Stereochemistry of 3-methylhexahydrophtalide.

Complementary Diastereoselective Reduction of Cyclic γ-Keto Acids: Efficient Access to Trisubsituted γ-Lactones

“…Although reductions of β-hydroxyacids are well developed, relatively few examples applying this concept to the reduction of γ-keto acids have appeared . Several reports have detailed the diastereoselective reduction of cyclic and acyclic 1,4-keto acid derivatives providing the product lactones in good yield and selectivity. We envisioned that treatment of the 4-oxocarboxylic acids with a particular reducing agent ([H - ] A ) would potentially provide the syn -lactone A , while treatment of the starting material with a separate hydride source ([H - ] B ) may supply the paired anti -lactone B (Scheme ).…”

“…With efficient entry to the syn diastereomer, we turned our attention to the search for conditions that would favor the corresponding anti isomer. Lithium trialkylborohydrides had been shown to provide the anti - lactones in similar systems . Subjection of keto acid 1 to 2.4 equiv of Super-Hydride (Et 3 BHLi) in THF provided the desired products after cyclization in 83% yield and an 85:15 ratio favoring anti - lactone 2 (entry 4).…”

“…Aromatic ketones also participate in the reaction. Phenyl keto acid 14 undergoes a highly selective reduction under Super-Hydride conditions, supplying the anti -lactone in superb yield 10c. Unfortunately, when keto acid 14 is reduced with the PhMe 2 SiH/TFA system, the product lactone is produced as a 1:1 mixture of diastereomers.…”