Ring Cleavage of Cyclohexane-1,3-diones in the Aldol Cyclization Step of Robinson Annelations: A Novel Mechanism via Oxa-Twistanes and δ-Lactones

Article abstract of DOI:10.1021/jo00201a014

The pyrrolidine-induced aldol cyclization of methyl 2-methyl-2-(3-oxobutyl)-1,3-dioxocyclohexane-4-acetate (1) afforded methyl 1,2,3,4,6,7,8,8a-octahydro-8a-methyl-1,6-dioxonaphthalene-2-acetate (13) rather than undergoing lactonization-directed closure in the opposite sense.Mild base-induced cyclization of 1 with sodium methoxide in methanol or 1,8-diazabicyclo<5.4.0>undec-7-ene (DBU) in tetrahydrofuran (THF) effected cleavage of the cyclohexane-1,3-dione ring, giving mainly cyclohexenone acid 14a (2-(1,4-dimethyl-3-oxo-1-cyclohexen-2-ylmethyl)butanedioic acid monomethyl ester) and δ-lactone 15 (methyl (4aβ,8aβ)-octahydro-6,8a-dimethyl-2,5-dioxo-2H-1-benzopyran-4a-acetate).Prolonged exposure of 15 to sodium methoxide in methanol yielded mixtures of acyclic diester 17 and the isomeric γ-lactone 18 presumably via lactone methanolysis to ketol diester 16 followed by retroaldol ring opening or relactonization onto the acetate ester.The structure and stereochemistry of 18 were established by X-ray crystallography (Figure 1).Similar aldol cyclizations of 2-methyl-2-(3-oxobutyl)-1,3-cyclohexanedione (19) and its 4-methyl analogue (11) with sodium methoxide in methanol or DBU in THF afforded cyclohexenone acids 20a and 22a, respectively, the latter accompanied by δ-lactone 23.Bridged ketols 21 (from 19) and 24 and 25 (from 11) were also isolated from the reactions with DBU.A novel mechanism (Scheme I) involving bridging aldol cyclization to endo ketols (27 and 30), intramolecular hemiketal formation to oxatwistanones (28 and 31), ring cleavage to δ-lactones (29 and 32), and β-elimination of the δ-lactones having an available α-hydrogen to cyclohexenone acids is proposed to explain the formal retro-Claisen transformations in the absence of an external nucleophile (DBU/THF) and the apparent hydrolyses under anhydrous conditions.