Research Projects

Natural products have long served as a foundation of drug discovery, with nearly half of all small-molecule anticancer agents approved from 1940 to 2014 derived from or inspired by them. Among the prolific sources of bioactive compounds is the genus Cephalotaxus, which has yielded notable molecules such as homo-harringtonine, an alkaloid approved for treating chronic myeloid leukemia. Recent efforts have focused on structurally diverse norditerpenoids and diterpenoids from Cephalotaxus, particularly a rare and understudied subclass called cephalotane-type norditerpenoids. Ceforalide H represents the most highly oxidized member of this subclass isolated to date. It features a rare para-quinol (2,5-cyclohexadienone) A-ring, an oxidative motif not found in any previously known cephalotane. This “over-oxidized” scaffold acts as a soft electrophile prone to redox cycling and covalent binding to nucleophilic protein residues, suggesting high biological potential. Closely related phenolic cephalotanes inhibit NF-κB signaling and exhibit cytotoxicity against A-549, HL-60, and KB cells at low micromolar concentrations. However, ceforalide H’s extreme natural scarcity which is less than 1 mg per kg of seeds, prevents significant biological evaluation. Even large-scale extractions from plant material yield only trace amounts. This constraint necessitates an efficient, enantioselective total synthesis to enable biological studies and downstream medicinal chemistry efforts. Ceforalide H was first isolated from Cephalotaxus fortunei var. alpina, a conifer endemic to high-altitude regions (1800–3700 m) in southwest China. Biosynthetically, it likely arises from a C20 diterpenoid precursor that undergoes oxidative ring contraction and Baeyer–Villiger-type oxidation to form the cephalotane skeleton. Decarboxylation and aromatization yield a benzenoid A-ring, which undergoes further oxidative dearomatization either by enzymatically or non-enzymatically to produce the unique para-quinol motif. Several research groups have advanced cephalotane chemistry. The Cai group isolated ceforalides A–D in 2017 and reported NF-κB and cytotoxic assays. In 2018, the Zhao group accomplished total syntheses of ceforalides B and C via Pd-catalyzed cascade and sp³ C–H oxidation. The Sarpong group achieved unified syntheses of ceforalides A–D in 2021 using oxidative dearomatization. More recently, the Xie group developed a gram-scale Pd/norbornene cascade to build the 6/6/6/5 tetracyclic core in just six steps, enabling late-stage oxidation studies. Despite these advances, no enantioselective total synthesis of ceforalide H has been achieved. Existing routes yield racemates, and the compound remains untested in direct biological assays. Its electrophilic para-quinol unit is particularly intriguing, as it may act as a Michael acceptor for cysteine residues in regulatory enzymes and transcription factors. Our proposed synthesis of ceforalide H begins with aryl bromides prepared by known methods. A Nozaki-Hiyama-Kishi (NHK) coupling generates the enantiopure secondary alcohol, which then undergoes an intermolecular Diels-Alder reaction to forge the tetracyclic core. Hydroxyl protection on the C-ring ensures stereoselective epoxidation. The sequence ends with BCl₃-mediated demethylation to reveal the phenol, followed by oxidative dearomatization to form the para-quinol A-ring. This synthetic route will enable scalable access to ceforalide H and analogues, supporting biological evaluation, SAR studies, and the development of novel anticancer and anti-inflammatory agents.