Total Synthesis of Alanense A through an Intramolecular Friedel–Crafts Alkylation

The first total synthesis of cadinane sesquiterpenoid alanense A, in which an intramolecular dehydrative Friedel–Crafts alkylation of 2,5-diaryl-2-pentanol is incorporated as a key step, has been achieved. The combinatorial use of p-TsOH·H2O as a catalyst and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as a solvent provides 1,1-disubstituted tetrahydronaphthalene in 97% yield. It was also found that the combination of p-TsOH and HFIP is effective for the removal of phenolic MOM ether

Total Synthesis of Alanense A through an Intramolecular Friedel–Crafts Alkylation

The first total synthesis of cadinane sesquiterpenoid alanense A, in which an intramolecular dehydrative Friedel–Crafts alkylation of 2,5-diaryl-2-pentanol is incorporated as a key step, has been achieved. The combinatorial use of p-TsOH·H2O as a catalyst and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as a solvent provides 1,1-disubstituted tetrahydronaphthalene in 97% yield. It was also found that the combination of p-TsOH and HFIP is effective for the removal of phenolic MOM ether

Elucidation of the <i>E-</i>Amide Preference of <i>N</i>‑Acyl Azoles

The conformational properties of <i>N</i>-acyl azoles (imidazole, pyrazole, and triazole) were examined. The <i>N</i>-2′,4′,6′-trichlorobenzoyl azoles were stable in methanol at room temperature, and no hydrolyzed products were observed over 7 days in the presence of 5% trifluoroacetic acid or 5% triethylamine in CDCl₃. The high stability may be explained by the double-bond amide character caused by the steric hindrance due to the <i>ortho</i>-substituents in the benzoyl group. While specific <i>E</i>-amide preferences were observed in <i>N</i>-acyl pyrazoles/triazoles, the amides of the imidazoles gave a mixture of <i>E</i> and <i>Z</i>. One of the conceivable ideas to rationalize this conformational preference may be repulsive interaction between two sets of lone-pair electrons on the pyrazole 2-nitrogen (n_N) and the carbonyl oxygen atoms (n_O) in the <i>Z</i>-conformation of <i>N</i>-acyl pyrazoles/triazoles. However, analysis of orbital interactions suggested that in the case of the <i>E</i>-conformation of <i>N</i>-acyl pyrazoles, such electron repulsion is small because of distance. The interbond energy calculations suggested that the <i>Z</i>-conformer is involved in strong vicinal σ–σ repulsion along the amide linkage between the σ_N1N2 and σ_C1C2 orbitals in the <i>anti</i>-periplanar arrangement and between the σ_N1C5 and σ_C1C2 orbitals in the <i>syn</i>-periplanar arrangement, which lead to the overwhelming <i>E</i>-preference in <i>N</i>-acyl pyrazoles/triazoles. In the case of <i>N</i>-acyl imidazoles, similar vicinal σ–σ repulsions were counterbalanced, leading to a weak preference for the <i>E</i>-conformer over the <i>Z</i>-conformer. The chemically stable and <i>E</i>-preferring <i>N</i>-acyl azoles may be utilized as scaffolds in future drug design