Macrolides and Polyethers

The previously known and notorious aplysiatoxin (a cause of swimmer s itch ) (7) is a protein kinase C inhibitor and has been the object of a structure-activity study (1582). The causative agents of a red alga Gracilaria coronopifolia poisoning 

The highly complex chlorinated pyrrole-containing macrolide colubricidin A (1626) is produced in cultures of an unidentified Streptomyces species (1595). This metabolite displays excellent activity against Gram-positive bacteria. The Dominican sponge Spirastrella coccinea produces spirastrellolide A (1627), which is a potent and selective inhibitor of protein phosphatase 2A (1596) (revised later (1597)). 

Another Palauan sample of this blue-green alga identified the related bromine-containing lyngbyaloside B (1636) (1604). 

A novel ansamycin, naphthomycin K (1641), was isolated from a Streptomyces strain of the medicinal plant Maytenus hookeri (1616). This compound was cytotoxic (P388 and A-549 cell lines) but inactive against Staphylococcus aureus and Mycobacterium tuberculosis. An Amycolatopsis sp. has furnished the ansacarbami-tocins A-F, Al, B1 (1642-1649), which are similar to the ansamitocins (1617). 

The Red Sea sponge Latrunculia corticata (Fig. 3.23) has afforded latrunculino-sides A (1667) and B (1668), which contain the unusual saccharides /i-D-olivose, jS-L-digitoxose, a-L-amicetose, and /i-D-oliose (1630). 

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The Prelog-Djerassi lactone (abbreviated here as P-D lactone) was originally isolated as a degradation product during structural investigations of antibiotics. Its open-chain equivalent 3 is typical of the methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. The compound serves as a test case for the development of methods of control of stereochemistry in such polymethylated structures. There have been more than 20 different syntheses of P-D lactone.24 We focus here on some of those that provide enantiomerically pure product, as they illustrate several of the methods for enantioselective synthesis.25... 

Acyclic stereocontrol has been a striking concern in modern organic chemistry, and a number of useful methods have been developed for stereoregulated synthesis of conformationally nonrigid complex molecules such as macrolide and polyether antibiotics. Special attention has therefore been paid to the aldol reaction because it constitutes one of the fundamental bond constructions in biosynthesis. 

The Prelog-Djerassi lactone (abbreviated as P-D-lactone) was originally isolated as a degradation product during structural investigation of antibiotics. Its open-chain precursor 1, is typical of methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. 

Macrolides and polyethers such as erythromycin A (4), FK 506, rapamycin or avermectin A (5, Scheme 1) are products of modular type I polyketide-synthases. These compounds are distinguished by extraordinary structural diversity and complexity [1,2]. Because of their biological potency, members of this structural class as well as the aromatic polycyclic products of type II polyketide-synthases, tetracyclines and anthara-cyclines, e.g. adriamycin (6), became useful as pharmaceuticals (antibiotics, cytostatics, immunosuppressives) [1,2],... 

The (3-methyl homoallylic alcohol moiety of both anti- and 5yn-configurations is a characteristic structural element of a number of macrolides and polyether antibiotics. Reactions of crotylmetal (2-butenylmetal) reagents with carbonyl substrates provide access to acyclic stereo- and enantioselective syntheses of p-methyl homoallylic alcohols. The alkene moiety of these alcohols can be further elaborated into aldehydes by oxidative cleavage of the double bond, leading to aldol-type products. 

Work concerned with providing solutions to the difficult stereochemical problems encountered in the synthesis of the macrolide and polyether antibiotics continues, and in this field pride of place must go to the total synthesis of erythromycin which has been completed by the collaborators of the late R. B. Woodward. 

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