.sup.u has the meaning defined under (i). 
Examples of such groups include benzoyl, substituted benzoyl (e.g. 
aminobenzoyl), 4-isoxazolyl- and substituted 4-isoxazolylcarbonyl, 
cyclopentanecarbonyl, sydnonecarbonyl, naphthoyl and substituted naphthoyl 
(e.g. 2-ethoxynaphthoyl), quinoxalinylcarbonyl and substituted 
quinoxalinylcarbonyl (e.g. 3-carboxy-2-quinoxalinylcarbonyl). Other 
possible substituents for benzoyl include alkyl, alkoxy, phenyl, phenyl 
substituted by carboxy, alkylamido, cycloalkylamido, allylamido, 
phenyl(lower) alkyl amido, morpholinocarbonyl, pyrrolidinocarbonyl, 
piperidinocarbonyl, tetrahydropyridino, furfurylamido or 
N-alkyl-N-anilino, or derivatives thereof and such substituents may be in 
the 2- or 2- and 6-positions. Examples of such subsituted benzoyl groups 
are 2,6-dimethoxybenzoyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. Where 
the group R.sup.u represents a substituted 4-isoxazolyl group, the 
substituents may be as set out above under (i). Examples of such 
4-isoxazolyl groups are 3-phenyl-5-methyl-isoxazol 4-yl carbonyl, 
3-o-chlorophenyl-5-methyl isoxazol-4-yl carbonyl and 
3-(2,6-dichlorophenyl)-5-methyl-isoxazol-4-yl carbonyl. 
(viii) 
##STR32## 
where R.sup.u has the meaning defined under (i) and X is amino, 
substituted amino (e.g. acylamido or a group obtained by reacting the 
.alpha.-aminoacylamido group of the 6-side chain with an aldehyde or 
ketone e.g. acetone, methylethylketone or ethyl acetoacetate), hydroxy, 
carboxy, esterified carboxy, triazolyl, tetrazolyl, cyano, halogeno, 
acyloxy (e.g. formyloxy or lower alkanoyloxy) or etherified hydroxy group. 
Examples of such acyl groups are .alpha.-aminophenylacetyl and 
.alpha.-carboxyphenylacetyl. 
(ix) 
##STR33## 
where R.sup.x, R.sup.y and R.sup.z which may be the same or different may 
each represent lower alkyl, phenyl or substituted phenyl. R.sup.x can also 
be hydrogen. An example of such an acyl group is triphenylmethylcarbonyl. 
(x) 
##STR34## 
where R.sup.t is as defined above for R.sup.u or may be hydrogen, lower 
alkyl or halogen substituted lower alkyl, An example of such a group is 
Cl(CH.sub.2).sub.2 NHCO 
(xi) 
##STR35## 
where X has the meaning defined under (viii) above and r is an integer of 
from 1 to 4. An example of such an acyl group is 
1-aminocyclohexanecarbonyl. 
(xii) R.sup.a CH(NH.sub.2)(CH.sub.2).sub.k CO where R.sup.a is as defined 
above for R.sup.u or is a hydrogen atom or an alkyl, aralkyl or carboxy 
group and k is an integer from 1 to 10 or NH.sub.2 C.sub.h H.sub.2h 
Ar(CH.sub.2).sub.g CO where g is zero or is an integer from 1 to 10, h is 
0, 1 or 2 and Ar is an arylene group, e.g. p-phenylene or 1,4-naphthylene. 
Examples of such groups are disclosed in British Pat. No. 1,054,806. A 
group of this type is the p-aminophenylacetyl group. Other acyl groups of 
this type include those, e.g. .delta.-aminoadipoyl, derived from naturally 
occurring amino acids and derivatives thereof e.g. 
N-benzoyl-.delta.-aminoadipoyl or N-chloroacetyl-.delta.-aminoadipoyl. 
(xiii) Substituted glyoxylyl groups of the formula R.sup.b.CO.CO-- where 
R.sup.b is an aliphatic, araliphatic or aromatic group, e.g. a thienyl 
group, a phenyl group, or a mono-, di- or tri-substituted phenyl group, 
the substituents being, for example, one or more halogen atoms (F, Cl, Br, 
or I), methoxy groups, methyl groups or amino groups, or a fused benzene 
ring. Included in this group are also the .alpha.-carbonyl derivatives of 
the above substituted glyoxylyl groups, formed for example with 
hydroxylamine, semicarbazide, thiosemicarbazide, isoniazide or hydrazine. 
Preferred amine protecting groups are the hydrocarbyloxycarbonyl groups 
(wherein the amino group forms part of a urethane), in particular 
alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and, most 
preferaby, t-butoxycarbonyl groups, which may carry substituents such as 
halogen atoms as in the 2,2,2-trichloroethoxycarbonyl group, as well as 
aralkoxy carbonyl groups such as benzyloxycarbonyl, 
p-methoxybenzyloxycarbonyl and diphenylmethoxycarbonyl groups. 
Cycloalkoxycarbonyl groups are also advantageous, especially the 
adamantyloxycarbonyl group. The p-nitrobenzyloxycarbonyl group, which can 
be selectively removed by reduction e.g. hydrogenolysis, is also useful. 
Such penicillins carrying protecting groups of this type may be prepared 
from 6-aminopenams by conventional methods for example by reaction with an 
appropriate haloformic ester. 
Where R.sup.3 in formula I is a group --SR.sup.5, R.sup.5 may, for example, 
be an alkyl group preferably containing 1-6 carbon atoms, e.g. a methyl, 
ethyl, butyl or iso-butyl group; an aralkyl group, preferably containing 
1-6 carbon atoms in the alkyl portion, e.g. a benzyl, phenethyl or 
phenylpropyl group; a cycloalkyl group which may contain 5-7 carbon atoms 
in the ring and in which other aliphatic ring substituents containing up 
to 6 carbon atoms may be present; or a monocyclic aryl group such as a 
phenyl or substituted phenyl group. Such groups may be saturated or 
unsaturated and may carry substituents. The group R.sup.5 may subsequently 
be made to cyclise with the .beta.-lactam nitrogen or a grouping attached 
thereto as described in the copending Application Ser. No. 167,875 and so 
may advantageously possess substituents or reactive bonds permitting 
cyclisation with the .beta.-lactam nitrogen or a group attached thereto. 
Such substituents include reactive ester substituents for example, halogen 
atoms and aromatic and aliphatic sulphonyl groups, carboxyl or esterified 
carboxyl groups or amino groups. 
Where R.sup.3 is an aliphatic, araliphatic or aromatic group, this may 
advantageously be one of the groups specifically described above in 
relation to R.sup.5. A further useful group is the 
3,4-dihydro-2H-pyran-5-yl grouping. 
Where R.sup.3 is an acyl group, this is preferably a group of the formula 
R.sup.6 CO-- where R.sup.6 is an aliphatic, araliphatic or aromatic group 
which may advantageously be one of the groups specifically described for 
R.sup.5. 
Where R.sup.2 in formula III is a group 
##STR36## 
R.sup.4 may be hydrogen or a blocking group to prevent the carboxyl group 
from entering into side reactions and can vary very widely since it does 
not appear in the final product. 
In general R.sup.4 may be hydrogen or an organic group having 1-20 carbon 
atoms. While the blocking group may be one which is readily removed by 
hydrolysis, this is not essential since it is not necessary that R.sup.4 
is removed during the removal of the side chain R.sup.2 from the compound 
of formula III. It is preferred that R.sup.4 is the residue of an alcohol 
or phenol, for example a cyclic or acyclic, straight or branched alkanol, 
advantageously containing 1-8 carbon atoms, e.g. methanol, ethanol, 
n-butanol, t-butanol, hexanol, octanol, cyclohexanol or adamantyl alcohol, 
which may carry substituents such as sulpho, esterified carboxyl, acyloxy, 
alkoxy, aralkoxy, alkylthio, alkoxyphenyl or aromatic heterocyclic groups 
or halogen atoms. Preferred substituted alkanols include 
2,2,2-trichloroethanol and 4-pyridylmethanol. Residues of aralkyl alcohols 
are also useful, especially benzyl and substituted benzyl alcohols, e.g. 
those carrying electron-attracting groups such as sulpho or esterified 
carboxy groups which are readily split off by alkaline hydrolysis, and 
those carrying electron-donating groups such as alkoxy groups which are 
often readily removable by acid hydrolysis. Suitably substituted benzyl 
groups include p-methoxybenzyl, di-p-methoxyphenylmethyl, triphenylmethyl, 
diphenylmethyl and p-nitrobenzyl; closely analogous groups include 
benzoylmethyl, benzoyloxymethyl and furfuryl groups. Residues of phenols 
include, for example, phenyl, p-methoxyphenyl and p-nitrophenyl groups. 
Compounds of formula III in which R.sup.1a and R.sup.3a together represent 
a group 
##STR37## 
may be prepared from penicillanic acid 1-oxides by treatment with a 
trivalent phosphorus compound. The trivalent phosphorus compound may be a 
tri(lower alkyl)phosphite, e.g. trimethylphosphite. 
The starting compounds of formula III in which R.sup.1a is a 
phenylacetamido group and R.sup.3a is an acyl group are also new compounds 
and thus constitute a further feature of the invention. They may be 
obtained from penicillanic acid 1-oxides by treatment with a trivalent 
phosphorus compound in the presence of an acylating agent, for example an 
anhydride or mixed anhydride of a carboxylic acid. The trivalent 
phosphorus compound may, for example, be a tri-lower alkyl phosphite, e.g. 
trimethyl phosphite. The reaction is preferably effected in an inert 
solvent, e.g. a hydrocarbon solvent such as benzene or toluene; or an 
ester such as ethyl acetate or an excess of acylating agent, where liquid, 
may serve as solvent. Improved yields may be obtained by including an 
alkaline earth metal carbonate in the medium, for example calcium 
carbonate. 
Where R.sup.3 is a group --SR.sup.5, the starting material may be prepared 
by the methods described in the copending Application Ser. No. 167,848, 
filed July 30, 1971 now U.S. Pat. No. 3,872,086. 
Where R.sup.3 is an aliphatic, araliphatic or aromatic group, the starting 
material may be prepared by the process described in the copending 
Application Ser. No. 167,875, filed July 30, 1971, now abandoned. 
Where R.sup.3 is a dihydropyranyl group the starting material may be made 
by the method of Barton et al (Chem.Comms. 1970, pp 1683-4). 
For a better understanding of the invention, the following Examples are 
given by way of illustration only. All temperatures are in .degree.C. 
Column chromatography was carried out using Merck silica gel; the solvents 
used are given in the individual Examples. NMR spectra were obtained on a 
Varian HA 100 instrument, unless otherwise stated. The integrals agreed 
with the numbers of protons indicated. Signs were not determined for the 
coupling constants (J).