Different Reaction Modes for the Oxidative Dimerization of Epoxyquinols and Epoxyquinones. Importance of Intermolecular Hydrogen-Bonding

Abstract

An oxidative dimerization reaction, involving the three successive steps of oxidation, 6 pi-electrocyclization, and Diels-Alder reaction, has been experimentally and theoretically investigated for the three 2-alkenyl-3-hydroxymethyl-2-cyclohexen-1-one derivatives epoxyquinol 3, epoxyquinone 6, and cyclohexenone 10. Of the sixteen possible modes of the oxidation/6 pi-electrocylization/Diels-Alder reaction cascade for the epoxyquinone 6, and eight for the cyclohexenone 10, only the endo-anti(epoxide)-anti(Me)-hetero and endo-anti(Me)-hetero modes are, respectively, observed, while both endo-anti(epoxide)-anti(Me)-hetero and exo-anti(epoxide)-anti(Me)-homo reaction modes occur with the epoxyquinol 3. Intermolecular hydrogen-bonding is found to be the key cause of formation of both epoxyquinols A and B with 3, although epoxyquinone 6 and cyclohexenone 10 both gave selectively only the epoxyquinol A-type product. In the dimerization of epoxyquinol 3, two monomer 2H-pyrans 5 interact with each other to afford intermediate complex 28 or 29 stabilized by hydrogen-bonding, from which Diels-Alder reaction proceeds. Theoretical calculations have also revealed the differences in the reaction profiles of epoxyquinone 6 and cyclohexenone 10. Namely, the rate-determining step of the former is the Diels-Alder reaction, while that of the latter is the 6 pi-electrocyclization.

Enantioselective Synthesis of Natural Epoxyquinoids

“…Shoji's first generation syntheses of ECH (8) Diels-Alder reaction in the presence of a chiral auxiliary to generate the required asymmetry (scheme 33) [128][129][130]. Diels-Alder reaction between furan and chiral acrylate 203, derived from Corey's chiral auxiliary, in the presence of HfCl 4 at low temperature , preferentially yielded the endo adduct 204 with high diastereoselectivity.…”

“…Suzuki crosscoupling with 1-propenylborate followed by deprotection gave the monomeric ECH (8), which upon oxidation of the hydroxymethyl chain triggered the biomimetic cascade involving a 6electrocyclization and Diels-Alder dimerization [130] to form epoxyquinols A (28) and B (29). Reduction and protection delivered 209, which upon oxidation and SiO 2 treatment, underwent elimina-tion with oxirane opening to construct the enone moiety.…”

A Chemoenzymatic Formal Synthesis of Epoxyquinols A and B

“…[5][6][7] This, along with the challenge of asymmetrically constructing their densely functionalized cyclohexanone core, prompted interest from the synthetic organic chemistry community, resulting in a number of total syntheses. 14,[17][18][19][20][21][22][23][24][25] Despite this work, we sought to develop general routes to epoxyquinoid natural products that would provide access to their full range of structural diversity (substitution pattern, stereochemical configuration, oxidation state, etc.) to facilitate their study as potential therapeutics and biochemical probes.…”

Recent Advances in Cascade Reactions Initiated by Alcohol Oxidation

“…The stereochemistry of the major products, epoxyquinols A and B, is controlled by the need for the C9 and C19 methyl groups to take up a specific orientation that minimizes steric interactions when the two molecules approach and that allows the intermolecular hydrogen bonding that has been shown to exist by both theoretical calculations and experimental results. [98a] The steric hindrance caused by the methyl groups is so large that unless the methyl group of the diene monomer is oriented anti to its reacting face and that of the dienophile monomer is oriented anti to its reacting face, the transition state energies are over 16 kcal mol −1 . Hence epoxyquinol A is formed by an endo ‐Diels–Alder reaction with an anti (epoxide)– anti (Me)‐hetero arrangement and epoxyquinol B is formed by an exo‐ Diels–Alder reaction with an anti‐ (epoxide)– anti (Me)‐homo approach in the dimerization of epoxyquinol (+)‐ 117 .…”