Polyenal macrolides

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. 

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. 

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. 

Scheme 23 Synthesis of the 1,3-polyol substructure of the polyene macrolide (-l-)-roxaticin...

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). 

Amphotericin-B, an amphoteric polyene macrolide remains the most effective for severe systemic mycoses. It is indicated for systemic mycoses such as disseminated candidiasis, cryptococcosis, aspergillosis, mucormycosis, coccidioidomycosis, histoplasmosis, extracutaneous sporotrichosis and blastomycosis. It is a fungicidal antibiotic without antibacterial activity. It binds to ergosterol in the... 

Amphotericin B (AmB) is a polyenic macrolide used in fungal infections and leishmaniasis, despite severe side effects (Figure 4.60). Fluorination of the macrolide skeleton has been performed using Selectfluor for F NMR studies on the mechanism of ion-channel formation in membranes by amphotericin B. ... 

Cfiemical class Amphoteric polyene macrolide Clinical Pharmacology ... 

The effectiveness of this method has been demonstrated in a convergent asymmetric synthesis of (2S,4f ,65, 8R)-l,2,4,6,8,10-decanehexol (overall yield 27%), a degradation product of the polyene macrolide lienomycin52. Starting from methyl (,S )-3,4-dihydroxybu-tanoate, the key intermediate (4S, 6>S )-2,2-dimethyl-6-phenyllhio-4-triisopropylsiloxymethyl-1,3-dioxane was obtained51. 

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). 

Nystatin is a polyene macrolide much like amphotericin B. It is too toxic for parenteral administration and is only used topically. Nystatin is currently available in creams, ointments, suppositories, and other forms for application to skin and mucous membranes. It is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract. As a result, nystatin has little toxicity, although oral use is often limited by the unpleasant taste. 

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. 

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