Total Synthesis of Lobatamides A and C

The total synthesis of lobatamides A (1 a) and C (1 c) via a common bislactone intermediate is reported. The allylic aryl moiety including a trisubstituted Z‐olefin was constructed by hydroboration of a 1,1‐disubstituted allene and subsequent Migita‐Kosugi‐Stille coupling. Although the seco acid pro...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2024-04, Vol.63 (17), p.e202402335-n/a
Main Authors: Yasui, Soichiro, Banjo, Shona, Nagashima, Yoshiyuki, Okada, Yuto, Yoshikawa, Kao, Nakata, Keisuke, Chida, Noritaka, Okamura, Toshitaka, Sato, Takaaki
Format: Article
Language:English
Subjects:
Alkynes
amide
Amides
copper
Coupling
Hydroboration
Iodination
macrolactonization
Synthesis
total synthesis
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The total synthesis of lobatamides A (1 a) and C (1 c) via a common bislactone intermediate is reported. The allylic aryl moiety including a trisubstituted Z‐olefin was constructed by hydroboration of a 1,1‐disubstituted allene and subsequent Migita‐Kosugi‐Stille coupling. Although the seco acid proved to be highly unstable even in the presence of weak bases, Zhao macrolactonization under acidic conditions via the α‐acyloxyenamide successfully provided the common bislactone intermediate. Hydrozirconation‐iodination of the terminal alkyne and subsequent copper‐mediated coupling with primary amides proceeded successfully in the presence of the sensitive bislactone framework. The developed synthetic route enables the late‐stage installation of enamide side chains, which are crucial structures for V‐ATPase inhibition. Lobatamides are the most complex salicylate enamide natural products known and are expected to be a new class of antitumor agents through V‐ATPase inhibition. The instability of the β‐salicyloxy ester has prevented the late‐stage installation of the enamide side chains, which play a crucial role in the biological activity. Now a common bislactone intermediate has been used for the total synthesis of lobatamides A and C.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202402335