Macrolide lactones, examples

The reaction illustrates a typical example of the preparation of macrolides. Lactones with more than 12 members can be obtained in even better yields. For example, 15-hydroxypentadecanoic lactone (m.p. 35-37°) and 17-hydroxyheptadecanoic lactone (m.p. 40-41°) were prepared by the submitters in about 95% yield in a practically pure form, with no trace of the corresponding dilactones. 

The basic structure of the macrohde antibiotics is characterized by a lactonic cycle with two osidic chains, and they are classified according to the number of carbon atoms in the cycle 14-membered macrohdes (for example clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin), 15-membered macrolides (for example azithromycin), and 16-membered macrolides (for example josamycin, midecamycin, spiramycin). 

Masamune has made use of this property for synthesis of medium ring lactones (macrolides), for example, zearalenone dimethyl ether ethylene ketal (5) from the hydroxy ester (4). On treatment with mercuric trifluoroacetate at 25°, (4) is converted within 5 min. into the lactone (5) in >90% yield (recrystalhzed). 

Few topics are closer to the heart of the medicinal chemist than heterocycles. Heterocyclic compoxmds form the centerpiece of the most important classes of antibiotics, such as the beta-lactams (penicillin), macrolide lactones (erythromycin), and more recently the quinolones, but the reach of heterocyclic structures in bioactive molecules goes far beyond these examples. One needs to only consider the antimalarials quinine and artemisinin, the anti-HIV reverse-transcriptase inhibitors (e.g., AZT and 3TC), and the important anticancer agents— vincristine and pemetrexed— to begin to see the role that heterocycles play in our world today. 

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-... 

Many natural products are lactones, and it is not unusual to find examples in which the ring size is rather large. A few naturally occuning lactones are shown in Figure 19.8. The macrolide antibiotics, of which erythromycin is one example, are macrocyclic (large-ring) lactones. The lactone ring of erythromycin is 14-membered. 

Macrocyclic derivatives are of considerable importance in biological areas and as complexing agents, particularly for metals. Macrocyclic examples are given in MACROLIDES FROM CYCLIZATION OF w-BROMOCARBOXYLIC ACIDS 11-HYDROXYUNDECANOIC LACTONE and MACROCYCLIC POLY AMINES 1,4,7,10,13,16-HEX AAZ ACYCLOOCT ADE-... 

The macrolide antibiotics provide us with excellent examples of natural products conforming to the acetate pathway, but composed principally of propionate units, or mixtures of propionate and acetate units. The macrolides are a large family of compounds, many with antibiotic activity, characterized by a macrocyclic lactone ring, typically 12, 14, or 16 membered, reflecting the number of units utilized. Zear-alenone (Figure 3.59), a toxin produced by the... 

Macrolides. A new method of lactonization involves intramolecular alkylation of an Qj-haloalkyl 2-phenylthiomethylbenzoate. An example is shown in equation (1). The 15-membered lactone corresponding to 3 was also obtained readily in this way, but the method failed in attempted eycli/ation to a 12-membcred lactone. 

Lactonization of ta-hydroxy esters to macrolides. Gerlach and co-workers have reported that silver salts can catalyze the cyclization of v-hydroxy-2-pyridinethiol esters to macrolides (6, 246 7, 142). Nimitz and Wollenberg have found that silver perchlorate has an even more pronounced and consistent effect on the cyclization of (u-hydroxy thiolesters of 2-amino-4-mercapto-6-methylpyrimidine, Optimal yields are obtained with use of 1.1 equiv. of the silver salt. In addition, high dilution is not necessary. In the example cited, the yield of the lactone in the absence of the catalyst is 41%. 

Cyclization via intramolecular olefination of complex phosphonates remains the most important method of synthesis for complex natural macrocycles. Examples include syntheses of 20-membered macrolide antibiotic, aglycones of venturicidins A and B,108 oleandomycin (a 14-membered macrolide antibiotic), 109 the 19-membered macrocyclic antibiotic, anti-tumour agent (-t-)-hitachimycin,ll0 and the macrocyclic lactones (183).1H Cyclization of the phosphonate (184) under Masamune-Roush conditions has been used to synthesize the 28-membered macrolactam myxovirescin B.112... 

Aside from alkylcuprates, alternate methods for the introduction of a second methyl group via olefination reactions have been proposed, as shown below. An illustrative example of this strategy will be given in conjunction with synthetic approaches to the Prelog-Djerassi lactone [46,47], a degradation product of the macrolide antibiotic methymycin and a key intermediate on the way to polypropionate products. 

The simplest way of macrolactonization is the use of acid or base catalysis so that after the ring closure no tedious separation of the lactone from auxiliary by-products is required. However, there are only very few such examples. The 16-membered macrolide ring of milbemycin 3 is closed very efficiently by simply treating the hydroxy ester (349) with potassium hydride. OH deprotonation induces ring formation with retention of configuration to (350 equation 125). 

As noted in the discussion of ( )-selective alkene formation, Kishi has found that a-substituted aldehydes reacted with trimethylphosphonopropionate and KOBu to produce the (Z)-alkene selectively. A strongly dissociating base is critical to this approach. In addition to the examples already presented in the discussion of ( )-alkene formation, the (Z)-selective reaction has recently been applied to the synthesis of macrolide antibiotics. In this example, a trisubstituted alkene was formed and closed to the lactone (148 equation 33). In an application to diterpenoids. Piers encountered an example of how substrate-specific the alkene formation can be. With a-dimethoxyphosphonyl-y-butyrolactone (150), the reactions with simple aldehydes proceeded with very high selectivity [(Z) ( ) = 99 1]. On application of the reaction to the more complex aldehyde (149) the (Z) ( ) stereoselectivity dropped to 3 1 in 58% yield (equation 34). No selectivity was observed on reaction with benzaldehyde. Although for hindered substrates, strongly basic conditions with a dimethyl phosphonate can be a simple and effective method for the synthesis of (Z)-isomers, the reaction is not general. In 1983, Still and coworkers introduced methodology that used bis(trifluoroethyl)phosphonoesters (153) to provide a facile approach to (Z)-aIkenes (154) when reacted with aldehydes (equation 35). " ... 

The antibacterial spectrum of these macrolides is broader. For example, the clinical modification at C6 [e.g., O-methylation (clarithromycin)] or at C9 [e.g., some 9-ether oxime derivatives (roxithromycin and dirithromycin)] stabilizes 14-membered lactone rings in acidic media, even when the modified drugs have been orally administered. Drugs with an expanded erythromycin A-lactone ring (e.g., azithromycin) are also more stable in acidic media and display better antigram-negative activity than does erythromycin A. 

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