Enantioselective synthesis of chromanone and thiochromanone derivatives

Abstract

Chromanones are an important subgroup of bioactive flavonoids which are widely distributed in natural products, pharmaceutical molecules and biologically active compounds. Morita-Baylis-Hillman (MBH) carbonates could not only serve as a three-membered synthon when phosphine catalysts are used, but also a frequently used allylation reagent. Nucleophilic phosphine-catalyzed reactions of MBH carbonates with chromones could be an appealing strategy to synthesize chromanone derivatives with two or more chiral centers under mild conditions. Thiochromanones, the sulfur counterparts of chromanones, also have various biological activities. Nevertheless, development of asymmetric synthesis of substituted thiochromanones is greatly inadequate, which may be attributed to the affinity of sulfur with transition metals, thereby the relevant catalytic reaction might become complicated. Thus, it is challenging to synthesize enantio-enriched thiochromanones under mild condition. Chapter 1 gives a short introduction of flavonoids and thioflavonoids. The synthetic approaches toward the synthesis of substituted (thio)chromanones which serve as a major group among (thio)flavonoids are also presented. Chapter 2 introduces a bifunctional phosphine-catalyzed enantioselective [3+2]-cycloaddition of 3-cyanochromones with MBH carbonates under mild condition. A wide range of special cyclopentene-fused chromanones can be generated in good to high yield with high diastereoselectivity and stereoselectivity. DFT calculations have been carried out to investigate the mechanism, regio- and diastereo-selectivity of the reaction. Chapter 3 describes a metal free phosphine-catalyzed alkoxy allylation of 3-cyanochromones with unsubstituted MBH carbonates. The reaction provides a facile method to various 3-allyl-2-alkoxychromanones in high yield with excellent diastereoselectivity. Control experiments reveal that the nucleophilic addition of chromanone-based intermediate to phosphonium species take places via an SN2′ pathway. In Chapter 4, a copper catalyzed asymmetric formal conjugate addition of thiochromones with terminal alkynes is delineated. The reaction exhibits a good tolerance on functional groups with different steric and electronic properties. Control experiments show that the counter ion from silane is crucial for the reaction. Derivatizations of some products have also been carried out to demonstrate that the process enables efficient access to diverse thiochromanone derivatives.

Date of Award	2020
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology