Pharmaceutical Chemistry

Biography

Biography: Emmanuel Roulland

Abstract

Tiacumicin B is an antibiotic endowed with the remarkable ability to interact with a new biological target giving it an inestimable potential in the context of the ever-growing and worrisome apparition of resistances of bacteria and mycobacteria to antibiotics. The development of an efficient synthesis of this complex molecule will allow accessing valuable analogues. We have achieved the total synthesis of the tiacumicin B aglycone featuring the DFT-guided strategy concept. Macrolactone thus obtained is ready for subsequent glycosylation step. Starting from known alcohol (±)-3, this 16 steps synthesis was performed in a 3.6 % overall yield, only 4 steps dealing with the installation or the removal of protective groups. Relying on DFT predictions, we dared to use an unprecedented [2,3]-Wittig rearrangement of the propargyl ether of tertiary allylic alcohol to synthesis the most densely functionalized fragment of the target. We also accessed the tetrasubstituted C12-C15 diene stereoselectively using an innovative strategy based on the sequence allene-alkyne Pd/Cu-catalyzed cross-coupling / selective hydrosulfuration / Pd-catalyzed Kumada-Corriu cross-coupling of an alkenylsulfide function. To end this synthesis the E configuration of the C4=C5 bond was controlled thanks to a selective cross-metathesis of vinylborate, and a Suzuki cross-coupling was used to install the missing C1-C3 fragment. The final macrolactonization step was found to be ring-size-selective as again predicted by DFT.