Absolute stereochemistry, Mitsunobu reaction

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. 

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

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