An Unusual Domino Retro‐Ene–Conia Reaction: Regio‐ and Stereoselective One‐Carbon Ring Expansion of Fenchol Derivatives

Abstract

AbstractThe 2‐exo‐substituted fenchol derivatives 1–7, easily prepared from (−)‐fenchone in good‐to‐excellent yields, were pyrolyzed by dynamic gas‐phase thermo‐isomerization (DGPTI). At temperatures of ca. 620°, the substrates with a hydroxyallyl (1–4) or a hydroxypropargyl moiety (6) underwent an initial retro‐ene reaction under cleavage of the C(2)C(3) bond to form enol‐ene intermediates with no loss of optical activity. These intermediates then experience either tautomerization to the corresponding α,β‐unsaturated ketones or subsequent Conia rearrangement under one‐carbon ring expansion of the fenchone system to a bicyclo[3.2.1]octane framework. In the case of the isopropenyl substrate 3, the sterically crowded Conia product underwent a new type of ‘deethanation’ reaction by stepwise loss of two Me radicals, giving rise to the thermodynamically favored enone 21. A similar relaxation behavior was observed in the case of the ethynyl substrate 6, which showed a remarkable 1,3‐Me shift after the Conia reaction, leading to the α,β‐unsaturated cyclic ketone 25. The homolytic cleavage of the weakest single bond in 1–3 turned out to be a competing reaction pathway. Intramolecular H‐abstraction within the generated diradical intermediates produced the monocyclic ketones 8, 16, and 19, besides the products obtained by tautomerization and Conia reaction. In contrast, a Ph substituent at C(2) in 7 allowed only the passage through a diradical species to provide phenone 26, which was converted by regioselective Baeyer–Villiger oxidation to the optically active cyclopentanol 29. Both reaction channels, the domino retro‐ene–Conia rearrangement and the diradical‐promoted H‐transfer, have been shown to proceed highly stereoselectively. The absolute configuration of the newly formed stereogenic centers in all compounds was assigned by 1H‐NOE experiments. The reaction mechanism of the novel domino retro‐ene–Conia reaction was established by both a series of 2H‐ and 13C‐labeling experiments, as well as by a detailed computational analysis.