Epoxide-Opening Cascades in the Synthesis of Polycyclic Polyether Natural Products

The structural features of polycyclic polyether natural products can, in some cases, be traced to their biosynthetic origin. However in case that are less well understood, only biosynthetic pathways that feature dramatic, yet speculative, epoxide-opening cascades are proposed. We summarize how such epoxide-opening cascade reactions have been used in the synthesis of polycyclic polyethers (see scheme) and related natural products. The group of polycyclic polyether natural products is of special interest owing to the fascinating structure and biological effects displayed by its members. The latter includes potentially therapeutic antibiotic, antifungal, and anticancer properties, and extreme lethality. The polycyclic structural features of this class of compounds can, in some cases, be traced to their biosynthetic origin, but in others that are less well understood, only to proposed biosynthetic pathways that feature dramatic, yet speculative, epoxide-opening cascades. In this review we summarize how such epoxide-opening cascade reactions have been used in the synthesis of polycyclic polyethers and related natural products

Enantiomere Naturstoffe: Vorkommen und Biogenese

In der Natur werden chirale Substanzen meist in enantiomerenreiner Form synthetisiert – manchmal entstehen aber auch beide Enantiomere. Solche enantiomeren Naturstoffe können von einer Art oder von verschiedenen Gattungen und/oder Arten gebildet werden. Intensive Forschungen wurden über viele Jahre durchgeführt, um die Biogenese natürlich vorkommender Enantiomere zu verstehen, doch viele faszinierende Rätsel und stereochemische Anomalien sind nach wie vor ungelöst. Bild und Spiegelbild in der Natur: Die Bildung von natürlich vorkommenden Enantiomerenpaaren ist bekannt, wenn auch selten (siehe Beispiel). Bis heute sind noch viele Rätsel und stereochemische Anomalien bei der Biogenese dieser einmaligen Naturstoffe ungelöst, auch wenn im Laufe der Jahre viel Arbeit investiert worden ist, um die Entstehung enantiomerer Metaboliten zu verstehen.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91315/1/4886_ftp.pd

Enantiomeric Natural Products: Occurrence and Biogenesis

In nature, chiral natural products are usually produced in optically pure form—however, occasionally both enantiomers are formed. These enantiomeric natural products can arise from a single species or from different genera and/or species. Extensive research has been carried out over the years in an attempt to understand the biogenesis of naturally occurring enantiomers; however, many fascinating puzzles and stereochemical anomalies still remain. Two sides to the story : The formation of enantiomerically opposite natural products by nature is known, although rare (see examples). To date, many puzzles and stereochemical anomalies remain regarding the biogenesis of these unique natural products, despite the substantial body of research that has been carried out over the years in an attempt to understand the biogenesis of enantiomeric metabolites.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92098/1/4802_ftp.pd

Studies on antibiotic biosynthesis

This thesis describes biosynthetic studies on three antibiotics - narasin, nonactin and tylosin, which belong to the polyether, macrotetrolide and macrolide classes of antibiotics, respectively. In order to determine the origins of the oxygen atoms, and so to investigate the biosynthetic pathway to narasin, feeding experiments with sodium [1-13C,18O2] labelled acetate and butyrate were carried out, using cultures of S. aureofaciens. A culture was also grown under an atmosphere of 18O2. In this manner, the biosynthetic origins of the oxygen atoms at C(20), C(25), C(28) and C(29) were identified as arising from molecular oxygen, and the remaining oxygen atoms from primary precursors. A biosynthetic pathway to narasin, based upon the polyepoxide cyclization model, has been proposed, and is consistent with these results. The biosynthesis of the macrotetrolide antibiotic nonactin has been studied in cultures of S. griseus. The synthesis of both isotopically labelled and unlabelled forms of the methyl ester derivatives (58) and (60), and the N-caprylcysteamine thiol derivative (67), of (2E,6RS)-6-hydroxy-2-methyl-8-oxo-2-nonenoic acid are described. The absolute incorporations of (58), (60) and (67) into nonactin by cultures of S. griseus were 10-25%. Syntheses of the (6R,8R)- and (6S8S-(2E)-6,8-dihydroxy-2-methyl-2-nonenoic acids and their corresponding methyl ester and thiol ester derivatives, in both labelled and unlabelled forms, are also described. The incorporation of the (2E,6R8R) acids (86) and (88), and of their N-caprylcysteamine thiol ester derivatives (87) and (89) into nonactin by cultures of S. griseus were 4% and 20% respectively. For the (2E,6S,8S)-acid (81), and its corresponding methyl ester (73), absolute incorporations of 20% were observed, whilst for the corresponding thiol ester (82), an incorporation of 40% was seen. Importantly, the incorporation of the thiol ester derivatives (87), (89) and (82) into nonactin was shown to occur stereospecifically, thus providing evidence for their intact incorporation by the microorganism. These results provide strong evidence for the involvement of the diols (82) and (89), and possibly the keto-alcohol (67) in the form of thiol esters, as real intermediates on the nonactin biosynthetic pathway. In order to study the late stages of tylactone formation, the first detectable intermediate in tylosin biosynthesis, a synthesis of an isotopically labelled, fully functionalized, open chain derivative of tylactone, activated as its N-caprylcysteamine thiol ester was carried out, based upon synthetic modification of tylactone. This material, in tritiated form, was incorporated into tylactone by S. fradiae, thereby providing the first indication that the last step in tylactone formation involves closure of the macrolide ring.</p