Macrocylic lactones

Products from silicon-modified acyloin condensations have also been used successfully in syntheses of macrocylic lactones. For example, decan-9-olide (a defensive secretion of Phoracantha synonyma) has been synthesized from... 

There are diverse formulations and delivery systems for macrocylic lactones in ruminants, including injectable, oral, sustained-release bolus and transdermal ("pour on") products. In Europe, it is popular clinical practice to administer injectable solutions of ivermectin intravenously (i.v.) to horses. This constitutes extra-label (unlicensed) use and there are no objective data to support the perceived improved efficacy following administration by this route. Specifically, in relation to hypobiotic cyathostome larvae, Klei et al (1993) reported no increase in efficacy when horses were administered 10 pg/kg, which is five times the recommended dose rate. 

The best known example of this class of compounds is erythromycin—a metabolite produced by the microorganism Streptomyces erythreus. The structure (Fig. 10.73) consists of a macrocylic lactone ring with a sugar and an aminosugar attached. The sugar residues are important for activity. 

Cyclic diol protecting groups are not always conducive to a successful RCM. For example, when Banwell and McRae submitted acetonide-protected 1,3-diol 28 to the Grubbs first-generation catalyst, none of the desired macrocyle was produced, but cyclohexene 29 was obtained in 81% yield, probably because the acetonide protecting group facilitated interaction of the double bonds of the carboxylic acid portion of the molecule (Scheme 2.11) [24]. To circumvent this problem, substrate 30 was synthesized, where the diol was protected as two silyl ethers, and RCM of this compound led to the desired 18-membered lactone 31 in 70% yield under the same reaction conditions. 

A second period of macrocyclic chemistry was signaled by the isolation of the first macrolide antibiotic from an Actomyces culture in 1950. Brockmann and Henkel [6][7] named it picromycin (Pikromycin) (1/4), because of its bitter taste. This antibiotic contains a 14-membered ring. Since then a large number of macrocyclic lactones, lactams and cycloalkane derivatives have been discovered. Some of these compounds have a considerable physiological importance for humans and animals. Because of these physiological properties it was necessary to prepare larger quantities of these macrocylic compounds by chemical syntheses [8]. 

As described before, TBS ethers can be cleaved under acidic conditions. Hence, treatment of 34 with 1 M HCl in a mixture of methanol and dichloromethane for six hours at room temperature affords the desired diol 86 in 60 % yield. Then, 86 is subjected to RCM, mediated by Grubbs second-generation catalyst 28, which has already been used for the preparation of lactone 29 In order to have optimal conditions for an intramolecular ring-closing reaction the reaction is performed with a highly diluted solution of 86 in dichloromethane (0.001 M) in the presence of 10 mol-% of catalyst 28 thus providing macrocyle 35 with (8 -configuration in 82 % yield. 

Cembranoids, a macrocylic class of diterpene hydrocarbon were first isolated from pine oleoresins [156, 157] and the tobacco plant [158]. Since then, the structures of circa 300 naturally occurring cembranoids have been elucidated and a comprehensive compilation of these diterpenes published through 1990 has been published [159]. Known cembranoids include both hydrocarbons and oxygen-containing compounds such as epoxy, oxo, hydroxy, and lactone functions. Most congeners are polyoxygenated. 

The macrocylic diterpene alcohol, verticillol (3) was isolated from the wood of Sciadopitys verticillata Sieb. Et zucc. (Taxodiaceae) [13]. The structure of verticillol (3) was elucidated from NMR-LIS studies on it as well as its correlation to the diepoxide (14) whose structure was established by direct single crystal X-ray analysis. The absolute configuration of verticillol (3) was determined by CD data of the verticillol norketodiepoxide (15). The carbocyclic framework of verticillol (3) is somewhat akin to at of cleomeolide (1). However, the presence of the substituents(3-OH and C-8—>C-4 lactone) in appropriate positions in (1) facilitates its conversion to compounds analogous to taxane diterpenes. 

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