Total Synthesis and Biological Activity of Neopeltolide and Analogues

• Published in: Chemistry : a European journal Vol. 14; no. 35; pp. 11132 - 11140
• Main Authors: Vintonyak, Viktor V., Kunze, Brigitte, Sasse, Florenz, Maier, Martin E.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag 08.12.2008; Wiley
• Subjects: allylation; Animals; Biological Products - chemical synthesis; Cattle; Cell Death - drug effects; Cell Line; Chemistry; Chemistry, Multidisciplinary; Lactones; Macrolides - chemical synthesis; Macrolides - pharmacology; mitochondria; Myocardium - ultrastructure; NAD - drug effects; NAD - metabolism; natural products; neopeltolide; Oxazoles; Physical Sciences; prins cyclization; Science & Technology; Structure-Activity Relationship; Submitochondrial Particles - metabolism; LEUCASCANDROLIDE-A; ALPHA,BETA-UNSATURATED THIOESTERS; mitochondria; neopeltolide; FORMAL TOTAL-SYNTHESIS; THIOL ESTERS; MARINE NATURAL-PRODUCTS; natural products; (+)-LEUCASCANDROLIDE-A MACROLACTONE; ENANTIOSELECTIVE CONJUGATE ADDITION; STEREOCONTROLLED TOTAL-SYNTHESIS; prins cyclization; STEREOSELECTIVE-SYNTHESIS; allylation; GRIGNARD-REAGENTS
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200801398

Combining the core structure of neopeltolide, lactone 16 a, with the oxazole‐containing side chain 23 via a Mitsunobu reaction provided the cytotoxic natural product neopeltolide (2). The side chain 23 was prepared from oxazolone 24 via the corresponding triflate. Key steps in the preparation of 23 were a Sonogashira coupling, an enamine alkylation, and a Still–Gennari Horner–Emmons reaction. By changing the Leighton reagent in the allylation step, the 11‐epimer of lactone 16 a, compound 50 was prepared. This led to 11‐epi‐neopeltolide 51. The 5‐epimer of neopeltolide, compound 52, could be obtained from the minor isomer of the Prins cyclization. Furthermore, a range of analogues with modifications in the side chain were prepared. All derivatives were checked for toxicity effects on mammalian cell cultures and inhibitory effects on NADH oxidation in submitochondrial particles of bovine heart. Modifications in the lactone part are tolerated to some degree. On the other hand, shortening the distance between the oxazole and the lactone causes a significant drop in activity. Analogue 65 with an additional double bond is equally or even more active than neopeltolide itself. The novel marine natural product neopeltolide (3) was prepared from lactone 1 and acid 2 (see scheme). In addition, several analogues (5‐epi, 11‐epi, side chain derivatives) were synthesized. Modifications in the lactone part are tolerated to some degree, whereas shortening the distance between the oxazole and the lactone resulted in a significant loss in activity.