Tandem cyclization-addition reactions are an efficient synthetic route toward 2,6-disubstituted tetrahydropyran derivatives. Addition of carbon-based nucleophiles generally occurs via highly-selective axial attack on a putative cyclic oxocarbenium ion. With more active enol ether and ketene silyl acetal nucleophiles, however, stereoselectivities are lower.  In order to probe stereoelectronic effects at the electrophilic carbon, we incorporated electron-donating and withdrawing moieties (e.g., R1 = Me, Et, Pr, Bu, trifluoromethyl, 4-trifluoromethylphenyl-, etc.) into the cyclization precursors. Trifluoromethyl moieties were also incorporated into nucleophilic reagents such as enol ethers.  Although overall selectivities were excellent for the trans-2,2,6-trisubstituted tetrahydropyrans using alkyl-substituted ketone starting materials,  trifluoromethyl ketone reactants degraded under the reaction conditions, indicating that pathways other than those involving an oxocarbenium ion become competitive. 

Effects of electron-donating and withdrawing substituents on the stereochemical outcome of cyclization-addition reactions toward trisubstituted tetrahydropyrans

244th National Meeting (2012)

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