4- Acetoxy /?-lactams

Lee and coworkers reported in 2004 the preparation of a key l- 3-methylcarba-penem intermediate (III, Fig. 15) by condensation of 4-acetoxy-(3-lactam with a titanium enolate of 2 -hydroxypropiophenone [279]. The resulting ketone was converted into the corresponding carboxylic acid (IV, Fig. 15) by a dry ozonation method. 

The synthesis involved formation of the (3-lactam 159 which was converted into its enolate and subjected to direct aldol condensation with excess of acetaldehyde to give 160 as a mixture of diastereomers in 80.9% yield. Further elaboration of the styryl group by known procedures afforded the ( )-4-acetoxy-(3-lactam 161 as intermediate of the 6P-methylcarbapenem derivative 162. 

N-Buienylimide 7 displays C symmetry. The carbonyl groups are therefore homotopic, and it is irrelevant which of the two is reduced to a hydroxy group. The reduction products from both carbonyl groups are identical. Once reduction is accomplished, the resulting hydroxy group is acetyl ated to give acetoxy lactam 8. 

Oxidation of 31 followed by treatment with AC2O afforded the acetoxy lactam 33, which was treated with BF3 -OEt2 to provide the tetrahydroindolizinone 34. Hydrogenation of 34 followed by reduction and then heating with 2 M HCl afforded 37. 

Preparation of the temporary connection was achieved by reaction of acetoxy lactam 316 with allyl(chloro)silane 317, generating the A -silyl species 318. Exposure to TMSOTf at 0 °C effected in situ formation of the /V-acyliminium species, which was trapped by the pendant allyl nucleophile, providing two out of the possible four dia-stereoisomeric cyclized products, 319 and 320 in a 4 1 ratio (Scheme 10-102). Formation of the two products may be accounted for by cyclic T. S.s where addition occurs onto the re face of the azetinone, anti to the sterically demanding silyl ether group through a chair-like or boat-like conformation. 

Based on a similar literature method,116 stereoselective coupling reactions between various 3-acetoxy-4-alkyl-/3-lactams and in situ-generated titanium enolates of cyclohexanone117 or propiophenone derivatives were developed, yielding the corresponding a,/3-disubstituted /3-lactams. 

Zirconium enolates of various carbonyl compounds have also been investigated for Mannich-type reactions with different electrophiles. According to Shibasaki s method,148 the coupling reaction between a 3-acetoxy-4-alkyl-/3-lactam and the in r(/ -generated zirconium enolate 96 of a cyclohexanone derivative was realized as a key step during the total synthesis of an anitibiotic (Scheme 42).117,149... 

A monoacetoxylation may be obtained via an electrodecarboxylation of heterocycles ()3-lactam [193, 194] or oxazo-lidine derivatives [195]) having a carboxylic group in a-position, as shown in Scheme 106 for the preparation of 4-acetoxy-2-azetidinones. 

Cephalosporins are -lactam antibiotics that block microbial cell wall synthesis. The original cephalosporin. Cephalosporin C, has only weak antibiotic activity. Therefore much more powerful second generation cephalosporins were developed by side-chain modification. Modifications at Cl are most effective but modifications at position 3 are also important so as to increase in vivo activity. Synthesis of the second generation cephalosporin cefuroxime requires the replacement of the C3 acetoxy side-chain of the precursor with a caibamate group. Chemical methods proceed via a hydroxylated intermediate which causes problems due to a tendency to lactonise at low pHs. Therefore development of a biocatalysis step was initiated in order to achieve selective reaction nnder mild conditions. 

Indium mediated allylation of 4-acetoxy-2-azetidinones gave the products 57 in high yield <99SL447> and similar reactions with azetidin-2,3-diones gave 3-substituted 3-hydroxy-P-lactams 58 <98H97>. 

Chiral, nonracemic, monocyclic y-lactams have been alkylated. One such lactam, 5-ethoxy-4-hy-droxy-l-isopropyl-2-pyrrolidone (5), is obtained as an 82 18 mixture of the (4S,5Jt)- and (4S,5S)-isomers from (S )-2-hydroxybutanedioic acid (4), via the crystalline, enantiomerically pure (A)-3-acetoxy-1 -isopropyl-2,5-pyrrolidinedione, in a five-step procedure with 57 % overall yield19,20. 

Antisera to cloxacillin/oxacillin/dicloxacillin and cefuroxime were also produced by similar procedures and successfully utilized in methods for the detection of these antibiotics in milk (34). Unfortunately, a number of other -lactams including aminopenicillins and some cephalosporins were not amenable to this mixed anhydride procedure. Thus, a carrier protein derivatization procedure was used to allow cross-linking of cephalosporins, such as cephataxime that has an acetoxy side chain, to ovalbumin. Because acetoxy groups react readily with the heterocyclic nitrogen atoms, the latter were introduced into ovalbumin through the carbodiimide-mediated derivatization of protein carboxyl groups with amino-methylpyridine (34). 

METHOXYCARBONYL-1,1,6-TRIMETHYL-1,4,4a,5,6,7,8,8a-OCTAHYDRO-2,3-BENZOPYRONE, an intramolecular Diels-Alder reaction is responsible for the diastereoselectivity. The stereoselective 1,4-functionalization of 1,3-dienes is exemplified by a two-step process leading to cis- and trans-1-ACETOXY-4-(DICARBOMETHOXYMETHYL)-2-CYCLOHEXENE. The effectiveness of a silyl hydride in providing a means for erythro-directed reduction of a p-keto amide is applied in a route to ERYTHRO-1 -(3-HYDROXY-2-METHYL-3-PHENYL-PROPANOYLJPIPERIDINE. This is followed by an asymmetric synthesis based on a chiral bicyclic lactam leading to (R)-4-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE. The stereoselectivity with which acetoxy migration can operate to an adjacent radical center is reflected in the one-step reaction that gives rise to 1,3,4,6-TETRA-O-ACETYL-2-DEOXY-a-D-GLUCOPYRANOSE. 

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. 

The stereochemistry of the Staudinger reaction was highlighted [86] using as substrates polyaromatic imines and acetoxy, phenoxy, or phthalimido acid chloride. The stereochemistry of the resulting p-lactams seemed to vary depending on the substituents present in the imines and the acid chlorides. For instance, if the polyaromatic moiety was linked to the iminic nitrogen, the reaction produced //Y/n.v-p-lactams if the same moiety was linked to the iminic carbon, cA-p-lactams were isolated. 

Lactams with polyaromatic substituents at C-4 have been reported to be synthesized, via Staudinger reaction [99]. The reaction of polyaromatic imines with acetoxy, phenoxy and phthalimido acid chloride in the presence of triethylamine at... 

The addition of lithium bis(methylenecyclopropyl)cuprates to acetoxy azetidi-nones has been reported to give methylenecyclopropyl azetidinones (Fig. 4) which could be further converted into various /V-functionalized (3-lactams [249]. 

An efficient route to 4/5/6 polycyclic (3-lactams (IV, Fig. 16) by enzyme metathesis and Diels-Alder reactions has been described starting from 4-acetoxy-... 

Cainelli and coworkers have reported in 2006, some further advances in the preparation of 4-alkyliden-(3-lactams starting from 4-acetoxy azetidinones and diazoesters [294]. 

In 2003, the group of Banik has assayed some 2-azetidinones against nine human cancer cell lines as a measure of cytotoxicity [86]. Structure-activity studies have revealed that A-chrysenyl- and A-phenantrenyl-3-acetoxy-4-aryl-2-azetidinones (Fig. 46), respectively, have potent anticancer activity. The comparable /V-anthra-cenyl, A-pyrenyl, and A -naphthalenyl derivatives became inactive. It is evident that the minimal structural requirement of the aromatic moiety for cytotoxicity is at least three aromatic rings in an angular configuration. The presence of the acetoxy group at the C-3 position of the (3-lactams has proved to be obligatory for their antitumor activity [86]. 

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