Synthesis of functionalised isochromans: epoxides as aldehyde surrogates in hexafluoroisopropanol

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Abstract

The oxa-Pictet-Spengler reaction is arguably the most straightforward and modular way to construct the privileged isochroman motif, but its scope is largely limited to benzaldehyde derivatives and to electron-rich β-phenylethanols that lack substitution along the aliphatic chain. Here we describe a variant of this reaction starting from an epoxide, rather than an aldehyde, that greatly expands the scope and rate of the reaction (<1 h, 20 °C). Besides facilitating the initial Meinwald rearrangement, the use of hexafluoroisopropanol (HFIP) as a solvent expands the electrophile scope to include partners equivalent to ketones, aliphatic aldehydes, and phenylacetyl aldehydes, and the nucleophile scope to include modestly electronically deactivated and highly substituted β-phenylethanols. The products could be easily further derivatised in the same pot by subsequent ring-opening, reductions, and intra- and intermolecular Friedel-Crafts reactions, also in HFIP. Finally, owing to the high pharmacological relevance of the isochroman motif, the synthesis of drug analogues was demonstrated.

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Muller, C., Horký, F., Vayer, M., Golushko, A., Lebœuf, D., & Moran, J. (2023). Synthesis of functionalised isochromans: epoxides as aldehyde surrogates in hexafluoroisopropanol. Chemical Science, 14(11), 2983–2989. https://doi.org/10.1039/d2sc06692k

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