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

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.