Unified, Efficient, and Scalable Synthesis of Halichondrins: Zirconium/Nickel‐Mediated One‐Pot Ketone Synthesis as the Final Coupling Reaction

• Published in: Angewandte Chemie International Edition Vol. 56; no. 36; pp. 10796 - 10800
• Main Authors: Yahata, Kenzo, Ye, Ning, Ai, Yanran, Iso, Kentaro, Kishi, Yoshito
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 28-08-2017
• Edition: International ed. in English
• Subjects: Chemical synthesis; halichondrins; Ketones; Natural products; Nickel; nickel catalysis; total synthesis; Zirconium; natural products; halichondrins; total synthesis; ketones; nickel catalysis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201705523

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.
Crucial coupling: The halichondrin natural products were obtained by unified, efficient, and scalable total syntheses. A newly developed zirconium/nickel‐mediated one‐pot ketone synthesis was used to couple the two halves of the final product at a late stage of the total synthesis.