Sulfoxide ester

Although menthyl esters, especially 19, are most often used to prepare sulfoxides, esters derived from optically active alcohols other than menthol have been prepared . Ridley and Smal prepared arenesulfmic esters of 1,2 5,6-di-O-cyclohexylidene-a-D-glucofuranose. Unfortunately, these diastereomers were oils, except for the mesityl derivative, with the major epimer having configuration R at sulfur and so they offered no advantage over the menthyl esters. Separation of the epimers by chromatography failed. 

Aminopenici11 anic acid (I) is acylated, oxidized and esterified to give the sulfoxide ester (II). Sulfoxide ester (II) is converted to its C-6 epimer (III) by treatment with trimethyl chiorosilane and triethyl amine. Rearrangement of III using triphenyl phosphine yields the epioxazoline (IV). 

About one-third of the commercial cephalosporins are derived from 7-ADCA. Due to the lower cost of penicillin, 7-ADCA is usually produced from penicillin G by ring expansion of a penicillin sulfoxide ester to yield a cephalosporin ester. The removal of the ester group is followed by cleavage of the phenylacetyl side chain to give 7-ADCA. Two-thirds of the commercial cephalosporins are derived from 7-ACA, that is produced from CPC by either chemical or enzymatic deacylation. 

Ozonolysis has also been demonstrated to play a role in the production of another important intermediate in (3-lactam synthesis, hydroxyl-cepham sulfoxide esters 92.84 Ozonolysis plays a role in the conversion of a methylene group in compound 93 into the required hydroxy group in compound 92 (Scheme 11.25). 

When the thiazine ester (708) was treated with an isocyanate such as (709), an imidazo[5,l-c][l,4]thiazine (710) was produced (8UAP8161384). Treatment of certain penicillin sulfoxide esters (711) with ethoxycarbonyl isocyanate results in a ring expansion of both rings to afford an imidazo[5,l-c][l,4]thiazine (712) (81JOC3026). 

Another approach to asymmetric sulfoxide Diels-Alder reactions involves the stereoselective oxidation of a sulfide. Modena and coworkers [73] obtained sulfoxide-ester 9.74 (R = H) from chiral thiol 9.73 by addition to methyl propiolate and oxidation with MCPBA. The cycloaddition of 9.74 with cyclopentadiene at -5°C is highly selective due to the rigidification of the dienophile by internal hydrogen bonding (Figure 9.40). 

Scheme 2.64 Resolution of sulfoxide esters by Pseudomonas sp. lipase...

The metamorphosis of penicillin V sulfoxide ester (XIII) into a de-acetoxy cephalosporin (XIV) has been reported in detail by Morin and co-workers. The introduction of the acetoxy function into the 3-methyl group of XIV generating a cephalosporanic acid (XV) has now been accomplished . ... 

A new and efficient method for the preparation of penicillin sulfoxide esters has been developed (Bywood et al., 1975). This procedure involved treatment of the penicillin sulfoxide with a hydrazone in the presence of an oxidizing agent (e.g., iodine) (Barton et al., 1974). This method appeared to be especially useful for the synthesis of benzhydryl esters (Scheme 2). The hydrazide (1) was reported to be a useful alternative... 

Reaction of the sulfoxide ester (47) (via the sulfenic acid) with trimethylsilyl succinimide, however, gave rise to the sulfenamide (48) in... 

The nature of the products produced in a penicillin sulfoxide rearrangement are determined, in part, by the nature of the 3-substituent. In the normal acid-catalyzed rearrangement of a penicillin sulfoxide ester... 

The rearrangement of a penicillin sulfoxide ester to a A -cephem, originally accomplished using toluenesulfonic acid, has also been achieved with a variety of reagents [e.g., dipyridinium phosphate (Barton et al., 1972 Baldwin et al., 1973), diethyl azodicarboxylate (Tereo et al., 1972), a,a-azobis-N-methylformamide (Tereo et al., 1972), and diethylphos-phorocyanidate (Ninomiya et al., 1976)]. This latter reagent was disclosed as also yielding small amounts of the A - and exomethylenecephem isomers. 

More recently, an in-depth study (Chou et al., 1978) of the reaction of the penicillin sulfoxide ester (55) with a positive chlorine source (i.e., A -chlorophthalimide) aptly illustrated the capriciousness of this reaction. In the presence of traces of acid (e.g., HCI), a rapid autocatalytic reaction ensued which liberated hydrogen chloride and gave two major new products 99 and 100. On continued heating 99 was also converted to 100. A minor product (101) could be obtained as the major product if the reaction was conducted at ambient temperature. By heating in the presence of chlorine, 101 could also be converted to 99 and 100. Treatment of 101 with methanol gave the thiazoline 102. These results indicated that under certain conditions a penicillin sulfoxide could cleave at the S—C-5 bond, a previously unrecognized site for cleavage. 

The thiazoline (208) was first reported several years ago as the product obtained by reaction of penicillin sulfoxide ester (209) with trimethyl-phosphite (Cooper and Jose, 1970). It was recognized as a potentially useful synthetic intermediate for the construction of modified 3-lactam structures and in recent years numerous publications have appeared substantiating this concept. 

To determine which carbon atom of the isopropenyl functionality in the azetidinone sulfinyl chloride participates in the ring closure, the above sequence of steps was repeated starting with the penicillin sulfoxide ester deuterated at the C-2 methyl position. The stereochemistry of this compound (70) had been previously established (Cooper, 1970). The NMR spectrum of the final product, methyl phthalimido-2-dideutero-3-methy-lenecepham-4-carboxylate (71), showed clearly a selective incorporation of deuterium at the C-2 position. It was, therefore, concluded that the olefinic carbon in the intermediary sulfinyl chloride was involved in the S—C-2 bond formation. 

The yield of the sulfinyl chloride intermediate from 6-acylaminopeni-cillin sulfoxides such as 6-phenyl- and 6-phenoxyacetamidopenicillin sulfoxide esters (in contrast to 6-phthalimidopenicillin sulfoxide esters) di-... 

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