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Unified, Efficient, and Scalable Synthesis of Halichondrins: Zirconium/Nickel‐Mediated One‐Pot Ketone Synthesis as the Final Coupling Reaction
Author(s) -
Yahata Kenzo,
Ye Ning,
Ai Yanran,
Iso Kentaro,
Kishi Yoshito
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201705523
Subject(s) - ketone , yield (engineering) , chemistry , combinatorial chemistry , natural product , zirconium , stereochemistry , organic chemistry , materials science , metallurgy
Unified, efficient, and scalable syntheses of the halichondrin natural products are reported. A newly developed Zr/Ni‐mediated one‐pot ketone synthesis was used to couple the two halves of the final product at a late stage in the synthesis. With the use of a slight excess of the left halves, the desired ketones were isolated in yields of 80–90 %. The halichondrins were obtained from these ketones in two steps, namely desilylation and [5,5]‐spiroketal formation. The new synthetic route was effective for the total synthesis of all members in the homohalichondrin subgroup. The scalability of this process was demonstrated with halichondrin B; 150 mg of halichondrin B (68 % overall yield) were obtained from 200 mg of the right‐half precursor.