Studies on the Synthesis of Engelhardione and Acerogenin via Sequential Borrowing Hydrogen Concept and Ullmann Coupling Reactions

Abstract

The use of natural products and their bioactive analogues are irreplaceable part of medical chemistry used to treat a variety of diseases. The synthesis of these bioactive natural products has been a well-established practice since the 19th century. The first successful synthesis of a natural product (urea) was carried out in 1828 by Friedrich Wöhler, marking a significant milestone in organic synthesis and demonstrating the feasibility of natural product synthesis. Engelhardione is a type of natural product belonging to the class of Combretastatin D. "Combretastatin D and its analogues are also classified as cyclic diaryl ether heptanoid (DAEH) macrocycles." Engelhardione is derived from the Engelhardia tree, which predominantly grows in Southern and Southeastern Asia. It shows promise in combating drug-resistant Mycobacterium tuberculosis and pathogenic bacterial infections. Although Engelhardione has enormous medical applications, only one synthetic route has been reported till now. However, a more efficient and general approach with step economy to access Engelhardione and associated natural products is required in this area. To this end, borrowing Hydrogen catalysis is more attractive for the macrocyclization via C-C bond formation in which alcohols were used as starting materials. However, borrowing Hydrogen catalysis was not studied towards the Engelhardione. Therefore, we have proposed to study this catalysis for the synthesis of Engelhardione. The required alcohols and ketones were prepared and optimized for the borrowing hydrogen catalysis. Through systematic variation of reaction parameters and screening of Ru- and Ir-based catalysts, C-C bond formation was achieved successfully. However, a debrominated byproduct also formed due to an undesired side reaction, consequently, we encountered difficulties in the late-stage Ullmann coupling reaction. Our primary objective was to achieve the borrowing hydrogenation followed by the Ullmann coupling. The presence of a aryl bromide is crucial for the Ullmann coupling intramolecularly to ultimately yield the desired macrocyclic ether compound. Additionally, we explored late-stage bromination reactions where a complicated reaction mixture was observed due to multiple side products. The optimization efforts are still ongoing in our laboratory.