Exploring NiCl2, PdCl2 and PtCl2 as a catalyst for [3+2] cycloaddition in Kopsane alkaloid synthesis by density functional theory study

Abstract

Kopsane alkaloids possess a complex heptacyclic scaffold and exhibit significant biological activities, including cholinergic, anti-inflammatory, and anti-cancer effects. While we previously reported PtCl2 -catalyzed [3 + 2] cycloaddition for their synthesis, the high cost and toxicity of platinum necessitate sustainable alternatives. In this study, we employed density functional theory (DFT) to investigate MCl2 (M = Ni, Pd, and Pt) catalyzed [3 + 2] cycloaddition in Kopsane alkaloid synthesis. Our results indicate consistent reaction characteristics across all metals, with the second cyclization acting as the diastereoselectivity-determining step. The calculated energy gaps between transition states (TS2s) for NiCl2, PdCl2 , and PtCl2 were 5.57, 1.45, and 12.25 kcal/mol, respectively. These energy profiles suggest that NiCl(2 )can achieve high diastereoselectivity similar to PtCl2 due to its significant energy gap (> 4 kcal/mol). The implementation of this computational chemistry technique provides theoretical evidence that could help to improve the efficiency of the catalyst designing process.