Synthetic Studies of Alkaloids Containing Pyrrolidine and Piperidine Structural Motifs

Our molecules of interest were mainly 2-substituted pyrrolidine and piperidine alkaloids containing 1, 3-aminoketone and 1, 3-aminoalcohol units which are of special synthetic interest (Figure 1). Hygrine and norhygrine belong to the class of tropane alkaloids. The rest of the alkaloids are isolated from 60 species of the genus Sedum and are usually referred as Sedum alkaloids which are of immense interest due to their memory-enhancing properties and application as anti-Alzheimer agents. These species have now become more important to industry due to their vast pharmaceutical applications. Our method involves “chiral pool” strategies, wherein the starting material can easily be accessed from the naturally available sources like amino acids. Though such a method requires a lot of synthetic maneuvering, it still is the best bet for chiral integrity and suitability for industrial applications. Commercially available l-proline and l-pipecolinic acid, with one existing chiral center, were found to be appropriate chiral sources to access these pyrrolidine and piperidine alkaloids respectively. We developed a Henry–Nef protocol in order to synthesize the key intermediates leading to the total synthesis of these natural products. The Henry–Nef protocol involves two major synthetic steps: the formation of the nitro functionality from carbonyls and the successive transformation to the next carbonyl unit mainly by oxidative or reductive methods. Even though this method is well documented in the literature, surprisingly, it is not well explored for synthetic applications, which got our attention. The