Total synthesis and biological evaluation of (+)-neopeltolide and its analogues.

Abstract

The stereocontrolled total synthesis of the originally proposed (1) and correct (2) structures of (+)-neopeltolide, a novel marine macrolide natural product with highly potent antiproliferative activity against several cancer cell lines as well as potent antifungal activity, has been achieved by exploiting a newly developed Suzuki-Miyaura coupling/ring-closing metathesis strategy. Alkylborate 44, which was generated in situ from iodide 34, was coupled with enol phosphate 8 by a Suzuki-Miyaura coupling. Ring-closing metathesis of the derived diene 45 followed by stereoselective hydrogenation afforded tetrahydropyran 47 as a single stereoisomer in high overall yield from 34. Our convergent strategy enabled us to construct the 14-membered macrolactone core structure of 2 in a rapid and efficient manner. Total synthesis and biological evaluation of synthetic intermediates and designed synthetic analogues, performed to establish the structure-activity relationships of 2, led to the discovery of a structurally simple yet potent cytotoxic analogue, 9-demethylneopeltolide (54).

• Authors: Haruhiko Fuwa, Asami Saito, Shinya Naito, Keiichi Konoki, Mari Yotsu-Yamashita, Makoto Sasaki
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 15 Issue 46 Pg. 12807-18 (Nov 23 2009) ISSN: 1521-3765 [Electronic] Germany
• PMID: 19882704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Macrolides
• Phosphates
• Pyrans
• neopeltolide
• Iodine

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Inhibitory Concentration 50
• Iodine (chemistry)
• Kinetics
• Macrolides (chemical synthesis, chemistry, pharmacology)
• Mice
• Phosphates (chemical synthesis, chemistry)
• Pyrans (chemistry)
• Stereoisomerism
• Structure-Activity Relationship