The piperidine scaffold is prevalent in many FDA approved drugs, making it an important pharmacophore that is privileged in the field of drug discovery. Piperidines are the building blocks for over 70 different types of commercial drugs, such as Ritalin and Evista. By investigating new methods to construct this scaffold, economic and chemical challenges can be mitigated to bring new small molecule therapies to market. The overarching goal of this project is to develop a robust catalytic, asymmetric synthesis of piperidine rings from feedstock petrochemicals. In an initial study of the N-sulfonyl iminium ion Pictet-Spengler cyclization with N-para-toluenesulfonyl and N-tert-butanesulfonyl homoveratrylamine and 3-phenylpropanal, a screen of metal triflates was examined. The hypothesis is that transition metal triflates are sufficiently Lewis acidic to activate relatively inert sulfonamide nitrogen atoms to condense with the aldehyde to trigger the intramolecular cyclization forming piperidines. Initial results indicated that scandium (III), stannous (II), and copper (II) triflates gave the fastest conversion to the N-sulfonyl piperidine, while triflates such as lanthanum (III), sodium (I) and magnesium (II) gave little to no conversion under the allotted time. However, the triflates that proved successful with the N-para-toluenesulfonyl did not produce the same conversion when screened against the N-tert-butanesulfonyl. Based upon accepted knowledge of the mechanism we propose that the cyclization proceeds through an N-sulfonyliminium ion intermediate. Future studies will focus on the use of chiral ligands to induce asymmetry in the cyclization event. These experiments will examine the enantioselectivity of the Pictet-Spengler cyclization in comparison to earlier results with analysis by chiral HPLC.

Transition metal triflates are viable acid promoters for the Pictet-Spengler cyclization with sulfonamides

ACS Spring Meeting 2021

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