I am facing a similar synthetic problem as Boekman Jr. et al noted in their synthesis of Tetronolide. I will quote their’s rather than disclosing my actual synthetic problem, but note that the key element — an α-hydroxy-γ-lactone is identical.
The authors’ intended convergent synthesis involves coupling the two compounds 1 and 2 shown in scheme 1 in a ‘tandem ketene-trapping/[4+2] cycloaddition’, which requires the free hydroxy group in 1 to nucleophilicly attack the ketene.
Scheme 1: Tandem reaction attempted by Boekman Jr. et al; would include a nucleophilic attack of 1’s hydroxide onto 2’s ketene motif.
However, as indicated this reaction did not produce 3. The authors note:
However, despite considerable experimentation, all attempts to couple lactone  with  to afford β-ketoester lactone  failed. We surmised that the failure stemmed from impaired nucleophilicity of the tertiary OH group owing to a stereoelectronic effect resulting from the enforced alignment of the lactone carbonyl π-orbitals and the adjacent CO bond. (Compound numbers adapted to fit this scheme.)
Instead, the authors used alcohol 4, which readily reacted with the masked ketene 2 to give the ester 5 as shown in scheme 2.
Scheme 2: Successful tandem reaction attempted by Boekman Jr. et al; included a nucleophilic attack of 4’s hydroxide onto 2’s ketene motif.
My experimental findings have confirmed a similar effect for my compound. However, I have a bit of trouble discerning which electronic effects exactly cause this unreactivity. My first assumption is that the conformation of the five-membered ring forces the hydroxy group into an angle of approximately $90^\circ$ with respect to the carbonyl-π system. This should allow mixing of σ and π orbitals of whichever kind.
My second assumption was tracing the problem back to the anomeric effect. In that effect, a nonbonding electron pair interacts with an adjacent σ* orbital, lowering its own energy but reducing the σ bond strength. The required electrons could be supplied by the π system, resulting in the effect being π and σ*. However, I do not quite see yet, how this kind of mixing would reduce the nucleophilicity of the oxygen atom.
Thus, the questions are:
- Which electronic interactions exactly are responsible for this effect?
- Has this been the topic of a research paper?
R. K. Boekman Jr., P. Shao, S. T. Wrobleski, D. J. Boehmler, G. R. Heintzelman, A. J. Barbosa, J. Am. Chem. Soc. 2006, 128, 10572. DOI: 10.1021/ja0581346.