Non-hydrolytic Anomalous Lactone Ring-Opening

These compounds were also studied by combining stractural and molecular biological methods, and the hPPARa selective lead compound 7 (BMS-687453) emerged from these studies. Its EC50 was 10 nM for hPPARa, and it exhibited 410-fold selectivity versus hPPARy. The X-ray co-crystal structure of 7, in complex with PPARa LBD, was also determined [12]. 

In the next section, the synthetic highlights along the path to this lead structure and its analogues are described, in particular, non-hydrolytic, anomalous lactone ring opening, and stereo-uniform formation of the ether bond at the stereogenic centre through apphcation of the Mitsunobu or Williamson-type reaction. 

As stated in the introductory chapter, research towards anew drug entity (NDE) is a shuttle process, in which synthetic organic chemistry is often the initial step. As the research process advances, the targets and methods of synthetic organic chemistry are modified to deal with the increasing substance quantities required. 

In the succeeding steps, we first encotmter ether bond formation between 12 and 13, at step V, which proceeds with inversion of the configuration at the stereogenic centre in the chiral building block 13. Anomalous lactone ring opening in 14, step vi, is a key step in the whole process and will be discussed in more detail. Hydrogenolysis of iodine in 15 leads to the (S)-2-hydroxybutanoate unit in the final product, 1. 

Step vi is particularly obscure . It is not apparent to the usual retrosynthetic analysis and requires the imagination of an experienced synthetic chemist. It is crucial to the synthetic direction, however, offering an elegant solution to the key 

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Synthetic highlights A critical step in the synthesis of the compound involves non-hydrolytic anomalous lactone ring-opening by TMSl. To avoid racemization, the Mitsunobu reaction was applied in the formation of the ether bond. Optimization of the Mitsunobu reaction was finally achieved without loss of enantiomeric purity. 

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