Polyene macrolide

Amphotericin is an amphoteric polyene macrolide (polyene = containing many double bonds macrolide = containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water and is therefore prepared as a colloidal suspension of amphotericin and sodium desoxycholate for intravenous injection. Several new formulations have been developed in which amphotericin is packaged in a lipid-associated delivery system (Table 48-1 and Liposomal Amphotericin B). 

A large variety of macrolides have been isolated from natural sources. Macrolides have various ring sizes up to 62 and exhibit various characters spiroacetal-fused macrolides, polyene macrolides, macropolylides, and macrolides containing amino nitrogen, amide nitrogen, oxazole rings, or thiazole rings in their skeletons. 

Many of the naturally occurring secondary metabolites from bacteria and plants are glycosylated, mostly by 6-deoxyhexoses derived from dTDP-glucose (deoxythymidine 5 -diphospho glucose). 6-Deoxyhexose derivatives are present in a variety of antibiotics from actinomycetes, including macrolides, polyenes, and aminoglycosides, among others. 

Large family of natural macrolactones commonly referred to as macrolides can be grouped into polyoxo macrolides, polyene macrolides, ionophoric macrohdes, and ansamycin macrohdes. 

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... 

A related strategy of orthogonal nucleophilic and electrophilic activation was later employed in the synthesis of the polyene macrolide roflamycoin [32]... 

Next we will describe the synthesis of filipin III (114) in greater detail, to bring to light some of the issues that arise in the total synthesis of a complex polyene macrolide [7,8]. 

The polyene macrolide filipin was isolated in 1955 from the cell culture filtrates of Sterptomyces filipinensis, and was later shown to be a mixture of four components [36]. Although too toxic for therapeutic use, the filipin complex has found widespread use as a histochemical stain for cholesterol and has even been used to quantitate cholesterol in cell membranes [37]. The flat structure of filipin III, the major component of the filipin complex, was assigned from a series of degradation studies [38]. Rychnovsky completed the structure determination by elucidating the relative and absolute stereochemistry [39]. The total synthesis plan for filipin III relied heavily on the cyanohydrin acetonide methodology discussed above. 

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-... 

HWE reaction has been used extensively for the synthesis of dienes and polyenes. Examples from recent literature are shown in Table 16 (dienes) and Table 17 (polyenes). HWE reaction also has been used for intramolecular cyclizations leading to polyene macrolides (Table 18). 

The natural products Mycoticin A (22, R = H) and B (22, R = Me) belong to the skipped-polyol-polyene class of antibiotics. Our analytical interest here is to use this very complex molecular structure to demonstrate some of the tools employed, mainly for the elucidation of the polyene part of the molecule. This family of polyene macrolide class was discovered in 195045 with the finding of Nystatin (23), which is produced by the Streptomyces bacteria. The exact structure was elucidated only in 1970 by Chong and Rickards46 and, in 1971, Nystatin Ai (23) and A2 (not shown in this review) were separated. 

Sowinski and coworkers40 reported a structure of vacidin A (63), an aromatic hep-taene macrolide antibiotic. The constitution of vacidin A, a representative of the aromatic heptaene macrolide antibiotics, was established on the basis of 13C and H- H double quantum filtered correlated spectroscopy, rotating frame nuclear Overhauser effect spectroscopy, 7-resolved 11 as well as H-13C correlation NMR spectra. The geometry of the polyene chromophore was determined as 22E, 24E, 26E, 28Z, 30Z, 32E, 34E. 

The 13C NMR spectrum of 64, an amide of 63, showed sixty-two carbon signals of which partial assignments, shown in Table 16, were made based upon distortionless enhancement by polarization transfer(DEPT), H-13C correlation experiments and literature data describing 13C NMR analysis of polyene macrolides. 

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. 

Rochet and Lancelin50 reported revised 1H and 13C NMR assignments of the polyene antibiotic Filipin m (83). This macrolide which was isolated from Streptomyces filipinensis was reinvestigated in DMSO-dg solution using homonuclear and heteronuclear correlation spectroscopy. In addition to several corrections to previous 1H NMR... 

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. 

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