Unexpected Tethering in the Synthesis of Methyl‐Substituted Acetyl‐1‐oxaspiro[4.5]decanes: Novel Woody–Ambery Odorants with Improved Bioavailability

To study the olfactory properties of spirocyclic analogs of Iso Gamma ( 3 ) with improved water solubility and bioavailability, it was envisaged to spiroannulate 1‐acetyl‐1,2‐dimethylcyclohexanone at the 4‐position with a 3,3‐dimethyltetrahydrofuran‐2‐yl moiety that would mimic the polarity of the double bond by its ether function. 3,3‐Dimethyl‐4‐methylenehex‐5‐en‐1‐ol ( 9 ) was prepared by copper(I)‐mediated 1,4‐conjugate addition of the Grignard reagent of chloroprene ( 7 ) to 3‐methylbut‐2‐enal with subsequent LAH reduction. However, the Diels–Alder reaction of diene 9 with ( E )‐3‐methylpent‐3‐en‐2‐one in the presence of Me 2 AlCl unexpectedly provided exclusively the undesired meta adduct 10 , as was discovered after cyclization to 11 with MeSO 3 H. The wrong selectivity was due to a tethering effect of the Lewis acid, and this could be evaded by changing the carbonyl function of the dienophile to a hydroxy group. Thereby the (5′ R *,7′ S *,8′ S *)‐configured 1‐(4′,4′,7′,8′‐tetramethyl‐1′‐oxaspiro[4.5]decan‐7′/8′‐yl)ethan‐1‐ones 11 and 14 , as well as the like ‐configured 1‐(4′,4′,7′‐trimethyl‐1′‐oxaspiro[4.5]decan‐7′/8′‐yl)ethan‐1‐ones 16 and 19 , were prepared selectively and studied for their odor characters, threshold values, and octanol/water partition coefficients. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)