Synthesis of functionalised isochromans: epoxides as aldehyde surrogates in hexafluoroisopropanol

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.

Scheme 1. Biological relevance of the isochroman motif and synthetic pathways.

Scheme 2. Scope of the reaction. ^aTfOH 40 mol% (increments of 10 mol%). ^bCorrected yield. ^c3 equiv. epoxide. ^dDiastereoisomers were separated. ^e16 h.

Scheme 3. Variations of the standard reaction.

Scheme 4. Application to the synthesis of tetrahydroisoquinolines. ^aTfOH (30 mol%), 60 °C, 72 h.

Scheme 5. Post-functionalisation of the isochroman products.