Preparation and Application of Catalysts for the Stereospecific Reduction and Photooxygenation of Olefins in Continuous Operations: A Novel Method for the Production of Artemisinin

摘要

Over the last two centuries, the discovery and application of catalysts has had a substantial impact on how and what chemicals are produced. Given their broad significance, our group has focused on developing new catalyst systems that are recoverable and reusable, in an attempt to reduce concomitant costs.;Our efforts have centered on constructing a recyclable chiral heterogeneous catalyst capable of effecting asymmetric hydrogenations of olefins with high stereoselectivity. A class of phosphinoimidazoline ligands, developed by researchers at Boehringer-Ingelheim, known as BIPI ligands, have proven efficacious in the asymmetric reduction of alkenes. However, these chiral ligands are homogeneous and coordinated to precious metals, rendering them irrecoverable and expensive. To address these issues, our group has derivatized the BIPI ligand-metal complex and immobilized it to the surface of graphene oxide as well as polystyrene. Their efficacy and recyclability toward the asymmetric hydrogenation of a functionalized olefin have been evaluated.;Another facet of our work has included developing a cost effective synthetic process to artemisinin, the gold standard drug in the treatment of malaria. As a natural product, artemisinin's worldwide supply remains highly unpredictable, contributing to great price volatility. Combining the benefits of catalysis and the advantages of continuous flow chemistry, our research has sought to develop an economical approach to convert a biosynthetic precursor, artemisinic acid, to artemisinin in three chemical transformations.;High-throughput experimentation allowed us to screen a prodigious number of catalysts and identify those effective in the asymmetric hydrogenation artemisinic acid to dihydroartemisinic acid, the first step in the transformation. This screening directed us to an inexpensive, heterogeneous ruthenium catalyst. The second step of the process includes the photooxygenation of dihydroartemisinic acid, which involves photochemically generated singlet oxygen. We have evaluated a commercially available heterogeneous photocatalyst packed in a transparent bed, surrounded by light emitting diodes in the continuous photooxygenation of dihydroartemisinic acid to dihydroartemisinic acid hydroperoxide. The third and final step, an acid induced hock cleavage, initiates an intricate cascading reaction that installs an endoperoxide bridge to deliver artemisinin. Our process afforded a 57% yield from dihydroartemisinic acid to artemisinin.