hydrides which may explain their behavior. Another common problem associated with RCM is the risk of catalyst degradation due to the high dilution required for some cyclizations. High dilution is also a limiting factor in industrial applications due to the large amount of waste generated from large-scale reactions at a low concentration. Efforts have been made to increase reaction concentration without compromising selectivity. Synthetic applications Ring-closing metathesis has been used historically in numerous organic syntheses and continues to be used today in the synthesis of a variety of compounds. The following examples are only representative of the broad utility of RCM, as there are numerous possibilities. For additional examples see the many review articles. Ring-closing metathesis is important in total synthesis. One example is its use in the formation of the 12-membered ring in the synthesis of the naturally occurring cyclophane floresolide. Floresolide B was isolated from an ascidian of the genus Apidium and showed cytotoxicity against KB tumor cells. In 2005, K. C. Nicolaou and others completed a synthesis of both isomers through late-stage ring-closing metathesis using the 2nd Generation Grubbs catalyst to afford a mixture of E- and Z- isomers (1:3 E/Z) in 89% yield. Although one prochiral center is present the product is racemic. Floresolide is an atropisomer as the new ring forms (due to steric constraints in the transition state) passing through the front of the carbonyl group in and not the back. The carbonyl group then locks the ring permanently in place. The E/Z isomers were then separated and then the phenol nitrobenzoate protective group was removed in the final step by potassium carbonate to yield the final product and the unnatural Z-isomer. In 1995, Robert Grubbs and others highlighted the stereoselectivity possible with RCM. The group synthesized a diene with an internal hydrogen bond forming a β-turn. The hydrogen bond stabilized the macrocycle precursor placing both dienes in close proximity, primed for metathesis. After subjecting a mixture of diastereomers to the reaction conditions, only one diastereomer of the olefin β-turn was obtained. The experiment was then repeated with (S,S,S) and (R,S,R) peptides. Only the (S,S,S) diastereomer was reactive illustrating the configuration needed for ring-closing to be possible. The olefin product’s absolute configuration mimics that of Balaram’s disulfide peptide. The ring strain in 8-11 atom rings has proven to be challenging for RCM; however, there are many cases where these cyclic systems have been synthesized.