Antibiotics polyene macrolide

SEVEN-, EIGHT-MEMBERED AND LARGER HETEROCYCLIC RINGS 

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Configurational assignment of polyene macrolide antibiotics using the [ C]ace-tonide analysis 98ACR9. 

The body of chemistry described above for amphotericin B (1) allowed, for the first time, the preparation of a series of novel derivatives of this polyene macrolide antibiotic and set the stage for a total synthesis of this target molecule. Below we unfold the adventure that led to the accomplishment of this goal.910... 

The described procedure has been widely used by Smith III and coworkers [250] in the efficient total synthesis of natural products containing extended 1,3-hydroxylated chains. This architecture is often found as a structural element in polyene macrolide antibiotics [251] such as mycotoxin A and B, dermostatin, and roxaticin. The Smith group used the above-mentioned approach (e. g., as five-component coupling) for the synthesis of the pseudo-C2-symmetric trisacetonide (+)-2-471 [252], which was employed by Schreiber and coworkers [253] within the synthesis of (+)-mycotoxin A (2-470a) (Scheme 2.108). Thus, lithiation of 2.5 equiv. dithiane 2-462b followed by treat-... 

Hirota and coworkers41 reported a planar structure of new polyene macrolide antibiotic YS-822A (65), which they isolated. XH and 13C NMR spectra of 65 showed a number of broad and overlapping signals, but the 1H-1H and 13C- H COSY spectra implied the existence of a mycosamine moiety and several other partial structures. The connectivity of these partial structures was established by extensive 2D NMR experiments, including homonuclear Hartmann-Hahn and heteronuclear multiple-bond connectivity measurements, which led to the determination of the gross planar structure of 65. 

Zotchev SB (2003) Polyene macrolide antibiotics and their applications in human therapy. Curr. Med. Chem. 10 211-223. 

As an example of the usefulness of the Sharpless asymmetric epoxidation the enantioselective synthesis of (-)-swainsonine and an early note by Nicolaou on the stereocontrolled synthesis of 1, 3, 5...(2n + 1) polyols, undertaken in connection with a programme directed towards the total synthesis of polyene macrolide antibiotics, such as amphotericin B and nystatin Aj, will be discussed. 

Shimagaki et al. reported the synthesis of the C11-C16 fragment of the penta-mycin based in the stereoselechve C—C bond formation reaction catalyzed by FBPA [45]. Pentamycin is a polyene macrolide antibiotic, whose configurations at C15 and C14 would correspond to those of the C3 and C4 posihons of an aldol constructed from addihon of DHAP-derived from FBP by use of FBPA and TIM-to the corresponding aldehyde catalyzed by FBPA (Scheme 4.19). 

The complex polyene macrolide antibiotics are clinically effective as antifungal agents. Scott Rychnovsky of the University of California at Irvine has reported (Angew. Chem. hit. Ed. 2004,43, 2822) the first synthesis of rimocidinolide methyl ester 4, the aglycone of rimocidin 1. The key step in the synthesis is the condensation of the aldehyde 2 with the phosphonate 3, leading to 4. 

The (R)-1-benzyloxy-4-penten-2-ol produced using enantiomerically-enriched starting material in this reaction is a useful precursor in the synthesis of the polyol section of the polyene macrolide antibiotic roflamycoin (Scheme 1). This molecule... 

A. F. Sviridov, A. Yu. Romanovich, and O. S. Chizhov, Synthetic studies in polyene macrolide antibiotics. 1. Synthesis of C1-C6 and C7-C12 fragments of amphothericin-B from carbohydrate precursors, Bioorg. Khim., (1987) 1665-1671. 

Martin JF (1984) Biosynthesis, regulation, and genetics of polyene macrolide antibiotics. In Omura S (ed) Macrolide antibiotics Chemistry Biology, and Practice Academic Press, Orlando, 405... 

This reaction can be extended to synthesis of alternating polyol chains found in polyene macrolide antibiotics. Thus reaction of the dibromide 5 with 2 equiv. of the cyanohydrin anion of 6 provides, after reductive cyanation, the protected polyol 7 in good yield. 

Amphotericin B [am foe TER i sin] is a naturally occurring polyene macrolide antibiotic, produced by Streptomyces nodosus. In spite of its toxic potential, amphotericin B is the drug of choice used in the treatment of the systemic mycoses. It is sometimes used in combination with flucytosine so that lower (less toxic) levels of amphotericin are possible. 

The Evans-Chapman-Carreira reaction was used in the total synthesis of mac-rolactin A(3), one of the polyene macrolide antibiotics, which shows inhibition of HIV replication in T-lymphoblast cells in preliminary studies2(Scheme 4.2c). 

Although the absolute configuration has only been established for a few polyene macrolide antibiotics, the search for new, efficient, and selective strategies for the synthesis of their polyol structures is in full swing. A number of the synthetic procedures presented here will certainly be used in future syntheses of this class of natural products [19]. 

Sato/Kaneko [104] and Carreira [105] have independently employed acetoacetate-derived O-silyl dienolates as Si-substituted nucleophiles in asymmetric catalytic aldol reactions. The aldol products, d-hydroxy-/3-ketoesters, and the derived syn- and anti-yS,d-diol esters are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotics. These structural subunits are also found in chemotherapeutics, most notably compactin analogs [106] that have been studied as... 

Bolard J. How do the polyene macrolide antibiotics affect the cellular membrane properties Biochim Biophys Acta 1986 864(3-4) 257-304. 

A recent example involves the synthesis of N-glycosyl derivatives of polyene macrolide antibiotics, such as the preparation of N-(deoxyfructosyl)nystatin (128) by reaction of nystatin with (+)-glucose (Scheme 30)."°... 

Hirota and coworkers reported a planar structure of new polyene macrolide antibiotic YS-822A (65), which they isolated. and C NMR spectra of 65 showed a number of broad and overlapping signals, but the H- H and COSY spectra implied... 

In a separate, elegant use of 165, Rychnovsky and coworkers have carried out a diastereoselective addition of methyl acetate-derived silyl ketene acetal to aldehyde 174 to afford adduct 175 in high diastereomeric purity (Scheme 15) [102]. Hydroxy ester 175 was subsequently employed as an intermediate in the total synthesis of the polyene macrolide antibiotic Roflamycoin. This work highlights a novel application of the chiral catalyst system in reagent-controlled coupling of chiral functionahzed substrates which by themselves display only mod-... 

Amphotericin B (AmB) a polyene macrolide antibiotic with strong activity against a broad spectrum of fungal infections has long been identified as nephrotoxic. The toxic mechanism is assumed to be that binding of AmB to sterols in the cell membrane results in the formation of aqueous pores, which leads to a dis-regulation of volume and ion concentrations within the cells [216]. However, Hsu et al. postulated by using... 

Amphotericin B (AmB) and MS-8209 (Fig. 7D) are polyene macrolide antibiotics that have a ring strucmre containing a hydrophobic and a... 

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