Of 4-acetoxy-p-lactam

Additionally to the above described acid chloride-imine methodology we [46] and others [47] considered alternative pathways toward the synthesis of 4-acetoxy p-lactams 79 (Scheme 13). Georg has reported on the utilization of... 

A 4-acetoxy substituent on a p-lactam is replaced by thio-acid salts in a zinc halide mediated reaction in non-protic medium (94TL3379) whereas copper salts and copper enolates are recommended for the replacement of a 4-phenylthio group (94TL5887). Intermolecular coupling reactions of 4-phenylseleno P-lactams are used to prepare tribactams (94CC441). 

It is well known that the most direct access to 4-acetoxy-P-lactams is the addition of CSI to the corresponding vinyl acetate [17]. Kametani and coworkers [18] were the first to accomplish the total synthesis of antibiotic ( ) PS-5 by reaction between 3-ethyl-4-acetoxyazetidin-2-one 12 and the lithium enolate of r-butyl a-diazoacetylacetate and further ring closure in the resulting p-lactam 15 by the carbene insertion reaction developed by Merck (Scheme 2). The same authors [19] reported the synthesis of antibiotic ( ) PS-6 starting from the corresponding 4-acetoxyazetidin-2-one 13. 

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>. 

One method for the synthesis of hydroxyalkyl-substituted P-lactams is by the Staudinger reaction, the most frequently used method for the synthesis of P-lactams.86 This method for the preparation of 4-acetoxy- and 4-formyl-substituted P-lactams involves the use of diazoketones prepared from amino acids. These diazoketones are precursors for ketenes, in a diastereoselective, photochemically induced reaction to produce exclusively tram-substituted P-lactams. The use of cinnamaldimines 96, considered as vinylogous benzaldimines, resulted in the formation of styryl-substituted P-lactams. Ozonolysis, followed by reductive workup with dimethyl sulfide, led to the formation of the aldehyde 97, whereas addition of trimethyl orthoformate permitted the production of the dimethyl acetal 98 (Scheme 11.26). 

Addition and substitution. Addition of allylindium reagents to allenyl carbinols affords linear products. A net l,3-butadien-2-ylation at the (3-carbon of p-acetoxy-p-lactams results when they are treated with indium and l,4-dibromo-2-butyne. ... 

The P-lactam 128 thus prepared was treated with LDA at — 78 °C in THF as solvent and the resulting solution quenched with fourfold excess of an electrophile to furnish the expected trans 3,4-disubstituted P-lactam suitable for further chemical manipulation. For instance, the trans 3-(l-hydroxyethyl) P-lactam 129 was obtained in 98% yield as an equimolar mixture of dia-stereomers epimeric about the hydroxyl group. The mixture of epimers, after protection of the hydroxyl group as acetoxy derivative, was subjected to low... 

A number of research groups have been interested in die synthesis of aminodiol 22. This compound is believed to mimic the transition state for the renin-catalyzed hydrolysis of the peptide angiotensinogen and therefore can be useful as a potential antihypertensive drug. The enzymatic resolution of the 3-acetoxy-P-lactam 23 (Fig. 6) by lipase PS-30 has been demonstrated by Spero et al. [37]. A new approach to the BOC-protected aminodiol 24 via opening of 3,4-cis-disubstituted j3-lactam has been demonstrated. 

As mentioned above, in describing the synthesis of sanfetrinem (see section 3.1.1.1), enantiomerically pure 4-acetoxy-substituted azetidin-2-one 1 is the key starting material for the preparation of a variety of p-lactam antibiotics of the carbapenem and penem families. About 30 different syntheses of this compound have been reported in the literature [46,66], but only a few are industrially viable. 

The acetoxy group was hydrolyzed using hydrazine to give (46). Nucleophilic substitution of the fluorine atom produced the tricyclic p lactam (47). A diastereoselective aza-Diels-Alder reaction was used in a synthesis of (—)-lasubine (I). Tin tetrachloride-mediated reaction of complex (48) with Danishefsky s diene afford 2,3-dihydro-4-pyridone (49) as a single diastereomer (Scheme 86). Chiral benzaldehyde imines can be allylated with high diastereoselectivity to give optically active homoallylic amines (Scheme 87). 

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 p-lactams [249]. 

Buynak and coworkers [23] introduced an interesting entry to synthesize 4-acetoxy-3-alkylidene-P-lactams (Scheme 5). The strategy involved addition of CSI to the allenyl acetate 31 followed by careful reductive workup to give the 4-acetoxy-3-(l-methylethylidene)-2-azetidinone 32 in 30% yield. Further... 

Racemic 4-acetoxy-3-unsubstituted azetidinone 10 and homochiral (3R,4R)-3-(IR)-hydroxyethyl derivative 11, commercially available intermediates industrially prepared by the so-called CSI route , testify to the importance of this ring formation strategy. By using vinyl acetate as the olefin partner in the chlorosulfonylisocyanate-alkene cycloaddition, in 1974, Clauss et al. [10] laid down the basis of this approach in the field of p-lactam antibiotics. The most recent efforts have been directed to the key intermediate 11 and its synthetic equivalents 12, 13. Starting from methyl 3R-hydroxybutyrate [11], three independent methodologies have been realized, the main difference being the type (ether, thioether, ester) of enolate used. 

The aldehyde 12 was easily oxidized by potassium permanganate to the corresponding carboxylic acid(20) 13 in nearly quantitative yield. As mentioned previously, the 4-acetoxy derivatives of P-lactams are the key intermediates for the synthesis of thienamycin and related penems. In our case the conversion of the acid 13... 

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. 

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