Total synthesis of hainanolide, an atypical diterpene from Cephalotaxus with potent cytotoxic activity – HAINANOLIDE

Hainanolide, also called harringtonolide, was isolated by us from Cephalotaxus harringtonii var. drupacea. It is a known compound, previously described in 1978, which has been the subject of scarce biological essays showing cytotoxic and phytotoxic activities. In our laboratories, the phytochemistry of the Cephalotaxus trees has been studied and we isolated several new alkaloids of the cephalotaxin family and also this original norditerpene. Biological essays enabled us to measure accurately the cytotoxicity on human KB cells (nasopharynx carcinoma), at IC50 = 43 nM which is better than the alkaloid harringtonine from the same tree (71 nM) or camptothecin (150 nM) or 5-fluorouracil (470 nM). The cytotoxic activity on HT29 cells (colon carcinoma) was 130 nM, and ca. 400 nM on murin fibroblast cell lines 3T3 EF and 3T3 (oncogenic and non-oncogenic, respectively). Therefore these last tests showed a non specific activity, at least on the fibroblast cell lines. We also recorded a moderate antifungal activity on Candida tropicalis. Hainanolide is an asymmetric norditerpene (19 carbons) featured with a compact cup-shaped architecture. It belongs to a tiny family of natural products of which only 5 compounds have been yet described. It has four fused carbocycles and two oxygenated bridges (a lacton and an ether). One of the carbocyles is a tropone ring whose bromination results in complete loss of cytotoxic activity. This bromination in position 2 allowed us to determine the absolute configuration of the natural product by X ray crystallography. Combined interesting biological activities and atypical structure of the compound led us to embark on a total synthesis program four years ago. Yet only one total synthesis has been described by Mander et al. in the racemic form. We propose to make the asymmetric total synthesis of hainanolide, starting from the chiral pool. We already showed that D-glucose furnishes an appropriate starting material for the synthesis of the natural enantiomer of hainanolide, and an advanced stage of the synthesis has been worked out by the past four years, especially with the PhD work of one of coordinator's student. The proposal therein aims at improving and shortening our synthetic strategy in order to complete the total synthesis of hainanolide within the next three years. Key steps involved a stereoselective intramolecular Diels-Alder reaction making the central asymmetric C ring, an enyne metathesis reaction preparing the last cycloaddition step, a stereoselective epoxidation followed by a cascade cyclization to build at the same time both ether and lactone bridges, and the [4+2+1] or [4+2] cycloaddition of a dienyne towards the tropone ring of hainanolide.