Synthetic Pathways to 2,2-Dimethyl-6-oxo-1-cyclohexaneacetic Acid, a Useful Isoprenoid Building Block

Abstract

Six new synthetic routes to 2,2-dimethyl-6-oxo-1-cyclohexaneacetic acid (1) from readily available starting materials have been evaluated. The most efficient method (yield 35%) involves alkylation of Hagemann's ester with ethyl bromoacetate followed by hydrolysis of the resultant ethyl 3-(ethoxycarbonyl)-2-methyl-6-oxo-1-cyclohexeneacetate to unsaturated keto acid 2-methyl-6-oxo-1-cyclohexeneacetic acid (19) and then treatment of 19 with Me2CuLi. A method from mesityl oxide is longer and slightly less efficient (30%). These two methods are suitable for a large-scale preparation of 1.

A Formal Total Synthesis of Salvadione

“…[12] Reaction of the cyclohexenone 18 with dimethylcuprate, followed by trapping of the enolate with the electrophile methyl 2-bromoacetate provided the keto ester 19 in good yield (Scheme 2). [13][14][15] This was followed by acetalization of the keto function with glycol and reduction of the ester group with lithium aluminium hydride to provide the primary alcohol 21. This compound is somewhat sensitive to acid in that it can undergo intramolecular transacetalization in the presence of traces of acid.…”