Antibiotics, ionophore

Biological systems have evolved to exploit the reactivity of epoxides in the synthesis of a number of secondary metabolites (Fig. 4.1) [1], including ionophore antibiotics such as monensin (1) [2], terpene ethers, represented by thyrsiferol (2) [3], ladder toxins, represented by brevetoxin (3) [4], and annonaceous acetogenins, represented by murisolin (4) [5]. Chemical synthesis of cyclic ethers also frequently utilizes epoxides, often in the context of cascade cyclizations in which the hydroxyl group that is liberated 

The purpose of this chapter is to describe the use of epoxides as biosynthetic precursors for cyclic ethers. The advances that allow for predictable chemical synthesis based on epoxide opening, including the development of models for regiocontrol in intramolecular ring-opening reactions and stereoselective synthesis, will be described. Numerons examples of epoxide cascade reactions in natural product synthesis will conclude the chapter. 

These studies and observations on the stereochemical arrangements in related natural products led to the classic Cane-Cehner-Westley hypothesis [9]. This work formalized 

From Biosynthesis to Total Synthesis Strategies and Tactics for Natural Products, First Edition. Edited by Alexandres L. Zografos. 2016 John Wiley Sons, Inc. Published 2016 by John Wiley Sons, Inc. 

The epoxide-opening reactions in the monensin synthetic pathway lead to the formation of tetrahydrofuran structures through nucleophilic addition to the proximal carbon. An alternative pathway would proceed through nucleophilic addition to the distal carbon, which would provide a tetrahy-dropyran structure. The formation of tetrahydrofurans is preferred over the formation of tetrahydropyrans under mildly acidic conditions, as will be discussed later in this chapter. Therefore questions arose as to whether enzymes are involved with the epoxide cascade reaction. Enzymatic involvement was demonstrated during studies on the biosynthesis of lasalocid A (8). The precursor of 8 should be diepoxide 9 in accord with the Cane-Cehner-Westley hypothesis. However, the formation of the tetrahydropyran in the 

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Coccidiosis is a proto2oal disease of the intestinal tract of animals that leads to severe loss of productivity and death. The development and widespread use of anticoccidials has revolutionized the poultry industry. The estimated world market for anticoccidial agents in 1989 was 425 million and this was dominated by the polyether ionophore antibiotics monensin, salinomycin [53003-10-4], n imsm [55134-13-9], la.s9locid, and maduramicin [84878-61-5] (26). 

Chemical modification of monensin, polyether ionophoric antibiotic with bound tetrahydropyran, two tetrahydrofuran, and octahydrospiro-2,2 -furopyran fragments 97YZ583. 

The ionophoric antibiotic nonactin is a 32-membered macrocycle that contains two units of (-)-nonactic acid and two units of (+)-nonactic acid in an alternating sequence. 

Other ionophore antibiotics such as gramicidin and valinomycin are channel-forming ionophores because they open pores that extend through the membrane. 

Attachment of carbonyl groups to crowns makes these products more akin structurally to the natural ionophore antibiotics such as valinomycin. The dioxo-derivative (179) of 18-crown-6 was prepared in 35% yield by condensation of tetraethylene glycol and diglycolic acid chloride in benzene at 50 °C for 48 hours (Izatt et al., 1977a and 1977b). This product gives binding constants for Na+, K+ and Ba2+ in methanol which are 102—104 times less stable than for the parent crown - the lower constants are a reflection of less favourable AH values for complexation in these... 

The frequent occurrence of /Thydroxy carbonyl moiety in a variety of natural products (such as macrolide or ionophore antibiotics or other acetogenics) has stimulated the development of stereocontrolled synthetic methods for these compounds. Indeed, the most successful methods have involved aldol reactions.13... 

After protection, the a-hydroxy esters can be reduced by DIBAL-H into O-protected a-hydroxyaldehydes that are very useful synthetic intermediates (e.g., leukotrienes,7-9 ionophore antibiotics,10 insect pheremones,11 etc.). The secondary hydroxyl group of the a-hydroxy esters may also be substituted with inversion of configuration after activation as triflates of nosylates (p-nitrobenzenesulfonates) to give a-alkyl esters12 ora-amino esters.13... 

Three broad groupings, of the antibiotic substances presently used in animal production, include (a) broad-spectrum antibiotics, including penicillins and tetracyclines, which are effective against a wide variety of pathogenic and non-pathogenic bacteria (b) several narrow-spectrum antibiotics that are not used in human medicine and. (c) the ionophore antibiotics, monensin. lasalocid and salinomycin Monensin and lasalocid are used as rumen fermentation regulators in beef cattle, and the three ionophores are used as coccidiostats in poultry production. The ionophores. which are not used in human medicine, were first introduced in the 1970 s and account for most of the increase in antibiotic usage in animal production since the 1960 s. 

Weiss and MacDonald (87) recently reviewed methods for determination of ionophore antibiotics. lonophores approved for use in animal agriculture in the U.S. are lasalocid, monensin, and salinomycin. An HPLC ( ) and GLC-MS ( ) procedure have been described for lasalocid. For other ionophores, TLC-bioautography is the preferred procedure because of lack of any useful UV absorbance. However, a few TLC colorimetric procedures have been described for monensin residues in tissues (90-92). 

The behaviour of valinomycin is typical of a group known as ionophore antibiotics. The antibiotic forms a lipid-soluble complex with K+ which readily passes through the inner mitochondrial membrane, whereas K alone in the absence of valinomycin penetrates only very slowly. Valinomycin binds K+ more strongly than Na. Thus, valinomycin interferes with oxidative phosphorylation in mitochondria by making them... 

Figure 1. Clyme, crown, cryptand, and ionophore antibiotic.

We now proceed to more complicated ionophores in order to testify the validity of this extrathermodynamic relationship and its hypothetical interpretation as an attempt to understand the nature of supramolecular interactions more generally and deeply. The thermodynamic parameters are plotted in Figures 16-19 for long glymes, (pseudo)cyclic ionophore antibiotics, lariat ethers with donating side-arm(s), and bis(crown ethers), whose structural changes upon complexation are schematically illustrated in Figure 20. 

Recently, Nicolaou et al.167) reported an elegant asymmetric synthesis of the ionophore antibiotic X-14547 A (153) isolated at Hoffmann-La Roche from Strepto-myces antibioticus NRRL 8167. The key step in this synthesis was an enantioselective a-alkylation of n-butanal via its SAMP-hydrazone (151) to produce the intermediate (152). The asymmetric induction as determined by NMR-spectra of the product SAMP-hydrazone, was 95 % e.e. 

Fig. 5.4 Chemical structures of commonly used polyether ionophore antibiotics.

The a-pyrone (635) undergoes an exothermic Diels-Alder reaction with 1-diethylamino-1-propyne to afford the cycloadduct (636) (77JOC2930). Only a single regioisomer is produced, which is in line with the expected polarization of these reagents (Scheme 144). A Diels-Alder reaction of the same a-pyrone with 1-dibenzylamino-l-propyne affords an aniline derivative which has been employed in a chiral synthesis of the aromatic portion of the ionophore antibiotic lasalocid (80JA6178). 

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