Azetidinone sulfoxides

A similar intramolecular nucleophilic capture of an allylic sulfenate generated thermally from the corresponding sulfoxide was also reported for the facile transformation of the azetidinone 61 into a new 3-acetylthio-2-thiacephem ring system 62 (equation 29)127. 

A protocol has been reported based on a cyclization procedure followed by hydrolysis and oxidation, which allowed the preparation of a-keto-(3-lactams (Scheme 11), [59]. The cyclization of imines with acetylglyoxylic acid, in the presence of POCI3 and Et3N, gave 3-acetoxy-(3-lactams in good yields as cis-isomers, prevalently. These latter were hydrolyzed to alcohols in excellent yields under very mild conditions. Subsequent oxidations were performed by treatment with dimethyl sulfoxide (DMSO) in the presence of phosphorous pentoxide to give a-keto-(3-lactams. More 2-azetidinones were synthesized varying the substituent of the acetyl moiety. 

Sulopenem (CP-70429 see Tables 1 and 7) has been prepared via this reaction as the key step (G=0/C=S reductive coupling). The total synthesis utilizes L-aspartic acid to generate the chiral precursor 78 of the C-2 side chain, a modified chiron 76 (X = C1) to improve the preparation of the trithiocarbonate intermediate 79, a chemoselective oxalofluoride-based azetidinone N-acylation to give 80 (a procedure that avoids sulfoxide O-acylation), and mild final deprotection conditions of hydroxyl and carboxyl functions. In particular, the chloroallyl ester 81 has been selected, owing to its smooth cleavage by a palladium-mediated transesterification procedure (Scheme 42) <1992JOC4352>. 

Several new examples of the known transformation of penicillin sulfoxides into isothiazolones, through the corresponding azetidinone sulfenic acid, have been reported <1998TL6983>. 

Penicillin sulfoxides are converted on heating with trimethyl orthoacetate or excess ethyl 2-thioacetate into isothiazolin-3-ones. The azetidinone disulfide, formed when one equivalent of ethyl... 

A second, isolated example of construction of useful chiral azetidinones by the N-C4 bonding strategy utilizes the phenylsulfinylpropionamide 93a as starting material. Treatment of this compound with TMSOTf/TEA promoted a Pummerer rearrangement concerted with lactamization to 93b [43a]. Starting from the ( — )-sulfoxide enantiomer, obtained by HPLC resolution with a chiral stationary fase (cellulose tribenzoate), the 4/ -phenylthio enantiomer was obtained in 67% optical yield [43b]. Hydroxyethylation of this intermediate is described in Sect. 3.1. 

The thermal equilibration between penam sulfoxides and azetidinone-4-sulfenic acids 109 opens the way to a number of methodologies for obtaining azetidinone 4-thioesters. The oldest one, discovered in 1970 by Hatfield et al. [86], simply involves heating of the penam sulfoxide with a carboxylic anhydride and trimethyl phosphite thioesters 137 are obtained through a mechanism representable by the formation and collapse of penta-coordinate phosphorous intermediate 135. 

Instead, cyclization occurred between a sulfenic acid at azetidinone C4 and an alkyne moiety at nitrogen [206]. The ( )-2-alkylidenepenams 374 were selectively obtained by thermolysis of appropriate 4-rert-butylthioazetidinone precursors, through the intermediacy of transient sulfenic acids 373. The high stereoselectivity of the reaction is suggestive of a pericyclic ring closure. Sulfoxide reduction of 374 was achieved with PBZ3 in DMF. 

The existence of an equilibrium between penicillin sulfoxide and the azetidinone sulfenic acid was first explored in 1969 and further substantiated by several groups (Cooper and Spry, 1972). The intermediate, however, had never itself been isolated. Indeed, an isolable sulfenic acid was a rare entity. Chou and co-workers (1974) observed that a mixture was obtained after an ethyl acetate solution of the sulfoxide (17) was refluxed and rapidly cooled. Separation, by fractional crystallization, yielded the starting sulfoxide (17) and a second compound identified as the sulfenic acid (19). Cyclization of 19 to the sulfoxide occurred readily (/1/2 3 hr at 38°C in chloroform). NMR data indicated that the structure of the sulfenic acid was best represented by isomer a rather than iso mer b. 

During the initial studies on the chemistry of the suifenic acid functionality, Shelton and Davis (1967) observed that t-butylsulfenic acid (103) underwent conjugate addition to a propiolic ester to produce the vinyl sulfoxide (104). Similarly, the azetidinone suifenic acid (105), thermally generated from penicillin sulfoxide (106), was also found to undergo a conjugate addition with dimethyl acetylenedicarboxylate to yield a mixture of epimeric sulfoxides 107 and 108 (Barton et al., 1973 1974). This isomeric mixture could be reduced to the single sulfide (109). The double bond was isomerized to the a,p-unsaturated compound 110 which on progressive ozonolysis first produced the thiooxalate (111) and then the oxamide (112). 

In contrast to several other rearrangements of the penicillin sulfoxide, the reaction with 155 was also successful with the free acid (4) wherein 157 was isolated with no reported decarboxylation. Treatment of the acid (157) with sodium bicarbonate afforded a disproportionation-recombination reaction resulting in the azetidinone disulfide U58) and the benzthiazoyl disulfide (159). 

Other azetidinone derivatives useful for the synthesis of new p-lactam structures have been prepared by variations in the reaction of a trialkyl-phosphite with the sulfenic acid derived from a penicillin sulfoxide. 

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. 

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