In 1997, Fürstner reported a facile synthesis to access jasmine ketolactone (E/Z) through a final RCM step. At the time, no previous 10-membered ring had been formed through RCM, and previous syntheses were often lengthy, involving a macrolactonization to form the decanolide. By adding the diene and catalyst over a 12-hour period to refluxing toluene, Fürstner was able to avoid oligomerization and obtain both E/Z isomers in 88% yield. CH2Cl2 favored the formation of the Z-isomer in 1:2.5 (E/Z) ratio, whereas, toluene only afforded a 1:1.4 (E/Z) mixture. In 2000, Alois Fürstner reported an eight step synthesis to access (−)-balanol using RCM to form a 7-member heterocycle intermediate. Balanol is a metabolite isolated from erticiullium balanoides and shows inhibitory action towards protein kinase C (PKC). In the ring closing metathesis step, a ruthenium indenylidene complex was used as the precatalyst to afford the desired 7-member ring in 87% yield. In 2002, Stephen F. Martin and others reported the 24-step synthesis of manzamine A with two ring-closing metathesis steps to access the polycyclic alkaloid. The natural product was isolated from marine sponges off the coast of Okinawa. Manzamine is a good target due to its potential as an antitumor compound. The first RCM step was to form the 13-member D ring as solely the Z-isomer in 67% yield, a unique contrast to the usual favored E-isomer of metathesis. After further transformations, the second RCM was used to form the 8-member E ring in 26% yield using stoichiometric 1st Generation Grubbs catalyst. The synthesis highlights the ability for functional group tolerance metathesis reactions as well as the ability to access complex molecules of varying ring sizes. In 2003, Danishefsky and others reported the total synthesis of (+)-migrastatin, a macrolide isolated from Streptomyces which inhibited tumor cell migration. The macrolide contains a 14-member heterocycle that was formed through RCM. The metathesis reaction yielded the protected migrastatin in 70% yield as only the (E,E,Z) isomer. It is reported that this selectivity arises from the preference for the ruthenium catalyst to add to the less hindered olefin first then cyclize to the most accessible olefin. The final deprotection of the silyl ether yielded (+)-migrastatin. Overall, ring-closing metathesis is a highly useful reaction to readily obtain cyclic compounds of varying size and chemical makeup; however, it does have some limitations such as high dilution, selectivity, and unwanted isomerization. See also Olefin Metathesis Ring-opening metathesis polymerization Alkane