Synthesis of the Macrolactone Cores of Maltepolides via a Diene–Ene Ring-Closing Metathesis Strategy

Abstract

Synthesis of the C19-truncated maltepolide E has been accomplished via a diene–ene RCM strategy without damage to the C11–C14 alkenyl epoxy unit. Upon release of the C17-OH group, it attacked at the C14 position with double bond migration and epoxide ring-opening to furnish the C19-truncated maltepolide A and B as proposed for the biosynthesis of maltepolides. Preliminary cytotoxicity data of the synthesized C19-truncated maltepolides against L929 mouse fibroblast cell line suggest irrelevance of the vinyl epoxide and importance of the conjugated dienyl keto unit for the observed anticancer activity.

Synthesis of the Macrolactone Cores of Maltepolides via a Diene–Ene Ring-Closing Metathesis Strategy

“…Maltepolide E ( 5 ) was proposed as the precursor of maltepolides A–D and F ( 1 – 4 and 6 , Figure a), , and it was isolated from the myxobacterium Sorangium cellulosum So ce1485 originally collected from island of Malta. An intramolecular vinylogous epoxide ring-opening cyclization within 5 was assumed to form a favorable 2,5- trans -tetrahydrofuran (THF) ring in 1 along with the minor product 2 possessing a 2,5- cis -THF ring.…”

“…Unique morphological changes were observed in the dividing transformed PtK 2 cells caused by maltepolides A and E. , Total synthesis of maltepolide C ( 3 ) was reported by Ghosh and co-workers, featuring an intramolecular Heck reaction to construct the C6–C9 diene moiety followed by C5 oxidation to secure the labile diene keto subunit. , However, the 13 C NMR chemical shift of most likely the C22-OMe group does not match with the reported value of 3 . We envisioned that synthesis of maltepolide E ( 5 ) should be much more rewarding because it provides quick access to other maltepolide core structures, although it would be very challenging to concurrently handle two vinyl epoxide moieties during the synthesis. We envisioned use of a diene–ene ring-closing metathesis (RCM) strategy to build up the macrocyclic core of maltepolide E. According to the three key bond disconnections (see 5 in Figure a) at the macrolactone C­(O)–O bond, the C8/C9 double bond, and the C19/C20 single bond, building blocks 7 – 9 were required (Figure b).…”