Macrolactone rings

Erythronolide B, the biosynthetic progenitor of the erythromycin antibiotics, was synthesized for the first time, using as a key step a new method for macrolactone ring closure (double activation) which had been devised specifically for this problem. Retrosynthetic simplification included the clearance of the stereocenters at carbons 10 and 11 and the disconnection of the 9,10-bond, leading to precursors A and B. Cyclic stereocontrol and especially the Baeyer-Villiger and halolactonization transforms played a major role in the retrosynthetic simplification of B which was synthesized starting from 2,4,6-trimethylphenol. 

From the active site topology it seems that there is room for substrate flexibility. Indeed, experiments with the closely related P450eryF have demonstrated that some substitutions within the macrolactone ring of the substrate are possible [28] for example, reduction of the C9 oxo to the hydroxy group is well tolerated. However, any changes with impact on the overall confonnation of the substrate, thus changing the trajectory between the reactive C-H bond and the iron-bound oxy-... 

Erythromycin A (Figure 8.2, 1) is a clinically important antibiotic produced by Saccharopolispora erythraea. It consists of a 14-membered macrolactone ring to... 

The DesVll desosaminyl transferase naturally transfers D-desosamine to both 12- and 14-membered macrolactones, which is an example of inherent flexibility towards the acceptor aglycone. This unusual property of DesVll has been exploited to generate novel macrolide derivatives that differ in size of the macrolactone ring and in their oxygenation/reduction state. A Streptomyces lividans strain in which the genes involved in the biosynthesis and transfer of D-desosamine were... 

A large part of the early SAR work on epothilones has focused on modifications of the epoxide moiety at positions 12/13 of the macrolactone ring. These studies have demonstrateded that the presence of the epoxide ring is not an indispensible prerequisite for efficient microtubule stabilization and potent antiproliferative activity. Thus, Epo C (10) and D (11) (Figure 1-1) are virtually equipotent inducers of tubulin polymerization as Epo A and B, respectively. They are also potent inhibitors... 

In addition to analogs incorporating an olefinic double bond as a linker between the macrolactone ring and different types of heterocycles, we have also studied a new family of side-chain modified structures, which are characterized by rigidifica-tion of the entire side-chain manifold (exemplified for quinoline-based analogs 30 and 31). ... 

Nishida. A.. Yagi, K., Kawahara, N., Nishida, M., and Yonemitsu, ()., Chemical modification of erythromycin A. Synthesis of the C1-C9 fragment from erythromycin A and reconstruction of the macrolactone ring. Tetrahedron Lett., 36, 3215, 1995. 

Amphidinolides have a variety of backbone skeletons and different sizes of macrolactone rings (12- to 29-membered rings), and more than half of the amphidinolides have odd-numbered macrolactone rings (Table 2). Most of the amphidinolides contain a vicinally located one-carbon branch and cxo-methylene unit, and some of them exhibit potent cytotoxicity and antitumor activity. Due to their diverse functionality, stereochemical complexity, low natural abundance, and encouraging bioactivity, amphidinolides have attracted great interest as challenging targets for total synthesis. Synthetic study of amphidinolides is also important to establish the structure of these macrolides in case the amount of natural compound was very limited. 

Amphidinolides R (17) and S (18) are minor congeners of amphidinolide J (9). The structure of amphidi-nolide R (17) was assigned as a regioisomer of amphidinolide J (9) having a 14-membered macrolactone ring, since treatment of amphidinolide J (9) and amphidinolide R (17) with sodium methoxide yielded an identical linear methyl ester. On the other hand, amphidinolide S (18) was concluded to be the 9-didehydro form of amphidinolide J (9) by spectroscopic data. ... 

Motamedi, H. Shafiee, A. The biosynthetic gene cluster for the macrolactone ring of the... 

A highly effective method for the construction of macrolactone ring ii is the intramolecular lactonization of the corresponding seco-acid i (Fig. 2). Thus, various effective methods for the synthesis of macrolactones were developed during the 1970s and 1980s and have been successfully apphed to the total synthesis of macroUde antibiotics. In the 1990s, new methods for macrolactonization were reported [35] however, they have not yet been applied frequently to macrolide synthesis. Thus, in this section, the established methods applied to macrolide synthesis are introduced, and selected recent applications are shown in Scheme 12 and Section III.F. 

Macrolides are a class of valuable antibiotics which include a 16- or 14-membered macrolactone ring, generally at least one appended sugar unit, and, in most cases, additional epoxide and/or hydroxyl groups. These functional groups contribute to structural diversification and serve to improve the bioactivity profiles of natural products (Figure 3.96). 

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. 

Nystatin Al, initially named fungicidin, is a polyene macrolide with a 38-membered macrolactone ring and was isolated in 1950 from Streptomyces noursei [127, 128], and patented in 1964 [129], The stmcture 146 was assigned to it by Borowski and coworkers in 1971, while the stereochemistry of the molecule was unraveled several years later (Figure 7.46) [130, 131], Nystatin is mainly used for topical treatment of candidiasis [132], and represents a commercial product with a world market estimated to be in the range of US 250-300 million per year. In spite the commercial interest, very limited reports have appeared on biosynthesis of nystatin. 

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