Efficient Synthetic Approach to Potent Antiproliferative Agent Hippuristanol via Hg(II)-Catalyzed Spiroketalization

Abstract

The steroidal natural product hippuristanol targets eukaryotic translation initiation factor (eIF)4A which plays a pivotal role in translation in eukaryotic cells. Now an efficient synthesis of hippuristanol from 11-ketotigogenin is reported. The synthesis features a rapid construction of a spiroketal unit via Hg(OTf)(2)-catalyzed oxidation/spiroketalization of the 3-alkyn-1,7-diol motif.

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

“…Additionally, the use of hippuristanol in vivo is limited by its relatively low solubility. Although synthetic derivatives have been generated [121][122][123] there has yet to be an equipotent analogue identified.…”

Total Synthesis of Aphadilactones A–D

“…Then 1-methoxy-3-methyl-1, 3-butadiene 16 (4.9 g, 50.0 mmol, 1.00 equiv) was added, and the mixture was stirred at room temperature for 18 h. The reaction was diluted with 1-Methoxy-3-methylbuta-1,3-diene (16). To a suspension of tBuOK (9.12 g, 80.0 mmol) in anhydrous Et 2 O (100 mL) under argon at 0°C was added (methoxymethyl)triphenylphosphonium chloride 19 But-2-ynal (17). To a solution of compound S10 (3.50 g, 50.0 mmol, 1.00eq ) in CH 2 Cl 2 (150 mL) was added PCC (19.44 g, 90.0 mmol, 1.80 equiv) at 0°C, and then warmed to room temperature slowly.…”

The biological and therapeutic relevance of mRNA translation in cancer

“…143 The drug has potent activity against tumor cell lines and studies have focused on manufacturing it synthetically. [144][145][146] Further preclinical development of hippuristanol and its derivatives is awaited.…”