Enantioselektive Totalsynthese des Actin-bindenden Cytotoxins Rhizopodin
Final Report Abstract
The aim of the present project was to realize an enantioselective approach to Rhizopodine 1. So far, three out of four building blocks necessary for the synthesis of 1 were synthesised successfully. Component 4 was synthesised in 20% overall yield from known substrate 38 which was derived from Diethyl 3-hydroxyglutarate in five high yielding steps according to literature. This synthesis employs a stereoselective, substrate controlled alkyne addition as crucial step. Synthesis of building block 5 has advanced to intermediate 17 and should be completed in due course. The crucial step in the synthesis of intermediate 5 is a stereoselective allylation with an ally borane derived from (+)-α-pinene. The originally anticipated synthesis of 6 via an organocatalytic amino hydroxylation was despite considerable effort not successful. Nevertheless, building block 6 was successfully obtained in 11% overall yield employing an asymmetric Sharpless epoxydation and subsequent copper mediated epoxide opening. Finally, compound 7 was obtained, also in 11% overall yield, employing the hydrochloride of the amino acid serine. Preliminary studies yielded conditions suitable for the anion addition anticipated for the connection of intermediates 5 and 7. To validate the feasibility of the anticipated endgame strategy, several experiments were conducted to evaluate the planned macrolactonization via an Intramolecular Heck reaction. Model compound 87 - which only lacked the side chaine of 1 - gave the monorhizopodine core in a good yield of 71% based on recovered starting material, however with 6E8Z configuration of the diene system. Fortunately, the Intermolecular Heck reaction yielded the desired 6E8E product as minor compound in a 2:1 mixture of isomers. Screenings of suitable sets of reaction conditions to increase the amount of the desired 6E8E isomer are currently underway. To finish the synthesis of 1, Brown crotylboration in the synthesis of 5 are to be addressed next.
