Membered Macrolides

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-... 

Intramolecular 1,4-addition is useful for macrolide synthesis. An unusual molecule of punctaporonin B (272) has been synthesized by this 1,4-addition of 271(160]. Cyclization to form the seventeen-membered ring macrolide 273 was carried out at 0.1-0.5 vi concentration[161. The choice of ligands seems to be important in the macrocyclization. The 26-membered ring model 274 for a synthesis of the ring system of tetrin A was obtained in 92% yield by using triisopropyl phosphite as a ligand[162]. 

The few macrolides having 12-membered rings are Hsted in Table 2. Methymycin (12, R = OH, R = H), isolated from culture broths of a Streptomjces species (29), was the first macroHde stmcture elucidated (30). It is comprised of the aglycone methynolide (13, R = OH, R = H) and the aminosugar desosamine (1, R = OH, R = H) (31,32). Methymycin was also the first conventional macroHde made by total synthesis (33). 

Natural Products. Naturally occurring 14-membered macrolides are given in Table 3. 

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. 

Chemical biology of epotilones A-E, 16-member macrolide antitumor antibiotics 98AG(E)2015. 

Stereostructure and synthesis of aplyronine A (macrolide with 24-member lactone ring), an antitumor substance of marine origin 96YGK1077. 

A distinguishing feature of the Nicolaou synthesis of rapamycin is the use of a palladium-mediated tandem inter-/intramolecular Stille coupling to construct rapamycin s 31-membered macrolide ring and conjugated triene moiety. This maneuver was unprecedented in the macrolide field,9 and it can be applied to a fully deprotected seco substrate (vide infra). 

An intramolecular palladium(o)-catalyzed cross-coupling of an aryl iodide with a trans vinylstannane is the penultimate maneuver in the Stille-Hegedus total synthesis of (S)-zearalenone (142) (see Scheme 38).59 In the event, exposure of compound 140 to Pd(PPh3)4 catalyst on a 20% cross-linked polystyrene support in refluxing toluene brings about the desired macrocyclization, affording the 14-membered macrolide 141 in 54% yield. Acid-induced hydrolysis of the two methoxyethoxymethyl (MEM) ethers completes the total synthesis of 142. 

Macrolides are a group of antibiotics, produced in nature by many actinomycetes strains, that are composed of a 12- to 16-membered lactone ring, to which one or more sugar substituents is attached. They target the peptidyl transferase center on the 50S ribosomal subunit and function primarily by interfering with movement of the nascent peptide away from the active site and into the exit tunnel. 

Another group of antibiotics that can be inactivated by hydrolysis are 14- and 15- membered macrolides [2]. Esterases cleave the lactone ring. The plasmid encoded ere genes are found in members of the Enter-obacteriaceae and increase the intrinsic resistance. Furthermore, these esterases can also be found in some isolates of erythromycin resistant staphylococci. 

MsrA 14-, 15-Membered macrolides, streptogramin type B Staphylococci Plasmid... 

Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

A sequence of RCAM followed by transannular cycloaromatization in Fiirst-ner s total synthesis of the natural 11-membered macrolide (+)-citreofuran (461) nicely demonstrates that RCAM has a broader scope than just the prepa-... 

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-... 

The macrolide antibiotics are characterized by possessing molecular structures that contain large (12-16-membered) lactone rings linked through glycosidic bonds with amino sugars. 

Rgr 5.12 Extunplcii of 14 membered macrolides A, ro iiihroftiyfliil D, claTiihi4i(i]fCin,... 

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