Convergent Total Synthesis of Ixabepilone and Its Analogues Enabled by Highly Efficient Asymmetric Hydrogenations

Dong Li; Hao Yan; Yan Zong; Renwei Xiao; Shuo Li; Haidong Xia; Yao Zhang; Ya-Nan Duan; Gen-Qiang Chen; Xumu Zhang

doi:10.1002/chem.202404643

Convergent Total Synthesis of Ixabepilone and Its Analogues Enabled by Highly Efficient Asymmetric Hydrogenations

Chemistry. 2024 Dec 27:e202404643. doi: 10.1002/chem.202404643. Online ahead of print.

Authors

Dong Li¹, Hao Yan², Yan Zong², Renwei Xiao², Shuo Li³, Haidong Xia¹, Yao Zhang¹, Ya-Nan Duan⁴, Gen-Qiang Chen⁵, Xumu Zhang⁶

Affiliations

¹ Guangdong Laboratory of Chemistry and Fine Chemical Engineering, Department of Chemistry, 1088 Xueyuan Avenue, Shenzhen, Shenzhen, CHINA.
² Southern University of Science and Technology, Department of Chemistry, 1088 Xueyuan Avenue, Shenzhen, Shenzhen, CHINA.
³ Southern University of Science and Technology, Medi-X Pingshan, 1088 Xueyuan Avenue, Shenzhen, Shenzhen, CHINA.
⁴ Guangdong Laboratory of Chemistry and Fine Chemical Engineering, Department of Chemistry, 1088 Xueyuan Avenue, Shenzhen, Shenzhen, CHILE.
⁵ Southern University of Science and Technology, Shenzhen Grubbs Institute, 1088 Xueyuan Avenue, Shenzhen, Shenzhen, CHINA.
⁶ Southern University of Science and Technology, Chemistry, 1088 Xueyuan Avenue, 518055, Shenzhen, CHINA.

PMID: 39731264
DOI: 10.1002/chem.202404643

Abstract

The convergent total synthesis of ixabepilone and its analogues in a 13-step longest linear sequence is reported. The crucial chiral centers at challenging C3-O, C8-C and C15-N positions on the scaffold of the ixabepilone were installed via highly efficient asymmetric hydrogenations (up to 95% yield and up to 99% e.e.) and all three fragments could be prepared on gram scale. The key aldol reaction bridges the aldehyde and keto fragments with high yield and exquisite diastereo control (8:1 d.r.). Finally, a novel RCM reaction conformationally controlled by a bulky silyl group was reported, which allows the facile synthesis of ixabepilone and its analogues.

Keywords: Grubbs metathesis; Ixabepilone; Total Synthesis; asymmetric hydrogenation.