Carbonate synthesis, carbapenem

Joining the effort at this time were Drs. Kai Rossen and Phil Pye, specifically to work on a practical carbonate synthesis. In thinking about how to approach this problem (Figure 8), their thoughts led back to the acetoxyazetidinone, which, in fact, was defined as a viable carbapenem synthon by Dr. Paul Reider and yours truly back in the early 1980 s. In the intervening years it has become an article... 

Dehydrobromination. Dehydrobromination with AgF-pyridine was first reported some time ago.1 It has recently proved to be the method of choice in a total synthesis of thienamycin, a carbapenem broad-spectrum antibiotic. I- or example, attempted dehydrobromination of 1 with DBU in DMSO resulted in elimination of HBr and also carbonate to give a mixture (2) of two ene lactams. The desired reaction was effected in 70% yield with AgF in pyridine.2... 

A double cyclization of the aminophosphonoacetate derived -hydroxy acids 181 was utilized by Miller et al. [67] in the synthesis of the bicyclic -lactams 182 as potent antibiotics. The carbon framework for the carbapenems was constructed by an asymmetric aldol condensation utilizing the cysteine-derived thiazolidinethione and subsequent direct coupling of the resulting -hydroxy acid equivalent 183 with dimethyl aminophosphonoacetate (Scheme 43). Two... 

Since the first report by Bergbreiter and Newcomb in 1980 [72] on the utilization of lithium enolates of esters in place of Reformatsky reagents for the construction of the azetidinone ring (Fig. 4), several research groups have applied such approach to the synthesis of carbapenem compounds. Most notably, the recent review by Georg [5g] on the synthesis of thienamycin and related P-lactams delineated the most recent advances in the P-lactam field and focuses great attention on the utilization of optically active esters of 3-hydroxy-butyric acid for an effective control of the relative and absolute stereochemistry at the carbon atoms T and 3 of the 3-(l -hydroxyethyl)azetidin-2-one 132. Inversion of the configuration at the hydroxyethyl side chain by Mitsunobu s reaction [42] and further elaboration of the peripheral functionalities leads to the formation of a variety of carbapenem precursors. 

Through this approach formation of chiral P-hydroxy carboxylic acids with appropriate carbon frameworks is the key step of the method. Evans [92] reported an asymmetric synthesis of the carbapenem PS-5 in which the two stereocenters of the P-lactam ring were efficiently established via an asymmetric aldol addition reaction (Scheme 34). In this approach, the boron enolate 214 was... 

The first application of silylimines in our laboratory is concerned with the synthesis of trans (3S,4/ )-3-hydroxyethyl-4-acetoxy-azetidinone with the natural R configuration of carbon bearing hydroxyl group (Scheme 4). This compound constitutes a most useful intermediate for the synthesis of both penems and carbapenems which can be easily obtained following the well established Merck and Farmitalia procedures respectively. ... 

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