Ring-closing metathesis macrolides

P2N2 dianionic macrocycle, 1, 69 pyridinophane macrocycles, 1, 69 Macrolides, via ring-closing metathesis, 11, 239 Macromolecular materials overview, 12, 295-411 polymers (, see Polymers)... 

Jennings strategy for obtaining the macrolide skeleton was Yamaguchi esterification and ring closing metathesis (RCM) with 175 and 176 (Scheme 36). Construction of the key 2,6-cis-tetrahydropyran in 176 was carried out via diastereoselective axial reduction of an oxonium cation. The precursor, a pyranone, was prepared via RCM of divinyl ester 177. An asymmetric center was made by Brown s asymmetric allylation. 

Finally, the application of ring closing metathesis for the synthesis of large size unsaturated heteroatom macrocycles such as crown ethers [45] or various unsaturated macrolides [46] is further illustrated in Eqs. (37) and (38). 

Tadano utilized the Hiyama reaction in a formal synthesis of the antimicrobial tricyclic macrolides tubelactomicins. The intramolecular Hiyama cross-coupling reaction of 64 aided in the synthesis of a 24-membered macrolactone equipped with all the requisite functionalities, which then triggered the transannular Diels-Alder reaction to give 65. The 24-membered lactone formation was also achieved by the intramolecular ring-closing metathesis reaction. 

To assemble the framework of the cytotoxic macrolide Amphidiaolide X 3, Felix Urpl and Jaume Vilarrasa of the Universitat de Barcelona devised Organic Lett. 2008, 70, 5191) the ring-closing metathesis of the alkenyl silane 1. No Ru catalyst was effective, but the Schrock Mo catalyst worked well. 

Wang B, Forsyth CJ. Stereoselective synthesis of the phorboxazole A macrolide by ring-closing metathesis. Org. Lett. 2006 8 5223-5226. 

Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

Advent of ring-closing olefin metathesis reaction has influenced the synthetic strategy of pheromones very much. For example, the racemate of a macrolide pheromone such as (5Z,13S)-5-tetradecen-13-olide (29) (aggregation pheromone of the flat grain beetle, Cryptolestes pusillus) could readily be synthesized as shown in Scheme 42 [67]. Unfortunately, ( )-29 prepared by this method was a mixture of c/s, trans-isomers (Z/E=69 31). (S)-5-Hexadecanolide (27) was also synthesized by means of ring-closing olefin metathesis as shown in Scheme 43 [68]. 

In recent years, ring-closing olefin metathesis (RCM) has attracted organic chemists as a versatile cyclization method via carbon-carbon bond formation, and had a great impact on the synthesis of natural products [29,30]. In the syntheses of dihydropyrans of marine macrolides, allyl homoallyl ethers 28 have been cyclized to dihydropyrans 29 via RCM. This methodology has been seen in the syntheses of laulimalide by Mulzer [31,32], Crim-mins [33], and Nelson [34] (Scheme 9). 

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