Synthesis of unstrained Criegee intermediates: inverse α-effect and other protective stereoelectronic forces can stop Baeyer-Villiger rearrangement of γ-hydroperoxy-γ-peroxylactones.

How far can we push the limits in removing stereoelectronic protection from an unstable intermediate? We address this question by exploring the interplay between the primary and secondary stereoelectronic effects in the Baeyer-Villiger (BV) rearrangement by experimental and computational studies of γ-OR-substituted γ-peroxylactones, the previously elusive non-strained Criegee intermediates (CI). These new cyclic peroxides were synthesized by the peroxidation of γ-ketoesters followed by in situ cyclization using a BF3·Et2O/H2O2 system. Although the primary effect (alignment of the migrating C-Rm bond with the breaking O-O bond) is active in the 6-membered ring, weakening of the secondary effect (donation from the OR lone pair to the breaking C-Rm bond) provides sufficient kinetic stabilization to allow the formation and isolation of stable γ-hydroperoxy-γ-peroxylactones with a methyl-substituent in the C6-position. Furthermore, supplementary protection is also provided by reactant stabilization originating from two new stereoelectronic factors, both identified and quantified for the first time in the present work. First, an unexpected boat preference in the γ-hydroperoxy-γ-peroxylactones weakens the primary stereoelectronic effects and introduces a ∼2 kcal mol-1 Curtin-Hammett penalty for reacquiring the more reactive chair conformation. Second, activation of the secondary stereoelectronic effect in the TS comes with a ∼2-3 kcal mol-1 penalty for giving up the exo-anomeric stabilization in the 6-membered Criegee intermediate. Together, the three new stereoelectronic factors (inverse α-effect, misalignment of reacting bonds in the boat conformation, and the exo-anomeric effect) illustrate the richness of stereoelectronic patterns in peroxide chemistry and provide experimentally significant kinetic stabilization to this new class of bisperoxides. Furthermore, mild reduction of γ-hydroperoxy-γ-peroxylactone with Ph3P produced an isolable γ-hydroxy-γ-peroxylactone, the first example of a structurally unencumbered CI where neither the primary nor the secondary stereoelectronic effect are impeded. Although this compound is relatively unstable, it does not undergo the BV reaction and instead follows a new mode of reactivity for the CI - a ring-opening process.

Five Roads That Converge at the Cyclic Peroxy-Criegee Intermediates: BF3-Catalyzed Synthesis of ß-Hydroperoxy-ß-peroxylactones.

We have discovered synthetic access to ß-hydroperoxy-ß-peroxylactones via BF3-catalyzed cyclizations of a variety of acyclic precursors, ß-ketoesters and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals, with H2O2. Strikingly, independent of the choice of starting material, these reactions converge at the same ß-hydroperoxy-ß-peroxylactone products, i.e., the peroxy analogues of the previously elusive cyclic Criegee intermediate of the Baeyer-Villiger reaction. Computed thermodynamic parameters for the formation of the ß-hydroperoxy-ß-peroxylactones from silyl enol ethers, enol acetates, and cyclic acetals confirm that the ß-peroxylactones indeed correspond to a deep energy minimum that connects a variety of the interconverting oxygen-rich species at this combined potential energy surface. The target ß-hydroperoxy-ß-peroxylactones were synthesized from ß-ketoesters, and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals were obtained in 30-96% yields. These reactions proceed under mild conditions and open synthetic access to a broad selection of ß-hydroperoxy-ß-peroxylactones that are formed selectively even in those cases when alternative oxidation pathways can be expected. These ß-peroxylactones are stable and can be useful for further synthetic transformations.