Anomalous lactone ring-opening

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. 

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. 

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. 

Nrai-hydrolytic Anomalous Lactone Ring-Opening... 

Scheme 3.7 Mechanism of EtOH-promoted anomalous lactone ring opening by MejSil...

Chelate systems can also occur in certain cases. Rasmussen and Brattain [6] have observed this in a-acetyl-7-butyrolactone, which has the j3-keto ester structure. The non-enolised form gives rise to bands at 1773 cm (five-membered ring lactone) and 1718 cm (ketone), but there is also a band at 1656 cm , which the authors attribute to a chelated carbonyl group similar to those observed in open-chain products. Halogen substitution in the a-position also raises the carbonyl frequencies. In the extreme case, perflouro-butyrolactone absorbs at 1873 cm due to the influence of the fluorine atoms [29], 2-bromobutyrolactone [12] absorbs at 1797 cm . Anomalous frequencies also occur when electronegative substituents are present on the carbon atom of 7-lactones. Brugel et al. [60] have cited a number of such cases, of which 7-acetoxy-7-valerolactone which absorbs at 1797 cm is a typical example... 

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