Preparation of Phthalides via [2+2+2] Cycloaddition: Application of Solid-phase Synthesis.

RIVEIRA, M.; MATA, ERNESTO G

Sitges

Simposio; 17th Tetrahedron Symposium; 2016

Elsevier B.V.

The preparation of 3H-isobenzofuran-1-ones (phthalides) has received considerable attention in organic synthesis as these are found in several natural products that exhibit a wide spectrum of biological activities.The transition-metal-catalysed [2+2+2] cycloaddition of alkynes is a powerful atom-economical synthetic tool for the construction of aromatic systems and has been naturally used for the preparation of these benzolactones in solution. The control of the regioand chemoselectivity of the process is usually challenging and these reactions can potentially lead to complex unuseful mixtures. In order to address such limitations, we envisaged that by immobilising the mono-alkyne component to a solid support, homodimers of type 4 would only form in solution-phase which can be easily separated by simple filtration. Cross-cycloadducts 3, on the other hand, can be then selectively cleaved from the solid support by an appropriate reagent. This strategy differentiates from standard solid-phase synthesis approaches in which excess of soluble reagents and side-products are generally discarded during filtration work-up. We are currently using this methodology to prepare a small phthalide library for further biological studies. For example, resin 1b, prepared in four steps from commercially available Merrifield resin, indeed allowed for the simultaneous solid- and solution-phase synthesis of benzolactones 3 and 4,respectively.