Macrocyclic lactone synthesis

Rees, G. D., Robinson, B. H., and Stephenson, G. R., Macrocyclic lactone synthesis by lipases in water-in-oil microemulsions, Biochim. Biophys. Acta, 1257, 239-248, 1995. 

Fig. 16 (a) macrocyclic lactone synthesis by cyclorelease via a sulfur ylide and (b) macrocyclization via intramolecular Suzuki-... 

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). 

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. 

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. 

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). 

For reviews on the synthesis of macrocyclic lactones, see Nicolaou Tetrahedron 1977, 33, 683-710 Back Tetrahedron 1977, 33, 3041-3059 Masamune Bates Corcoran Angew. Chem. Ini. Ed. Engl. 1977, 16, 585-607 [Anger, Chem. 89, 602-624). 

Macrocyclic lactones. Ireland and Brown1 have adapted the Eschenmoser contraction of sulfides to a synthesis of five- and six-membered lactones. An example is formulated in equation (1). A hydroxy thioamide is esterified to give a chloro ester, which is then treated in sequence with Nal and phosphine I. The inelhod can also be used for preparation of macrocyclic lactones under high-dilution... 

Lactones and the macrocyclic lactones, like the y- and 5-lactones, are of importance since these ring systems are found widespread in nature. The simpler substituted lactones are important building blocks in the synthesis of many natural products, e.g. in the fields of antibiotics, anticancer pharmaceuticals, pheromones and prostaglandins to name but a few. 

The coupling was extended to the synthesis of the macrocyclic lactone I containing a dienone group. In this case a stoichiometric amount of Pd(II) is necessary to effect ring closure.2... 

An effective new method for the synthesis of macrocyclic lactones has been developed by Corey and Nicolau (75). In this method both the hydroxyl and the carboxyl groups have been activated by formation of a 2-pyridin-ethiol ester. Vertaline was obtained in 67% yield when this procedure was applied to the corresponding hydroxyacid (76). 

Scheme VIII/32. Synthesis of macrocyclic lactones with an annelated aromatic ring by ring enlargement [100] [101].

Cesium salts of substituted pyridine-3,5-dicarboxylic acids were used first by Krui-zinga and Kellogg for the synthesis of macrocyclic lactones [51]. Kellogg obtained the bis-lactone 46 in a one-pot reaction of the cesium carboxylate 44 and the dibro-mo compound 45 in 85 % yield without application of high dilution conditions [1]. By comparison with other alkali metal carbonates he proved the yield-increasing effect of the cesium ions ... 

Sato and coworkers [137] reported the synthesis of macrocyclic lactones via intramolecular alkylation of n-allylic nickel complexes, based on the facile reactivity of n-allylic nickel complexes toward alkyl halides. As shown in Scheme 75, this method was applied to the synthesis of the macrolide recifeiolide 227). The linear precursor 226 in benzene was added slowly over 1 h to nickel carbonyl in benzene at 50 °C. After additional 1.5 h at 50 °C, 227 was obtained in 32% yield. 

The problem of macrolactonization became especially crucial in the 1960s as intensive studies were directed at the synthesis of biologically active antibiotics containing the macrocyclic lactone (macrolide) moiety. As a result of these studies,the problem of macrolactonization, regardless of the size of lactone ring or the complexity of the acyclic precursor, was solved. 

Synthesis of maerolides. The intramolecular coupling reaction of allylic halides (I, 722-723 2, 290-292 3, 211) has now been shown to be applicable to the synthesis of maCrocyclic lactones. Thus addition of the dibromo ester (1) to 6 eq. of nickel carbonyl in N-methylpyrrolidone effects cyclization to the macrolide (2) as the major product. 

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