PREPARATION OF PHTHALIDES VIA [2+2+2] CYCLOADDITION: APPLICATION OF SOLID-PHASE SYNTHESIS

RIVEIRA, M. J.; MATA, E. G.

Sitges

Simposio; 17TH TETRAHEDRON SYMPOSIUM; 2016

Elsevier

The preparation of 3H-isobenzofuran-1-ones (phthalides) hasreceived considerable attention in organic synthesis as these are found inseveral natural products that exhibit a wide spectrum of biological activities.1The transition-metal-catalysed [2+2+2] cycloaddition of alkynes is a powerful atom-economicalsynthetic tool for the construction of aromatic systems and has been naturally usedfor the preparation of these benzolactones in solution.2 The controlof the regio- and chemoselectivity of the process is usually challenging andthese reactions can potentially lead to complex unuseful mixtures. Our initial studies on theintermolecular two-component version using propargylamines (1) and 1,6-diyne esters (2) revealed that Rh(I) readilycatalyses the formation of phthalide-type products (e.g. 3aa and 4a, Scheme 1). Althoughthe formation of self-trimerisation products was minimal, the difficultseparation of cross- from self-cycloadducts (3 and 4) eventually renderedthe whole process impractical.Scheme 1In order to face such limitations, weenvisaged that by immobilising the mono-alkyne component to a solid support, homodimersof type 4 would only form insolution-phase which can be easily separated by simple filtration.Cross-cycloadducts 3, on the otherhand, can be then selectively cleaved from the solid support by an appropriatereagent. This strategy differentiates from standard solid-phase synthesisapproaches in which excess of soluble reagents and side-products are generallydiscarded during filtration work-up. We are currently using this methodology toprepare a small phthalide library for further biological studies. For example,resin 1b, prepared in four stepsfrom commercially available Merrifield resin, indeed allowed for thesimultaneous solid- and solution-phase synthesis of benzolactones 3 and 4, respectively (Scheme2).Scheme 2 References1- Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev.2014, 114, 6213-6284.2- Tanaka,K.; Osaka, T.; Noguchi, K.; Hirano, M. Org.Lett. 2007, 9, 1307-1310.