Natural macrolide

Progress in the synthesis of chiral natural macrolide antibiotics epothione B and tartrolonB 99JHC1421. 

Very large ring lactones are called macrolides, and are found in the natural macrolide antibiotics. Typically, these may have 12-, 14-, or 16-membered lactone rings, though other sizes are encountered. Erythromycin is a... 

Glucolipsin A, a glycolipid possessing glycokinase-activating properties, was discovered at Bristol-Myers Squibb, but the absolute stereochemistry of the natural product remained elusive. A. Furstner and co-workers elucidated the absolute stereochemistry via synthesis and spectroscopic analysis of the natural macrolide and its Cj-symmetric stereoisomers." In their approach, they utilized the Evans aldol reaction that provided the syn aldol product with good yield and excellent diastereoselectivity. 

Although it would be impossible to collect all natural macrolides reported thus far, more than 2000 compounds have been detected using databases [4-6]. Table I covers most of them. Table I classifies the macrolides according to ring size and compound type, together with the numbers of compounds found for each category. Skeletal structures of these macrolides are characteristically depicted in Fig. 1. 

We describe the details of natural macrolides in the following sections classifying according to each producing organism. 

Actinomycetes are the largest source of natural macrolides. They produce more than three hundred 16-membered macrolides (including spiroacetals) and nearly one hundred 14-membered macrolides (Table III). They also produce various sizes of macrolides up to a 60-membered ring, including polyene macrolides, macrodiolides, macrotetrolides, and immunosuppressive macrolide lactams. Compounds already described in the first edition of this book [1] are mentioned here briefly. 

Despite having the same spectram of action as that of other natural macrolides, ketolides have better in vitro activity against streptococci and other gram-positive microorganisms, including oxacillin-resistant Staphylococcus spp. and vancomycin-resistant enterococci [204-206], because a remarkable decrease takes place in the water solubility of those ketolides (Table I). 

The rather unusual natural macrolide pyrenolide B (411) has been prepared by a route which features an oxidative cleavage [(409)— ... 

The covalent-template approach has been used to carry out intramolecular esterification of co-hydroxy carboxylic acids in the presence of catalytic amounts of stannoxanes to form monomacrolactones, including natural macrolide antibiotics such as nodusmicin, pyrenophorin, vermiculine and ingramycin. The course of the synthetic reaction is shown in Scheme 7-4 [21-23]. 

The Vhc couplings have been applied by Menche et al. in stereochemical determination of etnangien, a potent novel analogue of the natural macrolide antibiotic a highly potent RNA polymerase inhibitor from the mycobacterium Sorangium cellulosum. 

Fluvirucin B1 (172) is one of the first natural macrolides being synthesized by RCM, and one of the few examples utihzing [Moj-I efficiently. This antifungal agent, isolated from Actinomadura SCC 1777, was obtained through a high yielding and totally stereoselective RCM of compound 170 (Scheme 5.40) [72]. 

---