Thiazoline-azetidinone

Thiazoline-azetidinones 1 derived from penicillins G and V4) are potential intermediates for penicillin-cephalosporin conversion, where the oxidative functionalization of the methyl group of the 3-methyl-3-butenoate moiety is an essential step. The direct chlorination of 1 with chlorine (25 °C, 3 days) or /-butyl hypochlorite (—60% yields) gives the corresponding chlorinated compounds 2, bearing benzyl, phenyl, p-tolyl, and phenoxymethyl groups as the R3 substituents 5). 

Direct transformation of thiazoline-azetidinones 2 into 3 -thio-substituted cephalosporins 6 has been performed by ring opening of the thiazoline moiety with sulfenyl chloride followed by ring closure with ammonia in dimethylformamide and simultaneous displacement of the allylic chlorine atom with the leaving thiolates. 

Thiazoline-azetidinone 36 is a versatile intermediate for the synthesis of varieties of beta-lactam antibiotics 24>. The most straightforward route to 36 must be the removal of the feta-lactam A-substituents of thiazoline-azetidinone 35, which is readily obtained from penicillins by Copper s method 4>. This has usually been done by the two-step operation, involving ozonolysis and subsequent methanolysis 25). Direct transformation of 35 to 36 also has been achieved by oxidation with potassium permanganate or osminum tetraoxide, but yields are unsatisfactory (—37%)25). An efficient method for the removal of A-substituents of 35 is the electrochemical acetoxylation procedure which may lead to the compound 36 along with 37 (Scheme 2-12)3). For example, the... 

An alternative electrochemical route to the thiazoline-azetidinone 36 also has been developed. Carboxylic acid 39 prepared from penicillin G can be converted to 36 via 40 by electrochemical decarboxylative acetoxylation followed by hydrolysis (Scheme 2-13)The electrolysis of 39 in an AcOH/DME—AcONa—(C) system at 0 °C... 

Woodward s Phosphorane Route. The first penem synthesis, shown in Figure 2, utilized an intramolecular Wittig reaction to form the [2,3] double bond of the thiazoline ring (84). Reductive acylation of the penicillin derived disulfide (44) gave the thioester (45). Ozonolysis of the latter provided the oxalimide (46) which on mild methanolysis gave the azetidinone (47). Well established methods were applied to convert (47) to the phosphorane (48) which underwent thermal cydization to the penem ester (49). Catalytic hydrogenation gave the penem acid [64370-39-4] (50) which was shown to possess antibacterial activity in spite of its rather limited stability. 

Synthesis of the Azetidinone Precursors 2.1 Thiazoline vs. Azetidinone Ring Closure... 

The penem system has always been assembled by late formation of the thiazoline ring. No attempt to obtain penems by closing the azetidinone ring as the last step has ever been reported, though this strategy is well documented on penicillins [3, 4]. Approaches based either on the dehydrative condensation of thiazoline acetic acids 4 or on ketene addition to thiazoles 5, reactions known to... 

The thermolysis of azetidinone ( -lactam) disulphides (89) yields the iso-thiazolin-3-ones (90), amongst other products these, in turn, can be converted (in high yield) into 3-alkyl-(or aryl-)aminoisothiazoles (91) by reaction with methyl fluorosulphonate followed by ammonia, as shown in Scheme 6. 

Several alternate pathways for the synthesis of thiazoline azetidinones have been reported however, none appear to be as efficient as the initial synthesis. Rearrangement of the thioamide (210), prepared either by direct acylation or by treatment of the iminochloride (211) with hydrogen sulfide, gave an initial unstable product (212) which decomposed under a variety of conditions to give 213 as the major product (Tanida et al., 1975b,c). 

The chemistry of these thiazoline azetidinones was dependent upon... 

The success achieved with phthalimidopenicillin and the knowledge accumulated in these model experiments encouraged Shionogi scientists to examine this reaction sequence with both penicillin V and G. At this point they elected to employ the known thiazoline azetidinone compound 163 which is easily prepared by the method published earlier by Cooper and Jose (1970). They reasoned that the terminal double bond in 163 was suitable for the removal of a one-carbon unit to afford the expected ozonized product. And indeed, when the bicyclic derivative (163) was ozonized in methylene chloride-methanol at -78°C followed by reduction of the ozonide with an excess of dimethyl sulfide, the desired enol ester (164) was isolated in 70% yield (see also Volume 1, Chapter 1). 

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... 

The interaction of 2-alkylthio-A -thiazoline and 3-methyl-4-p-chloro-phenylthio-2-azetidinone (175) (in the presence of catalytic amounts of l,4-diazabicyclo[2,2,2]octane) at 120 X under nitrogen affords 16% yields of 6-methyl-5-oxo-5H-2,3-dihydrothiazolo[3,2-a]pyrimidine (176). This and analogous reactions of the azetidinone are promoted by the good leaving properties of its arylthio-group. " ... 

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