Penicillin sulphoxide

Oxidation of phenyl hexyl sulphide with sodium metaperiodate gave also only a trace amount of the corresponding sulphoxide72. On the other hand, Hall and coworkers73 prepared benzylpenicillin and phenoxymethyl penicillin sulphoxides from the corresponding benzyl esters by oxidation with sodium metaperiodate in dioxane solution with a phosphate buffer. A general procedure for the synthesis of penicillin sulphoxides was reported later by Essery and coworkers74 which consists in the direct oxidation of penicillins or their salts with sodium metaperiodate in aqueous solution at pH 6.5-7.0. 1-Butadienyl phenyl sulphoxide 4475 and a-phosphoryl sulphoxides 4576 were also prepared by the same procedure. 

Parr method 995 Pauling s electronegativities 561 Penicillin sulphoxides epimerization of 750 synthesis of 246 Peptides 854, 864-866... 

As far as the unsettled problem of anhydropenicillin is concerned, the /3-lactam ring of this compound seems electronically overcompensated , similarly maybe to the penicillin sulphoxides, disregarding the differences in the thiazolidine rings, which is a factor of great uncertainty. 

From Benzothiazolyldithioazetidinone Type C). The disulphides (6), which are obtained by the reaction of penicillin sulphoxides and 2-mercaptobenzothiazole, give different products with bases, dependent on the structure of the substituents on the -lactam nitrogen e.g., [6 R = CH(C02H)C(Me)=CH2] gives (7) whilst [6 R = C(=CH2)C02CH2CCl3] gives (8). "... 

An interesting transformation of penicillin sulphoxides to 5,6-dithia-8-aza-7-neoctem derivatives (225) is to be mentioned here. 

Grignard reagents behave similarly,and a thioborane gives an un-symmetrical sulphide with a sulphenate ester. Tris(diethylamino)-phosphine converts cystine derivatives into corresponding lanthionines [NH2 CH(C02H) CH2]2S, 2 and the disulphide formed between penicillin sulphoxide and Bu SH (36 fine s in place of Me at S) forms the ethyl sulphide (36 Et in place of Me at S) by treatment with triethylphosphine. ... 

Sulphenic acids (199) have been produced transiently by thermolysis of penicillin sulphoxides and trapped both intra- and inter-molecularly. ... 

A convenient high yield synthesis of 3-iodo-3-methylcephams (373) and 3-alkoxy-3-methylcephams is by reaction of the thiazoline azetidinone (372) with iodine or sulphenyi halides. Cooper first reported that (374), a degradation product of penicillin, gave a mixture of penicillin sulphoxide (376) and desacet-oxycephalosporin sulphoxide (377) when treated with /w-chloroperoxybenzoic acid in the presence of TFA, and this transformation was used in Kishi s biogenetic-type synthesis of penam and cephem derivatives- The results are not always... 

Optically active 4-acyloxyazetidin-2-ones are readily available from penicillin sulphoxides by reaction with trimethyl phosphite and a carboxylic acid (Scheme 91). The thiazolidine ring of penicillin sulphoxides may also be cleaved to give... 

From Penicillins (Type C). The important problem of the relationship between penicillin, cephalosporin, and isothiazole derivatives has recently interested several research groups. This topic is also considered in Chapter 16. The anion of azetidinesulphenic acid (20) undergoes spontaneous fragmentation and re-cyclization, giving the isothiazolone derivative (21) in high yield. Direct treatment of penicillin sulphoxides with bases has previously given isothiazoles similarly, and further examples continue to be reported. The 4-mercapto-... 

The base-catalysed epimerization of penicillins and their sulphoxides has been described recently. Epimerization of penicillin sulphoxides (23) in the presence of l,5-diazabicyclo[4,3,0]non-5-ene ( DBN ) is attended by the production of the isothiazolone (24), presupposing the occurrence of j3-elimination. The possible... 

Epimerization of the penicillin sulphoxide (48 c,x) with diazabicyclononene leads rapidly to a 2 3 mixture of (48) and 6-epi-(48). However, p-nitrobenzyl ester (48 c,R = CH2C6H1NO2-4) under identical conditions gave a 6 4 1 mixture... 

A similar penicillin sulphoxide-cephalosporin transformation, initiated with acetyl chloride-pyridine, has also been described. The disulphide (93 b) and sulphenanilide (94 b) have been prepared from the sulphenic acid (80). These sulphenyl derivatives readily cyclize to penicillins (95 b) and cephems (96 b). 

Cleavage of the 1,2-bond has also been achieved by chlorination or bromin-ation of penicillin sulphoxides. The resulting sulphinyl bromide (103 y) or chloride (104 t) cyclizes readily to the A -cephalosporin sulphoxide (2 X = H). The reaction of (103 t) with diazomethane, however, gives a mixture of three novel cepham sulphoxides (105 t), (106 t), and (107 t) as well as the chloromethyl sulphoxide (109 t). These products are believed to result from a diazo-sul-phoxide (108 t), which undergoes a rapid intramolecular cyclization, via either the sulphoxocarbene (110) or the pyrazoline (111). Cephalosporins (112) and (113), derived from these sulphoxides, exhibited weak antibacterial activity. 

An improved method for the transformation of the j8-lactam thiazoline (176) into the penicillin nucleus has been reported. Oxidation of (176) with m-chloroperoxybenzoic acid gave the sulphoxide (177), which underwent a radical-initiated rearrangement to the penicillin sulphoxide (1) in high yield. 

Reactions of Sulphenic Acids.—In continuation of previous work, penicillin sulphenic acids have been trapped with vinyl ethers and keten acetals, " " with thiols, alkenes, and alkynes. A variety of products from thermolysis of N-benzyloxycarbonyl-L-(S-t-butyl)cysteinyl-L-valine methyl ester S-oxide must derive from an intermediate sulphenic acid, and isothiazolones and thiazinones formed from penicillin sulphoxides are also satisfactorily accounted for on the same basis. "... 

Sulphenyl Halides.—Sulphenyl chlorides are readily available by chlorinolysis of disulphides, and this remains the most commonly used method of synthesis. Chlorinolysis of penicillin esters gives the sulphenyl chloride, and a route to an azetidinone sulphenyl chloride has been devised in which the relatively unstable sulphenic acid produced by penicillin sulphoxide pyrolysis is treated with SOCh in CCl, to give [43 R =C1, R =CH(C02Me)CMe=CH2]. Sulphenyl iodides may be important intermediates in reactions at disulphide bridges in peptides and proteins, and a report of the preparation of a stable sulphenyl iodide is notable. The observation that methanesulphenyl chloride dimerizes (in SO2 in the presence of a Lewis acid) to give MeSSMeCl Cl MeS=SMeCl Cl may be useful in explaining the course of certain electrophilic reactions of sulphenyl chlorides, and should stimulate a search for new reactions of aliphatic compounds of this series. 

R =OH) derived from a penicillin sulphoxide, thus leading to a mixture of diastereoisomeric sulphinyl chlorides which proved to be inseparable. ... 

Hypochlorite oxidation of suitable penicillin derivatives has allowed a more direct route to 6a-methoxypenicillins. Thus N-chlorina-tion-dehydrochlorination of the penicillin sulphoxide (27 b, y) in a borate buffer generated the acylimine (29 y, = PhOCHj) uio the N-chloro-amide... 

The first general method of transforming a penicillin into a cephalosporin, the acid-catalysed rearrangement of penicillin sulphoxides, continues to receive attention. That this rearrangement proceeds via a sulphenic acid derivative has been further confirmed by isolation of the crystalline sulphenic acid (74 f, y) from the thermal rearrangement of the penicillin sulphoxide (27 f, y). This intermediate slowly reverts to the penicillin at 38 0, and, on treatment with methanesulphonic acid in dimethylacetamide, cyclizes to cephalosporin (75 f, y). Trapping of (74) by oxidation to the sulphinyl chloride (76 f, y) has been reported cyclization to a cephalosporin sulphoxide was accomplished under base catalysis/ Treatment of penicillin sulphoxides with azo-compounds also effects rearrangement to... 

The sulphenic acids produced on thermal rearrangement of penicillin sulphoxides have been trapped by a variety of reagents, including thiols and acetylene and olefin derivatives such as norbomadiene, keten dimer, vinyl ethers, keten acetals, and acetylenedicarboxylates. Removal of the nitrogen substituent of the resulting 2-azetidinones, e.g. (98 c,v), was achieved by addition of diazomethane to the olefin followed by base treatment or reduction of the intermediate pyrazoline (99). ... 

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