Large-ring lactones

Many natural products are lactones and it is not unusual to find examples m which the ring size is rather large A few naturally occurring lactones are shown m Figure 19 8 The macrohde antibiotics of which erythromycin is one example are macrocychc (large ring) lactones The lactone ring of erythromycin is 14 membered... 

Synthesis of large ring alkanes and lactones from smaHer ring ketones via peroxides... 

An interesting footnote to the general synthesis of macrocyclic crown ether-type esters is found in the work of Ors and Srinivasan . These workers used cinnamate esters and diesters as precursors to large ring lactones. Depending on orientation, either truxil-... 

Both alcohols and phenols add to ketenes to give carboxylic esters (R2C=C= O+ROH —> R2CHC02R). This has been done intramolecularly (with the ketene end of the molecule generated and used in situ) to form medium- and large-ring lactones. In the presence of a strong acid, ketene reacts with aldehydes or ketones (in their enol forms) to give enol acetates. 

This is a valuable procedure because medium and large ring ethers are not easily made, while the corresponding thiono lactones can be prepared from the readily available lactones (see, e.g., 10-23) by Reaction 16-10. 

Dienes can react intermolecularly or intramolecularly. Intermolecular reactions generate rings, usually alkenes or dienes. Alkenes methasis can be used to form very large rings, including 21-membered lactone rings. Metathesis with vinyl-cyclo-... 

CO-Hydroxycarboxylic acids give, after silylation to bis(trimethylsilylated) intermediates and subsequent treatment with mild Lewis acdds, small- and large-ring lactones in high yields. Thus co-hydroxytridecanoic acid 332 (n= 12) affords, via 333 n= 12), at room temperature, the macrolide 334 in 89% yield [115]. The medium-sized 8- and 9-membered lactones are, however, not formed, only diolides. Likewise, trimethylsilyl 6-trimethylsilyloxyhexanoate 333 is readily lactonized in the presence of 4-trifluoro-... 

Good yields of large ring lactones are achieved by this method. 

Various electrophilic selenium reagents such as those described in Scheme 4.3 can be used. V-Phenylselenylphthalimide is an excellent reagent for this process and permits the formation of large ring lactones." The advantage of the reagent in this particular application is the low nucleophilicity of phthalimide, which does not compete with the remote internal nucleophile. The reaction of phenylselenenyl chloride or V-phenylselenenylphthalimide with unsaturated alcohols leads to formation of (3-phenylselenenyl ethers. 

Phase-transfer catalysis can be used to mimic high dilution reaction conditions and has been utilized to good effect in the synthesis of large ring lactones [67J. Macrocyclic nitrolactones have also been obtained by rearrangement of 2-(3-hydroxy-propyI)-2-nitrocycloalkanones using a stoichiometric amount of tetra-n-butyl-ammonium fluoride [68]. 

Very large ring lactones are called macrolides, and are found in the natural macrolide antibiotics. Typically, these may have 12-, 14-, or 16-membered lactone rings, though other sizes are encountered. Erythromycin is a... 

This provides a cyclic transition state in which hydrogen bonding can enhance the reactivity of the carbonyl group.119 120 Excellent yields of large-ring lactones are achieved by this method. 

A similar inversion of a large-ring lactone has been reported.2... 

Major classes of antibiotics include more than 200 peptides such as the gramicidins, bacitracin, tyrocidines and valinomycin (Fig. 8-22)k more than 150 penicillins, cephalosporins, and related compounds tetracyclines (Fig. 21-10) the macrolides, large ring lactones such as the erythromycins (Fig. 21-11) and the polyene antibiotics (Fig. 21-10). 

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