Acid‐Mediated Intramolecular Cationic Cyclization Using an Oxygen Atom as Internal Nucleophile: Synthesis of Substituted Oxazolo‐, Oxazino‐ and Oxazepinoisoindolinones.

Abstract

For Abstract see ChemInform Abstract in Full Text.

Asymmetric Synthesis of 3,3-Disubstituted Isoindolinones Enabled by Organocatalytic Functionalization of Tertiary Alcohols

“…A subsequent intramolecular process employing the oxygen as a nucleophile has rarely been exploited. 7…”

“…The addition of 5-Å molecular sieves or a lower concentration of 1a proved to be beneficial in terms of the enantioselectivity of the reaction, though a slight decrease of the yield was observed (Table 1 , entries 11–13). 7 14b Finally, the temperature was increased to 15 °C to ensure reaction completion and did not have a detrimental effect on the asymmetric induction (Table 1 , entry 14). Reaction of 1a was performed on a gram scale.…”

“…2e 15 Inspired by the recent success of the chiral Brønsted acid catalyzed asymmetric alkoxylation 16 of tertiary allylic alcohols developed by our group 17 and others, 16 we hypothesized that an oxygen-centered nucleophile tethered to prochiral 3-hydroxyisoindolinone may undergo intramolecular cationic cyclization involving N -acyliminium species to form isoindolinone derived N , O -acetals stereoselectively. However, this seemingly straightforward process may encounter several challenges such as the difficulty of chirality control over intramolecular nucleophilic trapping of the N -acyliminium intermediate by the hydroxyl moiety 7 14b and the competition between 1,2- and 1,4-regioselectivity upon the in situ generation of α,β-unsaturated N -acyliminium ions. We herein describe a solution to this challenge based on chiral Brønsted acid catalysis that is compatible with intramolecular cationic cyclization involving the addition of oxynucleophiles to tertiary N -acyliminium species and provides isoindolinone derived N , O -acetals with control of the stereochemistry at a fully substituted carbon center.…”