Diastereodivergent Piperidine Synthesis via Hydrogen-Bond Donor Catalysis

About This Grant

Project Summary Piperidines are the most common nitrogen-containing, privileged scaffold, present in numerous FDA- approved drugs. However, to derive desired physiochemical properties, biological activities, and target selectivity, chiral substituents are added to the piperidine core in enantio- and diastereoselective manners. Accordingly, medicinal chemists prepare various stereoisomers of the drug candidate to test and compare their properties, but the traditional preparation of chiral piperidines drugs are a target-oriented synthesis which that relies on chiral ligands, catalysts, and auxiliaries for every derivative. Therefore, chiral piperidine synthesis remains a bottleneck in drug optimization campaigns. To address this challenge, I propose that a hydrogen-bond donor (HBD) catalyst can generate a common chiral environment that enables a general, diastereoselective strategy for selectively accessing highly substituted diastereomeric piperidine products bearing an epoxide moiety. Once the common HBD/iminium ion intermediate is created upon the addition of a Lewis acid, two subsequent synthetic pathways emerge: the “oxidation-first” pathway and the “nucleophile-first” pathway. Hence, the proposed diastereoselectivity will be controlled by order of addition of nucleophiles and oxidants; since the positive charge of the common intermediate persists when the oxidant is added first, the HBD catalyst is still bound to the substrate which presents an opportunity to set different chiral centers. If nucleophile is added first, then the positive charge of the iminium ion is quenched, and the stereochemistry of the subsequent epoxidation will be controlled by the d.r. of the substitution at the C2 position. This proposed system will be realized by two aims. First, the prochiral piperidine substrate will be rapidly diversified by adding amine-, alcohol-, and TMS-based nucleophiles to form new C-N, C-O, and C-C bonds at the C2 position. To ensure success of this aim, the structure of HBD catalyst will be rigorously optimized by tuning its pyrrolidine arm, anion-binding bridgehead, and electron-withdrawing substitutions. Once optimal catalysts and conditions are found for each type of nucleophile, mechanistic studies will be performed to understand molecularity, rate-, and selectivity-determining steps. Then, the resulting epoxide moiety in the chiral piperidine product will be further functionalized through nucleophilic ring-opening strategies. In the second aim, a concurrent, reigodivergent reduction of the epoxide moiety of the HBD/iminium ion intermediate will be carried out to achieve net reductive resolution and 1,2- transposition of the 4-OH group of the piperidine substrates. This goal will be achieved by using magnesium catalysts with butyl and bistriflimide ligands that facilitate regioselective hydride attack at the epoxide. Overall, the transformations outlined in this proposal closely mirror the crucial principles of drug design, lowering the barrier to accessing valuable chiral piperidine building blocks.