Macrocycles continue to attract interest in light of their unique properties and abundance in natural products. Over the past decade, ring-closing olefin metathesis (RCM) has not only emerged as a powerful method for macrocyclization [1] but has inspired the development of ring-closing alkyne metathesis (RCAM) [2] and macrocyclic ene-yne metathesis.

Efficient direct en-yne metathesis of strained macrocyclic systems is possible using highly active Grubbs-Hoveyda second-generation catalyst and when exploiting fluoroarene-arene gearing interactions. These interactions are effective even under high reaction temperatures and in the presence of a competitive pi-rich solvent such as toluene. These results suggest that efficient pi-pi stacking or pi-lp interactions between auxiliaries containing pentafluorophenyl and 3,5-bis(trifluoromethyl)phenyl groups are responsible for the good yields of macrocyclization products. The 3,5-bis(trifluoromethyl)benzyl gearing elements provide higher yields and greater E-selectivity in the macrocyclic en-yne metathesis to form model paracyclophanes that could be applied toward the preparation of members of the longithorone family of natural products.

2,3,4,5,6-Pentafluorobenzyl and 3,5-bistrifluoromethylbenzyl ester auxiliaries can enable difficult macrocyclizations to afford rigid all-carbon paracyclophanes. The effectiveness of these auxiliaries has been demonstrated in preparing the carbon skeleton of the macrocyclic natural product longithorone C.

Macrocycles continue to attract interest in light of their unique properties and abundance in natural products. Over the past decade, ring-closing olefin metathesis (RCM) has not only emerged as a powerful method for macrocyclization [1] but has inspired the development of ring-closing alkyne metathesis (RCAM) [2] and macrocyclic ene-yne metathesis.

The formation of various macrocyclic cyclophanes via ring-closing olefin metathesis is possible through the use of a pendant pentafluorobenzyl ester group. A quadrupolar interaction between the cyclophane core and the auxiliary is proposed to act as a gearing element facilitating cyclization. The development of these noncovalent interactions as gearing elements as well as the investigation of the effect of the site of metathesis upon the macrocyclization process is described.