Lactams sulfenylated

In general, none of the 7(6)-alkylated (acylated) cephalosporins or penicillins reported showed enhanced biological activity relative to their unsubstituted parents. These disappointing results, coupled with the concomitant discovery of cephamycins, led researchers to explore the latter more promising area. Among the earliest methods employed for 7(6)-methoxyl introduction was initial -lactam sulfenylation or halogenation,... 

P-lactams Aceto(carbonyl)cyclopenta-dienyl-(triphenylphosphine)iron. Benzene-sulfenyl chloride. Chlorodicarbonylrho-dium(I) dimer. 2-Chloro-l-methylpyridin-ium iodide. Dimethylformamide-Thionyl chloride. Ketene bis(trimethylsilyl)-ketals.p-Tolylsulfinylacetic acid. Triphenyl-phosphine-Diethyl azodicarboxylate. Zinc. 

The sulfmylation of esters, - lactones, carboxylic acids, > amides and lactams may be effected by reacticm of the corresptHiding lithium enolates in THF at -78 to 0 C with dimethyl or difdie-nyl disulfides, or, less conunmily, with methyl or fdienyl sulfmyl halides. The enolates of ketones, however, are insufficioitly nucleq diilic to react with dialkyl sulfides unless HMPA is added to the re-acticm mixture, although they do react smoothly with diaryl sulfides. This difference allows the selective sulfenylation of esters in the presence of ketones (entry 5, Table 3). ... 

In 2005, the application of cinchona alkaloid derivatives as catalysts for enantiose-lective a-sulfenylation of activated C—H bonds in lactones, lactams, and P-dicarbonyl compounds 146 by electrophilic sulfur reagent 147 was reported by Jorgensen and coworkers (Scheme 6.44) [73]. Optically active a-sulfenylated products 148 were obtained in good to excellent yields and up to 86% ee in the presence of 10 mol% (DHQD)2PYR in toluene solvent at —30 or —40°C. Furthermore, the diastereose-lective reduction of a-sulfenylated (3-keto esters to give optically active a-sulfenylated (5-hydroxy esters was also demonstrated. 

A more general route for this type of chiral bicyclic lactam is based on a metalation from a Meyers lactam (198) followed by alkylation, acylation, or sulfenylation to give the a-substituted bicyclic unsaturated lactams. These compounds were converted to a, -unsaturated derivatives (199) by a metalation-selenation-oxidative elimination sequence that proceeded in good overall yields (Scheme 35) <90T495l>. 

Chlorination of Activated Methylene Groups. Triflyl chloride was used for the high yielding chlorination of carbon acids, and this reaction was applied to the synthesis of simple 2,2-disubstituted heterocycles. This method has been extended to the preparation of heterocycles fused with -lactams. Treatment of a hydroxyphenylazetidinone with triflyl chloride and triethy-lamine afforded a hemiaminal in 90% yield, through the chlorination of the dibenzyl malonate moiety (eq 11). Performing the same transformation on a mercapto- -lactam precursor led to the formation of a sulfenyl chloride intermediate rather than to chlorination of the malonate moiety. ... 

In addition to direct introduction, other methods that rely on acylimine chemistry have also been developed to construct 7(6)-substituted p-lac-tams. Spitzer and Goodson (1973) utilized acylimines to convert 7(6)-sulfenylated p-lactams to their corresponding methoxy derivatives. 6a-Methylthiopenicillins (89) (for preparation see p. 288), were treated with chlorine in methylene chloride at -78°C, followed by methanol and triethylamine. The desired 6a-methoxypenam (90) was obtained in 65% yield. The reaction probably involved acylimine formation (94) triggered by chlorosulfonium ion (93). Other alcohols could be introduced at C-6 by the same procedure (91 and 92). This sequence was also employed... 

Concurrent with the above, a group at the Squibb Institute (Gordon et al., 1977, 1980) independently reported a different approach to 7(6)-a-methoxylation of p-lactams, which also relied upon sulfenimines as key intermediates. These workers found that reaction of amine esters with 3 equiv of toluenesulfenyl chloride or methylsulfenyl chloride in methylene chloride containing propylene oxide-molecular sieves to act as an acid scavenger, afforded sulfenimines 230-232 in about 80% yield. This reaction presumably proceeds by successive sulfenylation of amine... 

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