Macrolide antibiotics, 16-membered

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. 

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

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... 

There are also known macrolides with a 12-membered lactone ring, which received the name of patulolides, as well as those with a 16-membered lactone ring, which are called isenamycins. Today, there are about 100 compounds that make up this group of macrolide antibiotics, and they are generally produced by streptomycetes. 

A type of ROM-RCM based tandem reaction was discovered by Lazarova al When various natural 16-membered macrolide antibiotics with a 1,3-diene unit in the marocyclic core (e.g., josamycin 422) were exposed to catalyst E (20mol%) in the presence of 1-hexene (2 equiv.), an ROM-RCM sequence occurred with excision of... 

Tacrolimus is a 23-membered lactone chain isolated in 1984 from Streptomyces tsukubaensis, although it was originally found in a soil fungus. It is a macrolide antibiotic, and its name is derived from Tsukuba macrolide immunosuppressant. ... 

Theriault RJ, Karwowski JP, Jackson M, Girolami RL, Sunga GN, Vojtko CM, Coen LJ (1987) Tiacumicins, A Novel Complex of 18-Membered Macrolide Antibiotics I. Taxonomy, Fermentation and Antibacterial Activity. J Antibiot 40 567... 

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... 

N. K. Kochetkov and A. F. Sviridov, Stereocontrolled synthesis of the main aglycons of 14-member macrolide antibiotics from carbohydrates, Mendeleev Khim. Zh., 6 (1991) 389-400. 

This sugar is one of the two sugar units found in chalcomycins (155), 16-membered macrolide antibiotics,230 and in lankamycin (156), a 14-membered macrolide produced by Streptomyces sp. 231 The similar macrolide neutramycin (157) has been isolated with several analogues containing 4,6-dideoxy-D-xy/u-hexose (153) instead of chalcose (152) from cultures of S. luteoverticillatus.232... 

At the start of the analysis when you have done no more than recognise the FGs and note special features (such as rings) or easy disconnections, note also the number of chiral centres and their relationship to each other. The Prelog-Djerassi lactone 1 is an important intermediate in the synthesis of macrolide antibiotics.1 It has a six-membered lactone ring and a separate carboxylic acid. More to the point, it has four chiral centres la. Three (1-3) are adjacent and one (5) separate. We might say that the three adjacent centres should be easy to control because they are next to each other but that we might have trouble with C-5. Another way to look at it is to say that the three round the six-membered ring (2, 3 and 5) should be easy to control, as the... 

Presence (+) or absence (—) of acyltransferase activity for 16-membered macrolide antibiotics. b Presence (+) or absence (—) of hybridizing band(s) in Southern blot analysis using acyA or acyBl as a probe. " Weakly hybridizing bands were detected. 

HA Kirst, M Debono, KE Willard, BA Truedell, JE Toth, JR Turner, DR Berry, BB Briggs, DS Fukuda, VM Daupert, AM Felty-Duckworth, JL Ott, FT Counter. Preparation and evaluation of 3,4"-ester derivatives of 16-membered macrolide antibiotics related to tylosin. J Antibiot 39 1724-1735, 1986. 

Since ketene is probably the intermediate of the Wolff rearrangement, the choice of solvents dictates the nature of the product. Indeed, water gave carboxylic acids, whereas alcohols or amines led to esters and amides, respectively. These combinations have been applied to the synthesis of more complex molecules. For example, the total synthesis of carbonolide B, a 16-membered macrolide antibiotic, relied on Amdt-Eistert homologation. In this sequence, a protected furanuronic acid was transformed to the corresponding a-diazoketone, which was then converted to its homologous carboxylic ester. The reaction was achieved using catalytic amounts of silver benzoate and excess of triethylamine in methanol (Scheme 3.4).11... 

Lazar ova et al. described the ring contraction of 16-membered ring macrolide antibiotics such as josamydn (57) to their 14-membered analogs [42]. In the presence of... 

A second period of macrocyclic chemistry was signaled by the isolation of the first macrolide antibiotic from an Actomyces culture in 1950. Brockmann and Henkel [6][7] named it picromycin (Pikromycin) (1/4), because of its bitter taste. This antibiotic contains a 14-membered ring. Since then a large number of macrocyclic lactones, lactams and cycloalkane derivatives have been discovered. Some of these compounds have a considerable physiological importance for humans and animals. Because of these physiological properties it was necessary to prepare larger quantities of these macrocylic compounds by chemical syntheses [8]. 

Acetals and hemiacetals imbedded in 5- and 6-membered rings are remarkably stable and their deliberate conversion to the acyclic carbonyl derivatives can be a problem. The high thermodynamic and acid stability of the corresponding 5,5-acetals can be used to liberate a carbonyl by using a 2-stage transprotection protocol. During a synthesis of the macrolide antibiotic Erythronolide B, Martin... 

Macrolide antibiotics consist of a central lactone ring from which extend various functional groups and sugar substituents (Fig. 4.6). Macrolides are divided into three subgroups depending on the number of atoms in the lactone ring 14-mem-bered, 15-membered and 16-membered. Inhibition of protein translation by macrolides has two distinct characteristics. Firstly, macrolides will neither bind to... 

Lactonization. Esters and lactones can be prepared using a trichlorobenzoic mixed anhydride, prepared by reaction of an acid with trichlorobenzoyl chloride. Thus the anhydride reacts with an alcohol in the presence of 4-dimethylamino-pyridine to form an ester in yields usually >90%. The same method can be used for lactonization. Nine- to thirteen-membered rings can be prepared in 35-65% yield. This method was used for synthesis of methynolide (6), a macrolide antibiotic, from a sequence shown in equation (I). 

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