14-membered macrolactone macrolides

Reducing Antibacterial Effects of 14- and 15-Membered Macrolactone Macrolides... 

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... 

The resorcylic acid lactones (RALs) are a family of benzannulated macrolides, which are produced by a variety of fungi and show versatile biological activities (6). According to their name, they consist structurally of a partially substituted p-resorcylic acid scaffold, which is linked to a 12- or 14-membered macrolactone moiety. Selected members of this group are shown in Fig. 9.1. 

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). 

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. 

Tadano utilized the Hiyama reaction in a formal synthesis of the antimicrobial tricyclic macrolides tubelactomicins. The intramolecular Hiyama cross-coupling reaction of 64 aided in the synthesis of a 24-membered macrolactone equipped with all the requisite functionalities, which then triggered the transannular Diels-Alder reaction to give 65. The 24-membered lactone formation was also achieved by the intramolecular ring-closing metathesis reaction. 

Matsushima, T., Horita, K., Nakajima, N., and Yonemitsu, O. (1996) Synthetic studies of 18-membered antitumor macrolide, tedanolide. Computer-aided conformational design of a seco-acid derivative for efficient macrolactonization. Tetrahedron Lett., 37, 385-388. 

The simplest way of macrolactonization is the use of acid or base catalysis so that after the ring closure no tedious separation of the lactone from auxiliary by-products is required. However, there are only very few such examples. The 16-membered macrolide ring of milbemycin 3 is closed very efficiently by simply treating the hydroxy ester (349) with potassium hydride. OH deprotonation induces ring formation with retention of configuration to (350 equation 125). 

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. 

Pike, the P-450 hydroxylase in the pikromycin gene cluster catalyzes hydroxylation of the initial macrolide products (YC-17/narbomycin) and displays unparalleled flexibility toward the macrolactone core of its macrolide substrates. Both 12-membered ring YC-17 (4) and 14-membered ring narbomycin (5) are produced after glycosylation with desosamine. Interestingly, PikC catalyzes hydroxylation at CIO or C12 of the... 

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. 

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