Convergent Total Synthesis of Hikizimycin: Development of New Radical-Based and Protective Group Strategies

Abstract

AbstractHikizimycin (1) is an architecturally complex nucleoside antibiotic with potent anthelmintic and antibacterial activities. Its unique 4-amino-4-deoxyundecose core (hikosamine) includes a C1–C11 linear chain with ten contiguous stereocenters flanked with nucleobase (cytosine) and 3-amino-3-deoxyglucose (kanosamine) at the C1 and C6O positions, respectively. These structural features make its chemical construction exceptionally challenging. This chapter describes our successful efforts leading to convergent total synthesis of 1 from three hexose derivatives (5b, 11-β, and 12) and bis-TMS-cytosine 6. First, efficient one-step construction of hikosamine core 7-α was achieved by devising a novel radical coupling reaction between α-alkoxy telluride 10d-α and aldehyde 8c, which were derivatized from 11-β and 12, respectively. At this stage, the importance of the specific protective group pattern of 10d-α and 8c was revealed for stereoselective C5(sp3)–C6(sp3) coupling. By taking advantage of strategically introduced protective groups, 6 and 5b were regio- and stereoselectively installed on 7-α to produce protected hikizimycin 36b. Finally, the three amino and ten hydroxy groups of 36b were detached in a single step to furnish 1. Consequently, the newly developed radical-based and protective group strategies allowed us to achieve total synthesis of 1 from 11-β in 17 steps.