The piperidine heterocycle is a privileged motif that appears in countless bioactive molecules, including natural products and drugs. As the most prevalent nitrogen-containing heterocycle in chemical therapeutics, the piperidine motif is featured in a plethora of blockbuster drugs. Due to the prevalence of piperidines, new and innovative methodologies to access this motif remain highly sought after. Strained alkyne intermediates such as benzyne and piperidyne have proven to be useful intermediates towards this end, however cycloadditions to these scaffolds typically lead to the introduction of sp2 centers. The use of highly reactive cyclic allenes introduces an added layer of complexity by building an sp3 center and vicinal stereocenters. The proposed research aims to develop the first 3,4-azacyclohexylallne Diels-Alder reaction capable of accessing decorated piperidines that possess quaternary centers. This new strategy will then be employed to complete a concise total synthesis of the manzamine alkaloid Acantholactone.
Nitrogen containing heterocycles are exceedingly prevalent in various molecules of importance, including drugs and natural products. Due to their pervasiveness, there is a need to develop efficient and powerful methods to access heterocyclic motifs. In order to address this demand, the aim of the proposed research is to develop a strain-promoted Diels-Alder methodology using substituted 3,4- azacyclohexylallenes as a new method to access complex piperidine scaffolds and complete the first total synthesis of Acantholactone.
| Barber, Joyann S; Yamano, Michael M; Ramirez, Melissa et al. (2018) Diels-Alder cycloadditions of strained azacyclic allenes. Nat Chem 10:953-960 |
