Chemistry of Cyclic Acetals

Activations Through Cyclic Acetals

Intramolecular reactions represent the most important venues in synthetic organic chemistry because they can expeditiously bring forth a great deal of complexity for a diverse array of structural motifs in highly regioselective and stereoselective reaction manifolds. While there are many different ways of tethering reactive partners together in a given intramolecular reaction, acetals [inclusive for both acetals and ketals], albeit well known as protecting groups for carbonyls and diols, have not been extensively utilized as tethers, whether temporary or permanent, and their role as an activating group in organic synthesis has been underappreciated. We intend to develop chemistry of cyclic acetals for constructing natural products.

A. Cyclic Acetal-Tethered Strategies

Cyclic acetal tethered intramolecular reactions, specifically intramolecular Diels-Alder [IMDA] and RCM reactions, which are areas that have not been widely studied, are discussed here, as well as an approach to fusidilactone C, a spiroketal-containing natural product that first provoked our interest in cyclic acetal tethered strategies. These investigations are of significance because they can lead to conceptually and fundamentally different approaches to spiroketal-related complex natural products such as our recent success with a total synthesis of aigialospirol.

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B. Cationic [2 + 2] Cycloadditions of Vinyl Acetals

We have been developing thermally driven [2 + 2] cycloadditions for constructing cyclobutanes, which is an effort that will contribute significantly to an area of cycloaddition chemistry that is under-explored. A successful cationic version of [2 + 2] cycloaddition would also represent a bio-mimetic process to cyclobutanes. Specifically, we have succeeded in an intramolecular Gassman’s cationic [2 + 2] cycloaddition and are currently exploring its application in natural product syntheses.

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