Lactones macrocyclic, synthesis

We will turn our attention toward the synthesis of macrocyclic lactones, macrocyclic lactams, cyclopeptides, and macrocarbocycles, which are abundant in nature. Retrosynthetic cleavage of the lactone function, lactam function, and cycloalkanes provides an co-hydroxy-acid, an oo-amino-acid, and an open-chain hydrocarbon deriv-... 

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-... 

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). 

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-... 

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. 

An intramolecular variant of the Stille coupling is suitable for the construction of macrocycles. An example is the ring-closing step to form a 14-membered lactone ring 8 in a synthesis of zearalenone as reported by Stille et al. ... 

Natural product total syntheses are particularly valuable when they are attended by the development of general utility methods of synthesis. In some instances, the successful completion of a natural product total synthesis requires the development and application of a new synthetic method. The total synthesis of erythronolide B by Corey et al. is one of these instances. The double activation macro-lactonization method was a fruitful innovation that was introduced in response to the challenge presented by the macrocyclic structures of the erythromycins. Several other methods to achieve the same objective, and numerous applications followed. 

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. 

TE-catalyzed cyclization is not limited to the synthesis of macrocyclic peptides by catalyzing the formation of aC N bond. These enzymes are also responsible for the cyclization of NRP depsipeptide and PK lactone. Indeed, a di-domain excised from fengycin synthase was... 

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]. 

Micafungin (21 Mycamine / Funguard ) FR901379 Macrocyclic lipopeptido- lactone Semi-synthetic NP Microbial Antifungal Inhibits fungal cell wall synthesis 186, 208-210, 248-260... 

Although RCM gives brilliant results for the synthesis of medium-ring carbo-cycles, it is also effective for the synthesis of macrocyclic lactone as shown in Eqs. (6.25)-(6.27). Prior to RCM, macrolactonization was the most common method for the synthesis of macrocyclic lactone. However, we can now obtain the desired macrocyclic lactone from diene having an ester moiety in a chain by RCM followed by hydrogenation ... 

One of the very first uses of the intramolecular nitrile oxide cycloaddition involved the synthesis of macrocyclic lactones. Asaoka et al. (238) conceived this approach to the 16-membered ring antibiotic A26771B (277). Nitro compound 274 [obtained from 11-acetoxydodecanal (273)] was dehydrated with 4-chlorophenyl isocyanate-triethylamine and this was followed by dipolar cycloaddition, which gave isoxazoline 275 as a 4 1 mixture of diastereomers (Scheme 6.100). 

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