Macrocycles, lactones

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

The term macroHde was introduced to denote the class of substances produced by Streptomjces species containing a macrocyclic lactone ring (27). 

The crown esters are actually macrocyclic lactones, the bulk of which rings are ethyl-eneoxy units. By far, the largest number of such compounds have been prepared by Bradshaw and his co-workers. Representative examples of such compounds are shown below. The name crab ethers has occasionally been applied to such structures, but as with the aquatic species noted above, this name has not found wide acceptance. 

There is probably no better evidence for a template effect than its application directly in the solution of a synthetic problem. Rastetter and PhiUion have utilized a substituted 19-crown-6 compound (shown below in Eq. 2.9) in the formation of macrocyclic lactones. Although there were certain experimental variations and the the possibility of intermolecular potassium ion complexation, the overall formation of lactone was favorable. 

When 2-chloronicotinoyl chloride is allowed to react with pentaethylene glycol and sodium hydride in benzene solution, acylation followed by nucleophilic aromatic substitution occurs resulting in the formation of a macrocyclic lactone (48% yield) as shown in Eq. (2.8), in Chap. 2. 

From their structures, it appears that the hydrolytic stability of macrocyclic lactones must necessarily be inferior to macrocyclic polyethers. Ease of synthesis of the cyclic esters is therefore one of the aspects which commend them to interest. It is probably for this reason that such lactones have not been made more often by the interesting approach of Kdgel and Schroder . These workers report the ozonolysis of dibenzo-18-crown-6 in a mixture of methanol and dichloromethane at —20°. Reduction of the ozon-ide at —75° using dimethylsulfide followed by warming and addition of acetone led to formation of 6 in 14% yield. The bis-oxalate had mp 164—165° from acetone, very similar to that of the starting crown. The transformation is illustrated below in Eq. (5.9). 

Intramolecular Pd(0)-catalyzed Stille reaction of organotin reagents with electrophiles leading to C—C a-bond formation in synthesis of heterocycles, particularly, macrocyclic lactones 99JCS(P1)1235. 

Strategies for stereoselective synthesis of molecules with remote stereoge-nic centers across a double bond of fixed configuration in particular, for synthesis of heterocycles, especially unsaturated macrocyclic lactones 99JCS(P1)1899. 

Polymer-supported synthesis of natural macrocyclic lactones and other 0-heterocycles 99AG(E)1903. 

Chemistry, biology, and medicine of tubulin polymerizing macrocyclic lactones 99PAC989. 

Glycosylated macrocyclic lactones from resins of Ipomoea family plants 97MI23. 

Rapamycin is a macrocyclic lactone produced by Streptomyces hygroscopious. This bacterium was originally cultured from a soil sample collected on Easter Island (known locally as Rapa Nui hence the name rapamycin). Parenthetically, rapamycin shares an interesting mode of action with two other antifungal and immunosuppressive compounds, FK506and cyclosporin A. Inside cells, rapamycin first binds to FKBP12, a small protein receptor known as an immunophilin. FKBP12 is not an essential protein but is an important cofactor required for rapamycin to bind and inhibit TOR. 

Kruizinga, W. H., and Kellogg, R. M., Simple and high yield synthesis of macrocyclic lactones by ring-closure of caesium salts of to-halogenoaliphatic acids, J. Chem. Soc.. Chem. Com-mun.. 286-288, 1979. 

Gonzalez and Holt (1981) have shown how macrocyclic lactones can be made conveniently in microemulsion media. Thus, intramolecular e.sterification of (o-hydroxy alkanoic acids can be carried out with a very small amount of acid catalysts like p-toluene sulphonic acid, and rates are markedly higher as compared to simple media. 

Ivermectin, a macrocyclic lactone, is also utilized to control parasites. An immunoassay was developed to determine ivermectin residues in bovine liver by Crooks etal. The sample preparation procedure was complex, involving tissue homogenization in acetonitrile, centrifugation, extraction with hexane (to remove lipids), evaporation and reconstitution in ethyl acetate, and passage through an SPE column followed... 

This methodology has been applied to both acyclic esters and macrocyclic lactones. 

Dianions derived from cyclic a-nitro ketones have been used for the preparation of the natural product phoracanthlide and related macrocyclic lactones (see Scheme 5.2).13 Alkylation of dianion of a-nitro cyclic ketones is followed by radical denitration with Bu3SnH (see Section... 

There is a need for development of new anthelmintics, as resistance in livestock has been recorded against benzimidazoles, imidothiazoles and the avermectin/macrocyclic lactones, in addition to older drugs... 

For an example of use in macrocyclic lactone formation see B. Seuring and D. Seebach, Justus Liebigs Ann. Chem., 2044 (1978), and references therein. 

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