Leading Question

The ester hydrolysis step is completed with greater than 80% yield, meaning that when lithium hydroxide attacks it selects the correct ester with at least that percentage accuracy. Why does this occur? The main justification decided on by our group was the steric hinderence presented by the isobutyl group over the methyl group (Figure 3).

Figure 3.

Other than this factor, the compounds are almost completely identical, are both equally stablilized by the THF solvent in which this reaction takes place, and are both very similar in terms electronics, resonence, and functionality. Thus when a hydroxide attempts to attack at the carbonyl, the geometry of the molecule must present a very unfavorable route when an isopropyl is present relative to the significantly smaller methyl group.

In a natural product synthesis of marine cyanobacterial cyclodepsipeptide apratoxin A, a selective esterfication takes place by similar means (Chen, J.; Forsyth, C.J. P. Natl. Acad. Sci. USA. 2004, 101, 12067-12072.). Initially a TBS group is added to the molecule to protect one site where hydrolysis could occur, and then a hydrolysis is undergone.

Figure 4.

The other possible sites are protected by steric means with a tert-butyl group and a TBS group, making the oxygens much higher more difficult and energetically unfavorable to reach, making the primary product a hydrolysis at the benzoate group (Figure 4, the hydrolysis takes place from step 66 to 67.