Of polyene macrolides

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

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. 

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. 

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... 

In their landmark total synthesis of polyene macrolide Amphotericin B [92], Nicolaou and coworkers designed a mycosamine precursor 57 and coupled it with a highly functionalized aglycon (O Scheme 32). Inversion of the C2-OH followed by the azide reduction and deprotections competed the total synthesis. 

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)."°... 

A convergent total synthesis of polyene macrolide roflamycoin was achieved by S.D. Rychnovsky and co-workers." " In their approach, they introduced the C25 stereocenter via an asymmetric catalytic Mukaiyama aldol reaction utilizing Carreira s chiral titanium catalyst." ... 

Fig. 7. Antiscrapie drugs of four different classes. (A) Pentosan polysulfate as a powerful drug belonging to the polyanion family. (B) IDX a derivative of doxorubicin. (C) Congo red belonging to the diazo dyes. (D) Amphotericin B and MS-8209 belonging to the family of polyene macrolide antibiotics.

The intramolecular HWE cyclizations using phosphonoacetate (t-PrOLi or LHMDS, HMPA, THF-PhH) or ketophosphonate (NaH, DME or Na, PhMe) under high dilution conditions were developed as variable methods for the construction of macrolactones by Stork and Nakamura [89] and Nicolaou et al. [90], respectively. The very mild and efficient conditions for the intramolecular HWE reaction of (3-ketophosphonate or phosphonoacetate were reported (1) treatment with K2CO3, in the presence of 18-crown-6 [91], or (2) treatment with tertiary amines such as EtjN or Hunig s base in the presence of LiBr or LiCl [92]. These methods are applied to the total synthesis of polyene macrolides [93a-95] such as amphotericin B (170) [96] and polyoxomacrolides [97-100]. 

Floyd and Fritz s Synthesis of Polyene Macrolide Mimics. 177... 

The polyene segment [84] A practical route to the synthesis of bifunctional all-tran5 polyenes using an adaptation of a Wittig reagent developed by Vedejs and Bershas [91] was reported by Hanessian and Botta [84] in a version of potential usefulness in the area of polyene macrolides. A polyene synthesis with functional groups at both ends for further chemical manipulations is illustrated in Scheme 14. 

Pimaricin, also called natamycin, is a member of the family of polyene macrolides. These compounds consist of large macrolactone rings that have a characteristic series of conjugated double bonds, an exocyclic carboxyl group, and an unusual mycosamine sugar. In this chapter, we deal with pimaricin because this compound is the only one bearing an epoxy functionality. The other polyene macrolides such as nystatin, amphotericin, and candicidin will be treated in Sections 7.11.1 and 7.11.2. 

Although separation of polyene macrolide antibiotics is difficult, considerable progress has been achieved in their purification by HPLC and in the determination of (heir complex chemical structure by sensitive analytical methods, such as proton magnetic resonance, x-ray, and mass spectrometry. 

Figure 3 Chemical structures of the sugar moieties of polyene macrolide antibiotics.

The three different moieties of polyene macrolides (i.e., the macrolide ring, the aromatic moiety, and the aminosugar moiety) are synthesized by three separate pathways (7). Initial results obtained in the case of candicidin indicated that, at least, the genes involved in the biosynthesis of the aromatic moiety and the macrolide ring are clustered. 

No in vitro studies have been carried out specifically on the biosynthesis of the aminosugar moieties of polyene macrolide antibiotics however, the similarity with the biosynthesis of aminosugars of nonpolyene macrolides and bacterial lipopotysaccharides provides some data on the probable biosynthetic pathway. 

The availability of the cloned genes opens the way for studies on gene expression and regulation by phosphate and other well-known effectors of polyene macrolide biosynthesis. 

Martin ]F. Biosynthesis of polyene macrolide antibiotics. Annu Rev Microbiol 1977 3 M 3-38. 

Cybulska B, Mazeiski J, Borowski E, Gaty-Bobo CM. Haemolytic activity of aromatic heptaenes. A group of polyene macrolide antifungal antibiotics. Biochem Pharmacol 1984 1 4 M6. 

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