A Reverse Approach to the Total Synthesis of Halichondrin B

A new strategy is described for the total synthesis of halichondrin B featuring reversal of the sequential construction of a number of its cyclic ethers from the classical approach by instead forming C–O bonds first followed by C–C bond formation. Employing the Nicholas reaction to generate linear e...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Chemical Society 2021-06, Vol.143 (24), p.9267-9276
Main Authors: Nicolaou, K. C, Pan, Saiyong, Shelke, Yogesh, Das, Dipendu, Ye, Qiuji, Lu, Yong, Sau, Susanta, Bao, Ruiyang, Rigol, Stephan
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A new strategy is described for the total synthesis of halichondrin B featuring reversal of the sequential construction of a number of its cyclic ethers from the classical approach by instead forming C–O bonds first followed by C–C bond formation. Employing the Nicholas reaction to generate linear ethers as precursors for the total synthesis of halichondrin B and other members of the halichondrin and eribulin families of compounds, this novel approach provides new opportunities for the development of improved syntheses of these complex and valuable compounds. In this Article, we report the syntheses of defined fragments I, MN, EFG, and A. Fragments I and MN were then coupled and elaborated to advanced intermediate IJKLMN, which was joined with fragment EFG to afford, after appropriate elaboration and macrolactonization, the more advanced polycyclic intermediate EFGHIJKLMN. Elaboration of the latter and coupling with fragment A followed by further functionalization completed the total synthesis of halichondrin B through a short and convergent pathway.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.1c05270