Studies Toward The Total Synthesis Of Steenkrotin A

(±)-steenkrotin A is a novel diterpenoid which was isolated by Hussein and co-workers from the ethanol extract of leaves of Croton steenkampianus (Euphorbiaceae) in 2008. Steenkrotin A possesses an intricate [3,5,5.6,7] pentacycliccarbon framework consisting of a sterically congested hydroxytetrahydrofuran subunit. The molecule contains eight stereogenic centers, of which six are contiguous including one all-carbon quaternary center. Preliminary antiplasmodial test revealed that steenkrotin A has mild activity against the chloroquine-resistant strain Dd2 (IC50=5.8 μg/mL) of Plasmodium falciparum.The unprecedented structures as well as the intriguing biological activities rendered steenkrotins A as an attractive target for synthetic studies. Our synthetic studies toward this natural product are mainly devided into three Charpters.Firstly, in Charpter 2, we synthesized the [6,7] bicycle of steekrotins A via an intramolecular nitrile oxide/alkene [3+2] cycloaddition strategy. However, attempts to construct the [5,6,7] tricyclic structure of steekrotins A via Cope rearrangement met with failure. Alternatively, by using Diels-Alder reaction as key step, we successfully accessed the [5,6,7] tricyclic core structure of steekrotins A.Secondly, in Chapter 3, after extensive investigations, we found that gem-dimethylcyclopropane cannot be installed on the complex substrates such as [5,6,7] tricyclic or [6,7] bicyclic structures of steekrotins A. Alternatively, it could be constructed efficiently via the cyclopropanation of dimethyl carbene on simple seven membered ring. Subsequent Rh-catalyzed O-H bond insertion followed by an intramolecular carbonyl-ene cyclization to built up the tetrahydrofuran subunit. Two successes SmI2 mediated Ueno-Stork reaction and ketyl-olefin reaction to afford the [5,7] spirobicyclic skeleton. The [3,5,5,6,7] pentacyclic skeleton of steenkrotin A was achieved by an intramolecular aldol condensation and oxidation/reduction operation. Moreover, a cascade vinylogous-retro aldol/aldol process was found and developed to invert the configuration at C7.Finally, in Charpters 4, based on above studies, the first total synthesis of (±)-steenkrotin A was accomplished in 18 steps. Moreover, the asymmetric synthesis of natural (+)-steenkrotin A could be achieved by enantioselective construction of starting material for further chemical and biological investigations.